W T ; Etoh

T ; Hayashi

M ; Komiyama

K ; Kam

T.-S Org

Lett

Jun E ; ; Deguchi

Alfarius E Nugroho

Yusuke Hirasawa

Takahiro ; Hosoya

Osamu Shirota

; Khalijah

N ; Uchiyama

Y ; Goda

K ; Awang

Total Synthesis of Eucophylline. A free-Radical Approach towards Total Synthesis of Cytotoxic Leucophyllidine

Keywords: Eucophylline, Synthèse totale, alcaloïdes bisindoliques, carbocyanation, amides contraints Eucophylline, Total synthesis, Bisindole alkaloids, Carbo-Cyanation, Twisted amides Acetyl MeCN: Acetonitrile atm: Atmospher AIBN: Azobis(isobutyronitrile)

The thesis describes the first total synthesis of Eucophylline, the south fragment of the Leucophyllidine alkaloid recently isolated from Leuconotis griffithii and L. eugenifolius. The 10-step synthesis encompasses a new straightforward method to access to the azabicyclo[3.3.1]nonane skeleton through a free-radical three-component olefinic carbo-oximation process. During these studies, we also isolated enamines exhibiting unusual stabilities resulting from their strained bicyclic conformation. The synthesis of the Eburnane part, the north fragment of Leucophyllidine, was developed relying on a new free-radical three-component Carbo-Cyanation reaction. This new reaction showed high tolerance toward different functional groups and provided an efficient mean to install the nitrile group in complex structures and to introduce quaternary centers. The biomimetic coupling between the Eburnane and Eucophylline fragments was finally studied using structurally similar models. Preliminary results of this model study showed that absence of a gemdimethyl effect in the Eburnane model probably prevents the formation of the cyclic imine, key intermediate for the desired coupling.

Synthèse totale de l'Eucophylline. Approches radicalaires vers la synthèse totale de la Leucophyllidine Résumé : La thèse décrit la première synthèse totale de l'Eucophylline, le fragment sud de l'alcaloïde Leucophyllidine récemment isolé à partir de Leuconotis griffithii et L. eugenifolius. La synthèse en 10 étapes comprend une nouvelle méthode d'accès au squelette azabicyclo[3.3.1]nonane par un processus de carbooximation radicalaire d'oléfines à trois composants. Au cours de ces études, nous avons également isolé des énamines présentant des stabilités inhabituelles résultant de leur conformation bicyclique tendue. La synthèse de la partie éburnane, le fragment nord de la Leucophyllidine, a été réalisée grâce à une nouvelle réaction radicalaire de carbo-cyanation à trois composants. Cette réaction radicalaire s'est révélée efficace pour installer le groupement fonctionnel nitrile sur des oléfines, et éventuellement former des centres quaternaires, notamment dans des structures complexes, puisqu'une bonne tolérance aux différents groupes fonctionnels a été observée. Le couplage biomimétique entre le squelette éburnane et l'Eucophylline a finalement été étudié en utilisant des modèles de structure similaire. Les résultats préliminaires de cette étude ont montré que l'absence d'effet gem-diméthyle dans le modèle éburnane empêche probablement la formation de l'imine cyclique, intermédiaire-clé dans le couplage désiré.

At the beginning, I incredibly grateful for my Family especially my Father and Mother who have supported me morally as well as encouraged me to excel throughout my studies. They created the sense of research inside me since I completed my bachelor studies. They also supported me through their patience on my long absence during these three years and even they pushed me harder to complete my studies with excellence.

Definitely, I would like to express my sincere and deep gratitude to my advisor Prof. Yannick LANDAIS for giving me the opportunity to join his group and doing a cutting edge research in synthetic organic chemistry. I would like also to thank him for his support, kindness, patience, motivation and commitment to excellence throughout the course of this research. His immense knowledge, intelligence, efficiency and organization have always been a source of inspiration for me to become a distinguished researcher. His guidance directed me in all the time of research and during writing of this dissertation.

I would like also to extend my sincere and deep gratitude to my co-advisor Dr. Frederic ROBERT for his valuable advices, continuous guidance and encouragement as well as helpful discussion during the progress of this dissertation. I would like also to thank him for his carful revision, precise corrections and the quest for perfection during the writing of this dissertation.

I would like also to express my deep thanking to Dr. Emmanuel LACÔTE, Prof. Cyril BRESSY and Prof. Patrick TOULLEC for accepting to judge this work and participating in the doctoral dissertation committee. I want also to extend my thanking to Prof. Vincent DALLA to be the president of this committee.

I would like to extend my sincere gratitude to my best friend Dr. Redouane BENIAZZA for his professional advices as a very skillful and intelligent chemist who guided me during the first days in the group of prof. LANDAIS. He also inspired my research during these three years. Also I would like to thank him for his friendship here in Bordeaux, which helped me a lot to adapt very quickly in the French community and to find my way here. I am so proud of you.

My sincere thanks also go to Dr. Valerie DESVERGNES for her management of the laboratory during my first year and for her encouragement.

I would also like to sincerely thank Dr. Aravindu KUNCHE and Dr. Dayvson PALMEIRA for their friendship, good sense of humor and the exceptional times that we spent together. I want also to deeply thank Dr. Nitin DANGE for his valuable advices, supporting me during searching for my postdoctoral position and also for his friendship.

I would like to thank especially Dr. Simon GRELAUD, who started with me this journey in the laboratory since three years, for his kindness, support and sense of humor. I greatly appreciate his advices in the laboratory, the fruitful discussions and his efforts to show the generous French culture. I also would like to thank Mr. Vincent PIRENNE, the next man in total synthesis of Leucophyllidine, and Dr. Thanh Vy HOANG for their friendship and kindness.

I thank also Ms. Maren WISSING and Ms. Chahinaz KHIAR, the cooperators who worked with me in screening the carbo-cyanation scope. I also extended my thanking to Mr. Takenori TOTOKI, for the fruitful cooperation in developing the micro-flow reactions.

I would like also to thank all the former and current members of the LANDAIS research group (Dr.

Virginie, Dr. Igancio, Dr. Paul, Dr. Clément, Dr. Alexandre, Dr. Jessica, Dr. Benjamin, Dr. Shireen, Mr. Anthony, Mr. Ashique and Mr. Ahmed) whom I had the pleasure of working with throughout my doctoral research. They have created a stimulating research environment where the mutual exchange of ideas was always welcomed and also they set very high standards to follow.

For sure also, I would like to extend my thanking to Dr. Christophe Deraedt and Dr. Amalia Rapakousiou from the group of professor Astruc for their friendship and good humor.

I would like of course to thank the technical team of the group Ms. Muriel, Mr. Jean-Michel, Ms.

Clothilde, and especially Mr. Jonathan, for their availability and good mood.

I also would like to thank the CESAMO team especially Dr. Cybille, Ms. Christelle, Ms. Claire, Ms.

Patricia and Mr. Noël for their availability and assistance in the NMR and Mass analysis. I also want to thank Mr. for X-ray crystallography.

I would like to deeply acknowledge GreenIT-Erasmus Mundus exchange program for the very generous PhD Scholarship during the three years of my doctoral research. I would like also to thank the international office of Bordeaux University especially Ms. Anna GERYKOVA and Ms. Olga IVANOVA for their kind assistance, facilitating the administrative procedures and their efforts in guiding me to identify the French Culture and French language.

Finally, I want to thank my friends here in Bordeaux especially Dr. Mohammed BOUAMAMA, Dr.

Ibrahim ABDULHABEEB and Dr. Faouzia ZER for their availability, support and friendship.

EWG: Electron Withdrawing Group EDG:

Electron Donating Group FMO: Florisil:

Frontier Molecular Orbitals Synthetic magnesium silicate g: Gram h: IC 50 : Im:

SOMO:

Singly Occupied Molecular Orbital τ:

Torsional angle χ N :

Pyramidalization at nitrogen t-= tert-Tertio TBDPS: TBDMS:

Résumé en Français

Cette thèse décrit la première synthèse totale de l'Eucophylline, alcaloïde isolé récemment de Leuconotis eugenifolius, et présentant un motif vinylquinoléine unique incorporant un système bicyclique. Une approche vers la synthèse totale de la Leucophyllidine, un nouvel alcaloïde bisindolique cytotoxique isolé de Leuconotis griffithii est également décrite. Dans les deux synthèses, nous nous sommes appuyés sur de nouvelles réactions radicalaires multi-composants, montrant l'utilité et l'efficacité des radicaux libres dans l'élaboration de structures complexes et la construction de centres quaternaires.

