N'-Diisopropylethylamine Dma

Keywords: synthèse totale, indoles alcaloïdes, cyclobutanes, ouverture de cycle, borure de nickel, chimie radicalaire, photocatalyse, synthèse asymétrique. Radical Additions onto Functionalized Chiral Cyclobutenes total synthesis, indole alkaloids, cyclobutanes, ring-opening, nickel boride, radical chemistry, photocatalysis, asymmetric synthesis

Additions Radicalaires sur des Cyclobutènes Chiraux Fonctionnalisés. Application aux Synthèses Totales de l'Eucophylline et de l'Eburnamine.

Approche Biomimétique à la Leucophyllidine Résumé : Cette thèse décrit une nouvelle approche à la sulfonyl-cyanation de cyclobutènes chiraux à l'aide d'un simple photosensibilisateur, le p-anisaldéhyde. Cette réaction a permis d'introduire un centre quaternaire tout-carboné d'une manière régio-, stéréo-et diastéréocontrôlée, via un processus par transfert d'énergie. Différentes stratégies d'élimination du groupement sulfonylé et d'ouverture de cycle des cyclobutanes correspondants ont ensuite été examinées afin de donner accès à une nouvelle bibliothèque de dérivés fonctionnalisés. Un processus basé sur l'utilisation de borure de nickel a permis de mettre au point une séquence en cascade en " un-pot " de réduction de la fonction nitrile / cyclisation / ouverture de cycle donnant accès à un lactame cyclique à six chaînons à partir des cyclobutanes ci-dessus. Cette chimie a été appliquée à la synthèse totale énantiosélective de l'eucophylline, le fragment sud de la leucophyllidine, un alcaloïde terpène bis-indole cytotoxique isolé de Leuconotis griffithii et L. eugenifolius. La synthèse racémique de l'éburnamine, le fragment nord, a également été réalisée en 10 étapes à partir d'un substrat commercialement disponible. Le couplage biomimétique de ces deux fragments a ensuite été examiné en utilisant un modèle de l'eucophylline.

Acknowledgment

First, I would like to thank the Jury members: Dr. Guillaume Vincent, Dr. Fabrice Dénès, Dr.

Géraldine Masson, and Dr. Dario M. Bassani for accepting to judge my work, for taking time to read my manuscript, and for the valuable scientific discussions we had during the Ph.D. defense. I would like to thank my supervisor, Professor Yannick Landais, for giving me the opportunity to work on this project. Such work allowed me to invest in a well-diversified organic synthesis, to visit many chemical reactions, and to manipulate under very different conditions. This rich experience will stay with me wherever I go. Needless to say, I am not anymore that same rookie who started her research three years ago. Huge thanks also for our scientific discussions on various reactions and retrosynthetic plans. But also, for providing me with all the necessary reagents and lab materials, and two fume hoods to use as I please, a luxury I will miss dearly! I also thank my co-supervisor, Dr. Frédéric Robert, for the positive encouragment throughout these years, and for always having faith in me. I am grateful for the time we spent analyzing complex NMR spectra and weird unexpected products, for discussing mechanisms, techniques, and ideas.

Thanks again to Dr. Dario M. Bassani for our fruitful collaboration during the mechanistic studies of the p-anisaldehyde photosynthesized sulfonyl-cyanation reaction. Thank you for your kind help and explanation of the photochemical principles. I valued our collaboration a lot.

Huge thanks to the Ministry of Higher Education and Research of France for the Ph.D. grant, and the University of Bordeaux and the doctoral school for giving me this opportunity and the needed facilities. Thanks to the ISM administration team, you made my Ph.D. much easier, with all the administration papers and the week-end accesses that went smoothly. I can't thank you enough. I am so grateful for the analytical platform CESAMO! You were enormously helpful. Thanks for facilitating my analyses even when it wasn't obvious and easy.

Thanks to Jonathan for the HPLC analyses and for always caring to provide all the needed materials and reagents. Also, thanks to my labmates: Claire, Damien, Martin, Camille, Gülbin, Nivesh, Suman, Govind, Anthony, Paul, Alix, Matteo, Dickson, Shuai… And all my friends in Bordeaux.

Finally, I would like to thank the French singers of the 80s and 90s, without you, my lab work wouldn't be the same. And thank you Martin and Damien for "tolerating" my singing and my music preferences. I know it wasn't your cup of tea!!

Résumé de Recherche

Titre : Additions Radicalaires sur des Cyclobutènes Chiraux Fonctionnalisés.

Application aux Synthèses Totales de l'Eucophylline et de l'Eburnamine.

Approche Biomimétique à la Leucophyllidine

Mots clés : synthèse totale, indoles alcaloïdes, cyclobutanes, ouverture de cycle, borure de nickel, chimie radicalaire, photocatalyse, synthèse asymétrique.

La leucophyllidine 6, un alcaloïde indole cytotoxique, a été isolée il y a dix ans par Kam et ses collègues 1 de l'écorce de tige de Leuconotis griffithii, une apocynacée malaise (Schéma I). Mis à part sa structure originale, les études biologiques ont montré qu'elle présente une cytotoxicité in vitro prononcée envers les cellules KB humaines résistantes à la vincristine (IC50 = 2,92 μg / ml), ce qui en fait une cible potentielle comme agent antitumoral. 2 Cette thèse vise à élaborer la première synthèse de cet alcaloïde dimérique par le couplage biomimétique de ses deux fragments, l'éburnamine 18 et l'eucophylline 8. Les synthèses totales de ces alcaloïdes ont été planifiées à partir de synthons cyclopropène I et cyclobutène II, respectivement. Pour atteindre cet objectif, de nouvelles méthodologies ont été développées afin d'accéder aux stéréocentres quaternaires toutcarbonés présents dans ces substrats. L'ouverture de cycle des dérivés obtenus a délivré une série de molécules chirales fonctionnalisées adaptées à leur application dans les stratégies de synthèse totale.

Schéma I. Rétrosynthèse de la leucophyllidine 6.

Au cours de la première partie de la thèse, une synthèse énantiosélective efficace de cyclobutènes 169 a été décrite, inspirée des travaux de recherche de Narasaka et de ses collaborateurs [START_REF]C-13 or C-14[END_REF] sur les cycloadditions [2+2] asymétriques pour fournir le cyclobutène 117. Les cyclobutènes 169 fonctionnalisés ont été ensuite obtenus par une réaction de désulfuration sur une échelle pouvant atteindre la dizaine de grammes, avec d'excellents rendements et énantiosélectivités (Schéma II).

Schéma II. Synthèse de cyclobutènes par désulfuration. X = oxazolidinone.

La réactivité de ces cyclobutènes en conditions radicalaires a été étudiée à partir de différents types de radicaux. Dans ce contexte, les réactions de carbo-alcynylation, carbo-cyanation et d'addition de radicaux par transfert d'atome (ATRA) sur les cyclobutènes ont été étudiées. Les haloalcanes ont ainsi pu être additionnés au système π de cyclobutènes par réaction ATRA donnant accès aux cyclobutanes correspondants 180 avec des rendements bons à élevés (Schéma III). La diastéréosélectivité est contrôlée dans un premier temps par le groupement oxazolidinone puis ensuite par l'intermédiaire du fragment carboné additionné par voie radicalaire.

Schéma III. Réaction ATRA sur les cyclobutènes.

Le cyclobutène 180b dérivé du processus ATRA a été modifié ultérieurement. Par exemple, l'atome de brome a été échangé pour un motif cyanure avec une diastéréosélectivité modeste pour donner le cyano-cyclobutane 194 en 45% de rendement (Schéma IV). De même, l'allyl cyclobutane 195 a été obtenu par échange de l'atome bromure par un groupement allyl dans les conditions de Keck. 4 Plusieurs essais pour ouvrir le cycle 180b en milieu basique n'ont pas conduit aux résultats escomptés. En présence de K2CO3, une contraction de cycle a été observée après ouverture du cyclobutane suivie d'une cyclisation et du déplacement de l'atome de brome pour fournir le cyclopropane 193 en un rendement de 60%.

Schéma IV. Dérivés obtenus à partir du cyclobutane 180b.

La sulfonyl-cyanation d'oléfines en utilisant l'éosine-Y comme photocatalyseur sous irradiation à la lumière visible, précédemment développée dans le groupe, 5 a été appliquée aux cyclobutènes.

Dans ce procédé, les cyanures d'alkylsulfonyle se sont révélés d'excellents agents de transfert radicalaires pour fournir une série de dérivés polyfonctionnalisés présentant des centres quaternaires tout-carbonés, avec de bons rendements et excellentes diastéréosélectivités (Schéma V). Schéma V. Sulfonyl-cyanation de cyclobutènes catalysée par l'éosine-Y.

En raison de rendements modérés, une méthode de sulfonyl-cyanation plus efficace a été développée en utilisant le p-anisaldéhyde, comme photosensibilisateur (Schéma VI). Dans l'ensemble, les réactions sont plus propres avec ce dernier qu'avec l'éosine-Y, sont plus faciles à réaliser, ne nécessitant aucun traitement aqueux en fin de la réaction et les purifications du produit final sont plus simples même à grande échelle. Finalement, cette méthode s'est avérée compatible avec une série de groupements fonctionnels et a permis de réaliser des montées en échelle importantes sans affecter les rendements. Par exemple, 181b a été obtenu avec un rendement de 87% sur une échelle de 21 mmol, tandis qu'avec l'éosine-Y, le même produit a été isolé avec un rendement de 48% sur une échelle de 5 mmol.

Schéma VI. Sulfonyl-cyanation de cyclobutènes photosensibilisée par le p-anisaldéhyde.

Les études mécanistiques ont montré que cette réaction procédait probablement via un mécanisme de transfert d'énergie impliquant l'état triplet excité du photosensibilisateur (Figure I). Ces modèles polyfonctionnalisés ont ensuite été soumis à une ouverture de cycle par fragmentation radicalaire en utilisant le diiodure de samarium (Schéma VII). Les γ-nitriles acycliques 199 résultants ont été obtenus avec des rendements bons à élevés montrant la compatibilité de ce protocole avec une variété de substituants.

Schéma VII. Scope de la réaction d'ouverture de cycle médiée par SmI2.

Les produits ouverts ont ensuite été transformés démontrant leur utilité dans la synthèse de nouveaux composés chiraux. Par exemple, le groupement sulfonyl peut être éliminé dans les conditions de réarrangement de Ramberg-Bäcklund pour fournir l'oléfine 235 avec un rendement de 40% (Schéma VIII). Bien que l'oléfine souhaitée soit obtenue, cette réaction souffre d'un problème de reproductibilité en raison des conditions dures peu compatibles avec le groupement nitrile. A partir du γ-nitrile acyclique 199, une réaction de lactonisation a également été développée pour donner accès à un nouveau type de lactone 240a portant un centre quaternaire tout-carboné, avec un rendement de 63%.

Schéma VIII. Dérivés du composé 199 issus de l'ouverture de cycle.

Le cyclobutane 181 a également été transformé en d'autres " synthons ˮ utiles (Schéma IX). Par exemple, le fragment sulfone a été éliminé sous conditions basiques après plusieurs optimisations, pour donner le cyclobutène carboxylate 258 avec d'excellents rendements et reproductibilité sur une série de cyclobutanes et sur des échelles de 15-20 mmol. De nouvelles méthodes d'ouverture de cycle ont ensuite été testées sur ces cyclobutènes. Premièrement, sous des conditions d'ozonolyse, le cyclobutène carboxylate 258a fourni le composé tricarbonyle 266 avec un rendement de 84%. Cet αcétoester-aldéhyde s'est avéré instable, et plusieurs tentatives de fonctionnalisation afin d'obtenir un dérivé stable ont échoué. Des amines, alcools, le nitrométhane ou encore des malonates ont été additionnés avec succès sur la double liaison de l'énone, pour donner les produits de Michael correspondants avec des rendements élevés à excellents. Par exemple, l'addition nucléophile d'une pyrrolidine au cyclobutène carboxylate a produit un amino-cyclobutane 284 donneur-accepteur.

L'activation de ce système "push-pullˮ à l'aide d'un acide de Brønsted ou de Lewis n'a pas permis l'ouverture du cyclobutane en raison de la présence du fragment nitrile. La réduction de ce nitrile en amine n'a malheureusement pas contribué à favoriser l'ouverture du cycle dans le sens désiré. Le traitement des malonyl cyclobutanes en conditions basiques n'a pas non plus permis l'ouverture du cyclobutane. En général, les difficultés rencontrées lors de l'ouverture du cycle ont été attribuées à la présence du fragment nitrile sur le cyclobutane.

Schéma IX. Dérivés obtenus à partir du cyclobutane 181.

Un dérivé de ces composés, le cyclobutyl malonate 332, a été engagé dans une réaction de réduction en utilisant le borure de nickel comme catalyseur (Schéma X). Après optimisation, la réduction de la fonction nitrile, la cyclisation et l'ouverture du cyclobutane dans un processus en " un-pot ˮ a été appliquée à plusieurs cyclobutanes comportant des chaînes latérales variées. Les lactames 380 résultants ont été en outre manipulés pour générer le azabicyclo [3.3.1]nonane avec des rendements faibles à modérés. Schéma X. Réduction du nitrile, cyclisation et ouverture du cyclobutane, médiées par le borure de nickel.

Plus tard, la synthèse totale énantiosélective de l'eucophylline 8, un alcaloïde comportant un squelette naphthyridine unique isolé de Leuconotis eugenifolius, a été envisagée basée sur la stratégie développée ci-dessus. La synthèse a été réalisée en 17 étapes à partir du but-1-yne ou 1,1-dibromobut-1-ène, avec un rendement moyen de 85% et un rendement global de 5,9% (Schéma XI). Les analyses HPLC ont confirmé l'excès énantiomérique élevé du produit naturel (ee = 98%). Dans cette synthèse, aucun groupe protecteur n'a été utilisé et seulement 9 étapes ont nécessité une purification par chromatographie. L'approche synthétique comprend la préparation d'un cyclobutène chiral permettant d'incorporer le stéréocentre quaternaire asymétrique tout-carboné selon une approche photocatalytique. Les analyses de diffraction aux rayons X ont permis d'obtenir la première structure cristalline de 8 qui a confirmé la synthèse de l'énantiomère naturel.

Schéma XI. Synthèse totale énantiosélective de l'eucophylline.

En parallèle, les synthèses de l'éburnamonine racémique 423, de l'épi-éburnamonine 520, de l'éburnamine 18 et de l'épi-éburnamine 424 ont été réalisées à partir de la 2-pipéridinone 379 commercialement disponible (Schéma XII). La transformation de ce lactame a permis l'élaboration de l'amine (±)-517a qui contient le centre quaternaire tout-carboné présent dans les squelettes de l'éburnane. Après plusieurs tentatives infructueuses, la synthèse totale racémique de la série éburnane a finalement été achevée, reposant sur des étapes finales établies précédemment par Wenkert. 6 l'éburnamine 18 et l'épi-éburnamine 424 ont été obtenus en 10 étapes, avec un rendement moyen d'environ 81% et un rendement global de 9,5%.

Schéma XII. Synthèse totale de l'éburnamine racémique.

La synthèse énantiosélective de (+)-517a envisagée à partir d'un cyclopropène chiral 31 (Schéma XIII) repose en partie sur la stratégie établie en série synthèse racémique. La synthèse de l'amine 517a a été étudiée sur un modèle cyclopropène comportant une chaîne latérale de type propyle.

Cependant, par manque de temps, l'extension de cette approche au cyclopropène 31 n'a pu être réalisée.

Schéma XIII. Synthèse totale énantiosélective de la série éburnane à partir d'un cyclopropène.

Enfin, la synthèse de la leucophyllidine 6 a été envisagée. Le couplage biomimétique entre ses deux fragments 8 et 18 a été étudié en utilisant l'éburnamine racémique et un modèle avancé de l'eucophylline, la nor-éthyleucophylline 417 (Schéma XIV). Des résultats préliminaires ont montré que le couplage en milieu faiblement acide provoque une protonation de l'azote de la nor-éthyleucophylline, laquelle altère probablement la nucléophilie de l'hétérocycle et empêche le couplage.

Schéma

General Introduction

1. From nature to chemotherapeutic agents: the story For centuries, scientific minds were constantly inspired and often challenged by Mother Nature, to invent in their laboratories new technologies and sophisticated architectures of high value. The chemical society, for example, showed a particular interest in recreating molecules with significant therapeutic activities. Among these, come the anti-cancer agents.

During a plant screening program for the search for potential medication, Paclitaxel (TAXOL ®

[Bristol-Myers Squibb Co., Princeton, NJ]) 1 was isolated in the 1960s from the bark of Pacific yew tree, Taxus brevifolia, and it took several years to get it in its pure form (Figure 1). 7 This molecule, a member of the taxanes family, presented an interesting chemical structure and a level of cytotoxicity that led to deeper investigations. Nowadays, TAXOL ® is the best-selling chemotherapeutic drug ever manufactured, and it is used for the treatment of lung, breast, and ovarian cancers, as well as leukemia and Kaposi's sarcoma. 8 Other molecules, Vinblastine (Vincaleukoblastine; Velban ® or Velbé ® ) 2 and Vincristine (leurocristine; Oncovin ® ) 3 were isolated from Madagascar periwinkle, Catharantus roseus, previously called Vinca rosea. These Vinca alkaloids have been used over the last 50 years, for the treatment of cancer diseases including Hodgkin's disease and leukemia. 9,10 Inspired by their structures, Potier and co-workers 11 pursued the development of new synthetic analogs, by altering the original templates. Their efforts produced vinorelbine 4 (anhydrovinblastine) as the first active semisynthetic Vinca alkaloid. This was later introduced to the market by the French pharmaceutical company Pierre Fabre Medicaments under the name Navelbine ® , for the treatment of several types of cancers, like breast and non-small cell lung cancers. The research division of Pierre Fabre also launched Vinflunine (Javlor ® ) 5, a gem-difluoro derivative of vinorelbine. Preclinical results showed that vinflunine is more active than vinorelbine, vinblastine, and vincristine against many cancer cells. 12 This case demonstrated that the Vinca alkaloids drug family is a prospective area, and that the design of a new generation of alkaloids with promising pharmacological properties, is always possible. 13 Other anti-cancer agents isolated from natural resources are continuously emerging, such as epothilones, camptothecin, Manzamine A, and others. 14,[START_REF]Ring-opening through ozonolysis (S)-ethyl 4-cyano-4-formyl-2-oxo-6-((triisopropylsilyl)oxy)hexanoate (266) A solution of the cyclobutene 258a (50.0 mg, 0.14 mmol, 1.0 eq.) in CH2Cl2 (5.0 mL, 0.028 M) was cooled to -78 °C and O3/O2 was bubbled through it until the solution turned blue (10 min). The residual ozone was then discharged by bubbling with oxygen until it became clear again (5 min). Dimethyl sulfide (15.0 μL, 0.21 mmol, 1.5 eq.) was added and the reaction mixture was warmed to 20 °C with continuous stirring for another 1 h. The solvents were concentrated under reduced pressure to obtain the crude product as a viscous, colorless oil (45.0 mg, 84% crude, not stable in isolated form)[END_REF] Some of them are already available in the market and approved by the Food and Drug Administration (FDA). 16 Despite their presence in nature, these bioactive substances are often isolated in very low yields, not enough to supply the human needs and the advanced clinical trials. For instance, paclitaxel is present in the Pacific yew in a yield of 0.001% to 0.01% of the dry bark weight depending on the tree's age. 17 To carry out the early clinical studies of its activity, toxicity, and its drug compatibility, no less than 9,000 yew trees have been cut down in the North American forests to result in 27,000 kg of dry bark. 8,18 Besides, 2,500 trees would be needed to treat about 300 patients, while the number of candidates for paclitaxel therapy was estimated in tens of thousands in the 90s alone. 19 Similarly, the vinblastine's actual content in Madagascar periwinkles is extremely low with an average of 0.002%. 20 For the pharmaceutical production, approximately half a ton of dry leaves is needed to isolate, after extraction, only 1 gram of vinblastine. 21 For comparison, one could imagine needing a truck of 10 tons of dry Catharantus roseus to provide only a tablespoon of vinblastine, the equal of 20 grams (Figure 2). Even if the natural resources can be grown at a large scale, the production of trees of a certain age is revealed much more delicate, impracticable, and time-consuming. In addition, the isolation and purification of the abovementioned substances from many by-products, are rather tedious. Such rarity and difficulty of purification were well translated into the high cost of these chemical agents. For example, 1 kg of vinblastine 2 costs around a million-dollar or ~18 times the current price of gold per kg, while the world annual production is 12 kg. Similarly, 1 kg of vincristine 3 costs 3.5 million dollars, and the world annual production is about 1 kg. 22 At this point comes the duty of chemists in developing straightforward and time-and costefficient strategies, to synthetically access these compounds, without depleting the ecological system.

In the 1980s, chemists discovered that the leaves of the European yew (Taxus baccata), as abundant and renewable resources, contain a high amount of 10-deacetylbaccatin III, a structure close to paclitaxel. This precursor was synthetically converted to paclitaxel and completely solved the supply problems. 8,23 In the case of vinblastine, a semi-synthesis was also optimized, combining nature's gems and chemists' creativity. Two molecules, vindoline and catharanthine, more abundant within the periwinkle of Madagascar, were efficiently coupled by means of chemical reactions, leading to the dimer alkaloid vinblastine. 24,25 At the biological level, the vinca alkaloids' mode of action was found to be like the paclitaxel's in that they bind to tubulin molecules. By binding, they interrupt the microtubule dynamics during the cell division, which leads to mitosis inhibition and apoptosis. 26 Still, the taxanes bind at a different site than the vinca alkaloids and cause slow cell division by blocking the degradation of microtubules and preventing their shrinkage, rather than destabilizing the microtubules and inhibiting their polymerization (Figure 3). Despite this bioactivity and the developed clinical therapies, new generations of cancer cells have been showing mutation and became more resistant to these drugs. 27 Herein rises the need for new analogs with enhanced activity and efficiency. As well, a better selectivity for the sick cells is required to limit the severe side effects caused by the toxicity of the current drugs. Therefore, the isolation and identification of natural products as new chemotherapeutic agents became a principal aim in this dynamic area.

Leucophyllidine: isolation, structure, and biological activity

In this context, leucophyllidine 6, a potential therapeutic agent, was isolated a decade ago by Kam and co-workers 1 as a minor alkaloid from the stem-bark of Malayan Leuconotis griffithii, in a yield of 0.00071 g/kg. Subsequent crystallization from Et2O/EtOAc gave pale yellowish crystals with m. p. = 215-217 °C and [α]D = -138° (CHCl3, c = 0.18). X-ray studies of these crystals in combination with other spectroscopic data indicated an unprecedented structure of a bis-indole alkaloid. This dimer results in the union between an eburnan unit 7 (northern fragment) and a novel tetrahydrobenzo-[b] [1,8]naphthyridine template 8 (southern fragment) (Figure 4). The chromophore 8 was isolated a year later by Morita et al. 2 from Leuconotis eugenifolius and named Eucophylline. 2 Leucophyllidine 6 was also found in the same plant extract and was isolated in a yield of 0.044%. The leucophyllidine structure was regarded as original and complex because it represents the first member of new structural bis-indole alkaloids based on the constituent monomeric units. 28 As well, the naphthyridine half, the eucophylline, is a new unprecedented vinylquinoline skeleton.

Stereochemically, this dimeric natural product features four stereogenic centers, where two of them are all-carbon quaternary centers. These characteristics eventually, make the molecule a challenging target at the synthetic level.

Besides its intricate architecture, the eburnan-quinoline dimer 6 exhibits a pronounced in vitro selective cytotoxicity towards drug-sensitive and vincristine-resistant human KB cells (VJ300), with half inhibitory concentrations (IC50) of 2.95 and 2.92 μg/mL, respectively. 1 Also, Morita et al. 2 found that leucophyllidine 6 inhibits the NO production stimulated by LPS dose-dependently with IC50 of 7.1 μM, and shows high cell viability of J774.1 at a concentration of 7.1 μM.

Monoterpene indole alkaloids: origin and dimers biosynthesis

Leucophyllidine and dimeric alkaloids are proposed to be formed through the coupling of monomeric subunits belonging to the monoterpenoid indole alkaloids class. 29 This class contains over 3000 known members and more than 40 structural types. It represents one of the largest natural product families that have intriguing structural complexity and significant biological profile. 30 Monoterpene indole alkaloids were mainly isolated from three plant families:

Rubiaceae/Naucleaceae RUB, Loganiaceae/Strychnaceae LOG, and Apocynaceae APO.

Leucophyllidine and the before cited Vinca alkaloids 2 and 3 for example, belong to the latter family.

In spite of their structural diversity, the monoterpene indole alkaloids are all biosynthetically derived from a basic intermediate, strictosidine 9. Strictosidine, in turn, is obtained by the condensation between a secoiridoid unit, secologanin 10, and an indole segment, tryptamine 11, through a strictosidine synthase-catalyzed Pictet-Spengler reaction (Scheme 1). [30][31][32] Both the chemo-and stereoselectivities of the enzyme were proven to be high in vitro (i.e., under cell-free conditions). 29 Scheme 1. Nature's synthesis of the key precursor of indole alkaloids.

Subsequently, strictosidine 9 undergoes controlled germination through series of cyclization, rearrangement, ring contraction, ring expansion, or oxidation reactions, to provide a collection of skeletally diverse natural products (Scheme 2). 33 These tryptamine-derived alkaloids can be classified into several classes based on the type of the rearranged skeleton I, II, or III. Further discussion of the structural variation of those types of alkaloids is out of the scope of this manuscript. Yet, one could appreciate the design intelligence of Mother Nature creating so many diverse structures in elegant and thought-provoking ways.

Scheme 2. System of monomeric indole alkaloids derived from Secologanin. 29 The coupling of type I, II, and III monomeric alkaloids leads to quite common heterodimeric indole alkaloids (having two different basic skeletons) and more rarely to homodimeric indole alkaloids (having the same basic skeleton). A chemotaxonomic network could be found between different monomeric indole alkaloids in plants (Table 1). This biogenetic network was established based on the three-dimensional structure, taxonomic structure, and standard reaction mechanisms.

From the chemotaxonomic point of view, the presence of heterodimers proves that the different monomers coexist in the species from which they were isolated. Therefore, their biogenetic relatedness is rather evident.

Table 1. Summary of the chemotaxonomic relationships between indole alkaloids. 29 The presence of these intricate dimeric structures in nature led to the development of biogenetic hypotheses during the 1950s, and they were experimentally verified years later through in vivo feeding experiments with radioactively labeled precursors. 34 As well, these biogenetic pathways were often taken into serious consideration when a synthetic design is proposed. For instance, the proposed biogenetic synthesis of vinblastine 2 involves a direct coupling between vindoline 12 and catharanthine 13, having respectively a plumeran (type III) and ibogan (type II) skeletons (Scheme 3). 35 This hypothesis was verified in vivo by the incorporation of radiolabeled precursors (tritium), as well as synthetically through several reported total syntheses. 36,37 Scheme 3. Vinblastine biogenetic synthesis through dimerization between vindoline and catharanthine.

This coupling was proposed to result from a peroxidase-catalyzed reaction, where catharanthine 13 is oxidized into a hydroperoxide 14 (Scheme 4). 38 An electronic reorganization results in the departure of the hydroperoxide as a leaving group, to give an electrophilic intermediate 15. The latter undertakes a nucleophilic addition of the C-5 center of vindoline elaborating an adduct which is later reduced by NADH (Nicotinamide Adenine Dinucleotide). Vinblastine is then obtained through oxidation at the C-20 carbon center.

Scheme 4. Peroxidase-catalyzed biosynthesis of vinblastine. 38 During their studies, Morita and co-workers proposed biogenetic pathways for several alkaloids through a Mannich-type coupling reaction between type I and III skeletons. [39][40][41] For example, an eburnan-aspidosperma alkaloid, bisleuconothine A 16, isolated from Leuconotis griffithii, is believed to result from a Mannich-type reaction between a plumeran 17 and an eburnan 7 skeletons (Scheme 5). 42

Scheme 5. Proposed biomimetic coupling of bisleuconothine A. 42 About the leucophyllidine, the team directed by Kam proposed a similar Mannich-type coupling between the vinylquinoline alkaloid 8 and the eburnamine-type motif 7 to furnish the bis-indole 6 (Scheme 6). 1 Scheme 6. Proposed biosynthesis of leucophyllidine, by Kam et al. 1

Initial retrosyntheses of leucophyllidine, eucophylline and eburnamine

The three natural substances leucophyllidine 6, eburnan 7 and eucophylline 8 are present in the Leuconotis species. In addition, Morita and co-workers 2 isolated both leucophyllidine and eucophylline from the same source, Leuconotis eugenifolius. These findings altogether suggest that the biogenetic analysis proposed by Kam et al., 1 would most probably produce leucophyllidine 6 through a Mannich-type reaction. Using acidic sources, the biomimetic coupling would proceed between the C-1' electron-rich center of eucophylline 8 and the C-7 electrophilic center of eburnan 7 (Scheme 7). The latter itself derives from eburnamine 18. Methoxy-eucophylline 19 may also be envisioned in the coupling process as another reactive analog of 8 in the Mannich reaction.

Scheme 7. Retrosynthesis of leucophyllidine 6.

The fact that leucophyllidine presents a complex molecular framework with four stereocenters, requires an attentive investigation and a development of solid enantio-and diastereo-controlled strategies. Indeed, the construction of quaternary centers has been a challenging synthetic topic over the years. More specifically, all-carbon quaternary stereocenters (carbon atoms bonded to four carbon substituents) are difficult to create with high level of stereoselectivity. [43][44][45] Such an issue is of considerable importance in the domain of the synthesis of natural molecules.

In this work, it was suggested that manipulating small chiral ring systems, would allow the control of the stereochemistry of the synthesized molecules. As in cyclic systems, the diastereoselectivity is more predictable than in the acyclic counterparts. 46 Such rings would be functionalized through radical approaches, as suitable ways for the formation of all-carbon quaternary centers. This center would be created by the addition of a carbon fragment such as a nitrile. The corresponding compound would serve as a key precursor for a broad spectrum of synthetic applications (e.g., reduction of the nitrile to access the amino-methyl group). Subsequently, the nucleophilic amino group would react with various electrophilic agents to create complex structures, such as indole rings. Apart from the interest in generating stereo-controlled all-carbon quaternary centers, the reactivity of small rings towards radical reactions will be revisited, as little is known in this domain. This would add knowledge to the already-known facts about these carbocycles.

Considering the number of carbon atoms necessary to build the chiral part of eucophylline, its synthesis would be developed starting from an enantiopure cyclobutene unit I (Figure 5). Such a ring is not reported in the literature; thus, the establishment of a new method to access the desired fragment will be studied first. In the meantime, the eburnamine would arise from a chiral cyclopropene analog II, where an efficient synthesis of a such molecule has been documented before. 47 For the eucophylline, the first steps of its retrosynthesis are based on the total synthesis of the racemic form, reported by Landais et al. 48 The incorporation of a vinyl unit would be established at a late stage through a Suzuki coupling from the corresponding triflate, bromide or diazonium salt (Scheme 8). The eucophylline tetracyclic core would arise from a Friedländer-type annulation of an unusual bicyclic lactam 20 with a functionalized aniline, followed by cyclization under basic conditions. For the bicyclic lactam 20 itself, it would derive from an SN2 reaction of a post-activated alcohol 21. The latter would be produced after the reduction of the nitrile function and a spontaneous cyclization with the carbonylated function in 22, while the enantiopure acyclic skeleton bearing an all-carbon quaternary center 23, would arise from a highly functionalized cyclobutane 24. This would be constructed from a radical carbo-or sulfonyl-cyanation of an enantiopure cyclobutene 25.

Scheme 8. Initial retrosynthesis of (+)-eucophylline 8.

The beginning of the eburnamine retrosynthesis would be based on formal syntheses, by tailoring the last ring using a suitable base, followed by reduction of the molecule's carbonyl groups (Scheme 9). The tetracyclic template 26 would be synthesized by selective oxidation of the methine site αto the nitrogen. Its precursor, the ester 27, would derive from the alkylation of a cyclic lactam 28 with tryptophyl bromide. The lactam ring would result from a cyclopropane ring-opening of 29, which itself comes from the nitrile reduction and cyclization of a polyfunctionalized cyclopropane 30. The latter originates from the diastereoselective free-radical carbo-cyanation of cyclopropene 31, thus incorporating the quaternary center bearing a nitrile functional group. 47 The enantiopure cyclopropene would be accessed inspired by previous reports, starting from suitable alkyne and diazoester reagents. 47,49 Scheme 9. Initial retrosynthesis of eburnamine 18.

Thesis outline

This Ph.D. manuscript will be presented in six chapters. The first chapter will be dedicated in its first part to the various aspects of the free-radical reactions, including the stability, structure, and reactivity of radicals. The major transformations in this field, especially the transformations involving the sulfonyl derivatives, will also be described. In the second part, however, a general overview of the photoredox catalysis concepts will be examined, followed by a brief application of this powerful tool in the elaboration of diversified synthetic architectures.

The second chapter will present the properties, reactivity, and stability of three-and fourmembered ring systems. The most common pathways to access these templates will also be highlighted.

Chapter three will discuss the Ph.D.'s results on the development of an efficient approach to access a library of enantiopure cyclobutenes. The stereocontrolled functionalization of these scaffolds through various radical additions will also be presented. In this transformation, different radical traps will be tested using classic radical chemistry or the newly developed photocatalyzed radical addition reactions. The second part of this chapter will be dedicated to the formation of a broad range of skeletons as derivatives of cyclobutanes, including the investigated approaches to carbocycles ringopening.

The fourth chapter will report the total synthesis of (+)-eucophylline, starting by the development of a chiral azabicyclo [3.3.1]nonane scaffold created from a cyclobutane unit. Such transformation was possible thanks to the challenging nickel boride reduction reaction of the corresponding intermediate. The aspects and optimizations of this reaction will be presented in detail. Later, the completion of the natural product's synthesis will be reported, and its structural characterization will be discussed carefully.

Chapter five will describe the different strategies to access the eburnane series. The total synthesis of the eburnamine will be discussed and the pathway to access the chiral natural product from an enantiopure cyclopropene skeleton will be presented.

The sixth and final chapter deals with the biomimetic coupling of leucophyllidine and the performed coupling studies between the eburnamine and a structurally similar model of eucophylline.

Chapter I Free-Radical Chemistry & Photoredox Catalysis Part I

Free-radical chemistry:

General aspects and reactivity

Free-radicals: a historical perspective

Pioneering works on free radicals go back to the eighteenth century when Gay-Lussac reported in 1815 that heating mercuric cyanide led to the formation of cyanogen dimer, which was explained by the creation of cyanide radicals ( • CN) as intermediates. 50 Kolbe 51 and Frankland 52 also claimed, respectively, in 1849, the formation of methyl radical ( • CH3) by decarboxylation of potassium acetate, and "ethyl" radical ( • C2H5) from the reaction of ethyl iodide with zinc. Yet, these findings and few others, 53 were neglected in front of the flourishing concept of carbon tetravalency (e.g., by forming four bonds) and the lack of suitable techniques for free-radical detection and isolation.

The key breakthrough came half a century later, when Gomberg 54 proved the existence of radical species by discovering the triphenylmethyl radical (trityl for short), the first stabilized radical example. Upon treatment with silver metal, triphenylmethyl chloride yielded a yellow solution that was attributed to the trityl radical. Its character was demonstrated by its facile reaction with oxygen to give the corresponding peroxide. However, this bold announcement faced skeptics who insisted that such trivalent carbon could not exist. Not until a decade later, the existence of this radical was confirmed by Schlenk and colleagues 55 through the preparation of tris(4-biphenylyl)methyl radical.

These two examples provided evidence for the existence of stabilized arylmethyl radicals, but aliphatic radicals (such as methyl and ethyl) were still a subject of doubt. In 1929, Paneth and his coworkers 56 reported the existence of alkyl radicals through their experiments of thermolysis of the vapor phase of organometallic compounds such as tetramethyllead. Shortly after, radicals were postulated as key intermediates in the mechanistic explanation of the so-called "abnormal reactions".

For instance, the Kharasch reaction and mechanism, an anti-Markovnikov addition of HBr to alkenes, became the first demonstration of a free radical chain mechanism. 57 These results encouraged scientists to investigate the generation of carbon-centered radicals and the measurement of their reaction kinetics in the following decades. This was greatly helped by the development of spectroscopic methods such as Electronic spin/Paramagnetic Resonance (ESR/EPR) and Nuclear Magnetic Resonance (NMR) Spectroscopy in the 60s and 70s. 58 Since then, free-radical chemistry expanded as a powerful tool in organic synthesis. Indeed, Giese described the addition of nucleophilic radicals onto unactivated olefins. 59 Barton also proposed new methods to produce carbon-and heteroatom-centered radicals. 60,61 In the 90s, Curran achieved bright syntheses of complex natural products through tandem radical cyclizations. 62,63 While Parker and co-workers 64,65 prepared (-)-morphine using a radical cascade process installing the all-carbon quaternary stereocenter and the tricyclic system of the alkaloid in a single step. Recently, the radical cascade chemistry was applied in the synthesis of 47 monoterpene alkaloids. 66 Despite its uncertain beginning, the topic of free-radicals holds today a central place in modern organic synthesis, from the fundamental studies (e.g., electronic distribution of spin and charge) and the synthetic applications (novel polymers, natural products), to the elucidation of biochemical processes (photosynthesis, tissue damage, and aging process). This amplified interest demanded, therefore, more understanding of the structural and reactivity features of such species. So, what are free-radicals?

Free-radicals: concept

Free-radicals are chemical species that contain a singly occupied orbital. Generally, they tend to be very unstable and reactive. Their high reactivity is due to the unpaired electron, which has an affinity to pair with a second electron to produce a filled outer shell. 67 Radicals are often generated through homolytic bond cleavage, from radical initiators such as peroxides or azo-bis derivatives.

The decomposition of the initiator is triggered by thermolysis (heat) or photolysis (light). Many radical reactions are chain reactions including an initiation step, a propagation step, and a termination step. The cleanness, efficiency, and selectivity of these reactions are related to the reactivity of carbon-centered radicals. This has been shown to be influenced by many factors including the structure and stability of the radical and the thermodynamic of the reaction (the energetic summary of the broken and formed bonds during the radical reaction steps).

Structure of carbon-centered radicals

In studying their structure, physical methods have provided insights that the trivalent carbon radical may adopt different geometrical configurations depending on the number and nature of the ligands attached to the radical center (Figure I.1). Specifically, the ESR spectrum of the methyl radical led to the conclusion that its structure could adopt sp 2 hybridization, thus a planar structure (with angles equal to 120°), or could adopt sp [START_REF]C-13 or C-14[END_REF] hybridization, with a pyramidal structure (109.5°) with a very low barrier of inversion (1.2 kcal/mol). 68 Other trivalent alkyl radicals are generally planar and are located in a p orbital. As a consequence of the planar shape, the stereochemical information is lost during the process of bond breaking/bond formation. 69 However, depending on the steric hindrance (constrained systems e.g., adamant-1-yl radical) and the electronic character (electron-donating groups αto the radical e.g., trifluoromethyl radical) of the substituent, pyramidalization of the radical may occur because the barrier of inversion slightly increases. 70 For divalent radicals (e.g., aryl, alkenyl, and acyl radicals), the unpaired electron resides in an sp 2 orbital bent shaped, unless constrained in a small ring (e.g., in phenyl radical). The inversion of this radical is possible and the transition state exhibits a linear geometry at C • with the radical in a p orbital. 69 Finally, for monovalent radical species, the radical adopts a linear shape with an sp hybridized orbital.

Stability of radicals

Carbon radicals can be stabilized by both electronic and steric effects. In general, alkyl radicals are stabilized by inductive effects, hence, they obey the following order: methyl < ethyl < i-propyl < t-butyl. This phenomenon can also be explained by the hyperconjugation between the SOMO (Single Occupied Molecular Orbital) in which resides the unpaired electron, and the neighboring C-H σ bonding molecular orbital (Figure I.2). 71 Therefore, alkyl radical stability follows carbocation stability. Resonance (orbital overlap with an adjacent π bond or lone pair) also contributes to radical stability. Hybridization also affects radical stability; the more s character is present on the SOMO, the more the radical is destabilized. This explains the low stability of alkynyl radicals. On the other hand, the kinetic stability of radicals can be influenced by the steric hindrance around the radical center. The more the radical is sterically hindered, the more it is stable and longlived (e.g., Gomberg's trityl radical). This longevity/unreactivity is explained by a combination of electronic and kinetic stabilization and low probability of recombination. This kind of radicals is often referred to by the term "persistent radicals". 72 Thus, the radical stability and reactivity are strongly related; the more the radical is stable, the less it is reactive.

Polarity effect on radical reactivity

The reactivity and the successful radical addition onto π-systems also depend on the nature of both the radical and the unsaturated systems. In a radical addition reaction, an electrophilic radical will react faster with an electron-rich alkene, whereas a nucleophilic radical will react faster with an electron-deficient alkene. This is known as matched or complementary polarities. In the case of polarity mismatch, the reaction rate is slow. These polar effects are best explained by the frontier molecular orbitals theory (FMO) 73 which provides a better understanding of the radical reactivity (Figure I.4). The radical SOMO possesses energy between the HOMO (Highest Occupied Molecular Orbital) and the LUMO (Lowest Unoccupied Molecular Orbital) of the olefin. With a nucleophilic radical (higher SOMO) and an electron-poor alkene (lower LUMO), the SOMO-LUMO interaction dominates because they are close in energy (i.e., the energy barrier is small). In contrast, with an electrophilic radical and an electron-rich alkene, the SOMO-HOMO interaction is preferred. In both cases, the interaction results in a gain of energy relative to the newly formed σ bond at the expense of a weaker π bond, making the reaction thus, exothermic. Taking into consideration the polarity effect helps significantly in predicting and designing successful and chemoselective radical reactions. However, there are always exceptions when it comes to radical chemistry; some may arise from the borderline polarity of radical species or other components (Figure I.5). 74 6. Radical reactions

Radical fragmentation

The radical fragmentation is an elementary reaction that cleaves a bond to one of the atoms adjacent to a radical center. The α-and β-fragmentation (other names α-and β-cleavage or scission) are usually endothermic (Scheme I.1). β-fragmentation, for instance, takes place when a weak σ-bond β-related to a radical center cleaves to generate two fragments; an unsaturated compound and a new radical. 75 Typically, this weak σ-bond is a carbon-heteroatom bond such as C-SR, C-SO2R, C-Br, Scheme I.1. Radical fragmentation reactions.

Radical fragmentations show similar kinetic effects to those observed in radical additions. The stability of the formed radical plays an important role in the rate of fragmentation reactions. The more stable the radical is, the faster is the reaction. For instance, in the series of substituted cyclopropylcarbinyl radicals, the stability of the formed radical influences the rate of the ring-opening reaction (Table I

Radical chain reactions

Before the 1980s, the radical reactions were considered messy, unpredictable, and non-selective.

Kinetic data relative to the generation and reactions of radical species were then gathered, allowing the development of controllable chemo-and regioselective chain reactions. This remarkable evolution allowed the chemistry of radical species to participate to the construction of complex building blocks for synthesis and material applications. Chain reactions are considered the major method in radical chemistry nowadays. Such reactions require the generation of a small amount of reactive radicals in the initiation phase through homolysis (thermolysis or photolysis). Once radicals are formed, they react with the precursor generating for instance a new carbon-centered radical, which enters into the propagation cycle (Scheme I.2).

Scheme I.2. Mechanism of a generalized radical chain reaction.

The process of transmitting the radical character from one species to another allows the propagation of the radical chain while releasing continuously the final product. However, when oddelectron species undergo direct radical-radical recombination, the radical character is lost to form a non-radical adduct. The chain reaction is stopped and this step is called termination. In order to avoid this undesirable event, low concentrations of radicals are required, and small quantities of initiators are used. Propagation steps often involve substitution (atom abstraction), addition, or fragmentation (α-and β-elimination) as the most common processes in radical reactions. For the reader's convenience, a non-exhaustive description of some radical processes is provided.

Radical chain mediators

The use of radical initiators is required to produce the first radicals that will enter into the propagation stage. Despite its use in sub-stoichiometric amounts, the initiator is not a catalyst because it is irreversibly transformed into radicals. Some reactions do not need an additional reagent to allow a complete conversion of the precursor (e.g., Kharasch reaction), however, many reactions need an additional reagent called a radical mediator. A mediator is a reagent involved in the conversion of the precursor by sustaining the radical chain. The most popular mediators were so far the organotin compounds (tri-n-butyltin hydride, bis(tri-n-butyltin)), organosilanes (tris(trimethylsilyl)silane), germanes and boranes (triethylborane). 78 For clarity reasons, only the major radical processes are discussed and are categorized depending on the nature of the radical acceptor.

Hydrogen transfer reactions

Tri-n-butyltin hydride (n-Bu3SnH) is well known as a hydrogen donor in radical reactions.

Generally, radical reactions with Bu3SnH initiated by azobisisobutyronitrile (AIBN) proceed effectively in benzene. 79 Upon initiation, the hydrogen abstraction of n-Bu3SnH leads to the tributyltin radical (Scheme I.3). In the propagation step, the mediating Bu3Sn • radical abstracts a halogen atom from the organohalide 34 to generate a carbon-centered radical R • . This radical can then be directly reduced by n-Bu3SnH to form the dehalogenated product Rn-H 35 or can be transformed to another radical Rn • , which is then subjected to the hydrogen transfer reaction providing the alkane 36 and a Bu3Sn • radical, thereby closing the cycle. 80,81 Scheme I.3. Generalized Bu3SnH-mediated hydrogen transfer mechanism.

To address the toxicity issues of tin hydride and the challenging removal of its residues from organic compounds, chemists introduced other reagents as a hope to escape from "the tyranny of tin" as described by Walton. 82 Tris(trimethylsilyl)silane and organoboranes are among the potential replacements of tin hydride catalyst. 78

Atom transfer reactions or halogen group transfer

The Atom Transfer Radical Addition (ATRA) reaction was first reported by Kharasch 83 and later developed by Curran,84 Oshima, 85 and others (Scheme I.4). In this reaction, electrophilic precursors such as organohalide compounds (e.g., CCl4, iodomalonate, bromomalonate…) add to the electronrich olefins 37 in the presence or absence of tin reagents. In the example of Kharasch, diacetyl peroxide (MeCO2)2 was used as an initiator, which upon thermolysis generated a methyl radical, which upon chlorine abstraction from CCl4 led to a • CCl3 radical and promoted its addition onto the olefin's double bond. The newly generated nucleophilic radical 38 reacted then with carbon tetrachloride to deliver the ATRA product 39 and regenerate the carbon trichloride radical.

Scheme I.4. Mechanism of the ATRA reaction developed by Kharasch. 83

Radical carbo-allylation reactions

Besides the xanthate group additions developed by Zard, 86 the allyl addition is considered as one of the most popular group transfer reactions. The allyl group transfer from allyltrimethyltin reagent was first discovered in 1973 by Pereyre et al. 87,88 and Migita et al. 89 and developed later by Keck et al. 90 with allyltributyltin 41a (Scheme I.5).

Scheme I.5. Allyl transfer reaction reported by Keck et al. 90 Under refluxing conditions, a small amount of stannyl radicals are generated, which abstract the halide from the organohalide substrate 34. The generated electrophilic radical (R • ) is later added to the allylstannane 41 to form a C-C bond followed by a β-elimination to provide the allylation product 43 and regenerate the stannyl radical, which in turn propagates the radical chain (Scheme I.6).

Scheme I.6. Mechanism of radical carbo-allylation reaction.

In this context, Russell et al. 91 reported examples of allylation reactions using vinyl thioethers, sulfoxides, and sulfones, showing the ability of these reagents to undergo fragmentation after the addition of alkyl radical onto the allyl reagent. Based on these results, Keck et al. 92 described the first application of allylsulfones fragmentation as a key step in the synthesis of the natural product (+)pseudomonic acid C (Scheme I.7). These examples opened the way for the use of sulfone groups in radical reactions.

Scheme I.7. Application of the sulfone fragmentation as a key step in (+)-pseudomonic acid C synthesis. 92

Carbo-alkenylation and alkynylation reactions

The electrophilic property of sulfonyl radicals and the easy access to a wide range of sulfone substituents motivated research groups to explore their reactivity as radical acceptors. These features were directed towards the addition of alkenyl and alkynyl groups onto olefin backbones, a challenging task that was first taken by Fuchs et al. 93 Thus, alkynyltriflone derivatives were developed as radical traps in the alkynylation of alkanes C-H bonds.

In a tin-free process, the initiator generates an electrophilic trifluoromethyl radical, which abstracts hydrogen from an alkane 47 (Scheme I.8). The resulting nucleophilic alkyl radical then adds onto the alkynyltriflone 48 followed by the β-fragmentation of the alkenyl radical to deliver the coupling product 49 and an unstable sulfonyl radical. The latter then undergoes α-scission with loss of sulfur dioxide to generate a trifluoromethyl radical that propagates the radical chain. The βfragmentation rate of sulfonyl radical depends on the stability of the intermediate. 94,95 These conditions allowed functionalizing poorly reactive alkanes such as cyclohexane, cycloheptane, norbornane, and adamantane. This strategy was then extended to the alkenylation and allylation of alkanes with vinyl-and allyltriflones, respectively. [96][97][98] The method, however, showed limitation by the necessity of using the CF3 group in the radical acceptor backbone.

Scheme I.8. Mechanism of alkynylation of C-H bond, by Fuchs et al. 93 Three-components (3-MCR) carbo-alkenylation and -alkynylation of olefins were also described by Landais et al. 99 In this method, two functional groups could be added across the π-system of unactivated olefins 51. Starting from a broad range of carbonyl precursors 50 (ketone, nitrile, malonate, amide) as radical precursors, the addition of the alkyl radicals on alkenyl-and alkynylsulfones 52 proceeded smoothly to deliver the unsaturated products 53 in good to excellent yields (Scheme I.9).

Scheme I.9. Carbo-alkynylation and alkenylation of olefins by Landais et al. 99

Free-radical carbo-cyanation of olefins

Landais and co-workers 100 also developed an efficient three-components carbo-cyanation reaction of olefins 55 using the commercially available tosyl cyanide 56 (Scheme I.10). Nitrilefunctionalized all-carbon quaternary centers 57 were produced in good yields and this strategy was applied to a large library of olefins.

Scheme I.10. Free-radical carbo-cyanation of olefins, by Landais et al. 100

Free-radical carbo-oximation reaction

Kim et al. [101][102][103] were the first to use sulfonyl oximes in tin-mediated radical additions. Their studies showed that the electron density on the oxime's carbon (C=N) is low, making them good radical traps. Hence, the less electron density on the carbon is, the better is the radical acceptor. 104,105 The addition of an alkyl radical 61 (generated from alkyl iodide 58) onto a sulfonyl oxime 59 afforded, after β-elimination of the phenylsulfonyl radical, the alkylated oxime 60 in moderate to excellent yields (Scheme I.11). The hydrolysis of the oxime product 60 in formaldehyde and HCl gave access to the corresponding aldehyde (R2 = H) or ketone (R2 = Me). It is worth noting that the sulfone group decreases the energy difference between the SOMO of the alkyl radical and the LUMO of the radical acceptor, which in turn increases the rate of addition of the alkyl radical onto the oxime.

Scheme I.11. Alkylation of sulfonyl-oxime/radical acylation of alkyl halides by Kim et al. Inspired by this work, an efficient four-components radical process (4-MCR) was developed by

Landais and co-workers. 106 Instead of hydrolyzing the oxime group, the oximated product was allowed to react with an alkyl radical or an allylzinc reagent to afford multi-substituted piperidinones 68 and 69 in good yields and high trans-favored diastereoselectivity (Scheme I.12).

Scheme I.12. Synthesis of functionalized piperidinones through a 4-MCR carbo-oximation. 106 This strategy was used in the development of three-components carbo-oximation as a key step in the total synthesis of (±)-eucophylline, proving thus, the utility of a such approach (Scheme I.13). 48

Scheme I.13. 3-MCR carbo-oximation as a key step in (±)-eucophylline synthesis. 48 The three-components free-radical carbo-oximation is categorized as "ADA" system (Acceptor-Donor-Acceptor system) (Figure I.6). 74 In this system, the tin radical abstracts a halide or a xanthate from the corresponding alkyl halide or xanthate, generating the first electrophilic alkyl radical (Acceptor). The latter then adds onto the less hindered end of an electron-rich olefin (Donor). The nucleophilic intermediate radical thus formed is then rapidly trapped by the electrophilic sulfonyl oxime (Acceptor). The sulfonyl radical, generated after β-fragmentation, propagates the chain by reacting with a stoichiometric amount of bis(tributyltin) producing new stannyl radicals that sustain the radical chain. This sequence represents a straightforward strategy to access highly substituted oximes in a one-pot operation.

Conclusion

Along this section, free-radical chemistry was briefly discussed as a central theme in organic synthesis. Its advantages reside in high functional groups tolerance, high selectivity in the presence of unprotected groups (e.g., ketone, alcohol), and efficient access to complex molecular architectures, notably through well-designed cascade processes. Considering the aforementioned transformations, radical chain reactions allow the integration of a wide range of functional groups (halides, alkyl, allyl, cyanide, azide, alkene, alkyne, acyl, oxime, and xanthate…) which explain the high interest in this promising field. Yet, many of these reactions require, as propagation mediators, a stoichiometric quantity of toxic reagents such as organotin derivatives. Besides their toxicity, these mediators generate large amounts of tin residues that contaminate the final products. 107,108 These strategies cannot be considered for agrochemical and pharmaceutical uses, even if the results in terms of organic synthesis are excellent and efficient. Much less toxic but more effective radical mediators have been developed to replace organotins, and among them, tris(trimethylsilyl)silane, samarium (II) iodide, and triethylborane. In the last two decades, the need for greener radical transformations were at the roots of the blooming of attractive alternatives including, the photoredox catalysis, which became an increasingly important and appealing tool in organic synthesis.

Part II

Photoredox catalysis:

Basic concepts and applications

Photoredox catalysis in organic synthesis

Visible light-mediated photoredox chemistry has emerged in the last decade as a powerful tool to perform organic reactions through energy transfer or single electron transfer (SET) processes, inaccessible otherwise. Since most organic molecules are transparent to visible light, bench-stable metal complexes and organic dyes were developed and used to mediate radical reactions, advantageously replacing initiators usually employed in classical radical chemistry. These photocatalysts mediate chemical transformations under very mild conditions, at room temperature, and in a green and clean manner. 109 Although the first applications were described by Kellogg 110 and Deronzier 111,112 According to the quantum theory (wave-particle duality), electromagnetic radiation can also be seen as a flux of photons (or quanta). A photon is characterized by its energy related to the frequency of the radiation,  according to the following equation:

𝐸 = ℎ𝜈 = ℎ 𝑐 𝜆 (Eq. I.2)
where h is the Planck's constant (6.63 x 10 -34 J.s). Typically, using light (200 to 1000 nm range), a molecule receives energy between 9.95 x 10 -19 and 1.99 x 10 -19 J, which corresponds to 599 kJ and 120 kJ for one mole. These values are of the same order of magnitude of those required for the bond dissociation energies of some typical carbon-heteroatom or carbon-hydrogen bonds (e.g., 190 kJ mol -1 for the Br-Br bond of Br2 or 416 kJ mol -1 for the C-H bond of CH4). Thus, this energy is significant to realize chemical transformations. 116

Absorption of light

According to the Grotthuss-Draper law, only the light absorbed by an investigated species is effective. Therefore, it is important to measure the absorption of the medium to determine the energy of the light absorbed. The absorbance of the species is defined by the Beer-Lambert law (Eq. I.3).

This equation describes the absorption of a monochromatic beam light by a substance dissolved in a transparent medium.

I = I 0 × 10 -𝜀𝑏𝑐 or A = log ( I 0 I ) = 𝜀𝑙𝑐 (Eq. I.3)
where I is the intensity of the transmitted light, I0 is the intensity of the incident light, A is the absorbance, ε is the molar absorption coefficient (M -1 cm -1 ), l is the optical path (cm) and c is the solution concentration (M). 116

Excited states

When excited by a photon with a given energy, a molecule is promoted from its initial ground state to an electronically excited state. 116 This phenomenon causes changes in the electronic structure of the molecule. Since the chemical and physical properties depend on the electronic structure, a molecule in the excited state holds chemical and physical properties different from that of the ground state. The excitation of a molecule X is generally expressed as:

X + ℎ𝜈 → X * (Eq. I.4)

X refers to the ground state molecule, hν is the absorbed photon and X * corresponds to the electronically excited state. After excitation, X * possesses greater electronic energy than X.

Deactivation pathways of excited states

After reaching an excited state, a molecule X becomes reactive (X * ) and it usually relaxes back to the ground state in a given time interval through different deactivation modes (physical or chemical) (Figure I.8). 116 In a photophysical process, the original molecule is recovered after returning to its ground state. This deactivation is accompanied by the emission of light (luminescence)

or by the dissipation of heat. In a photochemical process, the excited species enter in chemical reactions, and a new product is formed. These processes can occur at intra-or intermolecular levels. When a molecule absorbs light, it goes from the ground state S0 to a higher electronic state (excited state) Sn possessing a higher vibrational level (Franck-Condon state). This electronically excited species then disperses the additional vibrational energy (as heat) and returns to the population of S1 (Kasha's rule). This process is called vibrational relaxation (v.r.) and it usually happens in picoto nanoseconds timescale. Relaxation from an upper excited state to a lower excited state (isoenergetic states) involves an intramolecular radiationless transition process. When the relaxation happens within the same multiplicity (spin-allowed, Sn → S1 and Tn → T1), the process is called internal conversion (i.c.). This transition happens at a rapid rate between the upper excited states (10 -14 to 10 -11 s) because the difference in energy is relatively small, whereas it is slower between S1 and S0 (10 -9 to 10 -7 s) due to the large energy gap. When the transition happens between isoenergetic states of different multiplicities (spin-forbidden, e.g., S1 → T1), the relaxation process is called intersystem crossing (i.s.c.), and it is slower than that of the internal conversion (10 -11 to 10 -8 s timescale).

If the transition from an excited state to the ground state was accompanied by the emission of a photon, the deactivation is called radiative and the energy excess is released as light. If the photon emission occurred between states of the same multiplicities (spin-allowed emission, S1 → S0), the transition is defined as fluorescence (10 -12 to 10 -6 s typical timescale). When the transition occurs between states of different multiplicities (spin-forbidden emission, T1 → S0), the phenomenon is called phosphorescence (10 -3 to 10 2 s typical timescale).

Intermolecular deactivation of excited states

The deactivation of an excited state can also occur through an intermolecular interaction by the means of chemical transformations. This involves oxidation or reduction of the species, where an ion pair is formed. During an energy transfer deactivation, the electronically excited state of a molecule (the donor) is deactivated by transferring energy to the lower electronic state of another molecule (the acceptor). The donor is known as a sensitizer and the acceptor is known as a quencher.

Photoinduced electron transfer (PET)

Photoinduced electron transfer (PET) corresponds to the primary photochemical process of the excited state species, X * , where X * can be an electron donor or an electron acceptor when reacting with another molecule, Y (Figure I.11). When X * acts as an electron donor, it is oxidized (oxidative electron transfer):

X * + Y → X •+ + Y •-
When X * acts as an electron acceptor, it is reduced (reductive electron transfer): In a photoinduced electron transfer process, an electron is transferred between an excited-state and a ground-state species, therefore, this exchange requires orbital overlap. 116

X * + Y → X •-+ Y •+

Thermodynamics of ET and PET

When designing a given reaction involving photoinduced electron transfer, it is important to know whether it is thermodynamically favored or not. 117 For this reason, the measurement of the reduction potentials of both the photocatalyst and the substrate is required. The obtained values can then be applied in the adequate equation. To calculate the free energy of a single electron transfer (ΔGET), the equation below is used:

∆G ET = -𝐹(E 𝑟𝑒𝑑 -E 𝑜𝑥 ) = -𝐹[E 1/2 (𝐀 𝐀 •- ⁄ ) -E 1/2 (𝐃 •+ 𝐃 ⁄ )] (Eq. I.5)
where F is the Faraday constant (23.061 kcal V -1 mol -1 ), Ered and Eox are the ground state redox For a photoinduced electron transfer process, the free energy (ΔGPET) is commonly determined by the following equation:

∆G PET = -𝐹[E 𝑜𝑥 (𝐃 •+ 𝐃 ⁄ ) -E 𝑟𝑒𝑑 (𝐀 𝐀 •- ⁄ )] -𝑤 -E 0,0 (Eq. I.6)
where w is an electrostatic work term and is usually omitted because the correction of w to ΔGPET is relatively small. E0,0 represents the excited state energy for a given catalyst. This equation is normally used in the selection of an appropriate photoredox catalyst for the desired transformation. ΔGPET is also represented by the simplified equations I.7 and I.8, in the case of an oxidant and reductant photoredox catalyst cat * , respectively. This allows the calculation of the excited state redox potential of the photocatalyst cat.

∆G PET = -𝐹[E 𝑟𝑒𝑑 * (𝐜𝐚𝐭 * 𝐜𝐚𝐭 •- ⁄ ) -E 𝑜𝑥 (𝐬𝐮𝐛 •+ 𝐬𝐮𝐛 ⁄ )]
(Eq. I.7)

∆G PET = -𝐹[E 𝑟𝑒𝑑 (𝐬𝐮𝐛 𝐬𝐮𝐛 •- ⁄ ) -E 𝑜𝑥 * (𝐜𝐚𝐭 •+ 𝐜𝐚𝐭 * ⁄ )] (Eq. I.8)
When a photoredox catalyst acts as an excited state oxidant (Eq. I.7), E 𝑟𝑒𝑑 * is positive and must be more positive than the substrate sub E 𝑜𝑥 , for the photoinduced oxidation to occur. Similarly, when a photoredox catalyst acts as an excited state reductant, E 𝑜𝑥 * is negative and must be more negative than the substrate sub E 𝑟𝑒𝑑 to be a thermodynamically favored photoinduced transfer.

The reduction potential of an excited state cat * is related to its ground state reduction potentials and to the zero-zero excitation energy (in eV). This can be estimated using the equations below:

E 𝑟𝑒𝑑 * (𝐜𝐚𝐭 * 𝐜𝐚𝐭 •- ⁄ ) = E 𝑟𝑒𝑑 (𝐜𝐚𝐭 𝐜𝐚𝐭 •- ⁄
) + E 0,0 (Eq. I.9)

E 𝑜𝑥 * (𝐜𝐚𝐭 •+ 𝐜𝐚𝐭 * ⁄ ) = E 𝑜𝑥 (𝐜𝐚𝐭 •+ 𝐜𝐚𝐭 ⁄ ) -E 0,0 (
Eq. I.10) E0,0, also written as E0,0(cat * /cat), refers to the electronic spectroscopic energy of the excited state of a catalyst. The term cat * corresponds to the S1 or T1 singlet excited states, with the corresponding E0,0 value (E 0,0 𝑆 1 or E 0,0 𝑇 1 ). The E 0,0 is usually estimated by the intersection of the absorbance and the emission spectra (Figure I.12). 117

Energy transfer

The energy transfer is a process by which the excited state X * is deactivated by interaction with a quencher Y (Eq. I.11). The excited state Y * then undergoes deactivation through radiative or nonradiative processes (luminescence or reaction). The energy transfer process is considered favored if the energy of Y * is lower than that of X * . 116

X * + Y → X + Y * (Eq. I.11)

Radiative energy transfer, also called trivial energy transfer, takes place when X * emits a photon that is reabsorbed by Y. In non-trivial energy transfer, the excited state undergoes resonant energy transfer (Förster mechanism), or electron exchange energy transfer (Dexter mechanism) (Figure I.16).

In Förster Resonance Energy Transfer (FRET) mechanism, a donor initially in its electronic excited state transfers energy to an acceptor through nonradiative dipole-dipole coupling, this transfer can operate over long distances. The energy transfer through Dexter mechanism occurs when an excited electron is transferred from a donor to an acceptor through a non-radiative route. This process requires considerable overlap between the molecular orbitals of X and Y, which involves close transfer distances.

p-Anisaldehyde-mediated energy transfer reaction

Melchiorre and co-workers 122 developed a metal-free photochemical method to perform an intermolecular ATRA reaction. They successfully engaged a simple organic molecule, panisaldehyde, in the radical addition of haloalkanes 82 onto olefins 37 in an efficient and selective manner (Scheme I.17). In their report, the reaction occurred under 23 CFL irradiation using olefins in excess, and in the presence of a base, 2,6-lutidine, as a scavenger. The optimal conditions were applied to a broad range of halides and olefins to afford the ATRA derivatives 86 in high to excellent yields.

Scheme I.17. Photocatalytic ATRA reported by Melchiorre et al. 122 The mechanistic studies showed that the reaction follows an energy-transfer pathway (Figure I.17). Visible light irradiation (near UV region) promotes p-anisaldehyde to a singlet excited state which after intersystem crossing (i.s.c.) reaches the triplet state. The latter leads the haloalkane 82 to a triplet excited state through an energy transfer mechanism. This sensitization causes the homolytic cleavage of the C-X bond, which generates radical species, then reacting onto the alkenes' π-system.

The bond dissociation energies of the alkyl halides used in this ATRA methodology are around 260-300 kJ.mol -1 . These values are similar to the energy of the triplet excited state of p-anisaldehyde (300 kJ.mol -1 ), which is consistent with an energy transfer mechanism.

Quantum yield of a photochemical reaction

The efficiency of a photocatalyst can be assessed by comparing the photochemical quantum efficiency for the formation of the desired product in the absence and presence of the sensitizer. 116 The quantum yield (Φ) is defined by the ratio of the number of formed products per unit of time to the number of photons absorbed per unit of time. It is expressed by the following equation:

Φ = 𝑛 𝑝𝑟𝑜𝑑𝑢𝑐𝑡 /𝑠 𝑛 𝑝ℎ𝑜𝑡𝑜𝑛𝑠 𝑎𝑏𝑠 /𝑠
(Eq. I.12)

The quantum yield is determined by irradiating the reaction vessel under a monochromatic light for a suitable time interval. Its value normally falls in the range between 0.0 and 1.0. To avoid secondary reactions, the measurement is usually limited to a conversion below 10%.

In order to calculate the quantum yield of a photochemical reaction, the number of absorbed photons on the reaction vessel has to be measured first. This measurement can be done using a chemical actinometer (potassium ferrioxalate, uranyl oxalate…) or a physical device (energy-meter, photodiode, solar cell…). A chemical actinometer, for instance, is a reference substance that undergoes a photochemical reaction with a known quantum yield. With the known quantum yield, this reaction can be used to determine the number of absorbed photons. After irradiation, the number of formed products is measured by analytical techniques (GC-MS, NMR…).

Among the chemical actinometers, potassium ferrioxalate (Parker's actinometer) is widely used as the most reliable reference for UV and visible light (< 420 nm). After irradiation of the aqueous solution of K3[Fe(C2O4)3], it decomposes into CO2 (Scheme I.18). After decomposition of [Fe(C2O4)3] 3-, two Fe 2+ ions are formed. The quantity of Fe 2+ ions formed during the irradiation is then determined by adding phenanthroline which forms an orange-red complex [Fe(phen)3] 2+ with a maximum of absorbance at λ = 510 nm (ε = 11100 M -1 cm -1 ). The quantity of Fe 2+ can then be obtained by using UV-visible spectrometer and applying the Beer-Lambert law. Finally, the calculation of the quantum yield using ferrioxalate actinometer depends on the studied wavelength; for instance, the quantum yield of the formation of Fe 2+ is 1.24 at 313 nm while it is 1.11 at 436 nm.

Scheme I.18. Decomposition of potassium ferrioxalate under visible light irradiation. 116

Sulfonyl radicals in photoredox catalysis

Sulfonyl derivatives have been used in organic synthesis as excellent radical traps due to their ability to undergo radical fragmentations through α-scission. New photocatalytic methods were developed, especially in the last years, to activate these radical precursors under very mild conditions.

Among the precursors widely used, one can cite sulfonyl halides, tri/difluoromethylsulfones, thiosulfones, sulfonyl selenides, sulfonyl azides, sulfonyl cyanides, sulfinates, etc. 123 In this section, only a few examples focusing on sulfonyl cyanide precursors will be described for illustrative purposes.

Photocatalyzed cyanation reactions

As stated in the general introduction, nitriles are considered among the most interesting functional groups in organic synthesis. The development of efficient and mild methods to introduce such a functional group onto an organic backbone is highly relevant. Sulfonyl cyanides (p-TsCN or MeSO2CN), trimethylsilyl cyanide (TMSCN) and cyanobenziodoxolone (CBX) are commonly used as cyanide sources and they can be activated by the means of photoredox catalysis.

Tosyl and mesyl cyanides were used by

Photoredox-catalyzed sulfonyl-cyanation of olefins

Sulfonyl cyanides can also be activated photochemically to generate sulfonyl radicals as radical traps. The first photochemical addition of sulfonyl cyanides to olefins was reported in 1971 by Pews and co-workers (Scheme I.22). 127 In this report, the commercially available p-toluenesulfonyl cyanide 56 was used as a sulfonyl cyanide source and was added to olefins 98 under UV-activation (254 nm).

In this reaction, the olefin is used as a co-solvent.

Scheme I.22. Photochemical sulfonyl-cyanation reported by Pews et al. 127 The sulfonyl cyanation of olefins was also reported in 1992 by Barton and co-workers (Scheme I.23). 128 The photolysis of Barton's ester at low temperature gave access to a range of functionalized derivatives 101. This method presents few drawbacks such as its restriction to electron-rich olefins 100 that are used in large excess (10 eq.) and the limitation of the sulfonyl cyanide source to mesyl and tosyl cyanides.

Scheme I.23. Reported sulfonyl-cyanation by Barton et al. 128 Recently, Chu and co-workers 129 reported a visible light-mediated sulfonyl-cyanation of olefins using p-toluenesulfonyl cyanide 56 as a sulfonyl source (Scheme I.24). The reaction was catalyzed by eosin-Y as a cheap photocatalyst to elaborate a broad scope of β-sulfonyl nitriles 99 in good to high yields.

Conclusion

In the second part of this chapter, a brief overview of the basic concepts and principles of photoredox catalysis was discussed. Photoredox catalysis allows the smooth generation of radical intermediates under very mild conditions, and its impact on the development of selective radical reactions is noticeable, explaining its current blooming. Photocatalyzed reactions circumvent the use of radical mediators including tin reagents. This chemistry allows the formation of multiple chemical bonds and the assembly of structurally complex molecules in a green and economic manner, with a foreseen impact on the way of preparation of useful pharmaceuticals and agrochemical drugs.

Furthermore, the sulfonyl derivatives proved to be excellent radical traps and showed their ability to generate new carbon-centered radicals under photocatalytic conditions. Photoredox catalysis represents nowadays one of the most efficient methods to initiate radical processes through electron or energy transfer.

Chapter II

The Chemistry of Small Rings 1. Carbocyclic small-sized rings in nature

Cyclopropanes and cyclobutanes, as the smallest monocyclic all-carbon rings, are encountered frequently in the plant kingdom, microorganisms, and marine organisms as well as in biomolecules including proteins, lipids, carbohydrates, nucleic acids, and pheromones (Figure II.1). [130][131][132][133][134][135] The structural novelty and potential biological properties of the cyclopropane and/or cyclobutanecontaining natural products have attracted a wide interest from synthetic chemists and pharmaceutical companies.

Besides their presence in nature, small-sized rings have emerged in the past decade as extremely useful intermediates for chemical synthesis. They can be engaged in complex transformations 134 or submitted to ring-expansion and ring-cleavage reactions to provide a variety of carbocycles, heterocycles, and acyclic derivatives. [136][137][138] Their strained skeletons allowed their functionalization in a creative manner and inspired for the development of innovative stereoselective tactics. [139][140][141] Despite these attractive characteristics, their synthesis may still constitute a hurdle, mostly because of this same strained nature. Therefore, understanding the relationship between their geometry, electronic structure (bond lengths, angles…), strain energy on one side and their reactivity on the other side is very important for the development of new synthetic approaches.

Geometry of small carbocyclic rings

Cyclopropane with C3H6 molecular formula is the smallest cycloalkane. It was discovered and characterized by August Freund in 1882. 142 Its industrial production began around 1930 after the discovery of its very powerful anesthetic properties. 143 Cyclobutane, as the second smallest carbocycle with C4H8 molecular formula, was first synthesized in 1887. 144 Although it has only one extra carbon atom compared to cyclopropane, this small difference has a big impact on its electronic structure and the spatial organization of atoms. Cyclobutane shows very original geometric features and reactivity pattern that lies between the "unique" cyclopropane and the "normal" cycloalkanes (Table II.1). 145 These main features will be discussed in the following paragraphs.

Structure and bonding

Because of their small ring size, cyclopropane and cyclobutane possess strained structure not encountered in bigger sized cycles. This ring strain is divided into two main contributors; the angle strain and the torsional strain. 145,146 The former, also called Baeyer strain, results from the compressing of the bond angles to less than the ideal 109.5° tetrahedral value. The latter, also called Pitzer strain, results from the unfavorable eclipsing of bonds on neighboring atoms (Figure II.2). The geometry of the cyclobutane holds unique features that are absent in the cyclopropane. For instance, although the cyclobutane has less angle strain than the planar cyclopropane, it has more torsional strain because of its larger number of ring hydrogens. To reduce the hydrogen-hydrogen eclipsing interactions, the cyclobutane adopts a non-planar conformation where one carbon atom rotates out of the plane by ca 25°. This folded conformation is not rigid, it interconverts rapidly from one bent conformation to another due to its low inversion barrier (1 kcal/mol). Although this puckering relieves some torsional strain with a global gain of around 1.5 kcal/mol, it increases the bond angle strain (the C-C-C bond angle is reduced from 90° in square planar to 88° in puckered geometry). 147 Thus, the equilibrium geometry is a result of the tension between these two strain terms.

Another specific feature of the cyclobutane structure is that the methylene groups are rotated inwards the concave face. Bartell

Hybridization and molecular orbitals

The short bond lengths in cyclopropane are in part explained by the molecular orbital theory.

Since the cyclopropane is an equilateral triangle with an internuclear angle of 60°, in order to overlap effectively, the orbitals contributing in forming the C-C bonds of the ring possess a higher p-character than those in a normal sp 3 hybridization (with the ideal 109.5° tetrahedral angle). Consequently, the carbon orbitals forming the carbon-hydrogen bonds present more s-character (33% s-character vs. the normal value of about 25% s-character). 151 This increase in the s-character contributes to shortening and strengthening the C-H bonds.

In order to understand the electronic environment and the nature of bonding in cyclopropane,

Bond strengths

The aforementioned theoretical studies were found to be consistent with the C-H bond force constant (kC-H) and the bond dissociation energy (Table II.2). 159 Both are greater in cyclopropane than in cyclobutane. Concerning the latter, the properties of its C-H bonds are closer to those of the other cycloalkanes than those of cyclopropane, although there is an indication of increased s-character. The C-H bond lengths are therefore shortened, and the bond dissociation energy is calculated to be greater than that of cyclohexane in an order of 1.5 kcal/mol. These features confirm that cyclobutane has a hybridization between that of cyclopropane and cyclopentane, and is closer to the latter.

Energies of small carbocycles

Another aspect to consider is the strain energy. 145,146 It is defined as the difference in heat of formation between the compound of interest and that of an unstrained model. Strain energy is typically released when the constituent atoms of a given molecule are allowed to rearrange themselves in a chemical reaction. For instance, cyclohexane has no strain energy while cyclopentane has small strain energy resulting from the partial eclipsing of adjacent C-H bonds in addition to some bond angle strain (Table II The foregoing results may explain the origin of the unusual properties and unexpected reactivity of these rings. The reactivity of the cyclopropyl ring resembles more to that of the carbon-carbon double bonds than that of a cycloalkane of a larger size. The extra energy of cyclopropane makes the C-C bond cleavage thermodynamically favorable due to the large strain release. Cyclobutane with similar strain and homolytic fragmentation energy (61 kcal/mol for cyclopropane vs. 62.5 kcal/mol for cyclobutane), however, does not possess the same reactivity and is considered inert. 145 Due to its decreased reactivity, the cyclobutane template has been less studied compared to its three-membered counterpart. 138,[160][161][162][163]

Construction of cyclopropene/butene templates

Over the years, saturated small-sized rings have been synthesized through various pathways. 164- 166 Among the main approaches is the functionalization of their corresponding olefins. This route is particularly interesting as it gives an entry to a rich library of cyclopropanes/butanes with a variety of functionalities starting from the same cyclopropene/butene precursor. Since this strategy is appealing and was adopted during this work, the main synthetic aspects of cyclopropenes/butenes will be highlighted in the next section.

Synthesis of cyclopropenes

Unsaturated three-membered rings are well appreciated in organic synthesis as reactive substrates. They were synthesized through several synthetic approaches, yet two main routes were frequently employed (Scheme II.1). 167,168 The first one makes use of a pre-existing functionalized cyclopropane that undergoes 1,2-elimination (path A). The second route involves a [2+1] cycloaddition with alkynes (path B). This approach requires the use of highly reactive carbene intermediates, usually generated by decomposition of diazo compounds with transition metals.

Although both routes are reliable, only an illustrative example of the metal-catalyzed cyclopropenation (path B) will be provided here.

Scheme II.1. Main synthetic routes to prepare cyclopropenes.