La première synthèse totale de l'Eucophylline a été réalisée en 10 étapes et un rendement global de 10%, avec, comme réaction-clé, un processus de carbo-oximation radicalaire récemment développé au laboratoire et mettant en jeu un précurseur de radicaux de type α-iodothioester 337, une oléfine riche en électron 252 et une sulfonyloxime 233. Cette réaction clé nous a permis d'introduire le centre quaternaire de l'Eucophylline et de concevoir un nouvel accès direct au squelette azabicyclo[3.3.1]nonane de manière efficace (Schéma II).

Lors de l'étude de la réaction entre les lactames bicycliques pontés avec des nucléophiles, nous avons montré que des intermédiaires α-chloroénamines remarquablement stables sont formés. La réactivité unique de la fonction amide, présente dans les lactames bicycliques, nous a permis d'isoler et de fonctionnaliser ces α-chloroénamines bicycliques 369, illustrant l'importance de la conjugaison entre la paire d'électrons sur l'azote et le système  de l'énamine (Schéma III).

Lors de la synthèse du motif éburnane 2, le fragment nord de la Leucophyllidine, le processus de carbo-oximation, très utile lors de la synthèse de Eucophylline, s'est avéré beaucoup moins efficace, en raison probablement de l'encombrement stérique autour du radical nucléophile qui gêne le piégeage de ce radical par la sulfonyloxime. De plus, la conversion de l'oxime 546b en aldéhyde 549b ne s'est pas avérée très efficace dans les différentes conditions testées (Schéma IV).

A la recherche d'un groupe fonctionnel équivalent à un aldéhyde et compatible avec les processus radicalaires multi-composants, nous avons développé une nouvelle réaction radicalaire de carbocyanation. Les conditions de cette réaction ont montré une tolérance élevée vis-à-vis des différents précurseurs de radicaux et des oléfines. Par ailleurs, l'accepteur radicalaire, le cyanure de ptoluènesulfonyle 570, est disponible commercialement et permet d'éviter les synthèses souvent longues et fastidieuses des autres accepteurs de sulfonyle. La valeur A du groupe nitrile (0.21) explique probablement la facilité de ce petit groupement à réagir avec les radicaux nucléophiles, même ceux encombrés (Schéma V).

Cependant, le chauffage à température élevée d'un mélange d'aldéhyde masqué sous forme lactol 639 et de tryptamine permet d'obtenir un produit de Pictet-Spengler, dont le centre quaternaire est sur une position inattendue. La formation de ce produit tétracyclique peut être rationalisée par l'encombrement stérique au voisinage de la fonction aldéhyde. Le produit formé résulte probablement d'une migration d'iminium par une réaction rédox interne (Schéma VII).

La seconde approche est basée sur la condensation de Bischler-Napieralski. Le même produit de carbo-cyanation 579a, que celui utilisé auparavant, constitue le précurseur-clé de cette approche. La réduction du groupe thioester en aldéhyde 654 a ainsi permis, dans des conditions réductrices, la réaction de ce dernier avec la tryptamine pour donner l'amine secondaire 655. L'addition nucléophile de cette amine sur le nitrile a conduit au lactame 659, intermédiaire-clé pour la condensation de Bischler-Napieralski. Malheureusement, la présence de l'alcool libre sur le lactame 659 produit un hémiaminal 662 au lieu de l'alcool tétracyclique attendu. La protection de l'alcool libre, suivie de la réaction de Bischler-Napieralski a finalement donné le produit tétracyclique 668 désiré mais avec un rendement faible et de manière peu reproductible (Schéma VIII).

Le couplage biomimétique entre le motif éburnane 2 et l'Eucophylline 3 a été étudié à partir de modèles simplifiés. Ces derniers sont accessibles en un nombre d'étapes limitées à partir de matières premières disponibles dans le commerce. Les résultats préliminaires de cette étude de modèle ont montré que l'absence d'effet gem-diméthyle dans le modèle nord défavorise la formation de l'imine cyclique essentielle pour la réaction de couplage désirée (Schéma IX).

Introduction Introduction

In search for potent and natural anticancer agents, Leucophyllidine 1, an unprecedented bisindole alkaloid, stands out as a promising chemotherapeutic agent that deserve deep attention.

Leucophyllidine is a cytotoxic dimeric terpene bisindole alkaloid recently isolated by Kam and coworkers from the EtOH extract of the stem-bark of Malaysian Apocynaceae plant, Leuconotis griffithii. 1 This unprecedented bisindole alkaloid is constituted by an eburnane unit 2 and a novel tetrahydrobenzo- [b] [START_REF]Isolation of the desired diastereoisomer and re-equilibration of the tetracyclic epimer 463b by using BF 3 -etherate (according to Fuji's method) was performed[END_REF]8]naphthyridine ring system 3, recently isolated by Morita et al. from Leuconotis eugenifolius and named Eucophylline. 2 This complex alkaloid exhibits pronounced in vitro cytotoxicity towards drug-sensitive as well as vincristine-resistant (VJ300) human KB cells with IC 50 values of 2.95 and 2.92 μg/mL respectively. In addition, Leucophyllidine inhibits NO production stimulated by LPS dose-dependently with IC 50 7.1 μM. Both compounds, Leucophyllidine and Eucophylline, showed high cell viability in J774.1 cells at concentration of IC 50 7.1 μM.

Dimeric indole Alkaloids

Terpene indole alkaloids, including their dimeric forms constitute a family of more than 3000 members, in which only a few exhibit physiological effects on mammals. Amongst the dimeric members, vinca alkaloids vincristine 4 and vinblastine 5 (Scheme 2), isolated for Catharanthus roseus, 3 are the most well-known, the former is being used in the treatment of leukemia, while the latter was found active against Hodgkin's disease. Vinorelbine 6 (Navelbine®), a semi-synthetic vinca alkaloid obtained through extraction from catharanthus, was later introduced on the market by Potier and co-workers for the treatment of several types of cancers, including breast and non-small cell lung cancers. 4 However, all these compounds are rather expensive. For instance, 1 kg of Vinblastine 6 costs around a million $ and the annual production in the world is 12 kg. Similarly, 1 kg of Vincristine 4 costs 3.5 million $, while the world annual production is about 1 kg, emphasizing on the difficulty to isolate and purify these dimeric alkaloids from the numerous by-products in the plant. 5 These few indicators illustrate the value of such natural products but also their limited availability. Moreover, resistance tends to appear and research for new analogues becomes a priority. Promising fluorinated analogues of the above vinca alkaloids, including Vinflunine 7 have recently been launched and have shown anti-angiogenic activity, indicating that unusual functionalization of these dimeric indole alkaloids may still be a prospective area. 6

Biogenetic Pathways

Dimeric alkaloids are formed via the coupling of monomeric subunits belonging to the monoterpenoid indole alkaloids class. 7 There are 2500 indole alkaloids isolated originally from three families of plants (Rubiaceae/Naucleaceae, Loganiaceae/Strychnaceae and Apocynaceae) (Scheme 3). Leucophyllidine and the above vinca alkaloids belong to the latter family. These alkaloids are issued from secologanin 8 and tryptamine 9. This reaction is catalyzed by an enzyme, the strictosidine synthase, leading to strictosidine 10, the basic monomeric alkaloid intermediate in the biosynthesis of indole alkaloids. 8 As shown above (Scheme 3), these monomeric alkaloids can be classified into several classes based in the type of skeleton I, II or III resulting from the further rearrangement of strictosidine.

Rearrangement, ring contraction or extension may lead to more complex alkaloids. Depending on these different skeletons, dimers could be formed from the coupling of two monomeric indole alkaloids which will lead to more common heterodimeric indole alkaloids than homodimeric ones. Chemotaxonomic network could be found in the plant between these different alkaloids. Table 1 gives a summary about this network.