Among the most efficient ways to access cyclopropenyl esters, is the reaction discovered by Noels et al. 169 In this reaction, alkyl diazoacetates 32 were added to an excess of the appropriate alkyne 104 in the presence of a catalytic amount of rhodium acetate Rh2(OAc)4 to deliver the corresponding cyclopropenes 106 in excellent yields. An enantioselective version of this reaction was later developed. 49,170,171 Corey et al. 49 described the [2+1] cycloaddition of 32 to 104 in presence of 0.5 mol % of (R,R)-Rh2(OAc)(DPTI)3 105 as a catalyst to obtain the enantiopure desired adducts 106 (Scheme II.2). The chiral catalyst 105 was found highly efficient in terms of selectivity, yield and reaction scope.

Scheme II.2. Enantioselective synthesis of cyclopropene through metal-catalyzed [2+1] cycloaddition. 49

Synthesis of cyclobutenes

During the past decade, an increasing number of synthetic methods to prepare cyclobutene substrates have emerged. However, the access to enantioenriched cyclobutenes remains a demanding synthetic challenge. 164,165,172 The reported strategies are often based on the target molecule and very rarely, in order to obtain a general route to access enantiopure unsaturated four-membered rings. The [2+2] cycloaddition of alkynes with alkenes is regarded as a versatile approach to construct cyclobutenes. This has been achieved mainly by thermal reactions via biradical intermediates, photoreactions, Lewis acid-catalyzed cycloadditions, and transition-metal-catalyzed reactions. 164 Yet, the scope is still limited. Other catalytic methods for accessing cyclobutenes were also developed, such as ring expansions, 173 but they will not be discussed in this chapter.

Photochemical reactions

Concerted [2+2] photocycloadditions often employ a photosensitizer (e.g., benzophenone).

During this process, an energy transfer occurs from an excited-state photosensitizer to a cycloaddition substrate. Such intermolecular reactions usually suffer from low yields and low selectivity due to the poor regioselectivity and poor differentiation of the enantiotopic faces of the substrate (Scheme II.3). 174

Scheme II.3. Potential products of a photochemical [2+2] cycloaddition.

To address this issue, Bach and co-workers developed new chiral triplet sensitizers that allow enantioselective photocycloadditions to proceed. In these systems, the chiral catalyst is bound to the substrate through noncovalent interactions (hydrogen bonds). Upon excitation, the sensitizer maintains communication with the substrate and the energy transfer will favorably occur to the proximally bound substrate. Following this principle, the chiral xanthone 109 was specifically designed for the 2-pyridones 107 (Scheme II.4). Acetylenedicarboxylates 108 were thus added to the

Lewis acid-catalyzed reactions

The use of Lewis acid catalysts in the catalyzed cycloadditions has proven to be effective in the enantioselective synthesis of optically pure cyclobutenes. This approach typically involves the use of polarized alkynes and follows a stepwise reaction mechanism with generation of charged intermediates. One of the most efficient methods for enantioselective syntheses of cyclobutenes was developed by Narasaka and Hayashi. 3 The donor-acceptor [2+2] cycloaddition involves the use of a cheap chiral titanium complex 114 as a catalyst (Scheme II.5). The derived tartaric acid ligand 116 induces high enantioselectivity in the cycloaddition of alkynylsulfides 112 with oxazolidinone enamide 113 to give the enantiomerically pure cycloadducts 117 in high yields.

Scheme II.5. Lewis acid-catalyzed [2+2] cycloaddition by Narasaka et al. 3 Iguchi and co-workers 176,177 engaged the activated alkynylsulfide 118 in an enantioselective [2+2] cycloaddition with cyclopentenone derivative 119 (Scheme II.6). This reaction was catalyzed by the chiral ligand 120 in combination of CuCl2 and AgSbF6. Surprisingly, more common chiral catalysts such as Ti/TADDOL and Cu/BOX were found ineffective towards this transformation. The cycloadduct intermediate 121 was used in the total synthesis of (+)-tricycloclavulone 122.

Transition metal-catalyzed reactions

[2+2] cycloaddition reactions involving nonactivated alkynes were also reported. This class of reactions is usually catalyzed by transition metals that are capable of coordinating to the π-binding site of the carbon-carbon double bond, permitting thus, the reaction with the nonactivated alkynes. For instance, using ruthenium complex 125, Watanabe and co-workers 178 reported the cyclization of unactivated alkynes 124 with norbornene 123 to give the strained cyclobutenes 126 (Scheme II.7). It is worth noting that engaging ring-strained alkenes such as norbornene derivatives in cycloaddition reactions is one of the used strategies to make the transformation more practical.

Scheme II.7. Metal-catalyzed [2+2] cycloaddition with norbornene. 178 An enantioselective version of this reaction was later developed by Shibata and co-workers using norbornene derivative 123 as alkene source (Scheme II.8). 179 This reaction was promoted by the rhodium complex 128 and delivered the cyclobutene 129 in good yield and high enantioselectivity.

Scheme II.8. Rhodium-catalyzed [2+2] cycloaddition by Shibata et al. 179 Shao and co-workers 180 reported an iridium-catalyzed enantioselective [2+2] cycloaddition of bicyclic alkene 130 and terminal alkyne 131 giving the corresponding ring 133 in high yield and enantioselectivity in the presence of enantiopure para-cyclophane 132 (Scheme II.9). Mechanistic studies proposed an oxidative addition of iridium complex to 131 to generate a [hydrido(acetylene)iridium(III)] adduct 134. The latter then undergoes migratory insertion followed by reinsertion and reductive elimination to furnish the cyclobutene 133. 181 Scheme II.9. Iridium-catalyzed [2+2] cycloaddition. Cod = 1,5-cyclooctadiene. 180,181 Unlike cyclopropenes, the enantioselective synthesis of cyclobutene-type 137 is rare and only one racemic method was reported to date by Sakai and co-workers (Scheme II.10). 182 The group reported a direct access to cyclobutene 137 through a rhodium-catalyzed intermolecular [2+2] cycloaddition of terminal alkynes 104 with electron-deficient alkenes 135. The reaction was applied to a series of substrates and gave the corresponding cycloadducts 137 in good to high yields and excellent regioselectivity. Although the motif 137 is highly valuable, this reaction was not extended into enantioselective series and requires expensive rhodium catalyst 136 that must be prepared from [RhCl(cod)]2.

Scheme II.10. Rhodium-catalyzed intermolecular [2+2] cycloaddition of terminal alkynes by Sakai et al. 182

Reactivity: cyclopropene vs. cyclobutene

The functionalization of the above-described strained cyclopropenes/butenes was studied by many researchers, not only in order to give access to the corresponding saturated rings but also to understand the properties of their parents. Both olefin parents showed a difference in reactivity.

Cyclopropene behaves as both electrophile and nucleophile. 167,168,183,184 The highly acidic proton of the C(sp 2 )-H bonds, due to the ring strain, allows easy deprotonation and further functionalization with electrophiles. The addition of organometallic species (hydrides, Grignard reagents, organocuprates, zinc reagents…) also reveals the cyclopropene's electrophilicity. One of the examples that illustrate this behavior is the results published by Marek and co-workers. 185 During their studies, a diastereoselective carbometalation of cyclopropenes was developed, delivering a wide scope of polysubstituted cyclopropanes bearing an all-carbon quaternary stereocenter with excellent diastereomeric ratios (Scheme II.11). The extension of the carbometalation reaction to cyclobutene ester 140 was however unsuccessful. The difference of behavior between both carbocycles 106 and 140 towards the addition of organometallic species across the π-bond was rationalized by the difference in strain energy released during the carbometalation reaction (cyclopropene to cyclopropane: 30 kcal/mol; cyclobutene to cyclobutane: 6 kcal/mol).

Scheme II.11. Carbometalation reaction of cyclopropenes and cyclobutenes by Marek et al. 185 A similar pattern is observed with radical species. The reactivity of cyclobutenes was shown to be on the same order as that of cyclohexene ring and lower than that of cyclopropene. 186 Therefore, to ensure successful radical additions to cyclobutenes, highly electrophilic radicals are required.

During a radical addition, the generated cyclobutyl radical located in a p orbital is less reactive than the cyclopropyl radical located in an sp 3 orbital. This difference in reactivity is in contrast with the C-H bond dissociation energies. 187 In consistency with the main goal of this manuscript, reported examples of radical additions to cyclopropenes/butenes are provided.

Reported radical additions to cyclopropenes

The first cyclopropene strain-driven radical reaction was reported by Nakamura and co-workers in 1994 (Scheme II.12). 188 This reaction highlighted the efficient addition of tin radicals to the cyclopropene's π-system. Hydrostannation gave rise to the stannyl radical 143 which reacts further with tin hydride to give the hydrostannation adduct 144, alongside with the tin product 145, which is responsible for chain propagation.

Scheme II.12. Hydrostannation of cyclopropenes by Nakamura et al. 188 Saičić and co-workers 186 later developed new radical reactions on the same type of cyclopropenes (Scheme II.13). In this work, xanthates 146 were used as radical precursors under photochemical conditions to deliver the cyclopropanone acetals 148 in moderate yields and diastereoselectivities in favor of the trans isomer.

Scheme II.13. ATRA reactions on cyclopropenes by Saičić et al. 186 Ueda, Miyata and co-workers studied the radical addition reactions of trichloromethyl radicals on cyclopropene 106 (Scheme II.14). 189 In the presence of Et3B as an initiator, trichloromethyl radical is generated after abstraction of a hydrogen atom from chloroform. The addition of this radical onto the double bond delivers the cyclopropyl radical 149. The latter abstracts a hydrogen from chloroform in the presence of Et3B to furnish trichloromethylpropane carboxylate 150 in high yield. When dimethyl zinc is used as an initiator, cyclopropylzinc 151 is formed, which further undergoes elimination and ring-opening to give the unsaturated ester 152.

Scheme II.14. Addition of trichloromethyl radical to cyclopropenes. 189 In order to study further the reactivity of cyclopropene-type motifs 106, Landais and co-workers developed a radical carbo-cyanation approach to deliver polyfunctionalized cyclopropanes 154 in moderate yields and good diastereoselectivities (Scheme II.15). 47 This reaction used bis(trimethyltin) as a mediator and allowed the generation of an all-carbon quaternary stereocenter on cyclopropane 154, a highly valuable synthetic intermediate. This skeleton was further modified by activation of the cyclopropyl ester group using a soft enolization process to provide the opened product 155 in high yield. This obtained building block can serve as a valuable intermediate in the enantioselective total synthesis of natural products.

Scheme II.15. A diastereoselective carbo-cyanation of cyclopropenes by Landais et al. 47

Reported radical additions to cyclobutenes

The radical functionalization of cyclobutenes is far less documented than that of cyclopropenes.

Only a few reports have been published. 190 for instance, reported the addition of benzyl radical to hexafluorocyclobutene 156 and 1,2-dichlorotetrafluorocyclobutene 158 using toluene and di-t-butyl peroxide (DTBP). Two stereoisomers of 157 were obtained in favor of the trans configuration in which the hydrogen and benzyl groups are on the opposite sides of the carbocycle plane (Scheme II.16).

Scheme II.16. Addition of benzylic radical to fluorocyclobutenes by Kimoto et al. 190 On the other hand, Leigh and co-workers 191 reported a photochemical addition of trifluoromethyl iodide to bicyclo[4.2.0]oct-7-ene 160 (Scheme II.17). Further transformation by eliminating the iodine atom elaborated a new trifluorocyclobutene ring 162.

Scheme II.17. Photochemical addition of trifluoromethyl iodide on cyclobutene. 191 Kinney described the addition of alkyl radicals to cyclobutenyl stannane 163 giving the alkylsubstituted cyclobutenediones 164 in low to moderate yields (Scheme II.18). 192 This methodology was applied to the synthesis of an NMDA antagonist analog.

Scheme II.18. Addition of alkyl radicals to cyclobutenyl stannane by kinney. 192 Saičić and co-workers applied their xanthate transfer radical reaction to cyclobutenes 165 (Scheme II.19). 186 This reaction provided the functionalized rings 166 in moderate yields and diastereoselectivities privileging the trans isomer as the dominant product.

Scheme II.19. ATRA reactions on cyclobutenes by Saičić et al. 186 A concomitant work was published by Zard and co-workers 193 adding the xanthate radicals to cyclobutenes and cyclopropenes (Scheme II.20). The xanthate-transfer radical chain was promoted by lauroyl peroxide (DLP) as an initiator. Similar to Saičić, moderate yields were obtained, and the radical was added regioselectively at the less hindered site of the double bond, leading to a mixture of diastereomers with the trans isomer as the major product.

Conclusion

In conclusion, cyclopropanes and cyclobutanes, as the most strained small rings, have emerged in the past decades as potential synthetic tools for further complex transformations in natural products and drug discovery. Their unusual bonding and ring strain, at the origin of their properties and reactivity, are used as a driving force to facilitate chemical reactions. In this context, cyclopropanes have been widely studied compared to their four-membered counterparts. Radical additions on cyclobutene rings did not attract much attention due to their low reactivity towards radicals, and also due to the restricted access to enantiopure carbocycles. The fact that the major isomer obtained in all the cases stated above was the trans isomer, makes the investigation of the ATRA reaction on chiral four-membered rings even more intriguing, as excellent diastereoselectivity might be achieved. For these reasons, the development of a straightforward access to this class of olefins and the study of their reactivity towards free-radical species were envisioned during this Ph.D. thesis.

Chapter III Radical Additions onto Cyclobutenes & Further Derivatization

Part I

Synthesis and Radical Additions onto Chiral Cyclobutenes

Development of an enantioselective synthesis of cyclobutenes

In the aim of revisiting the reactivity of unsaturated four-membered rings towards radical additions, the synthesis of a new type of chiral cyclobutenes has been looked at. Hence, a two-steps sequence was planned inspired by the work of Narasaka and co-workers. [START_REF]C-13 or C-14[END_REF][194][195][196] The chiral carbocycle would be obtained through an asymmetric [2+2]-cycloaddition reaction between an α,β-unsaturated acid derivative, the N-acyloxazolidinone 113, and a series of alkynyl sulfides (Scheme III.1). This transformation would be catalyzed by a cheap chiral titanium reagent 116, coordinated with a 1,4diol chiral ligand 115. A reduction of the corresponding cyclobutenyl sulfides 117 through direct desulfurization would then furnish the corresponding cyclobutenes 169, ready for radical reactions.

Scheme III.1. Proposed two-steps strategy to access enantiopure cyclobutenes.

Synthesis of cyclobutene sulfides following Narasaka's procedure

To access cyclobutene sulfides, a series of alkynyl sulfides 112 were first synthesized in high yields through the deprotonation of the corresponding terminal alkynes 104, followed by the addition of dimethyl disulfide (Scheme III.2). 197 This reaction was found tolerant to functionalities such as silyl ethers and aryls, while with halogen, a lower yield was obtained due to the displacement of the chlorine atom by a thiomethyl group (112f and 112g).

Scheme III.2. Synthesis of alkynyl sulfides. Reagents and conditions: i) 1. alkyne 104 (1.125 eq.),

n-BuLi (1.06 eq.), THF (0.65 M), 0 °C, 30 min; 2. Me2S2 (1.0 eq.), 20 °C, 2 h.

Once synthesized, the alkynes 112 were engaged in the cycloaddition reaction with Nacyloxazolidinone, delivering various cyclobutenes bearing functionalized side chains (Scheme III.3). All examples gave high yields even on decagram scales (117a,c). A moderate yield (50%) was, however, obtained with more hindered substituents (117d). When the alkynyl sulfide 112g was used, the product 117g was obtained with only 40% of conversion and was found inseparable from the Nacyloxazolidinone 113. The partial conversion is probably due to the competitive coordination between the thiomethyl groups with the catalyst. Increasing the quantity of the catalyst and ligand to 0.7 and 0.77 equivalents respectively, did not increase the conversion further. Finally, although the alkynyl sulfides were used in excess, the unreacted material was recycled after purification.

Scheme III.3. Synthesis of functionalized cyclobutene sulfides, based on Narasaka's protocol. Reagents and conditions: alkyne 112 (1.5-2.0 eq.), (R)-115 (0.11 eq.), TiCl2(OiPr)2 116 (0.1 eq.), toluene (0.25 M), 4 Å MS, 0 to 20 °C, 12-66 h. X = oxazolidinone.

Enantiomeric excess measurements

In order to estimate the enantiomeric excesses of the above cyclobutanes, it was planned to synthesize racemic cyclobutene analogs using the same route, but in the absence of the Finally, the optical purity of the synthesized cyclobutenes was determined to range between 92 and 98% (Figure III.3). For products 117c and 117f, the separation of the two enantiomers was not sufficient to determine the enantiomeric excess.

Desulfurization of cyclobutyl sulfides

The direct desulfurization of cyclobutenes was then investigated. The desulfurization of thiomethyl group was already reported for aromatic sulfides, using palladium or nickel catalysts and trialkylsilanes as reducing agent (Scheme III.4). [199][200][201] Scheme III.4. Reported desulfurization of aromatic sulfides.

Fukuyama, on the other hand, described the reduction of thioesters 172 into aldehydes 173 in the presence of palladium on charcoal and triethylsilane (Scheme III.5). 202,203 Scheme III.5. Fukuyama's hydrosilylation-based reduction of thioesters.

The utility of Fukuyama's approach in organic synthesis was illustrated by the work of Evans and colleagues in their enantioselective synthesis of To avoid the over-reduction of their unsaturated thioester substrate, they conducted the reaction in the presence of Lindlar's catalyst and a sacrificial monosubstituted terminal olefin (hex-1-ene). Lindlar's catalyst, known to reduce alkynes into alkenes, seemed to be a good choice to allow the full conversion of the cyclobutyl sulfides 117, without over-reducing the latter. Thus, the reaction was conducted at 20-25 °C using an excess of Lindlar's catalyst (10 eq.) leading to a series of cyclobutenes 169 with excellent purity and without erosion of the enantioselectivity (Scheme III.6). This method was shown to be compatible with the presence of silyl ethers, chlorides, and aryls as functional groups.

Scheme III.6. Reduction of cyclobutyl sulfides. Reagents and conditions: i) Lindlar's catalyst (10 eq.),

Et3SiH (10 eq.), oct-1-ene 174 (10 eq.) acetone (0.1 M), 20 °C, 24-96 h. X = oxazolidinone.

Nevertheless, these conditions faced two problems on large scale. First, at a scale > 4 mmol, the conversion rate was very low, and the reaction took several days to reach completion (4-10 days). For instance, on a 7 mmol scale, desulfurization of 169a required 10 days to reach full conversion, affording the desired product in 87% yield (data not shown). Secondly, the use of a large excess of palladium on a large scale was not optimal, due to the high cost of the catalyst (CAS: 7440-05-3, TCI supplier: 225 €/25 g), even though the catalyst was usually recycled once or twice and reused without affecting its efficiency.

For these reasons, the model 117c was chosen for further optimization on large scale (5 mmol of substrate). By heating at 50 °C, the reaction time decreased from 50 to 16 h without affecting the yield (Table III.1, entries 1 and2). Similarly, subsequent decrease of the catalyst's quantity from 10.0 to 1.0 eq. led to a quantitative conversion in the same range of time (entries 3 to 7). When the reaction scale increased 6 times (32 mmol, ~ 13 g), the yield and the purity were not affected, and the desired cyclobutene 169c was obtained in quantitative yield after 24 h (entry 8).

entry [Pd] (eq.) temp (°C) time (h) isolated yield (%)

Table III.1. Optimization of the desulfurization reaction on large scale. Reagents and conditions: i) Substrate (5 mmol), Lindlar's catalyst, Et3SiH (10 eq.), oct-1-ene, acetone (0.1 M). a Substrate (32.0 mmol).

These optimized conditions were also applied to the cyclobutene 117a on 63 mmol scale (~ 16 g) leading to 75% yield of the final product 169a after 24 h (versus 87% on 7 mmol scale, for 10 days at 20 °C, and in the presence of 10 eq. of palladium catalyst) (Scheme III.7).

Scheme III.7. Optimized reduction reaction on large scale. Reagents and conditions: i) Lindlar's catalyst (1.0 eq.), Et3SiH (10-7 eq.), oct-1-ene (1.0 eq.), acetone (0.1-0.3 M), 50 °C, 24 h.

In conclusion, this multigram-scale reduction has demonstrated its robustness, a relatively broad scope, and reliability, even in the presence of sensitive functional groups. The developed two-steps sequence described here provides easy enantioselective access to a new type of cyclobutenes ready for further studies.

Radical additions onto enantiopure cyclobutenes

As stated before, cyclobutenes were described to react with radical traps with slow kinetics. It was envisioned to closely reexamine their behavior with highly electrophilic radical traps, reported to add successfully to acyclic alkenes. Furthermore, the radical additions onto cyclobutenes C-C double bond would be of high interest, since it would allow installing two functional groups on vicinal carbon centers in a single operation. This would furnish more complex architectures that are synthetically valuable. As a possible transformation, it was decided that the addition of two different carbon units across the cyclobutene π-system would also generate a very useful all-carbon quaternary stereocenter. Among useful 2-carbon units, alkynyl fragments are particularly attractive in organic synthesis, and can be introduced onto the π-system through a tin-free carbo-alkynylation process, as On the other side, the addition of carbon and heteroatom units across the cyclobutene π-bond in a one-step process is also possible. Particularly, the addition of alkyl halides onto the cyclobutenes would be investigated, through Atom Transfer Radical Addition (ATRA) processes, using suitable photocatalysts (Figure III.4.C). Further manipulations of the ATRA products would then be envisioned, by exchanging the halide groups with other substituents such as a nitrile or an alkyl, giving diversified carbocycles. The recently developed strategy of sulfonyl-cyanation by Landais et al. 5 would also be investigated on cyclobutenes (Figure III.4.D). This would install cyanide and sulfonyl fragments onto the double bond. The sulfonyl entity would be later modified leading to attractive synthons.

previously

Carbo-alkynylation of cyclobutenes

With the perspectives of adding carbon radicals onto cyclobutenes, the carbo-alkynylation was first investigated. While Fuchs studied the radical additions using trifluorosulfone 175a, it was envisioned that the replacement of CF3 with CCl3 would be more interesting for this work purpose, as the chlorine atoms could later be transformed into other functionalities, or eliminated (Scheme III.8). The preparation of 175b through adaptation of literature procedures 207,209 failed. The trichlorosulfone 175b was finally obtained successfully in 85% yield through the intermediacy of an alkynyl-iodonium salt 183. 210,211 This sulfone was found unstable on silica gel, and the pure product was obtained by trituration from diethyl ether.

Scheme III.8. Preparation of alkynyl sulfone 175b. Reagents and conditions: i) (CF3CSO2)2O (0.5 eq.), PhIO (1.0 eq.), CH2Cl2 (1.0 M), 0 °C, 1 h; ii) CCl3SO2Na (1.5 eq.), CH2Cl2 (0.1 M), 25 °C, 13 h.

With the desired alkyne in hand, the radical addition reaction was conducted on cyclobutene 169c

in the presence of AIBN as an initiator. When DCE was used as a solvent as described by Fuchs, 207 only 47% of the TIPS-deprotected alcohol 184 were isolated in a relatively clean reaction (Scheme III.9). However, in benzene, a complex mixture of products was obtained, with only trace amount of 184.

Scheme III.9. Attempts for carbo-alkynylation of cyclobutenes. Reagents and conditions: 175b (1.5 eq.), AIBN (0.2 eq. x 4), solvent (0.1 M), 85 °C, 45 h.

To evaluate the reactivity of the newly synthesized alkynyl sulfone, the reaction was also tested targeting simpler olefins. When hex-5-en-2-one 186 was submitted to the carbo-alkynylation reaction, the desired radical transformation took place to produce the alkynyl trichloride 185a in 77% yield (Table III.2, entry 1). With the phthalimide derivative 187, the desired product 185b was isolated in 55% yield (68% brsm) (entry 2). Interestingly, when the above conditions were applied to cyclopropene carboxylate 106a, a complex mixture of products was obtained, suggesting that acidsensitive substrates such as cyclopropanes may not be compatible with the reaction conditions (entry 3). Release of SO2 may generate strong acids in the medium (in the presence of traces of moisture), also explaining the TIPS deprotection above. In the literature, three-components processes were also described to introduce trihalo groups and alkynyl chains onto the double bond. For instance, Fang and co-workers 212 introduced CF3 and chlorine radicals onto olefins using N-methyl-9-mesityl acridinium as a photocatalyst and sodium triflate as a trifluoromethyl source (Scheme III.10.A). While Jin and colleagues 213 used iridium catalyst and the alkynyl sulfones 189 to promote the fluoroalkylation of various π-systems (Scheme III.10.B).

Scheme III.10. Three-components alkynyl-trifluoroalkylation of unactivated alkenes. 212,213 Applying the abovementioned conditions described by

Carbo-cyanation of cyclobutenes

The radical carbo-cyanation of olefins using carbo-cyanides is not an easy process due to the high bond dissociation energy of the C-CN bond (H3C-CN: 120.9 kcal/mol). Yet, Inoue and coworkers 214 successfully used trichloroacetonitrile in a copper-catalyzed carbo-cyanation of trisubstituted olefins (Scheme III.12). In their report, they rationalized the formation of the carbocyanation products 191 invoking an intramolecular nitrile transfer step, and the cleavage of the C-CN bond. This method was applied to a variety of olefins and cyanides affording the desired products in moderate to high yields.

Scheme III.12. Carbo-cyanation of trisubstituted olefins by Inoue et al. Interestingly, when trisubstituted alkenes were used as substrates, the ATRA transfer reaction on radical II was slow, in contrast with monosubstituted alkenes where the ATRA products were formed exclusively.

It was anticipated that this concept might work on the cyclobutenes to yield the carbo-cyanide cyclobutanes 179 bearing an all-carbon quaternary stereocenter. The application of Inoue's conditions on cyclobutene 169a, however, did not afford the desired outcome, and the expected products were not observed (Scheme III.13). Only traces of unidentified products were isolated.

Scheme III.13. Attempts for carbo-cyanation of cyclobutene 169a. Reagents and conditions: i) 176 (2.0 eq.), Cu(MeCN)4PF6 (0.5 eq.), 1,4-dioxane/CH3NO2, (0.2 M), 100 °C, 48 h.

Atom transfer radical addition of haloalkanes onto cyclobutenes

Synthesis of halo-cyclobutanes

The classic radical chemistry was first applied to cyclobutene 169a, using BrCCl3 as a halo source and bis(tributyltin) as a chain carrier. 99,215 The reaction conditions delivered the expected product in 40% yield as a single diastereomer (dr > 19:1:1:1) (Table III.3, entry 1). Stephenson's 121 modified conditions were also investigated, giving the cyclobutane 180a in 60% yield without optimization (entry 2). In both cases, the stereochemistry of the cyclobutane 180a was obtained in favor of the all-trans-product, as the major isomer, and was confirmed by X-ray diffraction studies (CCDC-1925745).

entry catalyst (eq.) additives (eq.) solvent yield (%) The excellent diastereocontrol was rationalized invoking the steric hindrance of the oxazolidinone moiety, leading the Cl3C • radical to approach the less hindered face of the cyclobutene π-system anti with respect to the oxazolidinone group. The nucleophilic radical generated on the neighboring carbon then combines with the bromine atom, which approaches trans to the trichloromethyl group, settling the third stereocenter in a controlled mode.

Attempts to remove a chlorine atom from CCl3 through various methods (Zn dust, THF, 66 °C;

Zn dust, AcOH, 116 °C; TTMSH, AIBN, PhH, 80 °C; SmI2, H2O, THF, -78 to 20 °C) to access more various attractive synthons unfortunately failed, leading to a complex mixture of products. Although the diastereocontrol was excellent, the failure in transforming the trichloromethyl group into useful derivatives thus directed the attention towards other haloalkanes.

Dialkyl bromo-malonates became then the focal point in the following studies as efficient atomtransfer agents, first because of the known high electrophilicity of the malonyl radicals, and second, for the possible transformations that could occur on these fragments to produce intermediates of high value. Under the iridium-mediated photocatalytic conditions, diethyl malonate radicals were successfully added onto the cyclobutene 169a, giving the functionalized cyclobutane 180b in high yield and satisfying diastereoselectivity (Table III.4, entry 1). This confirms that such radicals are electrophilic enough to add to the unreactive π-bond of the four-membered ring.

Similar to the observation in the previous case, the diethyl malonate approaches anti relative to the oxazolidinone. However, the malonyl chain proved unable to totally control the approach of the bromine atom, as shown by the 6:1 dr in the favor of the trans-trans product. The bulkier di-tert-butyl bromo-malonate 76b, was submitted to the same conditions to afford the cyclobutane 180c in 53% yield (69% brsm), and with higher diastereoselectivity (dr 8:1) as expected (entry 1). The organotin conditions were also studied for comparison; in this case, the reaction furnished both cyclobutanes 180b and 180c in 46% and 29% yields, in 5.7:1 and 7:1 dr, respectively (entry 2).

The addition of the malonyl radicals using other photocatalysts was also inspected. For instance, the cyclobutene 169a was submitted to the modified conditions of Melchiorre. 122 In this reaction, 2 equivalents of di-tert-butyl malonate 76b and 2,6-lutidine were used to afford the expected product 180c in 69%, and in 7.5:1 dr (entry 3). Interestingly, when the quantity of base has halved, the yield dropped to the half as well (entry 4), while in the absence of base no reaction occurred (entry 5).

These observations are in good agreement with reports by Melchiorre et al., 122 Finally, attempts to transform the cyclobutane 180c into a useful synthon by cleaving the tertbutyl groups with TMSCN/TBAF, TMSCN/SnCl4, or TFA gave complex mixtures of products.

Similarly, efforts to open the ring 180b in a basic medium by deprotonation of the proton αto the diester groups using MgBr2.OEt2/DIPEA, 47 Et3N or NaH gave negative results and the starting material was recovered. A complex mixture was also obtained using LDA as a base. In contrast, with K2CO3 in DMF at 70 °C, a ring contraction took place after displacement of the bromine atom, affording a new cyclopropane 193 in 60% yield as a mixture of two diastereomers (Scheme III.13).

Scheme III.13. Ring contraction of cyclobutane 180b in the presence of potassium carbonate. Reagents and conditions: i) K2CO3 (2.0 eq.), DMF (0.1 M), 70 °C, 14 h.

Bromine interchange with a cyanide substituent

Given the unsuccessful attempts to introduce diethyl malonate/cyanide radicals onto cyclobutenes in a one-pot operation, a two-steps sequence was planned instead. The substitution of the halide atom with cyanide was investigated using bis(tributyltin), as reported by Landais et al. 47 When a stoichiometric amount of tin reagent was used in the presence of DTBHN (di-tert-butyl hyponitrite) in refluxing benzene, 27% of the expected product 194 was obtained with moderate diastereoselectivity (Table III.5, entry 1). When a sub-stoichiometric quantity of bis(tributyltin) was used, the yield increased to 40% (entry 2), whereas, in refluxing DCE, the desired product was isolated in a 45% yield (entry 3).

entry (Bu3Sn)2 (eq.) solvent time (h) yield (%) Interestingly, the diastereoselectivity dropped from 6:1 in bromo-cyclobutane 180b to 2:1 in cyano-cyclobutane 194. This could be rationalized by the lower steric hindrance of the cyano group as compared to bromine (the nitrile group with an A-value of 0.21 represents one of the smallest functional group in synthetic organic chemistry). 219 Thus, the cyanide approaches in less differentiation of both faces, in favor of the trans configuration (Figure III.6).

Bromine exchange with alkyl substituents

Finally, the substitution of the bromine atom with an allyl chain was also looked at, applying Keck's conditions. 4 This led to a clean formation of the allylated product 195 in high yield, albeit in moderate stereocontrol (Scheme III.14). As observed before, the decrease in diastereoselectivity probably results from the smaller size of the allyl fragment in comparison to the bromine atom.

Scheme III.14. Cyclobutane allylation. Reagents and conditions: i) allyltri-n-butylstannane (5.0 eq.), AIBN (0.5 eq. x 3), benzene (0.1 M), 85 °C, 26 h.

Sulfonyl-cyanation of cyclobutenes

Eosin-mediated photocatalyzed sulfonyl-cyanation of cyclobutenes

Considering that only electrophilic radicals add efficiently onto poorly reactive cyclobutene rings, 5,220 highly electrophilic sulfonyl radicals were also envisaged for this study. A list of sulfonyl cyanides was then selected presenting simple alkyl chains or functionalized ramifications such as aryl, ester, methoxy, chloride, and trifluoroacetate (scheme III.15). The sulfonyl cyanides 88 were prepared according to the literature 5 with some modifications using 5 equivalents of trifluoroacetic anhydride and hydrogen peroxide instead of 10.

Scheme III.15. Preparation of the selected sulfonyl cyanides. Reagents and conditions: i) trifluoroacetic anhydride (5.0 eq.), H2O2 50 wt. % (5.0 eq.), CH2Cl2 (1.0 M), 40 min, 0 °C; then 196, 5 h, 40 °C.

The eosin-mediated sulfonyl-cyanation of olefins described by Landais et al. 5 was then applied to a series of cyclobutenes, using green LEDs as a light source (Scheme III.16). The reaction was found compatible with different functional groups present on the side chains of the cyclobutenes and sulfones. Hence, the corresponding cyclobutanes 181 were provided in moderate to good yields with trans products as major isomers (dr > 19:1:1:1). The stereochemistry of the products was assigned by NMR and confirmed by X-ray diffraction analyses for some substrates. 221 In this transformation, the addition of the bulky sulfonyl radical occurs in an anti-fashion relative to the oxazolidinone fragment, followed by the addition of the cyanide group in an anti-manner relative to the sulfonyl moiety.

Scheme III.16. Eosin-mediated sulfonyl-cyanation of cyclobutenes. Reagents and conditions: i) R1SO2CN (2.0-4.0 eq.), Eosin-Y (2 mol %), K2HPO4 (0.2 eq.), DMF (1.0 M), green LEDs, 30 °C, 24-96 h.

Although the excellent diastereocontrol was encouraging, the purification of the polar products from the eosin residues was challenging, and the yields were not satisfactory on a larger scale (> 1 mmol). Therefore, such results did not seem promising for future scale-up of the process. An alternative way to generate the electrophilic sulfonyl radicals was thus envisioned, under mild and efficient conditions.

p-Anisaldehyde photocatalyzed sulfonyl-cyanation of cyclobutenes

As mentioned before, the studies reported by Melchiorre et al. 122 showed that photocatalysts having high triplet energy levels [222][223][224][225] (around 70 kcal/mol) such as p-anisaldehyde and benzophenone, are able to promote the carbon-halide bond cleavage, and could be engaged in ATRA reactions. This system proved to be efficient when applied to cyclobutenes, generating cyclobutane 180c. In addition, benzophenone was described by Inoue et al. 218 to efficiently cleave the TolO2S-CN bond. Therefore, it was anticipated that these simple organic photosensitizers might be able to activate the alkylsulfonyl cyanides in a similar way. Since p-anisaldehyde was proven to be more efficient than benzophenone in the ATRA reaction on cyclobutene, it was chosen as a photosensitizer to conduct the following investigations.

The cyclobutenes 169 were thus submitted to the sulfonyl-cyanation reaction in the presence of suitable sulfonyl cyanides 88 and a catalytic quantity of p-anisaldehyde in acetonitrile. After irradiation under UV-A light for the necessary amount of time, the corresponding cyclobutanes 181

were successfully obtained in good to high yields and excellent diastereocontrol, illustrating thus, the first examples of a triplet photosensitized olefin sulfonyl-cyanation (Scheme III.17). Overall, the reactions were cleaner than those with eosin-Y, easier to carry out, requiring no aqueous treatment at the end of the reaction. Moreover, purifications were more straightforward even on a large scale.

Eventually, this method allowed achieving scale-ups without affecting the yields. For instance, 181b

was obtained in 87% yield on a 21 mmol scale, while with eosin-Y, the same product was isolated in 48% yield on a 5 mmol scale. As well, 181i presenting a silyl ether entity was obtained in 69% yield on a 14 mmol scale. In general, better yields were observed using less hindered sulfonyl cyanides (MeSO2CN), while the yield decreased significantly for hindered cyclobutenes (e.g., 181m bearing a bulky TBDMS substituent). In addition, this process showed high tolerance for chains bearing a chlorine atom (181l), silyl ethers (181h-j,m), or aryls (181k). The reaction was not restricted to methyl or arylsulfones, but it was extended to functionalized sulfonyl cyanides (181f), albeit with lower efficiency. Interestingly, these mild conditions also prevent desulfonylation of the alkanesulfonyl radicals and the formation of the corresponding alkyl radicals.

Scheme III.17. p-Anisaldehyde photosensitized sulfonyl-cyanation of cyclobutenes. Reagents and conditions: i) R1SO2CN (2.0 eq.), p-anisaldehyde (0.2 eq.), CH3CN (1.0 M), UV-A (325-400 nm), 30 °C, 23-100 h.

In contrast, sulfonyl cyanides 88d and 88e failed to react with cyclobutenes. The reaction of 88e with 169c gave a complex mixture of products, while the reaction of 88d with 169a and 169c gave back the starting material. Unexpectedly, when the cyclobutene 169c reacted with the sulfonyl cyanide 88d, a side product 197 was isolated in 16% yield, alongside with 80% of the recovered starting material (Scheme III.18). During this reaction, the sulfonyl unit displaced the O-protected fragment creating a C-S bond. The full analytical data confirmed the formation of the proposed structure, although the mechanism of this transformation is currently unknown.

Scheme III.18. Isolation of 197 as a side product of the sulfonyl-cyanation. Reagents and conditions: i) sulfonyl cyanide 88d (2.0 eq.), p-anisaldehyde (0.2 eq.), CH3CN (1.0 M), 325-400 nm, 30 °C, 42 h.

The sulfonyl cyanide 88d, however, was successfully added onto a simple olefin, oct-1-ene 174, using the p-anisaldehyde method, to give the corresponding sulfone 198a in a moderate yield of 50% (Scheme III.19).

Scheme III.19. Addition of sulfonyl cyanide 88d onto oct-1-ene. Reagents and conditions: i) 88d (2.0 eq.), p-anisaldehyde (0.2 eq.), CH3CN (1.0 M), UV-A (325-400 nm), 30 °C, 67 h.

Mechanistic studies

To understand the mechanistic pathway of the sulfonyl-cyanation reaction, and the efficiency of p-anisaldehyde as a photosynthesizer, several control experiments were performed.

UV-Vis absorption spectra of p-anisaldehyde, cyclobutene 169a and MeSO2CN

First, in order to choose the irradiation zone adequate for the sulfonyl-cyanation, the absorption wavelength of the reagents was measured using UV-vis analyses (Figure III.7). The UV-visible spectra were recorded in acetonitrile in 1 cm path quartz cuvettes. [The concentrations of the substrates are: 10 -4 M for p-anisaldehyde and 10 -3 M for cyclobutene 169a and methane sulfonyl cyanide 88a]. The spectra show that p-anisaldehyde highly absorbs around the zone 200-230 and 240-300 nm, while the cyclobutene's maximal absorption is around 200-225 nm. The sulfonyl cyanide 88a itself absorbs mostly in the zone 200-250 nm and continues absorbing in the region 360-600 nm, albeit in small amounts (not shown). Although the photosensitizer absorbs around 220 and 275 nm, these zones were avoided to limit the possible side reactions that might arise from the competitive absorption of cyclobutenes and reagents. Instead, the zone 325-400 nm was chosen, where the components absorb but more weakly.

Conditions screening

Using UV-A irradiation (325-400 nm), p-anisaldehyde effectively mediated the activation process of the O2S-CN bond, leading to the formation of 181b in high yield (Table III.6, entry 3).

This yield was higher than that observed with eosin-Y as a photocatalyst (entries 1 and 2). In the absence of p-anisaldehyde, 181b was also formed albeit in much lower yield as a result of the direct absorption of substrates 169a and 88a at 325-400 nm, as seen previously in the UV-vis studies (entry 4).

Benzophenone was also able to promote the sulfonyl-cyanation reaction, albeit less efficiently, giving the cyanosulfone 181b in 60% yield (entry 5). With p-TolSO2CN as a sulfone source, the corresponding cyclobutane 181j was obtained in a moderate yield of 50%, while only 7% of 181j

were formed in the absence of p-anisaldehyde (entries 6 and 7). This difference in reactivity between mesyl and tosyl cyanide was already observed by Barton under thermal conditions. 226 The reaction was also performed at 254 nm, leading to complete consumption of 169a and the formation of a complex mixture of products in which 181b was absent, in contrast to the literature's report 127 (entries 8 and 9). In this case, the high absorbance of the reactants at this wavelength probably favored side reactions or the decomposition of the cyclobutene. Using monochromatic wavelengths such as 334 nm, gave very low yields (entries 10 and 11), while, at 419 nm, a slightly better conversion was observed in the presence or absence of catalyst (entries 12 and 13). This observation was rationalized by the fact that MeSO2CN absorbs in this region, which probably promotes the addition reaction. At 344 nm, no reaction was observed with or without photosensitizer due to the narrow band of the light source and the insufficient energy absorbed at this wavelength (entries 14 and 15 The critical role of p-anisaldehyde in this process was also highlighted by using oct-1-ene 174 as olefin, which does not absorb light in the 325-400 nm zone. The sulfonyl-cyanation of oct-1-ene led to the desired product 198b with > 95% conversion (97% isolated yield) in the presence of panisaldehyde, and only 25% in its absence after 20 h of irradiation (Table III

Irradiation control

To investigate the importance of light in this process, an ON/OFF light experiment was performed. This experiment showed that the sulfonyl-cyanation reaction stops when the light was switched off and restarts when the light was switched on (Figure III.8).

Figure III.8. The effect of successive intervals of irradiation and dark periods on the reaction's kinetics. Reagents and conditions: i) MeSO2CN (2.0 eq.), p-anisaldehyde (0.2 eq.), CD3CN (0.2 M), 325-400 nm, 30 °C.

1.2.4.2.1.4

Quenching studies

When the sulfonyl-cyanation of 169a was carried out using MeSO2CN and p-anisaldehyde (20 mol %) but in the presence of a triplet quencher such as 2,5-dimethylhexa-2,4-diene (20 mol %), 181b could not be detected after 20 h of irradiation (Table III.8, entry 1). A similar result was observed in the presence of pyridazine, which possesses a triplet-state energy lower than that of panisaldehyde (entry 2). entry quencher yield (%)

1 2,5-dimethylhexa-2,4-diene 0 2 pyridazine 6
Table III.8. The sulfonyl-cyanation of 169a in the presence of triplet state quenchers. Reagents and conditions: MeSO2CN (2.0 eq.), p-anisaldehyde (0.2 eq.), quencher (20 mol %), CD3CN (0.2 M), 325-400 nm, 30 °C, 20 h.

Quantum yield determination

The calculation of the quantum yield was performed by Dr. Dario M. Bassani -ISM, UMR 5255.

The quantum yields for the formation of 181b from irradiation of acetonitrile-d3 solutions of 169a (0.16 M) and MeSO2CN (0.33 M) were carried out on an optical bench equipped with a 150 W high-pressure Hg-Xe lamp and a high-intensity monochromator set at 334 nm. The solutions (0.6 mL)

were placed in Young NMR tubes that were degassed by three cycles of freeze-pump-thaw. The tubes were placed in 1 cm quartz cuvettes filled with water to minimize lensing effects and irradiated.

Overall yields of 181b, determined by 1 H NMR-600 MHz, were 5% (19 h irradiation) and 8% (5.5 h irradiation) in the absence and presence of p-anisaldehyde (33 mM), respectively. From the relative molar extinction coefficients of 169a and p-anisaldehyde at 334 nm (71 and 15 L mol -1 cm -1 , respectively), the proportion of light absorbed by the p-anisaldehyde in the sensitized reaction was calculated to be 48.6% of the total incident light (evaluated to be 7.84 x 10 -10 Einstein using ferrioxalate actinometry with ΦFe(II) = 1.23 for a 6 mM solution of potassium ferrioxalate using the same volume and irradiation geometry as the samples).

The quantum yield for the formation of 181b upon direct irradiation of 169a was determined to be ΦS = 0.09 from the conversion measured in the absence of photosensitizer. In the case of the photosensitized reaction, the observed yield was corrected for the background reaction and internal filter effects, since 169a absorbs at the excitation wavelength. The overall conversion (χt) is given by the sum of the contributions from the sensitized (χPS) and direct (χS) irradiation, weighted by the fraction of light absorbed by each species:

χ 𝑡 = ε PS [PS] 𝜀 𝑆 [𝑆] + 𝜀 𝑃𝑆 [𝑃𝑆] χ 𝑃𝑆 + ε S [S] 𝜀 𝑆 [𝑆] + 𝜀 𝑃𝑆 [𝑃𝑆] χ 𝑆
where εS and εPS are the molar extinction coefficients at the irradiation wavelength of the substrate and photosensitizer, respectively. Similarly:

moles of 𝟏𝟖𝟏𝐛 = 𝑰 𝒕 [ ε PS [PS] 𝜀 𝑆 [𝑆] + 𝜀 𝑃𝑆 [𝑃𝑆] Φ 𝑃𝑆 + ε S [S] 𝜀 𝑆 [𝑆] + 𝜀 𝑃𝑆 [𝑃𝑆]
Φ 𝑆 ] 8% • 0.16M • 0.0006L = (7.84 • 10 -10 mol 𝑠 -1 )(1.98 • 10 4 𝑠)[0.54Φ 𝑃𝑆 + 0.46Φ 𝑆 ] 0.52 = 0.49Φ 𝑃𝑆 + 0.51Φ 𝑆 giving ΦPS = 0.96.

A value of 0.96 for the quantum yield of formation of 181b from excited p-anisaldehyde, is close to unity. This implies that the sequence of reactions leading to the formation of 181b is particularly efficient or that it may involve a radical chain reaction with a turnover > 1. Importantly, the transformation was found intrinsically 10-fold faster when sensitized versus direct irradiation. Oxidative quenching of 3 BP* and Electron Transfer (ET) to ethylsulfonyl cyanide

The free energy of a photo-induced electron transfer from benzophenone triplet state is given by the following relation: with the Faraday constant F = 23.061 kcal V -1 mol -1 and 3 Eox(An*/An +• ) = E°(An/An +• ) -E T 0,0 → 3 Eox(An*/An +• ) = +1.64 -(+3.04) = -1.41 V E°(An/An +• ) = +1.64 V, 227 and E T 0,0 = 3.04 V. 228 Electron transfer to EtSO2CN (Ered(RSO2CN/RSO2CN -• ) = -1.72 V (vs SCE) and

ΔGPET = -F [-1.72 -(-1.41)] ΔGPET = +7.2 kcal/mol
In conclusion, on the thermodynamic ground, the electron-transfer mechanism is not favored with both benzophenone and p-anisaldehyde.

Proposed mechanism

The above-mentioned results were found consistent with an energy transfer mechanism from the excited triplet state of the photosensitizer to the sulfonyl cyanide. Indeed, it is suggested that the energy transfer from the p-anisaldehyde 229 or Benzophenone 230,231 excited triplet state to R1SO2CN allows the generation of the sulfonyl cyanide excited triplet state (Figure III.9). This would later undergo a homolytic cleavage of the O2S-CN bond to form the sulfonyl radical. The electrophilic radical would then add onto the less substituted end of the cyclobutene's double bond to generate a β-sulfonyl radical. The latter would be trapped by R1SO2CN, leading to the expected product and R1SO2 • radical, ready to sustain the radical chain reaction. As stated earlier, alternative mechanisms involving photo-induced electron transfer from triplet p-anisaldehyde or benzophenone to the sulfonyl cyanide were calculated to be thermodynamically less favorable. However, the sulfonyl-cyanation of oct-1-ene using 9,10-dimethylanthracene, a strong electron donor but with a low triplet energy, led to the formation of the desired nitrile 198b with Φ = 0.13 (λex = 365 nm) (Scheme III.20). This observation keeps the door open for new investigations or observations in the future.

Scheme III.20. Sulfonyl-cyanation of 174 in the presence of an electron donor. Reagents and conditions: 88a (2.0 eq.), 9,10-dimethylanhracene (0.01 eq.), CD3CN/CD2Cl2: 3/2 (0.2 M), 365 nm, 30 °C, 2 h.

Conclusion

In the first part of this chapter, new functionalized enantiopure cyclobutenes were synthesized on decagram scale through a two-steps sequence. The first step was based on Narasaka's 195 early report of asymmetric [2+2]-cycloaddition to elaborate cyclobutenyl sulfides with high yields and enantiomeric excesses. These skeletons were later desulfurized to give the corresponding olefins. The π-system of cyclobutenes was found weakly reactive towards some electrophilic radical species.

However, the malonyl radicals were successfully added onto the double bond furnishing functionalized cyclobutane rings with good yields and diastereoselectivities. Subsequent modifications to incorporate a nitrile group in a fully enantio-and diastereocontrolled manner gave moderate results.

An unprecedented p-anisaldehyde-photosensitized sulfonyl-cyanation of cyclobutenes was established, allowing the addition of sulfonyl and cyanide radicals onto the cyclobutene's double bond. The mechanistic studies showed that the reaction proceeds through an energy transfer mechanism, giving the corresponding cyanosulfones in good to high yields. The sulfonyl-cyanation reaction was found ideal to incorporate a nitrile unit in a fully regio-, enantio-and diastereocontrolled manner. The sequence can be carried out on a multigram scale with excellent reproducibility, using small volumes of solvent, under mild conditions, and no workup (Figure III.10). Further functionalization of the synthesized cyclobutanes was envisioned in the next part of this chapter, to elaborate these useful intermediates 232,233 into more complex molecular architectures.

Part II

Ring-Opening Studies and Cyclobutane Derivatives

Development of cyclobutane ring-opening reactions

The successful synthesis of highly substituted cyclobutanes bearing an all-carbon quaternary center with excellent diastereocontrol is ideal for further manipulations to produce useful enantiopure derivatives. Such a backbone can be an advanced intermediate in the synthesis of azabicyclo [3.3.1]nonane 20, a key chiral core in the total synthesis of eucophylline (Figure III.11).

To achieve this goal, two modifications must be focused upon: a general method for the sulfonyl group elimination and an efficient route for the cyclobutyl ring-cleavage. Compared to the three-membered ring, the cleavage of the cyclobutane ring is harder due to the less important total strain within the molecule. Still, the ring-opening of the synthesized cyclobutanes can be triggered in various ways. Generating an unstable ketyl-type radical from the cyclobutyloxazolidinone would for instance induce the formation of a relatively stable radical αto the electron-withdrawing group, which could then trigger a straightforward ring fragmentation (Scheme III.21.A). The resulting acyclic chain can later be submitted to sulfone elimination using a suitable base.

In contrast, the sulfonyl group can be removed first, through an E1cb-type elimination process to generate a homochiral cyclobutene (Scheme III.21.B). The latter can be then submitted to a ringopening procedure through ozonolysis of the double bond, a ring-opening metathesis (ROM) with an appropriate olefin, or to 1,4-addition of a nucleophile. In the latter strategy, an electron-donating group, for example, can be introduced at the C1-position to the carbonyl fragment, which might allow further "push-pull" process. Since both groups, the carboxylate and the nitrile, are electronwithdrawing groups in this system, conditions have to be carefully studied to favor the pull effect on the desired side. Alternatively, the 1,4-addition of different reactive fragments might, under the appropriate conditions, induce the cyclobutyl ring-opening.

Scheme III.21. Various pathways towards cyclobutane ring-opening and sulfone elimination.

Ring-opening reaction through Samarium(II) diiodide

At first, the ring-opening process was developed through radical fragmentation. To meet this purpose, the formation of a ketyl radical species would be carried out using samarium(II) diiodide (SmI2), a well-known reagent for such transformation. 234 In the presence of SmI2 under suitable reaction conditions, a single electron would be transferred to the cyclobutane to generate a metalled ketyl radical αto the oxazolidinone fragment I (Scheme III.22), which would then trigger a regioselective ring cleavage leading to the formation of a radical αto the sulfone II. Such a process would deliver after the convenient treatment, the expected acyclic γ-amidonitrile 199.

Scheme III.22. Cyclobutane ring opening through SmI2-promoted radical fragmentation.

Samarium(II) diiodide in organic synthesis

Samarium(II) diiodide was first introduced by Henri Kagan, in 1977. [235][236][237] Since then, this single-electron transfer reagent has found a diverse array of applications in organic synthesis, and it became widely appreciated as a reducing agent. 238 Interestingly, its reductive properties could be altered through the conjugation with a variety of suitable ligands and additives (HMPA, H2O, alcohol, amine, metal salts…). For instance, when coupled with water (500 eq.), its reductive potential in the ground state increases (SmI2 (Sm 2+ /Sm 3+ ): -1.5 V vs. Ag/AgNO3 in THF; SmI2(H2O)500: -1.9 V vs.

Ag/AgNO3 in THF), 239 which, therefore, increases its ability to induce a single-electron transfer.

Besides this property, water is preferred nowadays, as a proton donor, due to its benign nature compared to the toxic HMPA, and to its better selectivity than the SmI2/HMPA couple. 240,241,242 Hundreds of reactions were reported on functional groups reduction (ester, ketone, aldehyde, carboxylic acid, amide, nitrile, N-oxazolidinone, nitrone…), carbon-carbon and carbon-heteroatom bond formation and fragmentation. 238,243 Reduction of carbonyl compounds using oxophilic SmI2 leads to ketyl radicals, which under certain conditions are further reduced into samarium(III) enolate intermediates (Scheme III.23). 241 Such enolates can be quenched in situ with electrophiles to make new bonds, or experience rapid scission of a carbon-carbon bond αto the carbonyl group. [244][245][246][247][248][249] Compared to the former, the latter outcome is less documented.

Scheme III.23. Common mechanism of SmI2-promoted activation of carbonyl compounds.

Reported SmI2-mediated ring-opening processes

In correlation with this section, illustrative examples of the power of SmI2 in the ring-opening reaction are described. Kim et al. 250 reported a reductive ring-opening of cyclopropyl ketones 202 and 204 using the samarium complex in THF/MeOH at low temperature. The introduction of an electron-withdrawing group on the vicinal position to the ketone favored the fast and selective ring cleavage (Scheme III.24).

Scheme III.24. SmI2-mediated ring-opening of cyclopropyl ketone. 250 Similarly, the ring-opening of cyclopropane mono-and di-carboxylates 206 was reported by Yamashita and co-workers. 251 A large scope was studied in the presence of a proton source, to deliver the acyclic compounds 207 in good to high yields (Scheme III.25). This reaction showed high regioselectivity and a satisfying tolerance for different functional groups. This also illustrates the effect of the electron-withdrawing groups on the reactivity of the three-membered carbocycle towards the ring scission.

Scheme III.25. SmI2-mediated ring-opening of cyclopropane carboxylates. 251 Although studies on SmI2-mediated cyclobutanes cleavage are less popular than cyclopropanes, reports demonstrated its feasibility and utility in the synthesis of polycyclic targets. For instance, Comins et al. 252 exposed α-ketocyclobutane 208 to a single-electron transfer reaction using SmI2 coordinated with a Lewis base (DMPU). This scaffold undertook facile C-C disconnection to yield 81% of azaspiro [5.5]undecane 209 as a sole product (Scheme III.26).

Scheme III.26. Synthesis of spirocycle 209 through SmI2-promoted ring-opening. 252 An interesting study on the four-membered ring cleavage and expansion was described by Subjected to SmI2/HMPA/t-BuOH complex, bicyclo[4. Other examples on the ring-opening αto a ketone in unactivated cyclobutanes were also described elsewhere. 243,252,254,255 Scheme III.27. SmI2-mediated ring-opening reaction of bicyclo[4.2.0]octan-2-ones. 253 When it comes to carbonyls next to heteroatoms such as nitrogen, the reactivity of the organosamarium was far less studied. 241 Yet, Skrydstrup, 256 Procter,257,258 and others 259 succeeded at creating ketyl radicals from unactivated amides or N-acyloxazolidinones. Under suitable conditions, it was found that, when associated to water, the reductive potential of SmI2 is high enough to activate the oxazolidinone entity. 240 But, it was also stated that Sm(II) has a high affinity (due to its oxophilic character) towards N-acyloxazolidinone, which coordinates with SmI2 and behaves as a ligand, as observed with HMPA. 256,260 Skrydstrup and co-workers 256,261 utilized SmI2 assisted by H2O to promote a radical addition of acrylates and acrylamides 217 onto N-acyloxazolidinones 216 (Scheme III.28). This reaction furnished a wide variety of γ-ketoamides and γ-ketoesters 218 in good to high yields.

Scheme III.28. SmI2/H2O-mediated cross-coupling of N-acyloxazolidinones with acrylamides and acrylates. 256,261 The mechanistic studies showed that the acrylamide/acrylate 217a gets reduced into a radical anion after coordination with the Sm(II)-oxazolidinone complex 219 (Scheme III.29). The alkyl radical then undergoes intermolecular coupling with the N-acyloxazolidinone's carbonyl. 256 This reaction was also extended to N-acyloxazolidinones derived from amino acids and peptides as intermediates for more complex targets. 262,263 Scheme III.29. Mechanism of SmI2-mediated cross-coupling of N-acyloxazolidinones. 256 When a base such as triethylamine is added, a chemoselective reduction of unactivated amides and N-acyloxazolidinones into alcohols was observed (Scheme III.30). 257 The mechanistic data Scheme III.30. Chemoselective reduction of amide derivatives to alcohol using SmI2-H2O-Et3N complex. 257 Interestingly, in the presence of alcohol 227 and a catalytic amount of SmI2, unactivated Evanstype oxazolidinones 226 were converted into esters 228 through stable acyl radicals, as reported by

Collin and co-workers (Scheme III.31). 259 This reaction was applied to a broad scope to afford the expected products without racemization. The oxazolidinone moieties 229 were also recovered in good yields.

Scheme III.31. Conversion of N-acyloxazolidinones into esters using SmI2. 259

Application of SmI2-promoted reaction on sulfonyl cyclobutanes

The regioselective fragmentation of cyclobutanes then proceeded using SmI2-H2O mixture at -78 °C, to give access to enantiopure nitriles 199 γto a carbonyl group in good to high yields (Scheme III.32). The reaction conditions were found to tolerate functionalized alkyl groups, such as chlorides, silyl ethers, and aryls. The reaction was also suitable for different sulfonyl chains, although better yields were observed with methylsulfones (e.g., 199m vs 199l). Tosyl cyclobutane 181j on the other hand, gave the opened product 199f in a low yield, and the crude mixture was contaminated by other unidentified side products. This is indeed predictable since the arylsulfones are more sensitive to SmI2 reduction than the alkylsulfones. 264

Scheme III.32. Scope of SmI2-promoted ring-opening reaction. Reagents and conditions: i) SmI2 (3.5-4.5 eq.), H2O (12.0-18.0 eq.), THF (0.1-0.2 M), -78 °C, 1-4.5 h.

Overall, this sequence led efficiently to cyclic and acyclic β-sulfonylnitriles bearing an all-carbon quaternary stereocenter, starting from simple optically pure cyclobutenes. The generality of this methodology was illustrated by its applicability to cyclobutenes bearing a variety of functionalities.

The enantioselectivity of this sequence was monitored for each step after the synthesis of the racemic substrates. No racemization arose, and for the sequential substrates 117a, 169a, 181a and 199a the enantiomeric ratio exceeded 98% (Scheme III.33).

Scheme III.33. Evaluation of the enantioselectivity of the cyclobutanes sequence methodology. X = oxazolidinone.

The Ramberg-Bäcklund Rearrangement (RBR)

Following these results, above sulfonyl nitriles were ready for sulfonyl group elimination. It was envisioned that submitting the alkyl-sulfone 199 to the Ramberg-Bäcklund reaction conditions, would deliver the corresponding allyl-nitrile derivative 230 in an efficient and straightforward way (Scheme III.34). Such a synthon would then be prone to successive modifications, making it a valuable intermediate for the asymmetric synthesis of natural targets. For instance, hydrogenation under high pressure (e.g., H2, 50 atm, Raney ® -nickel) of such an alkene with the suitable R side chain (R = (CH2)3OPG), would promote the cyclization into a six-membered ring lactam 231, a direct precursor of the azabicyclo [3.3.1]nonane fragment of eucophylline.

Scheme III.34. Sulfone elimination reaction through RBR, and utility of the allylnitrile product in the total synthesis of eucophylline. X = oxazolidinone or alkoxy group.

Ramberg-Bäcklund reaction in the literature

In Consequently, Chan and co-workers 268 proposed another method, using alumina-supported potassium hydroxide and difluorodibromomethane as base and halogen sources, respectively. This reaction was carried out at room temperature for activated substrates (e.g., benzylic and allylic sulfones). However, for other substrates (alkyl sulfones), heating was essential to generate the required carbanion species which led to poor yields due to the loss of the low boiling CF2Br2. Franck

Application of the Ramberg-Bäcklund reaction

Meyers' original conditions (CCl4, KOH, t-BuOH/H2O) on the acyclic γ-nitrile 199n as a model, gave no typical alkene signals in the 1 H-NMR spectrum, the profile of which was rather complex (Table III.10, entry 1). Changing the halogen source to Chan's CBr2F2 employed in large excess due to its volatile nature, delivered the alkene 235 in 10% yield after column chromatography (entry 2).

Under such harsh conditions, the oxazolidinone-deprotection was observed to give the saponified analog 236. Other highly polar compounds were observed on TLC resulting probably from decomposition. Under Chan's conditions (CBr2F2, KOH/Al2O3), a partial conversion was observed, and 235 was isolated in 18% yield alongside with 30% of the saponified starting material 236 (entry 3). When chloroform was used as a co-solvent, full conversion of the starting material was observed, however, only 23% of 235 were isolated, with many spots seen on TLC (entry 4).

With the halogenating agents 1,2-dibromotetrachloroethane (C2Br2Cl4), 272 a non-volatile and ozone-friendly reagent, and hexachloroethane (C2Cl6) 273 only traces of the desired product were detected on the crude 1 H-NMR (entries 5 and 6). When combining Meyers' and Chan's conditions (CCl4, KOH/Al2O3) at 80 °C for 21 h, the product was isolated in 40% yield (entry 7), conditions which were not reproducible, likely as a result of the high polarity of the compounds, easily lost on column chromatography (entry 8). Unfortunately, increasing the reaction time did not afford a better yield (entry 9). Such harsh conditions are probably not compatible with the nitrile group, which may be hydrolyzed. The application of milder bases such as DBU and Et3N did not promote any reaction even at reflux, which was somehow expected, due to the low acidity of the proton αto the sulfone (entries 10 and 11). [X] = halogen source. Reagents and conditions: base (2.0 eq.), KOH/Al 2 O 3 (250 mg/0.1 mmol of substrate). [X]: CF2Br2 (10.0+10.0 eq.), C2Cl6

(5.0 eq.), C2Br2Cl4 (2.0 eq.). Solvent: 1/1. t-BuOH/CH2Cl2/H2O 1:1:0.2.

To solve the polarity problem, the oxazolidinone moiety in 199e was reduced in the presence of LiBH4 into alcohol 237, in 88% yield (experimental part). With 237 is in hand, the best conditions found previously were applied to give the expected product 238 in 35% yield, contaminated with inseparable impurities (Table III Besides the high polarity of the manipulated compounds, the poor yields could also be rationalized by the lower acidity of the alkyl proton αto the sulfone compared to benzylic proton used in the original paper (benzylic α-protons, pka ~ 23.4 vs. alkyl α-protons, pka ~ 31.0). The halogenation process could thus be controlled by introducing a chlorine atom αto the alkyl sulfone using n-BuLi and C2Cl6 as deprotonating and halogenating agents, respectively. 274 Yet, applying this strategy to 237 gave a complex mixture of unidentified products (Scheme III.36).

Scheme III.36. Attempt for halogenation of 237. Reagents and conditions: i) n-BuLi (2.2 eq.), C2Cl6 (3.0 eq.), THF (0.12 M), -78 to 20 °C, 3.5 h.

All the above observations suggest that in such a system, the nitrile might undergo hydrolysis or an intramolecular nucleophilic attack of the carbanion αto the sulfone, which led to look for other tactics to reach the desired goal.

Nitrile fragment hydrolysis and lactone synthesis

The next logical step was to transform the nitrile group under hydrolysis, reduction, or hydrogenation into a functionality compatible with the Ramberg-Bäcklund rearrangement. To start, it was planned to hydrolyze the nitrile in 237 into a carboxylic acid. This latter would be submitted in situ to a spontaneous nucleophilic attack of the alcohol six atoms away, to generate a δ-lactone ring 240 (Scheme III.37). Further manipulation of the lactone framework would deliver a lactol 241, which could evolve into an α-alkoxy ether 242 under suitable conditions. This substrate would be stable under the highly basic conditions of RBR and could be submitted to the sulfone elimination to give an unsaturated α-alkoxy pyran 243. This kind of functionalized heterocycles might be an interesting intermediate in the synthesis of complex targets, such as δ-lactoneand tetrahydropyran-containing natural products 275 like polyketides, 276 pheromones, 277 and anticancer agents. 278 For this project, pyran 243 would be a valuable synthon in the asymmetric synthesis of eburnamine 18. 279 Scheme III.37. Strategy towards lactone formation and further manipulation.

The intramolecular cyclization of a δ-hydroxy acid is considered one of the most straightforward protocols for the synthesis of δ-lactone frameworks. 280 Such lactones may also be prepared in a one-pot process from δ-hydroxy nitriles, after hydrolysis and subsequent lactonization under thermal acidic or basic conditions. Lakner and Frye prepared for instance the optically pure (R)-mevalolactone 245 using NaOH at high temperature (Scheme III.38.A). Acid-catalyzed lactonization of δ-hydroxy nitriles was also inspected; Tong and co-workers used aqueous sulfuric acid to promote the hydrolysis and lactonization sequence to obtain the cis-bicyclic lactone 250 in 90% yield (Scheme III.39.A). 284 The lactonization of hydroxy nitrile 251 also took place with p-toluenesulfonic acid in refluxing THF to give 252 in 63% yield, an advanced intermediate in the synthesis of ajmaline alkaloid (Scheme III.39.B). 285

Scheme III.39. One-pot hydrolyzation-lactonization process under thermal acidic conditions.

Application of hydrolytic lactonization on δ-hydroxy nitrile 237

When KOH in refluxing ethylene glycol was used on nitrile 237, only traces of the TIPSdeprotected lactone 253 were obtained (Table III.12, entry 1). In contrast, when the reaction was assisted with sodium hydroxide/hydrogen peroxide mixture, 56% of the deprotected lactone 253 were also obtained, alongside with 10% of the starting material (entry 2). The reprotection of 253 was carried out under standard conditions (TIPSCl, imidazole, CH2Cl2, 0 to 20 °C, 1.5 h) to afford 240a in a 91% yield. In the presence of a Brønsted acid, such as aqueous sulfuric acid, complete decomposition of the starting material was observed after 6 h (entry 3). However, with 2 equivalents of p-toluenesulfonic acid, 1% of the desired product 240a, 54% of the deprotected 253, and 1% of the starting material were isolated (entry 4). Interestingly, 10% of an acylated lactone 254 were also obtained. The formation of this product could be rationalized by the reaction of the hydroxy-lactone 253 with ethyl acetate in the presence of an excess of p-TsOH during the extraction process. Similarly, with a stoichiometric amount of acid, the reaction led to 1% and 54% of the desired product 240a and the alcohol 253 respectively, alongside with 26% of the initial substrate (entry 5). Running the reaction in refluxing toluene using a Dean-Stark, produced 63% of the expected product 240a, 26%

of 253, and 9% of the starting material in a clean fashion (entry 6). In this case, leaving the reaction for a long time did not improve the conversion of the substrate 237. From these studies, a straightforward hydrolytic cyclization of the sulfonyl nitrile 237 gave access to a substituted δ-lactone bearing an all-carbon quaternary center. The yield obtained was considered high enough to pursue the following steps.

The lactone 240a was then subjected to reduction under standard conditions (DIBAL-H, THF, low temperature). 286 With 1.5 equivalents of DIBAL-H, 9% of the expected lactol 241a were isolated as a mixture of two diastereomers (dr 6:1), alongside with an acyclic diol 255 in 46% yield (Table III.13, entry 1). Decreasing the amount of hydride source to 1.0 eq. afforded the lactol 241a and the diol 255 in 13% and 46%, respectively (entry 2). When modifying the workup procedure by stirring the crude mixture with the Rochelle's salt (potassium sodium tartrate) for 12 h, the diol 255 was isolated in 70% yield as the sole product (entry 3).

RBR reaction on diol 255

Before continuing the optimization measures, and with enough material in hand, the diol 255 was submitted to RBR conditions. Surprisingly, with the optimal conditions of KOH/Al 2 O 3 in t-BuOH/CCl4, a complex mixture of products was obtained (Table III.14, entry 1). With CBr2F2 as the halogenating agent, traces of a typical double bond signal were detected, but not enough for the product to be isolated and analyzed. Other bases were then studied; both potassium hydroxide and potassium tert-butoxide gave a complex mixture of products (entries 3 and 4). Accordingly, even after the modification of the substrates, RBR was still inefficient. At this stage, the elimination of the sulfone through Ramberg-Bäcklund strategy was abandoned, and shorter and more efficient routes were investigated.

Base-promoted sulfone elimination

The complexity of applying Ramberg-Bäcklund reaction on the γ-nitrile substrates 199, directed the focus towards other methods. 287,288 It was envisioned to eliminate the sulfone group directly from the cyclobutane 181 through a base-mediated β-elimination.

The reaction progress was monitored by TLC, using the substrate in 0.1 to 0.2 mmol scale. During the first attempts, no reaction was detected with DBU as a base after 24 h (Table III.15, entry 1).

Similarly, screening other non-nucleophilic bases such as the organolithiums n-butyllithium and lithium tetramethylpiperidide, sodium hydride in THF and benzene, or caesium carbonate in DMF led to complex mixtures of unidentified products (entries 2 to 6). When LDA, Cs2CO3 and phosphazene P1-t-Bu were used in the presence of ethanol as a solvent, the elimination of the oxazolidinone moiety was observed, and traces of the cyclobutene carboxylate 258a were identified on crude 1 H-NMR (entries 7, 8, and 9), while 17% of this product were isolated using phosphazene P2-Et as a base (entry 10). In the aforementioned cases, although the full conversion of the starting material was attained, low isolated yields were obtained. The purification and analysis data did not bring useful information about the side reactions that possibly took place.

The screening then continued with sodium ethoxide in ethanol; such conditions did not afford the desired outcome, for the crude 1 H-NMR showed no typical double bond. After purification on silica gel, traces of product 259a were isolated, where an ethoxy group was added to the reactive double bond (entry 11). 289 A different product, the β-sulfonyl ester 260a, was also isolated in 56% yield. In this case, only the transesterification occurred with no elimination of the sulfone moiety.

The quality of the sensitive sodium ethoxide was questioned, and in another try, the base was freshly prepared. These measures afforded the cyclobutene carboxylate 258a in 8% yield after 3 h, however with 3% of product 259a, and other degradation residues (entry 12). Although the elimination of the sulfone group was observed in this case, the yield was too low to attribute the better reactivity to the freshly prepared NaOEt.

At this point, the leaving group ability of the alkylsulfone was examined. Using the above conditions (freshly prepared NaOEt, EtOH, -78 °C) on the tosyl cyclobutane 181j afforded the cyclobutene carboxylate 258a in 50% yield after 2 h, in a clean fashion (data not shown). This unexpected result confirmed that the prepared base was of good quality and that the alkylsulfones are indeed less efficient leaving groups than the arylsulfones. Such a result contrasted with an observation reported elsewhere. 290 Although the result with the tosyl cyclobutane may seem more encouraging for optimization, the study was not pursued due to the moderate efficiency of the sulfonyl-cyanation step (50% yield).

With the aim of limiting the formation of side products, an attempt with only 1 equivalent of NaOEt was made, which led only to a new product 260a resulting from the nucleophilic displacement of the oxazolidinone. Leaving the reaction for an additional 84 h did not show any conversion, and 260a was then isolated in 33% yield with no observation of side reactions (entry 13). It is believed, based on these results, that the β-sulfonyl ester 260a is actually an intermediate in the reaction and that the oxazolidinone displacement occurs faster than the sulfonyl elimination.

DMF was also tried as a solvent instead of ethanol, leading to the absence of the desired product (entry 14), while the decomposition of the starting material was observed when potassium carbonate was used as a base (entry 15). With K2CO3, and in the presence of a mixture of ethanol and dichloromethane as solvents, 27% of 258a were isolated (entry 16). In contrast, with ethanol as the only solvent, the yield increased to 44% (entry 17). The previous experiments illustrate the important role of ethanol as a solvent in this transformation, and as noticed, during the whole screening, the initial desired product 257 was not detected. The weaker acidity of the proton to the oxazolidinone probably explain the failure of the -elimination, which only becomes efficient after formation of the ester, which is more easily converted into its enolate using a base. Performing the reaction in other alcohols such as methanol led to a complex mixture of products (entry 18).

Attempts to optimize the reaction by adding an excess of K2CO3 resulted in the decomposition of the starting material, and only traces of 258a were observed on the crude 1 H-NMR (entry 19).

Increasing the scale to 2.8 mmol of substrate under the optimal conditions, led to a lower yield of 25% (entry 20). Unexpectedly, repeating the reaction on the same scale did not give the same results;

after 3 h, a complete conversion was observed with a formation of 258a and 260a (entry 21). Leaving the reaction for another 2 h did not improve the conversion. Thus, the reaction was stopped to prevent exposing the double bond to undesirable transformations, and 258a and 260a were isolated in 7 and 66%, respectively. Even though this reaction was clean, and no significant loss of material was observed, the elimination of the sulfone was found problematic on large scale. Such results are not optimal for the development of a reliable method for further use in the total synthesis strategy. Base screening for sulfone elimination reaction. Reagents and conditions: base (2.0 eq.), solvent (0.1 M). a Complex mixture of products. b Freshly prepared NaOEt. c NaOEt (1.0 eq.). d K2CO3 (4.0 eq.). e 2.8 mmol scale.

In a desire to reduce the amount of side products and to control the behavior of this reaction, a two-steps sequence was designed for the sulfone elimination. The submission of cyclobutane 181i to DMAP in refluxing ethanol afforded the sulfone ester 260a in quantitative yield on a 10 mmol scale (Scheme III.40).

Scheme III.40. Transesterification of cyclobutane 181i using DMAP. Reagents and conditions: i) DMAP (0.5 eq.), EtOH (0.07 M), 78 °C, 12 h.

With enough material in hand, the sulfone elimination was investigated. Taking into account the results of the earlier attempts, 260a was first treated with 1 equivalent of K2CO3 in ethanol to give 41% of the desired product after 19 h, along with 12% of unreacted starting material (Table III.16, entry 1), while, with 1 eq. of NaOEt, no reaction was observed even after 53 h (entry 2). Increasing the quantity of K2CO3 to 2 eq. delivered 258a in 66% yield on 2.4 mmol scale (entry 3), but this yield was hardly reproducible. When performing the reaction at a higher temperature the yield dropped to 46% (entry 4). With an excess of potassium bicarbonate, only 1% of 258a was isolated with 40% of 259a (entry 5). The formation of 259a demonstrates the potential reactivity of the double bond toward 1,4-conjugate addition, a property that will be considered in further studies.

When DMF was used, traces of 258a were observed without decomposition of the starting material (entry 6). Interestingly, the same conditions provoked decomposition of 181i bearing the oxazolidinone fragment, as previously described. Changing the solvent to acetonitrile gave 258a in a good yield of 62%, and 27% of the starting material were recovered after 46 h (entry 7). Switching to a combination of DBU and DMAP in dichloromethane afforded 258a in 31% yield, while heating led to a decomposition (entries 8 and 9). With phosphazene P2-Et in DMF, only traces were formed with the recovery of the starting material (entry 10).

Sodium hydride was also inspected; the reaction gave 258a in a satisfactory yield of 64% after 5 h (entry 11), along with 10% of recovered starting material. Repeating the reaction for a longer time gave, surprisingly, a lower yield of 44% (entry 12). Washing the sodium hydride with pentane under argon atmosphere prior to reaction gave however, the sulfonyl carboxylic acid 261 in 68% yield as the sole product (entry 13), suggesting the presence of NaOH, responsible for the saponification.

Submitting the substrate 260a to caesium carbonate in dichloromethane afforded the product in traces only (entry 14), while heating at reflux increased the yield to 24% (entry 15). Further optimization by changing the solvent to DMF was performed. At room temperature, the reaction gave 41% of the product in a clean manner (entry 16). Increasing the temperature to 90 °C gave 65% of enone 258a

(entry 17), while performing the reaction at 70-75 °C led to reproducible results with 81-82% of yields (entries 18 and 19). Finally, these conditions were found reproducible also on large scale (78 and 71% on 3 and 10 mmol scale respectively). Reagents and conditions: base (2.0 eq.), solvent (0.1 M). a K2CO3 (1.0 eq.). b NaOEt (1.0 eq.). c 2.4 mmol scale. d K2CO3 (3.0 eq.). e DMAP (0.5 eq.). f Washed.

entry base solvent temp (°C) time (h) yield (%)

A final attempt to perform a one-pot reaction without submitting the sulfonyl ester intermediate to purification, led to the formation of 262 in 50% yield as two easily separable diastereomers, and only traces of the desired product 258a were observed (Scheme III.41). The oxazolidinyl cyclobutane responsible for various side reactions and shows the high reactivity of the conjugated cyclobutene 258a.

Scheme III.41. Attempts for one-pot sulfone elimination reaction. Reagents and conditions: i) DMAP (0.5 eq.), EtOH (0.07 M), 78 °C, 28 h; then Cs2CO3 (2.0 eq.), DMF (0.1 M), 70 °C, 16 h.

The optimized conditions were then applied to the cyclobutane 181b with a propyl side chain giving high yields. Precisely, the esterification step launched on 20 mmol scale delivered the desired ester 260b in 84% yield (Scheme III.42), while the second step of the sequence, was performed on 17 mmol scale to give the homochiral cyclobutene 258b in 82% yield. When the reaction was performed on a large scale, the medium was concentrated to ~ 0.4 M without affecting the yield.