As an archetypal example of such dimers, the synthesis of Vinblastine 6 was proposed, after a biogenetic analysis, to result from a direct coupling between a plumeran (type III) skeleton, represented by Vindoline 12, and an ibogan (type II) skeleton, represented by catharanthine 13 (Scheme 4). This hypothesis, 9 verified in vivo, has since been used by several synthetic chemists in their total synthesis plans. 10,11 Recently Morita studied the biogenetic hypothesis that showed a Mannich-type coupling reaction between type I and III skeletons. 12 For example, Bisleuconothine A 14, recently isolated form Leuconotis griffithii, showed this type of coupling (Scheme 5). 13

Isolation and structure of Leucophyllidine and Eucophylline

Leucophyllidine 1 was isolated as a minor alkaloid from the EtOH extract of the stem-bark of Leuconotis griffithii in yield of 7.10 mg/Kg. It was obtained after several chromatographic fractionation of the basic fraction from the EtOH, then crystallization from Et 2 O-EtOAc. The structure of Leucophyllidine was established unambiguously through X-ray diffraction studies (Figure 1). 1 While isolation of the tetracyclic vinylquinoline alkaloid, Eucophylline 3, was achieved from the alkaloidal fraction prepared from a MeOH extract of the bark of Leuconotis eugenifolius. 2 This fraction was introduced to Sephadex LH-20, silica gel, and amino silica gel columns and ODS HPLC to give Eucophylline 3 (1.9 mg; 0.00039%) along with Leucophyllidine, Eburnamine, configuration of C-20 was assigned by comparing the experimental CD Spectra (Circular dichroism calculation) with the calculate CD spectra performed by Turbomole 6.1(Figure 3). 14

Biogenetic Pathways to Leucophyllidine and Eucophylline

Since Leucophyllidine has an unprecedented structure, new biogenic pathways had to be proposed.

The originality of Leucophyllidine structure stems from two points. The first one is that Leucophyllidine represents the first member of new structural bisindole alkaloids based on the constituent monomeric halves. 15 The second point is the vinylquinoline half, Eucophylline, constituted from a new unprecedented tetrahydrobenzo [b] [START_REF]Isolation of the desired diastereoisomer and re-equilibration of the tetracyclic epimer 463b by using BF 3 -etherate (according to Fuji's method) was performed[END_REF]8]naphthyridine skeleton. So the proposed biogenetic pathway is based on the fact that all the alkaloids present in Leuconotis are monoterpenoid indoles. A first proposed biogenetic pathway starts from the Aspidosperma precursor 15. 1 This pathway was corrected later after an error in the configuration of the Aspidosperma precursor 15 (Scheme 6). 16 Nevertheless, another possible biogenetic pathway was proposed by Morita et al. 2 This pathway relies on the biogenesis of Aspidosperma precursor 15 to Leuconolam derivative through melodinustype alkaloid. Such transformation could be possible through an internal Michael addition. After ring closure, Eucophylline could be formed by the attack of piperidine NH onto the carbonyl then dehydration, (Scheme 7).

Biological Activity of Leucophyllidine and Eucophylline

Vinca alkaloid members showed a wide range of biological activity. Beside their fascinating complex structure, they proved themselves as potent chemotherapeutic agents towards the most dangerous and frightening disease, cancer. The most recognized members of this family, Vinblastine 5 and Vincristine 4, have been used for cancer treatment over the last 50 years. Their biological effects depend on the perturbations in the microtubule dynamics that lead to inhibition of mitosis in cancer cells. Both Vinblastine and Vincristine are efficacious clinical drugs and are used in combination therapies for treatment of Hodgkin's disease, testicular cancer, ovarian cancer, breast cancer, head and neck cancer, and non-Hodgkin's lymphoma or in the curative treatment regimens for childhood lymphocytic leukemia and Hodgkin's disease. 17 Despite this activity and clinical therapies and due to the mutation of cancer cells, a new generation of this cancer cells becomes more resistant to those medications. Chemists also developed new anticancer agents such as Fluorovinblastine that showed better activity and selectivity for these cells (Figure 4). With the increasing demand for more efficient and targetable antitumer agents, Leucophyllidine 1 stands out as a promising agent. It has already shown a promising in vitro cytotxicity toward vincristine-resistant human KB cells with IC 50 of less than 3 μg/mol. 1 While the level of activity is not outstanding, the selectivity toward resistant cells is of considerable interest. Morita et al. 2 also evaluated the effect of expression on iNOS protein in J774.1 cells stimulated by LPS by using western blotting analysis. When the cells were stimulated by LPS, iNOS protein in the cells was overexpressed, subjected to overproduction of NO. They found that Leucophyllidine 1 decreased the iNOS protein expression dose-dependently. Besides that, Leucophyllidine 1 and Eucophylline 3 showed high cell viability of J774.1 at concentration of 7.1 μM. 2 Based on the previously mentioned facts, Leucophyllidine 1 is a particular promising anticancer target, which retained our attention for two important reasons; Firstly, its selectivity and pronounced cytotoxicity and secondly, the unusual quinoline sub-structure that opens new perspectives for the discovery of potent drugs in cancer chemotherapy.

Synthetic approaches to dimeric indole alkaloids

The key step for forming the bisindole alkaloids is a biomimetic coupling between the two alkaloid monomers. Despite the logic of this disconnection, it has only scarcely been explored. We will discuss below only few examples that show the importance of biomimetic coupling in synthesis of bisindole alkaloids. One of the most important examples for the biomimetic approaches has been proposed by Boger and co-workers. 11 They were able, through Fe(III) mediated-coupling of Catharanthine 13 and Vindoline 12, to provide a straightforward and biomimetic access to vinblastine 5 (Scheme 8).

Recently, Haplophytine 26 attracted the attention of several groups. 18 This alkaloid is composed of two subunits linked by a quaternary carbon center. Recent investigations by Corey et al. 19 on the biomimetic approach to the core of Haplophytine showed that the formation of this quaternary center was very challenging. Haplophytine is composed of two indole moieties; one of them is Aspidophytine 27 that is also present in the plant. Acidic treatment of Haplophytine results in a 1,2cationic shift that generates upon rearrangement a new bis-iminium skeleton, which contain two indole fragments that are probably involved in the biosynthetic pathway (Scheme 9).

Based on these premises, Corey investigated coupling models between electron-rich arenes and Canthiphytine derivatives (Scheme 10). Several tries finally showed that biomimetic coupling is not operative to generate the benzylic quaternary center under the studied conditions, also pointing out the difficulties in finding proper conditions to initiate this sterically unfavorable coupling.

One of the important strategies in this kind of couplings is enamine-iminium chemistry. Such a process is very common in the biosynthesis of other classes of natural products. Based on this fact, Husson et al. 20 investigated the biomimetic approaches to link monomeric indole units to access the dimeric structure of natural product Ervafoline 28. Thus, authors demonstrated that α-cyanopiperidines are equivalent and stable forms of iminium salts. So they allowed the enamine 29 to react with α-cyano-piperidine 30 in presence of AgBF 4 to afford the dimer 31 in 20% yield. This reaction paved the way to access Ervafoline 28 and demonstrated the possible biogenetic pathway formation of two of the three bonds in Ervafoline 28 (Scheme 11). 20 Henriques, A.; Husson, H.-P. Tetrahedron lett. 1981, 22, 567-570.

Despite the apparent complexity of these biomimetic couplings, they may be very easy in some cases. For example, Vobparicine 32 results from the union of the two monoterpenic indole alkaloids, Apparicine 33 and Vobasinol 34. Biomimetically, treatment of Vobasinol with an excess of Apparicine under acidic conditions effectively led to Vobparicine (Scheme 12). 21 The coupling was speculated to occur through the reaction at C-3′ electrophilic center of Vobasinol and C-22 electronrich center of Apparicine.

General Retrosynthesis of Leucophyllidine and Eucophylline

In view of aforementioned facts, it is clear that Leucophyllidine 1 may be resulted from the biomimetic coupling between the Eburnane 2 and Eucophylline 3 through a Mannich type reaction between the C-7 electrophilic center of Eburnane and the C-1′ electron-rich center of Eucophylline.

This assumption, which is in good agreement with the proposed biogenic pathway by Kim 1, constitutes our first step in the retrosynthesis of Leucophyllidine (Scheme 13). 21 Van Beek, T. A.; Verpoorte, R.; Baerheim Swenden, A. Tetrahedron Lett. 1984Lett. , 25, 2057Lett. -2060. . The key step in the construction of the quaternary centers in both fragments, Eburnane and Eucophylline, is the multi-component free radical carbo-oximation reaction between the appropriate olefin, a sulfonyloxime and a xanthate ester (Scheme 14).