Scheme III.42. Application of the base-mediated sulfone elimination reaction on cyclobutane 181b. Reagents and conditions: i) DMAP (0.5 eq.), EtOH (0.33 M), 78 °C, 7 h; ii) Cs2CO3 (2.0 eq.), DMF (0.4 M), 70 °C, 14 h.

To sum up, the sulfone elimination was not a straightforward process, partly due to the sensitivity of the final product. The reaction time, the high temperature in certain cases, and the amount of base added were found critical. In addition, the reproducibility was challenging on large scales. The presence of the nucleophilic oxazolidinone fragment was also problematic. Finally, the best conditions include a two-steps sequence, using DMAP and Cs2CO3, respectively. With this method in hand, the potential ring-opening routes were then explored.

Ring-opening reaction through ozonolysis

Among the common methods for cycloalkenes ring-opening is the ozonolysis. 291 The reaction is a clean and cost-effective choice to perform a sustainable oxidative cleavage. It occurs under mild conditions, at low temperature in a dilute medium, and it is compatible with a wide range of functionalities due to its selectivity. 292 The only ozonolysis study on cyclobutenes was reported by

Jung and Deng 293 using a two-steps sequence (Scheme III.43). The ketoaldehyde 264 generated from ozonolysis was submitted without purification to Pinnick conditions using sodium chlorite, to give a monoester of α-ketoglutarate 265 in 84% overall yield.

Scheme III.43. Cyclobutene ring-opening under ozonolytic oxidative cleavage.

Application of ozonolysis on cyclobutenes

In the light of this study, the cyclobutene ring 258a was submitted to ozonolysis at low temperature, and the formed ozonide was treated with dimethyl sulfide, a mild reducing agent. The ester ketoaldehyde 266 was obtained cleanly and the full analysis confirmed the formation of the desired product in 84% crude yield (Table III.17, entry 1). This product, however, was found unstable on silica gel. In fact, after purification, the aldehyde function was missing, and a mixture of inseparable products was formed, the structure of which was found difficult to identify through 1 Hand 13 C-NMR. The mass analysis showed only one peak with the same molecular weight as for the keto aldehyde 266 (C19H32NO5Si [M-H] + , peak mass 382.20552). This suggests that the formed products are isomers, which were also detected after a few hours in the NMR tube containing the pure ozonolysis product.

Efforts were then invested to obtain more stable products. In the presence of ethanol or tosic acid in ethanol, the diethyl acetal 267 was not observed, and a complex mixture was obtained (entries 2 and 3). The investigations of Schreiber's conditions 294 to generate the desired acetal 268 or ester 269 all led to a mixture of decomposed products (entries 4, 5, and 6). When the workup was carried out under reductive conditions in the presence of sodium borohydride, the desired diol 270 was not observed, nor the intramolecular condensation of the alcohol (entry 7). When the isolated ketoaldehyde 266 was submitted to reduction, no product was isolated (entry 8). Under oxidative conditions in the presence of formic acid, a decomposition of the intermediate was observed (entry 9). However, under the conditions described by Jung, the same mixture of unidentified isomers observed before was obtained (entry 10). Alternatives to ozonolysis, i.e., Lemieux-Von Rudloff reagent (KMnO4/NaIO4), 295,296 or RuO4 species 297,298 as oxidizing agents, were also investigated, leading to the same isomers' mixture as before (entries 11 and 12). ii. Ac2O (5.0 eq.), Et3N (2.0 eq.),

CH2Cl2, 0 to 20 °C comp. mix. ii. NaBH4 (1.5 eq.), THF, 0 °C, 19 h comp. mix. ii. H3O + , 0 °C, 5 h unknown mix.

of isomers 12 RuCl3 (0.03 eq.), NaIO4 (6.0 eq.),

CH3CN/CCl4/H2O, 20 °C, 2 h unknown mix.

of isomers

Table III.17. Attempts for cyclobutene ring-opening through ozonolysis.

The cyclobutene 258a was then submitted to reducing conditions using DIBAL-H, which led to the alcohol 273 in 74% yield (Scheme III.44).

Scheme III.44. Reduction of the ester unit of cyclobutene 258a. Reagents and conditions: i) DIBAL-H (3.0 eq.), THF (0.1 M), -78 °C, 4 h.

The ozonolysis of this alcohol was then performed to give cleanly the desired product 274 as a 2.2:1 mixture of two diastereoisomers, as detected by 1 H-NMR of the crude reaction mixture (Table III.18, entry 1). Purification of the crude unfortunately led to a complete decomposition on silica gel, preventing full characterization of the unstable lactol product. The ozonolysis was finally carried out, followed by a rapid oxidation in the hope of obtaining the corresponding lactone 275. A complex mixture of products was, however, obtained (entry 2). Based on these results, this ring-opening strategy was abandoned and other approaches were envisioned. It is worth noting that the ring-opening metathesis (ROM) in the presence of a series of olefins was also investigated on cyclobutene carboxylate 258, however, in all cases, the starting material was recovered (data not shown).

Ring-opening reaction through Donor-Acceptor systems

Based on the previous observations, the reactivity of the enone functionality in cyclobutene carboxylate 258a could be utilized to promote the ring-opening through several pathways. For instance, an electron-donating fragment could be incorporated onto the cyclobutene through 1,4conjugate addition, creating, therefore, a donor-acceptor (DA) system with the C(O)X unit (Figure III.12). The constructed DA-cyclobutane might be activated later by a suitable Lewis or Brønsted acid species, to create a "push-pull" effect. Such force will weaken the adjacent C-C bond and trigger the ring cleavage to give 276 (pathway A). However, the nitrile fragment is also an EWG. push-pull in its direction would compete with the aforesaid pathway and favor the ring-opening on the undesired side to furnish 277 (pathway B). This problem might be minimized by the use of oxophilic acids which would activate the carbonyl group to favor pathway A.

Figure III.12. Construction of a "push-pull" system on cyclobutanes.

It was suggested that the 1,4-addition of an amine fragment onto cyclobutene carboxylate 278 would be strong enough to create an electron-donating effect. With suitable Lewis or Brønsted acid, the ring-opening would be favored to obtain the corresponding aldehyde 279 after hydrolysis of the iminium intermediate (Scheme III.45). This aldehyde could then be a precursor of allylnitrile 230 (Wittig reaction), the previously expected target of RBR, which would eventually be transformed into the bicyclic lactam 20.

Scheme III.45. Ring-opening reaction of an amino-cyclobutane under acidic conditions and further modification of the produced aldehyde.

Introduction to Donor-Acceptor (DA) ring systems

Small-ring systems are usually stable and quite resistant to bond cleavage except when activated.

The ring activation could be triggered by the vicinal incorporation of electron-donating and electronwithdrawing groups into the system, which could be referred to as a donor-acceptor (DA) system, a concept first introduced by Reissig in the 1980s. 299,300 Under certain conditions (usually Lewis acid), the C-C bond which link A and D becomes labile allowing various dipolar reactions to take place. 301 This mode of reactivity was extensively studied with cyclopropanes, [136][137][138]160,302 and recently extended to cyclobutanes. [303][304][305][306][307] Typically, under Lewis acid conditions, donor-acceptor cyclobutanes undergo ring-opening forming reactive 1,4-zwitterionic synthons (Scheme III.46). In such a structure, the positive charge is stabilized by the donor while the negative charge is stabilized by the acceptor. These distonic ions showed high reactivity towards electrophiles, nucleophiles, and dipolarophiles. 136 Compared to DAcyclopropanes, DA-cyclobutanes showed lower reactivity, partly due to their lower ring strain energy (27.5 kcal/mol for cyclopropanes vs. 26.3 kcal/mol for cyclobutanes). 308

Scheme III.46. Reactivity pattern of DA-cyclobutanes with nucleophiles (Nu), electrophiles (E), and dipolarophiles (X=Y). D = donor, A = acceptor.

Among the donor groups, the nitrogen substituted groups were chosen extensively to activate the cyclopropanes and cyclobutanes synthons. 138 The first report of formal cycloaddition of DAcyclobutanes was accomplished by Saigo et al. in 1991. 309 In this work, amino-activated cyclobutane 280 underwent Lewis acid-promoted [4+2] annulation with carbonyl compounds 63 in the presence of titanium(IV) chloride to afford tetrahydropyrans 281, albeit in low diastereoselectivity (Scheme III.47).

Scheme III.47. Synthesis of tetrahydropyranes through titanium-catalyzed ring expansion of aminocyclobutanes. 309 Fleming and Ware 310 studied the reactivity of the "push-pull" system created in the aminocyclobutanes skeleton 282 (Scheme III.48). Under acidic conditions, the ring-opening was observed to generate after hydrolysis, the corresponding aldehyde 283 in 90% yield.

Scheme III.48. Ring-opening reaction of amino-cyclobutane under acidic conditions. 310

Synthesis of amino-cyclobutane precursor and attempts for the ring cleavage

Based on the literature survey, the introduction of a nitrogen substituent onto the cyclobutene carboxylate 258a was envisioned through a conjugate addition. The conjugate additions of nitrogenated fragments onto cyclobutenes are well described in the literature. [311][312][313] The addition of pyrrolidine skeleton on the π-system delivered the trans tetra-substituted amino-cyclobutane 284 in excellent yield and diastereoselectivity (Scheme III.49). The nucleophilic amine was shown to approach anti relative to the alkyl side chain and ester. The ensuing protonation of the ester enolate finally occurs anti relative to the pyrrolidine ring.

Scheme III.49. Synthesis of DA amino-cyclobutane through 1,4-addition reaction. Reagents and conditions: i) pyrrolidine (4.0 eq.), THF (0.1 M), 66 °C, 5 h.

The efforts were then directed towards the ring-cleavage under acidic conditions. It was planned that under such a medium, the ring-opening would promote the formation of an iminium ion 285 which would deliver the corresponding aldehyde 286 after hydrolysis (Scheme III.50).

Scheme III.50. Envisioned acid-promoted ring-opening of amino-cyclobutane.

The activation of the DA-cyclobutane 284 in conc. HCl/H2O medium at reflux failed, however, to afford the desired transformation after 48 h (data not shown).

Reduction of the nitrile group in cyclobutane 284

The reduction of a nitrile on an all-carbon quaternary center is somehow difficult to perform. In preliminary attempts, the standard catalytic hydrogenation was performed on substrate 284, under atmospheric pressure or H-cube in the presence of Raney ® -nickel. Such conditions proved to be insufficient for the reaction to occur as higher pressure is likely required. 314 Nevertheless, the lack of a suitable apparatus led to pursuing alternative methods.

In literature, nitriles are reported to be efficiently reduced into the corresponding amines through strong metal hydride donors such as aluminum hydrides, boranes, [314][315][316] and diisopropylaminoboranes in the presence of a catalytic amount of lithium borohydride. 317 Non-borohydride-based methods were also described through single electron transfer using the SmI2-Et3N-H2O complex. 318 However, all these conditions lack selectivity in the presence of an ester group. Milder methods using hydrides have also been reported for the reduction of nitriles to the corresponding amines. For instance, Laval and co-workers 319 investigated the reactivity of hydrosiloxanes as hydride sources, using stoichiometric amounts of 1,1,3,3-tertramethyldisiloxane (TMDS) in conjunction with titanium(IV) isopropoxide (Scheme III.51). This method was applied to a scope of aliphatic and aromatic nitriles 287 giving the corresponding amines 288 in high yields, but no example on tetrasubstituted nitriles was documented.

Scheme III.51. Reduction of nitrile group using the TMDS/Ti(OiPr)4 system. 319

Applied to cyclobutane 284, these conditions were not found suitable to reduce the desired nitrile, even at higher temperatures (80 or 120 °C).

Sodium borohydride is a milder reducing agent than the aluminum hydrides (LAH) and aminoboranes, and thus does not normally reduce nitriles. Its reducing behaviour, however, changes drastically with the addition of transition metal salts (Ni, Co, Pd, Pt, Fe), which compensates the reactivity gap between LiAlH4 and NaBH4, creating new catalysts with various possible applications. 320-322 Among these, Ni(II) salts were widely used to modify the sodium borohydride's reactivity, generating in-situ nickel boride species (Ni2B) as the active catalyst.

In this area, Caddick and co-workers 323 reported the reduction of aliphatic and aromatic nitriles using a catalytic quantity of nickel(II) chloride (0.1 eq.) in combination with an excess of sodium borohydride (7 eq.). In the presence of di-tert-butyl bicarbonate (2 eq.) as a trapping agent, a broad range of nitriles 89 were converted into the corresponding primary protected amines 289 in high yields (Scheme III.52). Consequently, the isolated double bonds were hydrogenated. Amides, halogen, methoxy, and ester functional groups, however, were found tolerant under these conditions.

Scheme III.52. Reduction of nitriles to Boc-amines using nickel boride species. 323 In their previous paper, 324 they mentioned that the formation of free primary amines using NiCl2.6H2O/NaBH4/MeOH system was challenging and dimerization of the amine products occurred.

Therefore, amine traps such as acetylated compounds were necessary, and a special workup was needed. However, Khurana and Kukreja 325 described a successful reduction of aromatic nitriles into their corresponding primary amines, using a stoichiometric quantity of nickel chloride in conjunction with NaBH4. The in situ formation of the nickel boride active catalyst was achieved in anhydrous ethanol under ambient temperature. These conditions proved to be chemoselective in the presence of halogen, methoxy, and olefinic groups, and produced primary amines in high to excellent yields, with a low percentage of amine dimers (< 10%). They explained that by using ethanol as a solvent, primary amines were obtained by a simple workup procedure.

In the light of these reports, it was first intended to test Caddick's conditions 323 on nitrile 284 (Scheme III.53). This protocol thus allowed the isolation of the protected amino cyclobutane 290a in an encouraging 25% yield together with 60% of unreacted starting material, highlighting the particular reactivity of these sterically hindered nitrile towards reduction, as compared to their aliphatic and aromatic counterparts.

Scheme III.53. Reduction of amino-cyclobutane following Caddick's procedure. Reagents and conditions: i) NiCl2.6H2O (0.1 eq.), NaBH4 (7.0 eq.), Boc2O (2.0 eq.) MeOH (0.13 M), 0 to 20 °C, 5 h.

It was then proposed to modify the reducing system as suggested by Khurana et al. The NiCl2.6H2O/NaBH4/EtOH complex was thus used to obtain free amino-cyclobutanes, and NiCl2.6H2O/NaBH4/Boc2O/EtOH reagents system to produce the Boc-protected amino-cyclobutanes.

The application of this strategy to cyclobutane 284 was found to be efficient towards the sterically hindered cyano group. In the absence or presence of Boc anhydride, the nickel boride catalyst reduced the nitrile to free or Boc-protected primary amine respectively, in good yields (Scheme III.54). In both cases, the reduction proceeded chemoselectively, and no reduction of the ester functional group was observed. Using less than a stoichiometric amount of nickel catalyst, however, afforded lower yields (for instance, with 0.8 eq. of NiCl2.6H2O, 290b was obtained in 40% yield).

Scheme III.54. Reduction of 284 using nickel boride. Reagents and conditions: i) NiCl2.6H2O (1.0 eq.), NaBH4 (7.0 eq.), EtOH (0.07 M), 0 to 20 °C, 3 h. For 290a, Boc2O (2.0 eq.) was added.

Ring-opening investigations

With the reduced amino-cyclobutanes in hand, the cyclobutane ring-opening was investigated again under acidic medium. At first, the free-amino cyclobutane 290b was submitted to strong Brønsted acid conditions; in aqueous HCl, no ring-opening reaction was observed (Table III.19, entry 1), and heating at reflux led to the same result (entry 2). Changing to tosic acid in refluxing ethanol did not afford a better result (entry 3). In the above conditions, only traces of TIPS-deprotected alcohol were detected. Similarly, applying the first three conditions to the Boc-protected amine 290a

did not favor the ring-cleavage and only the deprotection was observed (entries 4, 5, and 6).

Switching to Lewis acids did not give successful outcomes either. The reaction with the oxophilic magnesium bromide failed at activating the DA system and gave back the starting material (entry 7).

The substrate remained unchanged using the borane-THF complex under reflux (entry 8). Transition metals, i.e., mild (indium triflate) or stronger (titanium derivatives) Lewis acids were, unfortunately, unreactive towards the substrate (entries 9, 10, and 11). Finally, a photocatalytic pathway was looked at, with the hope that, the photocatalyst would oxidize the tertiary amine into a radical cation, which would then trigger a radical fragmentation and deliver the ring-opened iminium species. The latter would furnish the corresponding aldehyde after hydrolysis. Examining this approach using iridium photocatalyst, however, gave similar results as above (entry 12). [Ir] = (Ir[dF(CF3)ppy]2(dtbpy))PF6. Reagents and conditions: reagent (2.0 eq.), solvent (1.0 M). a BH3.THF (5.0 eq.). b [Ir] cat. (0.01 eq.).

entry

Although the electron-donating character of an ether group is weaker than an amine, it was reasoned that the ring-opening reaction could presumably be carried out with alkoxy groups as EDG. 326 The oxy-cyclobutane 259b was subjected to nitrile reduction under the nickel boride conditions to afford the reduced cyclobutane 292 in 33% yield (Scheme III.55). The resulting product was then submitted to ring-opening under conc. HCl in water at reflux, however, no reaction was observed even after 48 h. Only some minor degradations were detected on TLC.

Scheme III.55. Reduction of oxy-cyclobutane using nickel boride and attempts for ring-opening under acidic catalysis. Reagents and conditions: i) NiCl2.6H2O (1.0 eq.), NaBH4 (7.0 eq.), EtOH (0.1 M), 0 to 20 °C, 4 h, 33%; ii) conc. HCl, H2O, 100 °C, 48 h.

Based on the above results, it can be conclude that a single ester group as an acceptor rather than geminal diesters generally used in literature is probably insufficient to trigger the push-pull process. 137 This approach was thus abandoned and other plans were envisioned.

Ring-opening through the transformation of malleable functions

8.1. Ring-opening through a hydroxide system

Having failed to obtain the desired aldehyde using a DA-system, it was suggested that other nucleophiles might serve to reach the expected goal. For instance, the 1,4-addition of a suitable alkoxy group as a masked alcohol might deliver a free alcohol 294, which could then undergo oxidation, or acid catalysis to trigger the ring-opening (Scheme III.56). Also, a silanol group could be added onto the cyclobutene carboxylate, before to be activated using a fluorine source, triggering the ringopening and generating the desired aldehyde 296. 327 Scheme III.56. Ring-opening through alcohol and silanol transformation.

Since the nitrile reduction in the presence of the enone double bond is a challenging task, 320 it was planned to introduce the nucleophilic substituent first. It was also hoped to find conditions that would break the expected C-C bond in the presence of nitrile.

The synthesis and manipulation of cyclobutanols and cyclobutanones have been established in the literature. [328][329][330][331][332] The addition of silanols into cyclobutanes was also reported in the literature. 335,336 For instance, Rousseau et al. 337 prepared the silyl acetals 306 in an efficient manner. In the presence of tetrabutylammonium fluoride, these molecules were transformed into the opened cyano esters 307 in excellent yields (Scheme III.59).

Scheme III.59. Ring-opening of cyclobutane silylacetals in the presence of TBAF. 337

Addition of masked alcohol onto cyclobutene

At first, the 1,4-addition of masked alcohol onto cyclobutene 258b was carried out with a stoichiometric amount of benzylic alcohol in the presence of sodium hydride as a base. After 2 h, the crude 1 H NMR showed a clean reaction, and the expected product 308 was obtained as a 2.3:1 mixture of two diastereomers. The purification of the crude mixture afforded the product 308 in only 15% yield (vs. 66% crude), as a result of degradation on silica gel (Scheme III.60).

Scheme III.60. Conjugate addition of benzyl alcohol onto cyclobutene. Reagents and conditions: i) benzyl alcohol (1.0 eq.), NaH (1.0 eq.), THF (0.1 M), 0 to 20 °C, 2 h.

The crude reaction mixture was thus submitted directly to the hydrogenation in the presence of palladium on charcoal (Scheme III.61). The crude 1 H NMR showed the successful deprotection of the benzyl group, but the cyclobutane was found particularly unstable, preventing any further manipulation.

Scheme III.61. Deprotection of the benzyl group. Reagents and conditions: i) H2 (1 atm), Pd/C (10% wt. %), EtOH (0.08 M), 25 °C, 18 h.

A contrasting behavior was observed during the conjugate addition of nucleophilic silanols.

When treated with a stoichiometric amount of triphenylsilanol, cyclobutene 258b led cleanly to the transesterification product 312 which gave the saponified cyclobutene 313 in 80% yield after chromatography on silica gel (Scheme III.62). Surprisingly, when 2 eq. of triphenylsilanol were used in the presence of 2 eq. of sodium hydride, the desired product was not observed and only the starting material was recovered.

Scheme III.62. Silanol addition onto cyclobutenes. Reagents and conditions: i) Ph3SiOH (1.0 eq.), NaH (1.1 eq.), THF (0.1 M), 0 to 20 °C, 5 h; ii) column SiO2.

Ring-opening through radical denitration

Nitroalkyl groups can also be introduced efficiently onto electron-deficient enones through 1,4addition of nitroalkanes. 338,339 Application of this strategy to cyclobutene carboxylate 258 was envisaged, that would then be followed by a radical denitration (following Ono reaction). The generated primary radical would then undergo an intramolecular ring fragmentation to deliver the allyl γ-nitrile 315 (Figure III.13). Interestingly, nitro-cyclobutanes such as 314 would also constitute attractive intermediates for the elaboration of optically pure synthons like aldehydes 317, 340 pyrrolidines 318, 341 or pyrrolidinones 319. 342 Scheme III.63. Synthesis of (±)-biotol through tandem radical cyclization. 343 Cyclobutene carboxylate 258a was submitted to Michael reaction with nitromethane. The latter may be easily deprotonated by a wide range of bases (CH3NO2, pka 10). 344 A preliminary study was carried out in the presence of sodium hydride and 2 equivalents of nitromethane, to give the desired product 314a in 17% yield (Table III.20, entry 1). When the nitromethane was used as a solvent in the presence of DBU, the yield increased dramatically to 69% (entry 2). Attempts to improve the reaction by concentrating the medium to 1 M lowered the yield to 43% (entry 3). The same yield was obtained when DBU was assisted with DMAP (entry 4). However, when a mixture of nitromethane and dichloromethane was used, the yield increased to 57% (entry 5), while heating under the same conditions led to the decomposition of the substrate (entry 6). The use of DBN as a base, however, gave a low yield of 7% (entry 7). With Amberlyst ® A21, 11% of 314a were isolated (entry 8).

Amberlyst ® A21 was described to assist the conjugate addition of functionalized nitroalkanes to α,βunsaturated alkenes. 345 Finally, caesium fluoride proved to be as efficient as DBU and the reaction afforded the nitro cyclobutane 314a in 64% yield (entry 9). The nitrocyclobutane 314a was isolated as a 1. The nitro adduct 314a was then submitted to Ono's conditions; 339 however, only a complex mixture of products was obtained. Repeating the reaction with slow addition of the hydrogen source (Bu3SnH) using a syringe pump (1 mL/h) did not give better results.

Efforts to reduce the nitro group under several conditions (zinc dust, HCl, EtOH/H2O, 80 °C; zinc dust, acetic acid, 110 °C; iron powder, acetic acid, 110 °C) led to a complex mixture of products, while under hydrogenation in the presence of palladium on charcoal (1 atm, EtOH, 20 °C; 20 atm, EtOH, 20 °C; 20 atm, EtOH, 50 °C) no reaction was observed. Similarly, the Nef reaction in the presence of DBU in acetonitrile at 60 °C led to the decomposition of the substrate.

Ring-opening through malonyl decarboxylation

The conjugate addition of activated methylenes onto enones is also well documented in the literature. 346,347 Thus, the 1,4-addition of the di-tert-butyl malonate 323a was envisioned, given the role of steric interactions in the control of the diastereofacial selectivity in these systems (vide supra).

The resulted cyclobutane would be deprotected using TFA to deliver carboxylic acid moieties, which would then decarboxylate under thermal conditions (Scheme III.64). The ring-opening process might be induced during the decarboxylation step, or later under basic conditions. Deprotonation of the acidic proton αto the malonate unit, might also deliver the corresponding acyclic system through a base-mediated ring opening.

Scheme III.64. Ring-opening strategy of di-t-butyl malonyl cyclobutane through decarboxylation or under basic conditions.

The addition reaction was conducted with di-tert-butyl malonate 323a on cyclobutene 258a, using sodium hydride as a base (Scheme III.65). The Michael product 324a was obtained as a 4.3:1 mixture of two diastereomers, easily separable by column chromatography, in a 75% combined yield.

The stereochemistry of the major component was unambiguously determined using 2D NOESY experiments, while that of the minor product, was obtained after a subsequent transformation. The NMR analyses indicates that the malonyl anion and the proton both adds anti to the bulky silyl ether chain (syn to the small nitrile group). For the minor isomer, the addition of the malonyl is also controlled by the bulky side chain but not the protonation of the enolate.

Scheme III.65. Synthesis of 324a. Reagents and conditions: i) 323a (1.0 eq.), NaH (1.0 eq.), THF (0.1 M), 0 to 20 °C, 4 h.

It was noticed that di-tert-butyl malonate 323a possesses the same retention factor as the major cyclobutane 324a, thus the addition of a slight excess of malonate (e.g., 1.1 eq.) complicates the efficient separation. It is also worth noting that under the above conditions, the reaction proceeds cleanly, and a purification step is generally not necessary. Although the two isomers were separable, the mixture was submitted to the nitrile reduction, using nickel chloride hexahydrate conditions. The reaction afforded the reduced substrate 328 in 40% (combined yield) along with 56% of recovered starting material (Table III.21, entry 1). Cobalt chloride led to the reduced products in 35% yield with a slight loss of material (entry 2). It was suggested that the modest conversion may be related to the steric hindrance on the side of the nitrile group, making the reduction process more challenging.

Nevertheless, in this case, too, both isomers were separable, and the minor diastereomer was analyzed to be (1R,4S)-cis by 2D NOESY NMR. The stereochemistry of its precursor minor-324a may then be assigned the same (1R,4S)-cis, based on the assumption that the Ni2B-mediated reduction occurs without epimerization. The cyclobutane 324a was then submitted to deprotection of the tert-butyl groups using TFA, which led to a mixture of polar products, difficult to identify on the crude 1 H NMR spectrum.

Although the t-butyl groups were clearly cleaved, purification of the crude mixture resulted in the isolation of only traces of unidentified products (Scheme III.66).

Scheme III.66. Deprotection attempt of tert-butyl fragments. Reagents and conditions: i) TFA/CH2Cl2 (1/1), 0 to 20 °C, 4 h.

Alternatively, the base-mediated ring-opening using LDA gave a complex mixture of products (Scheme III.67).

Scheme III.67. Attempt for base-mediated ring-opening of 324a. Reagents and conditions: i) LDA (2.0 eq.), THF (0.1 M), -78 to 20 °C, 23 h.

The difficult isolation of products after the deprotection step of t-butyl groups led to envisage another strategy, using instead a dibenzyl malonate 323b, the hydrogenation of which in the presence of palladium on charcoal, would afford the same diacid without side reactions. As above, the obtained cyclobutane would then be submitted to thermal conditions, to induce decarboxylation and ringopening, directly or by the assistance of a base (Scheme III.68).

Scheme III.68. Ring-opening strategy of dibenzyl malonyl cyclobutane through decarboxylation or under basic conditions.

For this purpose, dibenzyl malonate 323b was added to cyclobutene 258b in the presence of sodium hydride. Four isomers in a 4.5:3.4:1.1:1 ratio were formed in 96% combined yield, (Scheme III.69).

Scheme III.69. Synthesis of 330a. Reagents and conditions: i) 323b (1.0 eq.), NaH (1.0 eq.), THF (0.1 M), 0 to 20 °C, 13 h.

Unlike the former malonyl cyclobutane, these isomers were not separable using the standard column chromatography. Although the 1 H, 13 C, and 2D NMR spectra were clear enough to attribute the signals for each isomer, this was not the case for the correlation assignments by 2D NOESY experiments. The stereochemistry of the compounds was then assigned based on the diethyl malonate analog discussed below.

Similar to what was observed with the t-butyl cyclobutane 324a, the malonyl anion adds syn to the nitrile group, allowing the small-sized proton to approach from both sides of the ring to generate (1R, 4R)-trans-330a and (1R,4S)-cis-330a isomers, with the trans isomer being major. Two other isomers were also observed, albeit in lower amount, the (1S, 4S)-trans-330a and (1S,4R)-cis-330a.

The lack of control at C-1 during the reaction is likely the result of the lower steric hindrance created by the dibenzyl ester units as compared to the t-butyl esters (A-value Ph, 3.0 kcal/mol vs. t-Bu, > 4.5 kcal/mol).

The mixture of diastereomers 330a was deprotected using palladium on charcoal and hydrogen under atmospheric pressure (Scheme III.70). The analytical data showed that the deprotection occurred successfully in a quantitative (crude) yield. The mixture of the carboxylic acids 329b was then heated in toluene or DMF under reflux, leading to a complex mixture of products. 1 H and 13 The ring-opening by the intermediacy of a base was also investigated. However, a complex mixture of products was obtained using LDA as a base and no typical double bond was observed (Scheme III.71). It is also worth noting that the ring-opening of the malonyl cyclobutane 330a through radical fragmentation using SmI2 was also applied, but no reaction occured.

Scheme III.71. Attempt for base-mediated ring-opening of 330a. Reagents and conditions: i) LDA (2.0 eq.), THF (0.1 M), -78 to 20 °C, 20 h.

The 1,4-addition of diethyl malonate 323c on cyclobutene was finally studied, as described above (Scheme III.72).

Scheme III.72. Ring-opening strategy of diethyl malonyl cyclobutane through decarboxylation or under basic conditions.

Under the same conditions as before, the conjugate addition of diethyl malonate onto cyclobutene 258a delivered four diastereomers in a 6.25:4:1.25:1 ratio, and 78% combined yield (Scheme III.73).

With a slight excess of malonate substrate, no separation from the cyclobutane was possible.

However, using a strict stoichiometry, the reaction occurred cleanly, and no further purification was required. The first three diastereomers were separable using column chromatography, while the fourth one was contaminated with a fraction of the third isomer.

Scheme III.73. Synthesis of 332a. Reagents and conditions: i) 323c (1.0 eq.), NaH (1.0 eq.), THF (0.1 M), 0 to 20 °C, 4 h.

The correlation analyses by 2D NOESY experiments indicates that the major diastereomer possesses the (1R,4R)-trans configuration as explained before. The stereochemistry of the second isomer was identified as (1R,4S)-cis by NMR studies. For the other two isomers, the NOESY data confirmed the stereochemistry at the C-1 stereocenter to be 1S. However, the stereochemistry at C-4

was not totally clear, although the HRMS analyses confirmed that these two products are isomers of the first two. Further manipulations below, confirmed the assigned stereochemistry.

With ester 332a in hand, it was envisioned to carry out the cyclobutane ring-opening through a Krapcho deethoxycarbonylation reaction. 348,349 The Krapcho decarboxylation typically involves heating the substrate in a polar aprotic solvent (DMSO…) at high temperature, in the presence of a halide anion source (NaCl, LiCl…) as a nucleophile. The Krapcho's method led to a mixture of inseparable polar products without significant loss of material. The NMR analyses presented a complex profile and the HRMS confirmed the formation of the decarboxylation product 336 by showing a peak with a chemical formula of C14H21O5NNa [M+Na] + and a mass of 306.13084 (Scheme III.74). The mass spectrometry also indicated the presence of 337 with a peak corresponding to a chemical formula of C17H25O7NNa [M+Na] + and a mass of 378.15193. At this point, with a mixture of at least eight products, it was clear that the optimization of the reaction would not be an easy task. Therefore, it was focused on the selective ring-opening through deprotonation to access a compound lacking two stereogenic centers and thus, easier to analyze. The decarboxylation process would then be optimized on a simpler acyclic system.

Scheme III.74. Decarboxylation under Krapcho's conditions. Reagents and conditions: i) LiCl (2.0 eq.), DMSO/H2O: 1/1, 155 °C, 24 h.

Submitting 332a to DBU in dichloromethane did not induce any reaction (Table III The product 338 is obtained as a result of retro [2+2] cycloaddition reaction. This suggests that the deprotonation of the malonyl moiety has occurred, followed by a fragmentation of the cyclobutane ring on the undesired side (Scheme III.75).

Scheme III.75. Formation of 338 through retro [2+2] cycloaddition reaction.

Based on these premises, it was proposed to modify the strategy again and to open the ring after the nitrile reduction, which should produce an amine ready to cyclize and afford a bicyclic system 339 (Scheme III.76). This intermediate would then be manipulated further through decarboxylation and cyclobutane ring-opening to give access to the azabicyclo [3.3.1]nonane skeleton.

Scheme III.76. Alternative ring-opening strategy through nitrile reduction and cyclization.

Conclusion

In the second part of this chapter, studies on cyclobutene/ane ring-opening were performed, leading to an efficient radical fragmentation promoted by SmI2. Enantioenriched γ-nitrile systems bearing a functionalized all-carbon quaternary stereocenter were obtained in good to high yields.

Efforts to remove the sulfone moiety efficiently through Ramberg-Bäcklund reaction were unsuccessful. Alternatively, the sulfonyl group was removed under basic conditions before exploring the ring-opening strategies. Ring-cleavage through ozonolysis, metathesis, or push-pull system was unsuccessful, probably due to the high functionalization of the templates under study, and the presence of a nitrile group as a strong EWG. Transformation of the nitrile into other functionalities did not solve the problem, and the four-membered ring was found inactive towards these strategies.

The addition of different nucleophiles via 1,4-conjugate addition on the cyclobutene carboxylates with the aim of promoting the ring-opening was also deceiving. Apart from its complex and uncommon structure, eucophylline 8 constitutes the southern fragment of the leucophyllidine bis-indole alkaloid 6. As well, it showed high cell viability in J774.1 at a concentration of IC50 7.1 μM. 2 Considering these features, the development of a suitable total synthesis of this strained scaffold was envisioned.

Chapter IV Total Synthesis of (+)-Eucophylline

Reported total syntheses of eucophylline

The first total synthesis of (±)-eucophylline 8 was accomplished by Landais and co-workers 48 in 10 steps and 10% overall yield from α-iodothioester 352 (Scheme IV.3). The installation of the allcarbon quaternary center was based on a free radical three-component carbo-oximation process developed by the group, as the main step. 351 The adduct 353 was subjected to a chemoselective reduction of the thioester group into alcohol, followed by hydrogenolysis and cyclization of the oxime giving the hydroxy-lactam 21. The hydroxyl group was then activated by a mesylate as a leaving group, facilitating the construction of the strained bicyclic lactam 20 after deprotonation of the amide.

The coupling of the bridgehead lactam with benzonitrile 354 under Friedländer conditions afforded the amidine 355 in high yield. The latter underwent cyclization under basic conditions, to provide the amine 356, which proceeded to the triflate 357 by the intermediacy of a diazonium salt. The vinyl fragment was incorporated into the tetracyclic core at this stage through a Suzuki-type coupling, affording 19 in an 80% yield. Final O-demethylation of the aromatic core produced the (±)eucophylline 8 in 87% yield.

Scheme IV.3. Total synthesis of (±)-eucophylline by Landais and co-workers. 48 On the other hand, the first enantioselective total synthesis of (+)-eucophylline was described by Pandey and co-workers 352 (Scheme IV.4). In their strategy, the chiral lactam 358 was subjected to allylic oxidation in the presence of selenium dioxide followed by the protection of the resulting alcohol to give 359 in 68% yield over two steps. The chemoselective reduction of the ester moiety using DIBAL-H provided a mixture of aldehyde and alcohol which was then oxidized with IBX to furnish the aldehyde 360 as a single product. The latter was submitted to dithioacetalization giving the 1,3-dithiane 361, which itself was desulfurized and the amide function reduced to provide the piperidine adduct 362 in 78% yield over two steps. Further manipulation and oxidation afforded the corresponding aldehyde 363 which was engaged in a Friedländer-type reaction. The quinoline adduct 365 was oxidized using m-CPBA to provide the N-oxide derivative 366 in a 99% yield. The latter proceeded with further modifications including a copper-catalyzed intramolecular cyclization to give a crude tetracyclic N-oxide. Upon reaction with an excess of phosphorus oxychloride, it afforded 367 in 45% yield over three steps. The phenol 368 was engaged in a Stille coupling after O-demethylation, to produce the (+)-eucophylline 8 in 88% yield.

Scheme IV.4. Enantioselective total synthesis of (+)-eucophylline, by Pandey et al. 352 The authors noted that the eucophylline synthesis was achieved in 11 linear steps and 7.4% overall yield starting from the lactam 358. But, in this report, it was not taken into account the sequential steps of oxidation and reduction where the crude intermediates were isolated by extraction.

As well, the synthesis begins from the enantiopure lactam 358, which itself was constructed in several steps.

In a previous work of the group, 353 a method was established to install an all-carbon quaternary stereocenter at the C-3 carbon of lactams through a [3,3] sigmatropic rearrangement (Scheme IV.5).

The protected piperidinone 369a was submitted to LiHMDS in the presence of diethyl chlorophosphate to afford the alkylphosphonate 370. The latter was engaged in Horner-Wadsworth-Emmons (HWE) olefination with TBS-protected L-lactaldehyde to furnish the corresponding enone as a mixture of two diastereoisomers 371 and 372. TBS-protecting groups of 371 and 372 were cleaved separately to provide the alcohols 373 and 374 in quantitative yields. These two underwent a [3,3] sigmatropic shift (Johnson-Claisen rearrangement) to furnish the enantiomeric lactams 358 and 375 with excellent yields and enantiomeric excess in four-steps sequence.

Scheme IV.5. Synthesis of enantiopure lactams 358 and 375 through [3,3] sigmatropic rearrangement, by Pandey et al. 353 Based on the abovementioned statements, it is more accurate to report that the synthesis of eucophylline was accomplished in 21 steps and 4.8% overall yield from Bn-protected piperidinone 369a (the protection step of the commercially available 2-piperidinone 376 was not reported in the article, so, the overall yield was calculated starting from 369a).

Retrosynthetic strategy towards the synthesis of (+)-eucophylline

In the course of the studies to synthesize leucophyllidine 6, an asymmetric synthesis of the natural eucophylline 8 was intended. The key feature is the synthesis of an enantiopure 1azabicyclo [3.3.1]nonane nucleus containing the all-carbon stereogenic quaternary center, starting from a cyclobutene backbone.

The beginning of the retrosynthesis would be based on the racemic total synthesis of eucophylline described by Landais et al. 48 The synthesis of eucophylline 8 would rely on the late incorporation of a vinyl substituent through a Suzuki-vinylation process, from the corresponding diazonium salt, triflate or bromide 377 (Scheme IV.6). The 1,8-naphthyridine scaffold of eucophylline would arise from tailoring the ring B, upon base-mediated intramolecular cyclization of an amidine 378. The latter would be produced through a Friedländer-type annulation, after condensation of an ortho-aminobenzonitrile with a bridgehead lactam scaffold, 1-azabicyclo [3.3.1]nonane 20. This amide would ascend from a nucleophilic substitution after the conversion of alcohol 21 into a mesylate. The alcohol 21 would be generated from the cyclobutyl ring-opening of 339a, followed by decarboxylation and reduction of the ester moiety. The aforementioned cyclobutyl lactam 339a would arise from the malonyl cyclobutane 332b after the reduction of the nitrile unit and spontaneous cyclization with an ester fragment. The malonyl cyclobutane 332b itself would derive from the cyclobutene 169g bearing an ethyl side chain, after several transformations.

Scheme IV.6. Revised retrosynthesis of eucophylline through an azabicyclo [3.3.1]nonane intermediate.

Throughout this chapter, the different investigated approaches towards the development of (+)eucophylline alkaloid 8 will be presented, relying on the established method to access the polyfunctionalized cyclobutanes. In parallel, the main highlights on the preparation of the key bridged lactam and the nickel boride reaction will be examined.

Cyclobutane ring-opening through nitrile-reduction, cyclization and decarboxylation

In the last chapter, the development of acyclic chains from cyclobutanes bearing an all-carbon quaternary center, encountered difficulties, mainly due to the presence of a nitrile group.

Alternatively, it was envisioned to open the cyclobutane ring in a different manner, starting from 332a synthesized earlier from the addition of diethyl malonate onto cyclobutene 258a (Scheme IV.7).

Scheme IV.7. Earlier synthesis of diethyl malonyl cyclobutane 332a. Reagents and conditions: i) diethyl malonate (1.0 eq.), NaH (1.0 eq.), THF (0.1 M), 0 to 20 °C, 4 h.

It was reasoned that the malonyl cyclobutane 332 should undergo nitrile reduction using for instance nickel boride catalyst, to deliver an amine group which would react spontaneously with a malonyl ester fragment giving a cyclic lactam fused with the cyclobutane ring 339 (Scheme IV.8). In such case, only the diastereomers with the malonyl substituent in cis with the nitrile group (1R configuration) would undergo cyclization. Since the isomers possessing such configuration are the two major isomers (~ 80% combined ratio), this plan seemed reasonable. The resulting lactam ester 339 would later be decarboxylated under Krapcho's conditions. It is supposed that at this point, the decarboxylation would induce a subsequent cleavage of the cyclobutyl ring, with the release of the total strain as a powerful driving force. Otherwise, the ring-opening would be performed after decarboxylation, using a strong base like LDA. The base would abstract the acidic proton αto the carbonyl, which would then open the four-membered ring leading to an unsaturated cyclic lactam 340. Such moiety, would offer after reduction and cyclization, the azabicyclo [3.3.1]nonane 341, the key core of eucophylline (compound 20 with R = Et). Although this ring-opening strategy would not deliver an acyclic chain as previously planned, at least it would give access to the azabicyclic core, allowing the pursuit of the enantioselective total synthesis of eucophylline.

Scheme IV.8. Ring-opening strategy through nitrile reduction, cyclization and decarboxylation process.

Nickel borohydride-catalyzed reduction of cyano-cyclobutanes

As a first attempt, it was suggested to perform the reduction reaction on the mixture 332a issued from the addition of diethyl malonate to cyclobutene 258a, using the in situ prepared nickel boride (NiCl2.6H2O/NaBH4 in EtOH). Although the major diastereomers cis to nitrile, (1R,4R)-trans-332a and (1R,4S)-cis-332a, were separable by column chromatography, the reaction proceeded with the mixture, as the stereochemistry stereogenic center C-4 has no influence on the final step, and it will be lost upon the ring-opening. The minor trans-C1-C2 isomers (1S,4S)-332a and (1S,4R)-332a were expected to be reduced but not cyclized, giving polar amines. Thus, after the reduction step, the products will be much easier to separate. Based on this rationalization, two sets of products were expected to form, the bicyclic scaffold 339b and the amino-cyclobutane 379a (Scheme IV.9).

Scheme IV.9. Designed reduction reaction of 332a and the expected products.

However, the designed reaction gave a more complex mixture than predicted. Foremost, from the crude mixture of this reaction, a fraction was isolated in a 30% yield (Scheme IV.10).

Surprisingly, it was composed of a mixture of two different and inseparable products in a 70:30 ratio

( 1 H NMR). Based on 1D NMR ( 1 H, 13 C, and 13 C-DEPT-135) and 2D NMR ( 1 H-1 H COSY and 1 H- 13 C HSQC), it was proposed that the major product is the lactam 380a, present as two diastereomers of a 1:1 ratio, with the silyl ether and the two ester groups being left intact. In fact, the 13 C-DEPT-135 analysis of this major product presented signals for eight secondary carbons (CH2) and only one tertiary carbon (CH) instead of three (counting for one diastereomer). Such an observation suggested immediately that the cyclobutane ring has opened. The minor product, however, was most likely to be the bicycle 339b, also as a mixture of four diastereomers. Yet, the analysis of this product was not as clear as for the major one. The mass spectrometry analysis came later to confirm the presence of two products, where the major possesses a chemical formula of C24H45NO6SiNa [M+Na] + and a peak mass of 494.28961 that correspond to the opened ring 380a. Whereas, the minor presents two protons less with a chemical formula of C24H43NO6SiNa [M+Na] + and a peak mass of 492.28949 which correspond to the fused-rings system 339b.

From the reaction mixture, 17% of the starting material were also recovered featuring the major isomer (1R,4R)-trans-332a and the second isomer (1R,4S)-cis-332a in 30 and 70% 1 H NMR ratio, respectively. As anticipated, the minor isomers (1S,4S)-trans-332a, and (1S,4R)-cis-332a were reduced to give the amino-cyclobutane 379a as a mixture of two isomers in a 1:1 ratio ( 13 C NMR), in 16% overall yield. Since the crude NMR was too complex to analyze, the isomers' ratio was calculated after the purification step. The ratio of the amine isomers in the precursor was 1.25:1, slightly different from what obtained after reduction. This difference goes more likely to a possible loss of a small quantity during the treatment and purification step.

Scheme IV.10. Preliminary results of cyclobutane 332a reduction with nickel boride. Reagents and conditions: i) NiCl2.6H2O (1.0 eq.), NaBH4 (7.0 eq.), EtOH (0.07 M).

Based on these results, it was envisioned to optimize the reaction to favor the formation of the desired lactam 380a and drive the reaction into full conversion. As the first way of improvement, the nature of the transition metal salt was questioned, and NiCl2.6H2O was replaced by CoCl2.6H2O. The reaction under such conditions afforded a 6% yield of lactam 380a and cyclobutane 339b in 80:20 ratio, respectively (Table IV.1, entry 2). 37% of the starting material were also recovered as a mixture of the two diastereomers (1R,4R)-trans-332a and (1R,4S)-cis-332a in a 42:58 ratio respectively. The reduced cyclobutane 379a was however obtained in a correct yield of 16%. This result indicates that cobalt boride is a less powerful reductant than its nickel analog, at least in this transformation (entries 1 and 2).

On this basis, the conditions were further optimized using nickel species, changing the nickel source. Khurana and Kukreja observed that nickel chloride hexahydrate was much less efficient than the dehydrated nickel. 325 For this reason, they modified the nickel chloride's surface by drying it in the oven (~ 250 °C) then under vacuum, transforming the green-colored salts into a yellow one. 354

This protocol was followed, and indeed, the color of the salt changed to yellow after dehydration.

Yet, once the modified catalyst was used in the reaction, the lactam 380a and cyclobutane lactam 339b were obtained in a 9% yield, while 17% of the starting material were isolated together with 8% of the amino-cyclobutane 379a (entry 3). Besides the low efficiency of this catalyst, an important loss of material was detected. In fact, in all previous cases, the loss of material was clear (the change of the treatment method: extraction or filtration over celite, did not show a significant improvement of the yield or recovery of the material). It is possible that depending on the nature of the nickel boride nanoparticles, unconsumed starting material may be irreversibly bonded to the catalyst's matrix, or that a large quantity of the substate degraded.

The fact that the nickel chloride's source influences the nature of the formed nanoparticles, inspired testing the commercial anhydrous nickel chloride using the same reduction system.

Interestingly, the yield increased to 53% of lactams 380a and 339b in 75:25 ratio, respectively (entry 4). The starting material was recovered in 23% yield. In this case, no significant loss of material of the major diastereomers was noticed. However, the cyclobutane 379a was isolated in only 5% yield, likely due to its high polarity and difficulties during the isolation step. It is worth adding here that a few milligrams fraction with a polarity between the lactams and the amines was also isolated, the structure of which was too complex to be identified, although few signals relate to the cyclobutane core.

Using unpurified ethanol lowered the yield of lactams 380a and 339b to 46%, and the reduction rate was slightly retarded (entry 5), while the starting material was isolated in 21% yield with 15% of cyclobutane 379a. This observation is in agreement with what reported by Khurana and co-workers, that the use of 95% ethanol decreased the yield of the reaction, and they insisted on working with a dry solvent. This too, shows that the quality of the solvent is a parameter to consider.

Although studying the physical properties of the generated nanoparticles is beyond the purpose of this research, it was suggested to study the influence of the stirring nature on the reactivity of the catalyst. Therefore, after setting up the reaction at 0 °C and warming it gradually to room temperature, the reaction flask was submitted to sweeping using ultrasounds to activate the nanoparticles. After 19 h, the formation of a complex mixture was detected on TLC and by NMR spectroscopy (entry 6).

Besides the mechanical stirring and under ultrasounds for a long period of time, the temperature reached 25-30 °C, which most likely affected the reactivity too. Big-sized black precipitate was also observed indicating the formation of nickel aggregates, which eventually reduced the catalyst's efficiency.

entry salt (eq.) NaBH4 (eq.) time (h) yield % (ratio) a 380a:339b 332a(trans:cis) 379a Next, the time frame was studied; doubling the reaction time did not help to fully convert the starting material, which was recovered in 27% yield as a mixture of (1R,4R)-trans-332a and (1R,4S)cis-332a in 30:70 ratio, while cyclobutane 379a was isolated in 7% yield (entry 7). Lactams were isolated in 50% combined yield and surprisingly, in > 95% ratio of the lactam 380a. Only traces of the cyclobutane lactam 339b were detected through 1 H NMR spectrum. Such a result suggests that the reduction step precedes the ring-opening. In addition, if the cyclobutane ring-opening occurred first, reduction of the nitrile into an amine could be followed by reaction with the ester function at C-experiments (such as in entry 4), the shorter reaction time led to a mixture of the cyclized lactams with or without the cyclobutane ring-opening. These data were supported by another experiment where the same result was observed; with a reaction time of ~ 22 h (on 0.29 mmol scale), a mixture of the closed-and opened-ring compounds was formed. The re-submission of this fraction to the nickel boride reducing system, gave the ring-opened lactam in a quantitative yield. This confirms that the reducing system induces the ring-opening of the cyclobutane.

In contrast, this shows that the reaction time had no influence on the full conversion of the starting material under these conditions. Thus, it was looked carefully at the amount of nickel salt present in the reaction mixture, because of the inherent instability of nickel boride. To confirm this, an experiment was conducted using 2.2 eq. of NiCl2. A large quantity of the starting material was reduced and only 8% were recovered (entry 8). The cyclobutane 379a itself was isolated in 14% yield.

While the lactams 380a and 379b were isolated in 52% yield, unexpectedly, in a 70:30 ratio. This indicates that not only time is important for the ring-opening to occur, but also the nature of the nickel boride nanoparticles. Many groups pointed out the influence of the stoichiometric ratio of NiCl2/NaBH4 on the reaction's result. 320 It is believed that at a specific stoichiometry, the active nickel boride nanoparticles are formed. Thus, it was decided to increase the quantity of sodium borohydride to 20 eq. to have a large excess of hydride and boron source in the medium, and compensate for the catalytic decomposition of the borohydride by the newly-formed nickel boride. Such conditions allowed obtaining the lactam 380a in 54% yield with only traces of the lactam 339b, yet, the full conversion of the starting material was not observed and 6% were recovered (entry 9). From the reaction mixture, cyclobutane 379a was also isolated in 6% yield.

Increasing the amount of nickel chloride to 3 eq. to fully convert the starting material, led a complex mixture after 19 h (entry 10). At this point, it was decided to find out unambiguously whether the isomer (1R,4S)-cis-332a endures full reduction or not. The isolated diastereomer (1R,4S)-cis-332a

was submitted to the reduction system used in entry 9, in the presence of 2.2 equivalents of NiCl2.

After 27 h of reaction, the opened product 380a was obtained in 36% yield, as a mixture of 2 isomers in a ratio of 1:1 (data not shown). 43% of the starting material were also recovered. This confirms that this isomer is prone to reduction albeit in a much slower rate.

Knowing that it is possible to reduce the isomer (1R,4S)-cis-332a allowed the pursuit of the optimization. It was proposed that by changing the size of the nickel boride nanoparticles or improving their dispersity, these particles would be able to reduce the cyclobutane ring. For this reason, the concentration of the medium was questioned since such a factor would eventually change the dynamic of the medium and then, the nature of the particles. 355 Thus, the reaction concentration was lowered to 0.025 M, and indeed, a full conversion of the starting material occurred (entry 11).

Under these conditions, the major isomers were fully transformed into the lactam 380a in a 60% yield, while the minor isomers produced 13% of the amino-cyclobutane 379a. In general, a concentration between 0.02 and 0.03 M was found to be optimal for this reaction.

For comparison, cobalt chloride was utilized again under the optimized conditions; a considerable difference in reactivity was noticed. Only 4% of the lactam 380a were isolated together with 56% of the starting material (entry 12). The latter showed the presence of both major diastereomers in approximately the same ratio (56:44), and a small quantity of the minor isomers was present. The reduced cyclobutane 379a itself was isolated in 6% yield. The fact that 380a was detected, indicates that the cobalt boride is also capable of opening the cyclobutane ring after the cyclization step, albeit in a much less efficient manner.

Finally, the original conditions with 1 eq. of NiCl2 were repeated in a 0.025 M concentrated medium (entry 13). Compared to entry 7, the lactams 380a and 339b were isolated in a similar yield of 52%, however, the ring-opening was less efficient giving both products in 82:18 ratio. In contrast, the isomer cis (1R,4S)-332a was almost completely reduced and only 3% were recovered, as compared to 27% with 0.07 M concentration. Cyclobutane 379a was also isolated in a higher yield of 16%.

During these investigations, the precursors were purified before use, but, for later studies, it was observed that using the crude precursor had no effect on the efficiency of the reaction. Based on observations in manipulating heterogeneous catalysis, the reactions were performed from the beginning under good stirring to prevent the formation of aggregates. Sodium borohydride was the last reagent to add to the reaction mixture, which is already set at 0 °C. The formation of the characteristic borides is exothermic, and usually, it is accompanied by vigorous H2 evolution. When the reaction was carried out on a large scale (2.0-4.5 mmol), NaBH4 was added slowly for 15-20 minutes, and the reaction was set up at 0-5 °C for at least 1 hour even if no more bubbling was observed. If not, the temperature rises and an explosion happens (violent reaction).

This work advocates the statements in the literature 320,356,357 that this reaction needs to be studied carefully, as a parameter may change the behavior of the reducing agent. Yet, this also leaves a possibility to inspire new transformations using transition metals/borohydrides to access new frameworks in an efficient way. The work on the ring-opening showed how this process is highly related to the substrate's structure and to different other factors at the same time.

Finally, for comparison consideration, the cyclobutane 332a was submitted to hydrogenation under 20 atm using Raney ® -nickel in ethanol. This reaction resulted in recovery of the starting material, and no conversion was observed (data not shown). Such an outcome is in agreement with the claimed higher reactivity of nickel boride compared to Raney ® -nickel. 358

Reported nickel boride-mediated ring-opening

Two months after establishing this reaction, an interesting article came to light. 359 The report describes the cyclopropane ring-opening of cyclopropane-fused benzomorphan substrates 381, by the intermediacy of nickel boride (Scheme IV.11). Depending on the substitution present on the molecule (oxo or thio), a selective opening of the cyclopropane ring was observed. This method gave access to fused indenopiperidine and bridged benzomorphanone derivatives 382 and 383 starting from oxo and thio analogs of 381, respectively. The authors mentioned that the cyclopropane ring-opening was found to be a combination of electronic effects and ring tensions resulting from the bridged structures, which constitute a powerful driving force towards this end. Remarkably, this reaction was performed in a concentration range of 0.026-0.033 M, the same range that was found optimal for the reduction of cyclobutanes with nickel boride.

Scheme IV.11. Cyclopropane ring-opening in oxo and thio benzomorphan derivatives, with nickel boride. 359

Attempts to access mono-ester lactams

Although the diester lactam 380a was obtained in an efficient cascade sequence, this, however, requires removal of the ester αto the amide to further access the final target. Thus, it was suggested that the 1,4-addition of an ethyl acetate fragment on the cyclobutene carboxylate 258 would shorten the sequence (Scheme IV.12). Moreover, the outcome of this reaction would provide insights into the role of the ester αto the amide in lactam 380a above.

Scheme IV.12. Strategy towards the synthesis of a mono-ester lactam backbone.

Foremost, an attempt to add an ethyl acetate anion to the enone 258b was investigated using Lithium tetramethylpiperidide (LiTMP) as a non-nucleophilic base (Scheme IV.13). However, after 24 h of reaction, no conversion was observed and the starting material was recovered unchanged.

Scheme IV.13. Preliminary attempt for ethyl acetate addition onto enone 258. Reagents and conditions: i) EtOAc (2.0 eq.), LiTMP (2.0 eq.), THF (0.1 M), 0 to 20 °C, 24 h.

It was then proposed that such a scaffold could be accessed through the Mukaiyama version of the Michael reaction. 360 It was believed that the cyclobutene 258b could be activated by coordination of a strong Lewis acid with the carbonyl functional group, facilitating the nucleophilic attack of the ketene silyl acetal 386, and delivering the corresponding Michael adduct 333a (Scheme IV.14). The use of titanium tetrachloride as the Lewis acid, however, did not provide any reaction even after several days, and the starting material was recovered (Scheme IV.14, entry 1). Similarly, no reaction occurred using indium trichloride 361 in a solvent or under neat conditions (entries 2 and 3). These results correlate with what was observed during the studies on the "push-pull" system, and it is possible that these pseudo-acidic conditions are not strong enough to activate the enone 258b. Thus, this strategy was not investigated further.

Scheme IV.14. Attempts for ethyl acetate addition onto enone 258b through Mukaiyama-Michael reaction.

Reagents and conditions: 386 (2.0 eq.), LA (0.2 eq.), CH2Cl2 (0.1 M).

Synthesis of bicyclic lactam model bearing a protected alcohol chain

Considering the above failure, it was decided to work on diester 380a, and more precisely on the decarboxylation of the β-amidoester. The Krapcho conditions 348,349 led only to traces of the product with other degradations (Scheme IV.15).

Scheme IV.15. Application of Krapcho's conditions to lactam 380a. Reagents and conditions: i) LiCl (2.0 eq.), DMSO/H2O, 155 °C, 18 h.

During their work on the total synthesis of aspidophytine, Padwa and co-workers also observed unsatisfying results and low yields using Krapcho's conditions. 362 Instead, they heated an advanced intermediate in refluxing wet acetonitrile in the presence of MgI2, playing with the chelating properties of Mg(II) cations. 363 Unfortunately, when applied, Padwa's protocol led to no reaction and the starting material was recovered (Scheme IV.16).

Scheme IV.16. Application of Padwa's conditions to lactam 380a. Reagents and conditions: i) MgI2 (3.0 eq.), wet CH3CN (0.05 M), 82 °C, 23 h.

Alternatively, it was suggested to submit the diester 380a to basic hydrolysis, generating a carboxylic acid next to the carbonyl, which would undergo decarboxylation once heated (Scheme IV.17). A selective mono-saponification was however anticipated to be challenging as shown below.

Scheme IV.17. Alternative hydrolysis and decarboxylation plan.

Thus, submitting the amide 380a to 1 equivalent of lithium hydroxide led to various products, suggesting that the saponification occurred on both sites, giving a mixture of mono-and dicarboxylic acids in addition to the remaining starting material. Although these products were not isolated, the addition of another equivalent of LiOH to the reaction mixture converted the majority of the remained esters into the dicarboxylic acid. The NMR showed that a small quantity of ester signals was still present in the mixture.

Therefore, the saponification was repeated in the presence of an excess of lithium hydroxide, to afford the dicarboxylic acid 388a as a very polar product in 90% crude yield on a 2 mmol scale (Scheme IV.18). The extraction was eventually optimized to furnish 388a in an optimal and clean manner. The crude dicarboxylic acid 388a was then heated in THF to afford the monocarboxylic acid 389a in a quantitative yield. It is worth noting that 389a was isolated by simple evaporation of THF and dryness under vacuum. A temperature of 70 °C was found to be ideal to afford the desired scaffold in a clean manner and complete conversion after 0.5-4 h, depending on the scale. If the heating proceeded for a long time (e.g., > 24 h) degradation of the substrate was observed. Other solvents such as toluene or m-xylene afforded the desired product but less cleanly. Refluxing dichloromethane, however, did not succeed at decarboxylating the substrate 388a.

Scheme IV.18. Saponification and decarboxylation of diester 380a. Reagents and conditions: i) LiOH (5.0 eq.), EtOH/H2O: 4/1, 20°C, 12 h; ii) THF (0.08 M), 70 °C, 3 h.

Once decarboxylated, the cyclic lactam 389a was submitted to chemoselective reduction conditions in the presence of the amide functionality. At first, reducing the acid group into alcohol using the borane-THF complex gave only traces of the desired product (Table IV.2, entry 1).

Increasing the temperature did not give better results even after 18 h (entry 2). With LAH solution, 31% of the desired alcohol were isolated (entry 3). However, when diethyl ether was used instead of THF as a solvent, the yield decreased to 21% (entry 4). Although the desired product was successfully obtained, with such a low yield the transformation was not considered efficient. The product issued from decarboxylation was then submitted to a fast esterification using (trimethylsilyl)diazomethane, to regenerate the alkylated ester in a quantitative yield (Scheme IV.19).

The ester 391 was then reduced with LAH in THF to afford the alcohol 390a in 91% crude yield.

Performing the reaction in diethyl ether as the solvent, under the optimized conditions, gave the hydroxy-lactam 390a in 45% yield. Although organoboranes such as NaBH4 and LiBH4 were described to selectively reduce esters into alcohol, no reaction was observed with these reagents even after 18 h. The reported yields describe the results after optimization of the extraction protocol (details in the experimental part). Most importantly, these reactions were clean and no purification was needed to pursue the following steps.

Scheme IV.19. Esterification and reduction of 389a into alcohol. Reagents and conditions: i) TMSCHN2

(1.5 eq.), CH2Cl2/MeOH: 5/1 (0.12 M), 0 to 20 °C, 1 h; ii) LAH (1.25 eq.), THF (0.02 M), 0 to 20 °C, 8 h.

It is worth mentioning that the decarboxylation-esterification-reduction process was performed by subsequent addition of reagents/concentration of solvents in a one-pot fashion without any isolation of the reaction intermediates. Thus, this sequence was considered as a one-step transformation.

The free alcohol 390a was then activated by introducing a mesylate as a leaving group, in a quantitative yield (Scheme IV.20).

Scheme IV.20. Activation of free alcohol 390a by mesylate. Reagents and conditions: i) MsCl (1.2 eq.), Et3N (2.0 eq.), CH2Cl2 (0.09 M), 0 to 20 °C, 6 h.

This group was then submitted to displacement under the commonly reported conditions. 364,365 However, no reaction was observed in DMF at room temperature (Table IV.3,entry 1). When heated at 40 °C, a partial conversion occurred to deliver the bicyclic lactam 341a in 10% yield (entry 2).

Heating at a higher temperature did not lead to a better conversion, and 341a was isolated in a 6% yield (entry 3). Changing the solvent to THF did not produce any conversion at room temperature (entry 4), while under reflux, a decomposition of the substrate took place (entry 5 This bridgehead amide (also called anti-Bredt molecule) possesses an oily aspect at room temperature but it solidifies in the freezer, a characteristic that was observed with the derivatives of this molecule. 366 The infrared spectrum showed a sharp, strong carbonyl absorption (stretching υC=O) at 1684 cm -1 , while the 13 C NMR for the carbonyl carbon at 184.7 ppm indicates that this lactam 341a has a moderate distortion of the amide bond, as observed for the twisted amides reported by Buchanan and co-workers. 367

Synthesis of bicyclic lactam model bearing a propyl chain

Based on the results discussed above, another cyclobutene model was manipulated to confirm the efficiency of the developed strategy. The cyclobutene 258b bearing a propyl side chain was submitted to 1,4-conjugate addition of diethyl malonate to deliver the cyclobutane 332c in a quantitative yield (Scheme IV.21).

Scheme IV.21. Conjugate addition on cyclobutene 258b. Reagents and conditions: i) 323c (1.0 eq.), NaH (1.0 eq.), THF (0.1 M), 0 to 20 °C, 5 h.

The cyclobutyl malonate 332c was then submitted to the nickel boride's optimized conditions, to afford the lactam 380b in 75% yield on a 4 mmol scale, alongside with the amine 379b in 10% yield (Table IV.3, entry 1). To confirm whether the medium's concentration would have an effect on the reduction reaction of this model, the reaction was performed in a 0.07 M solution of ethanol. As expected, the products 380b and 379b were isolated in 44 and 10% yields respectively, altogether with the minor diastereomer (1R,4S)-cis-332c, which was recovered in 10% yield (entry 2). This transformation is thus relatively independent of the steric hindrance that might be created by the cyclobutane's side chain.

entry concentration time (h) yield (%) The lactam 380b was then saponified to give the carboxylic acid 388b in 80% crude yield (Scheme IV.22). This product was decarboxylated in refluxing THF to afford 389b in a quantitative yield. Subsequent modification afforded the ester 391b also in a quantitative crude yield, which was then reduced by LAH into the alcohol 390b in 74% yield. Finally, the alcohol was activated into a better leaving group by the incorporation of a mesylate fragment, giving the mesylate lactam 392b in a quantitative crude yield.

1 0.025 M 70 380b (
Scheme IV.22. Sequential synthesis of mesylate 392b. Reagents and conditions: i) LiOH (5.0 eq.), EtOH/H2O: 3/1 (0.15 M), 20 °C, 12 h; ii) THF (0.08 M), 70 °C, 3 h; iii) TMSCHN2 (1.5 eq.), CH2Cl2/MeOH: 5/1 (0.12 M), 0 to 20 °C, 1 h; iv) LAH (1.25 eq.), THF (0.1 M), 0 to 20 °C, 3 h; v) MsCl (1.2 eq.), Et3N (2.0 eq.), CH2Cl2 (0.05 M), 0 to 20 °C, 6 h.

Finally, the mesylate 392b was submitted to nucleophilic substitution in the presence of sodium hydride. When DMF was used, a partial conversion was observed at room temperature after 24 h (Table IV.4, entry 1). When the temperature was increased to 70 °C, a full conversion was observed after 10 h, and 341b was isolated in 15% yield after column chromatography. The reaction was then repeated by heating directly at 70 °C. The full conversion was observed after 14 h and the purification was carried out using neutralized silica gel to isolate 40% of the bicyclic lactam 341b over 4 steps (entry 2). When using THF as the solvent, no reaction occurred at room temperature (entry 3) nor at reflux (entry 4), and the starting material was recovered unchanged. This anti-Bredt molecule possesses a low melting point as observed with lactam 341a. The infrared spectrum showed a sharp, strong carbonyl absorption (stretching υC=O) at 1682 cm -1 , and the 13 C NMR for the carbonyl carbon at 184.7 ppm indicates too, that 341b has a moderate distortion of the amide bond with a twist angle (τ) ≈ 20°.

Synthesis of bicyclic lactam model bearing an ethyl side chain

To apply this developed method to the synthesis of eucophylline, a bicyclic lactam 20 bearing an ethyl side chain has to be synthesized (Scheme IV.23). This would arise from cyanosulfone 181q

with the installed quaternary center after submitting the cyclobutene 169g to the sulfonyl-cyanation reaction. The cyclobutene bearing the ethyl side chain itself has to derive from the [2+2] cycloaddition of N-acyloxazolidinone with alkyne sulfide 112h. The latter would be obtained from the corresponding alkyne, but-1-yne 33.

Scheme IV.23. Possible alkyne precursor necessary for the synthesis of eucophylline. X = oxazolidinone.

Since but-1-yne is a gas at room temperature (boiling point: ~ 8 °C), the reaction previously applied to introduce a thiomethyl fragment into alkynes was modified using but-1-yne in excess (~ 3 eq.) (experimental part). The expected product was isolated after distillation in 33% yield as a colorless liquid with a low boiling point (Scheme IV.23). The low yield was related to the traces of water possibly present in the medium, which quench the organolithium reagent. When lower stoichiometry of but-1-yne was used, only traces of the desired product were obtained.

Scheme IV.23. Synthesis of butyne sulfide 112h from but-1-yne. Reagents and conditions: i) 1. But-1-yne (3.0 eq.), n-BuLi (1.06 eq.), THF (0.65 M), 0 °C, 30 min; 2. Me2S2 (1.0 eq.), 20 °C, 2 h.

Further optimization of this method was not possible due to the lack of additional supply of but-1-yne. In fact, this reagent is highly expensive (CAS: 107-00-6; Sigma Aldrich supplier; 646 €/100 g), which restricted its use. Thus, a cheaper method was developed.

Corey and Fuchs transformed aldehydes 173 by chain extension into dibromo olefins 393 using carbon tetrabromides and triphenylphosphine (Scheme IV.24). 368 The brominated substrates are then transformed into lithium acetylides 394 in the presence of 2 equivalents of n-BuLi. Such intermediates could be transformed into the corresponding terminal alkynes 104 by quenching 394 with water, or into acetylene carboxylic acids 395 under CO2 atmosphere.

Scheme IV.24. Synthesis of acetylene derivatives from aldehydes.

Based on this report, it was proposed that the organolithium intermediate would react with dimethyl disulfide to generate the desired butyne sulfide. This approach was applied to propionaldehyde 173a to generate 1,1-dibromobut-1-ene 393a in a 67% yield (Scheme IV.25). The latter was then submitted to an excess of n-BuLi to generate the butynyl-lithium intermediate which was quenched in situ with dimethyl disulfide, furnishing the thiomethyl butyne 112h in 80% yield.

This reaction was repeated several times to give the butynyl derivative in 60-80% yield range.

Scheme IV.25. Synthesis of butyne sulfide 112h from propionaldehyde. Reagents and conditions: i) CBr4 (2.0 eq.), PPh3 (4.0 eq.), CH2Cl2 (0.22 M), 0 to 20 °C, 3 h; ii) 1. n-BuLi (2.3 eq.), THF (0.65 M), -78 °C, 1 h, then 20 °C, 1 h; 2. Me2S2 (1.0 eq.), 0 to 20 °C, 2 h.

After succeeding at developing a reliable method for the synthesis of butyne sulfide 112h, this alkyne was engaged in a [2+2]-cycloaddition with N-acyloxazolidinone, to deliver the chiral thiomethyl-cyclobutene 117h bearing an ethyl side chain, in a quantitative yield (on ~ 18 mmol scale)

and an excellent enantiomeric excess of 99% (Scheme IV.26). The cyclobutene was then submitted to reduction under the optimized conditions with Lindlar's catalyst, furnishing the cyclobutene 169g in 94% yield on a 10 mmol scale (84% yield on a 19 mmol scale after 24 h of reaction). In fact, when the reaction was left after full conversion for a longer time, traces of over-reduced cyclobutane were observed, which was not the case in previous examples. This could be rationalized by the small size of the ethyl chain, which favors the over-reduction step. This undesired transformation could be controlled when necessary, by diluting the reaction's concentration, adding more equivalents of oct-1-ene, or simply by stopping the reaction directly once finished.

The synthesized cyclobutene 169g was then engaged in the p-anisaldehyde catalyzed sulfonylcyanation to deliver the cyclobutane 181q in high yield (on a 15 mmol scale) and diastereoselectivity.

Interestingly, in the schlenk tube used for the reaction, the sulfonyl-cyanation product was formed as a white precipitate. Hence it was isolated from the reaction mixture by simple washing. This product was found insoluble in several solvents except dimethyl sulfoxide (and as traces in dichloromethane).

It is interesting to notice how this molecule (melting point = 267 °C) has very different physical properties compared to the cyclobutane 181b with only one carbon more on the side chain (melting point = 70 °C).

Scheme IV.26. Synthesis of highly functionalized cyclobutane 181q. Reagents and conditions: i) 3acryloyloxazolidin-2-one (1.0 eq.), (R)-115 (0.11 eq.), TiCl2(OiPr)2 (0.1 eq.), toluene (0.25 M), 4 Å MS, 0 to 20 °C, 24 h; ii) Lindlar's catalyst (1.0 eq.), Et3SiH (7.0 eq.), oct-1-ene (1.0 eq.), acetone (0.3 M), 50 °C, 16 h; iii) MeSO2CN (2.0 eq.), p-anisaldehyde (0.2 eq.), CH3CN (1.5 M), 325-400 nm, 48 h.

The cyclobutane 181q was then transformed by transesterification into cyclobutane carboxylate 260c in a quantitative yield (Scheme IV.27). Interestingly, the starting material was not soluble in ethanol even at reflux. Decreasing the reaction concentration to 0.02 M or adding a 3/1 mixture of EtOH/DMF or CH2Cl2 did not help to solubilize the product or to accelerate the reaction. Anyway, the transformation occurs in a heterogeneous mixture to deliver the desired soluble product after 48 h. The ester 260c was then desulfonylated under Cs2CO3 conditions to generate the cyclobutene carboxylate 258c in a 90% yield. Unlike the other cyclobutene carboxylates 258a and 258b, this product was found unstable and decomposes at room temperature after several hours. Once the product was formed, it was thus purified on short column chromatography then submitted to the next transformation without the need for storage.

Scheme IV.27. Synthesis of cyclobutene carboxylate 258c. Reagents and conditions: i) DMAP (0.5 eq.), EtOH (0.09 M), 78 °C, 48 h; ii) Cs2CO3 (2.0 eq.), DMF (0.2 M), 70 °C, 13 h.

The addition reaction of diethyl malonate on the Michael acceptor 358c occurred smoothly to afford the cyclobutane 332b in 95% as a mixture of four diastereomers (Scheme IV.28). Such reaction was very clean and there was no need for purification of the crude reaction mixture. In fact, the same yields were obtained with or without purification.

Scheme IV.28. Conjugate addition on cyclobutene 258c. Reagents and conditions: i) diethyl malonate (1.0 eq.), NaH (1.0 eq.), THF (0.1 M), 0 to 20 °C, 3 h.

2 mmol of malonyl-cyclobutane 332b were then submitted to the reduction/cyclization/ringopening sequence under the optimal nickel boride conditions, to give the cyclic lactam 380c in 68% yield together with the reduced cyclobutane 379c in 10% yield (Scheme IV.29).

Scheme IV.29. Synthesis of cyclic lactam 380c using nickel boride. Reagents and conditions: i) NiCl2 (2.2 eq.), NaBH4 (20.0 eq.), EtOH (0.025 M), 0 to 20 °C, 70 h.

The cyclic lactam 380c was then transformed through the above straightforward sequence into the bicyclic lactam 20 (Scheme IV.30). The saponification reaction gave the diacid 388c in a 91% yield. In the first run, by using the same extraction method as before, 388c was isolated in 40% yield.

The re-extraction of the aqueous phase succeeded at isolating 50% of the product. This observation suggests that this product is much more polar than the other synthesized lactams 388a and 388b.

Hence, the extraction method was optimized again, to deliver the expected yields in other runs. In refluxing THF, the decarboxylation occurred smoothly to give the desired lactam carboxylic acid 389c in a quantitative yield. This was then esterified quantitatively in a one-pot process, followed by the ester reduction to afford the alcohol 21 in 98% under the optimized treatment. The alcohol was then activated to give the mesylate 392c in quantitative yield.

Scheme IV.30. Preparation of mesylate lactam 392c. Reagents and conditions: i) LiOH (5.0 eq.), EtOH/H2O: 4/1 (0.15 M), 20 °C, 4 h; ii) THF (0.08 M), 70 °C, 3 h; iii) TMSCHN2 (1.5 eq.), CH2Cl2/MeOH: 5/1 (0.12 M), 0 to 20 °C, 1 h; iv) LAH (1.25 eq.), THF (0.035 M), 0 to 20 °C, 12 h; v) MsCl (1.1 eq.), Et3N

(1.1 eq.), CH2Cl2 (0.07 M) , 0 to 20 °C, 3 h.

The mesylate 392c was later submitted to nucleophilic substitution with sodium hydride in DMF.

In contrast to what was observed with the other lactams, the reaction occurred at room temperature to give the bicyclic lactam 20 in 50% yield over four steps starting from 380c (the transformation from 388c to 21 is considered as one step since the intermediates were not isolated), and in an excellent enantiomeric excess as shown by HPLC analysis (Scheme IV.31). This reaction was repeated several times to give the bicyclic lactam in 30-50% yield range over four steps.

Scheme IV.31. Synthesis of bicyclic lactam 20. Reagents and conditions: i) NaH (1.5 eq.), DMF (0.1 M), 0 to 20 °C, 12 h.

This sequence could certainly be shortened to some extent, for example, by performing a onepot transesterification-sulfone elimination using K2CO3 in ethanol, or by reducing the carboxylic acid directly into alcohol. However, the present sequence offers much better yields and reproducibility, with minimum purification steps and time consumption. Therefore, this sequence gives a straightforward access to strained chiral azabicyclo [3.3.1]nonane derivatives with different side chains. The bicyclic lactam 20 was obtained in 11 steps starting from 1,1-dibromo but-1-ene 393a in ~ 15% overall yield. While the racemic bicyclic amide reported by Landais et al. 48 was obtained in 4 steps and 31% overall yield. The full analyses of the bicyclic lactam were in good agreement with those reported for the racemic template.

This twisted amide possesses an oily aspect at room temperature and solidifies in the freezer. So, it could not be recrystallized to be analyzed by X-ray diffraction studies. The infrared spectrum showed a sharp, strong carbonyl absorption (stretching υC=O) at 1676 cm -1 , and the 13 C NMR for the carbonyl carbon at 184.8 ppm indicate that 20 has a moderate distortion of the amide bond. Hall et al. 366 reported that these lactams are hydrolyzable in water and polymerize on standing. Indeed, when leaving lactam 20 for weeks on the bench, decomposition started to occur.

Construction of the tetracyclic scaffold of eucophylline

The construction of the tetracyclic template of eucophylline from a bicyclic lactam would be achieved through a Friedländer-type annulation from an aniline derivative. Such a strategy could take place through two pathways, allowing the installation of a vinyl fragment on the tetracyclic core at an early-or a late-stage (Scheme IV.32). A propenylaniline 396a for example, would be condensed with the bridgehead lactam 341 in the presence of a dehydrating agent to deliver the amidine intermediate 397 holding the vinyl fragment. This intermediate would undergo dehydration to deliver the methoxy-eucophylline core 398 in situ in a one-pot process, or in a two-steps sequence.

Alternatively, a POCl3-assisted annulation would proceed with the aminobenzoic nitrile 354 to give the amidine nitrile intermediate 399, which would follow further treatment to allow the cyclization and the vinyl unit incorporation at a later stage.

Scheme IV.32. Proposed pathways to access the eucophylline tetracyclic backbone, with possible incorporation of the vinyl unit at an early-or a late-stage.

Construction of tetracyclic scaffold using ortho-propenylanilines

The first envisioned pathway consists of installing the vinyl group on the aromatic backbone at an early stage. For this, the ortho-propenylaniline precursors were synthesized as a first step. The nitro benzaldehyde 400 was subjected to Grignard reaction using vinyl magnesium bromide as the reagent, to deliver the desired Grignard adducts 401a and 401b in high yields (Scheme IV.33). [369][370][371] The reduction of the nitro group was accomplished using zinc dust, giving 396a and 396b in 75 and 98% yields respectively. 372 Product 396b was found to be more sensitive and prone to degradation than 396a.

Scheme IV.33. Synthesis of propenylaniline derivatives. Reagents and conditions: i) vinyl magnesium bromide (1.5 eq.), THF (0.23 M), -78 to 20 °C, 12 h; ii) Zn dust (15.0 eq.), NH4Cl (5.0 eq.), EtOH/H2O: 4/1 (6.0 M), 20 °C, 7-12 h.

With the propenylaniline 396a in hand, the POCl3-assisted Friedländer reaction was performed using the bridged lactam 402 373 as a model. Under such conditions, only the α-chloroenamine 405 was isolated in 15% yield (Table IV.5, entry 1). This unusually stable chloroenamine was observed by Landais et al. as the intermediate of the Friedländer annulation and was fully analyzed and characterized. 48 Although the POCl3-assisted condensation was found by the group to be optimal to favor the amidine synthesis, it was intended to investigate once more the reactivity of the bridged lactam, and the possibility to induce the condensation with the aromatic aniline.

The formation of the quinoline backbone was well reported through the modified Friedländer annulation, especially in the studies of camptothecin synthesis. 374 Thus, adding 4 Å molecular sieves as a dehydrating agent to drive the equilibrium towards the product formation, led to the decomposition of 396a, while the bicyclic lactam remained intact (entry 2). In the presence of a Brønsted acid such as p-toluenesulfonic acid, anilines are condensed with ketones to deliver quinoline templates, 375 however, with the bicyclic lactam, such conditions did not work and only the decomposition of the propenylaniline was observed (entry 3). Based on this, it is clear that the propenylaniline does not survive in dehydrating or acidic conditions. entry reagents (eq.) solvent a temp (°C) yield (%)

Construction of tetracyclic scaffold using amino benzonitrile 354

After failing at developing a short pathway to access the vinyl tetracyclic core, it was planned to make the aminoquinoline instead, and incorporate the vinylic fragment at a later stage. The POCl3assisted Friedländer reaction gave the amidine target 399a in a high yield of 73% after a basic workup (Scheme IV.34). The connection between the rings was then achieved under t-BuOK conditions to deliver the amino-tetracyclic product 406 in a 78% yield.

Scheme IV.34. Synthesis of amino-quinoline 406. Reagents and conditions: i) 354 (1.5 eq.), POCl3 (1.1 eq.), CH2Cl2 (0.05 M), 60 to 50 °C, 24 h; ii) t-BuOK (2.7 eq.), THF (0.05 M), 0 to 20 °C, 15 h.

Pathways towards the vinyl-quinoline construction from the amine precursor

With the amino-naphthyridine 406 in hand, the incorporation of a vinylic fragment was planned relying on a Suzuki-type coupling. 376 Considering the poor nucleophilicity of the amino group, the amine fragment has to be transformed into a better leaving group such as a diazonium (Scheme IV.35). In the reported racemic synthesis of eucophylline, this diazonium was first converted into an alcohol then a triflate, which was finally engaged in the Suzuki coupling to incorporate the vinyl substituent. An alternative pathway to access the vinyl-quinoline template might proceed through the corresponding bromo-quinoline intermediate, generated in situ from the diazonium salt.

Scheme IV.35. Possible pathways to access vinyl-quinoline 398a through a diazonium intermediate.

Incorporation of the vinyl fragment through a diazonium salt

The generation of a diazonium salt is possible through a reaction of aromatic amines with nitrites (NaNO2) or alkyl nitrites (t-BuONO, isoamylONO). The arenediazonium salts such as 410, can undergo Pd-catalyzed cross-coupling delivering complex 411 (Scheme IV.36). This can be effectively functionalized with palladium species, after the loss of nitrogen gas. 377 Counter-anions were described to play an important role in the stability of the diazonium salt; 378-380 for instance, counter-anions with low nucleophilicity such as tetrafluoroborate and hexafluoroborate among others, are often used as they can be isolated and manipulated without risk of explosion or decomposition.

Scheme IV.36. Palladium-catalyzed cross coupling through diazonium salts.

Based on this, the first efforts were directed towards the isolation of diazonium salts containing tetrafluoroborates as counter-anions. Using a t-BuONO/BF3.OEt2 mixture in an organic solvent such as CH2Cl2, a characteristic red-colored diazonium salt was isolated after filtration (Table IV.7, entry 1). The infrared spectrum showed a weak peak at 2259 cm -1 (the typical peak of a diazo fragment is usually observed between 2250 and 2290 cm -1 ). 381 Other analytical data showed, however, that the obtained product might be the protonated amino-quinoline which was isolated in 85% yield. In fact, the HRMS analysis detected a product with a chemical formula C16H20ON3Na that corresponds to [M+Na+H + ] and a mass of 293.12559. Such a result suggests that the structure 413 was probably obtained since the nitrogen center on the quinoline is the most basic site of the molecule (based on DFT calculations), yet, the structure needs to be confirmed. The obtained salt was soluble only in methanol, and the 1 H and 13 C NMR spectra were in agreement with the proposed structure. After a basic workup (sat. NaHCO3) the starting material was recovered, confirming that only protonation occurred during this reaction.

Since only a small peak characteristic of a diazonium was observed by IR, it was suggested that probably this signal is a mere artifact or only a small quantity of the diazonium was formed. To favor the formation of the desired product, an excess of acid was added, however, the same result was obtained and the salt 413 was isolated in quantitative yield (entry 2). Changing the solvent to THF or DMF did not give any reaction, and the starting material was recovered unchanged (entries 3 and 4).

Changing the acid source to AcOH did not provide better results, even when excess was added (entries 5 and 6). When sodium nitrite was used in association with fluoroboric acid, only the product 413 was isolated (entries 7 and 8).

entry X - conditions yield (%)

1 BF4 -t-BuONO (1.2 eq.), BF3.OEt2 (1.5 eq.), CH2Cl2 413 (85) 2 BF4 -t-BuONO (1.2 eq.), BF3.OEt2 (10.0 eq.), CH2Cl2 413 (quant.) 3 BF4 -t-BuONO (1.2 eq.), BF3.OEt2 (1.5 eq.), THF -4 BF4 -t-BuONO (1.2 eq.), BF3.OEt2 (1.5 eq.), DMF -5 AcO -t-BuONO (1.2 eq.), AcOH (1.5 eq.), DMF -6 AcO -t-BuONO (1.2 eq.), AcOH (4.0 eq.), DMF -7 BF4 -NaNO2 (10.0 eq.), HBF4 (50% aq., 11.2 eq.), H2O 413 (50) 8 BF4 -NaNO2 (10.0 eq.), HBF4 (50% aq., 22.4 eq.), H2O 413 (72)

Incorporation of the vinyl fragment through a triflate

The unsuccessful attempts to isolate a diazonium salt led to alternatively follow the method described by Landais et al. and performing the coupling using a triflate. 382 This would be accessible after transforming the amine into an alcohol through in situ generation of a diazonium. The diazotation of amino-quinoline 406 was performed in the presence of an excess of sodium nitrite and sulfuric acid, followed by hydrolysis to give the hydroxy-quinoline 408 in 56% yield, together with 44% of the remaining starting material (Scheme IV.37). Increasing the quantity of the acid and nitrite sources to 10 equivalents gave similar yields, and the full conversion of the starting material was not attained. In addition, increasing the reaction time to 5 days, or decreasing the medium concentration to 0.1 M gave yields between 47 and 56%, with the recovery of unreacted starting material. No significant loss of material was observed during this reaction. These results suggested to follow another route to incorporate the vinyl fragment, by first generating the corresponding bromoquinoline through a Sandmeyer reaction. This would shorten the synthesis sequence by one step, and avoid the use of expensive Comins' reagent. 383 Scheme IV.37. Synthesis of hydroxy-quinoline 408. Reagents and conditions: i) NaNO2 (5.0 eq.), H2SO4 (5.0 eq.), H2O (0.48 M), 0 to 20 °C, 8 h.

Incorporation of the vinyl fragment through a bromide

The incorporation of a bromine atom onto the tetracyclic core is possible through the venerable Sandmeyer reaction. This reaction consists in the conversion of an aryldiazonium intermediate into an aryl halide in the presence of copper(I) salts, and likely proceeds through a radical-pathway. [384][385][386] Usually, the NaNO2/H2SO4 mixture is used to generate the aryl diazonium salt, which in the presence of copper(I) bromide then delivers the corresponding aryl bromide. However, it was observed in the present study, that the NaNO2/H2SO4 reaction conditions are inefficient, and do not provide a complete conversion of the starting material. In this context, Yagi and co-workers 387 reported the transformation of amino-quinoline 415 into bromo-quinoline 416 under very mild conditions, using t-BuONO as a nitrosyl cation source (Scheme IV.38). Such conditions seemed adequate to the tetracyclic core under study.

Scheme IV.38. Synthesis of bromo-quinoline 416 through Sandmeyer reaction. 387 The conditions described by Yagi et al. were applied to the amino-quinoline 406 to deliver the brominated product 409 in 57% yield, together with 10% of unreacted starting material and another 10% of the hydroxyquinoline 408 (Table IV.8, entry 1). The fact that the phenol 408 was obtained indicates that traces of water were present in the medium, and participated in the hydrolysis of the diazonium intermediate. The traces of water may come from the solvent distilled several days before, or from the copper bromide known to be moisture-and air-sensitive.

Besides the necessity to prohibit the formation of the hydroxyquinoline 408, optimizations are needed to fully convert the initial substrate. Usually, the reaction is completed within 3-4 h; leaving it for a longer time had no effect on the conversion of the starting material. As a precaution, the following reactions were performed in freshly distilled acetonitrile. The use of an excess of t-BuONO (3 eq. added in two portions within 1 h interval), led to almost complete conversion of the starting material, and only traces of the initial substrate remaining. After column chromatography, 409 was isolated in 45% yield while the alcohol 408 was formed in 16% yield (entry 2). Once the quantity of copper bromide was increased to 2 equivalents, the starting material was fully converted, even when only 1.5 eq. of t-BuONO were used, giving the bromide 409 and alcohol 408 in 55 and 8% yields, respectively (entry 3). Using a different batch of copper bromide, under the same stoichiometry, afforded the desired product in 62% yield with only traces of 408 (entry 4), indicating that the quality of copper salt is an important factor.

Although a full conversion of the material was achieved, and the formation of alcohol was almost prevented, the yield was still moderate. Thus, the aqueous phase was extracted again after saturation with sodium chloride. 3% of the bromo-quinoline were recovered, indicating that a certain amount of 409 was lost during the treatment process (before extraction, the reaction mixture was filtered over celite, as described in Yagi's protocol). Therefore, it was suggested to purify the crude mixture through column chromatography directly without treatment, after removing the solvents under vacuum. This procedure increased the yield of 409 to 81%, always with traces of 408 (entry 5). When a freshly ordered bottle of copper bromide was used, the same yield of 409 was obtained, and no traces of alcohol were formed (entry 6). Decreasing the quantity to 1.8 eq., however, slightly decreased the yield to 75% (entry 7).

entry CuBr (eq.) t-BuONO (eq.) workup yield (%)

Suzuki coupling and O-demethylation

With the bromide 409 in hand, the vinylic fragment was installed through Suzuki coupling with the commercially available potassium vinyltrifluoroborate, in the presence of potassium carbonate. 382,388,389 The desired vinyl naphthyridine scaffold 398a was isolated in an excellent yield of 96% (Scheme IV.39). This reaction was repeated several times to give 398a in yields between 80 and 100%.

Scheme IV.39. Synthesis of vinyl quinoline 398a through Suzuki coupling. Reagents and conditions: i) Potassium vinyltrifluoroborate (1.5 eq.), Pd(PPh3)4 (0.1 eq.), K2CO3 (1.0 eq.), DME/H2O (0.06 M/0.12 M), 95 °C, 12 h.

Once the vinyl naphthyridine 398a was successfully synthesized, the O-demethylation was achieved with BBr3. With 1.5 equivalents of BBr3, only a partial conversion was observed on TLC.

During the extraction process using saturated Na2SO4, both the substrate and the product were decomposed and no trace of the typical double bond signals was found on the crude 1 H NMR spectrum (Table IV.9, entry 1). In a second run, a large excess of boron reagent was added to attain a full conversion after 12 h. Although the substrate was fully consumed, the final product was isolated in only 53% yield after extraction with aqueous HCl and purification on a short column (entry 2). The aqueous layer was then evaporated and analyzed after washing several times with organic solvents,

showing that a quantity of the desired product went into the aqueous phase. Similarly, the extraction with a small amount of saturated NaHCO3 gave a moderate yield and some quantity was lost in the aqueous phase (entry 3). Such findings are not surprising since the chromophore core 417 present both acidic and basic sites. To avoid the extraction step, a better alternative was established by quenching the reaction mixture with methanol, followed by a simple evaporation and purification.

This procedure afforded the nor-ethyleucophylline 417 in a quantitative yield (entry 4) and was repeated several times to give 417 in yields between 82 and 100%.

entry BBr3 (eq.) time (h) workup yield (%)

1 a 1.

Application towards the enantioselective synthesis of eucophylline

Once the methodology was optimized on the studied model, the chiral bicyclic lactam 20 was submitted to Friedländer reaction, to generate the amidine 355 in 70% yield (Scheme IV.40). The latter was then engaged in a cyclization process using LDA, to furnish the desired amine 356 in 74% yield.

Scheme IV.40. Synthesis of chiral amino-quinoline 356. Reagents and conditions: i) 354 (1.5 eq.), POCl3 (1.1 eq. x 2), CH2Cl2 (0.05 M), 60 to 50 °C, 48 h; ii) LDA (3.0 eq.), THF (0.05 M), 0 to 20 °C, 48 h.

At a later stage, the amino-quinoline 356 was transformed under Sandmeyer conditions to bromoquinoline 418 in 80% yield, ready for the final vinylation through Suzuki coupling (Scheme IV.41).

This reaction proceeded smoothly in a schlenk tube to furnish the vinyl-quinoline 19 in a 96% yield.

Both reactions were repeated several times to give yields between 80 and > 95%.

Scheme IV.41. Synthesis of methoxy-eucophylline 19. Reagents and conditions: CuBr (2.0 eq.), t-BuONO (1.5 eq.), CH3CN (0.1 M), 40 °C, 3 h; ii) Potassium vinyltrifluoroborate (1.5 eq.), Pd(PPh3)4 (0.1 eq.), K2CO3 (1.0 eq.), DME/H2O (0.06 M/0.12 M), 95 °C, 12 h.

With the methoxy-eucophylline 19 in hand, the last step of O-demethylation was achieved using 10 equivalents of BBr3. The (+)-eucophylline 8 was isolated in 93% yield with an observation of traces of unconverted starting material after 12 h of reaction. Increasing the quantity of BBr3 to 12 eq. led to a complete conversion, and the natural product was obtained as a yellow solid in 95% yield (Scheme IV.42).

Scheme IV.42. Synthesis of (+)-eucophylline 8. Reagents and conditions: i) BBr3 (12.0 eq.), CH2Cl2 (0.02 M), 0 to 20 °C, 14 h.

Analytical data of (+)-eucophylline

The natural product was reported to be isolated as a brownish powder from plants, as well as from the previously reported syntheses. While it was isolated as a yellow powder in its pure form, it became brownish at room temperature after a week, suggesting that the eucophylline might be prone to some oxidation.

The TLC retention factor of the product was reported to be 0.6 in CH2Cl2/MeOH: 98/2 mixture. 48,352 Yet, in this work, the eucophylline was found to be much more polar and possesses an Rf of ~ 0.2 in CH2Cl2/MeOH: 96/4 (the Rf was found to be between 0.19 and 0.23 with room for manipulation error). Spotting the racemic eucophylline alone and in co-spot with the chiral one, gave similar Rf. As well, the nor-ethyleucophylline possesses a low Rf value (0.11 in CH2Cl2/MeOH: 98/2 mixture). Such a range of values might be explained by the amphoteric nature of eucophylline structure, which holds two basic amine sites and an acidic phenol entity.

The HRMS of the synthesized (+)-eucophylline ([M+H] + = 295.18018) was found to be in good agreement with that reported for the authentic eucophylline ([M+H] + = 295.1816). 2 The melting point (164.6-166.3 °C) was slightly higher than the values reported by Landais (159-160 °C) 48 and Pandey (158-159 °C). 352

The 1D NMR ( 1 H, 13 C, and 13 C DEPT-135) and 2D NMR ( 1 H-1 H COSY, 1 H- 13 C HSQC, and 1 H- By closely comparing the values of 13 C NMR, a more significant shift was observed especially for the C-10 next to the alcohol fragment, which appears at 104.7 ppm instead of 109.1 ppm (Table IV.11). Pandey's 13 C NMR results (Table IV.12) were found be closer to the natural product's data than those of this work or the 13 C NMR reported by Landais et al. (Table IV.13). To check whether the product is complexed with external atoms (e.g., metalloid such as boron), the eucophylline samples were extracted with HCl (1 M) or sat. NaHCO3. In both cases, the same 13 C NMR was obtained.

The C-10 of nor-ethyleucophylline 417 was found to be lower than expected as well (103.6 ppm in CD3OD). Analyzing nor-ethyleucophylline 417 in other deuterated solvents to minimize the interactions between the molecule and the solvent, showed C-10 at 103.1 and 102.7 ppm in acetonitrile-d3 and dichloromethane-d2, respectively. In chloroform-d, the solubility was very low precluding any analysis, while in acetone-d6, C-10 appeared at 104.5 ppm. It was envisioned that the naphthyridine nucleus might be in its protonated form. To confirm this, 0.1 eq. of p-TSA was added to the NMR tube (in acetone-d6) leading to a shift of the C-10 from 104.5 to 105.7 ppm (Table IV.14),

showing that the lower chemical shift is not related to the protonated nitrogen next to C-10, and that the synthesized product is not protonated. 13 C NMR data for nor-ethyleucophylline in acetone-d6, without and with p-TSA.

When analyzing the nor-ethyleucophylline 417 in acetone-d6 several weeks later (for the "without acid" sample, the NMR tube was prepared again), C-10 shifted to 110.5 ppm and other small peaks were detected (Figure IV.4). The explanation behind this shift is not clear. In the case of (+)-eucophylline, the C-10 chemical shift appeared at 105.8 ppm using acetone-d6 as a solvent.

Repeating the analyses after several weeks were not accomplished for this molecule. After leaving the NMR tube for more than 2 days, white precipitates were observed. These precipitates were not crystalline, do not deviate the polarized light, and they were not soluble in organic solvents.

Albeit the sense of the optical rotation matched what was reported in the literature, the specific optical rotation value of (+)-eucophylline was found to exhibit a higher value than that in the isolation Although it has to be taken into account that the experimental values could hold ±10° error, the results in this work were obviously much higher. Using methanol as commercially received or purified did not give different results. Attempts to measure the specific rotation in chloroform did not seem useful, due to the low solubility of eucophylline in this solvent. The measurement of the specific rotation of known molecules with reported [α]D values confirmed that the problem does not come from the polarimeter. For instance, the [α]D of the ligand 115 synthesized in chapter III, was remeasured giving the expected value.

By searching in the literature for an explanation, it was found that some groups also found a difference between the [α]D values of their synthetic samples and the ones reported for the natural products. 390,391 Their explanations seem to fit this case, where the difference could be attributed to the impurities present in the isolated natural product, as seen on the reported 1 H and 13 C NMR spectra, or it could be related to the low quantity available for accurate measurement of the specific rotation (1.9 mg isolated natural product).

Circular dichroism analysis was also performed and compared with the literature data (Figure 5). According to the CD spectra, the absolute configuration at the C-20 position was deduced to be (R), as expected. The UV spectrum was also found in good agreement with that of the isolated natural eucophylline (λmax = 227 nm, 346 nm; lit. 2 λmax = 227 nm, 347 nm). To dismiss all doubts about the structure of the tetracyclic core, crystals were grown to perform X-ray analysis. 17 Finally, the abovementioned observations may be related to the amphoteric nature of eucophylline. In the presence of traces of acid or base, different forms could be generated (Scheme IV.43). In the presence of a base, a phenolate I is formed, while in the presence of acid, the protonation of the eucophylline's nitrogens would be favored. The protonation might occur on the quinoline's

nitrogen II or less probably on the bridgehead nitrogen III.

Scheme IV.43. Different forms of eucophylline in basic or acidic medium.

Conclusion

In summary, this chapter disclosed the enantioselective total synthesis of natural eucophylline 8 in 17 steps starting from 1,1-dibromobut-1-ene, with an overall yield of 5.9%, and an average yield of 85%. The HPLC analysis confirmed the high enantiomeric excess of the natural product (ee = 98%). In this synthesis, no protecting groups were used and only 9 steps proceeded with purification on column chromatography. The synthetic approach features the construction of a chiral cyclobutene which was further functionalized to introduce the asymmetric all-carbon quaternary stereocenter through a photocatalytic approach (Figure IV.9). Most notably, this synthesis takes advantage of a nickel boride-mediated cascade, allowing a nitrile reduction/cyclization/ring-opening sequence in a one-pot process. This transformation gave access to a six-membered cyclic lactam starting from a cyclobutane scaffold. The lactam was further manipulated to deliver a highly strained bridgehead amide. The elaboration of the eucophylline tetracyclic core continued after several optimizations. The natural product was fully characterized and an X-ray structure confirmed its successful synthesis.

Chapter V Total Synthesis of Eburnane Alkaloids

1. Eburnane-vincane alkaloids: isolation, biogenesis, and structure

The pentacyclic northern fragment of leucophyllidine 6, the eburnamine 18, belongs to the eburnane-vincane family, which is a well-known group of the monoterpene indole alkaloids. 392 The eburnane-vincane alkaloids have been isolated from numerous species of the plant family

Apocyanaceae, but also from Hunteria, Kopsia, Rhazya stricta, Leuconotis, and Vinca species. [393][394][395] Their template possesses the same fundamental secologanin skeleton 420 already noted in the Aspidosperma series. It is, however, incorporated into the former system in a rather different fashion, which defines the backbone's architecture of the group (Figure V.1). 392 Kopsia, while the opposite enantiomers (20S,21S) were isolated from Chinese Kopsia. 393,406 These observations provide evidence for the biosynthetic pathway that could be traced to the achiral secodine intermediate. 30,[407][408][409] Speaking of the eburnane skeleton, it also constitutes the half part of several pharmacologically active bis-indole alkaloids like leuconoline 435, pleiomutine 436, and kopsoffine 437 (Figure 410,411 as well as two bis-indole alkaloids, bisnicalaterines B and C 438 and 439 consisting of eburnane-and corynanthe-type skeletons, which were isolated from the bark of Hunteria zeylanica.

V.3),
Each of them was shown to be in an atropoisomeric relationship towards the other, and they showed potent vasorelaxant activity on isolated rat aorta. 412

Bioactivity and pharmacological potential of indole alkaloids

Since isolation, scientists gave special attention to aspidosperma-type alkaloids, not only for their sophisticated structures as mentioned above but also for the popularity of plants that produce these substances in folk medicine. 413 Specifically, the eburnane-vincane indole alkaloids were found to exhibit strong vasodilatation activity which brings about an enhancement of the overall cerebral blood flow. 414 They also exert other potent pharmacological activities on cell multiplication, the cardiovascular system, and the brain functions as cerebroprotective agents. 415,416 For example, (-)-eburnamonine 423, also known as (-)-vincamone, has been shown to prevent cerebrovascular disorders, whereas (+)-vincamine 422 (Vincarutine ® ) is a marketed peripheral vasodilator for treatment of primary degenerative and vascular dementia. 410,415,417 The pharmacological studies showed (+)-eburnamonine to be less effective than vincamine or (-)eburnamonine. In addition to its lower toxicity, (-)-eburnamonine was found to be a more active and selective cerebral vasodilator than (+)-eburnamonine. 418,419 Investigations on the chemical modification of eburnamine derivatives were aimed at finding pharmacologically more effective derivatives and safer to administer than the natural plant alkaloids themselves. Most of these derivatives were obtained by the introduction of substitutions at the aromatic ring or by functional modification at C-16 (see Figure V.1 for the numbering). For instance, vinpocetine 433 has been found to be pharmacologically more effective than vincamine itself. 420 Since its introduction to the market as a neuroprotective agent (Cavinton ® ), clinical studies proved the usefulness of vinpocetine in the treatment of post-ischaemic stroke disease and various disorders of cerebrovascular origin. 415 In 2010, Rosenberg described vinpocetine and eburnamine derivatives as having the ability to promote bone growth, thus illustrating, the wide array of potential pharmacological applications of this type of compounds. 421 Beyond this, it is important to develop new syntheses to obtain these substances efficiently without the necessity of extraction from natural sources.

Common approaches towards the eburnane pentacyclic core

The potential pharmacological activity and the notable array of structures inherent to the eburnane-vincane alkaloids family provided the opportunity for considerable diversification in the synthetic approaches towards these molecules. 398,410 Undoubtedly, it will not be possible, within the limitations in scope and length of this chapter to provide a detailed discussion of all the advances that have been made in this area. It is hoped that the present selection of the synthetic pathways will provide some appreciation of the various strategies followed during the construction of the common ABCDE pentacyclic framework. Strategically, the most common route towards this particular family is to first establish the ABCD key ring system 441 and then to complete the synthesis of the specific target by tailoring the final E-ring (Scheme V.1). 422 The majority of syntheses follow the design of first building the ABD fragment of the molecule, then closing the C-ring via C-2/C-3 bond formation. Typically, The condensation of a tryptamine template with an aldehyde-ester 442 through Pictet-Spengler reaction, 423 or the intramolecular condensation of a lactam 445, followed by reduction through Bischler-Napieralski 424 are among the most exploited transformations towards this end (Scheme V.1.A). 408,425 An inherent drawback, however, associated with these approaches, is the lack of diastereocontrol of the crucial quaternary center at C-20 and the adjacent methine at C-21. The insignificant steric difference between an ethyl and an ester group at C-20 prohibits the differentiation of the two faces of the neighboring iminium function. 426 Other pathways proceeded through an easily accessible ABC nucleus, 3,4-dihydro-β-carboline 448, upon which the remaining rings were built (Scheme V.1.B). 427,428 This approach involves usually an intramolecular Mannich reaction, leading to Oppolzer's intermediate derivatives 451 with moderate diastereoselectivity. 429 Finally, the construction of the B ring starting from a non-indole portion was also investigated (Scheme V.1.C). The key step in the ring system assembly is a photoredox radical-based cascade approach. 66,[430][431][432] Another version of this reaction type has also been developed with full diastereocontrol. 433 In the following section, a few examples of the most characteristic synthetic approaches of eburnamonine 423 and eburnamine 18, will be provided for illustrative purposes.

Scheme V.1. Common synthetic strategies towards eburnane indole alkaloids.

Illustration of the most popular syntheses of eburnamonine and eburnamine

The structure elucidation and the first synthesis of the eburnane series: eburnamine 18, epieburnamine 424, and eburnamonine 423 were achieved by Bartlett and Taylor in 1960. 395,434 In this synthesis, the condensation of substituted adipic acid derivative 455 with tryptamine through an acidcatalyzed ring closure afforded 3-oxoeburnaminone 456. Reduction of the latter gave a mixture of eburnamine 18 and epi-eburnamine 424, which were oxidized to eburnamonine 423 under Sarett conditions (Scheme V.2).

Scheme V.2. Taylor synthesis of (±)-eburnamine and (±)-eburnamonine. 395,434 The Pictet-Spengler approach used by Barton and Harley-Mason, involved an unsaturated aldehyde-ester 457 as the condensing unit. The higher reactivity of the aldehydic carbonyl function privileged the reaction at this site (Scheme V.3). 435 The produced tetracyclic olefin 458 was subjected to oxidative scission under Lemieux-Johnson conditions, to provide the C-16 aldehyde function.

Reduction then gave (±)-eburnamine 18. The intermediate 458 was also used for the synthesis of aspidospermidine derivatives following the aspidosperma-eburnea rearrangement pattern.

Scheme V.3. Barton and Harley-Mason synthesis of (±)-eburnamine. 435 A different approach to the pentacyclic nucleus of eburnamonine was developed by Wenkert and Wickberg. 408 The cyclic amide 460 was prepared from the cyclization of tryptamine with bromoester Basic and acidic treatment of the latter gave dilactam 456, which upon reduction, afforded (±)eburnamonine 423. The asymmetric synthesis of cyclopropane 464 was described later by the group, offering an enantioselective pathway to (+)-and (-)-eburnamonine. 438 Scheme V.5. Winterfeldt's synthesis of (±)-eburnamonine. 437 Wenkert et al. 6 proposed a second synthesis of (±)-eburnamonine following two parallel routes to lead to the lactone intermediate 473 (Scheme V.6). The latter was obtained either from the alkylation of carbinolamine lactone 470 with tryptophyl bromide 471a or from the condensation of bromolactol 472 with tryptamine 11. Under acidic and thermal conditions, the carbinolamine lactone 473 underwent cyclization, leading directly to eburnamonine 423. The aminolactone 470 was later used by several groups for the synthesis of eburnane family or for other synthetic purposes. 410 Alternative syntheses have also been described for the preparation of this aminolactone. 439,440 Scheme V.6. Synthesis of (±)-eburnamonine by Wenkert et al. 6 Magnus et al. 441 based their synthesis of (±)-eburnamonine on the rearrangement of an aspidosperma-type intermediate (Scheme V.7). The pentacyclic amide 474 was treated with cyanogen chloride to furnish the cis-chlorohydrin 475 and the geminal dichloroimine 476. Under acidic conditions, 476 rearranged rapidly by the intermediacy of acyliminium species, to 3-oxoeburnamonine 456. 456 was then transformed into (±)-eburnamonine 423 by consecutive reduction-oxidation sequence.

Scheme V.7. Synthesis of (±)-eburnamonine by Magnus et al. 441 The first syntheses of the enantiopure (+)-eburnamine 18, (-)-eburnamenine 483, and (-)eburnamonine 423 was reported by Takano and co-workers. 442 Chiral lactone 477 was synthesized in sequential reactions starting from L-glutamic acid. Its condensation with tryptamine afforded δlactam 478 and the amide 479 in 14 and 81% yields, respectively (Scheme V.8). The amide 479, cyclized under Bischler-Napieralski conditions to afford the iminium salt 480 that was reduced by a hydride source to give the tetracyclic core 481 in 62% overall yield. After hydrolysis of the dithiane group, the formed aldehyde 482 underwent spontaneous cyclization to afford (+)-eburnamine 18 and (-)-eburnamenine 483 in 27 and 3% yields, respectively. Further oxidation of (+)-eburnamine 18 with pyridinium dichromate elaborated (-)-eburnamonine 423 in a 75% yield.

Scheme V.8. Takano's synthesis of (+)-eburnamine and (-)-eburnamenine. 442 Pandey et al. 352 synthesized eburnamine 18 from the enantiopure lactam 475 (Scheme V.9). The latter was obtained by a similar approach to the lactam used in the eucophylline synthesis. Ozonolysis of 475 gave the aldehyde 484, the subjection of which to Wittig reaction was not successful. The Scheme V.10. Synthesis of (±)-eburnamonine by Zhu et al. 426 Considering the aforementioned syntheses and the literature reports, the common two pathways to access the tetracyclic core of eburnan alkaloids are either through Pictet-Spengler reaction or Bischler-Napieralski intramolecular condensation. This brief survey also showed the diversity of approaches developed to access the pentacyclic skeleton. Some of these syntheses are distinguished by the stereospecificity of the crucial constructive steps, others are characterized by their generality and versatility, whereas others followed biosynthetic pathways.

In most cases, the challenging task is to construct the non-tryptamine part in a short and efficient strategy. The construction of this non-tryptamine part usually takes at least 7 to 10 steps, except for a few examples. 435 To date, many approaches have been reported for the synthesis of the racemic and chiral non-tryptamine fragment, a task that will be undertaken in the following discussion.

Revised retrosynthetic strategy towards enantioselective eburnamine

Following the results obtained in chapter IV, a revised retrosynthesis of chiral eburnamine was proposed based on three connections of the indole core to tailor the C-D-E rings (Scheme V.11).

Strategically, the beginning of the eburnamine retrosynthesis would be based on formal syntheses, by tailoring the last ring (ring E) using a suitable base, followed by reduction of the molecule's carbonyl groups. Installing the quaternary stereocenter at C-21 would be envisioned by selective oxidation of the site αto the ring D's nitrogen to generate an iminium ion and favors the nucleophilic attack of the indole fragment on the carbocation, tailoring thus, the C ring regioselectively. From this disconnection, the ring D would be introduced to the eburnamine's scaffold through alkylation of lactam 28 with tryptophyl bromide 471a (or its derivatives) to form the first connection to the indole backbone. The six-membered lactam 28, as a key intermediate, would be provided by a strategy similar to that used in the synthesis of (+)-eucophylline. Applying the nickel boride conditions to the polyfunctionalized cyclopropane 30 would result in nitrile reduction, cyclization, and ring-opening of the three-membered carbocycle in a one-pot process. The diastereoselective free-radical carbocyanation of cyclopropene 31 would construct the all-carbon quaternary center bearing the nitrile functional group with good diastereocontrol to generate 30. 47 The enantiopure cyclopropene 31 itself would be accessed by adapting the previous cyclopropenation reports starting from the suitable alkyne 33 and diazoester 32. Thus, the key chiral lactam 28 would be obtained in three straightforward steps starting from but-1-yne 33.

Scheme V.11. Revised retrosynthesis of chiral eburnamine skeleton 18.

Although this plan seemed reasonable at the beginning, efforts to promote the alkylation of the tryptophyl bromide 417a or its Boc protected form 471b with a lactam model similar to 28 or with the commercially available 2-piperidinone 379 under strong basic conditions, have all failed. It was suspected that the problem may come from the protecting group; but this reaction was not studied further and the synthesis strategy was modified.

Modified retrosynthetic strategy of eburnamine

After failing at alkylating the cyclic lactam backbone, it has been proposed that the removal of the lactam's carbonyl group would help to promote the alkylation by enhancing the nucleophilicity of the nitrogen atom. Although the reduction conditions will reduce the ester group at the same time, the alkylation of 501 must then occur smoothly under mild basic conditions (Scheme V.12). The presence of the alcohol group would be used to direct the generation of an iminium ion regioselectively through a 1,5-hydrogen atom transfer (HAT). The selective generation of an alkoxy radical will be challenging due to the complexity of the molecule. However, it might be possible to induce the cyclization and therefore to generate the iminium ion under acidic conditions and subsequent nucleophilic attack of the indole ring on the cationic carbon center at C-2. The aza-hemiacetal 498 could then be oxidized by Ley-Griffith's TPAP/NMO system with concomitant cyclization to deliver eburnamine 18 after a final reduction.

Scheme V.12. Modified retrosynthetic strategy of eburnamine.

Synthesis of the precursors

The next step was then to synthesize a piperidine model 501 with the alcohol chain at position-3, in a short and efficient way, to elaborate enough material for further investigation (Scheme V.13).

This could be accessed through path A (R = H) or B (R = Et). Path A would deliver the desired alcohol in fewer steps, while path B would give access to the racemic version of 501, mimicking the synthesis of the enantiopure synthon. 2-piperidinone 379 would be a cheap and readily available precursor for this strategy; the presence of the carbonyl group would direct the alkylation selectively at the position-3 after deprotonation of the acidic proton αto the carbonyl; the second alkylation (path B) would also take place selectively. Although the model 504 and the chiral 28 do not have the carbonyl group on the same side, this will not be a problem since this functionality will be reduced later to deliver the protected amino-alcohol 503. The deprotection of 503 will give access to the desired template 501 ready for further manipulation.

Scheme V.13. Synthetic strategies of the model study.

At first, the path A (R = H) was investigated. The Boc-protected piperidinone 369b, was chosen for the easiness of the deprotection step at a later stage. The alkylation of 369b with ethyl bromoacetate was performed under LDA conditions, however, the reaction gave an inseparable mixture of the desired product 506 and the double alkylated one 507 (Table V.1, entry 1). Using ethyl chloroacetate as the alkylating agent was believed to help, slowing down the reaction rate and hopefully control the alkylation process. Although the reaction was much slower, it gave the same mixture of products as in the previous case (entry 2). Changing the addition order of LDA and 2piperidinone provided also the same result (entry 3). Although the proton next to the carbonyl is supposed to be the most acidic, the presence of the Boc group activates the site next to the nitrogen (acidic proton). Therefore, two sites are activated and prone to deprotonation. It was then suggested that stirring the deprotonated product at -30 °C before the addition of the alkylating agent, would only generate the lithium enolate. This hypothesis was confirmed; however, the double alkylated 508 was obtained (entry 4), in agreement with observations reported in the literature. 443 When the Bn-protected lactam 369a was used, a complex mixture of products was obtained (entry 5), while no reaction was observed with the Bz-protected analog 369c (entry 6). This pathway was then abandoned and the efforts directed towards path B. Path B was designed as a model sequence to install the all-carbon quaternary center present in the eburnamine. Since the Boc protecting group was not the best choice to work with, the Bnprotected lactam 369a was submitted to alkylation. The use of KHMDS as a base gave no reaction after 9 h. However, following Stoltz's procedure 444 using LDA, the desired product was isolated in 92% in a clean manner on a 0.5 mmol scale (Scheme V.13). Increasing the scale to 7 mmol gave 505a in 73% without observation of undesired reactions.

Scheme V.13. Monoalkylation of 369a. Reagents and conditions: i) EtI (1.2 eq.), LDA (1.2 eq.), THF (0.1 M), 0 to -78 to 20 °C, 5 h.

The second alkylation with ethyl bromoacetate went smoothly following the same procedure used with ethyl iodide. The α-quaternary lactam 504a was obtained in 80% yield on 10.5 mmol scale (Scheme V.14). The reduction of the amide and ester groups with LAH under reflux afforded the alcohol 503a in 81% yield on a 5 mmol scale.

Scheme V.14 Sequential alkylation/reduction of the amide 505a. Reagents and conditions: i) Ethyl bromoacetate (3.0 eq.), LDA (1.5 eq.), THF (0.3 M), 0 to -78 to 20 °C, 20 h. ii) LAH (4.0 eq.), THF (0.05 M), 66 °C, 12 h.

With the amino-alcohol 503a in hand, the deprotection conditions were investigated. The best conditions were obtained under hydrogenation (1 atm) with Pearlman's catalyst in methanol at 50 °C (Scheme V.15). The reaction afforded the amino alcohol 501 in a quantitative yield on a 4 mmol scale. Other conditions were unsuccessful; no conversion was observed at 22 or 35 °C or using other solvents such as EtOAc and THF. No reaction was observed using palladium on charcoal at 22 °C. The tryptophylation of the amino-alcohol with indole 371 was then investigated to construct the molecular structure 500 necessary for the oxidation studies. The alkylation was first conducted with potassium carbonate in DMF to yield the desired product in 17% yield (Table V.2, entry 1). Better conditions using sodium carbonate as a base in refluxing acetonitrile afforded 500a in 74% yield (entry 2). The Boc-protected tryptophyl bromide 371b was also submitted to the alkylation with 500b

under the same conditions to afford the corresponding product in a 73% yield (entry 3). Once the amino-alcohol was alkylated as planned, the oxidation conditions were investigated.

Synthesis of hemiaminal 499 using hypervalent iodine

It was planned that the generation of an alkoxy radical from indole 500 could be promoted using PIDA or PIFA under irradiation or heating conditions (Scheme V.14). The 1,5-hydrogen atom transfer (1,5-HAT) reaction from the alkoxyl radical (I) would then allow the regioselective activation of the C(sp 3 )-H bond next to the nitrogen. The resulting alkyl radical (II) would then direct the generation of an iminium ion (III) followed by the nucleophilic attack of the alcohol to construct the hemiaminal skeleton 499.

Scheme V.14. Planned synthesis of hemiaminal 499.

The use of PIDA or PIFA in HFIP to generate the alkoxy radical from compound 500a led to a decomposition of the starting material after 2 h (Table V.3, entries 1 and 2). Reaction of 500a with PIDA in acetonitrile led to no conversion with only traces of degradation (entry 3). It was thought that the generated acetic acid from PIDA might be detrimental for the reaction; for this reason, 2 equivalents of sodium carbonate were added to neutralize the mixture. Still, no reaction was observed (entry 4), nor with dichloromethane as a solvent (entry 5). In the latter case, a prolonged stirring led to complete decomposition of the starting material. To favor the iodide bond breaking in PIDA, the reaction was performed under irradiation with blue LEDs. In this case, a complete degradation of the starting material was observed (entry 6). Adding a catalytic amount of iodine in the medium to favor the formation of the O-I bond, gave the same results (entry 7). Considering the above failure, the reaction was then performed on the Boc-protected indole 500b to limit the side reactions. However, using PIDA or PIFA, no conversion was observed and the starting material was recovered unchanged (entries 8 and 9). When the reaction was performed with a catalytic amount of iodine under irradiation, the decomposition of the starting material was observed (entry 10). Anticipating that the electron-rich piperidine nitrogen center might be oxidized under such conditions, 445

Synthesis of hemiaminal 499 under photooxidative conditions

Jia and co-workers 446,447 succeeded at generating an alkoxy radical using mild photocatalytic conditions, in the presence of cyclic iodine(III) reagent, BI-OAc, as the iodine source (Scheme V.15).

In their work, they mentioned that the cyclic iodine (III) reagents were more reactive and chemoselective compared to the non-cyclic analogs. Their methodology was applied to a wide scope of substrates giving the expected products in moderate to high yields.

Scheme V.15. C(sp 3 )-C(sp 3 ) bond cleavage and alkynylation using cyclic iodine(III) reagents. 447 It was suggested that these conditions would be able to generate an alkoxy radical in a more selective way. The alkoxy radical would then undergo 1,5-HAT to form the tetrahydrofuran ring after formation of the iminium and cyclization. However, applying their conditions to the substrate 500a led to a complex mixture of products (Table V.4, entry 1), while the protected analog 500b gave back the starting material (entry 2). Performing the reaction at 50 °C or in acetonitrile led also to decomposition (entries 3 and 4). Other catalysts such as [Ir(dtbbpy)(ppy)2]PF6 and Ir(ppy)3 gave back the starting material (entries 5 and 6). The presence of the N-piperidyl nitrogen is itself oxidable; in order to check if the alkoxy radical is formed, TEMPO was added to the reaction mixture (entry 7).

A complex mixture was however obtained with complete degradation of the starting material, which suggests that many sites are probably oxidized, leading to side reactions and degradation of the substrate. In order to check if the reaction would occur on simpler substrates lacking the reactive indole ring, 503a was chosen for further investigation. The reaction was performed in the presence of PIDA or PIFA, however, no reaction was observed and the starting material was recovered after column chromatography (Table V.5, entries 1 and 2). Applying the ruthenium conditions studied above led to a complex mixture of unidentified products (entry 3). The reaction with PIDA on the secondary amine 501 gave a complex mixture as expected (entry 4). As the experiments showed, the nitrogen atom on the non-indole part is most probably oxidized which makes the reactions messy and unpredictable. Another way to install the tetrahydrofuran ring was then looked for.

entry

entry R oxidant additive solvent time (h) yield

Synthesis of hemiaminal 499 under basic conditions

It was proposed that the indole 499 could be obtained from the alkylation of tryptophyl bromide with furane 512a (Scheme V.16). The latter could be constructed from alcohol 501. Scheme V.16. An alternative plan for the synthesis of 499.

Pandey and co-workers 448 reported the synthesis of hemiaminal derivative 512a in their total synthesis of leucolusine. 512a was synthesized from the amino-alcohol 501 in two steps after Nchlorination followed by elimination with sodium methoxide. Applying the described conditions led only to traces of the product 512a (Table V.6, entry 1). Repeating the reaction many times gave the same result. Increasing the amount of NCS to favor the formation of the chlorinated amine gave also traces of the product (entry 2). Changing the solvent to dichloromethane, however, gave a complex mixture of products (entry 3). Although the second step was messy, the first step using dichloromethane as a solvent gave, as described, a white semi-solid in a quantitative yield. Performing the elimination step with aqueous KOH in dioxane gave the desired product 512a in 70% yield (entry 4). These conditions were repeated many times to furnish the product in yields between 57-72% in a clean manner. Repeating the reaction using Et2O as a solvent in the first step, gave again only traces of the desired product (entry 5).

step i step ii

entry NCS (eq.) solvent conditions 3 steps yield The hemiaminal 512a was then submitted to alkylation with tryptophyl bromide 471a. Under the optimal condition obtained for the tryptophylation of amino-alcohol 501, a complex mixture was obtained (Table V.7, entry 1). The reaction was then performed with sodium carbonate in refluxing dioxane, but no conversion was observed and the crude 1 H NMR showed that the reactants remained unchanged (entry 2). Trying these conditions on the Boc-protected tryptophyl bromide 471b did not afford any conversion, however, traces of the indole 514 were identified by 1 H NMR (entry 3).

Refluxing the mixture in CH3CN gave the same results (entry 4) while starting from Bz-protected tryptophyl bromide 471c led to a complex mixture of products (entry 5).

entry

Construction of ring C under oxidative conditions

After the unsuccessful attempts to synthesize the compound 499, it was decided to submit the indole 500a to oxidative conditions following Fujii's procedure (Hg(OAc)2, NaBH4). 449 The application of this procedure delivered, however, the eburnane-type compound 515 in 70% yield as a 1:1 mixture of two separable diastereoisomers (Scheme V.17). This cyclization had placed the quaternary center away from the indole ring as originally expected.

Scheme V.17. Oxidation of 500a under Fujii's conditions. Reagents and conditions: i) 1. Hg(OAc)2 (3.0 eq.), EDTA-Na2 (3.0 eq.), EtOH/H2O: 1/2 (0.02 M), 78 °C, 4 h. 2. NaBH4 (10.0 eq.), CH2Cl2 (0.03 M), 0 to 20 °C, 12 h.

Alternative approach for the synthesis of eburnamine

It was then decided to modify the plans and to selectively reduce the lactam group without affecting the ester group present in compound 516 (Scheme V.18). This would give the amine 517a which would be transformed later into Wenkert's lactone 470. The latter would then be engaged in the construction of the pentacyclic core of eburnamine following Wenkert's approach. 451 This strategy would be also applied to the chiral lactam 20 to deliver the amine 517a after the selective reduction of the lactam's carbonyl. The straightforward synthesis of the natural product in an enantioselective fashion will then be investigated.

Scheme V.18. Alternative strategy to access racemic and chiral eburnamine.

Selective reduction of the lactam's carbonyl

The Bn-protected lactam 504a was then submitted to hydrogenation to deprotect the benzyl group and furnish the corresponding lactam 516 in 89% yield (Scheme V.19). This reaction was repeated several times to give 516 in 70-89% yield range after 2 to 4 days. The selective reduction was performed in the presence of BH3-Me2S, however, no reaction was observed with both the protected 504a and the deprotected 516, probably due to the steric hindrance at the all-carbon quaternary stereocenter next to the carbonyl (Table V.8, entries 1 and 2). In contrast with an excess of borane, 35% of 503a were isolated (entry 3). Since the selective lactam reduction was unsuccessful in the presence of the ester group, it was envisioned to remove the lactam's carbonyl after converting it to a thionyl group followed by desulfurization. Thus, the lactam adduct 504a was refluxed with Lawesson's reagent in toluene. 452 However, the corresponding thioamide 518a was not detected and only the starting material was recovered (Table V.9, entry 1). Performing the reaction on the deprotected lactam 516 did not give the desired product, even in the presence of 2 eq. of Lawesson's reagent (entries 2 and 3). In the presence of 0.6 eq. of P2S5 in refluxing toluene, no reaction was observed on 504a and 70% of the starting material were recovered with the observation of some decomposition (entry 4), whereas, using an excess of P2S5 led to a complete decomposition of the substrate (entry 5). In contrast with these results, when the reaction was performed on lactam 516, 65% of the desired thiolactam 518b

were isolated (entry 6). This reaction gave the product in a 46-65% yield range due to its sensitivity.

In order to optimize the yield further, the reaction was performed in benzene, but the product 518b

was isolated in 17% yield only, along with 50% of unreacted starting material (entry 7). With the thiolactam 518b in hand, the desulfurization was performed under H2 atmosphere in the presence of an excess of Raney ® -nickel to give smoothly the desired amine 517a in a quantitative yield in a clean manner (Scheme V.20). This product can be used in the next steps without purification. No reaction took place when a catalytic amount of Raney ® -nickel was used, or in the absence of H2 even when the mixture was heated at reflux. Scheme V.20. Desulfurization of 518b. Reagents and conditions: i) H2 (1 atm), Raney ® -nickel (excess), THF (0.02 M), 20 °C, 12 h.

Synthesis of carbinolamine lactone 470

The amine 517a was later submitted to NCS in order to obtain the N-chloroamine 519, which was directly submitted to aqueous KOH in refluxing dioxane (Scheme V.21). These conditions afforded the desired carbinolamine lactone 470 in 60% yield after several optimizations of the workup procedure.

Scheme V.21. Synthesis of carbinolamine lactone 470. Reagents and conditions: i) NCS (1.2 eq.), CH2Cl2, 20 °C, 4 h. ii) 20 % aq. KOH, dioxane (0.1 M), 100 °C, 6 h.

Construction of the eburnane alkaloids

Following the formal synthesis developed by Wenkert and co-workers, 451 lactone 470 was alkylated with tryptophyl bromide 471a under basic conditions to give the corresponding indole 473 in 83% yield (Scheme V.22). The reproducibility of this reaction gave the product in 75-83% yield range.

Scheme V.22. Synthesis of indole 473. Reagents and conditions: i) tryptophyl bromide (2.0 eq.), K2CO3 (3.5 eq.), dioxane (0.1 M), 100 °C, 12 h.

The lactone 473 was then refluxed in glacial acetic acid to give the (±)-eburnamonine 423 and (±)-epi-eburnamonine 520 in 45% and 54% respectively (87% combined yield), in 1:1.2 diastereomeric ratio (vs. dr 1:1.3 reported by Wenkert) (Scheme V.23). Unlike the report of Wenkert, the epi-eburnamonine 520 was the major diastereomer and not 423. Repeating the reaction gave the same diastereomeric ratio. Both diastereoisomers were easily separable through column chromatography and the analytical data were in agreement with those reported in the literature.

Scheme V.23. Synthesis of eburnamonine and epi-eburnamonine. Reagents and conditions: i) AcOH (0.04 M), 110 °C, 48 h.

Eburnamonine 423 was later submitted to the reduction conditions using LAH to give eburnamine 18 in a quantitative yield after 30 min of reaction as a mixture of two diastereomers (dr 3:1 or 75:25) (Scheme V.24).

Application towards the enantioselective total synthesis of eburnamine

In order to perform the enantiomeric version of the total synthesis of eburnamine, the cyclopropene model 106a was prepared based on the procedure reported by Landais et al. 47 The cyclopropenation of an excess of pentyne 104a with ethyl diazoacetate 32 in the presence of a catalytic amount of rhodium acetate gave the cyclopropene 106a in 86% yield (Scheme V.27).

Scheme V.27. Synthesis of cyclopropene 106a. Reagents and conditions: i) Rh2(OAc)4 (0.01 eq.), CH2Cl2 (0.5 M), 20 °C, 14 h.

This olefin was then functionalized through the carbo-cyanation reaction 47 to deliver the polyfunctionalized cyclopropane 154a presenting an all-carbon quaternary center in 43% yield (Scheme V.28).

Scheme V.28. Carbo-cyanation reaction of cyclopropene 106a. Reagents and conditions: i) (SnMe3)2 (2.0 eq.), DTBHN (0.4 eq.), benzene (0.2 M), 65 °C, 13 h.

The nickel boride-mediated reduction reaction was then performed on cyanide 154a.

Unexpectedly, the cyclopropane fused lactam 522 was isolated in 73% yield (Scheme V.29). In this reaction, the ring-opening did not occur, contrasting with observations made in the cyclobutane series.

Scheme V.29. Nickel boride-mediated reduction reaction of cyclopropane 154a. Reagents and conditions: i) NiCl2 (2.2 eq.) NaBH4 (20.0 eq.) EtOH (0.025 M), 0 to 20 °C, 48 h.

Re-submitting the cyclopropane 522 to nickel boride conditions did not provoke the ring-opening and the starting material was recovered (Scheme V.30). The absence of an ester moiety αto the carbonyl in 522 probably explains the difference in reactivity. Yet, further study is required to confirm this hypothesis.

Scheme V.30. Attempts for cyclopropane ring-opening of 522. Reagents and conditions: i) NiCl2 (2.2 eq.) NaBH4 (20.0 eq.) EtOH (0.025 M), 0 to 20 °C, 12 h.

The cyclopropane ring-opening would be possible, using a strong base such as LDA (Dr. Nitin Dange, post-doc). Such a base would deprotonate the proton αto the carbonyl to give the unsaturated compound 523 (Scheme V.31). After reduction of the double bond, the lactam 521 would be converted to the thiolactam 524. Desulfurization would then deliver the amine 525. Alternatively, treatment with P2S5 could be applied first to cyclopropane 522. Scheme V.31. Possible transformations to access amine 525.

In order to move forward towards the synthesis of the desired chiral cyclopropene 31, the cyclopropenation had to start from but-1-yne 33. Due to its high cost, it was decided to develop a synthesis of this gas following the reaction procedure described by Szántay and co-workers 453 (Scheme V.32.A). However, several attempts failed to deliver the desired product, probably due to the necessity to work on a large scale. Alternatively, the use of the Corey-Fuchs reaction 453 did not afford the desired but-1-yne (Scheme V.32.B).

Scheme V.32. Attempts for but-1-yne synthesis.

To solve this problem, it was envisioned to start from an alkyne functionalized with a good leaving group such as a mesylate, which would be easier to access and to manipulate. This leaving group would be eliminated several steps later during the nickel boride-reduction reaction. This strategy seemed efficient since no additional steps would be needed. Based on this plan, the cyclopropenation of alkyne 140b with ethyl diazoacetate was performed in the presence of chiral rhodium catalyst (S,S)-Rh2(OAc)(DPTI)3 105 (Scheme V.33). The latter was prepared in three steps starting from (1S,2S)-diphenylethanediamine. Cyclopropene 106b was isolated in 26% yield.

Scheme V.33. Synthesis of cyclopropene 106b. Reagents and conditions: i) (S,S)-Rh2(OAc)(DPTI)3 (0.05 eq.), CH2Cl2 (0.5 M), 20 °C.

The carbo-cyanation of cyclopropene 106b afforded the cyclopropane 154b in a low yield of 24% (Scheme V.34).

Scheme V.34. Carbo-cyanation reaction of cyclopropene 106b. Reagents and conditions: i) (SnMe3)2 (2.0 eq.), DTBHN (0.4 eq.), benzene (0.2 M), 65 °C, 6 h.

The application of the reduction reaction using nickel boride catalyst gave the desired lactam 29

with the ethyl side chain as expected (Scheme V.35). However, only 11% (2 mg) were obtained with formation of a complex mixture of products. The structure of compound 29 was confirmed by mass spectrometry and 1 H NMR, but other analyses were not performed due to the small isolated amount.

Due to the lack of time, this reaction was not studied further and the enantioselective synthesis could not be accomplished.

Scheme V.35. Nickel boride-mediated reduction reaction of cyclopropane 154b. Reagents and conditions: i) NiCl2 (2.2 eq.) NaBH4 (20.0 eq.) EtOH (0.025 M), 0 to 20 °C, 12 h.

Conclusion

In this chapter, the total synthesis of racemic eburnamonine and eburnamine was investigated.

This synthesis was not straightforward and the construction of the ring C of eburnamine proved to be complicated with the model under study. After several attempts, the total synthesis of (±)eburnamonine and (±)-epi-eburnamonine was achieved in 9 steps in 1:1.2 diastereomeric ratio, starting from a cheap commercially available 2-piperidinone (δ-valerolactam). After an easy separation through column chromatography, these compounds were then reduced in an additional step to give eburnamine and epi-eburnamine, respectively. Both alkaloids were thus obtained in 10 steps sequence, in ~ 81% average yield and 9.5% overall yield. Although this synthesis was developed as an entry towards the enantioselective synthesis of eburnamine, the latter was not accomplished due to the lack of time. Yet, the required steps were developed on a similar chiral model and they can be later applied to the desired target.

Chapter VI Biomimetic Coupling Studies Towards Leucophyllidine

Introduction

Morita and co-workers 2 isolated both leucophyllidine, eburnamine and eucophylline from leuconotis eugenifolius. This finding advocates that the biogenetic analysis proposed by Kam et al.,1 consisting of a coupling between the two fragments, eburnan 7 and eucophylline 8, will most probably produce leucophyllidine 6. Monomers coupling would proceed through a Mannich-type reaction between the C-7 electrophilic center of eburnan 7 and the C-1' electron-rich center of eucophylline 8

to afford the bis-indole template of leucophyllidine (Scheme VI.1).

Scheme VI.1. Retrosynthesis of leucophyllidine.

Biomimetic coupling in the synthesis of dimeric indole alkaloids

When considering the synthesis of these types of dimeric natural products, only a few syntheses were designed relying on the biomimetic couplings between two alkaloid monomers. Among the most well-known examples in the biomimetic coupling approaches is the synthesis of vinblastine 2 described by Boger and co-workers and several others before. 11,37 In Boger's work, the catharanthine 13 monomer was activated using Fe(III) to promote its coupling with vindoline 12, thus providing a biomimetic access to vinblastine 2 (Scheme VI.2). This reaction showed high stereochemical selectivity to produce exclusively the natural diastereomer.

Scheme VI.2. Biomimetic approach in the total synthesis of vinblastine. 37 Mechanistic studies showed that the reaction proceeds through free-radical oxidation. At first, an electrophilic radical is generated in catharanthine 13 monomer by single-electron oxidation of the indole ring by the Fe(III) salt (Scheme VI.3). Later, an intramolecular one-electron-two center bonding interaction between the radical site αto the carbomethoxy group and the iminium carbon stabilizes a conformation in which the upper face of the radical is sterically blocked. Finally, the addition of this radical to the electron-rich vindoline furnishes the natural diastereomer. 454

Scheme VI.3. Proposed mechanism for vinblastine biomimetic coupling. 454 The biomimetic coupling of haplophytine 528 was also studied by several groups. [455][456][457] In this alkaloid, the coupling between its two fragments occurs on an all-carbon quaternary stereocenter, which was found challenging to construct. 457 Knowing that the indole fragment aspidophytine 531 was also found in the plant, it was hypothesized that the treatment of haplophytine in acidic medium results in a 1,2-cationic shift. Upon rearrangement, this generates a new bis-iminium skeleton 529 that is probably involved in the biosynthetic pathway (Scheme VI.4).

Scheme VI.4. Hypothetic biosynthesis of haplophytine.

During the investigations in the total synthesis of haplophytine 528, Corey and co-workers studied the coupling process between two models of an electron-rich arene 533 and a canthiphytine derivative 532 (Scheme VI.5). 457 They concluded that it is not operative to generate a benzylic quaternary center under the studied conditions in order to promote this sterically unfavorable coupling.

Scheme VI.5. Model study towards the synthesis of Haplophytine. 457 Swenden and co-workers 458 described the biomimetic coupling of the monomer vobasinol 536

with an excess of apparicine 535 under acidic conditions to furnish the bis-indole alkaloid vobparicine 537 (Scheme VI.6). It was proposed that the coupling occurs through a reaction between the C-3' electrophilic center of vobasinol and the C-22 electron-rich center of apparicine 535.

Scheme VI.6. Biomimetic coupling of vobparicine 537. 458 Magnus and Brown 459 also described the successful synthesis of (-)-norpleiomutine 539. The synthesis of this bis-indole alkaloid occurred through the coupling between two fragments, eburnamine 18 and (-)-kopsinine 538, in 2% aqueous HCl (Scheme VI.7).

Scheme VI.7. Biomimetic coupling in (-)-norpleiomutine. 459 Szántay and co-workers 460 reported the biomimetic coupling between eburnamine 18 and vindoline 12 in a mixture of HCl/MeOH to give the non-natural bis-indole aspidosperma-eburnane 540 in 62% yield, thus proving the generality of this method (Scheme VI.8).

Scheme VI.8. Szántay biomimetic coupling in aspidosperma-eburnane bisindole 540. 460 Passarella and co-workers 461 reported the synthesis of aspidosperma-eburnane type alkaloid in 65% yield (Scheme VI.9). This alkaloid results from the biomimetic coupling between eburnamine 18 and 11-methoxytabersonin 541 in 3% HCl/MeOH solution.

Scheme VI.9. Passarella biomimetic coupling in aspidosperma-eburnane bis-indole 542. 461 Recently, Pandey and co-workers 352 reported the synthesis of molecule 543, the regioisomer of leucophyllidine 6 (Scheme VI.10). Eucophylline 8 and eburnamine 18 were heated in the presence of 2% HCl giving the wrong regioisomer 543 in 8-10% yield after 7 days. The coupling at the undesired position (C-12) was explained according to the stability of Wheland intermediates. Other attempts like the Petasis reaction with the boronic acid (X = B(OH)2) and the reaction between the lithiated eucophylline (from lithium-halogen exchange, X = Br) with the iminium generated in situ by the treatment of BF3.OEt2 failed to give the expected result. Although a Mannich-type coupling was proposed, and in spite of the precedent from the literature, as mentioned above, the obtained results suggest that probably a more complex mechanism is involved in this dimerization.

Scheme VI.10. Attempts for biomimetic coupling in leucophyllidine by Pandey et al. 352

Proposed strategy for the biomimetic coupling in leucophyllidine

Based on the aforementioned biomimetic approaches, the synthesis of leucophyllidine will be first studied through a direct Mannich-type coupling between the ortho-phenol fragment of eucophylline 8 (or the methoxy analog) and the iminium generated from eburnamine 18 (Scheme VI.11). Triggering the complete conversion of the eburnamine 18 to the corresponding iminium will be investigated under different conditions. It was anticipated that the stereochemistry might be controlled during the biomimetic coupling by the torsional effects generated at the transition state through the CH2 moiety adjacent to the iminium. The eucophylline 8 would approach the eburnan from the top face of the iminium intermediate, syn to the ethyl group on the quaternary center, providing thus, the desired diastereomer.

Scheme VI.11. Proposed biomimetic coupling in leucophyllidine 6.

Therefore, to save the available and valuable amount of eucophylline, the feasibility of this biomimetic coupling approach will be investigated through model 417 which is very similar to the south fragment, eucophylline, and the racemic eburnamine 18 (Scheme VI.12). These substrates will be tested under several reaction conditions, for which some of them were already investigated in the literature. These studies would provide information on the regio-and stereoselectivity of the coupling, as well as the nucleophilicity of the eucophylline and methoxy-eucophylline under the coupling reaction conditions. Based on these results, the coupling between the natural subunits will be performed to produce natural leucophyllidine 6.

Scheme VI.12. Proposed model synthesis of nor-ethylleucophyllidine 544.

Biomimetic coupling studies

With the desired subunits in hand, the investigations started by first submitting the reaction to acidic conditions (Table VI.1). When the nor-ethylmethoxyeucophylline 398a was used, no reaction was observed even after 6 days of heating in a 3% HCl/MeOH solution (entry 1). For the eburnamine, no change was observed on TLC, while the protonation of 398a was detected (TLC, visualization under 360 nm), which gave back the starting material after basic workup (sat. NaHCO3). It was also suggested that probably the expected iminium was not formed efficiently under these conditions. To ensure the formation of eburnan 7, the reaction was performed in an NMR Young tube and the eburnamine was submitted to triflic anhydride to generate the corresponding triflate (entry 2). After 5 min, as observed by 1 H-NMR, the proton at position-7 disappeared with the appearance of another peak at 9.5 ppm that probably corresponds to the iminium proton. Eucophylline model 398a dissolved in CD2Cl2 was then added. No reaction was observed at 25 °C after 6 h, while heating at 50 °C provided the protonated form of 398a in 50% of conversion after 3 days (the conversion was followed by NMR by studying the vinyl signals). After extraction with sat. NaHCO3, the starting materials were recovered. The protonation of the model's nitrogens is caused by the generated triflic acid in the medium. This probably affects the nucleophilicity of the quinoline 398a and circumvent the coupling process. To prevent the formation of acid in the medium, the eburnamine was treated with MsCl to form the corresponding mesylate in the presence of an excess of triethylamine as a scavenger (entry 3). Once the TLC showed total consumption of the eburnamine, model 398a was added to the medium. No reaction was observed after 24 h, while heating at 50 °C for another 24 h resulted in the formation of a new product alongside the starting materials. After column chromatography, a quantity of the eucophylline model was recovered, and surprisingly, the new product was found to correspond to the vinylquinoline fragment, suggesting that some degradation took place. It was then decided to perform the reaction under mild conditions using NaHCO3 as a buffer. When model 398a was used in CH2Cl2 no reaction was observed and the starting materials were recovered after column chromatography (entry 4). The submission of model 417 to the mesyl chloride and triflic anhydride conditions did not allow the coupling to take place, showing that this model wasn't a better choice than 398a under these conditions (entries 6 and 7). Simple heating at reflux of both subunits 18 and 417 in chloroform for a long time, also did not give the desired outcome, and the starting materials were recovered after column chromatography (entry 8). At this point, it was decided to increase the nucleophilicity of nor-ethyleucophylline template by generating the corresponding phenolate using concentrated aqueous potassium hydroxide. Under such conditions, the eburnamine backbone decomposed while the norethyleucophylline was recovered after column chromatography (entry 9). Finally, the vigorous mechanical stirring of 18 and 417 under neat conditions did not promote the coupling and both monomers were recovered (entry 10).

General Conclusion & Perspectives

General conclusion

In the first part of this thesis, an efficient enantioselective synthesis of cyclobutenes was described, inspired by the research work of Narasaka and co-workers. [START_REF]C-13 or C-14[END_REF] A series of functionalized cyclobutenes was obtained through a desulfurization reaction on scales up to 10-20 grams, in excellent yields and enantioselectivities. The reactivity of these cyclobutenes towards free-radical species was studied through the addition of various radical traps. In this context, the carboalkynylation, carbo-cyanation, and atom transfer radical addition (ATRA) on cyclobutenes were studied. Haloalkanes were thus shown to add to the cyclobutenes' π-system through ATRA reaction to give the corresponding cyclobutanes in good to high yields (Scheme VII.1). The diastereoselectivity was found to be controlled by the steric hindrance of the oxazolidinone and that of the added radical precursor.

Scheme VII.1. ATRA reaction on cyclobutenes.

The sulfonyl-cyanation of olefins using eosin-Y as a photocatalyst under visible light irradiation, previously developed by the group, 5 was applied to the four-membered rings. In this process, alkylsulfonyl cyanides were used as excellent radical traps giving a series of polyfunctionalized derivatives 181 presenting nitrile-functionalized all-carbon quaternary centers, in excellent diastereoselectivities and good yields (Scheme VII.2).

Scheme VII.2. Sulfonyl-cyanation reaction of cyclobutenes using eosin-Y as a photocatalyst.

A more efficient sulfonyl-cyanation method was developed using p-anisaldehyde, as a photosensitizer (Scheme VII.3). Overall, the reactions were cleaner than those with eosin-Y, easier to carry out, requiring no aqueous treatment at the end of the reaction, and the purifications were more straightforward even on large scale. Eventually, this method proved to be compatible with a series of functional groups and allowed achieving scale-ups without affecting the yields. These polyfunctionalized templates were later submitted to ring-opening through radical fragmentation using samarium diiodide (Scheme VII.4). The resulting optically pure acyclic γ-nitriles 199 were obtained in good to high yields showing the compatibility of this procedure with a variety of substituents. The opened products were then transformed into other derivatives showing their utility to access new complex chiral compounds. For instance, the sulfone group could be eliminated under Ramberg-Bäcklund rearrangement conditions to furnish the olefin 235 in 40% yield. Although the desired olefin was obtained, this reaction suffered from problem of reproducibility due to the harsh conditions that probably hydrolyze the nitrile group. From the ring-opened nitrile 199, a lactonization reaction was also developed to give access to a new type of lactone 240a bearing an allcarbon quaternary center, in 63% yield.

Scheme VII.4. SmI2-promoted ring-opening reaction and derivatives of the ring-opened compound 199.

Cyclobutane 181 was also transformed into other useful templates (Scheme VII.5). For instance, the sulfone fragment was eliminated under basic conditions after several optimizations, to give the cyclobutene carboxylate 258 in excellent yields. Good reproducibility was also observed on a range of cyclobutanes on 15-20 mmol scales. These cyclobutenes were manipulated further to develop new ring-opening methods. First, under ozonolysis conditions, cyclobutene carboxylate 258a gave the ring-opened tricarbonyl compound 266 in 84% yield. This α-ketoester-aldehyde was found unstable, and several attempts to functionalize it further failed. The enone 258 was found reactive towards nucleophiles through 1,4-conjugate additions. Amine, alcohol, nitromethane, and malonate derivatives were successfully added to the enone's double bond, to give the corresponding Michael products in high to excellent yields.

Scheme VII.5. Derivatives obtained from cyclobutane 181.

A derivative of these frameworks, the cyclobutyl malonate 332, was engaged in a reduction reaction using nickel boride as a catalyst (Scheme VII.6). After several optimizations, a new method was established, allowing the nitrile reduction, cyclization, and cyclobutyl ring-opening in a one-pot process. This sequence was applied to a series of cyclobutanes with different functionalized side chains. The resulting lactams 380 were further manipulated to generate the azabicyclo [3.3.1]nonane in low to moderate yields.

Scheme VII.6. Nickel boride-mediated nitrile reduction, cyclization, and cyclobutyl ring-opening.

Later, the enantioselective total synthesis of eucophylline 8, a unique vinylnaphthyridine alkaloid isolated from Leuconotis eugenifolius, was planned based on the above strategy. The synthesis was accomplished in 17 steps starting from the commercially available but-1-yne or 1,1-dibromobut-1ene, in 85% average yield, and 5.9% overall yield (Scheme VII.7). The HPLC analysis confirmed the high enantiomeric excess of the natural product (ee = 98%). In this synthesis, no protecting groups were used and only 9 steps required purification on column chromatography. The synthetic approach features the preparation of a chiral cyclobutene which was further functionalized to introduce the asymmetric all-carbon quaternary stereocenter through a photocatalytic approach. The X-ray analyses secured the first X-ray crystal structure of 8, which confirmed the successful synthesis of the natural enantiomer.

Scheme VII.7. Enantioselective total synthesis of (+)-eucophylline.

The synthesis of the racemic eburnamonine 423, epi-eburnamonine 520, eburnamine 18 and epieburnamine 424 was also accomplished starting from commercially available 2-piperidinone 379 (Scheme VII.8). The transformation of this lactam allowed the formation of the amine (±)-517a that holds the all-carbon quaternary center present in the eburnane skeletons. After several unsuccessful attempts, a racemic total synthesis of the eburnane series was finally accomplished, in which the last steps were based on Wenkert's approach. 6,451 Eburnamine 18 and epi-eburnamine 424 were both obtained in 10 steps sequence, in ~ 81% average yield and 9.5% overall yield.

Scheme VII.8. Total synthesis of racemic eburnane series.

The enantioselective synthesis of (+)-517a was planned starting from a chiral cyclopropene 31 (Scheme VII.9). The enantioenriched eburnane series would then be prepared from (+)-517a based on the strategy used for the racemic synthesis before. The Synthesis of the amine 517a was studied on a cyclopropene model with a propyl side chain. However, due to the lack of time, the extension of this work to cyclopropene 31 could not be carried out.

Scheme VII.9. Enantioselective total synthesis of the eburnane series starting from a cyclopropene ring system.

Finally, the synthesis of leucophyllidine 6, a cytotoxic indole alkaloid isolated from the stembark of Leuconotis griffithii, was investigated. The biomimetic coupling between fragments 8 and 18

was studied using racemic eburnamine and a structurally similar model of eucophylline, the norethyleucophylline 417 (Scheme VII.10). Preliminary results showed that the coupling in moderately acidic medium provokes protonation of the nor-ethyleucophylline's nitrogens, which probably alters its nucleophilicity and prevents the coupling. This reaction is still under investigation and will be reported in due course.

Scheme VII.10. Biomimetic coupling approach towards leucophyllidine's model.

Perspectives

The Furthermore, the amino-alcohols 390 and 557 obtained from cyclobutenes and cyclopropenes could be used in the construction of chiral pyrans 555 and furans 556, respectively, bearing an allcarbon quaternary center (Scheme VII.12). These heterocycles could be then used as intermediates in the synthesis of complex targets or natural products.

Scheme VII.12. Synthesis of functionalized pyrans and furans from cyclobutenes and cyclopropenes.

On the other hand, a new tin-free carbo-cyanation reaction on cyclobutenes and cyclopropenes is still needed in order to install an all-carbon quaternary center in a stereocontrolled manner, under mild and efficient conditions (Scheme VII.13). Due to the low reactivity of cyclobutenes towards radicals, such a reaction should be studied carefully to reach the desired goal. The sulfonyl-cyanation reaction could also be investigated on cyclopropenes using p-anisaldehyde as a photosensitizer (preliminary results: Mr. Matteo Cayla, Master 1 internship). Further studies towards the sulfone elimination could also be investigated under basic medium. This would offer a new pathway to access cyclopropanes/enes holding an all-carbon quaternary center in a stereocontrolled manner through a tin-free process. These studies would eventually offer access to a new library of highly valuable optically pure cyclic derivatives.

Scheme VII.13. Further carbo-and sulfonyl-cyanation reactions of small-sized rings.

For the enantioselective total synthesis of the eburnane series, this could be developed from cyclopropane 30 and following the strategy already applied on the cyclopropane model 154a with a propyl side chain to generate the ester 517a (Scheme VII.14).

Scheme VII.14. Enantioselective synthesis of eburnamine through a cyclopropane intermediate.

Experimental Part

Experimental Part -General Information

Chemical reagents and apparatus

All reactions were carried out under nitrogen or argon atmosphere with dry solvents under anhydrous conditions unless otherwise noted. The glass equipment and stirring bars were stored in an oven at 180 °C or heat gun-dried and evacuated prior to use. Dichloromethane (CH2Cl2), methanol (MeOH), tetrahydrofuran (THF), diethyl ether (Et2O), and toluene were dried over activated alumina columns on MBraun Solvent Purification System (SPS-800). Anhydrous dimethylformamide (DMF) and acetone AcroSeal™ packaging stored under argon were purchased from a chemical supplier (Acros Organics). Benzene (PhH) and tetrahydrofuran used for the organolithium reactions were distilled from sodium/benzophenone. Dry chlorobenzene (PhCl), 1,2-dichloroethane (DCE), 1,2dimethoxyethane (DME), n-hexane, and ethyl acetate (EtOAc) were obtained by distillation over CaH2 and they were all stored over oven-activated 4 Å molecular sieves. Dry 1,4-dioxane, acetonitrile (CH3CN), and ethanol (EtOH) were obtained by distillation over CaH2 and stored over oven-activated 3 Å molecular sieves. Diisopropylamine (DIPA), N,N'-diisopropylethylamine (DIPEA), triethylamine (Et3N), and 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) were distilled from CaH2 and stored over oven-activated 4 Å molecular sieves. 2,2,6,6-tetramethylpiperidine (TMP) was distilled from CaH2, under vacuum (0.8 mbar) at 70-80 °C and stored over oven-activated 4 Å molecular sieves. Hexamethylphosphoramide (HMPA) was distilled from CaH2, under vacuum (0.8 mbar) at 55 °C and stored over oven-activated 4 Å molecular sieves. Ti(OiPr)4 was distilled under vacuum (0.8 mbar) and used directly in the appropriate reaction. Triethylsilane (Et3SiH) was distilled and used directly in the appropriate reaction. Potassium carbonate (K2CO3) was dried in the oven for weeks prior to use. n-BuLi was titrated prior to use with N-benzylbenzamide (3 x). 462 water for reactions was purified by Millipore Direct-Q™ 3 Tap purification system, particle size 0.22 μm. Other commercial reagents were used as received without further purification unless otherwise stated.

Photochemical reactions were performed with commercial LEDs (7 W, 12 V, 500 mA) and a Rayonet ® RPR-200 Photochemical Reactor (Model RPR-200, 110/227 volts, 50/60 Hz, operating temp 30-40 °C) with UV-A light (2 x RPR 3500 Å Black Light Blue, 8 W, 12-inches, or 6 x Black Light fluorescent tube 8w/08 BLB 370 nm, 12-inches), UV-C light (6 x 254 nm, Philips TUV 16 W G16T5, 12-inches), and blue light (2 x RPR 4190 Å, 12-inches).

UV-vis absorption spectra were measured on a Cary 100 Scan UV-vis spectrophotometer (Varian, USA), using quartz cuvette (1 cm light path, Hellma 110-QS) in the 200-800 nm spectral range.