In case of Eburnane retrosynthesis, the oxime functional group will be later hydrolyzed to aldehyde 35, which will be allowed to react with tryptamine under Pictet-Spengler reaction conditions to afford the tetracyclic lactam 36. The latter will hopefully give, through a sequence of transformations, a straightforward access to Eburnane 2 (Scheme 14).

In the case of Eucophylline retrosynthesis, the fully functionalized oxime will be subjected to sequences of reductions and post activation of the free alcohol, followed by cyclization to afford the bicyclic lactam. This lactam will be coupled with a functionalized aniline 38 under Vilsmeier reaction conditions to afford amidine 39, which after cyclization and installation of the vinyl group will eventually lead to the desired natural product, Eucophylline 3 (Scheme 14).

This dissertation is composed of four chapters. We will discuss in the first one, various aspects of free radical reactions, including the stability of radicals and multi-component reactions along with their development in the group.

The second chapter will focus on the total synthesis of Eucophylline, starting by optimization of the key free radical carbo-oximation reaction, followed by the elaboration of the bicyclic lactam and the mechanism of the formation of these bicyclic systems under Vilsmeier-type reaction conditions.

Finally, completion of the total synthesis of Eucophylline will be discussed.

In chapter three, the synthesis of Eburnane through different pathways will be investigated along with the development of the new carbo-cyanation reaction. The scope of this new reaction and its advantages will be screened in details, followed by its application in the Eburnane synthesis.

Finally, in chapter four, the preliminary studies about the biomimetic coupling between Eburnane half and Eucophylline on model compounds, which were accessed easily, will be presented.

Chapter one

Free Radical Multi-Component Chemistry

Introduction to Radical Chemistry

It is actully two centuries, since the first carbon radical was discovered. Gay-Lussac in 1815 reported the formation of cyanogen (the dimer of • CN) by heating mercuric cyanide. 24 After this experiment, numerous experiments involving pyrolysis of organometallic compounds were done notably by Bunsen, 25 Frankland, 26 and Wurtz 27 in the 1840s. All of these experiments proposed the idea of the existence of carbon radicals, but there were no available physical methods to detect these radicals. Till 1900, when Gomberg reported the preparation of triphenylmethyl radical, 28 the first stable and free trivalent carbon radical.

A lot of scientific doubt pushed more scientists to prove the existence of carbon radicals, 29 until 1929, when Paneth and Hofeditz clearly reported the existence of alkyl radicals through their experiments of thermolysis of vapor phase of Pb(CH 3 ) 4 and other organometallic compounds. 30 Moreover, Staudinger in 1920 suggested that free radicals were involved in polymerization reactions of olefins. 31 After that, Flory came out with a definitive paper on the kinetics of vinyl polymerization reactions, which confirmed the nature of these reactions as free radical propagations. 32 Since then, great spurts in polymer industrial growth were achieved.

In the middle of the last century, with beginning of spectroscopic era, the discoveries of NMR and EPR and commercialization of them had a great effect on development of the radical chemistry. As a result of this development, Giese was able to add nucleophilic radicals onto unactivated olefins. 33 Barton also used thiohydroxamates in generating radicals and trapping them by other radical traps. 34 More than 80000 publications appeared focusing on EPR spectroscopy of radicals and more than half of those publications were devoted to carbon-centered radicals.

All of these important observation and reactions, besides the fact that radical chemistry has great compatibility with different functional groups with broad chemoselectivity, prompted synthetic chemists to use radical chemistry. Radical processes turned out to be important tools, which facilitates greatly the access to many important targets and natural products. 35 Along this chapter, the fundamentals of radical chemistry and multicomponent free radical reactions will be highlighted.

Structure and Stability of Radicals

The carbon-centered radical (R 3 C • ) may adopt several geometrical configurations. This trivalent radical may change its configuration from pyramidal to planar. This change is quite rapid and is affected by the type of substituents on the carbon bearing the radical. Trivalent radicals can thus change their hybridization from sp 3 to sp 2 depending on the nature of the substituent. For example, in the case of the methyl radical, the radical appears as planar as the barrier of inversion is very small (Scheme 15).

In the other side, the pyramidal structure of the radical increases in the following order: Ethyl < ipropyl < t-butyl. This phenomenon could be explained by the fact that the hyperconjugation between the SOMO and σ orbital of C-H bond stabilizes the pyramidal structure (Scheme 16). 36 Not only the pyramidal structure is favored in case of conjugation with adjacent C-H bonds, but also when the carbon bearing radical has π-donor substituents. For example, when fluorine or oxygen is one of the substituents on the carbon bearing the radical, the radical will be pyramidal. This could be rationalized due to the repulsion between the p orbital of the radical and the lone pair of oxygen or fluorine. That explains why • CF 3 is a pyrimadized radical. 35 (a) Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991Rev. , 91, 1237Rev. -1286 ; ;(b) The stability of a radical depends on thermodynamic and kinetic factors. The principal thermodynamic factor is hyperconjugation and delocalization of radical through mesomeric structures (Scheme 17).

Hybridization also has an influence on the stability of the radical. The more s character is present on the SOMO, the more the radical is destabilized. This could explain the fact that alkyl radicals are more stable than vinyl and alkynyl radicals (Scheme 18).

The thermodynamic stability of the radical R • could be measured through the bond dissociation energy of the R-H bond (BDE). In other words, the radical is formed more easily, if BDE of the broken bond is small (Scheme 19). 29 On the other hand, kinetic factors that affect the stability of radicals are more influenced by the steric hindrance around the radical center. The more the radical is sterically hindered, the more it is stable and long lived. For this reasons, Gomberg 28 was able to detect triphenylmethyl radical.

Stability and reactivity are strongly related. The more the radical is stable, the less it is reactive. The reactivity of different radical types will be discussed below.

Reactivity of Radicals

The reactivity of radicals can be determined through two important points. The first, which we discussed in the last section, is the stability of the generated radicals, in other words the structural factors. The second point, that we are going to discuss in this section, is the thermodynamic of the reaction; the energetic summary of the broken and formed bonds during the radical reactions steps.

From a thermodynamic point of view, the energy summary will give an idea if this reaction is possible or not. For example, the addition of a C-centered radical onto an olefin is possible, and as a result a gain in energy relative to the new formed σ bond will suggest that this reaction is exothermic. In the most cases, radical reactions are exothermic.

According to Hammond's postulate, in radical transformations, the transition state energy is close to the energy of the reaction components. Based on that, the Frontier Molecular Orbital theory (FMO) 37 can be applied, providing a satisfying explanation of the radical reactivity.

Let us consider a reaction between a radical R • and an olefin. The radical electron in SOMO can interact with HOMO or LUMO orbitals of the olefin. Based on the difference of energy between these orbitals (SOMO and HOMO or LUMO of olefin) the reactivity between the two molecules can be described. The rate of addition of the C-centered radical onto the olefin will depend on the energy difference between the SOMO orbital of the radical and the orbitals HOMO or LUMO of the olefin.

The closer the orbitals (i.e. energy barrier is small), the faster is the reaction. In all cases, there are two scenarios for this interaction (Figure 5):

1. A carbon radical that have electron donating groups (a nucleophilic radical) will have highly energetic SOMO orbital and then will add more easily to an energetically low LUMO orbital of an electron poor olefin (substituted by electron withdrawing groups).

2. In contrast, a C-centered radical having electron withdrawing groups (electrophilic radical)

will add more favorably to an electron rich olefin through an interaction between the low energetic SOMO orbital of the radical and the highly energetic HOMO orbital of the olefin.

37 Fleming, I. in Frontier Orbitals and Organic Chemical Reactions, Wiley, New-York, 1976, 5, 182-186.

From the aforementioned details, it is important to understand the behavior of the radical to classify them according to their polarities or according to the used substrates. In (Scheme 20), the different types of radicals and radical acceptors are categorized according to their polarities. 38 It is worth noticing that this classification is just to guide chemists to design their radical reactions taking into consideration the possible species that could react together. However, once the radical is generated, it is highly reactive and could react with different classes of radical acceptors. For example, an electrophilic radical may react with an electron-poor olefin, if there is no other choice.