Analytical thin layer chromatography (TLC) was performed using silica gel 60 F254 pre-coated plates (Merck) with visualization by ultraviolet light (mainly 254 nm). An ethanolic solution of vanillin or an aqueous solution of potassium permanganate/sodium carbonate and heat were used as developing agents. Merck silica gel (60, particle size 40-63 μm) was used for column chromatography. Diastereomers were described as mixtures, when it was not possible to separate them using classic column chromatography. Yields refer to chromatographically and spectroscopically ( 1 H and 13 C NMR) homogeneous materials unless otherwise stated. Diastereomeric ratios were estimated by 1 H or 13 C NMR analyses of the crude reaction mixture after a short filtration on column unless otherwise stated.

1D and 2D NMR analyses with the specified deuterated solvents were recorded at 20 °C on a Brüker Avance I 300 ( 1 H: 300 MHz, 13 C: 75.46 MHz), a Brüker Avance II 400 ( 1 H: 400 MHz, 13 C: 100.75 MHz) or a Brüker Avance III 600 ( 1 H: 600 MHz, 13 The mass spectrometric measurements were performed at the Centre d'Etude Structurale et d'Analyse des Molécules Organiques (CESAMO) at the Institut des Sciences Moléculaires (ISM, CNRS-UMR 5255, Talence, France). High-resolution mass spectrometry (HRMS) and lowresolution mass spectrometry (LRMS) were recorded on a QStar Elite ABSciex (ElectroSpray Ionization (ESI), Atmospheric Pressure Chemical Ionization (APCI)), on an AccuTOF JEOL (Electron Ionization (EI), Chemical Ionization (CI), Field Desorption (FD), Field Ionization (FI)), or on a Qexactive mass spectrometer (Thermo). The Qexactive instrument is equipped with an ESI source and the spectra were recorded in the negative/positive mode. The spray voltage was maintained at 3200 V and capillary temperature set at 320 °C. Samples were introduced by injection through a 20 mL sample loop into a 300 mL/min flow of methanol from the LC pump.

IR spectra were recorded between 4000 and 550 cm -1 on a Bruker IFS55 (OPUS/IR 3.0.2) FT-IR spectrometer, using a highly polished KBr crystal plate for liquid samples (thin films), or KBr pellet for powder samples (thin and transparent pellet). Optical rotation measurements were carried out on a JASCO P-2000ST polarimeter using a sodium lamp (589 nm) at 23-25 °C, and the reported values represent the average of 15 measurements. Melting points (m. p.) were recorded on a digital Buchi B-540 melting point capillary apparatus in open capillary tubes and are uncorrected.

The enantiomeric excess measurements were performed on a Jasco LC-NetII/ADC HPLC using a Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm) at 20 °C. For the racemic and chiral eucophylline 8, HPLC measurements were recorded on a Thermo Scientific Dionex Ultimate 3000 Diode Array Detector, using a Phenomenex ® column (Lux 5 µm Cellulose-3, 4.6 mmΦ x 250 mmL). Circular Dichroism (CD) spectra were recorded on a JASCO J-815 instrument in the wavelength range of 200-400 nm with a data pitch of 0.1 nm at 20 °C in a 2 mm quartz cell, under nitrogen flow (99.9%).

The X-ray structure analysis measurements were carried out at the CESAMO technical center, on a Brüker APEX 2 DUO. A single crystal was mounted and immersed in a stream of nitrogen gas [T = 150(2) K]. For compound 180a, crystallographic data were collected, using a microfocus sealed tube of Mo Kα radiation (k = 0.71073 Å) on a KappaCCD diffractometer. For eucophylline 8, data were collected, using a microfocus sealed tube of Cu Kα radiation (k = 1.54184 Å) on a KappaCCD diffractometer. For both compounds, data collection and cell refinement were performed using APEX2 2013.10-0 (Bruker AXS Inc.), and SAINT v8.34A (Bruker AXS Inc.). Data reduction was performed using SAINT v8.34A (Bruker AXS Inc.). Correction for absorption was performed using multi-scan integration as included in SADABS V2012/1 (Bruker AXS). Structure solutions were found by charge flipping methods SUPERFLIP 463 or EDMA 464 and refined using Shelx software suite. 465 The program Mercury 466 was used for analysis and drawing figures.

Visible-light irradiation system

A cylindric vial, containing all the reagents, was placed in the middle of an assembly of LEDs light strip fixed on a cylindric glass (diameter: 8 cm). The green LEDs-irradiation reaction system Experimental Part -Chapter III

The blue LEDs-irradiation reaction system

General procedures for chapter III

General procedure (A) for sulfonyl cyanides synthesis 5 Hydrogen peroxide (50 wt. % solution in water, 5.0 eq.) was added dropwise at 0 °C to a solution of trifluoroacetic anhydride (5.0 eq.) in CH2Cl2 (1.0 M) in a two-necked flask equipped with a condenser and a glass cap. After being stirred for 40 min at 0 °C, alkyl thiocyanate (1.0 eq.) was added dropwise without dilution and the reaction mixture was stirred at 40 °C silicon oil bath temperature for 5 h. At 0 °C, the reaction was quenched with water. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with water (x 2) and brine, dried over Na2SO4 and concentrated carefully under reduced pressure (volatile). The crude was pure enough to be used directly without further purification.

General procedure (B) for the synthesis of alkynyl sulfides

In a dried two-necked flask, the alkyne (1.125 eq.) was diluted in dry THF (0.65 M) and freshly titrated n-BuLi in hexane (1.06 eq.) was added dropwise at 0 °C. The reaction mixture was stirred for 30 min at 0 °C and dimethyl disulfide (1.0 eq.) was then added. The mixture was stirred for 2 h at 20 °C and quenched with 2-bromoethanol (1.25 eq.). After stirring further for 1 h, water was added. The aqueous layer was extracted with Et2O (x 3) and the combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The obtained crude mixture was then purified through column chromatography on SiO2 (eluents as noted).

General procedure (C) for Narasaka's asymmetric [2+2] cycloaddition 3

To a dried two-necked flask under inert atmosphere, TiCl2(OiPr)2 (0.1 eq.) and the chiral ligand (R)-115 (0.11 eq.) were introduced, followed by dry toluene (0.08 M), and the mixture was stirred for 1 h at 20 °C.

To a two-necked flask under inert atmosphere, 4 Å molecular sieves (39 mg/mmol of substrate) were introduced and activated by heat gun under vacuum. Dry toluene (0.25 M) was then added followed by the titanium complex prepared above and the reaction was transferred to 0 °C. 3acryloyloxazolidin-2-one (1.0 eq.) and the alkynyl sulfide (2.0-1.5 eq.) were then added successively to the mixture, and the reaction was stirred till completion at 20 °C. The reaction was then quenched with sat. aqueous NaHCO3 and the mixture was filtrated over a celite pad. The filtrate was extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: percentages as indicated) to obtain the desired cyclobutene.

General procedure (D) for racemic [2+2] cycloaddition reaction

Method A: without ligands To a two-necked flask under inert atmosphere, 4 Å molecular sieves (39 mg/mmol of substrate) were introduced and activated by heat gun under vacuum. Dry toluene (0.25 M) was added and the reaction was transferred to 0 °C. TiCl2(OiPr)2 (0.1 eq.), 3-acryloyloxazolidin-2-one (1.0 eq.) and the alkynyl sulfide (2.0-1.5 eq.) were then added successively to the mixture, and the reaction was stirred till completion at 20 °C. The reaction was quenched with sat. aqueous NaHCO3 and the mixture was filtrated over a celite pad. The filtrate was extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (cyclohexane/ EtOAc) to obtain the desired cyclobutene. Method B: with chiral ligands (R) and (S).

To a dried two-necked flask under inert atmosphere, TiCl2(OiPr)2 (0.1 eq.), the chiral ligand (S)-115 (0.055 eq.), and the chiral ligand (R)-115 (0.055 eq.) were introduced, followed by dry toluene (0.08 M), and the mixture was stirred for 1 h at 20 °C.

To a two-necked flask under inert atmosphere, 4 Å molecular sieves (39 mg/mmol of substrate) were introduced and activated by heat gun under vacuum. Dry toluene (0.25 M) was then added followed by the titanium complex prepared above and the reaction was transferred to 0 °C. 3acryloyloxazolidin-2-one (1.0 eq.) and the alkynyl sulfide (2.0-1.5 eq.) were then added successively to the mixture, and the reaction was stirred till completion at 20 °C. The reaction was quenched with sat. aqueous NaHCO3 and the mixture was filtrated over a celite pad. The filtrate was extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (cyclohexane/ EtOAc) to obtain the desired cyclobutene.

General procedure (E) for desulfurization reaction

Cyclobutene (1.0 eq.) was introduced to a two-necked flask under inert atmosphere. Acetone AcroSeal™ packaging (0.06-0.1 M) was added, followed by Lindlar's catalyst (5% on calcium carbonate poisoned with Lead, 1.0-10.0 eq.), and oct-1-ene (1.0-10.0 eq.). Freshly distilled triethylsilane (10.0 eq.) was added slowly at the end. The mixture was stirred at 20 or 50 °C silicon oil bath temperature, and the evolution of the reaction was monitored until complete conversion by aliquot NMR. After completion, the product was filtrated on a celite pad and purified through column chromatography on SiO2 (cyclohexane/EtOAc: percentages as noted) to obtain the pure reduced cyclobutene.

General procedure (F) for carbo-alkynylation

To a dried two-necked flask equipped with a condenser and under inert atmosphere, the olefin (1.0 eq.) was introduced followed by distilled DCE (0.1 M), and the alkyne (1.5 eq.). AIBN (0.2 eq.) was added and the reaction was heated at 85 °C silicon oil bath temperature. 0.2 eq. x 4 of AIBN were then added every 4-7 h. After 19 h, the reaction was quenched with water (3 mL) and extracted with CH2Cl2 (7 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4 then concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 95/5) to afford the pure desired product.

General procedure (G) for atom transfer radical addition reaction

A 10 mL sealed tube was charged with cyclobutene 169a (1.0 eq.), DMF/H2O: 4/1 (0.15 M), halogenoalkane (2.0 eq.), sodium L-ascorbate (2.0 eq.), LiBr (2.0 eq.) and [Ir(PPy)2(dtbbPy)]PF6 (0.02 eq.). The mixture was degassed by three cycles of freeze-pump-thaw and irradiated at 30 °C with blue LEDs (400-495 nm, the tube was positioned approximately 4 cm away from the light source). After completion, the reaction was quenched with water and extracted with EtOAc. The organic layer was then washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: eluants as noted) to afford the pure desired product.

General procedure (H) for eosin-photocatalyzed sulfonyl-cyanation reaction 5

A 10 mL sealed tube equipped with a stirrer was charged with cyclobutene (1.0 eq.), DMF AcroSeal™ packaging (1.0 M), sulfonyl cyanide (2.0-4.0 eq.), eosin-Y (2 mol %) and K2HPO4 (0.2 eq.) then the mixture was stirred 2 minutes for homogenization. The reaction mixture was degassed by argon sparging for 30 min, then it was irradiated at 30 °C under green LEDs light (500-565 nm, the tube was positioned approximately 4 cm away from the light source), and monitored by TLC.

After completion, the reaction mixture was diluted with EtOAc and aqueous HCl (1.0 M). The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was then purified through column chromatography on SiO2 (elution solvents as noted) to afford the desired cyclobutane.

General procedure (I) for p-anisaldehyde-photosensitized sulfonyl-cyanation reaction

A 10 mL side arm storage schlenk equipped with a stirrer was charged with cyclobutene (1.0 eq.), acetonitrile (1.0 M), sulfonyl cyanide (2.0-5.0 eq.) and p-anisaldehyde (0.2 eq.). The reaction mixture was degassed by three cycles of freeze-pump-thaw, then the tube was refilled with nitrogen. The reaction mixture was irradiated at 30 °C under UV-A light (325-400 nm, the tube was positioned approximately 10 cm away from the light source), and it was monitored by TLC under nitrogen atmosphere. After completion, the solvent was concentrated under reduced pressure and the crude mixture was purified through column chromatography on SiO2 (elution solvents as noted) to afford the desired cyclobutane.

General procedure (J) for p-anisaldehyde control experiments

The control experiments were carried out in Young NMR tubes, on 0.1 mmol scale of 169a in 0.5 mL CD3CN (0.2 M). Before irradiation, the mixture was degassed by three cycles of freeze-pumpthaw.

General procedure (K) for SmI2-mediated ring-opening reaction

In a dried two-necked flask, the starting material (1.0 eq.) was dissolved in dry THF (0.1-0.2 M), then distilled H2O (12.0-18.0 eq.) was added. The reaction was cooled down to -78 °C and stirred 5 min at this temperature. Afterwards, SmI2/THF (3.5-4.5 eq.), was added dropwise. The dark blue color of SmI2 was immediately quenched upon addition of each drop and became persistent after addition of certain volume of SmI2. The evolution of the reaction was monitored by TLC maintaining the temperature between -70 and -78 °C. After full conversion, the reaction was then quenched at -78 °C by addition of aqueous HCl (1.0 M) and air sparging for 5 min, the color changed to yellow. The reaction was then stirred at 20 °C for another 5 min, diluted with CH2Cl2 and extracted with aqueous HCl (1.0 M). The aqueous phase was back-extracted with CH2Cl2, and the combined organic layers were washed with aqueous sodium thiosulfate/Rochelle salt: 1/1, and brine, then dried over Na2SO4 and concentrated under reduced pressure. Purification of the crude mixture through column chromatography on SiO2 (CH2Cl2/EtOAc: percentages as noted) afforded the desired product.

Preparation of 0.2 M solution of SmI2/THF: 467 A two-necked flask containing Sm metal (Strem, 2.48 g, 16.5 mmol, 1.5 eq.) was flame-dried under vacuum then cooled to ambient temperature. The atmosphere was exchanged three times for argon, then freshly purified 1,2-diiodoethane (2.79 g, 11.0 mmol, 1.0 eq.) was added and the atmosphere was exchanged again three times for argon. Freshly dried THF (55.0 mL, 5.0 M) was then added and the mixture was stirred vigorously under argon. After 15 min the color turned from dark green to dark blue. After 2 h, the stirring was halted and the mixture was allowed to settle for 30 min prior to use. Purification of 1,2-diiodoethane: 467 1,2-diiodoethane (25.0 g) was dissolved in Et2O (250.0 mL) and washed with saturated Na2S2O3 (3 x 15 mL, aqueous solution) and distilled water (3 x 10 mL). The organic layer was dried over Na2SO4, concentrated under reduced pressure then dried under vacuum to give a white solid (23.0 g).

General procedure (L) for transesterification reaction

In a dried two-necked flask equipped with a condenser, the cyclobutane (1.0 eq.) was dissolved in distilled EtOH (0.07 M), then DMAP (0.5 eq.) was added and the reaction mixture was heated at 78 °C silicon oil bath temperature. The consumption of the starting material was followed by TLC, then the solvent was concentrated under reduced pressure and the crude mixture was purified through short column chromatography on SiO2 (eluents as noted) to afford the pure desired product.

General procedure (M) for base-mediated sulfone elimination reaction

In a dried two-necked flask equipped with a condenser, the cyclobutane (1.0 eq.) was dissolved in DMF AcroSeal™ packaging (0.1 M), then Cs2CO3 (2.0 eq.) was added and the reaction mixture was heated at 70 °C silicon oil bath temperature. The consumption of the starting material was followed by TLC, then the solvent was evaporated directly for small scales. For large scales, the reaction was washed with aqueous HCl (1.0 M) and extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through short column chromatography on SiO2 (eluents as noted) to afford the desired cyclobutene.

General procedure (N) for 1,4-conjugate addition of dialkyl malonate

To a flame-dried two-necked flask and under inert atmosphere, dialkyl malonate (1.0 eq.) was introduced followed by dry THF (0.2 M) and the reaction was set at 0 °C. NaH (60% suspension in oil, 1.0 eq.) was added portion-wise and the reaction was stirred for 10 min at the same temperature.

The cyclobutene (1.0 eq.) was dissolved in dry THF (0.17 M) and added slowly to the mixture. The reaction was stirred at 20 °C and followed by TLC. After completion, the reaction was quenched with sat. NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude as a mixture of diastereomers was pure enough to be used directly in the next step without further purification. [Purification of the crude for analysis was accomplished through short column chromatography on SiO2 (cyclohexane/ EtOAc: eluents as noted)].

Synthesis of starting materials (but-3-yn-1-yloxy)triisopropylsilane (S-1) 468

To a dried two-necked flask under inert atmosphere and set at 0 °C, 3-butyn-1-ol (9.0 mL, 119.0 mmol, 1.0 eq.) was introduced, followed by dry CH2Cl2 (100.0 mL, 1.2 M), imidazole (10.5 g, 154.7 mmol, 1.3 eq.), and TIPSCl (28.0 mL, 130.9 mmol, 1.1 eq.) was added slowly. The mixture was stirred at 20 °C and the evolution of the reaction was followed by TLC. After 2 h, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 90/10 then 70/30) and was obtained as a colorless liquid (24.3 g, 90%). TLC (cyclohexane/EtOAc: 80/20): Rf = 0.88 (UV active; KMnO4, stains yellow).

tert-butyldimethyl(prop-2-yn-1-yloxy)silane (S-2) 469

To a dried two-necked flask under inert atmosphere and set at 0 °C, prop-2-yn-1-ol (5.2 mL, 89.0 mmol, 1.0 eq.) was introduced, followed by dry THF (70.0 mL, 1.3 M), imidazole (7.9 g, 116.0 mmol, 1.3 eq.), and TBDMSCl (7.9 g, 116.0 mmol, 1.3 eq.) was added slowly. The mixture was stirred at 20 °C and the evolution of the reaction was followed by TLC. After 2 h, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified through column chromatography on SiO2 (pentane/EtOAc: 99/1) and was obtained as a colorless liquid (12.2 g, 80%). TLC (pentane/EtOAc: 95/5): Rf = 0.56 (UV active; KMnO4, stains yellow). To a dried flask under inert atmosphere, Ti(OiPr)4 freshly distilled under vacuum (6.4 mL, 21.0 mmol, 1.05 eq.), was introduced followed by distilled n-hexane (20.0 mL, 1.0 M). TiCl4 (2.2 mL, 20.0 mmol, 1.0 eq.) was then added dropwise at 20 °C. The color changed to pale-yellow and the solution was kept under stirring for 30 min. The stirring was then halted and the mixture was allowed to settle for 2 h at the same temperature to allow crystallization to happen. The solvent was then removed under inert atmosphere via syringe and the crystals were washed with cold hexane (3 x 3 mL) and dried under vacuum. The product (7.0 g, quant.) was obtained as white crystals and stored under argon atmosphere in the freezer.

(1,1-dimethoxyethyl)benzene (S-3) 198 To dry MeOH (40.0 mL, 4.25 M) in a two-necked flask under inert atmosphere, acetophenone (20.1 g, 170.0 mmol, 1.0 eq.) was added, followed by trimethyl orthoformate (27.3 g, 257.0 mmol, 1.5 eq.) and a catalytic amount of p-toluenesulfonic acid monohydrate (261.0 mg, 1.4 mmol, 0.8% eq.). The mixture was stirred at 65 °C silicon oil bath temperature for 20 h, and the reaction was followed by TLC. After completion, the solvents were evaporated, and the product was diluted in EtOAc, washed with water, then extracted. The organic layer was then washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The product (26.8 g, 95%) was obtained as a brown liquid, pure enough to be used in the next step without further purification. TLC (cyclohexane/EtOAc: 90/10): Rf = 0.89 (UV active; KMnO4, stains yellow). (4R,5R)-dimethyl 2-methyl-2-phenyl-1,3-dioxolane-4,5-dicarboxylate (S-4) 198 A dried two-necked flask was equipped with a condenser, and a dean stark system filled with dry toluene (10.0 mL) used to eliminate methanol. Under inert atmosphere, acetophenone dimethyl acetal (12.0 g, 72.19 mmol, 1.0 eq.) was introduced followed by dry toluene (40.0 mL, 1.8 M), (+)dimethyl L-tartrate (12.8 g, 72.19 mmol, 1.0 eq.) and a catalytic quantity of p-toluenesulfonic acid monohydrate (1.37 g, 7.22 mmol, 0.1 eq.). The brown solution was stirred at 120 °C silicon oil bath temperature for 48 h and the reaction was followed by TLC. The crude mixture was diluted in ethyl acetate and washed with NaHCO3 then brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 95/5). The product (10.6 g, 52%) was obtained as a brown oil. TLC (cyclohexane/EtOAc: 90/10): Rf = 0.2 (UV active; KMnO4, stains yellow). A dried two-necked flask was equipped with a condenser, and a dean stark system filled with dry toluene (10.0 mL) used to eliminate methanol. Under inert atmosphere, acetophenone dimethyl acetal (20.6 g, 124.0 mmol, 1.0 eq.) was introduced followed by dry toluene (69.0 mL, 1.8 M), (-)-dimethyl D-tartrate (22.1 g, 124.0 mmol, 1.0 eq.) and a catalytic quantity of p-toluenesulfonic acid monohydrate (2.36 g, 12.4 mmol, 0.1 eq.). The brown solution was stirred at 120 °C silicon oil bath temperature for 30 h and the reaction was followed by TLC. The crude mixture was diluted in ethyl acetate and washed with NaHCO3 then brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 90/10). The product (3.0 g, 9%) was obtained as a brown oil. TLC (cyclohexane/EtOAc: 90/10): Rf = 0.2 (UV active; KMnO4, stains yellow; vanillin, stains red).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 7.81-7.28 (m, 5H, H-10, H-11, H-12, H-13, H-14), 4.89-4.80 (m, 2H, H-5, H-6), 3.85 (s, 3H, H-1 or H-3), 3.74 (s, 3H, H-1 or H-3), 1.54 (s, 3H, H-8).

((4R,5R)-2-methyl-2-phenyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol) ((R)-115) 198

To dry THF (300.0 mL, 0.12 M) in a flame-dried flask under inert atmosphere and set at 0 °C, phenylmagnesium bromide (3.0 M in THF, 63.0 mL, 189.0 mmol, 5.0 eq.) was added. Afterwards, the prepared dioxolane S-4 (10.6 g, 37.8 mmol, 1.0 eq.) diluted in dry THF (7.0 mL) was added. The mixture was stirred for 15 h at 20 °C. After completion, the product was washed with sat. NH4Cl and extracted with EtOAc. The organic layer was then washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 90/10) to obtain it as a white amorphous solid (17.5 g, 87%). TLC (cyclohexane/EtOAc: 90/10): Rf = 0.46 (UV active; KMnO4, stains yellow; vanillin, stains red).

((4S,5S)-2-methyl-2-phenyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol) ((S)-115)

To dry THF (136.0 mL, 0.06 M) in a two-necked flask under inert atmosphere and set at 0 °C, phenylmagnesium bromide (1.0 M in THF, 41.6 mL, 41.6 mmol, 5.0 eq.) was added. Afterwards, the prepared dioxolane S-5 (2.33 g, 8.3 mmol, 1.0 eq.) diluted in dry THF (5 mL) was added. The mixture was stirred at 20 °C for 17 h. After completion, the product was washed with sat. NH4Cl and extracted with EtOAc. The organic layer was then washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 90/10) to obtain it as a white amorphous solid (1.7 g, 39%).

3-acryloyloxazolidin-2-one (113) 470

Synthesis of acrylic anhydride: To acrylic acid (11.9 mL, 174.0 mmol, 1.25 eq.) in a flame-dried flask, EtOAc (500.0 mL, 0.35 M) was added and the mixture was transferred to 0 °C. Distilled triethylamine (24.3 mL, 174.0 mmol, 1.25 eq.) was then added followed by acryloyl chloride (14.1 mL, 174.0 mmol, 1.25 eq.). After 30 min at 0 °C, the reaction was stirred for another 30 min at 20 °C. A white suspension was formed, it was filtrated on Büchner, and washed with EtOAc. The filtrate was concentrated under reduced pressure to obtain the product as a pale-yellow liquid and it was directly engaged in the next step.

To a two-necked flask under argon and set at 0 °C, 2-oxazolidinone (12.1 g, 139.2 mmol, 1.0 eq.) was introduced to dry THF (500.0 mL, 0.3 M), then lithium chloride (3.6 mL, 174.0 mmol, 1.25 eq.), distilled triethylamine (24.3 mL, 174.0 mmol, 1.25 eq.) and the acrylic anhydride (1.25 eq.) were added. The mixture was allowed to warm up slowly to 20 °C (exothermic reaction). After 7 h, the reaction was quenched with HCl aqueous solution (100.0 mL, 1.0 M). The product was extracted with CH2Cl2 and the organic layer was washed with sat. NaHCO3 then brine, dried over Na2SO4 and concentrated under reduced pressure. The obtained solid was washed with Et2O (3 x 5 mL) to get a white powder (15.7 g, 80% over 2 steps). The product was obtained pure enough to be used directly in the next step. TLC (cyclohexane/EtOAc: 50/50): Rf = 0.52 (UV active; KMnO4, stains yellow; vanillin stains colorless).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 7.49 (dd, J = 17.0, 10. 5 Hz, H-5), 6.55 (dd, J = 17.0, 1.8 Hz, 1H, H-6a), 5.90 (dd, J = 10.5, 1.8 Hz, 1H, H-6b), 4.44 (t, J = 8. 1 Hz, 2H, H-2), 4.08 (t, J = 8.0 Hz, 2H, H-3).

The 1 H NMR data are in agreement with those reported in the literature. 470

[(trimethylsilyl)ethynyl](phenyl)iodonium triflate (183) 210

To a flame-dried flask, iodosobenzene (3.4 g, 15.4 mmol, 1.0 eq.) was introduced followed by dry CH2Cl2 (15.4 mL). The mixture was set at 0 °C, then trifluoromethanesulfonic anhydride (1.0 M in CH2Cl2, 7.7 mL, 7.7 mmol, 0.5 eq.) was added slowly and the reaction was stirred at the same temperature until the suspension became a clear, homogeneous yellow solution (30 min). To the resulting Zefirov reagent, bis(trimethylsilyl)acetylene (2.6 g, 15.4 mmol, 1.0 eq.) dissolved in CH2Cl2 (15.4 mL) was added, and the solution was stirred at 0 °C for an additional 30 min. The solvents were concentrated under reduced pressure to give a beige solid. Trituration with Et2O (5 x 5 mL) gave the product (4.44 g, 64%) as a white solid after drying under vacuum. TLC: -1 H NMR (300 MHz, DMSO-d6): δ (ppm) = 8.30 (d, J = 7.7 Hz, 1H, H-8), 7.75 (t, J = 7.1 Hz, 1H, H-4), 7.62 (t, J = 7.5 Hz, 2H, H-5, H-7), 0.18 (s, 9H, H-TMS).

di-t-butyl hyponitrite (DTBHN) 471

To a flame-dried two-necked flask, Et2O (5.5 mL, 5.4 M) was introduced, followed by freshly distilled t-BuBr (34.0 mL, 296.0 mmol, 10.0 eq.). ZnCl2 (1.0 M in Et2O, 29.6 mL, 29.6 mmol, 1.0 eq.) was added dropwise at 0 °C, then sodium hyponitrite dried under vacuum the night before (3.14 g, 29.6 mmol, 1.0 eq.) was added portion-wise over 5 min. The reaction was stirred at 20 °C for 2 h. The mixture was filtered on Büchner, and the filtrate was washed with water and extracted with Et2O then dried over Na2SO4. The organic layer was concentrated under reduced pressure at 20 °C, then the white solid was dissolved in minimum of pentane (10 mL) and stored in the freezer overnight.

The pentane was then removed and the white crystals were weighed. The product (1.65 g, 32%) was covered with aluminium foil and stored under argon in the freezer.

di-tert-butyl 2-bromomalonate (76b) 472

To a flame-dried two-necked flask, di-tert-butyl malonate (1.0 mL, 4.46 mmol, 1.0 eq.) was introduced to dry THF (300.0 mL, 0.014 M) at 0 °C, then DBU (0.66 mL, 4.46 mmol, 1.0 eq.) was added slowly. The reaction was stirred at 20 °C for 1 h, then cooled down to -78 °C. CBr4 (1.48 g, 4.46 mmol, 1.0 eq.) was added and the mixture was stirred at the same temperature until completion and followed by TLC. After 5 h, the reaction was quenched with NH4Cl and extracted with CH2Cl2.

The organic layer was washed with brine, dried over Na2SO4 then concentrated under reduced pressure. The crude was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 70/30) to afford the product (1.44 g, quant.) as a pale-yellow oil. TLC (cyclohexane/EtOAc: 80/20): Rf = 0.70 (UV inactive; KMnO4, stains white-yellow).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.64 (s, 1H, H-1), 1.48 (s, 18H, H-t-Bu).

The 1 H NMR data are in agreement with those reported in the literature. 472

1-methoxy-2-thiocyanatoethane (S-6) 5 To a solution of ammonium thiocyanate (3.9 g, 51.0 mmol, 1.2 eq.) in EtOH (21.0 mL, 2.0 M) was added 1-bromo-2-methoxyethane (4.0 mL, 42.5 mmol, 1.0 eq.). The reaction mixture was heated at 78 °C silicon oil bath temperature for 14 h, then the reaction was allowed to reach 20 °C and the solid residues were filtered off and washed with CH2Cl2. The pooled liquids were washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to give the product (4.5 g, 90%) as a yellow-brown oil, pure enough to be used directly in the next step. TLC (cyclohexane/EtOAc: 80/20): Rf = 0.43 (UV active; KMnO4, stains yellow).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 3.73 (td, J = 5.8, 1.3 Hz, 2H, H-3), 3.42 (d, J = 1.5 Hz, 3H, H-4), 3.15 (td, J = 5.9, 1.4 Hz, 2H, H-2).

methanesulfonyl cyanide (88a) 5 Synthesized according to the general procedure (A), from hydrogen peroxide (50 wt. % solution in water, 11.9 g, 350.0 mmol, 5.0 eq.), trifluoroacetic anhydride (49.4 mL, 350.0 mmol, 5.0 eq.), CH2Cl2 (72.0 mL, 1.0 M) and methyl thiocyanate (4.7 mL, 70.0 mmol, 1.0 eq.) to afford the product (6.7 g, 90%) as a colourless liquid.

1 H NMR (300 MHz, CDCl3): δ (ppm) = 3.43 (s, 3H, H-1).

ethanesulfonyl cyanide (88b) 5 Synthesized according to the general procedure (A), from hydrogen peroxide (50 wt. % solution in water, 9.8 g, 289.0 mmol, 5.0 eq.), trifluoroacetic anhydride (40.8 mL, 289.0 mmol, 5.0 eq.), CH2Cl2 (60.0 mL, 1.0 M), and ethyl thiocyanate (5.0 mL, 58.0 mmol, 1.0 eq.) to afford the product (7.0 g, quant.) as a colourless liquid.

1 H NMR (300 MHz, CDCl3): δ (ppm) = 3.43 (q, J = 7.4 Hz, 2H, H-2), 1.60 (t, J = 7.4 Hz, 3H, H-1).

2-methoxyethanesulfonyl cyanide (88c) 5

Synthesized according to the general procedure (A), from hydrogen peroxide (50 wt. % solution in water, 6.5 g, 192.0 mmol, 5.0 eq.), trifluoroacetic anhydride (27.0 mL, 192.0 mmol, 5.0 eq.), CH2Cl2

(40.0 mL, 1.0 M), and 1-methoxy-2-thiocyanatoethane (4.5 mL, 38.4 mmol, 1.0 eq.) to afford the product (4.4 g, 82%) as a pale-yellow liquid.

1 H NMR (300 MHz, CDCl3): δ (ppm) = 3.94 (dd, J = 5.9, 5.0 Hz, 2H, H-2), 3.63 (dd, J = 5.8, 5.0 Hz, 2H, H-1), 3.45 (s, 3H, H-3).

chloromethanesulfonyl cyanide (88d) 5 Synthesized according to the general procedure (A), from hydrogen peroxide (50 wt. % solution in water, 6.5 g, 191.0 mmol, 5.0 eq.), trifluoroacetic anhydride (27.0 mL, 191.0 mmol, 5.0 eq.), CH2Cl2 (39.0 mL, 1.0 M), and chloro(thiocyanato)methane (3.0 mL, 38.2 mmol, 1.0 eq.) to afford the product (2.7 g, 50%) as a colourless liquid.

1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.81 (s, 2H, H-1).

Synthesis of alkynyl sulfides methyl(pent-1-yn-1-yl)sulfane (112a)

According to the general procedure (B), from pent-1-yne (6.9 g, 0.10 mol, 1.25 eq.), dry THF (100.0 mL, 0.8 M), n-BuLi (2.5 M in hexane, 34.4 mL, 86.0 mmol, 1.06 eq.), dimethyl disulfide (7.6 g, 81.0 mmol, 1.0 eq.), and 2-bromoethanol (7.2 mL, 0.10 mmol, 1.25 eq.). Purification through column chromatography on SiO2 (pentane: 100%) afforded the product (7.7 g, 84%) as a colourless liquid. TLC (pentane: 100%): Rf = 0.73 (UV active; KMnO4, stains yellow).

LRMS (GC-MS)

: calculated for C6H10S: m/z: 114 (M +• , 64%), 99 (17%), 85 (100%), 67 (51%), 55 (7%), 45 (27%), 39 (11%).

hept-1-yn-1-yl(methyl)sulfane (112b)

According to the general procedure (B), from hept-1-yne (5.8 mL, 45.0 mmol, 1.125 eq.), dry THF (60.0 mL, 0.65 M), n-BuLi (2.1 M in hexane, 20.0 mL, 42.4 mmol, 1.06 eq.), dimethyl disulfide (3.6 mL, 40.0 mmol, 1.0 eq.) and 2-bromoethanol (0.8 mL, 50.0 mmol, 1.25 eq.). Purification through column chromatography on SiO2 (cyclohexane/EtOAc: 90/10) afforded the product (5.6 g, 97%) as a yellow liquid. TLC (cyclohexane/EtOAc: 50/50): Rf = 0.85 (UV active; KMnO4, stains yellow). According to the general procedure (B), from TIPS-protected 3-butyn-1-ol S-1 (24.3 g, 107.4 mmol, 1.125 eq.), dry THF (150.0 mL, 0.65 M), n-BuLi (2.1 M in hexane, 46.0 mL, 101.2 mmol, 1.06 eq), dimethyl disulfide (8.6 mL, 95.5 mmol, 1.0 eq.) and 2-bromoethanol (8.5 mL, 119.4 mmol, 1.25 eq.).

Purification through column chromatography on SiO2 (cyclohexane/EtOAc: 90/10) afforded the product (27.3 g, quant.) as a yellow liquid. TLC (cyclohexane/EtOAc: 90/10): Rf = 0.88 (UV active; KMnO4 or vanillin, stains yellow).

triisopropyl((4-(methylthio)but-3-yn-1-yl)oxy)silane (112d)

According to the general procedure (B), from TBDMS-protected prop-2-yn-1-ol S-2 (4.13 g, 24.2 mmol, 1.125 eq.), dry THF (33.0 mL, 0.65 M), n-BuLi (2.1 M in hexane, 10.7 mL, 22.8 mmol, 1.06 eq.), dimethyl disulfide (2.0 mL, 21.5 mmol, 1.0 eq.) and 2-bromoethanol (1.9 mL, 26.8 mmol, 1.25 eq.). Purification through column chromatography on SiO2 (cyclohexane: 100%) afforded the product as a yellow liquid (5.0 g, quant.). TLC (cyclohexane/EtOAc: 90/10): Rf = 0.8 (UV active; KMnO4, stains yellow).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.40 (s, 2H, H-4), 2.37 (s, 3H, H-1), 0.91 (s, 9H, H-8, H-9, H-10), 0.12 (s, 6H, H-5, H-6). 13 C NMR (75 MHz, CDCl3): δ (ppm) = 91.9 (C-3), 76.9 (C-2), 52.6 (C-4), 26.0 (C-8, C-9, C-10), 19.1 (C-1), 18.4 (C-7), -4.9 (C-5, C-6).

IR (solution in

methyl(4-phenylbut-1-yn-1-yl)sulfane (112e)

According to the general procedure (B), from 4-Phenyl-1-butyne (3.0 mL, 21.0 mmol, 1.125 eq.), dry THF (29.0 mL, 0.65 M), n-BuLi (2.1 M in hexane, 9.5 mL, 20.0 mmol, 1.06 eq.), dimethyl disulfide (1.7 mL, 19.0 mmol, 1.0 eq.) and 2-bromoethanol (1.7 mL, 23.7 mmol, 1.25 eq.). Purification through column chromatography on SiO2 (cyclohexane: 100%) afforded the product as a colourless liquid (3.1 g, 82%). TLC (cyclohexane: 100%): Rf = 0.28 (UV active; KMnO4, stains yellow; vanillin, stains red then yellow).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 7.33-7.27 (m, 2H, H-7, H-11), 7.25-7.18 (m, 3H, H-8, H-9, H-10), 2.84 (t, J = 7.5 Hz, 2H, H-4), 2.58 (t, J = 7.6 Hz, 2H, H-5), 2.33 (s, 3H, H-1).

13 C NMR (75 MHz, CDCl3): δ (ppm) = 140.7 (C-6), 128.5 (C-7, C-11), 128.4 (C-8, C-10), 126.4 (C-9), 92.5 (C-3), 71.0 (C-2), 35.3 (C-5), 22.4 (C-1), 19.3 (C-4).

IR (solution in CH2Cl2

, thin film, KBr): νmax (cm -1 ) = 3027, 2926 (-C-H), 2189 (C≡C), 1602, 1495, 1453, 1312, 1077, 976, 747, 698, 507. HRMS (TOF, FI+): calculated for C11H12S [M] +• 176.06597, found 176.06600.

(

5-chloropent-1-yn-1-yl)(methyl)sulfane (112f)

According to the general procedure (B), from 5-chloropent-1-yne (2.2 mL, 20.8 mmol, 1.125 eq.), dry THF (40.0 mL, 0.4 M), n-BuLi (2.5 M in hexane, 8.4 mL, 17.6 mmol, 1.06 eq.), dimethyl disulfide (1.5 mL, 16.6 mmol, 1.0 eq.) and 2-bromoethanol (1.5 mL, 20.8 mmol, 1.25 eq.). Purification through column chromatography on SiO2 (pentane/Et2O: 100/0 to 99/1) afforded the product (484.0 mg, 20%) as a yellow liquid. TLC (cyclohexane/EtOAc: 50/50): Rf = 0.65 (UV active; KMnO4, stains yellow).

pent-1-yne-1,5-diylbis(methylsulfane) (112g)

This product was obtained as a side-product alongside with (5-chloropent-1-yn-1-yl)(methyl)sulfane 112f, as a yellow liquid (518.0 mg, 20%). TLC (cyclohexane/EtOAc: 50/50): Rf = 0.25 (UV active; KMnO4, stains yellow).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 2.57 (t, J = 6.4 Hz, 2H, H-6), 2.41 (t, J = 6.9 Hz, 2H, H-4), 2.34 (s, 3H, H-7), 2.08 (s, 3H, H-1), 1.78 (quint, J = 7.0 Hz, 2H, H-5).

Narasaka's asymmetric [2+2] cycloaddition (R)-3-(2-(methylthio)-3-propylcyclobut-2-enecarbonyl)oxazolidin-2-one (117a)

According to the general procedure (C), from the titanium complex: TiCl2(OiPr)2 (1.78 g, 7.52 mmol, 0.1 eq.) and (R)-115 (4.37 g, 8.27 mmol, 0.11 eq.) in dry toluene (93.0 mL, 0.08 M), 4 Å molecular sieves (1.72 g), dry toluene (170.0 mL, 0.25 M), 3-acryloyloxazolidin-2-one (10.6 g, 75.18 mmol, 1.0 eq.) and alkynyl thioether 112a (14. According to the general procedure (C), from the titanium complex: TiCl2(OiPr)2 (100.0 mg, 0.42 mmol, 0.1 eq.) and (R)-115 (247.0 mg, 0.47 mmol, 0.11 eq.) in dry toluene (5.0 mL, 0.08 M), 4 Å molecular sieves (168.0 mg), dry toluene (17.0 mL, 0.25 M), 3-acryloyloxazolidin-2-one (600.0 mg, 4.25 mmol, 1.0 eq.) and the alkynyl thioether 112b (900.0 mg, 6.4 mmol, 1.5 eq.) for 20 h. Purification through column chromatography on SiO2 (cyclohexane/EtOAc: 80/20) afforded the product (982.0 mg, 81%, 92% ee) as a white solid. TLC (cyclohexane/EtOAc: 50/50): Rf = 0.58 (UV active; vanillin, stains brown). m. p. = 64-65.5 °C (pentane/EtOAc).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.72 (dq, J = 5.2, 1.8 Hz, 1H, H-5), 4.43 (t, J = 8.0 Hz, 2H, H-2), 4.04 (t, J = 8.4 Hz, 2H, H-3), 2.76 (dd, J = 12.7, 4.9 Hz, 1H, H-6a), 2.51 (dq, J = 12.5, 1.5 Hz, 1H, H-6b), 2.23 (s, 3H, H-14), 2.17 (t, J = 7.4 Hz, 2H, H-9), 1.44 (q, J = 7.0 Hz, 2H, H-10), 1.35-1.25 (m, 4H, H-11, H-12), 0.88 (t, J = 6.8 Hz, 3H, H-13). According to the general procedure (C), from the titanium complex: TiCl2(OiPr)2 (1.34 g, 5.56 mmol, 0.1 eq.) and (R)-115 (3.29 g, 6.23 mmol, 0.11 eq.) in dry toluene (70.0 mL, 0.08 M), 4 Å molecular sieves (2.22 g), dry toluene (224.0 mL, 0.25 M), 3-acryloyloxazolidin-2-one (8.0 g, 56.6 mmol, 1.0 eq.) and the alkynyl thioether 112c (30.8 g, 113.2 mmol, 2.0 eq.) for 48 h. According to the general procedure (C), from titanium complex: TiCl2(OiPr)2 (201.0 mg, 0.85 mmol, 0.1 eq.) and (R)-115 (493.0 mg, 0.93 mmol, 0.11 eq.) in dry toluene (11.0 mL, 0.08 M), 4 Å molecular sieves (334.0 mg), dry toluene (33.0 mL, 0.25 M), 3-acryloyloxazolidin-2-one (1.2 g, 8.5 mmol, 1.0 eq.) and the alkynyl thioether 112d (2.7 g, 12.7 mmol, 1.5 eq.) for 66 h. Purification through column chromatography on SiO2 (cyclohexane/EtOAc: 70/30) afforded the product (1.5 g, 50%, 100% ee) as a white solid. TLC (cyclohexane/EtOAc: 50/50): Rf = 0.61 (UV active; vanillin, stains brown). m. p. = 98.8-101.5 °C (pentane/EtOAc).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.72 (dq, J = 5.3, 1.9 Hz, 1H, H-5), 4.44 (dd, J = 8.6, 7.5 Hz, 2H, H-2), 4.24 (qq, J = 14.1, 1.3 Hz, 2H, H-9), 4.05 (dd, J = 8.6, 7.5 Hz, 2H, H-3), 2.90 (ddt, J = 12.5, 5.0, 1.2 Hz, 1H, H-6a), 2.54 (dq, J = 12.6, 1.4 Hz, 1H, H-6b), 2.25 (s, 3H, H-16), 0.90 (s, 9H, H-13, H-14, H-15), 0.08 (s, 6H, H-10, H-11).

(R)-3-(2-(methylthio)-3-phenethylcyclobut-2-enecarbonyl)oxazolidin-2-one (117e)

According to the general procedure (C), from the titanium complex: TiCl2(OiPr)2 (38.0 mg, 0.16 mmol, 0.1 eq.) and (R)-115 (93.0 mg, 0.17 mmol, 0.11 eq.) in dry toluene (2.0 mL, 0.08 M), 4 Å molecular sieves (62.0 mg), dry toluene (6.5 mL, 0.25 M), 3-acryloyloxazolidin-2-one (225.0 mg, 1.6 mmol, 1.0 eq.) and the alkynyl thioether 112e (500.0 mg, 2.8 mmol, 1.7 eq.) for 12 h. Purification through column chromatography on SiO2 (cyclohexane/EtOAc: 70/30) gave the product (423.0 mg, 81%, 95% ee) as a pale-yellow solid. According to the general procedure (C), from the titanium complex: TiCl2(OiPr)2 (14.2 mg, 0.06 mmol, 0.1 eq.) and (R)-115 (35.0 mg, 0.066 mmol, 0.11 eq.) in dry toluene (0.8 mL, 0.08 M), 4 Å molecular sieves (23.0 mg), dry toluene (2.4 mL, 0.25 M), 3-acryloyloxazolidin-2-one (42.0 mg, 0.6 mmol, 1.0 eq.) and the alkynyl thioether 112f (150.0 mg, 1.0 mmol, 1.7 eq.) for 43 h.

Desulfurization reaction (S)-3-(3-propylcyclobut-2-enecarbonyl)oxazolidin-2-one (169a)

According to the general procedure (E), from cyclobutene 117a (16.08 g, 62.9 mmol, 1.0 eq.), dry acetone (200.0 mL, 0.3 M), Lindlar's catalyst (6.7 g, 62.9 mmol, 1.0 eq.), oct-1-ene (9.8 mL, 62.9 mmol, 1.0 eq.) and freshly distilled triethylsilane (70.0 mL, 440.0 mmol, 7.0 eq.) at 50 °C for 24 h. Purification through column chromatography on SiO2 (cyclohexane/EtOAc: 70/30 to 60/40) afforded the reduced cyclobutene (10.0 g, 75%, 98% ee) as a pale-yellow oil. TLC (pentane/EtOAc: 70/30): Rf = 0.67 (UV active; vanillin, stains dark purple).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 5.80-5.78 (m, 1H, H-8), 4.46-4.38 (m, 2H, H-2), 4.36-4.30 (m, 1H, H-5), 4.06-3.98 (m, 2H, H-3) According to the general procedure (E), from cyclobutene 117b (920.0 mg, 3.25 mmol, 1.0 eq.), dry acetone (33.0 mL, 0.1 M), Lindlar's catalyst (3.5 g, 32.5 mmol, 10.0 eq.), oct-1-ene (5.1 mL, 32.5 mmol, 5.0 eq.) and freshly distilled triethylsilane (5.2 mL, 32.5 mmol, 10.0 eq.) at 20 °C for 96 h. Purification through column chromatography on SiO2 (cyclohexane/EtOAc: 80/20) afforded the reduced cyclobutene (660.0 mg, 85%, 98% ee) as a colorless oil. TLC (cyclohexane/EtOAc: 50/50): Rf = 0.41 (UV active; vanillin, stains green).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 5.78 (q, J = 1.5 Hz, 1H, H-8), 4.42 (dd, J = 8.6, 7.5 Hz, 2H, H-2), 4.32 (dqd, J = 4.5, 2.2, 1.4 Hz, 2H, H-5). 4.04 (dd, J = 8.4, 7.4 Hz, 2H, H-3), 2.77 (ddt, J = 13.2, 4.5, 1.1 Hz, 1H, H-6a), 2.66 (ddt, J = 13.3, 2.1, 1.2 Hz, 1H, H-6b), 2.12-1.94 (m, 2H, H-9), 1.49-1.39 (m, 2H, H-10), 1.31-1.26 (m, 4H, H-11, H-12), 0.91-0.86 (m, 3H, H-13). According to the general procedure (E), from cyclobutene 117c (13.2 g, 32.0 mmol, 1.0 eq.), dry acetone (270.0 mL, 0.11 M), Lindlar's catalyst (3.4 g, 32.0 mmol, 1.0 eq.), oct-1-ene (5.0 mL, 32.0 mmol, 1.0 eq.) and freshly distilled triethylsilane (50.5 mL, 320.0 mmol, 10.0 eq.) at 50 °C for 24 h. Purification through column chromatography on SiO2 (cyclohexane/EtOAc: 80/20) afforded the reduced cyclobutene (11.8 g, quant.) as a pale-yellow oil. TLC (cyclohexane/EtOAc: 50/50): Rf = 0.63 (UV active; vanillin, stains purple).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 5.83 (q, J = 1.3 Hz, 1H, H-8), 4.42 (dd, J = 8.5, 7. IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2944 (-C-H), 2866 (-C-H), 1783 (4-C=O), 1695 (1-C=O), 1466, 1384, 1360, 1234, 1103, 1044, 882, 683. HRMS (TOF, ES+): calculated for C19H33NO4SiNa [M+Na] + 390.2082, found 390.2087.

[α]D 23 = -30.72 (c = 0.093, CHCl3).

(S)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobut-2-enecarbonyl)oxazolidin-2-one (169d)

According to the general procedure (E), from cyclobutene 117d (1.5 g, 4.15 mmol, 1.0 eq.), dry acetone (70.0 mL, 0.06 M), Lindlar's catalyst (4.4 g, 41.5 mmol, 10.0 eq.), oct-1-ene (6.5 mL, 41.5 mmol, 10.0 eq.) and freshly distilled triethylsilane (6.6 mL, 41.5 mmol, 10.0 eq.) at 20 °C for 60 h. Purification through column chromatography on SiO2 (cyclohexane/EtOAc: 70/30) gave the reduced cyclobutene (1.2 g, 94%) as a pale-yellow oil. TLC (cyclohexane/EtOAc: 50/50): Rf = 0.55 (UV active; vanillin, stains green). According to the general procedure (E), from cyclobutene 117e (1.06 g, 3.34 mmol, 1.0 eq.), dry acetone (28.0 mL, 0.12 M), Lindlar's catalyst (3.5 g, 33.4 mmol, 10.0 eq.), oct-1-ene (2.6 mL, 16.7 mmol, 5.0 eq.) and freshly distilled triethylsilane (5.3 mL, 33.4 mmol, 10.0 eq.) at 20 °C for 46 h. Purification through column chromatography on SiO2 (cyclohexane/EtOAc: 80/20) afforded the reduced cyclobutene (828.0 mg, 91%) as a pale-yellow oil. TLC (cyclohexane/EtOAc: 50/50): Rf = 0.41 (UV active; vanillin, stains green). According to the general procedure (E), from cyclobutene 117f (883.0 mg, 3.05 mmol, 1.0 eq.), dry acetone (31.0 mL, 0.1 M), Lindlar's catalyst (3.2 g, 30.5 mmol, 10.0 eq.), oct-1-ene (2.4 mL, 15.3 mmol, 5.0 eq.) and freshly distilled triethylsilane (4.9 mL, 30.5 mmol, 10.0 eq.) at 20 °C for 26 h. Purification through column chromatography on SiO2 (cyclohexane/EtOAc: 70/30) gave the reduced cyclobutene (530.0 mg, 72%) as a colorless oil. TLC (cyclohexane/EtOAc: 50/50): Rf = 0.47 (UV active; vanillin, stains green). 1634, 1478, 1374, 1228, 1110, 1042, 984, 870, 760. HRMS (TOF, ES+): calculated for C11H14ClNO3Na [M+Na] + 266.0554, found 266.0561.

[α]D 23 = -46.46 (c = 1.66, CHCl3).

Carbo-alkynylation reaction trimethyl(((trichloromethyl)sulfonyl)ethynyl)silane (175b)

To a dried two-necked flask under inert atmosphere, 183 (1.9 g, 4.2 mmol, 1.0 eq.) was introduced followed by CH2Cl2 (42.0 mL, 0.1 M), then CCl3SO2Na (1.3 g, 6.3 mmol, 1.5 eq.) was added. The reaction mixture was stirred at 25 °C for 13 h then extracted with water (2 x 3 mL) and CH2Cl2 (2 x 5 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude was obtained as a yellow oil that solidifies open to atmosphere. After trituration with Et2O, the product (1.0 g, 85%) was obtained pure enough to be used directly in the next step without further purification. The product was stored under inert atmosphere in the freezer. TLC:m. p. = 85-90.2 °C (CH2Cl2). According to the general procedure (F), from 5-hexen-2-one (11.0 μL, 0.1 mmol, 1.0 eq.), distilled DCE (1.0 mL, 0.1 M), 175b (42.0 mg, 0.15 mmol, 1.5 eq.) and AIBN (3.3 mg, 0.02 mmol, 0.2 eq.).

The crude mixture was purified to afford the pure product (24.0 mg, 77%) as a colorless oil. TLC (cyclohexane/EtOAc: 70/30): R f = 0.76 (UV active; KMnO4, stains yellow). According to the general procedure (F), from the olefin 187 (50.0 mg, 0.25 mmol, 1.0 eq.), distilled DCE (2.5 mL, 0.1 M), 175b (104.0 mg, 0.37 mmol, 1.5 eq.) and AIBN (8.0 mg, 0.05 mmol, 0.2 eq.).

The crude mixture was purified to afford the pure product (57.0 mg, 55%, 68% brsm) as a colorless oil. TLC (cyclohexane/EtOAc: 70/30): R f = 0.76 (UV active; KMnO4, stains yellow). According to the general procedure (G), from cyclobutene 169a (100.0 mg, 0.48 mmol, 1.0 eq.), DMF (2.0 mL), H2O (0.5 mL), BrCCl3 (0.1 mL, 0.96 mmol, 2.0 eq.), sodium L-ascorbate (190.0 mg, 0.96 mmol, 2.0 eq.), LiBr (83.0 mg, 0.96 mmol, 2.0 eq.) and [Ir(PPy)2(dtbbPy)]PF6 (9.0 mg, 9.6 μmol, 0.02 eq.). The crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 80/20) to afford the product (117.0 mg, 60%, dr > 19:1:1:1) as a white solid. TLC (cyclohexane/EtOAc: 50/50): Rf = 0.57 (UV active; vanillin, stains green). m. p. = 138-141 °C (CH2Cl2/Et2O). [α]D 23 = +47.92 (c = 1.8, CHCl3). X-Ray crystallography: the compound 180a was dissolved in CH2Cl2 (1 mL), followed by slow diffusion (CH2Cl2/Et2O) in a container pierced with an 18 Gauge needle, at 20 °C for 3 days. The crystal suitable for X-ray crystallographic analysis was obtained as a thin translucent crystal. According to the general procedure (G), from cyclobutene 169a (227.0 mg, 1.0 mmol, 1.0 eq.), DMF (3.5 mL), H2O (0.8 mL), bromo diethylmalonate 76a (0.35 mL, 2.0 mmol, 2.0 eq.), sodium Lascorbate (396.0 mg, 2.0 mmol, 2.0 eq.), LiBr (173.0 mg, 2.0 mmol, 2.0 eq.) and [Ir(PPy)2(dtbbPy)]PF6 (9.0 mg, 10.0 μmol, 0.02 eq.). The crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 70/30 to 60/40) to afford the mixture of diastereomers (326.0 mg, 73%, dr 6:1) as a colorless oil. TLC (cyclohexane/EtOAc: 60/40): Rf = 0.35 (UV active; KMnO4, stains yellow).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.53-4.30 (m, 3H, H-2, H-5), 4.17 (q, J = 7. A 10 mL sealed tube was charged with cyclobutene 169a (58.0 mg, 0.27 mmol, 1.0 eq.), acetonitrile (2.7 mL, 0.1 M), di-tert-butyl 2-bromomalonate 76b (163.0 mg, 0.55 mmol, 2.0 eq.), 2,6-lutidine (0.06 mL, 0.55 mmol, 2.0 eq.) and p-anisaldehyde (7.0 μL, 0.054 mmol, 0.2 eq.). The reaction mixture was degassed by three cycles of freeze-pump-thaw, then the tube was refilled with nitrogen. The reaction mixture was irradiated at 30 °C under UV-A light (325-400 nm, the tube was positioned approximately 10 cm away from the light source), and it was monitored by TLC under nitrogen atmosphere. After completion, the solvents were concentrated under reduced pressure and the crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 70/30 to 60/40) to afford the desired product (94.0 mg, 69%, dr 8:1) as a viscous, colorless oil. TLC (cyclohexane/EtOAc: 60/40): Rf = 0.5 (UV active; KMnO4, stains yellow; vanillin, stains blue then brown). To a dried schlenk, 180b (30.0 mg, 0.066 mmol, 1.0 eq.) was introduced, followed by dry DMF (0.7 mL, 0.1 M) and K2CO3 (18.0 mg, 0.13 mmol, 2.0 eq.). The reaction mixture was then heated at 70 °C silicon oil bath temperature. After 14 h, the reaction was quenched with aqueous HCl (1.0 M) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 70/30) to afford the product (15.0 mg, 60%, dr 1.5:1) as a yellow oil. TLC (cyclohexane/EtOAc: 60/40): Rf = 0.44 (UV active; KMnO4, stains yellow; vanillin stains colorless).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 7.14 (s, 0.63H, H-11 minor), 6.94 (s, 1H, H-11 major), 4.52-4.38 (m, 3.5H, H-2 major, H-2 minor), 4.37-4.16 (m, 7H, H-15 major, H-15 minor, H-16 major, H-16 minor), 4.14-3.93 (m, 3.5H, H-3 major, H-3 minor), 3.39 (dd, J = 7.9, 5.7 Hz, 1H, H-5 major), 3.09 (dd, J = 8.1, 6.5 Hz, 0.7H, H-5 minor), 1.81-1.55 (m, 6H, H-6a major, H-6 minor, H-8 major, H-8 minor), 1.53-1.40 (m, 4.5H, H-6b major, H-9 major, H-9 minor), 1.39-1.22 (m, 10H, H-17 major, H-17 minor, H-18 major, H-18 minor), 0.96-0.84 (m, 5H, H-10 major, H-10 minor).

To a dried two-necked flask equipped with a condenser, the cyclobutane 180b (40.0 mg, 0.09 mmol, 1.0 eq.) was introduced, followed by dry DCE (0.5 mL, 0.2 M) then (Bu3Sn)2 (0.07 mL, 0.13 mmol, 1.5 eq.), and the mixture was degassed through argon bubbling for 10 min. To this solution was added a degassed (argon bubbling for 10 min) solution of DTBHN (8.0 mg, 0.045 mmol, 0.5 eq.) and p-TsCN (33.0 mg, 0.18 mmol, 2.0 eq.) in DCE (0.5 mL, 0.2 M) dropwise, and the reaction mixture was heated at 85 °C silicon oil bath temperature. After 5 h, another 0.5 eq. of DTBHN was added and the heating continued and the reaction completion was followed by TLC. After 22 h, the solvent was concentrated under reduced pressure and the crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 70/30 to 60/40) to afford the product (16.0 mg, 45%, dr 2:1) as a pale-yellow oil. TLC (cyclohexane/EtOAc: 60/40): Rf = 0.16 (UV inactive; KMnO4, stains yellow after long heating; or vanillin, stains yellow after long heating). To a dried two-necked flask equipped with a condenser, 180b (830.0 mg, 1.85 mmol, 1.0 eq.) was introduced, followed by distilled benzene (18.5 mL, 0.1 M), allyltributylstannane (2.8 mL, 9.25 mmol, 5.0 eq.) and AIBN (152.0 mg, 0.92 mmol, 0.5 eq.) and the reaction mixture was heated at 85 °C silicon oil bath temperature. Another 0.5 eq. x 2 of AIBN were added with 5 h interval, and the reaction evolution was followed by TLC. After 26 h, the solvents were concentrated under reduced pressure and the crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 80/20 to 70/30) to afford the product (618.0 mg, 82%, dr 2.3:1) as a colorless oil. TLC (cyclohexane/EtOAc: 60/40): Rf = 0.30 (UV active; KMnO4, stains yellow; vanillin stains black). According to the general procedure (H), from cyclobutene 169a (150.0 mg, 0.7 mmol, 1.0 eq.), dry DMF (0.7 mL, 1.0 M), ethanesulfonyl cyanide 88b (341.0 mg, 2.87 mmol, 4.0 eq.), eosin-Y (9.2 mg, 14.3 μmol, 2 mol %) and K2HPO4 (24.9 mg, 143.0 μmol, 0.2 eq.) for 60 h. Purification through column chromatography on SiO2 (cyclohexane/EtOAc: 50/50) afforded the product (114.0 mg, 48%, 98% ee, dr > 19:1:1:1) as a white solid. According to the general procedure (H), from cyclobutene 169b (150.0 mg, 0.63 mmol, 1.0 eq.), dry DMF (0.7 mL, 1.0 M), ethanesulfonyl cyanide 88b (225.0 mg, 1.89 mmol, 3.0 eq.), eosin-Y (8.0 mg, 0.012 mmol, 2 mol %) and K2HPO4 (22.0 mg, 0.13 mmol, 0.2 eq.) for 24 h. Purification through column chromatography on SiO2 (CH2Cl2/EtOAc: 60/40) afforded the product (143.0 mg, 63%, dr > 19:1:1:1) as a white solid. TLC (CH2Cl2/EtOAc: 50/50): Rf = 0.62 (UV inactive; KMnO4, stains white). m. p. = 122.7-125 °C (Et2O/CH2Cl2). According to the general procedure (H), from cyclobutene 169b (160.0 mg, 0.7 mmol, 1.0 eq.), acetone (0.7 mL, 1.0 M), sulfonyl cyanide 88c (190.0 mg, 1.35 mmol, 2.0 eq.), eosin-Y (9.0 mg, 13.4 μmol, 2 mol %) and K2HPO4 (23.0 mg, 0.13 mmol, 0.2 eq.) for 96 h. Purification through column chromatography on SiO2 (CH2Cl2/EtOAc: 90/10) afforded the product (94.0 mg, 36% yield, 53% brsm, dr > 19:1:1:1) as a white solid. 31% of the starting material were recovered. According to the general procedure (H), from cyclobutene 169e (300.0 mg, 1.1 mmol, 1.0 eq.), dry DMF (1.1 mL, 1.0 M), ethanesulfonyl cyanide 88b (394.0 mg, 3.3 mmol, 3.0 eq.), eosin-Y (14.0 mg, 0.022 mmol, 2 mol %) and K2HPO4 (38.0 mg, 0.22 mmol, 0.2 eq.) for 48 h. Purification through column chromatography on SiO2 (CH2Cl2/EtOAc: 60/40) afforded the product (185.0 mg, 43%, 50% brsm, dr > 19:1:1:1) as a white solid. 14% of the starting material were recovered. TLC (CH2Cl2/EtOAc: 50/50): Rf = 0.57 (UV active; KMnO4, stains white). m. p. = 61.5-63 °C (Et2O/CH2Cl2). According to the general procedure (I), from cyclobutene 169a (4.4 g, 21.0 mmol, 1.0 eq.), acetonitrile (10.0 mL, 2.1 M), methanesulfonyl cyanide 88a (4.4 g, 42.0 mmol, 2.0 eq.) and panisaldehyde (0.5 mL, 4.2 mmol, 0.2 eq.) for 72 h. Purification through column chromatography on SiO2 (CH2Cl2/EtOAc: 90/10) afforded the product (5.77 g, 87%, dr > 19:1:1:1) as a white solid. TLC (CH2Cl2/EtOAc: 50/50): Rf = 0.45 (UV inactive; KMnO4, stains white). m. p. = 66-70 °C (EtOAc). According to the general procedure (I), from cyclobutene 169c (200.0 mg, 0.54 mmol, 1.0 eq.), acetonitrile (0.5 mL, 1.0 M), sulfonyl cyanide 88c (383.0 mg, 2.72 mmol, 5.0 eq.) and p-anisaldehyde (13.0 μL, 0.108 mmol, 0.2 eq.) for 47 h. 73% of conversion of the starting material was observed. Purification through column chromatography on SiO2 (CH2Cl2/EtOAc: 80/20) afforded the product (157.0 mg, 56%, 78% brsm, dr > 19:1:1:1) as a yellow oil. Another method to obtain the product 181f: According to the general procedure (H), from cyclobutene 169c (260.0 mg, 0.7 mmol, 1.0 eq.), dry acetone (0.7 mL, 1.0 M), sulfonyl cyanide 88c (203.0 mg, 1.36 mmol, 2.0 eq.), eosin-Y (9.0 mg, 13.6 μmol, 2 mol %) and K2HPO4 (24.0 mg, 0.136 mmol, 0.2 eq.) for 90 h. Purification through column chromatography on SiO2 (CH2Cl2/EtOAc: 80/20) afforded the product (105.0 mg, 28%, 87% brsm) as a yellow oil. 67% of the starting material were recovered. TLC (CH2Cl2/EtOAc: 50/50): Rf = 0.62 (UV inactive; KMnO4, stains white).

(1R,2R,3R)-2-(methylsulfonyl)-3-(2-oxooxazolidine-3-carbonyl)-1-(2-((triisopropylsilyl)oxy)ethyl)cyclobutanecarbonitrile (181i)

According to the general procedure (I), from cyclobutene 169c (5.0 g, 13.6 mmol, 1.0 eq.), acetonitrile (10.0 mL, 1.3 M), methanesulfonyl cyanide 88a (2.8 g, 27.2 mmol, 2.0 eq.) and panisaldehyde (0.33 mL, 2.72 mmol, 0.2 eq.) for 91 h. Purification through column chromatography on SiO2 (CH2Cl2/EtOAc: 90/10) afforded the product (4. According to the general procedure (I), from cyclobutene 169c (800.0 mg, 2.2 mmol, 1.0 eq.), acetonitrile (2.2 mL, 1.0 M), p-toluenesulfonyl cyanide (790.0 mg, 4.4 mmol, 2.0 eq.) and panisaldehyde (0.05 mL, 0.44 mmol, 0.2 eq.) for 71 h. Purification through column chromatography on SiO2 (cyclohexane/EtOAc: 80/20 to 50/50) afforded the product (600.0 mg, 50%, dr > 19:1:1:1) as a white solid. IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2944 (-C-H), 2867 (-C-H), 2237 (C≡N), 1784 (4-C=O), 1697 (1-C=O), 1390, 1322, 1150, 1111, 1040, 882, 672. HRMS (TOF, ES+): calculated for C27H40N2O6SSiNa [M+Na] + 571.2268, found 571.2278.

[α]D 25 = +159.39 (c = 0.073, CHCl3).

(1S,2R,3R)-2-(methylsulfonyl)-3-(2-oxooxazolidine-3-carbonyl)-1phenethylcyclobutanecarbonitrile (181k)

According to the general procedure (I), from cyclobutene 169e (150.0 mg, 0.55 mmol, 1.0 eq.), acetonitrile (0.55 mL, 1.0 M), methanesulfonyl cyanide 88a (116.0 mg, 1.1 mmol, 2.0 eq.) and panisaldehyde (13.0 μL, 0.11 mmol, 0.2 eq.) for 23 h. Purification through column chromatography on SiO2 (CH2Cl2/EtOAc: 90/10) afforded the product (180.0 mg, 87%, dr > 19:1:1:1) as a white solid. According to the general procedure (I), from cyclobutene 169f (220.0 mg, 0.9 mmol, 1.0 eq.), acetonitrile (0.9 mL, 1.0 M), methanesulfonyl cyanide 88a (189.0 mg, 1.8 mmol, 2.0 eq.) and panisaldehyde (21.0 μL, 0.18 mmol, 0.2 eq.) for 100 h. 91% of conversion of the starting material was observed. Purification through column chromatography on SiO2 (CH2Cl2/EtOAc: 90/10) afforded the product (217.0 mg, 70%, 76% brsm, dr > 19:1:1:1) as a white solid. According to the general procedure (I), from cyclobutene 169d (208.0 mg, 0.6 mmol, 1.0 eq.), acetonitrile (0.6 mL, 1.0 M), methanesulfonyl cyanide 88a (135.0 mg, 1.28 mmol, 2.0 eq.) and panisaldehyde (16.0 μL, 0.13 mmol, 0.2 eq.) for 100 h. Purification through column chromatography on SiO2 (CH2Cl2/EtOAc: 90/10) afforded the product (55.0 mg, 20%, dr > 19:1:1:1) as a white solid. According to the general procedure (I), from cyclobutene 169c (250.0 mg, 0.68 mmol, 1.0 eq.), acetonitrile (0.7 mL, 1.0 M), sulfonyl cyanide 88d (200.0 mg, 1.36 mmol, 2.0 eq.) and p-anisaldehyde (16.0 μL, 0.136 mmol, 0.2 eq.) for 42 h. Purification through column chromatography on SiO2 (CH2Cl2/EtOAc: 90/10) afforded the product (34.0 mg, 16%) as a yellow oil. 80% of the starting material were recovered. TLC (CH2Cl2/EtOAc: 90/10): R f = 0.27 (UV inactive; KMnO4, stains white). 1477, 1388, 1363, 1260, 1227, 1136, 1114, 1040, 971, 760. HRMS (TOF, ES+): calculated for C11H14ClNO5SNa [M+Na] + 330.0173, found 330.0172.

[α]D 23 = -31.70 (c = 0.06, CHCl3).

2-(((chloromethyl)sulfonyl)methyl)octanenitrile (198a)

According to the general procedure (I), from oct-1-ene (0.1 mL, 0.66 mmol, 1.0 eq.), acetonitrile (0.7 mL, 1.0 M), sulfonyl cyanide 88d (139.0 mg, 1.0 mmol, 2.0 eq.) and p-anisaldehyde (16.0 μL, 0.13 mmol, 0.2 eq.) for 67 h. Purification through column chromatography on SiO2 (CH2Cl2/EtOAc: 90/10) afforded the product (83.0 mg, 50%) as a pale-yellow solid. TLC (CH2Cl2/EtOAc: 70/30): R f = 0.57 (UV inactive; KMnO4, stains red-white). m. p. = 62.6-65.2 °C (pentane/EtOAc).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.69 (d, J = 13.0 Hz, 1H, H-2a), 4.50 (dd, J = 13.0 Hz, 1H, H-2b), 3.73-3.65 (m, 1H, H-1a), 3.29-3.14 (m, 2H, H-1b, H-3), 1.84-1.76 (m, 2H, H-5), 1.56 (dq, J = 13.8, 7.4 Hz, 2H, H-6), 1.38-1.28 (m, 6H, H-7, H-8, H-9), 0.90 (t, J = 6.6 Hz, 3H, H-10).

2-((methylsulfonyl)methyl)octanenitrile (198b)

According to the general procedure (I), from oct-1-ene (15.0 μL, 0.1 mmol, 1.0 eq.), acetonitrile (0.5 mL, 0.2 M), methanesulfonyl cyanide 88a (21.0 mg, 0.2 mmol, 2.0 eq.) and p-anisaldehyde (2.4 μL, 0.02 mmol, 0.2 eq.) for 24 h. Purification through column chromatography on SiO2 (CH2Cl2: 100%) afforded the product (21.0 mg, 97%) as a colorless oil . TLC (CH2Cl2/EtOAc: 90/10): R f = 0.53 (UV inactive; KMnO4, stains white-red).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 3.41 (dd, J = 14.1, 9.1 Hz, 1H, H-2a), 3.29-3.18 (m, 1H, H-3), 3.13 (dd, J = 4.4, 0.9 Hz, 1H, H-2b), 3.09 (s, 3H, H-1), 1.84-1.70 (m, 2H, H-5), 1.66-1.22 (m, 8H, H-6, H-7, H-8, H-9), 0.89 (t, J = 6.7 Hz, 3H, H-10). According to the general procedure (K), from cyclobutane 181a (82.0 mg, 0.24 mmol, 1.0 eq.), dry THF (2.4 mL, 0.1 M), distilled H2O (~ 78.0 μL, 4.32 mmol, 18.0 eq.) and SmI2/THF (0.15 M, 6.4 mL, 0.96 mmol, 4.0 eq.) for 30 min. Purification of the crude mixture through column chromatography on SiO2 (CH2Cl2/EtOAc: 50/50) afforded the product (61.0 mg, 77%, 98% ee) as a viscous, colorless oil. TLC (EtOAc: 100%): Rf = 0.53 (UV inactive; KMnO4, stains white). According to the general procedure (K), from cyclobutane 181b (66.4 mg, 0.21 mmol, 1.0 eq.), dry THF (2.1 mL, 0.1 M), distilled H2O (46.0 μL, 2.5 mmol, 12.0 eq.) and SmI2/THF (0.16 M, 5.3 mL, 0.84 mmol, 4.0 eq.) for 1 h. Purification of the crude mixture through column chromatography on SiO2 (CH2Cl2/EtOAc: 70/30) afforded the product (48.0 mg, 73%) as a viscous, yellow oil. TLC (CH2Cl2/EtOAc: 70/30): Rf = 0.16 (UV inactive; KMnO4, stains white). According to the general procedure (K), from cyclobutane 181c (50.0 mg, 0.14 mmol, 1.0 eq.), dry THF (1.4 mL, 0.1 M), distilled H2O (45.0 μL, 2.5 mmol, 18.0 eq.) and SmI2/THF (0.11 M, 4.5 mL, 0.5 mmol, 3.5 eq.) for 3 h. Purification of the crude mixture through column chromatography on SiO2 (CH2Cl2/EtOAc: 50/50) afforded the product (32.0 mg, 64%) as a viscous, colorless oil. TLC (CH2Cl2/EtOAc: 50/50): Rf = 0.48 (UV inactive; KMnO4, stains white). According to the general procedure (K), from cyclobutane 181d (78.0 mg, 0.2 mmol, 1.0 eq.), dry THF (2.0 mL, 0.1 M), distilled H2O (43.0 μL, 2.4 mmol, 12.0 eq.) and SmI2/THF (0.2 M, 4.5 mL, 0.91 mmol, 4.5 eq.) for 3.5 h. Purification of the crude mixture through column chromatography on SiO2 (CH2Cl2/EtOAc: 80/20) afforded the product (34.0 mg, 44%) as a viscous, colorless oil. TLC (CH2Cl2/EtOAc: 50/50): Rf = 0.53 (UV inactive; KMnO4, stains white). According to the general procedure (K), from cyclobutane 181i (1.43 g, 3.0 mmol, 1.0 eq.), dry THF (15.0 mL, 0.2 M), distilled H2O (1.0 mL, 54.0 mmol, 18.0 eq.) and SmI2/THF (0.2 M, 65.0 mL, 13.0 mmol, 4.3 eq.) for 1 h. Purification of the crude mixture through column chromatography on SiO2 (CH2Cl2/EtOAc: 80/20) afforded the product (993.0 mg, 70%) as a viscous, yellow oil. TLC (CH2Cl2/EtOAc: 80/20): Rf = 0.42 (UV inactive; KMnO4, stains white). According to the general procedure (K), from cyclobutane 181j (379.0 mg, 0.69 mmol, 1.0 eq.), dry THF (3.5 mL, 0.2 M), distilled H2O (0.22 mL, 12.4 mmol, 18.0 eq.) and SmI2/THF (0.2 M, 15.5 mL, 3.1 mmol, 4.5 eq.) for 3 h. Purification of the crude mixture through column chromatography on SiO2 (CH2Cl2/EtOAc: 95/5 to 90/10 to 80/20) afforded the product (102.0 mg, 27%) as a yellow oil. TLC (CH2Cl2/EtOAc: 70/30): Rf = 0.68 (UV active; KMnO4, stains white). According to the general procedure (K), from cyclobutane 181f (203.0 mg, 0.39 mmol, 1.0 eq.), dry THF (2.0 mL, 0.2 M), distilled H2O (0.13 mL, 7.02 mmol, 18.0 eq.) and SmI2/THF (0.2 M, 8.7 mL, 1.75 mmol, 4.5 eq.) for 4.5 h. Purification of the crude mixture through column chromatography on SiO2 (CH2Cl2/EtOAc: 90/10 to 80/20) afforded the product (119.0 mg, 59%) as a yellow oil. TLC (CH2Cl2/EtOAc: 70/30): Rf = 0.58 (UV inactive; KMnO4, stains white). -11), 56.2 (C-12), 42.6 (C-3), 38.8 (C-8), 37.9 (C-7), 31.5 (C-6), 30.9 (C-5), 18.1 (C-18, C-19, C-20, C-21, C-22, C-23), 11.9 (C-15, C-16, C-17). According to the general procedure (K), from cyclobutane 181g (140.0 mg, 0.32 mmol, 1.0 eq.), dry THF (3.2 mL, 0.1 M), distilled H2O (69.0 μL, 4.3 mmol, 12.0 eq.) and SmI2/THF (0.15 M, 8.6 mL, 1.3 mmol, 4.0 eq.) for 2.5 h. Purification of the crude mixture through column chromatography on SiO2 (CH2Cl2/EtOAc: 95/5) afforded the product (74.0 mg, 53%, 81% brsm) as a viscous, colorless oil. 36% of the starting material were recovered. TLC (CH2Cl2/EtOAc: 50/50): Rf = 0.42 (UV inactive; KMnO4, stains white).