And in this case, the reaction will occur with a slow rate.

Multi-component Reactions

In the beginning of 1990s, with the appearance of high-throughput screening in the pharmaceutical industry, the use of multi-component reactions (MCRs) became an important and attractive synthetic strategy. MCRs provide an easy and rapid access to large libraries of organic compounds with diverse substitution patterns.

MCRs are generally defined as reactions in which more than two reactants combine to form a product, which retains the majority of the atoms of the starting materials. Mannich (1912) 42 and Passerini (1921) 43 reactions. In the second half of the last century, in part due to the seminal contributions from Ugi (1959), 44 MCRs began to show its power in the synthesis of libraries of compounds. Since then, they became one of the cornerstones of combinatorial chemistry.

Figure 6. Graphical scheme illustrating the differences between conventional multi-stages synthesis and MCRs.

39 (a) Strecker, A. Justus Liebigs Ann. Chem. 1850, 75, 27-51 ; (b) Strecker, A., Ann. Chem. Pharm. 1850, 91, 349. 40 Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1-82. 41 (a) Biginelli, P. Ber. Dtsch. Chem. Ges. 1891, 24, 2962 ; (b) Biginelli, P. Ber. Dtsch. Chem. Ges. 1893, 26, 447. 42 Mannich, C.; Krösche, W. Arch. Pharm. 1912, 250, 647-667. 43 Passerini, M. Gazz. Chim. Ital. 1921, 51, 181-189. 44 (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbrucker, C. Angew. Chem. 1959, 71, 386 ;(b)

Conventional multi-stages synthesis

Multi-Component Reactions (MCR)

Energy waste Energy waste

Energy waste

MCRs fit well with green chemistry concepts. 45 As they respect the atom-, step-and energy-efficient synthesis rules. It is no longer sufficient to "make the molecule", but chemists have to synthesize it in an environmentally benign manner, with a minimal amount of resources, energy and wastes.

MCRs can also give access to complex structures in a simple and efficient one-pot process. For example, the synthesis of piperazine-2-carboxamide (the central part of Crixivan®, protease inhibitor for treatment of HIV) was achieved by a 4CR-Ugi reaction. The synthesis of nifedipine (Adalat®, a highly active calcium antagonist) was also made through a one-step 3CR-Hantsch reaction and is a striking example of the power of MCRs. 46 By integrating the advantages of MCRs such as selectivity, efficiency, compatibility and tolerance to different functional groups with the broad chemoselectivity of radical reactions, very powerful synthetic tools could be developed to access more complex targets in an efficient manner. During the following part of this chapter, we will overview the development of free radical multicomponent reactions.

Free-Radical Multi-Component Reactions

Radical MCRs are highly convergent processes which lead to complex structures, starting from simple and readily available materials. To design successful radical MCR, the polarities of the generated radicals during the reaction course must be taken in consideration. The polarity of radicals generated during each individual step, given by the classification depicted in (Scheme 20), must be chosen carefully to avoid the formation of undesired products. The collected data about radical kinetics and stabilities during last decades (additions, abstraction, fragmentations, etc.) helped greatly in predicting and designing radical MCRs.

Radical Carbo-allylation Reactions

One of the first radical MCRs, developed in 1988 by Mizuno et al. 47 47 Mizuno, K.; Ikeda, M.; Toda, S.; Otsuji, Y. J. Am. Chem. Soc. 1988, 110, 1288-1290. 48 Wu, J H.; Radinov, R.; Porter, N. A. J. Am. Chem. Soc. 1995, 117, 11029-11030.

Carbonylative Radical Reaction

Depending on the fact that carbon monoxide is a good radical acceptor, Lipscomb et al. 51 in 1956 were able to develop the first radical MCR by using high pressure of CO. Thus, through the radical addition of a thiyl radical 61 onto propene 60, the resulting radical 62 reacted with CO as the third component to form an acyl radical, which upon abstraction of hydrogen from the thiol gave the product 65 in low yield. This could be rationalized due to the formation of a sulfide side product 64 (Scheme 26). Later Tsuji was able to improve the yields by using [Co 2 (CO) 8 ] as a catalyst. 52 More efficient processes were developed by Ryu and Sonoda to synthesize unsymmetrical ketones by using CO in radical MCR. 53 Thus, by initiating the radical chain with AIBN, the alkyl radical 68, generated from the corresponding iodide 66, added to CO to form the nucleophilic acyl radical 69 which in turn reacted with the electron deficient olefins 67 to form the radical 70, which was finally reduced by tin hydride to form the product 71 in good yield (Scheme 27).

51 Foster, R. E.; Larchar, A. W.; Lipscomb, R. D.; McKusick, B. C. J. Am. Chem. Soc. 1956, 78, 5606-5611. 52 Susuki, T.; Tsuji, J. J. Org. Chem. 1970, 35, 2982-2986. 53 (a) Ryu, I.; Uehara, S.; Hirao, H.; Fukuyama, T. Org. Lett. 2008Lett. , 10, 1005Lett. -1008 ; ;(b)

Arylation radical reaction

Aryl radicals, generated from the corresponding aryl diazonium salts, have been known for the last century. 54 The well-known Meerwein reaction which involves the addition of aryl diazonium salts The final product 78 was obtained in excellent yield after electron transfer to Ti III (Scheme 28).

To increase the impact of these aryl radicals, the same group remarkably developed a threecomponent carbo-diazenylation reaction that involved addition of an aliphatic radical to diazonium salts. In a fruitful cooperation between Landais and Heinrich groups, they were able to develop the carbodiazenylation reaction that involved an intramolecular radical cyclization of diazonium-substituted allyl phenyl ethers, followed by radical trapping through carbohydroxylation, carbonitrosation, vinylation, and allylation reactions (Scheme 30). 57

Carbo-phosphorylation Radical Reaction

Introducing phosphorus-containing substituents onto organic structures constitutes an important challenge that organic chemist have faced for a long time.

Radical Addition to Imines

The reactivity of imines motivated a lot of chemists to explore the possibility to use them as radical acceptors. However, due to the easy hydrolysis of imines and the possibility of tautomerism, oxime ethers and hydrazones were more attractive. The aminyl radicals that are formed from the radical addition on imines are less stable than those resulting from additions to oxime ethers or hydrazones.

From a kinetic point of view, the radical addition to imines is relatively slow as compared to addition onto oxime and hydrazone. The reason is that the electron density on oxime's or hydrazones's carbon (C=N) is low (the less electron density on carbon, the better radical acceptor).

Accordingly the reactivity of these functional groups could be ordered as follows: hydrazone > oxime > imine. 60 Radical version of the Strecker and Mannich reactions were however developed recently.

Radical Strecker Reaction

The ionic version of the Strecker reaction, first developed about two centuries ago, gives an access Tetrahedron Lett. 1997, 38, 2487-2490. 61 Canella, R.; Clerici, A.; Panzeri, W.; Pastori, N.; Punta, C.; Porta, O. J. Am. Chem. Soc. 2006, 128, 5358 -5359 generated iminium (from condensation of amine 100 and aldehyde 101 in presence of Ti IV ). The resulting cationic radical 104 is finally reduced by Ti III to form an α-aminoamide 105 (Scheme 32).

This method provides an efficient and wide access to different aliphatic and aromatic αaminoamides in one-pot and in mild conditions. The same group later extended this methodology to ketones. 62

Radical Mannich Reaction

Similarly to the previous reaction, a radical version of the Mannich reaction was developed by Tomioka in 2003. 63 The reaction was initiated by dimethylzinc and oxygen. This generates a methyl radical, which can abstract hydrogen α-to the oxygen of THF 106. The radical thus formed then adds to the imine 110 generated in situ (resulted from condensation of amine 107 and aldehyde 108) to give the aminyl radical 111. This radical in turn reacts by homolytic substitution on dimethylzinc to give the zincate derivative 112 along with a methyl radical which sustains the radical chain.

Treatment of the zincate derivative eventually afforded β-aminoether 113 in good yields (Scheme

33).

62 Pastori, N.

Radical-Ionic Multi-component Reactions

Reducing or oxidizing radicals formed in the reaction medium can generate respectively anions or cations which may be trapped in classical ionic reactions. Following this idea, several research groups developed MCRs that combine radical and ionic mechanisms. This is generally featured by the metallic species which can selectively reduce or oxidize the formed radicals. During the following section, the different radical-ionic MCRs will be highlighted.

Radical-anionic MCRs

In this type of reactions, the formed radical is reduced by metal species having reducing properties to create a nucleophilic species which may then react with an electrophile in a standard ionic process. Researchers developed numerous tandem processes from this type by involving different metals species such as Cr, 65 Co, 66 Pd, 67 Sm 68 and Ti. 69 Among all of these metal species, boron and zinc derivatives received more attention due to their commercial availability. benzaldehyde, affording homoallylic alcohol 135 in good yield and excellent diastereoselectivity (Scheme 37).

Radical-cationic MCRs

Applying the same concept than with the radical-anionic MCRs, the radical-cationic MCRs rely on the capacity of the metal to oxidize the formed radical selectively and generate a true electrophile.

The common oxidants used in this type of processes are Mn or Ce. In case of Mn, and based on the work developed by Corey, 73 Fristad, 74 and Snider, 75 Ryu and Alper were able to oxidize the acyl radical by Mn III . 76 They used Mn III to do two tasks in this reaction. The first task is to generate an electrophilic malonyl radical 138 from malonate 136, which adds to olefin 137. The second task is to oxidize the acyl radical 140, resulting from the reaction of radical 139 with carbon monoxide, into an acylium cation 140. This cation is immediately trapped by the nucleophilic water to give the carboxylic acid 142 (Scheme 38).

More recently, Masson and coworkers 77 used CAN [Ce(NH 4 ) 2 (NO 3 ) 6 ] as oxidant to generate cationic radical from enamide 143. This radical could react with allylsilane 144 to give radical 147, which is oxidized by Ce IV followed by elimination of the silicon group to give iminium 148. The new iminium 148 is trapped by an alcohol 145 to give β-allylated α-amidoethers 149 in good yields (Scheme 39).

Photoredox-catalyzed Radical MCRs.

Since the beginning of the last century, scientists try to use sunlight to develop organic reactions.

But the major obstacle they faced is that most organic molecules are not able to absorb sunlight. Therefore, chemists developed photocatalysts, which are able to absorb the light and transfer this energy to perform chemical transformations. Researchers found that the most efficient catalysts are based on ruthenium (II) and iridium (III). With the idea in mind to use light to initiate radical-ionic processes, Masson's group studied oxyalkylation of ene-carbamates in the presence of iridium (III). 78 They proposed two mechanisms for generating the radical and oxidizing it. The first mechanism, proposed the formation of the electrophilic malonyl radical through transfer of one electron from Ir (III)* to bromomalonate 150. This radical attacks an ene-carbamate 151 to form the nucleophilic radical 153, that is oxidized quickly by Ir (III)* into an N-acyliminium cation 154. This cation is then trapped by an alcohol to form α-amidoethers 155 (Scheme 40). This oxidative mechanism did not rationalize the role of Et 3 N in the reaction. So the second mechanism proposed a reductive pathway, starting by reduction of Ir (III)* to Ir (II) by Et 3 N. Bromomalonate 150 could be reduced to the electrophilic malonyl radical 152 by Ir (II) . After addition of this radical to the enecarbamate 151, the generated α-aminyl radical 153 could be oxidized either by the bromomalonate

Free-Radical Multi-component Reactions with Sulfonyl Derivatives

The electrophilic nature of sulfonyl radicals, their availability and easy preparation made them good candidates for radical MCRs. Their electrophilicity allowed the addition of the sulfonyl radical to electron rich olefins and alkynes, the process being governed by the reversibility of the reaction and the ratio between the rate of addition and rate of β-fragmentation (Scheme 41).

Ueno et al. 79 first used allylthioethers as allylation agents to cyclize bromoaniline derivatives 156.

The reaction was initiated by AIBN, which abstracted the hydrogen of Bu 3 SnH to generate the tin radical. The latter then abstracted bromine to generate the intermediate radical 157. Cyclization of the latter, followed by fragmentation of the phenylthiyl radical afforded the cyclized product 158 (Scheme 42).

Later, Russell showed the utility of vinyl thioethers, sulfoxides and sulfones in allylation reactions, and their ability to fragment and afford the substituted olefins after the addition of alkyl radical. 80 As an application of these sulfones fragmentations, Keck et al. 81 were the first to use allylsulfones in synthesis of natural products (Scheme 43).

Through such examples, researchers shed light on the utility of these sulfones in radical reactions. In the next part of this chapter, we will focus on the development of sulfonyl derivatives in free radical MCRs. 82

Kinetic Aspects

The reversibility of the addition process of sulfonyl radicals to olefins depends on the rate of βfragmentation of this radical as shown above (Scheme 41).

Addition of nucleophilic radical R 1 to α-position of sulfone 163 provide an alkyl or a vinyl radical which may fragment to provide the alkene or alkyne 165 and a sulfonyl radical 166. The rate of βfragmentation of sulfonyl radical 166 is depending on the stability of the intermediate radical 164 (Scheme 44). 83 80 Russell, G. A.; Tashtoush, H.; Ngoviwatchai, P. J. Am. Chem. Soc. 1984, 106, 4622-4623. 81 Keck, G. E.; Tafesh, A. M. J. Org. Chem. 1989, 54, 5845-5846. 82 Ovadia, B.; Robert, F.; Landais, Y. Chimia 2016, 70, 34-42. 83 (a) Timokhin, V. I.; Gastaldi, S.; Bertrand, M. P.; Chatgilialoglu, C. J. Org. Chem. 2003, 68, 3532-3537;(b) The generated sulfonyl radical 166 may then evolve through two ways depending on R 3 substituent.

When R 3 is an aryl group, arylsulfonyl radicals are known to be relatively stable and cannot fragment (under the reaction conditions) and sustain the radical chain. Then, they will react with other radical chain propagator like tin derivatives or with other less toxic species like silane derivatives (e.g. TTMSS: (Me 3 Si) 3 SiH) which was developed by Chatgilialoglu. 84 It is worth noticing that in case of TTMSS, the concentration of the silane should be lower than the concentration of sulfone derivatives, otherwise the reduction product will be the only isolable product. When R 3 is an alkyl group, alkylsulfonyl radicals are less stable and tend to undergo αscission with extrusion of SO 2 to generate alkyl radicals which can also propagate the radical chain.

Zard et al. 85 showed that ethyl radical, which is generated from ethylsulfonyl radical after SO 2 extrusion, could propagate the radical chain in the absence of tin reagents. Also, when R 3 is CF 3 group, trifluoromethanesulfonyl radical decomposes very quickly to form the electrophilic trifluoromethyl radical (Scheme 44). 86 Fuchs et al. 87 used this phenomenon to propagate and sustain a radical reactions through electrophilic trifluoromethyl radical which cloud rapidly abstract hydrogen from alkane or from position α to oxygen of an ether and generate nucleophilic radical which add to the starting triflone and sustain the radical chain. The reaction between the three components was categorized as "ADA" free radical multi-component system (Acceptor, Donor, Acceptor systems). 38 In this system, the first electrophilic radical (acceptor), generated from the corresponding xanthates or alkyl halides after abstraction of halide or xanthate by tin radical, add to the less hindered end of an electron-rich olefin (donor). The newly formed nucleophilic radical can then be trapped by the electrophilic sulfone derivatives (acceptor).

The sulfonyl radical, generated after β-fragmentation, propagate the chain by reacting with stoichiometric amount of hexabutylditin (Scheme 49).

Based Similarly, Free radical carbo-alkynylation MCRs were developed in our group starting from alkynylsulfone 210, 211. The yields are in general good, but it was observed that the yields are better with alkynylsulfone 211 bearing a trimethylsilyl group. This may be due to the low polarization in silylalkynyl sulfone as compared to alkynylsulfone 210 (Scheme 52).