IR (solution in

1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.42 (t, J = 8. 1 Hz, 2H, H-2), 4.02 (t, J = 8.1 Hz, 2H, H-3), 3.95 (q, J = 13. 3 Hz, 2H, H-8), 3.36 (qAB, J = 1.6 Hz, 2H, H-10), 3.19-3.15 (m, 4H, H-5, H-11) According to the general procedure (K), from cyclobutane 181m (44.0 mg, 0.1 mmol, 1.0 eq.), dry THF (0.5 mL, 0.2 M), distilled H2O (32.0 μL, 1.8 mmol, 18.0 eq.) and SmI2/THF (0.2 M, 2.3 mL, 0.47 mmol, 4.5 eq.) for 3 h. Purification of the crude mixture through column chromatography on SiO2 (CH2Cl2/EtOAc: 80/20) afforded the product (23.5 mg, 56%) as a yellow oil. TLC (CH2Cl2/EtOAc: 80/20): Rf = 0.37 (UV inactive; KMnO4, stains white).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.44 (dd, J = 8.7, 7.5 Hz, 2H, H-2), 4.01-4.05 (m, 2H, H-3), 3.99 (d, J = 10.0 Hz, 1H, H-8a), 3.91 (d, J = 10.0 Hz, 1H, H-8b), 3.41 (q, J = 13.3 Hz, 2H, H-10), 3.19 (ddd, J = 8.4, 6.6, 2.8 Hz, 2H, H-5), 3.09 (s, 3H, H-11), 2.39-2.35 (m, 1H, H-6a), 2.21 (ddd, J = 14.4, 8.9, 6.8 Hz, 1H, H-6b), 0.91 (s, 9H, H-15, H-16, H-17), 0.12 (d, J = 2.9 Hz, 6H, H-12, H-13). According to the general procedure (K), from cyclobutane 181h (60.0 mg, 0.16 mmol, 1.0 eq.), dry THF (1.6 mL, 0.1 M), distilled H2O (52.0 μL, 2.9 mmol, 18.0 eq.) and SmI2/THF (0.15 M, 4.0 mL, 0.6 mmol, 3.5 eq.) for 2.5 h. Purification of the crude mixture through column chromatography on SiO2 (CH2Cl2/EtOAc: 90/10) afforded the product (30.0 mg, 52%, 76% brsm) as a viscous, colorless oil. 34% of the starting material were recovered. TLC (CH2Cl2/EtOAc: 60/40): Rf = 0.34 (UV inactive; KMnO4, stains white).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.44 (dd, J = 8.7, 7.4 Hz, 2H, H-2), 4.04 (t, J = 8.0 Hz, 2H, H-3), 3.64-3.58 (m, 2H, H-10), 3.31 (s, 2H, H-12), 3.24-3.09 (m, 4H, H-5, H-13), 2.45-2.30 (m, 2H, H-6), 2.30-2.20 (m, 1H, H-8a), 2.15-1.99 (m, 3H, H-8b, H-9), 1.44 (t, J = 7. 5 Hz, 3H, H-14). According to the general procedure (K), from cyclobutane 181l (200.0 mg, 0.57 mmol, 1.0 eq.), dry THF (2.8 mL, 0.2 M), distilled H2O (0.18 mL, 10.26 mmol, 18.0 eq.) and SmI2/THF (0.2 M, 12.5 mL, 2.5 mmol, 4.5 eq.) for 1. According to the general procedure (K), from cyclobutane 181e (95.0 mg, 0.24 mmol, 1.0 eq.), dry THF (2.4 mL, 0.1 M), distilled H2O (78.0 μL, 4.3 mmol, 18.0 eq.) and SmI2/THF (0.15 M, 5.6 mL, 0.84 mmol, 3.5 eq.) for 1.5 h. Purification of the crude mixture through column chromatography on SiO2 (CH2Cl2/EtOAc: 60/40) afforded the product (40.0 mg, 43%) as a viscous, colorless oil. TLC (CH2Cl2/EtOAc: 50/50): Rf = 0.42 (UV active; KMnO4, stains white). (t, J = 7.8 Hz, 2H, H-5), 3.13 (q, J = 7. 5 Hz, 2H, H-12), 2.88 (ddd, J = 10.2, 5.9, 3.7 Hz, 2H, H-9), 2.55-2.32 (m, 3H, H-6, H-8a), 2.18 (ddd, J = 14.1, 10.8, 6.2 Hz, 1H, H-8b), 1.44 (t, J = 7.5 Hz, 3H, H-13). According to the general procedure (K), from cyclobutane 181k (100.0 mg, 0.26 mmol, 1.0 eq.), dry THF (2.6 mL, 0.1 M), distilled H2O (56.0 μL, 3.12 mmol, 12.0 eq.) and SmI2/THF (0. In a dried two-necked flask, 199n (61.0 mg, 0.12 mmol, 1.0 eq.) was diluted in CCl4/t-BuOH: 1/1 (2.2 mL, 0.05 M). KOH/Al2O3 (308.0 mg, 250 mg/0.1 mmol of substrate) was added and the reaction mixture was stirred at 80 °C silicon oil bath temperature for 21 h. The reaction was quenched with aqueous HCl (1.0 M) and the aqueous layer was extracted with EtOAc (x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The obtained crude mixture was purified through column chromatography on SiO2 (CH2Cl2/MeOH: 98/2) to afford the alkene as a colorless oil (17.0 mg, 40%). TLC (CH2Cl2/MeOH: 90/10): Rf = 0.43 (UV active; KMnO4, stains yellow).

1 H NMR (600 MHz, CDCl3): δ (ppm) = 5.52 (dd, J = 17.0, 0.6 Hz, 1H, H-9a), 5.47-5.39 (m, 1H, H-8), 5.35 (dd, J = 10.0, 0.6 Hz, 1H, H-9b), 3.75-3.68 (m, 2H, H-7), 2.56 (ddd, J = 16.7, 11.0, 5.6 Hz, 1H, H-2a), 2.51-2.45 (m, 1H, H-2b), 2.11 (ddd, J = 14.0, 10.8, 5.5 Hz, 1H, H-3a), 1.94-1.80 (m, 2H, H-3b, H-5a), 1.76-1.61 (m, 3H, H-5b, H-6), 1.13-1.00 (m, 21H, H-11, H-12, H-13, H-14, H-15, H-16, H-17, H-18, H-19). In a dried two-necked flask, 199e (993.0 mg, 2.09 mmol, 1.0 eq.) was dissolved in dry Et2O/MeOH: 5/1 (18.9/3.7 mL, 0.1 M), then the reaction was cooled down to -5 °C. LiBH4 (68.4 mg, 3.14 mmol, 1.5 eq.) was added and the mixture was stirred for 5 min at the same temperature then at 20 °C. A complete conversion was observed after 2.25 h. Aqueous HCl (1.0 M) was added at 0 °C, then the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification through column chromatography on SiO2 (CH2Cl2/EtOAc: 90/10 to 70/30) afforded the product (726.0 mg, 88%) as a colorless oil. TLC (CH2Cl2/EtOAc: 50/50): Rf = 0.35 (UV inactive; KMnO4, stains white-red). (m, 21H, H-10, H-11, H-12, H-13, H-14, H-15, H-16, H-17, H-18, H-19). 13 C NMR (75 MHz, CDCl3): δ (ppm) = 120.9 (C-9), 62.0 (C-1), 60.3 (C-6), 59.0 (C-7), 43.5 (C-8), 38.7 (C-4), 38.6 (C-3), 33.3 (C-5), 27.7 (C-2), 18.1 (C-13, C-14, C-15, C-16, C-17, C-18), 11.9 (C-10, C-11, C-12). To a dried two-necked flask equipped with a condenser and a dean stark system filled with dry toluene, 237 (222.0 mg, 0.57 mmol, 1.0 eq.) dissolved in dry toluene (5.7 mL, 0.1 M) was introduced, followed by p-TsOH.H2O (108.0 mg, 0.57 mmol, 1.0 eq.). The mixture was heated at 120 °C silicon oil bath temperature, then the solvent was concentrated under reduced pressure and the crude was purified through column chromatography on SiO2 (CH2Cl2/MeOH: 99/1 to 95/5 to 90/10) to afford the product (142.0 mg, 63%, 70% brsm) as a pale-yellow oil. 9% of the starting material were recovered. TLC (CH2Cl2/MeOH: 90/10): Rf = 0.88 (UV inactive; KMnO4, stains white-red). The hydroxypyranone was obtained as a side product alongside with TIPS-protected lactone 240a, as a colorless oil (35.0 mg, 26%). TLC (CH2Cl2/MeOH: 95/5): Rf = 0.26 (UV inactive; KMnO4, stains white).

IR (solution in

Reprotection of the hydroxypyranone 253:

To a dried two-necked flask under inert atmosphere and set to 0 °C, hydroxypyranone 253 (66.0 mg, 0.28 mmol, 1.0 eq.) was introduced, followed by dry CH2Cl2 (0.6 mL, 0.5 M), imidazole (25.0 mg, 0.36 mmol, 1.3 eq.), and TIPSCl (65.0 μL, 0.3 mmol, 1.1 eq.) was added slowly. The mixture was stirred at 20 °C and the evolution of the reaction was followed by TLC. After 1.5 h, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (CH2Cl2/EtOAc: 90/10) and the desired product (100.0 mg, 91%) was obtained as a pale-yellow oil. To a dried two-necked flask equipped with a condenser, 237 (300.0 mg, 0.76 mmol, 1.0 eq.) dissolved in dry THF (7.6 mL, 0.1 M) was introduced, followed by p-TsOH.H2O (291.0 mg, 1.53 mmol, 2.0 eq.). The mixture was heated at 66 °C silicon oil bath temperature for 24 h. The solvent was then concentrated under reduced pressure and the crude mixture was purified through column chromatography on SiO2 (CH2Cl2/MeOH: 99/1 to 95/5) to afford the acetylated product 254 (29.0 mg, 10%) as a colorless oil, with 240a (2.5 mg, 1%) and 253 (97.0 mg, 54% In a dried two-necked flask, 240a (224.0 mg, 0.57 mmol, 1.0 eq.) was dissolved in dry CH2Cl2 (2.8 mL, 0.2 M) then the reaction mixture was cooled down to -78 °C. DIBAL-H (1.0 M in hexane, 0.6 mL, 0.57 mmol, 1.0 eq.) was added dropwise at this temperature. After 30 min the reaction mixture was stirred at 0 °C for another 4 h. Rochelle salt (10.0 mL) was then added at 0 °C, and the mixture was stirred for 30 min then extracted with EtOAc. Purification through column chromatography on SiO2 (CH2Cl2/MeOH: 99/1) afforded the product (30.0 mg, 13%, dr 6:1) as a colorless oil. TLC (CH2Cl2/MeOH: 95/5): Rf = 0.45 (UV inactive; KMnO4, stains white). -9), 28.0 (C-3), 18.1 (C-14, C-15, C-16, C-17, C-18, C-19), 12.1 (C-11, C-12, C-13).

Minor diastereomer: δ (ppm) = 100.9 (C-1), 66.0 (C-5), 63.6 (C-10), 56.7 (C-7), 50.5 (C-2), 44.3 (C-8), 33.6 (C-4), 28.7 (C-9), 27.9 (C-3), 18.1 (C-14, C-15, C-16, C-17, C-18, C-19), 12.1 (C-11, C-12, C-13). The diol 255 was obtained as a side product alongside with the lactol 241a as a yellow oil (105.0 mg, 46%).

IR (solution in

Another method to synthesize the diol 255:

In a dried two-necked flask, 240a (39.0 mg, 0.1 mmol, 1.0 eq.) was dissolved in dry CH2Cl2 (0.5 mL, 0.2 M) then the reaction mixture was cooled down to -78 °C. DIBAL-H (1.0 M in hexane, 0.1 mL, 0.1 mmol, 1.0 eq.) was added dropwise at this temperature. After 30 min the reaction mixture was stirred at 0 °C for another 2.5 h. Rochelle salt (5.0 mL) was then added at 0 °C, and the mixture was stirred for 12 h at 20 °C then extracted with EtOAc. Purification through column chromatography on SiO2 (CH2Cl2/MeOH: 99/1) afforded the product (28.0 mg, 70%) as a yellow oil. TLC (CH2Cl2/MeOH: 95/5): Rf = 0.38 (UV inactive; KMnO4, stains white). 1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.33 (d, J = 9.6 Hz, 1H, H-7), 4.22 (qd, J = 7.1, 1.0 Hz, 2H, H-2), 4.03-3.98 (m, 2H, H-11), 3.69 (q, J = 9.8 Hz, 1H, H-4), 3.02-2.95 (m, 4H, H-8, H-5a), 2.68 (dd, J = 11.9, 9.8 Hz, 1H, H-5b), 2.43 (t, J = 6.0 Hz, 2H, H-10), 1.29 (t, J = 7. 1 Hz, 3H, H-1), 1.11-0.97 (m, 21H, H-12, H-13, H-14, H-15, H-16, H-17, H-18, H-19, H-20). 13 C NMR (75 MHz, CDCl3): δ (ppm) = 170.9 (C-3), 120.7 (C-9), 62.3 (C-2), 62.1 (C-7), 60.7 (C-11), 42.3 (C-8), 37.0 (C-4), 34.9 (C-6), 33.0 (C-5), 32.6 (C-10), 18.1 (C-15, C-16, C-17, C-18, C-19, C-20), 14.2 (C-1), 11.9 (C-12, C-13, C-14). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2944 (-C-H), 2867 (-C-H), 2238 (C≡N), 1735 (3-C=O), 1464, 1315, 1237, 1148, 1132, 1103, 882, 744, 683. According to the general procedure (L), from cyclobutane 181b (6.31 g, 20.0 mmol, 1.0 eq.), distilled EtOH (60.0 mL, 0.33 M), and DMAP (1.22 g, 10.0 mmol, 0.5 eq.) for 7 h. According to the general procedure (M), from cyclobutane 260a (4.27 g, 9.9 mmol, 1.0 eq.), dry DMF (50.0 mL, 0.2 M), and Cs2CO3 (6.4 g, 19.8 mmol, 2.0 eq.) for 14 h. Purification through short column chromatography on SiO2 (cyclohexane/EtOAc: 90/10) afforded the desired cyclobutene (2.5 g, 71%) as a pale-yellow oil. TLC (cyclohexane/EtOAc: 80/20): Rf = 0.75 (UV active; KMnO4, stains yellow).

HRMS (TOF

1 H NMR (300 MHz, CDCl3): δ (ppm) = 6.77 (s, 1H, H-7), 4.22 (q, J = 16. 6 Hz, 2H, H-2), 3.95-3.97 (m, 2H, H-10), 3.21 (d, J = 13.8 Hz, 1H, H-5a), 2.90 (d, J = 13.8 Hz, 1H, H-5b), 2.11-1.94 (m, 2H, H-9), 1.30 (t, J = 7.1 Hz, 3H, H-1), 1.10-1.05 (m, 21H, H-11, H-12, H-13, H-14, H-15, H-16, H-17, H-18, H-19). 2), 60.7 (C-10), 41.3 (C-5), 38.8 (C-9), 37.4 (C-6), 18.1 (C-14, C-15, C-16, C-17, C-18, C-19), 14.3 (C-1), 12.0 (C-11, C-12, C-13). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2944 (-C-H), 2867 (-C-H), 2234 (C≡N), 1727 (3-C=O), 1464, 1319, 1106, 882, 735, 682. HRMS (TOF, ES+): calculated for C19H33NO3SiNa [M+Na] + 374.2121, found 374.2126.

[α]D CHCl3).

Procedure for "one-pot" base-mediated sulfone elimination reaction:

In a dried two-necked flask, the cyclobutane 181i (105.0 mg, 0.22 mmol, 1.0 eq.) was dissolved in distilled EtOH (2.2 mL, 0.1 M), then K2CO3 (61.5 mg, 0.44 mmol, 2.0 eq.) was added and the reaction mixture was stirred at 20 °C for 12 h. After completion, the solvent was concentrated under reduced pressure and the crude mixture was purified through short column chromatography on SiO2 (cyclohexane/EtOAc: 95/5) to afford the desired cyclobutene 258a (34.0 mg, 44%) as a pale-yellow oil. In a dried two-necked flask, the cyclobutane 181i (515.0 mg, 1.2 mmol, 1.0 eq.) was dissolved in distilled EtOH (12.0 mL, 0.1 M), then K2CO3 (497.5 mg, 3.6 mmol, 3.0 eq.) was added at 0 °C and the reaction mixture was allowed to warm to 20 °C. After 47 h, total consumption of the starting material was observed. The solvent was concentrated under reduced pressure and the crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 95/5 to 90/10) to afford the side product (190.0 mg, 40%) as a pale-yellow oil. Only 1% (5.0 mg) of the desired product 258a was isolated. TLC (cyclohexane/EtOAc: 80/20): Rf = 0.68 (UV inactive; KMnO4, stains yellow).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.16 (qd, J = 7.2, 1.1 Hz, 2H, H-2), 3.96-3.86 (m, 3H, H-7, H-12), 3.58 (q, J = 7.0 Hz, 2H, H-8), 3.28-3.19 (m, 1H, H-4), 2.52 (ddd, J = 12.0, 9.6, 0.9 Hz, 1H, H-5a), 2.11-1.92 (m, 3H, H-5b, H-11), 1.25 (dt, J = 8.9, 7. 1 Hz, 6H, H-1, H-9), 1.13-1.02 (m, 21H, H-13, H-14, H-15, H-16, H-17, H-18, H-19, H-20, H-21). In a dried two-necked flask, the cyclobutane 260a (311.0 mg, 0.72 mmol, 1.0 eq.) was dissolved in dry THF (7.2 mL, 0.1 M), then NaH (60% suspension in oil, 26.0 mg, 1.08 mmol, 2.0 eq.) was added at 0 °C. The reaction was stirred at 20 °C for 18 h, then quenched with sat. NaHCO3 (2 mL) and extracted with EtOAc (5 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was washed with CH2Cl2 and dried under vacuum to afford the side-product (200.0 mg, 68%) as a viscous white oil. TLC: -1 H NMR (300 MHz, CD3OD): δ (ppm) = 5.99 (d, J = 9.7 Hz, 1H, H-7), 5.65-5.48 (m, 2H, H-11), 5.00 (q, J = 9. 9 Hz, 1H, H-4), 4.59 (s, 3H, H-8), 4.41-4.33 (m, 1H, H-5a), 4.11 (dd, J = 11.5, 9.9 Hz, 1H, H-5b), 3.97 (t, J = 6.1 Hz, 2H, H-10), 2.68-2.65 (m, 21H, H-12, H-13, H-14, H-15, H-16, H-17, H-18, H-19, H-20). According to the general procedure (L), from cyclobutane 181i (1.0 g, 2.11 mmol, 1.0 eq.), distilled EtOH (30.0 mL, 0.07 M), and DMAP (128.0 mg, 1.05 mmol, 0.5 eq.) for 16 h. the solvents were evaporated under reduced pressure, then the crude cyclobutane (1.17 g, 2.72 mmol, 1.0 eq.) was dissolved in dry DMF (27.2 mL, 0.1 M), then Cs2CO3 (1.77 g, 5.44 mmol, 2.0 eq.) was added and the reaction mixture was heated at 70 °C silicon oil bath temperature. The consumption of the starting material was followed by TLC. After 16 h, the solvent was concentrated under reduced pressure and the crude as a mixture of two diastereomers (dr 1:1) was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 80/20) to afford the first diastereomer (304.0 mg, 25%) and the second diastereomer (300.0 mg, 25%) as yellow oils.

For the first diastereomer (trans diastereomer): TLC (cyclohexane/EtOAc: 70/30): R f = 0.47 (UV inactive; KMnO4, stains yellow).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 4. 46-4.38 (m, 3H, H-7, H-21), 4.25-4.14 (m, 3H, H-2, H-22a), 3.92-3.88 (m, 2H, H-10), 3.79-3.70 (m, 1H, H-22b), 3.63-3.53 (m, 1H, H-4) In a dried two-necked flask, the cyclobutene 258a (100.0 mg, 0.28 mmol, 1.0 eq.) was dissolved in dry THF (2.8 mL, 0.1 M), then the reaction mixture was cooled to -78 °C. DIBAL-H (1.0 M in hexane, 0.85 mL, 0.85 mmol, 3.0 eq.) was added and the consumption of the starting material was followed by TLC. After 2.5 h, Rochelle salt (3.0 mL) was added and the reaction mixture was stirred for 5 min then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 90/10) to afford the desired product (64.0 mg, 74%) as a colorless oil. TLC (cyclohexane/EtOAc: 70/30): Rf = 0.33 (UV active; KMnO4, stains yellow). In a dried two-necked flask, cyclobutene 258a (211.0 mg, 0.6 mmol, 1.0 eq.) was dissolved in dry THF (6.0 mL, 0.1 M) and pyrrolidine (0.2 mL, 2.4 mmol, 4.0 eq.) was added. The reaction mixture was stirred at 66 °C silicon oil bath temperature for 5 h. The mixture was then cooled down to 20 °C and the solvent was concentrated under reduced pressure. The obtained crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 80/20) to afford the product (242.0 mg, 95%, dr > 19:1:1:1) as a pale-yellow oil. TLC (cyclohexane/EtOAc: 80/20): Rf = 0.66 (UV active; KMnO4, stains white). (m, 2H, H-13), 1.81-1.77 (m, 4H, H-9, H-7.0 eq.), then the reaction mixture was stirred at 20 °C for 9 h. The solvent was evaporated, then the crude mixture was dissolved in EtOAc and filtrated over a celite pad. The filtrate was concentrated under reduced pressure and the crude mixture was purified through column chromatography on SiO2 (CH2Cl2/MeOH: 95/5) to afford the product (98.0 mg, 40%) as a yellow oil. TLC (CH2Cl2/MeOH: 90/10): Rf = 0.38 (UV inactive; KMnO4, stains yellow).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.13 (qd, J = 7.1, 2.2 Hz, 2H, H-2), 3.78-3.74 (m, 2H, H-14), 3.25-3.09 (m, 4H, H-4, H-7, H-12), 2.68-2.62 (m, 4H, H-8, H-11), 2.27 (dd, J = 11.8, 10.0 Hz, 1H, H-5a), 1.98-1.85 (m, 2H, H-13), 1.83-1.73 (m, 5H, H-5b, H-9, H-10), 1.24 (t, J = 7.1 Hz, 3H, H-1), 1.12-1.04 (m, 21H, H-15, H-16, H-17, H-18, H-19, H-20, H-21, H-22, H-23). According to the general procedure (N), from benzyl alcohol (20.0 μL, 0.2 mmol, 1.0 eq.), dry THF (1.0 mL, 0.2 M), NaH (60% suspension in oil, 8.0 mg, 0.2 mmol, 1.0 eq.) and the cyclobutene 258b (39.0 mg, 0.2 mmol, 1.0 eq.) in dry THF (1.1 mL, 0.17 M) for 2 h. The crude as a mixture of diastereomers (40.0 mg, 66% crude, dr 2.3:1) was obtained as a colorless oil and was pure enough to be used directly in the next step without further purification. [Purification of the crude for analysis was accomplished through column chromatography on SiO2 (cyclohexane/ethyl acetate: 90/10), and only 9.0 mg (15%) were recuperated. The product is not stable on column]. TLC (cyclohexane/EtOAc: 90/10): Rf = 0.29 (UV active; KMnO4, stains yellow). To a flame-dried two-necked flask equipped with a condenser, and under inert atmosphere, Ph3SiOH (71.5 mL, 0.258 mmol, 1.0 eq.) was introduced followed by dry THF (1.0 mL, 0.26 M) and the reaction was set at 0 °C. NaH (60% suspension in oil, 11.3 mg, 0.28 mmol, 1.1 eq.) was added portionwise and the reaction was stirred for 10 min at the same temperature. 258b (50.0 mg, 0.258 mmol, 1.0 eq.) was dissolved in THF (1.0 mL, 0.26 M) and added slowly to the mixture, the color changed to yellow. In a dried two-necked flask, the cyclobutene 258a (50.0 mg, 0.14 mmol, 1.0 eq.) was dissolved in distilled nitromethane (1.4 mL, 0.1 M), and the mixture was set at 0 °C, then DBU (0.04 mL, 0.28 mmol, 2.0 eq.) was added and the reaction was stirred at 20 °C. After 18 h, the solvent was concentrated under reduced pressure and the crude was directly purified through short column chromatography on SiO2 (cyclohexane/EtOAc: 95/5 to 85/15) to afford the mixture of diastereomers as a yellow oil (40.0 mg, 69%, dr 1.1:1). TLC (cyclohexane/EtOAc: 80/20): Rf = 0.45 (UV inactive; KMnO4, stains yellow).

Major diastereomer (trans):

1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.84 (dd, J = 14.3, 7. 1 Hz, 1H, H-20a), 4.78 (dd, J = 15.5, 6.2 Hz, 1H, H-20b) 4.23-4.13 (m, 2H, H-2), 3.96-3.89 (m, 2H, H-10), 3.36-3.30 (m, 1H, H-7), 3.16 (q, J = 9. 6 Hz, 1H, H-4), 2.75-2.68 (m, 1H, H-5a), 2.50-2.46 (m, 1H, H-5b), 2.16-1.98 (m, 2H, H-9), 1.30-1.24 (m, 3H, H-1), 1.09-1.05 (m, 21H, H-11, H-12, H-13, H-14, H-15, H-16, H-17, H-18, H-19). According to the general procedure (N), from di-tert-butyl malonate 323a (0.12 mL, 0.55 mmol, 1.0 eq.), dry THF (2.7 mL, 0.2 M), NaH (60% suspension in oil, 22.0 mg, 0.55 mmol, 1.0 eq.) and the cyclobutene 258a (195.0 mg, 0.55 mmol, 1.0 eq.) in dry THF (3.2 mL, 0.17 M) for 4 h. The crude as a mixture of two diastereomers (dr 4.3:1) was purified through column chromatography on SiO2 (cyclohexane/ethyl acetate: 98/2) to afford the major diastereomer (190.0 mg, 61%) and the minor diastereomer with traces of the major diastereomer (44.0 mg, 14%) as a colorless oil.

For the major diastereomer (1R,4R)-trans-324a: TLC (cyclohexane/EtOAc: 90/10): R f = 0.44 (UV inactive; KMnO4, stains yellow).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.13 (q, J = 7. 1 Hz, 2H, H-2), 3.88 (dd, J = 7.4, 4.7 Hz, 2H, H-10), 3.65 (d, J = 11.5 Hz, 1H, H-20), 3.23 (dd, J = 11.6, 9.0 Hz, 1H, H-7), 3.10 (q, J = 9. (m, 21H, H-11, H-12, H-13, H-14, H-15, H-16, H-17, H-18, H-19). 13 C NMR (75 MHz, CDCl3): δ (ppm) = 172.9 (C-3), 166.7 (C-21), 166.2 (C-22), 121.5 (C-8), 82.5 (C-23), 82.4 (C-24), 61.0 (C-2), 60.5 (C-10), 56.6 (C-20), 44.4 (C-7), 40.9 (C-9), 39.3 (C-4), 38.1 (C-6), 34.6 (C-5), 28.0 (C-25, C-26, C-27), 27.9 (C-28, C-29, C-30), 18.1 (C-14, C-15, C-16, C-17, C-18, C-19), 14.2 (C-1), 12.0 (C-11, C-12, C-13). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2943 (-C-H), 2868 (-C-H), 2232 (C≡N), 1735 (br, 3-C=O, 21-C=O, 22-C=O), 1463, 1369, 1254, 1165, 1143, 1105, 883, 683. HRMS (TOF, ES+): calculated for C30H53NO7SiNa [M+Na] + 590.3483, found 590.3477.

[α]D 25 = -25.55 (c = 0.16, CH3Cl).

For the minor diastereomer (1R,4S)-cis-324a: TLC (cyclohexane/EtOAc: 90/10): R f = 0.34 (UV inactive; KMnO4, stains yellow).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.15 (q, J = 7. 2 Hz, 2H, H-2), 4.02-3.86 (m, 2H, H-10), 3.71 (dd, J = 11.8, 9.7 Hz, 1H, H-7), 3.32 (d, J = 11.8 Hz, 1H, H-20), 3.00 (q, J = 9. 6 Hz, 1H, H-4) In a dried two-necked flask, the cyclobutane 324a (120.0 mg, 0.21 mmol, 1.0 eq.) was dissolved in distilled EtOH (2.1 mL, 0.1 M) and the reaction mixture was cooled down to 0 °C. NiCl2.6H2O (50.0 mg, 0.21 mmol, 1.0 eq.) was added followed by portion-wise addition of NaBH4 (55.0 mg, 1.48 mmol, 7.0 eq.) then the reaction mixture was stirred at 20 °C for 16 h. The solvent was concentrated under reduced pressure, then the crude mixture was dissolved in EtOAc and filtrated over a celite pad. The filtrate was evaporated and the crude mixture was purified through column chromatography on SiO2 (CH2Cl2/MeOH: 95/5) to afford the major diastereomer (30.8 mg, 26%) and the minor diastereomer (17.0 mg, 14%) with traces of the major diastereomer as a pale-yellow oil. 56% of the starting material were recovered.

For the major diastereomer (1R,4R)-trans-328: TLC (CH2Cl2/MeOH: 95/5): R f = 0.32 (UV inactive; KMnO4, stains yellow).

1 H NMR (600 MHz, CDCl3): δ (ppm) = 4.14-4.05 (m, 2H, H-2), 3.85-3.82 (m, 1H, H-10a), 3.76-3.72 (m, 1H, H-10b), 3.37-3.34 (m, 1H, H-20), 3.17 (d, J = 13.2 Hz, 1H, H-8a), 3.05-3.00 (m, 2H, H-7, H-8b), 2.91 (q, J = 9.2 Hz, 1H, H-4), 2.43 (br s, 1H, H-5a), 2.08-1.99 (m, 2H, H-5b, H-9a), 1.95-1.91 (m, 1H, H-9b), 1.44 (s, 9H, H-25, H-26, H-27), 1.40 (s, 9H, H-28, H-29, H-30), 1.23-1.20 (m, 3H, H-1), 1.16-1.10 (m, 3H, H-11, H-12, H-13), 1.07-1.05 (m, 18H, H-14, H-15, H-16, H-17, H-18, H-19). 6), 31.0 (C-5), 28.0 (C-25, C-26, C-27), 27.9 (C-28, C-29, C-30), 18.1 (C-14, C-15, C-16, C-17, C-18, C-19), 14.2 (C-1), 11.8 (C-11, C-12, C-13). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2941 (-C-H), 2867 (-C-H), 1730 (br, 3-C=O, 21-C=O, 22-C=O), 1462, 1368, 1256, 1156, 1097, 882, 685. HRMS (TOF, ES+): calculated for C30H58NO7Si [M+H] + 572.3977, found 572.3969.

[α]D 25 = -3.17 (c = 0.12, CH3Cl).

For the minor diastereomer (1R,4S)-cis-328: TLC (CH2Cl2/MeOH: 95/5): R f = 0.24 (UV inactive; KMnO4, stains yellow).

1 H NMR (600 MHz, CDCl3): δ (ppm) = 4.20-4.08 (m, 1H, H-2a), 4.06-3.98 (m, 1H, H-2b), 3.90-3.87 (m, 1H, H-10a), 3.79-3.73 (m, 2H, H-10b, H-20), 3.37-3.23 (m, 2H, H-7, H-8a), 3.19-3.06 (m, 2H, H-4, H-8b), 2.53-2.44 (m, 1H, H-9a), 2.38 (q, J = 10.3, 9.4 Hz, 1H, H-5a), 2.20-2.10 (m, 1H, H-5b), 1.52-1.48 (m, 1H, H-9b), 1.45-1.41 (m, 18H, H-25, H-26, H-27, H-28, H-29, H-30), 1.26-1.21 (m, 3H, H-1), 1.16-1.10 (m, 3H, H-11, H-12, H-13), 1.06-1.02 (m, 18H, H-14, H-15, H-16, H-17, H-18, H-19). -11, C-12, C-13). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2941 (-C-H), 2867 (-C-H), 1727 (br, 3-C=O, 21-C=O, 22-C=O), 1462, 1369, 1254, 1165, 1144, 1100, 882, 683. HRMS (TOF, ES+): calculated for C30H58NO7Si [M+H] + 572.3977, found 572.3964.

[α]D 25 = -7.12 (c = 0.12, CH3Cl). According to the general procedure (N), from dibenzyl malonate (1.19 g, 4.2 mmol, 1.0 eq.), dry THF (21.0 mL, 0.2 M), NaH (60% suspension in oil, 168.0 mg, 4.2 mmol, 1.0 eq.) and cyclobutene 258b (818.0 mg, 4.2 mmol, 1.0 eq.) in dry THF (25.0 mL, 0.17 M) for 4 h. The crude as a mixture of diastereomers (1.69 g, 84%, dr 4.5:3.4 According to the general procedure (N), from diethyl malonate 323c (0.25 mL, 1.7 mmol, 1.0 eq.), dry THF (8.5 mL, 0.2 M), NaH (60% suspension in oil, 68.0 mg, 1.7 mmol, 1.0 eq.) and cyclobutene (600.0 mg, 1.7 mmol, 1.0 eq.) in dry THF (10.0 mL, 0.17 M) for 4 h. The crude as a mixture of diastereomers (680.0 mg, 78%, dr 6.25:4:1.25:1) was obtained as a yellow oil and was pure enough to be used directly in the next step without further purification. [Purification of the crude for analysis was accomplished through column chromatography on SiO2 (cyclohexane/EtOAc: 85/15)].

For the major diastereomer (1R,4R)-trans-332a: TLC (cyclohexane/EtOAc: 90/10): R f = 0.31 (UV inactive; KMnO4, stains yellow).

1 H NMR (600 MHz, CDCl3): δ (ppm) = 4.24-4.17 (m, 2H, H-2), 4.17-4.10 (m, 4H, H-23, H-24), 3.90-3.86 (m, 2H, H-10), 3.82 (d, J = 11.5 Hz, 1H, H-20), 3.27 (dd, J = 11.4, 9.4 Hz, 1H, H-7), 3.16 (q, J = 9.5 Hz, 1H, H-4), 2.69 (dd, J = 12. [α]D 25 = -0.99 (c = 0.25, CHCl3).

2-methylene-4-((triisopropylsilyl)oxy)butanenitrile (338)

In a dried two-necked flask, the cyclobutane 332a (58.0 mg, 0.11 mmol, 1.0 eq.) was dissolved in dry DMF (1.1 mL, 0.1 M), and K2CO3 (32.0 mg, 0.22 mmol, 2.0 eq.) was added at the end. The reaction mixture was stirred at 70 °C silicon oil bath temperature for 23 h, then aq. HCl (1.0 M) (3 mL) was added and the reaction was extracted with EtOAc (7 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 90/10) to afford the side product (4.0 mg, 14%) as a colorless oil. TLC (cyclohexane/EtOAc: 70/30): R f = 0.8 (UV active; KMnO4, stains yellow). minimum amount of water (5-10 mL). The aqueous phase was saturated with 2 spoons of NaCl and extracted with EtOAc (5 x). The combined organic layers were washed with brine (5-10 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude was used directly in the next step without further purification. [Purification of the crude for analysis was accomplished through short column chromatography on SiO2 (CH2Cl2/MeOH/NH4OH: 95/4/1)]. The product was stored under inert atmosphere in the freezer.

General procedure (D) for mesylate formation 48

To a flame-dried flask and under inert atmosphere, the hydroxy piperidinone (1.0 eq.) was introduced followed by dry CH2Cl2 (0.07 M) and the reaction was set at 0 °C. MsCl (1.1 eq.) was added slowly followed by distilled Et3N (1.1 eq.) and the reaction was stirred at 20 °C for 3-4 h and followed by TLC. After completion, the reaction was quenched with minimum amount of water (5-10 mL) and extracted with CH2Cl2. The aqueous phase was saturated with 2 spoons of NaCl and extracted with CH2Cl2 (2 x). The combined organic layers were washed with brine (5 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was used directly in the next step without further purification. [Purification of the crude for analysis was accomplished through short column chromatography on SiO2 (CH2Cl2/MeOH/NH4OH: 95/4/1)]. The product was stored under inert atmosphere in the freezer.

General procedure (E) for chiral azabicyclo[3.3.1]nonane synthesis 48

To a flame-dried two-necked flask and under inert atmosphere, DMF AcroSeal™ packaging (0.1 M) was introduced and the reaction was set at 0 °C. NaH (60% suspension in oil, 1.5 eq.) was added followed by dropwise addition of the mesylate (1.0 eq.) dissolved in DMF (0.1 M), then the mixture was stirred at 20 °C for 3-4 h. After completion, the reaction was quenched with minimum amount of water (5 mL) and extracted with EtOAc. The aqueous phase was saturated with 2 spoons of NaCl and extracted with EtOAc (2 x). The combined organic layers were washed with brine (5 mL), dried over Na2SO4 and concentrated carefully under reduced pressure. The crude was purified through short column chromatography on SiO2 (eluants as noted) to afford the pure desired product. The product was stored under inert atmosphere in the freezer.

General procedure (F) for Sandmeyer reaction

To a flame-dried 10 mL schlenk tube equipped with a Teflon stopcock, the amino quinoline (1.0 eq.) was introduced, followed by CuBr (2.0 eq.), and the atmosphere was exchanged with vacuum/argon (3 x). Freshly distilled CH3CN (0.1 M) and t-BuONO (1.5 eq.) were added respectively and the black mixture was stirred at 40 °C silicon oil bath temperature for 3-4 h. After completion, the solvents were concentrated under reduced pressure and the crude mixture was purified through column chromatography on SiO2 (CH2Cl2/MeOH/NH4OH: percentages as noted) to afford the pure desired product. [All the solvents used for purification were distilled prior to use to remove the traces of impurities present in the commercial bottles].

General procedure (G) for Suzuki coupling reaction

To a flame-dried 10 mL schlenk tube equipped with a Teflon stopcock, the bromoquinoline (1.0 eq.) was introduced, followed by Potassium vinyltrifluoroborate (1.5 eq.) and anhydrous (oven dried) K2CO3 (1.0 eq.) and the atmosphere was exchanged with vacuum/argon (3 x). Freshly distilled DME (0.06 M) and distilled H2O (0.12 M) were added respectively and the mixture was degassed through argon bubbling for 30 min. Pd(PPh3)4 (0.1 eq.) was then added and the reaction mixture was stirred at 95 °C silicon oil bath temperature for 12 h. After completion, the solvents were concentrated under reduced pressure and the crude mixture was purified through micro-column chromatography on SiO2 (CH2Cl2/MeOH: 99/0 to 99/1 to 98/2) to afford the pure desired product as a yellow viscous oil. The purity of the column fractions was checked through the UV different wavelengths (254 nm and 365 nm). At 365 nm, PPh3 residues appear dark blue, the desired product appears light blue sky, and the starting material is inactive. [All the solvents used for purification were distilled to remove the traces of impurities present in the commercial bottles].

General procedure (H) for O-demethylation reaction

To a flame-dried flask and under inert atmosphere, the vinyl quinoline (1.0 eq.) was introduced, and the atmosphere was exchanged with vacuum/argon (3 x). CH2Cl2 freshly distilled from CaH2 (0.02 M) was added and the reaction mixture was set at 0 °C. BBr3 (1.0 M in CH2Cl2, 12.0 eq.) was then added dropwise, the color changed to yellow then brown with observation of orange precipitate. The reaction mixture was allowed to warm up slowly and stirred at 20 °C for 12 h. After completion, the reaction was quenched at 0 °C with dropwise addition of MeOH (0.1-0.2 mL), the addition of MeOH may continue till the disappearance of the white fume and the solubilization of the precipitate. the solvents were concentrated under reduced pressure and the crude mixture was purified through microcolumn chromatography on SiO2 (CH2Cl2/MeOH: 99/1 to 98/2) to afford the pure desired product as a yellow solid. The purity of the column fractions was checked through the UV different wavelengths (254 nm and 365 nm). At 365 nm, the desired product appears light blue sky. On TLC, when concentrated, the product appears yellow. [All the solvents used for purification were distilled to remove the traces of impurities present in the commercial bottles].

Synthesis of the starting materials 1,1-dibromobut-1-ene (393a) 368

To a flame-dried two-necked flask, dry CH2Cl2 (300.0 mL, 0.22 M) was introduced and the reaction was set at -10 °C (ice/acetone bath: 1/1). CBr4 (45.0 g, 136.0 mmol, 2.0 eq.) was added, followed by PPh3 (70.8 g, 270.0 mmol, 4.0 eq.), and the color turned to brown with orange precipitate. The mixture was stirred at the same temperature for 40 min, then propionaldehyde AcroSeal™ packaging stored under argon (4.9 mL, 67.5 mmol, 1.0 eq.) was added dropwise and the mixture was stirred for further 2.5 h at 0 °C, then allowed to warm to 20 °C. The solvents were concentrated under reduced pressure at 25-30 °C. the solid residue was washed with pentane, filtered through a silica plug, and the filtrate was concentrated under reduced pressure. The crude mixture was purified through short column chromatography on SiO2 (pentane: 100%). The product was concentrated carefully under reduced pressure (volatile) to afford the product (9.6 g, 67%) as a colorless liquid and stored under argon in the freezer. TLC (cyclohexane: 100%): Rf = 0.71 (UV active; KMnO4, stains yellow).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 6.39 (t, J = 7.2 Hz, 1H, H-1), 2.11 (quint, J = 7.5 Hz, 2H, H-2), 1.03 (t, J = 7. 6 Hz, 3H, H-3).

The 1 H NMR data are in agreement with those reported in the literature. 368

1-(2-nitrophenyl)prop-2-en-1-ol (401a) 473 To a flame-dried flask, 2-nitrobenzaldehyde (184.0 mg, 1.2 mmol, 1.0 eq.) was introduced and the atmosphere was exchanged with argon/vacuum (3 x). Dry THF (6.0 mL, 0.2 M) was added then the reaction was set at -78 °C. Vinylmagnesium bromide (1.0 M in THF, 1.82 mL, 1.82 mmol, 1.5 eq.) was added slowly and the reaction was stirred for 1 h at the same temperature, then at 20 °C for 12 h. The reaction was quenched with aqueous HCl (0.01 N) and extracted with EtOAc, the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 90/10) to afford the product (160.0 mg, 74%) as a yellow oil. The product was stored under inert atmosphere in the freezer. TLC (cyclohexane/EtOAc: 80/20): Rf = 0.36 (UV active; KMnO4, stains yellow).

1-(4-methoxy-2-nitrophenyl)prop-2-en-1-ol (401b)

To a flame-dried flask, 4-methoxy-2-nitrobenzaldehyde (100.0 mg, 0.55 mmol, 1.0 eq.) was introduced and the atmosphere was exchanged with argon/vacuum (3 x). Dry THF (2.7 mL, 0.2 M) was added then the reaction was set at -78 °C. Vinylmagnesium bromide (1.0 M in THF, 0.82 mL, 0.82 mmol, 1.5 eq.) was added slowly and the reaction was stirred for 1 h at the same temperature, then at 20 °C for 11 h. The reaction was quenched with aqueous HCl (0.01 N) and extracted with EtOAc, the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through short column chromatography on SiO2 (cyclohexane/EtOAc: 80/20) to afford the product (75.0 mg, 69%) as a yellow oil. The product was stored under inert atmosphere in the freezer. TLC (cyclohexane/EtOAc: 80/20): Rf = 0.30 (UV active; KMnO4, stains white).

1-(2-aminophenyl)prop-2-en-1-ol (396a) 372

To a dried flask, 401a (160.0 mg, 0.89 mmol, 1.0 eq.) was introduced followed by EtOH/H2O: 4/1 (8.8 mL, 0.1 M), NH4Cl (242.0 mg, 4.45 mmol, 5.0 eq.), and Zn dust (876.0 mg, 13.4 mmol, 15.0 eq.). The reaction was stirred at 20 °C for 11 h, then the ethanol was concentrated under reduced pressure and the reaction was diluted with CH2Cl2 then filtered over a short celite pad. The filtrate was then extracted with CH2Cl2/H2O, and the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 90/10 to 80/20) to afford the product (130.0 mg, 98%) as a yellow oil. The product was stored under inert atmosphere in the freezer. TLC (cyclohexane/EtOAc: 80/20): Rf = 0.17 (UV active, appears fluorescent; KMnO4, stains yellow; vanillin, stains red-brown then green after 5 min).

1-(2-amino-4-methoxyphenyl)prop-2-en-1-ol (396b)

To a dried flask, 401b (65.0 mg, 0.31 mmol, 1.0 eq.) was introduced followed by EtOH/H2O: 4/1 (3.0 mL, 0.1 M), NH4Cl (84.4 mg, 1.55 mmol, 5.0 eq.), and Zn dust (305.0 mg, 4.66 mmol, 15.0 eq.). The reaction was stirred at 20 °C for 7 h, then the ethanol was concentrated under reduced pressure and the reaction was diluted with CH2Cl2 then filtered over a short celite pad. The filtrate was then extracted with CH2Cl2/H2O, and the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 80/20) to afford the product (42.0 mg, 75%) as a yellow oil. The product was stored under inert atmosphere in the freezer, degradation of the product was observed within 24 h at 20 °C. TLC (cyclohexane/EtOAc: 70/30): Rf = 0.44 (UV active, appears fluorescent; KMnO4, stains yellow). To a flame-dried two-necked flask equipped with a condenser, the bicyclic lactam 402 (87.0 mg, 0.62 mmol, 1.0 eq.) was introduced followed by dry CH2Cl2 (6.2 mL, 0.1 M), and POCl3 (64.0 μL, 0.68 mmol, 1.1 eq.) was added dropwise. The reaction was stirred at 60 °C silicon oil bath temperature and the starting material consumption was followed by TLC. After 7 h, the reaction was cooled down to 20 °C and 2-amino-4-methoxybenzonitrile 354 (137.0 mg, 0.93 mmol, 1.5 eq.) dissolved in dry CH2Cl2 (5.8 mL, 0.1 M), was added dropwise. The reaction was stirred at 50 °C for 17 h, then the solvents were concentrated under reduced pressure and ice water (2.0 mL) was added to the reaction.

The aqueous layer was basified with sat. NaHCO3 till pH = 8, then extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (CH2Cl2/EtOAc/NH4OH: 90/9/1) to afford the product (122.0 mg, 73%) as a highly viscous yellow oil. To a flame-dried two-necked flask, the amidine 399a (119.0 mg, 0.44 mmol, 1.0 eq.) was introduced followed by dry THF (9.0 mL, 0.05 M), and the reaction was set at 0°C. t-BuOK (133.0 mg, 1.19 mmol, 2.7 eq.) was then added, and the color changed immediately to yellow-orange. The resulting solution was allowed to warm up slowly to 20 °C and stirred for 15 h. The reaction was quenched with sat. NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through a short column chromatography on SiO2 (CH2Cl2/MeOH/NH4OH: 97/2/1 to 95/4/1) to afford the product (92.0 mg, 78%) as a limestone-like white solid. The product was stored under inert atmosphere in the freezer. TLC (CH2Cl2/MeOH/NH4OH: 96/3/1): Rf = 0.05 (UV active, appears fluorescent; KMnO4, stains yellow after long heating). To a dried two-necked flask, the amino quinoline 406 (65.0 mg, 0.24 mmol, 1.0 eq.) was introduced followed by H2O (0.5 mL, 0.48 M), and the reaction was set at 0 °C. H2SO4 (64.0 μL, 1.2 mmol, 5.0 eq.) was then added, and NaNO2 (82.8 mg, 1.2 mmol, 5.0 eq.) dissolved in H2O (1.9 mL, 0.12 M) was added dropwise. The mixture color changed to intense red with observation of bubbles, and the reaction was allowed to warm up slowly to 20 °C. After 10 min the color disappeared. The resulting mixture was stirred at the same temperature for 16 h. The reaction was then basified at 0 °C till pH = 9 with sat. NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (CH2Cl2/MeOH/NH4OH: 98/1/1 to 94/5/1) to afford the product (36.0 mg, 56%, 72% brsm) as a white solid. According to the general procedure (F), from the amino quinoline 406 (25.0 mg, 0.092 mmol, 1.0 eq.), CuBr (26.6 mg, 0.185 mmol, 2.0 eq.), CH3CN (0.1 mL, 0.1 M) and t-BuONO (16.0 μL, 0.138 mmol, 1.5 eq.) for 4 h. The crude mixture was purified through column chromatography on SiO2 (CH2Cl2/MeOH/NH4OH: 98/1/1) to afford the desired product (25.0 mg, 81%) as a yellow solid. According to the general procedure (G), from the bromoquinoline 409 (40.0 mg, 0.12 mmol, 1.0 eq.), potassium vinyltrifluoroborate (24.0 mg, 0.18 mmol, 1.5 eq.), anhydrous K2CO3 (16.5 mg, 0.12 mmol, 1.0 eq.), freshly distilled DME (2.0 mL, 0.06 M), distilled H2O (1.0 mL, 0.12 M) and Pd(PPh3)4 (13.8 mg, 0.012 mmol, 0.1 eq.) for 12 h. The crude mixture was purified through column chromatography on SiO2 (CH2Cl2/MeOH: 98/2 to 96/4) to afford the pure desired product (32.0 mg, 96%) as a yellow viscous oil. TLC (CH2Cl2/MeOH/NH4OH: 94/5/1): Rf = 0.37 (UV active; KMnO4, stains intense yellow). According to the general procedure (H), from vinyl quinoline 398a (9.0 mg, 0.032 mmol, 1.0 eq.), CH2Cl2 (1.0 mL, 0.02 M) and BBr3 (1.0 M in CH2Cl2, 0.32 mL, 0.32 mmol, 10.0 eq.). The crude mixture was purified through short column chromatography on SiO2 (CH2Cl2/MeOH: 99/1 to 98/2) to afford the pure desired product (9.0 mg, quant.) as a yellow solid. According to the general procedure (A), from the crude cyclobutane 332a (50.0 mg, 0.1 mmol, 1.0 eq.), anhydrous NiCl2 (28.0 mg, 0.21 mmol, 2.2 eq.), freshly distilled EtOH (4.0 mL, 0.025 M), and NaBH4 (72.0 mg, 1.94 mmol, 20.0 eq.) for 42 h. The crude mixture was purified through column chromatography on SiO2 (CH2Cl2/MeOH: 98/2 to 95/5 to 90/10) to afford the desired mixture of diastereomers 580a (28.0 mg, 60%, dr 1:1) as a colorless oil, and the reduced amine 379a (6.5 mg, 13%, isolated dr 1:1) as a colorless oil. TLC (CH2Cl2/MeOH: 90/10): Rf = 0.48 (UV inactive; KMnO4, stains white). The reduced amine (6.5 mg, 14%, isolated dr 1:1) was obtained as a yellow oil, as a side product alongside with the cyclized product. TLC (CH2Cl2/MeOH: 90/10): R f = 0.27 (UV inactive; KMnO4, stains yellow). According to the general procedure (B), from 380a (859.0, 1.83 mmol, 1.0 eq.), EtOH/H2O: 4/1 (12.0 mL, 0.15 M) and LiOH (219.0 mg, 9.15 mmol, 5.0 eq.) for 12 h. The crude mixture of diastereomers (681.0 mg, 90%, dr 1:1) was obtained as a highly viscous colorless oil and was used directly in the next step without further purification. TLC (CH2Cl2/MeOH/AcOH: 90/9/1): Rf = 0 (UV inactive; KMnO4, stains yellow-white). According to the general procedure (C), from the crude diacid 388a (368.0 mg, 0.88 mmol, 1.0 eq.) and dry THF (10.0 mL, 0.08 M) for 3 h. The crude mixture 389a (337.0 mg, quant.) was obtained as a highly viscous white oil. The esterification reaction was accomplished from the crude 389a (442.0 mg, 1.2 mmol, 1.0 eq.) in CH2Cl2/MeOH: 5/1 (10.0 mL, 0.12 M), TMSCHN2 (2.0 M in hexane, 0.9 mL, 1.8 mmol, 1.5 eq.), and AcOH (0.02 mL, 0.36 mmol, 0.3 eq.). The crude 391a (476.0 mg, quant.) was obtained as a pale-yellow oil. The reduction reaction was accomplished from the crude 391a (476.0 mg, 1.23 mmol, 1.0 eq.) in dry THF (24.6 mL, 0.05 M), and LAH (1.0 M in Et2O, 1.54 mL, 1.54 mmol, 1.25 eq.) for 8 h. The crude 390a (400.0 mg, 91%) was obtained as yellow oil and was used directly in the next step without further purification. According to the general procedure (D), from the hydroxy piperidinone 390a (400.0 mg, 1.12 mmol, 1.0 eq.), dry CH2Cl2 (12.0 mL, 0.09 M), MsCl (0.1 mL, 1.34 mmol, 1.2 eq.) and distilled Et3N (0.31 mL, 2.24 mmol, 2.0 eq.) for 6 h. The crude mixture (420.0 mg, 85%) was obtained as a yellow oil and was used directly in the next step without further purification. According to the general procedure (E), from the mesylate 392a (40.0 mg, 0.09 mmol, 1.0 eq.), DMF (1.8 mL, 0.05 M) and NaH (60% suspension in oil, 5.5 mg, 0.137 mmol, 1.5 eq.). The mixture was stirred at 20 °C for 7 h then 40 °C for 12 h. The crude mixture was purified through short column chromatography on SiO2 (cyclohexane/EtOAc: 50/50) to afford the pure desired product (3.0 mg, 10% over 4 steps) as a colorless oil. Traces of TIPS group deprotection were observed. The product was stored under inert atmosphere in the freezer. TLC (CH2Cl2/MeOH: 95/5): Rf = 0.48 (UV inactive; KMnO4, stains yellow after long heating).

Propyl side chain model diethyl 2-((2R)-2-cyano-4-(ethoxycarbonyl)-2-propylcyclobutyl)malonate (332c)

According to the general procedure (N) in chapter III, from diethyl malonate (0.6 mL, 4.14 mmol, 1.0 eq.), dry THF (20.7 mL, 0.2 M), NaH (60% suspension in oil, 165.0 mg, 4.14 mmol, 1.0 eq.) and cyclobutene 258b (800.0 mg, 4.14 mmol, 1.0 eq.) in dry THF (24.3 mL, 0.17 M) for 4 h. The crude as a mixture of diastereomers (1.5 g, quant., dr 11.4:5.8 According to the general procedure (A), from the crude cyclobutane 332c (1.44 g, 4.07 mmol, 1.0 eq.), anhydrous NiCl2 (1.16 g, 8.95 mmol, 2.2 eq.), freshly distilled EtOH (162.0 mL, 0.025 M), and NaBH4 (3.04 g, 81.4 mmol, 20.0 eq.) for 70 h. The crude mixture was purified through column chromatography on SiO2 (CH2Cl2/MeOH: 95/5 to 90/10) to afford the desired mixture of diastereomers (965.0 mg, 75%, dr 1:1) as a pale-yellow oil, and the reduced amine 379b (150.0 mg, 10%, isolated dr 1:1) as a viscous yellow oil. TLC (CH2Cl2/MeOH: 90/10): Rf = 0.57 (UV inactive; KMnO4, stains white).

(5R)-5-(2-carboxyethyl)-2-oxo-5-propylpiperidine-3-carboxylic acid (388b)

According to the general procedure (B), from 380b (571.0, 1.82 mmol, 1.0 eq.), EtOH/H2O: 4/1 (12.0 mL, 0.15 M) and LiOH (218.0 mg, 9.1 mmol, 5.0 eq.) for 4 h. The crude mixture of diastereomers (375.0 mg, 80%, dr 1:1) was obtained as a viscous colorless oil and was used directly in the next step without further purification. TLC (CH2Cl2/MeOH/AcOH: 90/9/1): Rf = 0 (UV inactive; KMnO4, stains yellow-white). According to the general procedure (C), from the crude diacid 388b (350.0 mg, 1.36 mmol, 1.0 eq.) and dry THF (6.0 mL, 0.08 M) for 3 h. The crude mixture 389b (313.0 mg, quant.) was obtained as a white solid. The esterification reaction was accomplished from the crude 389b (245.0 mg, 1.15 mmol, 1.0 eq.) in CH2Cl2/MeOH: 5/1 (10.2 mL, 0.12 M), TMSCHN2 (2.0 M in hexane, 0.86 mL, 1.72 mmol, 1.5 eq.), and AcOH (0.02 mL, 0.345 mmol, 0.3 eq.). The crude 391b (291.0 mg, quant.) was obtained as a pale-yellow oil solidifies open to atmosphere. The reduction reaction was accomplished from the crude 391b (271.0 mg, 1.19 mmol, 1.0 eq.) in dry THF (24.0 mL, 0.05 M), and LAH (1.0 M in Et2O, 1.5 mL, 1.49 mmol, 1.25 eq.) for 6 h. The crude 390b (145.0 mg, 74%) was obtained as pale-yellow viscous oil and was used directly in the next step without further purification.

[Purification of the crude for analysis afforded the alcohol as a white solid]. According to the general procedure (E), from the mesylate 392b (50.0 mg, 0.18 mmol, 1.0 eq.), DMF (0.9 mL, 0.2 M) and NaH (60% suspension in oil, 11.0 mg, 0.27 mmol, 1.5 eq.). The mixture was stirred at 70 °C for 14 h. The crude was purified through short column chromatography on SiO2 (cyclohexane/EtOAc/NH4OH: 70/29/1) to afford the pure desired product (13.0 mg, 40% 4 steps) as a colorless oil. The product was stored under inert atmosphere in the freezer. TLC (CH2Cl2/MeOH: 90/10): Rf = 0.54 (UV inactive; KMnO4, stains yellow after long heating).

1 H NMR (600 MHz, CDCl3): δ (ppm) = 4.11 (ddd, J = 13. 1, 5.6, 1.5 Hz, 1H, H-11a), 3.18 (d, J = 13.3 Hz, 1H, H-1a), 2.72 (td, J = 12.6, 3.4 Hz, 1H, H-11b), 2.66 (d, J = 13.4 Hz, 1H, H-1b), 2.46 (td, J = 13.6, 13.2, 8.4 Hz, 1H, H-4a), 2.30 (ddd, J = 14.3, 5.7, 1.3 Hz, 1H, H-4b), 1.89 (ddd, J = 14.0, 8.4, 1.3 Hz, 1H, H-3a), 1.75-1.64 (m, 1H, H-10a), 1.54-1.48 (m, 1H, H-9a), 1.47-1.38 (m, 3H, H-3b, H-9b, H-10b), 1.38-1.31 (m, 1H, H-7a), 1.31-1.21 (m, 3H, H-6, H-7b), 0.92 (t, J = 7.0 Hz, 3H, H-8).

Total synthesis of (+)-eucophylline

but-1-yn-1-yl(methyl)sulfane (112h) Method A:

In a dried two-necked flask, approximately 4 g of acetone (approximative mass of the alkyne) were weighed and the level of the solvent was marked. The solvent was then removed and the flask was equipped with a cold trap condenser. The system was flame-dried, set under inert atmosphere then at -78 °C (acetone/dry ice bath, the trap was also filled with acetone and dry ice). The butyne gas bottle was equipped with a manometer and connected to an 18G needle. The gas flow was allowed to pass through the tubing before connecting the bottle to the reaction setup. 1-butyne 33 (~ 6.4 mL, 3.8 g, 72.0 mmol, ~ 3.0 eq.) was then condensed in the flask for 5 min to reach the predetermined mark. Once finished, the bottle was disconnected and dry THF (30.0 mL, 0.65 M) previously cooled to 0 °C was added, followed by dropwise addition of n-BuLi (1.8 M in hexane, 17.7 mL, 32.0 mmol, 1.6 eq.). The reaction mixture was then stirred at 0 °C for 30 min, then dimethyl disulfide (1.8 mL, 20.0 mmol, 1.0 eq.) was added slowly, and the reaction mixture was stirred at 20 °C for 2 h. The reaction was then quenched with 2-bromoethanol (1.8 mL, 25.0 mmol, 1.25 eq.) at 0 °C then stirred at 20 °C for 1 h. Water was added and the reaction mixture was extracted with Et2O. The organic layer was washed with brine, dried over Na2SO4 and distilled to remove the solvents. The crude was purified through column chromatography on SiO2 (pentane/Et2O: 98/2) then the fractions were distilled to remove the solvents, and the pure product (670.0 mg, 33%) was obtained as a colorless liquid.

Method B:

To a flame-dried two-necked flask, THF (40.0 mL, 1.0 M) was introduced, and the reaction was set at -78 °C. 1,1-dibromobut-1-ene 393a (9.5 g, 44.8 mmol, 1.125 eq.) was added slowly, then n-BuLi (1.8 M in hexane, 51.0 mL, 91.5 mmol, 2.3 eq.) was added dropwise, the color changed to dark orange. The reaction mixture was stirred at -78 °C for 1 h, then at 20 °C for another 1 h. Dimethyl disulfide (3.6 mL, 39.8 mmol, 1.0 eq.) was later added slowly at 0 °C, and the reaction mixture was stirred at 20 °C for 2 h (formation of suspension was observed). The reaction was quenched with 2bromoethanol (3.5 mL, 49.7 mmol, 1.25 eq.) at 0 °C then stirred at 20 °C for 1 h. Water was added and the reaction mixture was extracted with Et2O. The organic layer was washed with brine, dried over Na2SO4 and distilled to remove the solvents. The crude was purified through column chromatography on SiO2 (pentane: 100%) then the fractions were distilled to remove the solvents, and the pure product (3.6 g, 80%) was obtained as a colorless liquid. TLC (cyclohexane: 100%): Rf = 0.64 (UV active; KMnO4, stains yellow). b. p. = 105-110 °C.

1 H NMR (300 MHz, CDCl3): δ (ppm) = 2.35 (s, 3H, H-1), 2.30 (q, J = 7.5 Hz, 2H, H-4), 1.14 (t, J = 7. 5 Hz, 3H, H-5). According to the general procedure (I) in chapter III, from cyclobutene 169g (3.0 g, 15.3 mmol, 1.0 eq.), acetonitrile (10.0 mL, 1.5 M), methanesulfonyl cyanide 88a (3.2 g, 30.6 mmol, 2.0 eq.) and panisaldehyde (0.37 mL, 3.06 mmol, 0.2 eq.) for 48 h. A white precipitate was formed in the schlenk, the solvent was removed using a Pasteur pipette and the precipitate was washed with CH3CN (3 x 0.5 mL), then dried under vacuum to afford the product (3.32 g, 72%, dr > 19:1:1:1) as a white solid. TLC:m. p. = 266. 3-267.8 °C (CH2Cl2). 1477, 1393, 1306, 1205, 1132, 1039, 971, 760, 538. HRMS (TOF, ES+): calculated for C12H16N2O5SNa [M+Na] + 323.06721, found 323.06562.

[α]D 25 = +25.06 (c = 0.13, CHCl3).

(1R,2R,3S)-ethyl 3-cyano-3-ethyl-2-(methylsulfonyl)cyclobutanecarboxylate (260c)

According to the general procedure (L) in chapter III, from cyclobutane 181q (1.67 g, 5.56 mmol, 1.0 eq.), distilled EtOH (60.0 mL, 0.09 M), and DMAP (340.0 mg, 2.78 mmol, 0.5 eq.) for 48 h. Purification through short column chromatography on SiO2 (CH2Cl2/EtOAc: 90/10) afforded the desired product (1.44 g, quant.) According to the general procedure (M) in chapter III, from cyclobutane 260c (1.61 g, 6.2 mmol, 1.0 eq.), dry DMF (30.0 mL, 0.2 M), and Cs2CO3 (12.4 g, 4.0 mmol, 2.0 eq.) for 13 h. Purification through short column chromatography on SiO2 (CH2Cl2: 100%) afforded the desired cyclobutene (1.0 g, 90%) as a pale-yellow oil. The product was concentrated carefully under reduced pressure, and stored under inert atmosphere in the freezer. TLC (CH2Cl2/EtOAc: 70/30): Rf = 0.9 (UV active; KMnO4, stains yellow).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 6.74 (s, 1H, H-7), 4.23 (q, J = 7.1 Hz, 2H, H-2), 3.17 (d, J = 13.8 Hz, 1H, H-5a), 2.73 (d, J = 13.8 Hz, 1H, H-5b), 1.93-1.73 (m, 2H, H-9), 1.31 (t, J = 7.1 Hz, 3H, H-1), 1.14 (t, J = 7.4 Hz, 3H, H-10). According to the general procedure (N) in chapter III, from diethyl malonate (0.37 mL, 2.45 mmol, 1.0 eq.), dry THF (12.2 mL, 0.2 M), NaH (60% suspension in oil, 98.0 mg, 2.45 mmol, 1.0 eq.) and cyclobutene 258c (440.0 mg, 2.45 mmol, 1.0 eq.) in dry THF (14.4 mL, 0.17 M) for 3 h. The crude as a mixture of diastereomers (788.0 mg, 95%, dr 8.6:5.1:1.6:1) was obtained as a yellow oil and was pure enough to be used directly in the next step without further purification. [Purification of the crude for analysis was accomplished through short column chromatography on SiO2 (cyclohexane/EtOAc: 80/20)]. TLC (cyclohexane/EtOAc: 70/30): R f = 0.51 (UV active; KMnO4, stains yellow).

1 H NMR (600 MHz, CDCl3): δ (ppm) = 4.33-4.06 (m, 12H, all dia: H-2, H-14, H-15; H-11 dia-2), 3.89 (d, J = 12.5 Hz, 0.1H, H-11 dia-4), 3.87-3.80 (m, 0.1H, H-7 dia-4), 3.80 (d, J = 11.5 Hz, 1H, H-11 dia-1), 3.77-3.72 (m, 0.14H, H-7 dia-3), 3.48 (d, J = 11.9 Hz, 0.16H, H-11 dia-3), 3.41 (td, J = 9.8, 3.9 Hz, 0.1H, H-4 dia-4), 3.35-3.27 (m, 1.3H, H-7 dia-2, H-4 dia-2), 3.22 (dd, J = 11.5, 9.1 Hz, 1H, H-7 dia-1), 3.12 (q, J = 9.3 Hz, 1H, H-4 dia-1), 2.98 (q, J = 9.6 Hz, 0.13H, H-4 dia-3), 2.77-2.71 (m, 0.7H, H-5a dia-2), 2.71-2.67 (m, 0.1H, H-5a dia-4), 2.65-2.56 (m, 1.4H, H-5a dia-1, H-5a dia-3), 2.35 (dd, J = 12.7, 3.7 Hz, 0.1H, H-5b dia-4), 2.27-2.20 (m, 2H, H-5b dia-1, H-5b dia-2, H-5b dia-3), 2.08-1.97 (m, 2H, H-9a dia-1, H-9a dia-2, H-9a dia-3), 1.93 (dd, J = 13.5, 7.1 Hz, 0.1H, H-9a dia-4), 1.76-1.61 (m, 2.5H, all dia: H-9b), 1.32-1.23 (m, 20H, all dia: H-1, H-16, H-17), 1.06-0.99 (m, 6H, all dia: H-10). For the third diastereomer, dia-3, (1S,4S)-trans-332b:

δ (ppm) = 172.0 (C-3), 167.3 (C-12), 166.9 (C-13), 122.0 (C-8), 62.3 (C-14), 62.1 (C-15), 61.2 (C-2), 51.9 (C-11), 43.6 (C-7), 40.0 (C-6), 37.6 (C-4), 32.0 (C-5), 24.4 (C-9), 14.1 (C-1, C-16, C-17), 9.1 (C-10).

For the minor diastereomer, dia-4, (1S,4R)-cis-332b: δ (ppm) = 173.4 (C-3), 167.4 (C-12), 166.9 (C-13) According to the general procedure (A), from the crude cyclobutane 332b (698.0 mg, 2.05 mmol, 1.0 eq.), anhydrous NiCl2 (585.7 mg, 4.52 mmol, 2.2 eq.), freshly distilled EtOH (82.0 mL, 0.025 M), and NaBH4 (1.53 g, 41.0 mmol, 20.0 eq.) for 70 h. The crude mixture was purified through column chromatography on SiO2 (CH2Cl2/MeOH: 95/5 to 90/10) to afford the desired mixture of diastereomers (420.0 mg, 68%, dr 1:1) as a colorless oil, and the reduced amine (70.0 mg, 10%, isolated dr 1.25:1) as a yellow oil.

Scale-up reaction:

According to the general procedure (A), from the crude cyclobutane 332b (1.4 g, 4.0 mmol, 1.0 eq.), anhydrous NiCl2 (1.14 g, 8.8 mmol, 2.2 eq.), freshly distilled EtOH (160.0 mL, 0.025 M), and NaBH4 (2.99 g, 80.0 mmol, 20.0 eq.) for 70 h. The crude mixture was purified through column chromatography on SiO2 (CH2Cl2/MeOH: 98/2 to 95/5 to 90/10) to afford the desired mixture of diastereomers (744.0 mg, 62%, 77% brsm, dr 1:1) as a colorless oil, and the reduced amine (150.0 mg, 11%, isolated dr 1.25:1) as a yellow oil. 21% of the starting material were recovered and engaged again in the reduction reaction. TLC (CH2Cl2/MeOH: 90/10): Rf = 0.62 (UV inactive; KMnO4, stains white).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 5.78 (br s, 2H, H-6 dia-1/dia-2), 4.31-4.18 (m, 4H, H-12 dia-1/dia-2), 4.14 (qd, J = 7.1, 1.9 Hz, 4H, H-15 dia-1/dia-2), 3.44-3.31 (m, 2H, H-4 dia-1/dia-2), 3.18 (d, J = 12.3 Hz, 2H, H-1a dia-1/dia-2), 3.07-2.96 (m, 2H, H-1b dia-1/dia-2), 2.31-2.19 (m, 4H, H-10 dia-1/dia-2), 1.97-1.88 (m, 4H, H-9 dia-1/dia-2), 1.82-1.74 (m, 2H, H-3 dia-1), 1.73-1.65 (m, 2H, H-3 dia-2), 1.51-1.41 (m, 2H, H-7 dia-2), 1.39-1.32 (m, 2H, H-7 dia-1), 1.28 (dtd, J = 9.1, 7.1, 1.5 Hz, 12H, H-13 dia-1/dia-2, H-16 dia-1/dia-2), 0.87 (td, J = 7.5, 3.4 Hz, 6H, H-8 dia-1/dia-2). According to the general procedure (C), from the crude diacid 388c (303.0 mg, 1.24 mmol, 1.0 eq.) and dry THF (15.5 mL, 0.08 M) for 3 h. The crude mixture 389c (250.0 mg, quant.) was obtained as a colorless viscous oil. The esterification reaction was accomplished from the crude 389c (407.0 mg, 2.04 mmol, 1.0 eq.) in CH2Cl2/MeOH: 5/1 (17.0 mL, 0.12 M), TMSCHN2 (2.0 M in hexane, 1.5 mL, 3.06 mmol, 1.5 eq.), and AcOH (0.035 mL, 0.612 mmol, 0.3 eq.). The crude 391c (435.0 mg, quant.) was obtained as a pale-yellow oil. The reduction reaction was accomplished from the crude 391c (300.0 mg, 1.4 mmol, 1.0 eq.) in dry THF (40.0 mL, 0.035 M), and LAH (1.0 M in Et2O, 1.75 mL, 1.75 mmol, 1.25 eq.) for 12 h. The crude 21 (257.0 mg, 98%) was obtained as pale-yellow viscous oil and was used directly in the next step without further purification. [Purification of the crude for analysis afforded the alcohol as a pale-yellow viscous oil]. TLC (CH2Cl2/MeOH: 90/10): Rf = 0.32 (UV inactive; KMnO4, stains yellow). (5-C=O), 1463, 1436, 1309, 1196, 1170, 790. To a flame-dried two-necked flask equipped with a condenser, the bicyclic lactam 20 (49.0 mg, 0.29 mmol, 1.0 eq.) was introduced followed by dry CH2Cl2 (3.0 mL, 0.1 M), and POCl3 (30.0 μL, 0.328 mmol, 1.1 eq.) was added dropwise. The reaction was stirred at 60 °C silicon oil bath temperature and the starting material consumption was followed by TLC. After 12 h, another 1.1 eq. of POCl3 were added and the heating continued for another 12 h. After total consumption of the starting material, the reaction was cooled down to 20 °C and 2-amino-4-methoxybenzonitrile (66.0 mg, 0.44 mmol, 1.5 eq.) dissolved in dry CH2Cl2 (2.0 mL, 0.1 M), was added dropwise. The reaction was stirred at 50 °C for 24 h, then the solvents were concentrated under reduced pressure and ice water (2.0 mL) was added to the reaction. The aqueous layer was basified with sat. NaHCO3 till pH = 8, then extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (CH2Cl2/EtOAc/NH4OH: 99/0/1 to 90/9/1) to afford the product (60.0 mg, 70%) as a pale-yellow oil. TLC (CH2Cl2/MeOH: 98/2): Rf = 0.51 (UV active; KMnO4, stains yellow after long heating). LDA preparation: To a flame-dried flask, freshly distilled DIPA (68.0 μL, 0.48 mmol, 1.1 eq.) was introduced followed by dry THF (2.0 mL, 0.22 M) and the reaction was set at 0 °C. n-BuLi (1.4 M in hexane, 0.30 mL, 0.44 mmol, 1.0 eq.) was added dropwise. The reaction was stirred at 20 °C for 30 min.

To a flame-dried flask and under inert atmosphere, 355 (38.0 mg, 0.127 mmol, 1.0 eq.) was introduced, followed by dry THF (2.4 mL, 0.05 M) and the reaction was set at 0 °C. LDA prepared above (0.22 M, 1.74 mL, 0.38 mmol, 3.0 eq.) was added dropwise and the reaction was warmed up slowly to 20 °C. After 48 h, the reaction was quenched at 0 °C with sat. NH4Cl (0.1 mL) and extracted with H2O (0.5 mL)/EtOAc. The aqueous phase was extracted twice and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through short column chromatography on SiO2 (CH2Cl2/MeOH/NH4OH: 98/1/1 to 97/2/1) to afford the product (28.0 mg, 74%) as a yellow-brown solid. The product was stored under inert atmosphere in the freezer. [All the solvents used for extraction and purification were distilled to remove the traces of impurities present in the commercial bottles].

TLC (CH2Cl2/MeOH/NH4OH: 94/5/1): Rf = 0.20 (UV active, appears fluorescent; KMnO4, stains yellow after long heating).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 7.54 (d, J = 9.1 Hz, 1H, H-14), 7.21 (d, J = 2.6 Hz, 1H, H-13), 6.97 (dd, J = 9.1, 2.6 Hz, 1H, H-10), 4.56 (br s, 2H, H-19), 3.89 (s, 3H, H-11), 3.78-3.69 (m, 1H, H-8a), 3.13 (td, J = 12.9, 3.4 Hz, 1H, H-5a), 3.04 (dd, J = 13.1, 1.7 Hz, 1H, H-8b), 2.93 (dd, J = 13.0, 1.9 Hz, 1H, H-5b), 2.50 (dd, J = 16.2, 1. 5 Hz, 1H, H-3a), 2.31 (dd, J = 16.1, 1.7 Hz, 1H, H-3b), 1.96-1.65 (m, 1H, H-6a), 1.63-1.50 (m, 1H, H-6b), 1.38 (q, J = 7. 5 Hz, 2H, H-17), 1.33-1.21 (m, 2H, H-7), 0.97 (t, J = 7. 5 Hz, 3H, H-18). According to the general procedure (F), from the amino quinoline 356 (12.0 mg, 0.04 mmol, 1.0 eq.), CuBr (11.5 mg, 0.08 mmol, 2.0 eq.), CH3CN (0.4 mL, 0.1 M) and t-BuONO (7.1 μL, 0.06 mmol, 1.5 eq.) for 3 h. The crude mixture was purified through micro-column chromatography on SiO2 (CH2Cl2/NH4OH: 98/1) to afford the desired product (11.5 mg, 80%) as a yellow solid. TLC (CH2Cl2/MeOH/NH4OH: 95/4/1): Rf = 0.48 (UV active; KMnO4, stains red-yellow then intense yellow after 5 min). m. p. = 62.2-64.9 °C (CH2Cl2/pentane). According to the general procedure (G), from the bromoquinoline 418 (10.0 mg, 0.027 mmol, 1.0 eq.), potassium vinyltrifluoroborate (5.6 mg, 0.04 mmol, 1.5 eq.), anhydrous K2CO3 (3.7 mg, 0.027 mmol, 1.0 eq.), freshly distilled DME (0.45 mL, 0.06 M), distilled H2O (0.22 mL, 0.12 M) and Pd(PPh3)4 (3.1 mg, 2.7 μmol, 0.1 eq.) for 12 h. The crude mixture was purified through micro-column chromatography on SiO2 (CH2Cl2/MeOH/NH4OH: 99/0/1 to 98/1/1) to afford the pure desired product (8.0 mg, 96%) as a yellow viscous oil. TLC (CH2Cl2/MeOH/NH4OH: 95/4/1): Rf = 0.42 (UV active; KMnO4, stains intense yellow).

1 H NMR (600 MHz, CDCl3): δ (ppm) = 7.92 (d, J = 9.2 Hz, 1H, H-14), 7.27 (d, J = 2.6 Hz, 1H, H-13), 7.03 (dd, J = 9.2, 2.6 Hz, 1H, H-10), 6.84 (dd, J = 18.0, 11.7 Hz, 1H, H-19), 5.84 (dd, J = 11.8, 1.9 Hz, 1H, H-20a), 5.54 (dd, J = 17.9, 2.0 Hz, 1H, H-20b), 3.92 (s, 3H, H-11), 3.77 (d, J = 12.3 Hz, 1H, H-8a), 3.19 (td, J = 13.1, 3.4 Hz, 1H, H-8b), 3.07 (d, J = 13.1 Hz, 1H, H-5a), 2.94 (d, J = 13.2 Hz, 1H, H-5b), 2.72 (d, J = 17.6 Hz, 1H, H-3a), 2.55 (d, J = 17.8 Hz, 1H, H-3b), 1.76 (d, J = 13.5 Hz, 1H, H-6a), 1.64-1.57 (m, 1H, H-6b), 1.35 (q, J = 7. 6 Hz, 2H, H-17), 1.33-1.22 (m, 2H, H-7), 0.96 (t, J = 7. 6 Hz, 3H, H-18). According to the general procedure (H), from vinyl quinoline 19 (10.0 mg, 0.032 mmol, 1.0 eq.), CH2Cl2 (1.6 mL, 0.02 M) and BBr3 (1.0 M in CH2Cl2, 0.39 mL, 0.39 mmol, 12.0 eq.). The crude mixture was purified through micro-column chromatography on SiO2 (CH2Cl2/MeOH: 99/1 to 98/2) to afford the pure desired product (9.0 mg, 95%, 98% ee) as a yellow solid. TLC (CH2Cl2/MeOH: 96/4): Rf = 0.20 (UV active; KMnO4, stains yellow). m. p. = 164.6-166.3 °C (evaporation from CH2Cl2).

1 H NMR (600 MHz, CD3OD): δ (ppm) = 8.13 (d, J = 9.2 Hz, 1H, H-14), 7.22 (dd, J = 9.2, 2.4 Hz, 1H, H-13), 7.18 (d, J = 2.4 Hz, 1H, H-10), 7.03 (dd, J = 17.9, 11.9 Hz, 1H, H-19), 6.07 (dd, J = 11.9, 1.4 Hz, 1H, H-20a), 5.72 (dd, J = 17.9, 1.4 Hz, 1H, H-20b), 3.71 (dd, J = 13.7, 3.5 Hz, 1H, H-8a), 3.42 (td, J = 13.2, 3.7 Hz, 1H, H-8b), 3.19 (dd, J = 13.2, 1.9 Hz, 1H, H-5a), 3.00 (d, J = 13.1 Hz, 1H, H-5b), 2.85 (d, J = 17.7 Hz, 1H, H-3a), 2.70 (d, J = 17.7 Hz, 1H, H-3b), 1.82 (d, J = 11.5 Hz, 1H, H-6a), 1.68 (td, J = 13.2, 4.9 Hz, 1H, H-6b), 1.45 (q, J = 7. 5 Hz, 2H, H-17), 1.43-1.36 (m, 2H, H-7), 1.00 (t, J = 7. 6 Hz, 3H, H-18). 13 C NMR spectrum of (+)-eucophylline in CD3OD, 600 MHz. Experimental Part -Chapter V

Enantiomeric excess measurements

General procedures for chapter V General procedure (A) for indole alkylation reaction

To a flame-dried two-necked flask equipped with a condenser and under inert atmosphere, the amino alcohol 501 (1.0 eq.) was introduced followed by tryptophyl bromide (1.2 eq.), NaHCO3 (4.0 eq.) and distilled CH3CN (0.1 M). The reaction mixture was vigorously stirred at 80 °C. After 16 h, the reaction was cooled to 20 °C, then extracted with H2O/EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through short column chromatography on SiO2 (CH2Cl2/MeOH: 95/5 to 90/10) to afford the pure desired product.

Synthesis of the starting materials tert-butyl 3-(2-bromoethyl)-1H-indole-1-carboxylate (371b) 474

To a flame-dried two-necked flask under inert atmosphere, 3-(2-bromoethyl)indole (500.0 mg, 2.23 mmol, 1.0 eq.) was introduced, followed by di-tert-butyl dicarbonate (730.0 mg, 3.34 mmol, 1.5 eq.), DMAP (54.0 mg, 0.44 mmol, 0.2 eq.) and dry CH2Cl2 (7.4 mL, 0.3 M). Et3N (0.31 mL, 2.23 mmol, 1.0 eq.) was added at 23 °C and the reaction mixture was stirred for 5 h. The reaction was then quenched with water and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through short column chromatography on SiO2 (cyclohexane/EtOAc: 80/20) to afford the desired product (668.0 mg, 92%) as a white solid. TLC (cyclohexane/EtOAc: 80/20): Rf = 0.64 (UV active; KMnO4, stains yellow).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 8.14 (d, J = 8.2 Hz, 1H, H-9), 7.52 (ddd, J = 7.6, 1.5, 0.7 Hz, 1H, H-6), 7.48 (s, 1H, H-4), 7.37-7.22 (m, 2H, H-7, H-8), 3.64 (t, J = 7.5 Hz, 2H, H-1), 3.31-3.23 (m, 2H, H-2), 1.67 (s, 9H, H-t-butyl).

The 1 H NMR data are in agreement with those reported in the literature. 474

Total synthesis of (±)-eburnamine 1-benzylpiperidin-2-one (369a) 444

To a flame-dried two-necked flask under inert atmosphere, dry THF (44.0 mL, 1.0 M) was introduced followed by NaH (60% dispersion in mineral oil, 1.98 g, 49.7 mmol, 1.13 eq.) at 0 °C (ice/water bath). 2-Piperidinone (4.38 g, 44.0 mmol, 1.0 eq.) dissolved in THF (66.6 mL, 0.66 M) was added rapidly dropwise and the reaction mixture was warmed up slowly to 20 °C. After 15 min, a thick white gel was formed, the mixture was stirred further for 2 h then BnBr (~ 5.6 mL, 47.08 mmol, 1.07 eq.) was added dropwise and the reaction evolution was monitored by TLC. After 48 h, the mixture was quenched with sat. NH4Cl and extracted with Et2O. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through short column chromatography on SiO2 (cyclohexane/EtOAc: 80/20 to 50/50) to afford the desired product (8.34 g, quant.) as a pale-yellow oil. TLC (cyclohexane/EtOAc: 50/50): Rf = 0.16 (UV active; KMnO4, stains white).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 7. 38-7.20 (m, 5H, H-Ph), 4.60 (s, 2H, H-6), 3.24-3.13 (m, 2H, H-5), 2.51-2.40 (m, 2H, H-2), 1.90-1.68 (m, 4H, H-3, H-4). The NMR data are in agreement with those reported in the literature. 444

1-benzyl-3-ethylpiperidin-2-one (505a) 444 The compound 505a was prepared adapting the literature procedure. 444 To a flame-dried flask under inert atmosphere, freshly distilled diisopropylamine (0.23 mL, 1.65 mmol, 1.1 eq.) was added, followed by dry THF (3.0 mL, 0.5 M) and the solution was cooled to 0 °C (ice/water bath). n-BuLi (1.9 M in hexane, 0.8 mL, 1.5 mmol, 1.0 eq.) was added rapidly dropwise and the faint yellow solution was stirred at the same temperature for 20 min. Meanwhile, in another flame-dried flask, the protected lactam 369a (100.0 mg, 0.52 mmol, 1.0 eq.) was dissolved in dry THF (5.2 mL, 0.1 M) and the solution was cooled to 0 °C. The freshly prepared LDA (0.5 M, 1.24 mL, 0.62 mmol, 1.2 eq.) was then added rapidly dropwise to the lactam solution at 0 °C and the reaction mixture was stirred for 45 min. The mixture was then cooled to -78 °C (dry ice/acetone bath) and iodoethane (0.05 mL, 0.624 mmol, 1.2 eq.) was added dropwise. After 5 min, the yellow solution was placed in an ice/water bath and the temperature was warmed slowly to 20 °C. After 16 h, the reaction was quenched with NH4Cl and extracted with Et2O. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through short column chromatography on SiO2 (cyclohexane/EtOAc: 80/20 to 70/30) to afford the desired product (103.0 mg, 92%) as a yellow oil. The product was stored under argon in the freezer.

Scale-up reaction:

Following the same procedure above, from diisopropylamine (4.7 mL, 33.4 mmol, 1.1 eq.), dry THF (19.0 mL, 1.6 M), n-BuLi (1.8 M in hexane, 16.9 mL, 30.4 mmol, 1.0 eq.), the protected lactam 369a (4.5 g, 23.77 mmol, 1.0 eq.) in dry THF (225.0 mL, 0.1 M) and iodoethane (2.3 mL, 28.5 To a flame-dried flask under inert atmosphere, freshly distilled diisopropylamine (2.8 mL, 19.8 mmol, 1.1 eq.) was added, followed by dry THF (18.0 mL, 1.0 M) and the solution was cooled to 0 °C (ice/water bath). n-BuLi (1.8 M in hexane, 10.0 mL, 18.0 mmol, 1.0 eq.) was added rapidly dropwise and the faint yellow solution was stirred at the same temperature for 20 min. Meanwhile, in another flame-dried flask, the mono-alkylated lactam 505a (2.3 g, 10.5 mmol, 1.0 eq.) was dissolved in dry THF (35.0 mL, 0.3 M) and the solution was cooled to 0 °C. The freshly prepared LDA (1.0 M in THF, ~ 16.0 mL, 15.75 mmol, 1.5 eq.) was then added rapidly dropwise to the lactam solution at 0 °C and the reaction mixture was stirred for 45 min. The mixture was then cooled to -78 °C (dry ice/acetone bath) and ethyl bromoacetate (3.5 mL, 31.5 mmol, 3.0 eq.) was added dropwise. After 5 min, the yellow solution was placed in an ice/water bath and the temperature was warmed slowly to 20 °C. After 20 h, the reaction was quenched with NH4Cl and extracted with Et2O. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 90/10 to 80/20) to afford the desired product (2.59 g, 80%) as a yellow oil. The product was stored under argon in the freezer. TLC (cyclohexane/EtOAc: 50/50): Rf = 0.58 (UV active; KMnO4, stains white).

2-(1-benzyl-3-ethylpiperidin-3-yl)ethanol (503a)

To a flame-dried two-necked flask equipped with a condenser and under inert atmosphere, the starting material 504a (1.4 g, 4.6 mmol, 1.0 eq.) was added, followed by dry THF (90.0 mL, 0.05 M) and the solution was cooled to 0 °C (ice/water bath). LAH (1.0 M in Et2O, 18.4 mL, 18.4 mmol, 4.0 eq.) was added dropwise and the light-yellow solution was stirred at the same temperature for 5 min, then heated at 66 °C silicon oil bath temperature. The reaction completion was followed by TLC, and after 12 h, the solution became colorless. The reaction was quenched carefully at 0 °C by dropwise addition of EtOAc (5 mL), then water (5 mL). Once no more bubbles were observed, water (10 mL) was added again and the mixture was filtered to remove the white suspension. The crude mixture was extracted after addition of EtOAc (20 mL), then the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (cyclohexane/EtOAc: 90/10 to 80/20 to 60/40) to afford the desired product (866.0 mg, 76%) as a pale-yellow oil. The product was stored under argon in the freezer.

TLC (cyclohexane/EtOAc: 50/50): Rf = 0.19 (UV active; KMnO4, stains white).

1 H NMR (400 MHz, CDCl3): δ (ppm) = 7. 38-7.19 (m, 5H, H-Ph), 3.75 (ddd, J = 11.6, 8.7, 4.0 Hz, 1H, H-9a), 3.69-3.64 (m, 1H, H-9b), 3.64 (d, J = 12.8 Hz, 1H, H-10a), 3.27 (d, J = 12.8 Hz, 1H, H-10b), 2.75 (d, J = 9.1 Hz, 1H, H-5a), 2.67 (d, J = 11.5 Hz, 1H, H-1a), 1.87 (d, J = 11.7 Hz, 1H, H-1b), 1.82-1.48 (m, 6H, H-3a, H-4, H-5b, H-8), 1.33-1.12 (m, 3H, H-3b, H-6), 0.81 (t, J = 7.5 Hz, 3H, H-7).

2-(3-ethylpiperidin-3-yl)ethanol (501)

To a flame-dried flask equipped with a condenser and under inert atmosphere, the starting material 503a (770.0 mg, 3.1 mmol, 1.0 eq.) dissolved in MeOH (160.0 mL, 0.02 M) was introduced, and the corresponding solution was degassed by argon bubbling for 15 min using a metallic needle, which was passed through the condenser. Pd(OH)2/C (385.0 mg, 50 wt. %) was added and the solution was then bubbled with H2 for 15 min. Then, the H2 balloon was replaced with a new one and the reaction mixture was heated at 50 °C under vigorous stirring. After 41 h, the reaction mixture was filtered through a celite pad, and the solvents were concentrated under reduced pressure to afford the desired product (500.0 mg, quant.) as a pale-yellow oil, pure enough to be used in the next step without further purification. The product was stored under argon in the freezer. TLC (CH2Cl2/MeOH: 90/10): Rf = 0 (UV inactive; KMnO4, stains yellow-white).

2-(1-(2-(1H-indol-3-yl)ethyl)-3-ethylpiperidin-3-yl)ethanol (500a)

According to the general procedure (A), from 501 (127.0 mg, 0.8 mmol, 1.0 eq.), 371a (217.0 mg, 0.97 mmol, 1.2 eq.), NaHCO3 (267.0 mg, 3.2 mmol, 4.0 eq.) and CH3CN (8.0 mL, 0.1 M) to afford the desired product (179.0 mg, 74%) as a white solid. TLC (CH2Cl2/MeOH: 90/10): Rf = 0.14 (UV active; KMnO4, stains white; vanillin, stains purple). m. p. = 122.4-124.5 °C (CH2Cl2).

1 H NMR (300 MHz, CD3OD): δ (ppm) = 7.56 (d, J = 7.7 Hz, 1H, H-18), 7.35 (d, J = 8.0 Hz, 1H, H-15), 7. 13-7.08 (m, 2H, H-13, H-16), 7.06-6.98 (m, 1H, H-17), 3.67 (td, J = 7.0, 1.9 Hz, 2H, H-9), 3.03 (dd, J = 9.9, 6. 3 Hz, 2H, H-11), 2.83-2.78 (m, 3H, H-10, H-5a), 2.66 (d, J = 11.5 Hz, 1H, H-1a), 2.53 (br s, 1H, H-5b), 2.38 (d, J = 12.0 Hz, 1H, H-1b), 1.75-1.57 (m, 4H, H-4, H-8), 1.51-1.31 (m, 4H, H-3, H-6), 0.88 (t, J = 7.5 Hz, 3H, H-7). 13 C NMR (75 MHz, CD3OD): δ (ppm) = 138.1 (C-14), 128.6 (C-19), 123.2 (C-13), 122.3 (C-16), 119.6 (C-17), 119.2 (C-18), 113.2 (C-12), 112.2 (C-15), 63.7 (C-1), 60.8 (C-10), 59.0 (C-9), 55.5 (C-5), 38.9 (C-8), 36.5 (C-2), 34.3 (C-3), 23.1 (C-11), 22.6 (C-4), 7.7 (C-7). Note: C-6 was not seen, in HSQC the H-6 correlates with 29.9 ppm in 13 C NMR,however,no According to the general procedure (A), from 501 (141.0 mg, 0.89 mmol, 1.0 eq.), Boc-protected tryptophyl bromide 371b (381.0 mg, 1.17 mmol, 1.2 eq.), NaHCO3 (299.0 mg, 3.56 mmol, 4.0 eq.) and CH3CN (9.0 mL, 0.1 M) to afford the desired product (260.0 mg, 73%) as a highly viscous yellow oil. 100.0 mg of Boc-protected tryptophyl bromide 371b were recovered. TLC (CH2Cl2/MeOH: 90/10): Rf = 0.42 (UV active; KMnO4, stains white; vanillin, stains purple). To a flame-dried flask equipped with a condenser and under inert atmosphere, the starting material 504a (500.0 mg, 1.6 mmol, 1.0 eq.) dissolved in MeOH (80.0 mL, 0.02 M) was introduced, and the corresponding solution was degassed by argon bubbling for 15 min using a metallic needle, which was passed through the condenser. Pd(OH)2/C (250.0 mg, 50 wt. %) was added and the solution was then bubbled with H2 for 15 min. Then, the H2 balloon was replaced with a new one and the reaction mixture was heated at 50 °C under vigorous stirring. After 4 days, the reaction mixture was filtered through a celite pad, and the solvents were concentrated under reduced pressure to afford the desired product (300.0 mg, 89%) as a pale-yellow oil, pure enough to be used in the next step without further purification. The product was stored under argon in the freezer. TLC (cyclohexane/EtOAc: 50/50): Rf = 0.17 (UV inactive; KMnO4, stains white).

IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2924 (-C-H), 2853 (-C-H), 1734 (9-C=O), 1657 (1-C=O), 1466, 1403, 1180, 1042, 645. HRMS (TOF, ES+): calculated for C11H19NO3Na [M+Na] + 236.12571, found 236.12574.

(R)-ethyl 2-(3-ethyl-2-thioxopiperidin-3-yl)acetate (518b)

To a flame-dried two-necked flask equipped with a condenser and under inert atmosphere, the starting material 516 (100.0 mg, 0.43 mmol, 1.0 eq.) was added, followed by dry toluene (8.6 mL, 0.05 M) then crystallized P2S5 (58.0 mg, 0.25 mmol, 0.6 eq.). The yellow mixture was heated at 110 °C for 7 h then cooled to 20 °C and the solvents were rapidly concentrated under reduced pressure. The crude mixture was quickly purified through column chromatography on SiO2 (CH2Cl2/EtOAc: 100/0 to 90/10) to afford the desired product (65.0 mg, 65%) as a colorless oil. The product is unstable and it was used directly in the next step. In a flame-dried flask and under inert atmosphere, Raney ® -nickel (pinch, excess) was washed with THF (5 x). The starting material 518b (65.0 mg, 0.28 mmol, 1.0 eq.) dissolved in THF (14.0 mL, 0.02 M) was degassed by argon bubbling for 15 min then introduced to the reaction flask. The corresponding mixture was then bubbled with H2 for 15 min. The H2 balloon was replaced with a new one and the reaction mixture was left under vigorous stirring at 20 °C for 12 h. The reaction mixture was filtered through a celite pad, and the solvents were concentrated under reduced pressure to afford the desired product (57.0 mg, quant.) as a colorless oil, and used directly in the next step without further purification. TLC (CH2Cl2/MeOH: 90/10): Rf = 0 (UV inactive; KMnO4, stains white). To a flame-dried flask under inert atmosphere, the starting material 517a (105.0 mg, 0.53 mmol, 1.0 eq.) was introduced followed by dry CH2Cl2 (4.0 mL, 0.13 M) and the solution was cooled to 0 °C (ice/water bath). NCS (79.0 mg, 0.59 mmol, 1.1 eq.) was then added and the mixture was stirred at 20 °C for 4 h. The reaction was quenched with sat. NaHCO3 and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was then dissolved in 1,4-dioxane (3.5 mL) and 20% aq. KOH (2.5 mL) was added and the reaction mixture was heated at 100 °C for 6 h. The solvents were concentrated under reduced pressure and the pH was adjusted to 8 at 0 °C using conc. HCl then sat. NaHCO3 and extracted with EtOAc.

IR (solution in

The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (55.0 mg, 60%) as a pale-yellow oil, and used directly in the next step without further purification. TLC (EtOAc: 100%): Rf = 0.14 (UV inactive; KMnO4, stains yellow).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 5.11 (s, 1H, H-1), 2.98 (td, J = 11.3, 2.8 Hz, 1H, H-5a), 2.83-2.75 (m, 1H, H-5b), 2.41 (d, J = 16.5 Hz, 1H, H-8a), 2.20 (d, J = 16.6 Hz, 1H, H-8b), 1.85-1.35 (m, 6H, H-3, H-4, H-6), 0.90 (t, J = 7.5 Hz, 3H, H-7). To a flame-dried two-necked flask equipped with a condenser and under inert atmosphere, the lactone 470 (40.0 mg, 0.23 mmol, 1.0 eq.) was introduced followed by tryptophyl bromide 371a (105.0 mg, 0.47 mmol, 2.0 eq.), K2CO3 (111.0 mg, 0.8 mmol, 3.5 eq.) and 1,4-dioxane (2.3 mL, 0.1 M). The reaction mixture was vigorously stirred at 100 °C. After 12 h, the reaction was cooled to 20 °C, then the solvents were concentrated under reduced pressure. The crude mixture was purified through short column chromatography on SiO2 (CH2Cl2/MeOH: 100/0 to 98/2 to 95/5) to afford the pure desired product (60.0 mg, 83%) as a brown viscous oil. TLC (CH2Cl2/MeOH: 90/10): Rf = 0.35 (UV active; vanillin, stains purple). .71-1.51 (m, 3H, H-3a, H-4), 1.41-1.24 (m, 3H, H-3b, H-6), 0.83 (t, J = 7.5 Hz, 3H, H-7). To a flame-dried two-necked flask equipped with a condenser and under inert atmosphere, the lactone reaction mixture was heated at 110 °C. After 48 h, the solvents were concentrated under reduced pressure and the crude mixture was purified through column chromatography on SiO2 (CHCl3: 100%) to afford (±)-eburnamonine 423 (15.0 mg, 45%) as a white solid alongside with (±)-epi-eburnamonine 520 (18.0 mg, 54%) as a pale-yellow solid. TLC (EtOAc: 100%): Rf = 0.14 (UV active; KMnO4, stains yellow). m. p. = 196-199 °C (CH2Cl2).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 8.41-8.34 (m, 1H, H-15), 7.45-7.42 (m, 1H, H-18), 7.35-7.28 (m, 2H, H-16, H-17), 4.03 (s, 1H, H-1), 3.40-3.22 (m, 2H, H-10), 2.98-2.85 (m, 1H, H-11a), 2.64 (q, J = 16.8, 11.5 Hz, 2H, H-6), 2.50-2.40 (m, 2H, H-11b, H-8a), 2.16-1.97 (m, 1H, H-8b), 1.91-1.58 (m, 2H, H-5), 1.53-1.37 (m, 3H, H-4, H-3a), 1.05 (td, J = 13.6, 3.8 Hz, 1H, H-3b), 0.94 (t, J = 7.6 Hz, 3H, H-7). To a flame-dried two-necked flask and under inert atmosphere, (±)-eburnamonine 423 (14.0 mg, 0.047 mmol, 1.0 eq.) was introduced, followed by dry THF (2.0 mL, 0.023 M) and the solution was cooled to 0 °C (ice/water bath). LAH (1.0 M in Et2O, 0.1 mL, 0.1 mmol, 2.0 eq.) was added dropwise and the light-yellow solution was stirred at the same temperature for 30 min. The reaction was quenched carefully at 0 °C by dropwise addition of EtOAc (1 mL) then brine (1 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the eburnamine 18 (14.0 mg, quant., dr: 3:1) as a yellow oil. TLC (EtOAc: 100%): Rf = 0.13 (UV active; KMnO4, stains yellow).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 7.77-7.71 (m, 0.75H, H-18), 7.53-7.39 (m, 1.43H, H-15), 7.23-7.11 (m, 2.12H, H-16, H-17), 6.07 (d, J = 4.6 Hz, 0.25H, H-9 minor dia), 5.61 (dd, J = 9.6, 5.2 Hz, 0.75H, H-9 major dia), 3.91 (s, 1H, H-1), 3.37-3.18 (m, 2H, H-10), 3.00-2.89 (m, 1H, H-11a), 2.71-2.52 (m, 2H, H-11b, H-5a), 2.44-2.28 (m, 2H, H-5b, H-8a), 2.14-1.96 (m, 2H, H-4a, H-8b), 1.63-1.53 (m, 2H, H-4b, H-3a), 1.29-1.20 (m, 3H, H-3b, H-6), 0.99-0.80 (m, 3H, H-7).

Major diastereomer: 13 C NMR (75 MHz, CDCl3): δ (ppm) = 136.8 (C-14), 132.6 (C-13), 128.6 (C-19), 121.5 (C-16), 120.3 (C-17), 118.1 (C-18), 112.3 (C-15), 105.6 (C-12), 76.6 (C-9), 58.9 (C-1), 50.9 (C-10), 44.4 (C-5), 43.5 (C-8), 36.9 (C-2), 28.7 (C-3), 25.1 (C-6), 20.5 (C-4), 16.9 (C-11), 7.7 (C-7).

Minor diastereomer: 13 To a flame-dried two-necked flask and under inert atmosphere, (±)-epi-eburnamonine 520 (24.0 mg, 0.08 mmol, 1.0 eq.) was introduced, followed by dry THF (3.4 mL, 0.023 M) and the solution was cooled to 0 °C (ice/water bath). LAH (1.0 M in Et2O, 0.16 mL, 0.16 mmol, 2.0 eq.) was added dropwise and the light-yellow solution was stirred at the same temperature for 30 min. The reaction was quenched carefully at 0 °C by dropwise addition of EtOAc (1 mL) then brine (1 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the epi-eburnamine 424 (20.0 mg, 83%, dr: 7.4:1) as a yellow oil. TLC (EtOAc: 100%): Rf = 0.55 (UV active; KMnO4, stains yellow).

  Ce transfert d'énergie induisant une rupture homolytique de la liaison O2S-CN à partir du sulfonylcyanure à l'état excité, pour former le radical sulfonyle. Le radical électrophile s'ajouterait alors sur l'extrémité la moins substituée de la double liaison du cyclobutène pour générer un radical β-sulfonyle. Ce dernier serait piégé par R1SO2CN, conduisant au produit attendu 181 et à un radical R1SO2 • , capable de propager la réaction radicalaire en chaîne.

Figure I .

 I Figure I. Mécanisme proposé pour la sulfonyl-cyanation photosensibilisée par le p-anisaldéhyde.

Figure 1 .

 1 Figure 1. Examples of anti-cancer drugs derived from natural and synthetic sources.

Figure 2 .

 2 Figure 2. An illustration of the quantity of dry plants necessary for the isolation of 20 grams of vinblastine.

Figure 3 .

 3 Figure 3. Mechanism of action of vinca alkaloids and taxanes on microtubules. 26

Figure 4 . 1 (

 41 Figure 4. Structure of leucophyllidine 6 confirmed by X-ray diffraction analysis. 1 (Picture source: flickr.com)

Figure 5 .

 5 Figure 5. Small-ring systems as precursors for chiral natural products.

Figure I. 1 .

 1 Figure I.1. Structures and shapes of carbon-centered radicals.

Figure I. 2 .Figure I. 3 .

 23 Figure I.2. Stability of radicals via resonance effect.

Figure I. 4 .

 4 Figure I.4. The polar effect explained by FMO considerations.

Figure I. 5 .

 5 Figure I.5. Polarity matching between radical species and unsaturated systems. 74

Figure I. 6 . 3 -

 63 Figure I.6. 3-MCR carbo-oximation reaction mechanism.

116 Figure I. 7 .

 1167 Scheme I.14. Photoredox catalysis byYoon and MacMillan. 113,114

Figure I. 8 .

 8 Figure I.8. Deactivation pathways of an excited state.

Figure I. 9 .

 9 Figure I.9. Jablonski-Perrin diagram of an organic molecule. 116

Figure I. 10 .

 10 Figure I.10. Intermolecular deactivations.

Figure I. 11 .

 11 Figure I.11. Oxidative and reductive PET.

  potentials for species A (acceptor) and D (donor) describing the half reduction reaction for each species. Ered, also written as E1/2 (A/A •-), refers to the reduction potential of an acceptor A describing the single electron reduction according to the half-reaction A → A •-. Eox, also written as E1/2 (D •+ /D), corresponds to the oxidation potential of a donor D describing the half reduction reaction D •+ → D.

Figure I. 12 .Figure I. 13 .4. 1 . 2 .

 121312 Figure I.12. Estimation of the zero-zero excitation energy of an excited state.

Figure I. 15 .

 15 Figure I.15. Mechanism of the oxidative and reductive quenching cycles in ATRA reactions using [Ru(bpy)3]Cl2. 121

Figure I. 16 .

 16 Figure I.16. Representation of a resonant energy transfer and an electron exchange energy transfer. 116

Figure I. 17 .

 17 Figure I.17. Mechanism of an energy transfer in ATRA reactions. 122

Scheme I. 24 .

 24 Scheme I.24. Eosin-mediated sulfonyl-cyanation by Chu et al.129

Figure I. 18 .

 18 Figure I.18. Proposed mechanism of the sulfonyl-cyanation by Chu et al. 129

Figure I. 19 .

 19 Figure I.19. Proposed mechanism of sulfonyl-cyanation by Landais et al. 5

Figure II. 1 .

 1 Figure II.1. Selected cyclopropane/cyclobutane-containing natural products and drugs.

Figure II. 2 .

 2 Figure II.2. Comparison of the angle strain in cyclopropane and cyclobutane.

Figure II. 3 .

 3 Figure II.3. Proposed bonding models for cyclopropane.

excited 2 -

 2 Scheme II.4. Intermolecular photochemical [2+2] byBach et al. 175

Scheme II. 20 .

 20 Scheme II.20. Radical additions of xanthate derivatives on cyclobutenes byZard et al. 193

Figure III. 2 .

 2 Figure III.2. HPLC trace of racemic compound 117b, synthesized without (left) or with ligands (right). Analytical Chiralpak ® IA column, n-hexane/ethanol 90:10, 1 mL/min, 20 °C.

Figure III. 3 .

 3 Figure III.3. Evaluation of the enantioselectivity of the cyclobutene sulfides.

Figure III. 4 .

 4 Figure III.4. Possible candidates for radical additions onto cyclobutenes.

  Scheme III.12. Carbo-cyanation of trisubstituted olefins by Inoue et al.214

  Such a transformation relies on a radical-based pathway catalyzed by Cu(I)-mediated cleavage of the C-Cl bond (Figure III.5). The generated electrophilic radical I reacts then selectively on the less hindered carbon of the electron-rich olefin 98, yielding a new radical II. The latter undergoes intramolecular cyclization, forming the carbocyclic iminyl radical III. The ring-opening of the strained cyclobutane produces a more stabilized tertiary radical IV through 1,3-cyanide transfer. Finally, the delivery of a chlorine atom from Cu(II)Cl to IV yields the final product 191 and regenerates the Cu(I) catalyst.

Figure III. 5 .

 5 Figure III.5. Proposed radical mechanism for Cu(I)-catalyzed carbo-cyanation. 214

3 .

 3 ATRA reaction of BrCCl3 onto cyclobutene, and the ORTEP view of the product. [Ir] = [Ir(ppy)2(dtbbpy)]PF6. Reagents and conditions: i) BrCCl3 (2.0 eq.), solvent (0.1 M), DMF/H2O: 4/1, 24 h. a 65 °C. b blue LEDs.

Figure III. 6 .

 6 Figure III.6. Transition state model during the bromine-cyanide interchange on cyclobutane.

Figure III. 7 .

 7 Figure III.7. Left: UV-visible absorption spectra (200-450 nm) of the sulfonyl-cyanation reactants. Right: zoom on the UV-visible spectra showing the absorption profiles of the reactants in the 325-400 nm zone chosen for the irradiation reaction. Curves: Green: p-anisaldehyde; red: cyclobutene 169a; blue: MeSO2CN.

  (BP*/BP +• ) = -0.61 V 117 and the Faraday constant F = 23.061 kcal V -1 mol -1 Electron transfer to EtSO2CN (Ered(RSO2CN/RSO2CN -• ) = -1.72 V (vs SCE) and ΔGPET = -F [-1.72 -(-0.61)] ΔGPET = +25.6 kcal/molOxidative quenching of 3 An* and Electron Transfer (ET) to ethylsulfonyl cyanideThe free energy of a photo-induced electron transfer from p-anisaldehyde (An) triplet state is given by the following relation:

Figure III. 9 .

 9 Figure III.9. Proposed mechanism for the p-anisaldehyde-photosensitized sulfonyl-cyanation.

Figure

  Figure III.10. p-Anisaldehyde as a photosensitizer in the sulfonyl-cyanation reaction.

Figure III. 11 .

 11 Figure III.11. Sulfonylcyclobutanes as key-synthons in the synthesis of azabicyclo[3.3.1]nonane, an eucophylline's intermediate.

  2.0]octan-2-ones 210 met with different fates depending on their C-6 substituent. The alkyl-substituted bicyclo[4.2.0]octan-2-ones afforded the cyclohexanones 211 through the cleavage of the external C1-C8 bond (Scheme III.27.A). With an unsaturated side chain as a substituent, the radical intermediate 212 proceeded through 5-exo-trig cyclization to provide the spiro[4.5]decanone 213 in excellent yield (Scheme III.27.B). In contrast, in the presence of electron-withdrawing groups such as nitrile or ester, the regioselectivity was directed towards the formation of eight-membered ring derivatives 214 and 215 (Scheme III.27.C).

  indicate that the coordination of Sm(II) to the carbonyl and the Lewis basic nitrogen facilitates the electron transfer through a ketyl-type radical 223. After reduction into carbinolamine 224, the organosamarium intermediate undergoes selective C-N bond scission to provide access to a library of functionalized alcohols 225 in good to high yields. Similarly, the reduction of N-acyloxazolidinone 222a delivered the corresponding alcohol 225a in a high yield.

  1940, Ramberg and Bäcklund 265,266 discovered that treatment of α-halo-sulfones 232 with 2 N KOH, led to the corresponding alkenes 233 with Z-selectivity (Scheme III.35). The reaction was shown to proceed through the intermediate episulfone I, which collapses into alkene after fast SO2 extrusion.This two-steps sequence: halogenation/base-induced rearrangement being challenging (difficulties encountered in the preparation of α-halosulfones), Meyers 267 later developed a one-pot process, where the α-halo-sulfones are synthesized in situ. α-and α'hydrogen-bearing sulfones were thus treated with an excess of powdered KOH in the presence of t-BuOH and CCl4 as a halogenating agent. Although this chemistry gave excellent yields of regio-defined olefins 234, it was limited to the preparation of stilbenes and 1,1-diarylalkenes.

  Scheme III.35. Ramberg-Bäcklund rearrangement and key improvements proposed byMeyers, Chan, and Franck.

  /EtOH, -78 °C, 10 min, then Me2S (1.5 eq.), -78 to 20 °C, 1 h comp. mix.

  7i. O3, CH2Cl2, -78 °C. ii. NaBH4 (3.0 eq.), THF, -78 to 20 °C, 5 h comp. mix. 8 i. O3, CH2Cl2, Me2S, -78 °C, isolated.

Figure III. 13 .

 13 Figure III.13. Ring-opening of nitro-cyclobutane through denitration, and possible transformations of the nitro fragment.

1 .

 1 Isolation, structure, and biogenesis of eucophylline Eucophylline 8, a rare example of a tetracyclic vinylquinoline alkaloid, was isolated from the bark of Leuconotis eugenifolius species collected in Peninsular Malaysia, by extraction with methanol (Figure IV.1).2 The purification of the extract allowed the isolation of eucophylline 8 as a brown powder in 0.00039% yield (1.9 mg), together with leucophyllidine, eburnamine, leuconolam, and rhazinilam alkaloids. The fact that Morita and co-workers isolated eucophylline, eburnamine and leucophyllidine alkaloids in the same extract supports the proposed biogenesis of the dimeric alkaloid 6, involving a Mannich-type coupling between the eburnan backbone 7 and eucophylline 8.

Figure IV. 1 .

 1 Figure IV.1. Eucophylline 8 isolated from Leuconotis eugenifolius.(Picture source: Flickr.com)

  4S)-cis-332c(10)

13 C

 13 HMBC) spectroscopic data exhibit, when compared with the published data of the naturally isolated eucophylline, a slight shift in some 1 H-NMR signals (Figure IV.3 and TableIV.10). The previously published 1 H-NMR data of the synthetic samples showed too, some shift from the authentic product. This may be attributed to hydrogen bonding in methanol-d4 and also, as mentioned above, to the amphoteric nature of eucophylline.

Figure IV. 3 .

 3 Figure IV.3. The 1 H NMR spectra of natural and synthesized eucophylline, in CD3OD.

Figure IV. 4 .

 4 Figure IV.4. The 13 C NMR spectra of 417 in acetone-d6 with 26 days gap.

  paper: [α]D 25 = +72.16 (c = 0.53, MeOH) versus lit. 2 [α]D 27 = +27 (c = 0.75, MeOH). While Pandey found a closer value to that obtained for the authentic sample: [α]D 19.8 = +36.102 (c = 1.25, MeOH). 352

Figure IV. 5 .

 5 Figure IV.5. Comparison of CD and UV spectra of the eucophylline synthesized in this work (left) and the natural one 2 (right).

Figure IV. 6 .

 6 Figure IV.6. HPLC trace of chiral (+)-eucophylline. Analytical Phenomenex ® column (Lux 5 µm Cellulose-3, 4.6 mmΦ x 250 mmL), pure H2O/CH3CN: 75/25, 1 mL/min, 20 °C.

Figure IV. 7 .

 7 Figure IV.7. HPLC trace of (±)-eucophylline (synthesized by Landais et al.). Analytical Phenomenex ® column (Lux 5 µm Cellulose-3, 4.6 mmΦ x 250 mmL), pure H2O/CH3CN: 75/25, 1 mL/min, 20 °C.

  solvent mixtures were tested to finally succeed at obtaining crystals suitable for X-ray diffraction analysis by diffusion from CH2Cl2/Et2O. The X-ray structure confirmed the successful synthesis of the natural enantiomer crystallized with a water molecule appearing close to the quinoline's nitrogen atom (Figure IV.8). These analyses secured the first X-ray crystal structure of 8 which nicely illustrates the overall conformation of the molecule, showing the piperidine ring in a chair conformation.

Figure IV. 8 .

 8 Figure IV.8. ORTEP view of (+)-eucophylline obtained by X-ray diffraction, crystallized with a water molecule.

Figure IV. 9 .

 9 Figure IV.9. Total synthesis of (+)-eucophylline.

Figure V. 1 .

 1 Figure V.1. Secologanin skeleton present in aspidosperma and eburna-vinca alkaloids.

Figure V. 2 .

 2 Figure V.2. Selected examples of eburnane-vincane indole alkaloids.

Figure V. 3 .

 3 Figure V.3. Bis-indole alkaloids containing eburnane pentacyclic core.

459.

  Scheme V.4. Synthesis of (±)-eburnamonine byWenkert and Wickberg. 408

Scheme V. 9 .

 9 Scheme V.9. Enantioselective synthesis of eburnamine byPandey et al. 352

Scheme V. 15 .

 15 Scheme V.15. Deprotection of Bn-protected alcohol 503a under hydrogenation conditions. Reagents and conditions: i) H2 (1 atm), Pd(OH)2/C (40 wt. %), MeOH (0.03 M), 50 °C, 48 h.

450 Figure V. 4 .

 4504 Figure V.4. Possible cyclization under Fujii's conditions.

Scheme V. 19 .

 19 Scheme V.19. Deprotection of 504a. Reagents and conditions: i) H2 (1 atm), Pd(OH)2/C (50 wt. %), MeOH (0.02 M), 50 °C, 4 days.

Scheme VII. 3 .

 3 Scheme VII.3. Sulfonyl-cyanation reaction of cyclobutenes using p-anisaldehyde as a photosensitizer.

Figure VII. 1 .

 1 Figure VII.1. Proposed mechanism for the p-anisaldehyde-photosensitized sulfonyl-cyanation.

Finally, the

  intermediate-type I could also be interesting to prepare other indole alkaloids; for instance, with R = Et, amine 517a could be used in the total synthesis of quebrachamine 563, aspidospermidine 419 and goniomitine 564(Figure VII.2). Whereas, starting from a cyclopropane with a functionalized side chain R = (CH2)2OPG, the amine 562 could be manipulated to give access to larutensine 431 and eburnaminol 432 indole alkaloids.

Figure VII. 2 .

 2 Figure VII.2. Possible use of ester I in the synthesis of a series of indole alkaloids.

  C: 151.13 MHz) and were calibrated using residual undeuterated solvent as an internal reference [chloroform-d ( 1 H): δ = 7.26 ppm; chloroformd ( 13 C): δ = 77.16 ppm; DMSO-d6 ( 1 H): δ = 2.50 ppm; DMSO-d6 ( 13 C): δ = 39.52 ppm; methanol-d4 ( 1 H): δ = 3.31 ppm; methanol-d4 ( 13 C): δ = 49.00 ppm; acetonitrile-d3 ( 1 H): δ = 1.94 ppm; acetonitrile-d3 ( 13 C): δ = 118.26, 1.32 ppm]. The chemical shifts (δ) and coupling constants (J) are expressed in ppm and Hz respectively. The following abbreviations were used to describe the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, qAB = quartet in AB system, quint = quintuplet, dd = doublet of doublet, dt = doublet of triplet, dq = doublet of quartet, td = triplet of doublet, tt = triplet of triplet, tq = triplet of quartet, qd = quartet of doublet, qq = quartet of quartet, pd = quintuplet of doublet, ddd = doublet of doublet of doublet, ddt = doublet of doublet of triplet, dtd = doublet of triplet of doublet, dqd = doublet of quartet of doublet, tdd = triplet of doublet of doublet, qdt = quartet of doublet of triplet, dddd = doublet of doublet of doublet of doublet, m = multiplet, br s = broad singlet, br = broad signal.

Figure S. 1 .

 1 Figure S.1. The emission spectrum of the commercial blue LEDs (left; λmax = 451 nm) and the experimental setup used in the irradiation reactions (right).

Figure S. 2 .Figure S. 5 .Figure S. 6 .

 256 Figure S.2. The emission spectrum of the commercial green LEDs (left; λmax = 513 nm) and the experimental setup used in the irradiation reactions (right).

  are in agreement with those reported in the literature. 469 dichloro(diisopropoxy)titanium (116)198

  33), 128.6 (C-Ph), 128.4 (C-Ph), 128.2 (C-Ph), 128.18 (C-Ph), 128.1 (C-Ph), 127.7 (C-Ph), 127.6 (C-Ph), 127.4 (C-Ph), 127.35 (C-Ph), 127.3 (C-Ph), 127.1 (C-Ph), 127.0 (C-Ph), 126.9 (C-Ph), 126.6 (C-Ph), 124.8 (C-6, C-10), 111.4 (C-2), 83.3 (C-4), 81.7 (C-3), 79.0 (C-11), 78.5 (C-12), 30.1 (C-1). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3327 (br, OH), 1494, 1445, 1170, 1039, 698. HRMS (TOF, ES+): calculated for C36H32O4Na [M+Na] + 551.21928, found 551.21831. [α]D 25 = -77 (c = 0.53, CHCl3).

  in MeOH, thin film, KBr): ν max (cm -1 ) = 2252 (C≡C),2126, 1654, 1025, 824, 762, 626.

1 H

 1 NMR (300 MHz, CDCl3): δ (ppm) = 2.35 (s, 3H, H-1), 2.26 (t, J = 7.0 Hz, 2H, H-4), 1.53 (hex, J = 7.3 Hz, 2H, H-5), 0.97 (t, J = 7.4 Hz, 3H, H-6). in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2961 (-C-H), 2926 (-C-H), 2870 (-C-H),1460, 1432, 1314, 974.

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 93.3 (C-3), 69.8 (C-2), 31.1 (C-6), 28.5 (C-5), 22.3 (C-7), 20.1 (C-1), 19.3 (C-4), 14.0 (C-8). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3545, 2957 (-C-H), 2929 (-C-H), 2859 (-C-H), 1730, 1448, 1434, 1313, 976, 700. HRMS (TOF, FI+): calculated for C8H14S [M] +• 142.08162, found 142.08200.

  CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2955, 2929 (-C-H), 2857 (-C-H), 2189 (C≡C), 1254, 1093, 836, 777. HRMS (TOF, FI+): calculated for C6H9OSSi [M] +• 216.10080, found 216.10041.

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 92.1 (C-3), 70.8 (C-2), 33.2 (C-6), 28.1 (C-5), 19.3 (C-1), 19.2 (C-4), 15.5 (C-7). IR (solution in CH2Cl2, thin film, KBr): νmax (cm -1 ) = 2920 (-C-H), 2856 (-C-H), 2188 (C≡C), 1429, 1313, 1279, 976, 957. HRMS (TOF, FI+): calculated for C7H12S2 [M] +• 160.03804, found 160.03850.

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 172.9(C-4), 153.6 (C-1), 151.3 (C-7), 129.0(C-8), 62.3 (C- 2), 44.8(C-5), 42.7 (C-3), 33.7 (C-6), 31.7 (C-11 or C-12), 28.9 (C-9), 26.5 (C-10), 22.5(C-11 or C- 12), 15.9 (C-14), 14.1(C-13). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2925 (-C-H), 1789 (4-C=O), 1771, 1679(1- C=O), 1384, 1369, 1262, 1219, 1196, 1040, 757. HRMS (TOF, ES+): calculated for C14H21NO3SNa [M+Na] + 306.1134, found 306.1140.

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 172.4(C-4), 153.5 (C-1), 145.7 (C-7), 130.6 (C-8), 62.4 (C- 2), 59.3(C-9), 44.6 (C-5), 42.7 (C-3), 32.9(C-6), 26.0(C-13, C-14, C-15), 18.5(C-12), 15.2 (C-16), -5.1(C-10, C-11). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2929 (-C-H), 1789 (4-C=O), 1682(1-C=O), 1383, 1369, 1259, 1087, 1040, 839, 778. HRMS (TOF, ES+): calculated for C16H27NO4SSiNa [M+Na] + 380.1322, found 380.1327. [α]D 23 = +70.91 (c = 2.46, CHCl3).

  Purification through column chromatography on SiO2 (cyclohexane/EtOAc: 70/30) afforded the product (170.0 mg, 96%) as a pale-yellow oil solidifies open to atmosphere. TLC (cyclohexane/EtOAc: 50/50): Rf = 0.55 (UV active; vanillin, stains brown). m. p. = 63.1-64.2 °C (pentane/EtOAc). 1 H NMR (600 MHz, CDCl3): δ (ppm) = 4.75 (dq, J = 5.1, 1.8 Hz, 1H, H-5), 4.43 (t, J = 8.0 Hz, 2H, H-2), 4.04 (td, J = 5.1, 1.8 Hz, 2H, H-3), 3.55 (t, J = 6.6 Hz, 2H, H-11), 2.77 (ddt, J = 12.7, 4.9, 1.2 Hz, 1H, H-6a), 2.51 (dq, J = 12.6, 1.4 Hz, 1H, H-6b), 2.34 (tq, J = 8.3, 1.6 Hz, 2H, H-9), 2.25 (s, 3H, H-12), 1.97 (pd, J = 6.8, 2.3 Hz, 2H, H-10).13 C NMR (150 MHz, CDCl3): δ (ppm) = 172.7 (C-4), 153.5(C-1), 148.1 (C-7), 130.9 (C-8), 62.4 (C-2), 44.7 (C-5), 44.5(C-11), 42.7 (C-3), 33.8 (C-6), 29.8 (C-10), 26.4 (C-9),15.6 (C-12). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2923 (-C-H), 1778 (4-C=O), 1694(1-C=O), 1387, 1363, 1253, 1227, 1109, 1040, 760. HRMS (TOF, ES+): calculated for C12H16ClNO3SNa [M+Na] + 312.0431, found 312.0441.[α]D 23 = +38.76 (c = 2.2, CHCl3).

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 173.4 (C-4), 153.3 (C-1), 149.8 (C-7), 126.5 (C-8), 62.2 (C-2), 61.1 (C-10), 43.1 (C-5), 42.5 (C-3), 35.2(C-6), 34.5(C-9), 18.0(C-14, C-15, C-16, C-17, C-18, C- 19), 11.9(C-11, C-12, C-13).

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 173.1 (C-4), 153.4 (C-1), 150.7 (C-7), 125.8 (C-8), 62.4 in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3441, 2930 (-C-H), 2857 (-C-H), 1779 (4-C=O), 1695 (1-C=O), 1472, 1387, 1257, 1091, 1042, 840, 777. HRMS (TOF, ES+): calculated for C15H25NO4SiNa [M+Na] + 334.1445, found 334.1440.

  12, C-16), 128.4(C-13, C-15), 126.0(C-14), 125.8 (C-8), 62.4 (C-2), 42.8(C-5), 42.6 (C-3), 34.9(C-6), 32.8 (C-10), 32.7(C-9). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2922 (-C-H), 1779 (4-C=O), 1694(1-C=O), 1385, 1259, 1111, 1042, 759, 701. HRMS (TOF, ES+): calculated for C16H17NO3Na [M+Na] + 294.1100, found 294.1108.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2933 (-C-H), 1779 (4-C=O), 1692 (1-C=O),

1 H

 1 NMR (300 MHz, CDCl3): δ (ppm) = 7.85 (dd, J = 5.5, 3.0 Hz, 2H, H-3, H-6), 7.71 (dd, J = 5.4, 3.1 Hz, 2H, H-4, H-5), 4.02-3.77 (m, 2H, H-9), 3.09 (dd, J = 14.1, 7.3 Hz, 1H, H-12a), 3.06-2.97 (m, 1H, H-11), 2.83 (dd, J = 14.1, 3.2 Hz, 1H, H-12b), 2.16-1.88 (m, 2H, H-10), 0.09 (s, 9H, H-TMS). 13 C NMR (75 MHz, CDCl3): δ (ppm) = 168.3 (C-1, C-8), 134.1 (C-4, C-5), 132.2 (C-2, C-7), 123.4 (C-3, C-6), 106.5 (C-14), 98.2 (C-13), 88.4 (C-15), 59.2 (C-12), 36.0 (C-9), 33.7 (C-10), 28.9 (C-11), -0.05 (C-TMS). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2961 (-C-H), 2172 (C≡C), 1714 (1-C=O, 8-C=O), 1398, 1376, 1249, 844, 760, 719. HRMS (TOF, ES+): calculated for C18H20Cl3NO2SiNa [M+Na] + 438.02211, found 438.02199.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2965 (-C-H), 2937 (-C-H), 1778 (4-C=O), 1769 (13-C=O, 14-C=O), 1695(1-C=O), 1479, 1428, 1462, 1445, 1242, 1037, 760, 734.HRMS (TOF, ES+): calculated for C18H26BrNO7Na [M+Na] + 470.0784, found 470.0773. di-tert-butyl 2-((1S,2R,4S)-2-bromo-4-(2-oxooxazolidine-3-carbonyl)-2propylcyclobutyl)malonate (180c)

  , C-20, C-21, C-22), 18.7 (C-10),13.8 (C-11). Minor diastereomer (cis): δ (ppm) = 172.3(C-4), 167.3 (C-13), 166.4 (C-14), 153.9 (C-1), 82.1(C-15), 81.5(C-19), 71.8 (C-7), 62.1 (C-2), 58.5(C-12), 48.6 (C-8), 46.8 (C-9), 42.8 (C-3), 40.1(C-6), 37.4 (C-5), 28.3(C-16, C-17, C-18), 27.9(C-20, C-21, C-22), 19.3 (C-10), 14.0(C-11). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2974 (-C-H), 2937 (-C-H), 1779 (4-C=O), 1725 (13-C=O, 14-C=O), 1695(1-C=O), 1478, 1389, 1367, 1272, 1162, 1041, 846, 761, 707. HRMS (TOF, ES+): calculated for C22H34BrNO7Na [M+Na] + 526.14109, found 526.14051.

  61.6 (C-15), 61.5(C-16), 43.0(C-3), 33.3 (C-7), 33.2 (C-6), 27.0(C-5), 20.7 (C-8), 20.3 (C-9), 14.2(C-10, C-17, C-18). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2961 (-C-H), 2935 (-C-H), 1778 (4-C=O), 1728 (13-C=O, 14-C=O), 1688(1-C=O), 1383, 1243, 1217, 1039, 760, 734. HRMS (TOF, ES+): calculated for C18H25NO7Na [M+Na] + 390.15232, found 390.15122.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2957 (-C-H), 2922 (-C-H), 2232 (C≡N), 1778 (4-C=O), 1730 (13-C=O, 14-C=O), 1697(1-C=O), 1388, 1283, 1227, 1036, 864, 760. HRMS (TOF, ES+): calculated for C19H26N2O7Na [M+Na] + 417.16322, found 417.16328.

  5), 31.0(C-6), 17.3(C-10), 15.0 (C-11), 14.1 (C-17), 14.0(C-17). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2965 (-C-H), 2937 (-C-H), 1778 (4-C=O), 1726 (13-C=O, 14-C=O), 1701(1-C=O), 1387, 1269, 1226, 1039, 760, 734. HRMS (TOF, ES+): calculated for C21H31NO7Na [M+Na] +432.19927, found 432.19885.

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 170.1(C-4), 152.9(C-1), 121.3 (C-14), 62.9 (C-2), 57.5(C- 8), 48.9(C-9), 42.5(C-3), 38.4 (C-5), 36.1(C-7), 33.3 (C-11), 33.0 (C-6), 18.7 (C-12), 13.9 (C-13), 6.2(C-10). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2966 (-C-H), 2877 (-C-H), 2237 (C≡N), 1782 (4-C=O), 1691(1-C=O), 1468, 1391, 1317, 1286, 1229, 1130, 1041. HRMS (TOF, ES+): calculated for C14H20N2O5SNa [M+Na] + 351.0981, found 351.0985.

  48.8 (C-9), 42.4(C-3), 38.4 (C-5), 36.1 (C-7), 33.2(C-6), 31.4 (C-14), 31.0(C-12), 25.0(C-13), 22.6 (C-15), 14.0 (C-16), 6.1(C-10). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2931 (-C-H), 2237 (C≡N), 1783 (4-C=O), 1692(1-C=O), 1392, 1318, 1230, 1132, 1041, 736. HRMS (TOF, ES+): calculated for C16H24N2O5SNa [M+Na] + 379.1298, found 379.1311.

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 170.0(C-4), 153.0 (C-1), 121.3(C-12), 65.9 (C-10), 62.9 (C-2), 60.3(C-8), 59.4 (C-11), 55.1 (C-9), 42.5(C-3), 37.8 (C-5), 36.4 (C-7), 33.0 (C-6), 31.5(C-13), 31.2(C-15), 25.0 (C-14), 22.6 (C-16), 14.0(C-17). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2930 (-C-H), 2236 (C≡N), 2180, 1783 (4-C=O), 1694(1-C=O), 1391, 1321, 1228, 1131, 1116, 1041, 759. HRMS (TOF, ES+): calculated for C17H26N2O6SNa [M+Na] + 409.1403, found 409.1400.

  C-16, C-18), 126.6(C-17), 121.0(C-11), 62.9 (C-2), 57.4(C-8), 48.8 (C-9), 42.4 (C-3), 38.4 (C-5), 36.0 (C-7), 33.3(C-6), 33.0(C-13), 31.6 (C-12), 6.1(C-10). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2941 (-C-H), 2238 (C≡N), 1783 (4-C=O), 1692(1-C=O), 1391, 1316, 1229, 1132, 1040, 758, 735, 702. HRMS (TOF, ES+): calculated for C19H22N2O5SNa [M+Na] + 413.1141, found 413.1149.[α]D 23 = +47.98 (c = 1.93, CHCl3).

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 170.0(C-4), 153.0 (C-1), 121.3 (C-10), 63.0 (C-2), 59.7(C- 8), 42.50(C-9), 42.46(C-3), 38.7 (C-5), 35.9 (C-7), 33.1(C-6), 32.8 (C-11), 18.6 (C-12), 13.9(C- 13). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2964 (-C-H), 2932 (-C-H), 2876 (-C-H), 2237 (C≡N), 1782 (4-C=O), 1691(1-C=O), 1391, 1315, 1287, 1228, 1146, 1133, 1040, 759. HRMS (TOF, ES+): calculated for C13H18N2O5SNa [M+Na] + 337.0828, found 337.0833.

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 170.2 (C-4), 152.7 (C-1), 121.0 (C-12), 65.9 (C-10), 62.7 (C-2), 60.8 (C-8), 60.6 (C-14), 59.4 (C-11), 55.1 (C-9), 42.5 (C-3), 37.8 (C-5), 35.2 (C-7), 33.7 (C-6), 33.3 (C-13), 18.1 (C-18, C-19, C-20, C-21, C-22, C-23), 11.9 (C-15, C-16, C-17). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2943 (-C-H), 2867 (-C-H), 2238 (C≡N), 1785 (4-C=O), 1694 (1-C=O), 1390, 1322, 1226, 1116, 1040, 882, 759, 684. HRMS (TOF, ES+): calculated for C23H40N2O7SSiNa [M+Na] + 539.2228, found 539.2231. [α]D 23 = +38.33 (c = 0.086, CHCl3).

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 170.1(C-4), 152.7 (C-1), 121.0 (C-10), 62.8 (C-2), 60.6(C- 8), 60.3 (C-12), 42.6 (C-9), 42.5(C-3), 38.6 (C-5), 34.8 (C-7), 33.9(C-6), 33.0 (C-11), 18.1(C-16, C- 17, C-18, C-19, C-20, C-21), 11.9(C-13, C-14, C-15). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2944 (-C-H), 2867 (-C-H), 2237 (C≡N), 1786 (4-C=O), 1692(1-C=O), 1390, 1316, 1227, 1131, 1040, 882, 759, 683. HRMS (TOF, ES+): calculated for C21H36N2O6SSiNa [M+Na] +495.1955, found 495.1956.

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 169.3(C-4), 152.8 (C-1), 145.6 (C-12), 135.4 (C-9), 130.1(C-11, C-14), 128.2(C-10, C-15), 120.8 (C-16), 62.9 (C-2), 61.4 (C-8), 60.9 (C-18), 42.3(C-3), 36.7(C-5), 35.1 (C-7), 33.9(C-6, C-17), 21.6 (C-13), 18.0(C-22, C-23, C-24, C-25, C-26, C-27), 11.8 (C- 19, C-20, C-21).

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 169.8(C-4), 152.9 (C-1), 139.5(C-13), 128.7 (C-14, C-18), 128.6 (C-15, C-17), 126.6 (C-16), 121.0 (C-10), 62.9 (C-2), 59.7 (C-8), 42.9(C-9), 42.4 (C-3), 38.7(C-5), 36.0 (C-7), 33.3(C-6), 32.9 (C-11 or C-12), 31.7(C-11 or C-12). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2926 (-C-H), 2237 (C≡N), 1782 (4-C=O), 1692(1-C=O), 1390, 1314, 1228, 1133, 1039, 756. HRMS (TOF, ES+): calculated for C18H20N2O5SNa [M+Na] + 399.0985, found 399.0993.

  43.7 (C-13), 42.5(C-9), 42.4(C-3), 38.7 (C-5), 35.4 (C-7), 33.2 (C-6), 28.7(C-12), 28.6 (C-11). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2962 (-C-H), 2238 (C≡N), 1781 (4-C=O), 1692(1-C=O), 1391, 1314, 1229, 1228, 1133, 1039, 759. HRMS (TOF, ES+): calculated for C13H17ClN2O5SNa [M+Na] + 371.0438, found 371.0439.[α]D 23 = +15.39 (c = 0.1, CHCl3).

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 169.7(C-4), 153.0 (C-1), 120.5(C-10), 62.9 (C-2), 62.0(C- 11), 58.7 (C-8), 42.5(C-3), 42.0 (C-9), 38.4 (C-7), 37.3(C-5), 31.0(C-6), 25.8(C-15, C-16, C-17), 18.4 (C-14), -5.4(C-12, C-13). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2931 (-C-H), 2242 (C≡N), 1784 (4-C=O), 1694(1-C=O), 1391, 1309, 1144, 1112, 838, 781, 759. HRMS (TOF, ES+): calculated for C17H28N2O6SSiNa [M+Na] + 439.1329, found 439.1334.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2955 (-C-H), 2930 (-C-H), 2245 (C≡N), 1463, 1328, 1147, 1122. HRMS (TOF, ES+): calculated for C10H18ClNO2SNa [M+Na] + 274.0638, found 274.0648.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2930 (-C-H), 2859 (-C-H), 2244 (C≡N), 1303, 1134, 968, 513. HRMS (TOF, ES+): calculated for C10H19NO2SNa [M+Na] + 240.10287, found 240.10240.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2966 (-C-H), 2937 (-C-H), 2877 (-C-H), 2237 (C≡N), 1777 (4-C=O), 1699 (4-C=O), 1392, 1365, 1313, 1134, 1041. HRMS (TOF, ES+): calculated for C14H22N2O5SNa [M+Na] + 353.1142, found 353.1145.

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 171.4 (C-4), 153.8 (C-1), 120.9(C-11), 62.4 (C-2), 57.3 in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2966 (-C-H), 2933 (-C-H), 2876 (-C-H), 2237 (C≡N), 1777 (4-C=O), 1697(1-C=O), 1391, 1365, 1311, 1226, 1138, 1040, 761. HRMS (TOF, ES+): calculated for C13H20N2O5SNa [M+Na] + 339.0985, found 339.0988.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2932 (-C-H), 2236 (C≡N), 1778 (4-C=O), 1699 (1-C=O), 1391, 1314, 1227, 1134, 1040, 760. HRMS (TOF, ES+): calculated for C16H26N2O5SNa [M+Na] + 381.1454, found 381.1460. [α]D 23 = -1.03 (c = 1.4, CHCl3).

  for C21H38N2O6SSiNa [M+Na] + 497.2123, found 497.2115. [α]D 23 = -34.28 (c = 0.093, CHCl3). (R)-5-oxo-5-(2-oxooxazolidin-3-yl)-2-(tosylmethyl)-2-(2-((triisopropylsilyl)oxy)ethyl)pentanenitrile (199f)

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 171.4 (C-4), 153.7 (C-1), 145.5 (C-15), 137.5 (C-12), 130.1 (C-13, C-15), 128.1 (C-14, C-17), 120.2 (C-10), 62.3 (C-2), 60.2 (C-9), 59.5 (C-11), 42.6 (C-3), 39.0 (C-7), 38.5 (C-8), 31.4 (C-6), 30.8 (C-5), 21.8 (C-16), 18.0 (C-22, C-23, C-24, C-25, C-26, C-27), 11.9 (C-19, C-20, C-21). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2943 (-C-H), 2866 (-C-H), 2236 (C≡N), 1780 (4-C=O), 1701 (1-C=O), 1390, 1320, 1225, 1151, 734. HRMS (TOF, ES+): calculated for C27H42N2O6SSiNa [M+Na] + 573.24251, found 573.24086.

  CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2943 (-C-H), 2867 (-C-H), 2237 (C≡N), 1780 (4-C=O), 1701 (1-C=O), 1390, 1320, 1224, 1114. HRMS (TOF, ES+): calculated for C23H42N2O7SSiNa [M+Na] + 541.2374, found 541.2351. [α]D 25 = -34.57 (c = 0.086, CHCl3). (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-((ethylsulfonyl)methyl)-5-oxo-5-(2oxooxazolidin-3-yl)pentanenitrile (199h)

  or C-14), -5.5(C-13 or C-14). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2930 (-C-H), 2241 (C≡N), 1779 (4-C=O), 1700(1-C=O), 1390, 1315, 1257, 1227, 1123, 1040, 840, 781. HRMS (TOF, ES+): calculated for C18H32N2O6SSiNa [M+Na] + 455.1642, found 455.1648.[α]D 23 = -9.14 (c = 1.2, CHCl3).

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2937 (-C-H), 2238 (C≡N), 1777 (4-C=O), 1698(1-C=O), 1392, 1313, 1228, 1134, 1040, 760, 733. HRMS (TOF, ES+): calculated for C14H21ClN2O5SNa [M+Na] + 387.0751, found 387.0752.

  5 h. Purification of the crude mixture through column chromatography on SiO2 (CH2Cl2/EtOAc: 80/20 to 70/30) afforded the product (114.0 mg, 57%) as a yellow oil. TLC (CH2Cl2/EtOAc: 60/40): Rf = 0.27 (UV inactive; KMnO4, stains white). 1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.43 (dd, J = 8.7, 7.5 Hz, 2H, H-2), 4.02 (dd, J = 8.7, 7.5 Hz, 2H, H-3), 3.59 (t, J = 5.9 Hz, 2H, H-10), 3.40 (d, J = 2.3 Hz, 2H, H-12), 3.14 (t, J = 10.0 Hz, 2H, H-5), 3.07 (s, 3H, H-13), 3.34-3.28 (m, 2H, H-6), 2.25-2.11 (m, 1H, H-8a), 2.07-1.97 (m, 3H, H-8b, H-9). 13 C NMR (75 MHz, CDCl3): δ (ppm) = 171.2 (C-4), 153.8 (C-1), 120.4 (C-11), 62.4 (C-2), 57.0 (C-12), 44.0 (C-10), 43.6 (C-13), 42.6 (C-3), 38.5 (C-7), 33.8 (C-8), 30.6 (C-5 or C-6), 30.5 (C-5 or C-6), 27.7 (C-9). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2967 (-C-H), 2930 (-C-H), 2238 (C≡N), 1775 (4-C=O), 1697 (1-C=O), 1392, 1309, 1139, 760. HRMS (TOF, ES+): calculated for C13H20ClN2O5S [M+H] + 351.0775, found 351.0782.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2930 (-C-H), 2237 (C≡N), 1776 (4-C=O), 1698 (1-C=O), 1391, 1311, 1226, 1140, 1039, 759, 735, 702. HRMS (TOF, ES+): calculated for C18H22N2O5SNa [M+Na] + 401.1141, found 401.1135. [α]D 23 = -1.94 (c = 0.086, CHCl3).

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3200 (br, OH), 2944 (-C-H), 2892 (-C-H), 2867 (-C-H), 2238 (C≡N), 1716 (1-C=O), 1462, 1104. HRMS (TOF, ES+): calculated for C19H35NO3SiNa [M+Na] + 376.2278, found 376.2278.

  CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3340 (br, OH), 2943 (-C-H), 2867 (-C-H), 2238 (C≡N), 1463, 1310,1140, 1107, 883, 683. HRMS (TOF, ES+): calculated for C18H37NO4SSiNa [M+Na] + 414.2104, found 414.2104.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3426 (br, OH), 2928 (-C-H), 1757 (1-C=O), 1299, 1136, 1026. HRMS (TOF, APCI-): calculated for C9H15O5S [M-H] + 235.0645, found 235.0642. [α]D 25 = -30.75 (c = 0.49, CHCl3).

  CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3445 (br, OH), 2943 (-C-H), 2866 (-C-H),1462, 1303, 1135, 1102, 882, 681. HRMS (TOF, ES+): calculated for C18H38O5SSiNa [M+Na] + 417.2101, found 417. 2118.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3406 (br, OH), 2943 (-C-H), 2867 (-C-H), 1462, 1296, 1131, 1106, 882, 682. HRMS (TOF, ES+): calculated for C18H40O5SSiNa [M+Na] + 419.2257, found 419.2261. [α]D 25 = -99.47 (c = 0.066, CHCl3).

  According to the general procedure (L), from cyclobutane 181i (4.6 g, 9.74 mmol, 1.0 eq.), distilled EtOH (50.0 mL, 0.2 M), and DMAP (595.0 mg, 4.87 mmol, 0.5 eq.) for 12 h. Purification through short column chromatography on SiO2 (cyclohexane/EtOAc: 70/30) afforded the desired product (4.27 g, quant.) as a pale-yellow oil solidifies open to atmosphere. TLC (cyclohexane/EtOAc: 70/30): Rf = 0.4 (UV inactive; KMnO4, stains red-white). m. p. = 50.8-53.5 °C (pentane/EtOAc).

  , ES+): calculated for C20H37NO5SSiNa [M+Na] + 454.20539, found 454.20525.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2966 (-C-H), 2876 (-C-H), 2237 (C≡N), 1733 (3-C=O), 1314, 1148, 1037, 756. HRMS (TOF, ES+): calculated for C12H19NO4SNa [M+Na] + 296.0927, found 296.0923. [α]D 25 = +12.46 (c = 0.14, CHCl3).

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 172.3(C-3), 120.7 (C-10), 79.6 (C-7), 65.4 (C-8), 61.1(C- 12), 60.2 (C-2), 44.2 (C-4), 41.5(C-6), 40.2 (C-11), 28.7 (C-5), 18.1(C-16, C-17, C-18, C-19, C-20, C-21), 15.2 (C-9), 14.3 (C-1), 12.0(C-13, C-14, C-15). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2943 (-C-H), 2867 (-C-H), 2236 (C≡N), 1733(3-C=O), 1463, 1199, 1108, 882, 683. HRMS (TOF, ES+): calculated for C21H39NO4SiNa [M+Na] + 420.25406, found 420.25397.

  in MeOH, thin film, KBr): ν max (cm -1 ) = 3422 (br, OH), 2943 (-C-H), 2867 (-C-H), 2236 (C≡N), 1597 (3-C=O), 1462, 1412, 1305, 1144, 882, 682. HRMS (TOF, ES+): calculated for C18H33NO5SSiNa [M+Na] + 426.17409, found 426.17289.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2943 (-C-H), 2867 (-C-H), 2233 (C≡N), 1753 (br, 3-C=O, 20-C=O), 1463, 1419, 1224, 1103, 882, 683. HRMS (TOF, ES+): calculated for C22H38N2O5SiNa [M+Na] + 461.2442, found 461.2436. [α]D 25 = -29.52 (c = 0.27, CHCl3). For the second diastereomer (cis diastereomer): TLC (cyclohexane/EtOAc: 70/30): R f = 0.32 (UV inactive; KMnO4, stains yellow).

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3435 (br, OH), 2943 (-C-H), 2866 (-C-H), 2232 (C≡N), 1462, 1108, 882, 682. HRMS (TOF, ES+): calculated for C17H31NO2SiNa [M+Na] + 332.20163, found 332.20079.

  δ (ppm) = 171.8(C-3), 136.9(C-13), 128.7(C-15, C-17), 128.2 (C-16), 127.8 (C-14, C-18), 122.6 (C-8), 78.2 (C-7), 72.2(C-12), 61.2 (C-2), 43.8(C-9), 43.4(C-6), 38.0 (C-4), 27.1(C-5), 18.4 (C-10), 14.3 (C-1), 14.0(C-11). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2962 (-C-H), 2874 (-C-H), 2234 (C≡N), 1731(3-C=O), 1454, 1197, 1129, 741, 698. HRMS (TOF, ES+): calculated for C18H23NO3Na [M+Na] + 324.15701, found 324.15635.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3083 (br, OH), 2964 (-C-H), 2876 (-C-H), 2237 (C≡N), 1710(1-C=O), 1623, 1417, 1281, 1230, 1187, 741. HRMS (TOF, ES+): calculated for C9H10NO2 [M-H] + 164.07170, found 164.07120. Rf = 0.63 (UV active; KMnO4, stains white). 1 H NMR (300 MHz, CDCl3): δ (ppm) = 7.67-7.57(m, 2H, H-Ph), 7.48-7.31 (m, 8H, H-Ph), 7.25- 7.20 (m, 5H, H-Ph), 6.85 (s, 1H, H-5), 3.20 (d, J = 13.8 Hz, 1H, H-3a), 2.76 (d, J = 13.8 Hz, 1H, H- 3b), 1.82-1.73 (m, 2H, H-7), 1.67-1.48 (m, 2H, H-8), 0.99 (t, J = 7.3 Hz, 3H, H-9).

13 C

 13 NMR (150 MHz, CDCl3): δ (ppm) = 171.6 (C-3), 120.1 (C-8), 72.8 (C-20), 61.6 (C-2), 60.4 (C-10), 41.0 (C-7), 40.6 (C-4), 37.8 (C-6), 36.6 (C-9), 34.3 (C-5), 18.1 (C-14, C-15, C-16, C-17, C-18, C-19), 14.2 (C-1), 12.0 (C-11, C-12, C-13). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2941 (-C-H), 2870 (-C-H), 2232 (C≡N), 1733 (3-C=O), 1557, 1464, 1380, 1189, 1102, 883. HRMS (TOF, ES+): calculated for C20H36N2O5SiNa [M+Na] + 435.22857, found 435.22840.

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 174.1 (C-3), 168.3 (C-21), 166.5 (C-22), 82.7 (C-23), 82.2 (C-24), 60.6 (C-2), 59.6 (C-10), 54.1 (C-20), 46.2 (C-7), 43.6 (C-8), 42.8 (C-9), 40.8 (C-4), 37.8 (C-

  28.0(C-25, C-26, C-27), 27.9 (C-28, C-29, C-30), 18.1(C-14, C-15, C-16, C-17, C- 18, C-19), 14.1 (C-1), 11.8 (C

  Figure S.7. HPLC trace of racemic compound 117a, synthesized according to the general procedure (D)method A. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 90/10, 1 mL/min, 20 °C.

Figure S. 8 .

 8 Figure S.8. HPLC trace of chiral compound 117a. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 90/10, 1 mL/min, 20 °C.

Figure S. 9 .

 9 Figure S.9. HPLC trace of racemic compound 169a. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 90/10, 1 mL/min, 20 °C.

Figure S. 10 .

 10 Figure S.10. HPLC trace of chiral compound 169a. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 90/10, 1 mL/min, 20 °C.

Figure S. 11 .

 11 Figure S.11. HPLC trace of racemic compound 181a. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 75/25, 1 mL/min, 20 °C.

Figure S. 12 .

 12 Figure S.12. HPLC trace of chiral compound 181a. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 75/25, 1 mL/min, 20 °C.

Figure S. 13 .

 13 Figure S.13. HPLC trace of racemic compound 199a. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), ethanol: 100%, 1 mL/min, 20 °C.

Figure S. 14 .

 14 Figure S.14. HPLC trace of chiral compound 199a. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), ethanol: 100%, 1 mL/min, 20 °C.

Figure S. 15 .

 15 Figure S.15. HPLC trace of racemic compound 117b, synthesized according to the general procedure (D)method B. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 90/10, 1 mL/min, 20 °C.

Figure S. 16 .

 16 Figure S.16. HPLC trace of chiral compound 117b. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 90/10, 1 mL/min, 20 °C.

Figure S. 17 .

 17 Figure S.17. HPLC trace of racemic compound 169b. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 90/10, 1 mL/min, 20 °C.

Figure S. 18 .

 18 Figure S.18. HPLC trace of chiral compound 169b. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 90/10, 1 mL/min, 20 °C.

Figure S. 19 .

 19 Figure S.19. HPLC trace of racemic compound 117d, synthesized according to the general procedure (D)method B. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 95/5, 1 mL/min, 20 °C.

Figure S. 20 .

 20 Figure S.20. HPLC trace of chiral compound 117d. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 95/5, 1 mL/min, 20 °C.

Figure S. 21 .

 21 Figure S.21. HPLC trace of racemic compound 117e, synthesized according to the general procedure (D)method B. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 85/15, 1 mL/min, 20 °C.

Figure S. 22 .

 22 Figure S.22. HPLC trace of chiral compound 117e. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 85/15, 1 mL/min, 20 °C.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2925 (-C-H), 2853 (-C-H),1619, 1582, 1485, 1446, 1365, 1226, 1161, 1014, 791. HRMS (TOF, ES+): calculated for C16H18BrN2O [M+H] + 333.06080, found 333.05933. calculated for C16H17BrN2ONa [M+Na] + 355.04274, found 355.04126.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3370 (br, OH), 3060, 2929 (-C-H), 2853 (-C-H),1632, 1578, 1581, 1370, 1255, 1238, 1169, 1011, 732. HRMS (TOF, ES+): calculated for C17H19N2O [M+H] + 267.14919, found 267.14900.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2941 (-C-H), 2866 (-C-H), 1730 (br, 3-C=O, 21-C=O, 22-C=O), 1463, 1372, 1250, 1181, 1097, 882, 683. HRMS (TOF, ES+): calculated for C26H50NO7Si [M+H] + 516.3351, found 516.3336. (5R)-5-(2-carboxyethyl)-2-oxo-5-(2-((triisopropylsilyl)oxy)ethyl)piperidine-3-carboxylic acid (388a)

  ) = 172.6(C-3), 167.3 (C-13), 167.0(C-14), 121.7(C-8), 62.0(C-15, C-16), 61.2 (C-2), 54.6(C-12), 44.6 (C-7), 40.6 (C-9), 39.5(C-6), 38.3 (C-4), 33.0(C-5), 18.2 (C-10), 14.2 (C-1), 14.1(C- 17, C-18), 13.9 (C-11). For the second diastereomer, dia-2, (1R,4S)-cis-332c: δ (ppm) = 172.2 (C-3), 167.8(C-13), 167.1(C-14), 121.2 (C-8), 62.3(C-15), 61.9 (C-16), 61.3 in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2970 (-C-H), 2875 (-C-H), 2231 (C≡N), 1734 (br, 3-C=O, 13-C=O, 14-C=O),1466, 1372, 1301, 1245, 1181, 1032, 860. HRMS (TOF, ES+): calculated for C18H27NO6Na [M+Na] + 376.17306, found 376.17224. (5R)-ethyl 5-(3-ethoxy-3-oxopropyl)-2-oxo-5-propylpiperidine-3-carboxylate (380b)

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3219 (br, OH), 2957 (-C-H), 2872 (-C-H), 1716 (12-C=O, 13-C=O), 1635 (5-C=O), 1468, 1410, 1288, 807. HRMS (TOF, ES+): calculated for C12H19NO5Na [M+Na] + 280.11554, found 280.11507. (R)-5-(3-hydroxypropyl)-5-propylpiperidin-2-one (390b)

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2956 (-C-H), 2872 (-C-H), 1655(5-C=O), 1469, 1350, 1173, 1102, 974, 829, 528. HRMS (TOF, ES+): calculated for C12H23NO4SNa [M+Na] + 300.12400, found 300.12296.[α]D 25 = +3.70 (c = 0.18, CHCl3).

13 C

 13 NMR (150 MHz, CDCl3): δ (ppm) = 184.7(C-5), 57.6 (C-1), 51.0(C-11), 43.6 (C-6), 36.9(C- 2), 36.6 (C-9), 33.6 (C-4), 30.0 (C-3), 21.6 (C-10), 16.7 (C-7), 14.9(C-8).IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2954 (-C-H), 2932 (-C-H), 1682(5-C=O), 1458, 1377, 1127, 965, 744. HRMS (TOF, ES+): calculated for C11H19NONa [M+Na] + 204.13589, found 204.13572.[α]D 25 = +15.3 (c = 0.06, CHCl3).

13 C

 13 NMR (75 MHz, CDCl3): δ (ppm) = 94.6 (C-3), 69.4 (C-2), 19.4 (C-4), 14.0 (C-1, C-5). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2956 (-C-H), 2929 (-C-H), 2866 (-C-H), 2306 (C≡C). HRMS (TOF, ES+): not detected.

13 C

 13 NMR (150 MHz, DMSO-d6): δ (ppm) = 169.2 (C-4), 153.3 (C-1), 121.0 (C-10), 63.0 (C-2), 58.1 (C-8), 42.4 (C-3), 41.2 (C-9), 37.4 (C-5), 35.7 (C-7), 31.7 (C-6), 24.3 (C-11), 9.0 (C-12). IR (KBr pellet): ν max (cm -1 ) = 2991 (-C-H), 2977 (-C-H), 2244 (C≡N), 1787 (4-C=O), 1684 (1-C=O),

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2974 (-C-H), 2939 (-C-H), 2234 (C≡N), 1724 (3-C=O), 1461, 1317, 1278, 1240, 1153, 735. HRMS (TOF, ES+): calculated for C10H13NO2Na [M+Na] + 202.08385, found 202.08332. [α]D 25 = +5.98 (c = 0.08, CHCl3).

  δ (ppm) = 172.2(C-3), 167.8 (C-12), 167.1(C-13), 121.0 (C-8), 62.2(C-14), 61.9(C-15), 61.3(C- 2), 51.8 (C-11), 42.9 (C-7), 39.0(C-6), 36.8 (C-4), 32.5(C-5), 31.7 (C-9), 14.1(C-1, C-16, C-17), 9.1 (C-10).