The Mulliken population analysis, studied by DFT calculations, showed a partial negative charge on the alkyne carbon center αto the sulfone. The high polarization in case of alkynylsulfone 210 leads to mismatch reactivity towards the electron-poor radical species, generated from the radical precursor 208, which explain the modest yields in this cases. In contrast, little or no polarization was observed on silylalkyne 211, which may be due to the strong π-d interaction between silicon (a πacceptor) and the carbon center (Scheme 52). 91

Carbo-azidation

Renaud et al. 93 were the first to report the use of sulfonylazides as radical traps. With systems similar to the ones used in carbo-alkenylation, they were able to form C-C bond and C-N bond in one pot. In the same way, the electrophilic radicals, generated from corresponding alkyl halides 213, could add to the electron-rich olefins 214 to afford the nucleophilic radical which in turn was trapped by sulfonylazide 215 to finally give the azide product 216 in excellent yields (Scheme 53).

The potentiality of this reaction is illustrated with the straightforward synthesis of Lepadiformine 218, the tricyclic core being elaborated in only two steps using a carbo-azidation reaction as a key step. Access to spirolactams 217 was also easily achieved through a of carbo-azidation/reduction sequence (Scheme 53). 94 In a fruitful cooperation between Renaud and Landais teams, the stereocontrol in carbo-azidation reaction of acyclic chiral allylsilanes was investigated. 95 The level of diastereocontrol depends on the nature of the silicon group and on the R 1 substituent.

This diastereocontrol could be rationalized through Felkin-Ahn type model, which suggested pyramidalized transitional state and quasi-staggered confirmation to avoid gauche interactions between the most hindered groups SiR 3 and (CH 2 ) 2 CO 2 Et. According to that, the sulfonyl azide is believed to approach anti relative to the bulky silicon group from the side of the smallest H substituent. The formation of minor diastereomer would result from an approach of sulfonylazide 215 anti relative to the silicon group, but closer to the bulky R 2 substituent. It is also worth noticing that in such transition state, the developing positive charge β to silicon is best stabilized by overlapping with the quasi coplanar electron-rich C-Si bond (silicon β-effect) (Scheme 54).

As an application of this methodology, the first diastereoselective total synthesis of the potent glycosidase inhibitor (+)-Hyacinthacine A It is worth noticing that, using a sulfone in this reaction is crucial for two reasons. First, the sulfone group decreases the energy difference between the SOMO of the alkyl radical and the LUMO of the radical acceptor, which in turn will increase the rate of addition of the alkyl radical to the oxime.

This feature was not present when a PhS was used instead of a PhSO 2 group. The second point concerns the radical chain propagation through the reaction of the β-fragmented sulfone with bis(trialkyl)tin that showed much better efficacy than the propagation through a phenyl-thio radical.

Recently our laboratory devised a sequential four component carbo-oximation reaction. 98 adds to electron-rich olefin 232 to generate the nucleophilic intermediate radical which is rapidly trapped by the electrophilic sulfonyloxime 233 to afford, after reaction with an alkyl radical or an allylzinc reagent, the lactamized products 235, 236 in good yields and high diastereoselectivity (Scheme 57). This sequence represents a straightforward strategy to access to highly substituted piperidinones with up to three stereogenic centers generated in a one-pot operation.

Our group also devised new oximes that showed better synthetic utility. 99 For instance the SEMsulfonyl oxime 239, was found to be slightly more reactive than the OBn-sulfonyl oxime 233. Thus smoother hydrolysis of this new oxime, after the 3CR-carbo-oximation reaction, afforded an efficient access to an aldehyde, which underwent Pictet-Spengler/lactamization sequence to give a rapid and high yielding access to the tetracyclic core 240 of eburnane alkaloids (Scheme 58).

Considering the aforementioned reactions, the sulfonyl radical plays an essential role in chain propagation through its reaction with bis(trialkyl)tin derivatives. Thus, using stoichiometric amount of tin derivatives is required. But tin derivatives have drawbacks beside their toxicity. 100 The large amount of tin derivatives used in these reactions to sustain radical chain, generates large amounts of tin residue which contaminate the final products.

To avoid using tin derivatives in MCRs, our group devised new bifunctional reagents which incorporate both the oxime function and the radical precursor. The behavior of these bifunctional reagents relies on the α-scission of the alkylsulfonyl radical intermediate. 101 These new reagents play two roles in MCRs. First, they act as a source of electrophilic radicals, which add to the electron-rich olefin. Then, they can be trapped by the resulting nucleophilic radicals generated during the MCRs processes (Scheme 59).

Although the process can be carried out under tin-free conditions, a catalytic amount of (Bu 3 Sn) 2 was shown to increase the reaction yield. The initiation mechanism is interesting and starts by the abstraction of one of the two benzylic hydrogen atoms by the t-BuO radical, followed by the βfragmentation of the generated benzylic radical to release benzaldehyde, HCN and SO 2 and give the electrophilic radical 245. The latter then adds to the electron-rich olefin 242, generating the nucleophilic radical 246 which was trapped by the starting oxime 241 to afford the product 243.

According to this reaction mechanism, tin is not required in this reaction and its role in catalytic amount is not yet clear. It is envisioned that the tin nucleophilic radical could attack the sulfonyloxime 243 to generate a stabilized alkoxyaminyl radical, followed by a β-fragmentation to generate the electrophilic radical 245 more efficiently (Scheme 59).

101 Ovadia, B.; Robert, F.; Landais, Y. Org. Lett. 2015Lett. , 17, 1958Lett. -1961.

Conclusion

Along this chapter, we presented the state of the art in multi-component radical reactions. The combination of radical processes and multicomponent reactions showed its efficiency to access complex structures and form several bonds in one step. With this free radical MCRs, C-C, C-N, C-Cl bonds and different functional groups could be installed in one step and in an efficient way. We showed also the utility of sulfonyl radicals in MCRs and how they can propagate the radical chain, increase the rate of the reactions and integrate wide range of functional groups (azide, alkene, alkyne, oxime and alkyl). Moreover, the pronounced impact of these MCRs was highlighted through the synthesis of several natural products, which show that this synthetic tool may be utile in total synthesis of the natural products that will be presented in this dissertation, Leucophyllidine and Eucophylline. In the next chapter, we will focus on the optimization of the carbo-oximation MCR process and show how it was used to elaborate Eucophylline.

Chapter two

Total Synthesis of Eucophylline

Introduction

Eucophylline 3,102 the recently isolated tetracyclic vinylquinoline alkaloid from Leuconotis eugenifolius, retained our attention. This new skeleton has an unprecedented tetrahydrobenzo [b][1,8]naphthyridine chromophore, which posed questions about its biogenetic pathway. The access to the naphthyridine core which incorporates a bicyclic system with an ethyl group on the all-carbon quaternary stereocenter represents a challenging issue for organic chemists.

The synthesis of bicyclic systems, like the one present in Eucophylline, has not been well-reported before. Only few methods reported the synthesis of simple bicyclic systems without any substitution on the bridgehead carbon, making our mission more challenging. Besides, the synthesis of Eucophylline, the south fragment of Leucophyllidine 1, will pave the way for the total synthesis of cytotoxic bisindole alkaloid, Leucophyllidine. All of these motifs prompted us to develop an access to Eucophylline.

Along this chapter, the efforts towards total synthesis of Eucophylline will be presented, relying on the recently developed carbo-oximation reaction. In parallel, deep focus on the bridgehead bicyclic lactams and a remarkably stable bicycle α-chloroenamine will be discussed.

Retrosynthesis Analysis

The retrosynthesis analysis of Eucophylline is centralized around the synthesis of a challenging bicyclic system, the synthesis of which will be based on the recently developed free radical carbooximation multi-component reaction. 103 Two different disconnection strategies were proposed:

Iodoquinoline Strategy.

In this approach, the tetracyclic vinylquinoline could be formed after the reaction between piperidine NH and quinoline amide in 248 under Vilsmeier reaction conditions to form cycle C. The piperidine ring D would in turn be formed from the cyclization of a free amine on an alcohol, activated as a mesylate, both amine and alcohol being formed by reductions of respectively an oxime and an ester.