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2981 (-C-H), 2940 (-C-H), 2232 (C≡N), 1738 (br, 3-C=O, 12-C=O, 13-C=O),1464, 1373, 1308, 1253, 1237, 1187, 1037, 862. HRMS (TOF, ES+): calculated for C17H26NO6 [M+H] + 340.17546, found 340.17429.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2970 (-C-H), 2939 (-C-H), 2878 (-C-H), 1734 (11-C=O, 14-C=O), 1674(5-C=O), 1465, 1372, 1302, 1276, 1182, 1034, 861, 737. HRMS (TOF, ES+): calculated for C15H25NO5Na [M+Na] + 322.16249, found 322.16092. diethyl 2-((1S,2R)-2-(aminomethyl)-4-(ethoxycarbonyl)-2-ethylcyclobutyl)malonate (379c)

1 H

 1 NMR (300 MHz, CDCl3): δ (ppm) = 5.65 (br s, 1H, H-6),3.65 (br s, 2H, H-11), 3.05 (d, J = 2.6 Hz, 2H, H-1), 2.35 (t, J = 7.0 Hz, 2H, H-4), 1.64 (t, J = 7.0 Hz, 2H, H-3),1.54-1.29 (m, 6H, H-7in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3309 (br, OH), 2938 (-C-H), 2871 (-C-H), 1654(5-C=O), 1496, 1464, 1410, 1308, 1061, 732. HRMS (TOF, ES+): calculated for C10H19NO2Na [M+Na] + 208.13080, found 208.12978. [α]D 25 = +7.73 (c = 0.11, CHCl3). Rf = 0 (UV inactive; KMnO4, stains yellow, drags on TLC). 1 H NMR (300 MHz, CDCl3): δ (ppm) = 7.73 (br s, 1H, H-6), 3.05 (s, 2H, H-1), 2.41-2.18 (m, 4H, H-4, H-10), 1.73-1.60 (m, 4H, H-3, H-9), 1.45-1.31 (m, 2H, H-7), 0.85 (t, J = 7.4 Hz, 3H, H-8). 13 C NMR (75 MHz, CDCl3): δ (ppm) = 178.1 (C-11), 174.4 (C-5), 50.7 (C-1), 33.5 (C-2), 29.2 (C-9), 28.5 (C-3), 28.4 (C-4), 27.4 (C-10), 26.9 (C-7), 7.5 (C-8). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3277 (br, OH), 2938 (-C-H), 2878 (-C-H), 1712 (11-C=O), 1638 (5-C=O), 1496, 1231, 807. HRMS (TOF, ES+): calculated for C10H17NO3Na [M+Na] + 222.11006, found 222.10980. [α]D 25 = +7.16 (c = 0.26, CHCl3) crude value. hept, J = 7.2 Hz, 2H, H-7), 0.81 (t, J = 7.5 Hz, 3H, H-8). 13 C NMR (75 MHz, CDCl3): δ (ppm) = 173.9 (C-5, C-11), 51.8 (C-12), 50.7 (C-1), 33.6 (C-2), 29.6 (C-9), 28.8 (C-3), 28.3 (C-4, C-10), 26.5 (C-7), 7.4 (C-8). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2947 (-C-H), 2877 (-C-H), 1736 (11-C=O), 1663

1 H

 1 NMR (600 MHz, CDCl3): δ (ppm) = 8.00(d, J = 9.2 Hz, 1H, H-14), 7.25 (d, J = 2.5 Hz, 1H, H- 13), 7.13 (dd, J = 9.3, 2.5 Hz, 1H, H-10), 3.92 (s, 3H, H-11), 3.77 (d, J = 14.0 Hz, 1H, H-8a), 3.19 (td, J = 12.9, 3.4 Hz, 1H, H-8b), 3.07 (d, J = 13.3 Hz, 1H, H-5a), 2.91 (d, J = 13.3 Hz, 1H, H-5b), 2.80 (d, J = 18.0 Hz, 1H, H-3a), 2.70 (d, J = 18.1 Hz, 1H, H-3b), 1.80 (d, J = 12.8 Hz, 1H, H-6a), 1.60-1.55 (m, 1H, H-6b), 1.40 (q, J = 7.6 Hz, 2H, H-17), 1.37-1.29 (m, 2H, H-7), 1.00 (t, J = 7.5 Hz, 3H, H-18).13 C NMR (150 MHz, CDCl3): δ (ppm) = 162.2 (C-1), 160.8(C-9), 148.1(C-12), 135.9(C-16), 127.3 (C-14), 125.7 (C-15), 121.0 (C-2), 119.0 (C-10), 106.5(C-13), 57.7(C-5), 56.0(C-8), 55.7

13 C

 13 NMR (150 MHz, CD3OD): δ (ppm) = 162.7 (C-1), 160.2 (C-12), 152.0 (C-9), 143.7 in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3413 (br, OH), 3267 (br, OH), 3064, 2931 (-C-H), 2853 (-C-H), 1627, 1578, 1453, 1368, 1251, 1234, 1166. HRMS (TOF, ES+): calculated for C19H23N2O [M+H] + 295.18049, found 295.18018. [α]D 25 = +72.16 (c = 0.53, MeOH).

Figure S.23. 1 H

 1 Figure S.23. 1 H NMR spectrum of (+)-eucophylline in CD3OD, 600 MHz.

Figure

  Figure S.24.13 C NMR spectrum of (+)-eucophylline in CD3OD, 600 MHz.

Figure S. 25 .

 25 Figure S.25. HPLC trace of racemic compound 117h, synthesized according to the general procedure (D)method B in chapter III. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 90/10, 1 mL/min, 20 °C.

Figure S. 26 .

 26 Figure S.26. HPLC trace of chiral compound 117h. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 90/10, 1 mL/min, 20 °C.

Figure S. 27 .

 27 Figure S.27. HPLC trace of racemic compound 20. 48 Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 90/10, 1 mL/min, 20 °C.

Figure S. 28 .

 28 Figure S.28. HPLC trace of chiral compound 20. Analytical Chiralpak ® IA column (4.6 mmΦ x 250 mmL, particle size 5 µm), n-hexane/ethanol: 90/10, 1 mL/min, 20 °C.

Figure S. 29 .

 29 Figure S.29. HPLC trace of racemic eucophylline. 48 Analytical Phenomenex ® column (Lux 5 µm Cellulose-3, 4.6 mmΦ x 250 mmL), pure H2O/CH3CN: 75/25, 1 mL/min, 20 °C.

Figure S. 30 .

 30 Figure S.30. HPLC trace of chiral (+)-eucophylline. Analytical Phenomenex ® column (Lux 5 µm Cellulose-3, 4.6 mmΦ x 250 mmL), pure H2O/CH3CN: 75/25, 1 mL/min, 20 °C.

  are in agreement with those reported in the literature. 444 ethyl 2-(1-benzyl-3-ethyl-2-oxopiperidin-3-yl)acetate (504a)

1 H

 1 NMR (300 MHz, CDCl3): δ (ppm) = 7.34-7.22(m, 5H, H-Ph), 4.79 (d, J = 14.7 Hz, 1H, H-12a), 4.41 (d, J = 14.7 Hz, 1H, H-12b), 4.16-4.06 (m, 2H, H-10), 3.35-3.26 (m, 1H, H-5a), 3.21-3.13 (m, 1H, H-5b), 2.99 (d, J = 16.1 Hz, 1H, H-8a), 2.35 (d, J = 16.1 Hz, 1H, H-8b), 2.09-1.93 (m, 1H, H-6a), 1.90-1.63 (m, 5H, H-3, H-4, H-6b), 1.23 (t, J = 7.1 Hz, 3H, H-11), 0.91 (t, J = 7.5 Hz, 3H, H-7). in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2965 (-C-H), 2939 (-C-H), 1732 (9-C=O), 1636(1-C=O), 1454, 1185, 1033, 701. HRMS (TOF, ES+): calculated for C18H25NO3Na [M+Na] + 326.17266, found 326.17237.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3349 (br, OH), 2932 (-C-H), 1453, 1043, 741, 698. HRMS (TOF, ES+): calculated for C16H26NO [M+H] + 248.20089, found 248.20065.

1 H

 1 NMR (300 MHz, CDCl3): δ (ppm) = 4.07 (br s, 1H, NH),3.80-3.54 (m, 2H, H-9), 2.98 (dt, J = 11.4, 4.3 Hz, 1H, H-5a), 2.83 (d, J = 11.9 Hz, 1H, H-1a), 2.54 (td, J = 11.2, 3.2 Hz, 1H, H-5b), 2.37 (d, J = 11.9 Hz, 1H, H-1b), 1.81-1.64 (m, 2H, H-4a, H-8a), 1.60-1.46 (m, 3H, H-3a, H-4b, H-8b),1.29-1.19 (m, 3H, H-3b, H-6), 0.79 (t, J = 7.5 Hz, 3H, H-7).13 C NMR (75 MHz, CDCl3): δ (ppm) = 59.1(C-9), 55.6 (C-1), 46.6(C-5), 39.3 (C-8), 35.2 (C-2), 34.1(C-3), 33.9(C-6), 22.7 (C-4), 7.5(C-7).IR (solution inCH2Cl2, thin film, KBr): ν max (cm -1 ) = 3311 (br, OH), 2931 (-C-H), 2855 (-C-H), 1466, 1422, 1279, 1048. HRMS (TOF, ES+): calculated for C9H20NO [M+H] + 158.15394, found 158.15388.

  peak is observed in this place (baseline). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3262 (br, OH), 2925 (-C-H), 2853 (-C-H), 1457, 740. HRMS (TOF, ES+): calculated for C19H29N2O [M+H] + 301.22854, found 301.22711.

  22.7 (C-4), 22.2 (C-11), 7.6 (C-7). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3395 (br, OH), 2933 (-C-H), 1730 (20-C=O),1453, 1373, 1256, 1158, 1086, 746. HRMS (TOF, ES+): calculated for C24H37N2O3 [M+H] + 401.27987, found 401.27978.

  Rf = 0.72 (UV inactive; KMnO4, stains brown). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2924 (-C-H), 2853 (-C-H), 1731 (9-C=O), 1563, 1462, 1357, 1183. HRMS (TOF, ES+): calculated for C11H19NO2SNa [M+Na] + 252.10287, found 252.10293. (R)-ethyl 2-(3-ethylpiperidin-3-yl)acetate (517a)

  CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2923 (-C-H), 2853 (-C-H), 1732 (9-C=O), 1467, 1258, 1044, 762. HRMS (TOF, ES+): calculated for C11H22NO2 [M+H] + 200.16451, found 200.16447.

1 H

 1 NMR (400 MHz, CDCl3): δ (ppm) = 8.13 (s, 1H, NH), 7.62-7.58 (m, 1H, H-18), 7.36 (dt, J = 8.1, 1.0 Hz, 1H, H-15), 7.19 (dtd, J = 8.1, 7.0, 1.3 Hz, 1H, H-13), 7.11 (dtd, J = 8.0, 7.0, 1.1 Hz, 1H, H-16), 7.00 (d, J = 2.2 Hz, 1H, H-17), 5.09 (s, 1H, H-13),3.25-3.13 (m, 1H, H-10a), 3.11-2.94 (m, 3H, H-10b, H-11), 2.87-2.73 (m, 2H, H-5), 2.38 (d, J = 16.5 Hz, 1H, H-8a), 2.20 (d, J = 16.5 Hz, 1H, H-8b), 1

13 C

 13 NMR (100 MHz, CDCl3): δ (ppm) = 175.9(C-9), 136.3 (C-14), 127.6 (C-19), 122.0 (C-13), 121.7 (C-16), 119.3 (C-17), 118.8 (C-18), 113.9(C-12), 111.2 (C-15), 102.8 (C-1), 56.0 (C-10), 44.3 (C-5), 43.4 (C-2), 41.7 (C-8), 27.7 (C-3), 26.3 (C-6), 23.7 (C-11), 20.8 (C-4), 9.0 (C-7). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2926 (-C-H), 2849 (-C-H), 1742 (9-C=O), 1456, 1180, 1028, 720. HRMS (TOF, ES+): calculated for C19H25N2O2 [M+H] + 313.19105, found 313.19041.

  Rf = 0.57 (UV active; KMnO4, stains yellow). m. p. = 122.1-125.5 °C (CH2Cl2).

13 C

 13 NMR (100 MHz, CDCl3): δ (ppm) = 167.7(C-9), 135.2(C-14), 130.0(C-13), 130.0(C-19), 124.2 (C-16), 124.0(C-17), 118.2 (C-18), 116.3 (C-15), 113.1(C-12), 66.1 (C-1), 55.5 (C-10), 52.5(C-5), 44.4 (C-8), 39.6 (C-2), 31.9 (C-3), 21.6(C-6), 21.3 (C-4), 20.8 (C-11), 7.5(C-7). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2930 (-C-H), 2858 (-C-H), 1699(9-C=O), 1453, 1373, 1331, 1173, 751. HRMS (TOF, ES+): calculated for C19H23N2O [M+H] + 295.18049, found 295.17976.

  in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3327 (br, OH), 2929 (-C-H), 2853 (-C-H), 1456, 1320, 1061, 739. HRMS (TOF, ES+): calculated for C19H23N2O [M-H] + 295.18159, found 295.18150. calculated for C19H25N2O [M+H] + 297.19614, found 297.19544.

  XIV. Approche au couplage biomimétique et à la synthèse d'un modèle avancé de la leucophyllidine.

	DMAP Lindlar TEMPO	4-dimethylaminopyridine 5% Pd-CaCO3 + quinoline 2,2,6,6-tetramethylpiperidine-N-oxy radical
	DME LiTMP Tf	dimethoxyethane lithium tetramethylpiperidide triflate group
	DMF LRMS TFA	dimethylformamide Low Resolution Mass Spectrometry trifluoroacetic acid
	DMP LUMO TFAA	Dess-Martin periodinane Lowest Unoccupied Molecular Orbital trifluoroacetic anhydride
	DMPU m Tf2O	N,N'-dimethylpropyleneurea meta position triflic anhydride
	DMSO M THF	dimethylsulfoxide concentration (mole per liter) tetrahydrofuran
	dr TIPS M	diastereomeric ratio undefined metal triisopropylsilyl group
	DTBHN MHz TIPSCl	di-tert-butylhyponitrite megahertz triisopropylsilyl chloride
	ε TLC mmHg	molar extinction coefficient millimeter of mercury Thin Layer Chromatography
	E TMP mmol	undefined electrophile millimole 2,2,6,6-tetramethylpiperidine
	€ TMS mol	euro currency mole trimethylsilyl group
	E 0 TMSCHN2 mol %	standard reduction potential molar percentage (trimethylsilyl)diazomethane
	Eox m. p. TMSCl	oxidation potential melting point trimethylsilyl chloride
	Ered Ms TMSCN	reduction potential mesylate group trimethylsilyl cyanide
	EDCI MS TOF	1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride molecular sieves time-of-flight
	EDG MsCl p-Tol	Electron Donating Group methanesulfonyl chloride para-tolyl group
	EDTA MW TPAP	ethylenediaminetetraacetic acid molecular weight tetrapropylammonium perruthenate
	ee Ts ν	enantiomeric excess wavenumber tosyl group
	Eq. n TTMS	equation molar number tris(trimethylsilyl)silane
	eq. NaAsc UV	equivalent sodium L-ascorbate ultraviolet irradiation
	er UV-A NCS	enantiomeric ratio N-chlorosuccinimide electromagnetic spectral range between 325 and 400 nm
	ESI nd V-40	ElectroSpray Ionization not determined 1,1'-azobis(cyclohexanecarbonitrile)
	Et W-hυ nm	ethyl group nanometer (10 -9 meter) irradiation with a tungsten lamp
	eV NMO wt. %	electron volt N-methylmorpholine N-oxide weight percent
	EWG nOe X	Electron Withdrawing Group Nuclear Overhauser Effect undefined halogen
	F	NOESY	Faraday constant Nuclear Overhauser Effect SpectroscopY
	fac-Ir nr	facial-Iridium no reaction
	FD ns	Field Desorption nanosecond
	FI	Ns	Field Ionization nosyl group
	FID Nu	Flame Ionization Detector undefined nucleophile
	γ	o	gamma ortho position
	GC-MS [O]	Gas Chromatography-Mass Spectrometry oxidation
	[H] ORTEP	reduction Oak Ridge Thermal Ellipsoid Plot Program
	HAT p	Hydrogen Atom Transfer para position
	HFIP PC	1,1,1,3,3,3-hexafluoroisopropanol photocatalyst
	Hg-hυ [Pd]	irradiation with a mercury lamp palladium
	HMPA PDC	hexamethylphosphoramide pyridinium dichromate
	HOMO PE	Highest Occupied Molecular Orbital petroleum ether
	HPLC PET	High-Performance Liquid Chromatography Photoinduced Electron Transfer
	HRMS PG	High Resolution Mass Spectrometry protecting group
	HSQC Ph	Heteronuclear Single Quantum Coherence phenyl group
	hυ pH	photochemical activation potential of Hydrogen
	Hz PIDA	Hertz (diacetoxyiodo)benzene
	IBX PIFA	2-iodoxybenzoic acid (bis(trifluoroacetoxy)iodo)benzene
	IC50 pKa	half maximal inhibitory concentration -log10 (Ka), the negative logarithm, to the base 10, of the acid dissociation constant (Ka)
	IR PPA	Infrared Spectroscopy polyphosphoric acid
	J	ppm	coupling constant parts per million
	J	quant.	Joule quantitative
	k	R, Rn, R'	rate constant undefined alkyl group
	kcal Ra-Ni	kilocalorie Raney ® -nickel
	KHMDS Rf	potassium bis(trimethylsilyl)amide retention factor
	kJ rt	kilojoule room temperature (20-25 °C)
	λ	sat.	lambda/wavelength saturated
	L *	SN2	Undefined chiral ligand bimolecular nucleophilic substitution
	LA SOMO	Lewis acid Singly Occupied Molecular Orbital
	LAH t/tert	lithium aluminium hydride tertio
	LDA TBAF	lithium diisopropylamide tetrabutylammonium fluoride
	LED TBDMS/TBS	Light-Emitting Diode tert-butyldimethylsilyl group
	LiHMDS TBDMSCl/TBSCl tert-butyldimethylsilyl chloride lithium bis(trimethylsilyl)amide

  .1). the rate constants are similar except in the case of the highly stabilized benzyl

	radical. 77
	X	k (s -1 )	Y	k (s -1 )
	H	7 x 10 7	H	7 x 10 7
	Me	4 x 10 7	Me	1 x 10 8
	OMe	2 x 10 7	OMe	1 x 10 9
	CO2Et	2 x 10 8	CO2Me	7 x 10 10
	Ph	6 x 10 4	Ph	1.5 x 10 11

Table I . 1 .

 I1 Rate constants for the cyclopropylcarbinyl radical fragmentation.77

Table II . 1 .

 II1 Comparison of selected properties of cycloalkanes.

  .3). Cyclopropane and cyclobutane have similar strain energy (27.5 kcal/mol for cyclopropane vs. 26.3 kcal/mol for cyclobutane) with only 1.2 kcal/mol of difference. This appears hard to rationalize considering the significantly reduced C-C-C bond angles and their difference in hybridization. Dunitz and Shomaker proposed that the C-C transannular interactions absent in cyclopropane and present in cyclobutane are the reason behind this observation and contributesignificantly to the structure's strain energy.147,150

	compound	ΔHf	strain energy
	cyclopropane	12.7 ± 0.1	27.5
	cyclobutane	6.6 ± 0.3	26.3
	cyclopentane	-18.3 ± 0.2	6.3
	cyclohexane	-29.5 ± 0.2	0.0

Table

II

.3. Heats of formation and strain energy of some cycloalkanes, gas phase, 25 °C, kcal/mol.

145

R)-115. 198 Figure III.1.

  Comparison of the optical rotation of the ligand R-enantiomer reported byNarasaka et al., 198 and the S-enantiomer synthesized for this study.With both enantiomers in hand, the racemic cyclobutenes were re-synthesized using a mixture of 50% of the (R)-and 50% of the (S)-ligands (details are in the experimental part). This protocol afforded the racemic samples in 35-65% yields in the expected range of time (12-48 h). The optical purity of the cyclobutenes was then determined by chiral HPLC (an analytical Chiralpak

	the results. While the NMR spectra of the isolated products were clean, the HPLC profiles were
	complicated, and the separation of the enantiomers was not acceptable. To avoid these limitations,
	the ligand's enantiomer (S)-115 was synthesized from (-)-dimethyl D-tartrate by the same strategy as
	for (R)-115 (Figure III.1). Values of the optical rotation were relatively close ([α]D 25 = -77° (c = 0.53,
	CHCl3) for (S)-115) versus lit. 198 ([α]D 23 = +83° (c = 1.3, CHCl3) for (R)-115). All other analytical
	data were in agreement with those reported for the ligand (
	1,4-diol ligand
	115. Under such conditions, the cyclobutenes were obtained in very low yields (8-20%) after 4 to 7
	days (data not shown). Increasing the quantity of titanium catalyst 116 to 1 equivalent did not improve

® IA column was employed). In this case, both enantiomers were successfully separated showing a more reliable HPLC trace (Figure III.2, HPLC profiles without ligands versus with ligands).

# tR (min) area (%) height (%) # tR (min) area (%) height (%)

	1	9.880	49.872	58.548	1	9.880	46.259	56.003
	2	13.593	50.128	41.452	2	13.822	53.741	43.997

  Ramseier et al., 216 and

	Nebe et al., 217 suggesting that traces amount of acid (e.g., HBr) quenches the triplet state of the
	aromatic carbonyl sensitizers by protonation, inhibiting the process. The reactivity of benzophenone
	studied by Inoue et al. 218 was also tested. In the presence of 4 equivalents of 2,6-di-tert-butylpyridine,
	the expected product 180c was obtained in a moderate yield of 36% (entry 6), whereas, in the absence
	of base, no reaction occurred (entry 7).
	entry	catalyst (eq.)	additives (eq.)	solvent	180b	yield (%) 180c
	1 a	[Ir] (0.02)	LiBr (2.0), NaAsc (2.0)	DMF/H2O	73	53, brsm (69)
	2 b	(Bu3Sn)2 (0.5)	DTBHN (0.5)	PhH	46	29, brsm (8)
	3 c	p-anisald. (0.2)	2,6-lutidine (2.0)	CH3CN	/	69
	4 c	p-anisald. (0.2)	2,6-lutidine (1.0)	CH3CN	/	33, brsm (66)
	5 c	p-anisald. (0.2)	-	CH3CN	0	0
	6 c	benzoph. (0.5)	2,6-di-tert-butylpyridine (4.0)	CH3CN	/	36
	7 c	benzoph. (0.5)	-	CH3CN	/	0
	Table III.4. Radical additions of dialkyl bromomalonates onto cyclobutene. [Ir] = [Ir(ppy)2(dtbbpy)]PF6.
	Reagents and conditions: malonate (2.0 eq.), solvent (0.1 M), DMF/H2O: 4/1, 24 h. a blue LEDs. b 65 °C. c
			UV-A. dr calculated by 1 H and 13 C NMR.

). entry PC a R1 product hυ (nm) b solvent yield (%) c

	1	eosin-Y	Et	181a	513	DMF	48
	2	eosin-Y	Me	181b	513	DMF	48
	3	p-anisal.	Me	181b	325-400	CD3CN	80
	4	-	Me	181b	325-400	CD3CN	41
	5	BP	Me	181b	325-400	CD3CN	60
	6	p-anisal.	p-Tol	181j	325-400	CD3CN	50
	7	-	p-Tol	181j	325-400	CD3CN	7
	8	p-anisal.	Me	181b	254	CD3CN	-d,e
	9	-	Me	181b	254	CD3CN	-d,e
	10 f	p-anisal.	Me	181b	334	CD3CN	8
	11 g	-	Me	181b	334	CD3CN	5
	12	p-anisal.	Me	181b	419	CD3CN	26
	13	-	Me	181b	419	CD3CN	17
	14 h	p-anisal.	Me	181b	344	CD3CN	0
	15 h	-	Me	181b	344	CD3CN	0
	Table III.6. Conditions screening of the photocatalyzed sulfonyl-cyanation. Photocatalysts (PC): Eosin-Y (2
	mol %); p-anisal.: p-anisaldehyde (20 mol %); BP: benzophenone (20 mol %), 30 °C, 24 h. a R1SO2CN (2.0
	eq.). b Green LEDs (513 nm); UV-A (325-400 nm); UV-C (254 nm). c NMR yield. d Reaction performed in a
	quartz cell (1 cm).

e Complex mixture. f 5.5 h of irradiation. g 19 h of irradiation. h 9 h of irradiation.

  .7).

	entry	PC	yield (%) a
	1	p-anisal.	> 95
	2	-	25
	Table III.7. Sulfonyl-cyanation of oct-1-ene. Reagents and conditions: i) MeSO2CN (2.0 eq.),
	CD3CN (0.2 M), 325-400 nm, 30 °C, 20 h.

a NMR yield.

1.2.4.2.1.6 Calculation of the free energy of photo-induced electron transfer Evaluation of the photo-induced electron transfer process

	At first, the redox potentials of the sulfonyl cyanides were estimated through cyclic voltammetry
	(Table III.9): 5

substrate Ered a (V vs SCE)

	EtSO2CN	-1.72
	MeSO2CN	-1.88
	p-TsCN	-1.34

Table III .9. Reduction

 III potentials of the sulfonyl cyanides used in the control reactions. a Experiments were carried out at 25±0.5 °C using a glassy carbon working electrode, a Pt-wire counter-electrode, and Ag as a pseudo-reference electrode.

  281,282 Both cases afforded the expected product in high yields and excellent enantioselectivity. The Intramolecular hydrolytic cyclization of nitrile 247 in refluxing KOH went smoothly to construct O1-C2 bond in lactone 248 in 76% yield, via a δ-hydroxy acid (Scheme III.38.B).

283

Scheme III.38. Synthesis of δ-lactones from δ-hydroxy nitriles under thermal basic conditions.

Table III .

 III 13. Lactone reduction into lactol. Reagents and conditions: CH2Cl2 (0.2 M), -78 to 0 °C.

Table III

 III

.14. Conditions screening for the Ramberg-Bäcklund reaction. [X] = halogen source. Reagents and conditions: base (22.0 eq.), KOH/Al 2 O 3 (250 mg/0.1 mmol of substrate), CF2Br2 (10.0+10.0 eq.), C2Cl6 (5.0 eq.), solvent: 1/1, 12 h.

Table III .15.

 III

Table III

 III

.16. Base screening for sulfone elimination.

Table III

 III

.18. Attempts for ozonolysis on cyclobutene alcohol 273.

   developed a strategy to open the cyclobutanol rings using hypervalent iodine reagents as oxidant. Cyclobutanols 302 underwent regioselective oxidative cleavage in the presence of PIDA, to give access to a range of γ-hydroxy ketones 305 in excellent yields (Scheme III.58).

	Scheme III.58. PIDA-mediated oxidative cleavage of cyclobutanols. 334

Under suitable conditions, these frameworks can undergo ring cleavage, ring expansion, or functional transformation. One of the first examples of hydroxy-cyclobutane ringopening was reported by De Mayo and co-workers (Scheme III.57). 333 The addition of enolized 1,3diketones 299 onto alkenes 298 by [2+2] photo-cycloaddition, afforded acyl-cyclobutanol 300. The De Mayo product underwent then a spontaneous retro-aldol cyclobutane cleavage to afford the diketone 301. Scheme III.57. De Mayo reaction and spontaneous ring-opening of cyclobutane. 333

Interestingly,

  CNMR spectra of the crude reaction mixture were particularly complex. The absence of typical double bond signals indicates that the decarboxylation/fragmentation did not occur. The addition of a base such as DBU or Et3N did not afford better results.

	Scheme III.70. Attempts for decarboxylation and ring-opening of 330a. Reagents and conditions: i) 10%
	Pd/C, H2 (1 atm), EtOH, 20 °C, 23 h; ii) toluene or DMF, 120 °C.

  .22, entry 1), whereas a strong base such as LDA, gave a complex mixture of products (entry 2). With potassium carbonate in DMF at 70 °C, an unsaturated nitrile 338 was isolated in 14% yield (entry 3).

	entry	base	conditions	yield (%)
	1	DBU	CH2Cl2, 20 °C, 21 h	0
	2	LDA	THF, -78 to 20 °C, 24 h	comp. mix.
	3	K2CO3	DMF, 70 °C, 23 h	338 (14)

Table III

 III

.22. Base-mediated ring-opening of 332a. Reagents and conditions: base (2.0 eq.), solvent (0.1 M).

Table IV . 2 .

 IV2 Reduction of 389a into alcohol. Reagents and conditions: solvent (0.02 M), 0 to 20 °C.

	entry	reagent (eq.)	solvent	time (h) yield (%)
	1	BH3.THF (3.0)	THF	13	traces
	2 a	BH3.THF (3.0)	THF	18	traces
	3	LAH (1.25)	THF	12	31
	4	LAH (1.25)	Et2O	12	21

a 35 °C.

  ).

	entry solvent (0.05 M)	conditions	yield (%)
	1	DMF	20 °C, 7 h	0
	2	DMF	40 °C, 12 h	10
	3	DMF	70 °C, 19 h	6
	4	THF	20 °C, 10 h	0
	5	THF	66 °C, 16 h	comp. mix.

Table IV . 3

 IV3

. Synthesis of bicyclic lactam model 341a.

Table IV .

 IV

3.

Reduction of cyclobutane 332c using nickel boride. Reagents and conditions: i) NiCl2 (2.2 eq.), NaBH4 (20.0 eq.), EtOH, 0 to 20 °C.

  Contrary to what was observed with lactam 341a, no major decomposition of the substrate took place in refluxing THF.

	entry solvent (0.05 M)	conditions	yield (%)
	1	DMF	20 °C for 24 h, then 70 °C for 10 h	15
	2	DMF	70 °C, 14 h	40
	3	THF	20 °C, 16 h	0
	4	THF	66 °C, 10 h	0

Table IV.4. Synthesis of bicyclic lactam 341b bearing a propyl chain.

  was then suggested to perform the Friedländer annulation in a two-steps sequence starting from the α-chloroenamine intermediate 405. Under neutral conditions, no reaction was observed after 24 h, and both starting materials remained intact (TableIV.6, entry 1). Changing the solvent to toluene, while heating at a higher temperature did not lead to the desired product either (entry 2). This result shows the difference in reactivity between the propenylaniline and the o-aminobenzoic nitrile previously used by Landais et al. This might be related to steric issues, or to the lack of reactivity of the aniline 396. Using the propenylaniline analog 396b under neutral conditions did not lead to the desired product; instead, a mixture of decomposed products was obtained, illustrating the high instability of 396b (entry 3). The addition of a base to promote the reaction also gave negative results (entry 4).

	entry	R	reagent	solvent a temp (°C)	yield
	1	H	-	CH2Cl2	60	0
	2	H	-	toluene	120	0
	3	OMe	-	CH2Cl2	60	comp. mix.
	4	H	[pyr.] (0.1 eq.)	CH2Cl2	60	0
		1	POCl3 (1.1)	CH2Cl2	60	405 (15)
		2	4 Å MS	toluene	120	0
		3	p-TsOH (0.6)	toluene	120	0

Table IV.5. Attempts for allyl amidine synthesis starting from bridged lactam 402. Reagents and conditions: 396a (1.5 eq.), 6-16 h. a Solvent (0.06 M). It Table IV.6. Attempts for allyl amidine synthesis starting from 405. Reagents and conditions: 396 (1.5 eq.), 24 h. a Solvent (0.05 M). [pyr.] = 2,6-di-tert-butyl pyridine.

Table IV .

 IV 7. Conditions screening for the preparation of diazonium salt.

proton number natural (+)-eucophylline 2 1 H NMR, 700 MHz, CD3OD 1 H [δ, multiplet, J (Hz)] this work, synthetic (+)-eucophylline 1 H NMR, 600 MHz, CD3OD 1 H [δ, multiplet, J (Hz)]

				Δδ
	3a	2.76 (m)	2.85 (d, J = 17.7 Hz)	+0.09
	3b	2.60 (m)	2.70 (d, J = 17.7 Hz)	+0.1
	5a	3.10 (d, J =13.1 Hz)	3.19 (dd, J = 13.2, 1.9 Hz)	+0.09
	5b	2.90 (d, J =13.1 Hz)	3.00 (d, J = 13.1 Hz)	+0.1
	6a	1.78 (m)	1.82 (d, J = 11.5 Hz)	+0.04
	6b	1.59 (m)	1.68 (td, J = 13.2, 4.9 Hz)	+0.09
	7	1.32 (m)	1.43-1.36 (m)	+0.07
	8a	3.65 (dd, J =5.5, 5.5 Hz)	3.71 (dd, J = 13.7, 3.5 Hz)	+0.06
	8b	3.16 (m)	3.42 (td, J = 13.2, 3.7 Hz)	+0.26
	10	7.15 (d, J = 2.3 Hz)	7.18 (d, J = 2.4 Hz)	+0.03
	11	not seen*	not seen*	-
	13	7.00 (d, J =9.0 Hz)	7.22 (dd, J = 9.2, 2.4 Hz)	+0.22
	14	7.95 (d, J = 9.0 Hz)	8.13 (d, J = 9.2 Hz)	+0.18
	17	1.38 (q, J = 7.5 Hz)	1.45 (q, J = 7.5 Hz)	+0.07
	18	0.96 (t, J = 7.5 Hz)	1.00 (t, J = 7.6 Hz)	+0.04
	19	6.95 (dd, J = 17.9, 11.7 Hz)	7.03 (dd, J = 17.9, 11.9 Hz)	+0.08
	20a	5.95 (dd, J = 11.7, 1.7 Hz)	6.07 (dd, J = 11.9, 1.4 Hz)	+0.12
	20b	5.55 (dd, J = 17.9, 1.7 Hz)	5.72 (dd, J = 17.9, 1.4 Hz)	+0.17

Table IV .

 IV 10. Comparison table of 1 H NMR data for natural and synthetic (+)-eucophylline.

*Signal disappears in CD3OD.

carbon number natural (+)-eucophylline 2 13 C NMR, 175 MHz, CD3OD 13 C [δ (ppm)] this work, synthetic (+)-eucophylline 13 C NMR, 150 MHz, CD3OD 13 C [δ (ppm)]

  Table IV.11. Comparison table of13 C NMR data for natural and synthetic (

				Δδ
	1	162.3	162.7	+0.4
	2	122.6	123.3	+0.7
	3	37.6	36.9	-0.7
	4	31.7	32.4	+0.7
	5	58.5	57.9	-0.6
	6	37.0	36.3	-0.7
	7	20.5	20.9	+0.4
	8	56.8	57.8	+1.0
	9	148.9	152.0	+3.1
	10	109.1	104.7	-4.4
	12	160.0	160.2	+0.2
	13	118.8	120.4	+1.6
	14	127.6	129.1	+1.5
	15	120.0	119.9	-0.1
	16	146.5	143.7	-2.8
	17	36.1	35.6	-0.5
	18	7.4	7.3	-0.1
	19	133.1	132.0	-1.1
	20	123.6	125.9	+2.3

+)-eucophylline. carbon number natural (+)-eucophylline 2 13 C NMR, 175 MHz, CD3OD 13 C [δ (ppm)] synthetic (+)-eucophylline 352 13 C NMR, 100 MHz, CD3OD 13 C [δ (ppm)]

				Δδ
	1	162.3	162.5	+0.2
	2	122.6	122.7	+0.1
	3	37.6	37.8	+0.2
	4	31.7	31.8	+0.1
	5	58.5	58.7	+0.2
	6	37.0	37.2	+0.2
	7	20.5	20.6	+0.1
	8	56.8	56.9	+0.1
	9	148.9	149.3	+0.4
		109.1	109.5	+0.4
		160.0	160.0	0
		118.8	118.9	+0.1
		127.6	127.7	+0.1
		120.0	120.2	+0.2
		146.5	146.4	-0.1
		36.1	36.2	+0.1
		7.4	7.5	+0.1
		133.1	133.3	+0.2
		123.6	123.6	0

Table IV .

 IV 12. Comparison table of13 C NMR data for natural and synthetic (+)-eucophylline(Pandey et al.).352

carbon number natural (+)-eucophylline 2 13 C NMR, 175 MHz, CD3OD 13 C [δ (ppm)] synthetic (±)-eucophylline 48 13 C NMR, 75 MHz, CD3OD 13 C [δ (ppm)]

				Δδ
		162.3	160.9	-1.4
		122.6	117.3	-5.3
		37.6	36.2	-1.4
		31.7	30.2	-1.5
		58.5	57.1	-1.4
		37.0	34.6	-2.4
		20.5	19.0	-1.5
		56.8	55.3	-1.5
		148.9	147.7	-1.2
	10	109.1	107.9	-1.2
	12	160.0	158.4	-1.6
	13	118.8	121.1	+2.3
	14	127.6	126.1	-1.5
	15	120.0	118.6	-1.4
	16	146.5	144.8	-1.7
	17	36.1	35.6	-0.5
	18	7.4	5.97	-1.43
	19	133.1	131.7	-1.4
	20	123.6	122.0	-1.6

Table IV .13. Comparison

 IV

table of

13

C NMR data for natural and synthetic (±)-eucophylline

(Landais et al.)

.

48 carbon number nor-ethyleucophylline 13 C NMR, 150 MHz, acetone-d6 13 C [δ (ppm)] with p-TSA Δδ

  Table IV.14. Comparison table of

	1	162.0	161.8	-0.2
	2	122.8	122.6	-0.2
	3	31.9	32.0	+0.1
	4	27.1	27.0	-0.1
	5	52.7	52.6	-0.1
	6	31.1	31.2	+0.1
	7	20.4	20.1	-0.3
	8	58.3	57.6	-0.7
	9	151.8	150.6	-1.2
	10	104.5	105.7	+1.2
	12	159.3	160.0	+0.7
	13	120.3	120.0	-0.3
	14	128.5	128.2	-0.3
	15	119.3	119.2	-0.1
	16	142.4	145.7	+3.3
	17	131.8	132.0	+0.2
	18	125.8	125.3	-0.5

  Stirring at -78 °C for 2 h, then addition of ethyl bromo/chloroacetate at -78 °C. B: Addition of 369 to LDA. Stirring at -78 °C for 2 h, then addition of ethyl bromoacetate at -78 °C. C: Addition of 369 to LDA. Stirring at -78 °C for 2 h, then at -30 °C for 1 h. Then, addition of ethyl bromoacetate at -78 °C.

	entry	R1	time (h)	method	yield (%)
	1	Boc	4	A	506 + 507
	2 a	Boc	16	A	506 + 507
	3	Boc	5	B	506 + 507
	4	Boc	9	C	508
	5	Bn	8	C	nd
	6	Bz	6	C	nr

Table V.1. Alkylation attempts following path A. Reagents and conditions: ethyl bromoacetate (1.2 eq.), LDA (1.2 eq.), THF (0.1 M), -78 to 20 °C. a Ethyl chloroacetate was used. A: Addition of LDA to 369.

Table V .

 V

5.

Screening of the oxidation conditions. Reagents and conditions: i) oxidant (1.1 eq.), solvent (0.05 M), Ru(bpy)3(PF6)2 (0.1 eq.), BI-OAc (2.5 eq.), 20-30 °C. a Blue LEDs.

Table V

 V

.8. Attempts for selective reduction of the amide functional group. Reagents and conditions: i) THF (0.1 M), 0 to 20 °C, 24 h.

Table V .9. Synthesis

 V

of thiolactam 518. LR = Lawesson's reagent. Reagents and conditions: i) toluene (0.05 M), 110 °C. a Benzene.

  strategy developed to access a new type of enantioselective cyclobutenes 169 opens the door towards new investigation areas. These carbocycles could be further studied in radical functionalization reactions to incorporate new types of radicals onto the C-C double bond (Scheme

VII.11). The obtained derivatives could be manipulated further to develop new ring-opening strategies and give enantioselective access to a library of functionalized all-carbon quaternary stereocenters. The cyclobutene carboxylate 258 could also be studied further by adding different nucleophiles to the enone's double bond. A new reaction could be then designed to deliver valuable synthons for the total synthesis of indole alkaloids.

Scheme VII.11. Further examination of cyclobutenes 169 and 258.

  The 1 H NMR data are in agreement with those reported in the literature.198

1 H NMR (300 MHz, CDCl3): δ (ppm) = 7.56-7.07 (m, 25H, H-Ph), 5.18 (d, J = 5.5 Hz, 1H, H-2), 5.10 (d, J = 5.5 Hz, 1H, H-3), 2.34 (s, 1H, H-5), 2.21 (s, 1H, H-4), 1.34 (s, 3H, H-1).

  2H, H-3),2.77 (ddt, J = 12.7, 4.9, 1.2 Hz, 1H, H-6a), 2.57-2.46 (m, 1H, H-6b), 2.24 (s, 3H, H- 14), 2.22-2.10 (m, 2H, H-9), 1.57-1.41 (m, 2H, H-10), 0.93 (t, J = 7.3 Hz, 3H, H-11).

	column chromatography on SiO2 (cyclohexane/EtOAc: 80/20 to 60/40 to 50/50) afforded the product
	(16.08 g, 83%, 98% ee) as a white solid.
	TLC (pentane/EtOAc: 50/50): Rf = 0.7 (UV active; vanillin, stains purple).
	m. p. = 59-63 °C (pentane/EtOAc).
	1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.78-4.69 (m, 1H, H-5), 4.49-4.37 (m, 2H, H-2), 4.11-3.99
	(m,

6 g, 127.8 mmol, 1.7 eq.) for 40 h. Purification through

  ppm) = 4.73 (dq, J = 5.1, 1.8 Hz, 1H, H-5), 4.43 (t, J = 8.1 Hz, 2H, H-2), 4.04 (td, J = 5.1, 1.8 Hz, 2H, H-3), 3.80 (t, J = 6.8 Hz, 2H, H-10), 2.84 (dd, J = 8.0, 4.0 Hz, 1H, H-6a), 2.56(d, J = 16.0 Hz, 1H, H-6b), 2.52-2.38 (m, 2H, H-9), 2.25 (s, 3H, H-20), 1.07-1.04 (m, 21H, H-11, H-12, H-13, H-14, H-15, H-16, H-17, H-18, H-19).

	chromatography on SiO2 (cyclohexane/EtOAc: 90/10 to 70/30 to 50/50) afforded the product (19.6
	g, 84%) as a pale-yellow oil.
	TLC (cyclohexane/EtOAc: 50/50): Rf = 0.63 (UV active; vanillin, stains brown).
	Purification through column

1 H NMR (400 MHz, CDCl3): δ (

TLC (cyclohexane/EtOAc: 50/50):

  Rf = 0.52 (UV active; vanillin, stains brown). m. p. = 51-52.4 °C (pentane/EtOAc). ppm) = 7.29-7.27(m, 2H, H-13, H-15), 7.20-7.17(m, 3H, H-12, H- 14, H-16), 4.71 (dq, J = 5.1, 1.7 Hz, 1H, H-5), 4.42 (t, J = 8.1 Hz, 2H, H-2), 4.04 (td, J = 5.1, 1.8 Hz, 2H, H-3), 2.83-2.74 (m, 3H, H-6a, H-10), 2.57-2.45 (m, 3H, H-6b, H-9), 2.16 (s, 3H, H-17).

1 H NMR (600 MHz, CDCl3): δ (

  , 2.81-2.73 (m, 1H, H-6a), 2.70-2.62 (m, 1H, H-6b), 2.08-1.98 (m, 2H, H-9),1.55-1.40 (m, 2H, H-10), 0.92 (t, J = 7.4 Hz, 3H, H-11).

1 H NMR (300 MHz, CDCl3): δ

  (ppm)= 3.04 (dd, J = 14.3, 7.5 Hz, 1H, H-7a), 2.98-2.87 (m, 2H, H- 3), 2.76 (dd, J = 14.4, 3.2 Hz, 1H, H-7b), 2.67 (t, J = 7.4 Hz, 2H, H-4), 2.18 (s, 3H, H-9), 2.05-1.89(m, 1H, H-6a), 1.81-1.65 (m, 1H, H-6b), 0.14 (s, 9H, H-TMS).

1 H NMR (300 MHz, CDCl3):

	δ (ppm) = 5.92-5.67 (m, 1.45H, H-20 major, H-20 minor), 5.19-4.95
	(m, 3H, H-21 major, H-21 minor), 4.46-4.28 (m, 3H, H-2 major, H-2 minor), 4.23-4.12 (m, 4.5H, H-
	15 major, H-15 minor, H-5 major, H-5 minor), 4.11-3.90 (m, 6H, H-3 major, H-3 minor, H-16 major,
	H-16 minor), 3.61 (d, J = 11.9 Hz, 1H, H-12 major), 3.56 (d, J = 11.9 Hz, 0.45H, H-12 minor), 3.32-
	3.23 (m, 1.5H, H-8 major, H-8 minor), 2.46-2.20 (m, 2H, H-19 major), 2.18-2.08 (m, 1H, H-19 minor),
	2.08-1.87 (m, 3H, H-6 major, H-6 minor), 1.56-1.30 (m, 6H, H-9 major, H-9 minor, H-10 major, H-
	10 minor), 1.28-1.17 (m, 9H, H-17 major, H-17 minor, H-18 major, H-18 minor), 0.97-0.82 (m, 4.5H,
	H-11 major, H-11 minor).

1 H NMR (300 MHz, CDCl3):

	δ (ppm) = 7.40-7.27 (m, 6.5H, H-Ph dia-1/dia-2), 4.62 (s, 2H, H-12
	dia-1), 4.60 (d, J = 6.7 Hz, 0.3H, H-12a), 4.48 (d, J = 8.1 Hz, 0.3H, H-12b), 4.26-4.06 (m, 2.6H, H-2
	dia-1/dia-2), 3.94 (d, J = 7.8 Hz, 1H, H-7 dia-1), 3.87 (d, J = 7.7 Hz, 0.3H, H-7 dia-2), 3.58 (q, J =
	7.0 Hz, 0.3H, H-4 dia-2), 3.36-3.07 (m, 1.3H, H-4 dia-1, H-5a dia-2), 2.55-2.44 (m, 1H, H-5a dia-1),
	2.30-2.11 (m, 1H, H-5b dia-1), 1.89-1.37 (m, 5.5H, H-5b dia-2, H-9 dia-1/dia-2, H-10 dia-1/dia-2),
	1.34-1.18 (m, 4H, H-1 dia-1/dia-2), 1.02 (t, J = 7.1 Hz, 1H, H-11 dia-2), 0.94 (td, J = 7.2, 3.3 Hz, 3H,
	H-11 dia-1).

  The reaction was stirred at 20 °C for 3 h then at 66 °C silicon oil bath temperature for 16 h. The reaction was quenched with aqueous HCl (1.0 M) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure.

	The crude
	mixture (114.0 mg, quant.) was obtained as a yellow solid, and purified through column
	chromatography on SiO2 (cyclohexane/ethyl acetate: 80/20) to give the saponified product (34.0 mg,
	80%) as a pale-yellow solid.
	TLC (cyclohexane/EtOAc: 80/20): Rf = 0 (UV active; KMnO4, stains white).
	m. p. = 79.2-84.0 °C (CH2Cl2).
	1 H NMR (300 MHz, CDCl3): δ (ppm) = 9.56 (br s, 1H, OH), 6.87 (s, 1H, H-5), 3.20 (d, J = 13.8 Hz,
	1H, H-3a), 2.76 (d, J = 13.7 Hz, 1H, H-3b), 1.90-1.71 (m, 2H, H-7), 1.66-1.50 (m, 2H, H-8), 1.00 (t,
	J = 7.3 Hz, 3H, H-9).

  :1.1:1) was obtained as a pale-yellow oil and was pure enough to be used directly in the next step without further purification. [Purification of the crude for analysis was accomplished through column chromatography on SiO2 (cyclohexane/ethyl acetate: 80/20)].

	δ (ppm) = 172.1 (C-3), 167.5 (C-13), 166.8 (C-14), 135.1 (C-17), 135.0 (C-23), 128.9-128.2 (m, C-
	Ph), 121.1 (C-8), 67.9 (C-15), 67.7 (C-16), 61.4 (C-2), 51.8 (C-12), 43.2 (C-7), 41.2 (C-9), 39.3 (C-
	6), 37.0 (C-4), 32.5 (C-5), 18.2 (C-10), 14.1 (C-1), 13.9 (C-11).
	For the minor diastereomer, dia-3, (1S,4S)-trans-330a:
	δ (ppm) = 172.4 (C-3), 167.0 (C-13), 166.6 (C-14), 135.3 (C-17, C-23), 128.9-128.2 (m, C-Ph), 121.6
	(C-8), 67.8 (C-15), 67.6 (C-16), 61.2 (C-2), 51.7 (C-12), 44.8 (C-7), 41.7 (C-9), 39.5 (C-6), 38.4 (C-
	4), 33.1 (C-5), 18.3 (C-10), 14.1 (C-1), 13.8 (C-11).
	For the minor diastereomer, dia-4, (1S,4R)-cis-330a:
	δ (ppm) = 172.1 (C-3), 166.8 (C-13), 166.4 (C-14), 135.5 (C-17, C-23), 128.9-128.2 (m, C-Ph), 121.1
	(C-8), 67.9 (C-15), 67.7 (C-16), 61.4 (C-2), 49.5 (C-12), 43.9 (C-7), 41.7 (C-9), 39.5 (C-6), 36.9 (C-
	4), 32.4 (C-5), 18.2 (C-10), 14.0 (C-1), 13.8 (C-11).
	IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2961 (-C-H), 2835 (-C-H), 2231 (C≡N), 1733
	(br, 3-C=O, 13-C=O, 14-C=O), 1455, 1378, 1180, 1157, 745, 697.
	HRMS (TOF, ES+): calculated for C28H31NO6Na [M+Na] + 500.20436, found 500.20368.
	diethyl 2-((2S)-2-cyano-4-(ethoxycarbonyl)-2-(2-
	((triisopropylsilyl)oxy)ethyl)cyclobutyl)malonate (332a)
	TLC (cyclohexane/EtOAc: 80/20): R f = 0.48 (UV active; KMnO4, stains yellow).
	1 H NMR (300 MHz, CDCl3): δ (ppm) = 7.31-7.01 (m, 22H, H-Ph all dia), 5.17-4.65 (m, 9H, H-15
	all dia, H-16 all dia), 4.31-4.17 (m, 0.75H, H-12 dia-2), 4.12-3.88 (m, 3.75H, H-2 all dia), 3.83 (dd,
	J = 11.2, 2.5 Hz, 1H, H-7 dia-1), 3.79-3.62 (m, 0.44H, H-12 dia-3/dia-4), 3.53-3.43 (m, 0.25H, H-7
	dia-3), 3.34-2.85 (m, 4H, H-4 all dia, H-7 dia-2/dia-4, H-12 dia-1), 2.70-2.43 (m, 2.1H, H-5a all dia),
	2.32-2.04 (m, 2.2H, H-5b all dia), 1.84-1.55 (m, 2.1H, H-9a all dia), 1.55-1.00 (m, 13.6H, H-1 all dia,
	H-9b all dia, H-10 all dia), 0.96-0.65 (m, 7H, H-11 all dia).
	13 C NMR (75 MHz, CDCl3):
	For the major diastereomer, dia-1, (1R,4R)-trans-330a:

δ (ppm) = 172.5

(C-3)

, 167.0

(C-13), 166.6 (C-14)

, 135.0

(C-17, C-23), 128.9-128.2 (m, C-Ph), 121.6 (C-8)

, 67.8

(C-15)

, 67.6

(C-16)

, 61.2 (C-2), 54.5

(C-12)

, 44.7 (C-7), 40.4 (C-9), 39.5

(C-6), 38.4 (C- 4)

, 33.1

(C-5)

, 18.2 (C-10), 14.2 (C-1),

13.8 (C-11)

. For the second major diastereomer, dia-2, (1R,4S)-cis-330a:

1 H NMR (300 MHz, CDCl3):

	δ (ppm) = 5.92 (s, 1H, H-3a), 5.80 (s, 1H, H-3b), 3.88 (t, J = 6.1 Hz,
	2H, H-5), 2.47 (tdd, J = 6.1, 1.4, 0.7 Hz, 2H, H-4), 1.08-1.03 (m, 21H, H-6, H-7, H-8, H-9, H-10, H-
	11, H-12, H-13, H-14).

Synthesis of nor-ethyleucophylline (E)-2-(1-azabicyclo[3.3.1]nonan-2-ylideneamino)-4-methoxybenzonitrile (399a) 48

	1 H NMR (300 MHz, CDCl3): δ (ppm) = 7.05 (d, J = 8.3 Hz, 1H, H-5), 6.29 (dd, J = 8.3, 2.5 Hz, 1H,
	H-4), 6.25-6.10 (m, 2H, H-2, H-8), 5.39 (dt, J = 8.4, 1.5 Hz, 1H, H-9a), 5.34 (dt, J = 8.5, 1.6 Hz, 1H,
	H-9b), 5.23-5.17 (m, 1H, H-7), 4.19 (s, 2H, H-12), 3.81 (s, 3H, H-11), 1.99 (d, J = 4.6 Hz, 1H, H-
	10).
	13 C NMR (75 MHz, CDCl3): δ (ppm) = 160.5 (C-3), 146.6 (C-1), 138.6 (C-8), 129.3 (C-5), 115.3
	(C-6, C-9), 103.5 (C-4), 102.5 (C-2), 74.1 (C-7), 53.5 (C-11).

IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3371 (br, OH), 2930 (-C-H), 1608, 1509, 1209, 1169, 731. HRMS (TOF, ES+): calculated for C10H12NO [M+H-H2O] + 162.09134, found 162.09103.

3.

10-methoxy-3,4,5,6-tetrahydro-2H-1,5-methanoazocino[2,3-b]quinoline (409)

	TLC (CH2Cl2/MeOH/NH4OH: 96/3/1): Rf = 0.11 (UV active, appears fluorescent; KMnO4, stains
	yellow).
	1 H NMR (300 MHz, CDCl3): δ (ppm) = 8.27 (d, J = 8.9 Hz, 1H, H-14), 7.93 (br s, 1H, H-17), 6.87
	(dd, J = 9.0, 2.3 Hz, 1H, H-10), 6.59 (d, J = 2.4 Hz, 1H, H-13), 3.86 (s, 3H, H-11), 3.35 (dd, J = 13.2,
	4.5 Hz, 1H, H-8a), 3.19 (dd, J = 13.0, 2.6 Hz, 2H, H-5a, H-8b), 3.03 (d, J = 12.8 Hz, 1H, H-5b), 2.90
	(dd, J = 17.8, 7.8 Hz, 1H, H-3a), 2.54 (d, J = 17.7 Hz, 1H, H-3b), 2.20 (br, 1H, H-4), 1.95-1.74 (m,
	1H, H-6a), 1.72-1.57 (m, 2H, H-6b, H-7a), 1.35-1.19 (m, 1H, H-7b).
	7-bromo-

1 H NMR (600 MHz, CDCl3):

	δ (ppm) = 4.25-4.17 (m, 12H, dia-1/dia-2: H-2, H-23, H-24), 3.97 (m,
	1H, H-20 dia-1), 3.83-3.73 (m, 4H, H-10 dia-1/dia-2), 3.51 (d, J = 11.9 Hz, 1H, H-20 dia-2), 3.31-
	3.27 (m, 3H, H-4 dia-1, H-7 dia-1/dia-2), 3.08-2.85 (m, 5H, H-4 dia-2, H-8 dia-1/dia-2), 2.27-2.11
	(m, 4H, H-5 dia-1, H-5a dia-2, H-9a dia-1), 2.01 (t, J = 9.8 Hz, 1H, H-5b dia-2), 1.81 (dt, J = 13.6,
	5.6 Hz, 1H, H-9a dia-2), 1.68-1.57 (m, 2H, H-9b dia-1, H-9b dia-2), 1.28-1.22 (m, 18H, dia-1/dia-2:
	H-1, H-25, H-26), 1.06-1.03 (m, 42H, dia-1/dia-2: H-11, H-12, H-13, H-14, H-15, H-16, H-17, H-18,
	H-19).

yl)propanoate (391a) TLC (CH2Cl2/MeOH: 95/5): Rf

  [Purification of the crude for analysis afforded the alcohol as a pale-yellow oil solidifies in the freezer].

	HRMS (TOF, ES+): calculated for C19H39NO3SiNa [M+Na] + 380.2591, found 380.2577.
	[α]D 25 = -1.55 (c = 0.12, CHCl3).
	Isolation of the intermediates
	(S)-3-(6-oxo-3-(2-((triisopropylsilyl)oxy)ethyl)piperidin-3-yl)propanoic acid (389a)
	TLC (CH2Cl2/MeOH/AcOH: 90/9/1): Rf = 0 (UV inactive; KMnO4, stains yellow, drags on TLC).
	1 H NMR (300 MHz, CDCl3): δ (ppm) = 6.87 (br s, 1H, H-20), 3.78 (t, J = 6.3 Hz, 2H, H-7), 3.22-
	3.08 (m, 2H, H-1), 2.45-2.26 (m, 3H, H-4, H-18a), 1.91-1.56 (m, 5H, H-3, H-17, H-18b), 1.07-1.03
	(m, 21H, H-8, H-9, H-10, H-11, H-12, H-13, H-14, H-15, H-16).
	13 C NMR (75 MHz, CDCl3): δ (ppm) = 177.9 (C-19), 173.8 (C-5), 59.2 (C-7), 51.3 (C-1), 37.1 (C-
	6), 33.3 (C-2), 29.9 (C-4), 29.4 (C-3), 28.7 (C-17), 27.5 (C-18), 18.1 (C-11, C-12, C-13, C-14, C-15,
	C-16), 12.0 (C-8, C-9, C-10).
	IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3215 (br, OH), 2941 (-C-H), 2866 (-C-H),
	1704 (19-C=O), 1655 (5-C=O), 1462, 1097, 883, 682.
	HRMS (TOF, ES+): calculated for C19H37NO4SiNa [M+Na] + 394.2384, found 394.2376.
	[α]D 25 = +7.81 (c = 0.33, CHCl3) crude value.
	TLC (CH2Cl2/MeOH: 90/10): Rf = 0.22 (UV inactive; KMnO4, stains yellow).
	m. p. = 63.6-69.0 °C (EtOAc).
	1 H NMR (300 MHz, CDCl3): δ (ppm) = 5.65 (br s, 1H, H-21), 3.77 (t, J = 6.5 Hz, 2H, H-19), 3.65
	(br s, 2H, H-7), 3.22 (dd, J = 12.2, 2.1 Hz, 1H, H-1a), 3.09 (dd, J = 11.9, 2.6 Hz, 1H, H-1b), 2.45-
	2.31 (m, 2H, H-4), 1.79-1.49 (m, 8H, H-3, H-6, H-17, H-18), 1.09-1.03 (m, 21H, H-8, H-9, H-10, H-
	11, H-12, H-13, H-14, H-15, H-16).

13

C NMR (75 MHz, CDCl3): δ (ppm) = 172.2

(C-5)

, 63.2

(C-19)

, 59.5 (C-7), 52.0 (C-1), 37.3

(C- 6)

, 33.6 (C-2), 30.7

(C-4), 30.6 (C-3)

, 28.0 (C-17), 26.7 (C-18), 18.2 (C-11, C-12, C-13, C-14, C-15, C-16), 12.0 (C-8, C-9, C-10). IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3292 (br, OH), 2941 (-C-H), 2866 (-C-H), 1660 (5-C=O), 1463, 1097, 1068, 883, 682. (S)-methyl 3-(6-oxo-3-(2-((triisopropylsilyl)oxy)ethyl)piperidin-3-= 0.32 (UV inactive; KMnO4, stains yellow). 1 H

NMR (400 MHz, CDCl3):

	δ (ppm) = 6.61 (br s, 1H, H-21), 3.77-3.73 (m, 2H, H-7), 3.65-3.64 (s,
	3H, H-20), 3.16 (d, J = 12.4 Hz, 1H, H-1a), 3.05 (d, J = 12.1 Hz, 1H, H-1b), 2.39-2.22 (m, 4H, H-4,
	H-18), 1.89-1.52 (m, 6H, H-3, H-6, H-17), 1.13-0.95 (m, 21H, H-8, H-9, H-10, H-11, H-12, H-13, H-
	14, H-15, H-16).
	13 C NMR (100 MHz, CDCl3): δ (ppm) = 173.8 (C-19), 172.3 (C-5), 59.2 (C-7), 51.8 (C-1), 51.5 (C-
	20), 36.8 (C-6), 33.4 (C-2), 30.3 (C-4), 29.8 (C-3), 28.6 (C-17), 27.9 (C-18), 18.1 (C-11, C-12, C-13,
	C-14, C-15, C-16), 12.0 (C-8, C-9, C-10).
	IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2942 (-C-H), 2866 (-C-H), 1738 (19-C=O),
	1683 (5-C=O), 1462, 1250, 1171, 1097, 882, 682.
	HRMS (TOF, ES+): calculated for C20H39NO4SiNa [M+Na] + 408.2537, found 408.2540.

  :1.8:1) was obtained as a yellow oil and was pure enough to be used directly in the next step without further purification. [Purification of the crude for analysis was accomplished through column chromatography on SiO2 (cyclohexane/EtOAc: 90/10)].

	5a dia-
	3), 2.44-2.31 (m, 0.14H, H-5b dia-4), 2.32-2.17 (m, 2H, H-5b dia-1, H-5b dia-2, H-5b dia-3), 2.07-
	1.98 (m, 2H, H-9a dia-1, H-9a dia-2, H-9a dia-3, H-9a dia-4), 1.74-1.33 (m, 7H, H-9b all dia, H-10
	all dia), 1.34-1.19 (m, 20H, H-1 all dia, H-17 all dia, H-18 all dia), 1.07-0.86 (m, 6.2H, H-11 all dia).

TLC (cyclohexane/EtOAc: 80/20): R f = 0.48 (UV active; KMnO4, stains yellow). 1 H NMR (300 MHz, CDCl3): δ (ppm) = 4.34-4.06 (m, 12H, H-2 all dia, H-15 all dia, H-16 all dia, H-12 dia-2), 3.90 (d, J = 12.5 Hz, 0.1H, H-12 dia-4), 3.85 (d, J = 9.5 Hz, 0.1H, H-7 dia-4), 3.80 (d, J = 11.3 Hz, 1H, H-12 dia-1), 3.73 (dd, J = 11.7, 9.8 Hz, 0.2H, H-7 dia-3), 3.49 (d, J = 11.8 Hz, 0.17H, H-12 dia-3),

3.43-3.26 (m, 1.

2H, H-7 dia-2, H-4 dia-2, H-4 dia-4), 3.22 (dd, J = 11.2, 9.1 Hz, 1H, H-7 dia-1), 3.13 (q, J = 9.1 Hz, 1H, H-4 dia-1), 3.00 (q, J = 9.6 Hz, 0.15H, H-4 dia-3), 2.75 (dd, J = 12.6, 4.1 Hz, 0.6H, H-5a dia-2, H-5a dia-4), 2.62 (dd, J = 11.9, 9.1 Hz, 1.14H, H-5a dia-1, H-

(6-oxo-3-propylpiperidin-3-yl)propanoic acid (389b) TLC (CH2Cl2/MeOH/AcOH: 90/9/1): Rf

  The crude (200.0 mg, quant.) was obtained as a yellow viscous oil and was used directly in the next step without further purification. [Purification of the crude for analysis was accomplished through short column chromatography on SiO2 (CH2Cl2/MeOH/NH4OH: 95/4/1) to afford the product as a pale-yellow viscous oil].

	TLC (CH2Cl2/MeOH: 90/10): Rf = 0.55 (UV inactive; KMnO4, stains yellow).
	m. p. = 64.1-66.2 °C (CH2Cl2).
	1 H NMR (300 MHz, CDCl3): δ (ppm) = 6.76 (br s, 1H, H-6), 3.67 (s, 3H, H-13), 3.03 (d, J = 2.5 Hz,
	2H, H-1), 2.33 (t, J = 7.0 Hz, 2H, H-11), 2.28-2.18 (m, 2H, H-4), 1.77-1.66 (m, 2H, H-3), 1.61 (td, J
	= 7.0, 3.2 Hz, 2H, H-10), 1.37-1.15 (m, 4H, H-7, H-8), 0.95-0.88 (m, 3H, H-9).
	13 C NMR (75 MHz, CDCl3): δ (ppm) = 173.9 (C-12), 172.9 (C-5), 51.9 (C-13), 51.1 (C-1), 36.6 (C-
	7), 33.7 (C-2), 30.0 (C-10), 29.5 (C-3), 28.5 (C-4), 27.7 (C-11), 16.4 (C-8), 14.8 (C-9).
	IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 2955 (-C-H), 2872 (-C-H), 1736 (12-C=O),
	1664 (5-C=O), 1436, 1302, 1196, 1168, 727.
	HRMS (TOF, ES+): calculated for C12H21NO3Na [M+Na] + 250.14136, found 250.14050.
	[α]D 25 = +5.28 (c = 0.11, CHCl3).
	(R)-3-(6-oxo-3-propylpiperidin-3-yl)propyl methanesulfonate (392b)
	TLC (CH2Cl2/MeOH: 90/10): Rf = 0.4 (UV inactive; KMnO4, stains yellow).
	m. p. = 96.5-99.5 °C (CH2Cl2).
	1 H NMR (300 MHz, CDCl3): δ (ppm) = 6.02 (s, 1H, H-6), 3.64 (t, J = 6.1 Hz, 2H, H-12), 3.05 (d, J
	= 2.5 Hz, 2H, H-1), 2.37-2.32 (m, 2H, H-4), 1.64 (t, J = 7.0 Hz, 2H, H-3), 1.54-1.18 (m, 8H, H-7, H-According to the general procedure (D), from the hydroxy piperidinone 390b (138.0 mg, 0.69 mmol, 8, H-10, H-11), 0.92 (t, J = 6.9 Hz, 3H, H-9). 1.0 eq.), dry CH2Cl2 (10.0 mL, 0.07 M), MsCl (60.0 μL, 0.82 mmol, 1.2 eq.) and distilled Et3N (0.14 13 C NMR (75 MHz, CDCl3): δ (ppm) = 173.0 (C-5), 63.3 (C-12), 51.6 (C-1), 37.1 (C-7), 33.9 (C-2), 30.5 (C-10), 30.2 (C-3), 27.9 (C-4), 26.5 (C-11), 16.5 (C-8), 14.9 (C-9). mL, 1.03 mmol, 1.5 eq.) for 5 h.
	Isolation of the intermediates
	(S)-3-1 H NMR (300 MHz, CDCl3): δ (ppm) = 7.13 (br s, 1H, H-6), 3.06 (d, J = 2.5 Hz, 2H, H-1), 2.37 (t,
	J = 7.0 Hz, 2H, H-4), 2.27 (td, J = 7.3, 2.1 Hz, 2H, H-11), 1.75 (dd, J = 9.2, 7.1 Hz, 2H, H-3), 1.64
	(t, J = 7.0 Hz, 2H, H-10), 1.38-1.17 (m, 4H, H-7, H-8), 0.95-0.90 (m, 3H, H-9).
	13 C NMR (75 MHz, CDCl3): δ (ppm) = 178.1 (C-12), 174.3 (C-5), 51.0 (C-1), 36.9 (C-7), 33.6 (C-
	2), 29.6 (C-10), 29.1 (C-3), 28.6 (C-4), 27.4 (C-11), 16.4 (C-8), 14.8 (C-9).
	IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3280 (br, OH), 2933 (-C-H), 2872 (-C-H),
	1704 (12-C=O), 1636 (5-C=O), 1497, 1410, 1307, 1227, 802.
	HRMS (TOF, ES+): calculated for C11H19NO3Na [M+Na] + 236.12571, found 236.12523.
	[α]D 25 = +9.84 (c = 0.16, CHCl3) crude value.
	(S)-methyl 3-(6-oxo-3-propylpiperidin-3-yl)propanoate (391b)

IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3294 (br, OH), 2938 (-C-H), 2871 (-C-H), 1655 (5-C=O), 1495, 1410, 1364, 1059, 731. HRMS (TOF, ES+): calculated for C11H21NO2Na [M+Na] + 222.14645, found 222.14609. [α]D 25 = +3.29 (c = 0.10, CHCl3). = 0 (UV inactive; KMnO4, stains yellow, drags on TLC). m. p. = 111.7-113.6 °C (EtOAc/pentane). TLC (CH2Cl2/MeOH: 90/10): Rf = 0.59 (UV inactive; KMnO4, stains white-red).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 5.81 (br s, 1H, H-6), 4.22 (t, J = 6.3 Hz, 2H, H-12), 3.05 (t, J = 2.5 Hz, 2H, H-1), 3.01 (s, 3H, H-13), 2.34 (t, J = 7.0 Hz, 2H, H-4), 1.77-1.63 (m, 3H, H-3a, H-11), 1.52-1.14 (m, 7H, H-3b, H-7, H-8, H-10), 0.93 (t, J = 6.8 Hz, 3H, H-9).

  1 H NMR (300 MHz, DMSO-d6): δ (ppm) = 4.76(d, J = 9.4 Hz, 1H, H-8), 4.41 (t, J = 8.0 Hz, 2H, H-2), 4.29 (q, J = 9.7 Hz, 1H, H-5), 3.90 (t, J = 8.0 Hz, 2H, H-3), 3.00 (s, 3H, H-9), 2.56 (dd, J = 9.8, 2.7 Hz, 2H, H-6), 2.24-2.07(m, 1H, H-11a), 2.11-2.00 (m, 1H, H-11b), 1.02 (t, J = 7.3 Hz, 3H, H- 12)

(CH2Cl2/EtOAc: 70/30): R

  as a pale-yellow oil solidifies open to atmosphere. TLC

f = 0.82 (UV inactive; KMnO4, stains red-white). m. p. = 73.9-76.8 °C (CH2Cl2/pentane). 1 H

NMR (300 MHz, CDCl3): δ

  (ppm) = 4.30(d, J = 9.6 Hz, 1H, H-7), 4.24 (q, J = 7.1 Hz, 2H, H-2), 3.67 (q, J = 9.7 Hz, 1H, H-4), 2.97 (s, 3H, H-8), 2.67-2.59 (m, 1H, H-5a), 2.52 (dd, J = 11.8, 10.0 Hz, 1H, H-5b), 2.44-2.32 (m, 1H, H-10a), 2.20-2.05 (m, 1H, H-10b), 1.30 (t, J = 7.1 Hz, 3H, H-1),1.11 (t, J = 7.4 Hz, 3H, H-11).

  ppm) = 7.46(d, J = 8.6 Hz, 1H, H-14), 6.57 (dd, J = 8.8, 2.4 Hz, 1H, H-13), 6.31 (s, 1H, H-10), 4.30 (dd, J = 13.1, 5.1 Hz, 1H, H-8a), 3.81 (s, 3H, H-11), 3.15 (d, J = 13.4 Hz, 1H, H-5a), 2.90 (t, J = 12.6 Hz, 1H, H-8b), 2.65 (d, J = 13.4 Hz, 1H, H-5b), 2.34 (dd, J = 15.0, 5.3 Hz, 1H, H-3a), 2.28-2.12 (m, 2H, H-6), 1.74 (dd, J = 13.9, 7.7 Hz, 1H, H-3b), 1.60(d, J = 13.4 Hz, 1H, H-2a), 1.52-1.36 (m, 3H, H-2b, H-7), 1.31-1.25 (m, 2H, H-17), 0.87 (t, J = 7.5 Hz, 3H, H-18).

1 H NMR (600 MHz, CDCl3): δ (

  mmol, 1.2 eq.) for 16 h, to afford the desired product(3.6 g, 70%, quant. brsm). Rf = 0.50 (UV active; KMnO4, stains white). ppm) = 7.37-7.19 (m, 5H, H-Ph), 4.59 (s, 2H, H-8), 3.19 (dd, J = 7.1, 4.9 Hz, 2H, H-5), 2.31 (tdd, J = 9.1, 5.8, 4.2 Hz, 1H, H-2), 2.09-1.78(m, 3H, H-3a, H-4a, H-6a), 1.77-1.47 (m, 3H, H-3b, H-4b, H-6b), 0.97 (t, J = 7.4 Hz, 3H, H-7).

TLC (cyclohexane/EtOAc: 50/50): 1 H NMR (300 MHz, CDCl3): δ (

  Hz, 1H, H-18), 7.54-7.51 (m, 1H, H-15), 7.40 (s, 1H, H-13), 7.30 (td, J = 7.4, 1.2 Hz, 1H, H-17), 7.22 (td, J = 7.4, 1.2 Hz, 1H, H-16), 3.80 (ddd, J = 12.3, 8.6, 3.9 Hz, 1H, H-9a), 3.69 (dt, J = 11.6, 5.3 Hz, 1H, H-9b), 3.03-2.90 (m, 3H, H-5a, H-11), 2.81-2.65 (m, 3H, H-1a, H-10), 2.09-1.74 (m, 4H, H-1b, H-4a, H-5b, H-8a), 1.65 (s, 9H, H-tbutyl), 1.62-1.52(m, 3H, H-3a, H-4b, H-8b), 1.36-1.14 (m, 4H, H-3b, H-6), 0.83 (t, J = 7.5 Hz, 3H, H-7).

1 H NMR (300 MHz, CDCl3): δ (ppm) = 8.11 (d, J = 8.1

  ppm) = 7.69-7.59(m, 1H, H-18), 7.51-7.40 (m, 1H, H-15), 7.23- 7.07 (m, 2H, H-16, H-17), 5.96 (d, J = 5.1 Hz, 0.18H, H-9 minor diastereomer), 5.59 (dd, J = 9.2, 5.7 Hz, 0.82H, H-9 major diastereomer), 3.97-3.83 (m, 0.18H, H-1 minor diastereomer), 3.79-3.52 (m, 0.82H, H-1 major diastereomer), 3.18-2.97 (m, 2H, H-10), 2.97-2.79 (m, 1H, H-5a), 2.79-2.60 (m, 1H, H-5b), 2.54-2.40 (m, 2H, H-11), 2.36-2.12 (m, 1H, H-8a), 2.01-1.60(m, 4H, H-3a, H-4, H-8b), 1.63-1.50 (m, 2H, H-3b, H-6a), 1.19-1.00 (m, 1H, H-6b), 0.76 (t, J = 7.6 Hz, 3H, H-7).

	IR (solution in CH2Cl2, thin film, KBr): ν max (cm -1 ) = 3323 (br, OH), 2929 (-C-H), 2853 (-C-H),
	1456, 1320, 1302, 1061, 737.
	HRMS (TOF, ES+): calculated for C19H23N2O [M-H] + 295.18159, found 295.18137.
	calculated for C19H25N2O [M+H] + 297.19614, found 297.19532.

1 H NMR (300 MHz, CDCl3): δ (

DIPEA N

UV-light irradiation system

The experimental setup used for the UV-light irradiation reactions

CCDC number

Experimental Part -Chapter IV

General procedures for chapter IV General procedure (A) for nickel-catalysed lactamization reaction

To a flame-dried flask and under inert atmosphere, the crude cyclobutane 332 (1.0 eq.) was introduced followed by anhydrous NiCl2 (2.2 eq.), then freshly distilled EtOH (0.025 M). The reaction was set at 0 °C and NaBH4 (20.0 eq.) was added portion-wise for 5-10 min depending on the scale. The reaction was warmed up slowly to 20 °C and kept under vigorous stirring for the indicated time. After total consumption of the starting material as shown by TLC, the reaction mixture was concentrated under reduced pressure, then diluted with EtOAc and extracted with aqueous HCl (0.4 M). The aqueous phase was charged with 2 spoons of NaCl then extracted twice with EtOAc. The combined organic layers were washed with minimum quantity of brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through column chromatography on SiO2 (CH2Cl2/MeOH: eluants as noted) to afford the pure desired product and the reduced amine. The product was stored under inert atmosphere in the freezer.

General procedure (B) for saponification reaction

To a dried flask under inert atmosphere, the starting material (1.0 eq.) was introduced, followed by EtOH/H2O: 4/1 (0.15 M) then LiOH (5.0 eq.). The reaction was stirred at 20 °C and followed by TLC. After completion, the solvents were evaporated and the reaction was diluted with water and extracted with EtOAc. The aqueous layer was acidified with concentrated HCl till pH = 1, then charged with 2 spoons of NaCl and extracted with EtOAc (4 x). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude was used directly in the next step without further purification. The product was stored under inert atmosphere in the freezer.

General procedure (C) for hydroxy piperidinone formation

To a flame-dried flask equipped with a condenser and under inert atmosphere, the crude diacid (1.0 eq.) was introduced, followed by dry THF (0.2 M). The reaction was heated at 70 °C for 2-3 h, then cooled down to 20 °C. The solvent was concentrated under reduced pressure then the crude mixture (1.0 eq.) was set under inert atmosphere and dissolved in dry CH2Cl2/MeOH: 5/1 (0.12 M). TMSCHN2 (2.0 M in hexane, 1.5 eq.) was added at 0 °C and the mixture was stirred at 20 °C for 1 h. The reaction was quenched with AcOH (0.3 eq.) and stirred for 2 min then the solvents were concentrated under reduced pressure. [Purification of the crude for analysis was accomplished through short column chromatography on SiO2 (CH2Cl2/MeOH/NH4OH: 98/1/1 to 95/4/1)]. The crude mixture (1.0 eq.) was set again under inert atmosphere and dissolved in dry THF (0.05 M) then LAH (1.0 M in Et2O, 1.25 eq.) was added dropwise at 0 °C. The reaction was warmed up slowly to 20 °C and followed by TLC. After completion, it was diluted with EtOAc and extracted with