The quaternary center would be accessed relying on the free radical carbo-oximation reaction between the iodoquinoline 251, sulfonyl oxime 233, and olefin 252. The reactive vinylic fragment could be introduced after formation of piperidine cycle D through a Suzuki coupling (Scheme 61). It is worth noting that this approach is very similar to the proposed biogenetic pathway proposed by Morita and coworkers. 102

Azabicyclo[3.3.1]nonane Strategy

In this approach, the reactive vinylic fragment would be introduced in a late stageof the synthesis through a Suzuki coupling after formation of tetracyclic vinylquinoline 253. This tetracycle would be formed from the base-mediated cyclization of amidine 254 (Friedla nder type cyclization), which in turn would be formed from the coupling between simple trisubstituted aniline 38 and the azabicyclo[3.3.1]nonane 37 This bicycle 37 would be accessed after reduction of the fully functionalized oxime 254, followed by lactamization and cyclization. The oxime 254 could de synthesized relying on the free radical carbo-oximation reaction between the sulfonyl oxime 233, xanthate ester 219 and olefin 252 (Scheme 62)

First Strategy: Iodoquinoline Strategy.

Two questions had to be answered following this strategy. Would it be possible to generate a stable radical at C-9 of quinoline 255 and would this radical be electrophilic enough to add onto an electron-rich olefin?

The pioneering work by Parsons et al. 104 in generating radical in C-9 position of quinoline derivatives like 256 was a promising start for our approach. This group was able to alkylate quinoline 256 by olefin 257 through a reaction mediated by manganese (III) acetate in AcOH. The reaction started by initial oxidation of 256 to form radical 258 through formation of a manganese (III) enolate, which is favored in this type of reactions. 105 Then, the electrophilic radical 258 added to the electron-rich olefin 257 to form the secondary radical, which was oxidized by another equivalent of manganese (III) to generate cation 259. This cation was trapped by the enol hydroxyl group to form the five-membered ring 260 (Scheme 63).

Based on these promising results, a quinoline model was synthesized and tested under carbooximation reaction conditions. Therefore, the quinoline 263 was synthesized from the readily available aniline through protection of the free amine by a benzyl group, followed by a reaction with malonic acid to give the desired quinoline 263 in low yield (Scheme 64). 106Trials to improve the efficiency of the last step, either by reacting benzyl protected aniline with diethylmalonate 107 or by reacting with malonyl chloride, 108 did not improve the yield significantly (Scheme 65). This synthesis has not been optimized further since the goal was just to investigate the feasibility of this approach. With this hydroxyquinoline in hand, the next step was the iodination of this quinoline 263 through the reaction either with iodine and periodic acid in EtOH or by NIS in MeCN. The yields in both cases were low (Scheme 66). 109 With the iodoquinoline 264 in hand, we tested the first free-radical multi-component carbooximation process. 103 For this test, the electron-rich allylsilane 265 was used, with sulfonyloxime 233 in benzene. The reaction was initiated by the DTBHN/(Bu 3 Sn) 2 system (Scheme 67). 107 Mohamed, E. A. J. Chem. Soc. Pak. 1991, 13, 166-168. 108 There are two reasons which could explain the failure of these carbo-oximation MCRs. The first one could be the electrophilicity of the generated radical in quinoline ring, too low to add efficiently onto the electron-rich allylsilane. This explanation was supported by the results obtained from the free-radical two-component reaction between this quinoline 268 and allylsulfone 169 (Scheme 70).

Interestingly, instead of obtaining the allylated quinoline 271, the de-iodinated quinoline 267 was the only isolated product in 40% yield. This reaction showed that the generated radical in C-9 position of quinoline ring is likely not electrophilic enough to add onto the π-system of olefins. The second reason could be the free alcohol group, which showed in some cases incompatibility with this type of free-radical reactions. 103 Based on these results and assumptions, we decided to focus our attention on the second proposed strategy for accessing Eucophylline. It was envisioned that this strategy could provide a general and straightforward access for preparing bicyclic lactams and therefore an entry to the natural product Eucophylline 3.

Second Strategy: Azabicyclo[3.3.1]nonane Strategy

The key intermediate in this strategy is the bicyclic lactam 37 that contains the allcarbon stereogenic quaternary center. The synthesis of bicyclic systems, like the one present in Eucophylline, has not been well-reported before. Only few methods reported the synthesis of simple bicyclic systems without substitution in the bridgehead carbon.

In the following part we will shed light on the chemistry of bicyclic bridgehead lactams and the chemistry of twisted and strained amides.

Bicyclic Bridgehead Lactams

The low reactivity of amides usually stems from the planarity of the N-C=O system. This planar geometry allows strong resonance interaction between n N and π* C=O orbitals and hence more stability (Scheme 71). But some deviation of this planarity was observed in peptides, small molecules and in bicyclic systems. 111 The normal properties of amide bonds include (i) the relatively In these bicyclic bridgehead lactams, the non-planar geometry of the amide bond implies that the lone pair of electrons on nitrogen is not any more in conjugation with the adjacent π orbitals of the carbonyl group. 113 This has a strong influence on these amide properties as compared to those of planar amides. These twisted amides are more reactive towards amide hydrolysis and nucleophilic attack on the carbonyl carbon. 115 Also, they have different reactive sites for amide protonation and alkylation reactions. Consequently, spectroscopic and physical properties are completely different from those of planar amides. 116 The importance of these twisted amides has been extended to the peptide chemistry. As they are analogues to the transition state encountered by peptides amide bonds during a cis-trans isomerization, they can give more insight into the important feature of protein folding. 117

General Properties of Bridgehead Lactams

In this section we will focus on the physical properties of bridgehead lactams including the degree of distortion, bond lengths and spectroscopic properties. Also a comparison between these lactams and their counterparts in bridgehead olefins will be discussed. When the twist angle (τ) is 0°, the amide bond is planar without a tetrahedral character for nitrogen and carbon since χ N = χ C = 0°. In contrast, when twist angle (τ) is 90°, then the N-C(O) bond is orthogonal and χ N = χ C = 60° for fully pyramidalized amide bonds. Till now, only two bridged lactams with perfectly perpendicular amide bonds have been confirmed structurally (Scheme 73). 119,120 The other bridgehead lactams showed distorted geometries of amide bonds characterized by medium τ and χ N values.

It also worth notice that, for most of the reported bridgehead lactams, the χ C values are close to 0° regardless to the degree of distortion. This fact reflects the tendency of these lactams to be in the amino ketone resonance form. 121 Also the distortion of amides could be quantified by the sum of three bond angles at nitrogen (θ) (Figure 7). 122 For instance, the ideally sp 3 hybridized atom have θ = 328.4°, while the sp 2 atom have θ = 360.0°. As the distortion of amide bonds increase, the length of N-C(O) bond increase significantly and C=O bond shortens slightly. These observations showed the tendency of twisted amides to be in the amino-ketone resonance form and also indicate the gradual pyramidalization of the nitrogen atom. 123 The obvious example for this phenomenon is 1-aza-2-adamantanone 273, in which the N-C(O) bond is 1.475Å, longer than that of the corresponding N-methyl-δ-valerolactam by 0.15 Å. As a result, the C=O bond length is 1.196 Å, 0.037 Å shorter than for the planar analogue. 120 c) Spectroscopic Properties of Bridgehead Lactams.

The spectroscopic properties of these lactams exhibit values in the region between normal ketones and planar lactams. Therefore, the infrared carbonyl stretching frequencies of amide bonds are characterized by increased υ C=O values and more downfield 13 C=O resonance compared to planar amides. 124 For example, the perfectly twisted amide 273, showed υ C=O at 1732 cm -1 in IR and 200.0 ppm in 13 C NMR, which showed how these amides behave like amino-ketone rather than amide groups.

d) Similarities between Bridgehead lactams and Bridgehead Olefins.

Bridgehead lactams are also known as anti-Bredt lactams. This is due to the partial double bond character that appears during the resonating forms of these amides. 125 In general, Bredt's rule states that a double bond cannot be placed at the bridgehead of a bridged ring system, unless the rings are large enough. 126 Generally, bridgehead lactams are more stable and easier to prepare than the corresponding bridgehead olefins because the amide nitrogen atom can adopt sp 3 geometry in the amino-ketone resonance without violating the octet rule. 112 In 1981, Schleyer proposed the olefin strain energy parameter, which is defined as the difference between the strain energy of the olefin and that of its parent hydrocarbon and is directly related to the enthalpy of hydrogenation. 127 From this parameter, he showed that the bridgehead olefins with olefin strain energy below 17 kcal/mol could be isolated. Olefins with strain energy between 17 and 21 kcal/mol could be observed. But, those with olefin strain energy higher than 21 kcal/mol are classified as unstable. In comparison between bridgehead lactams and their analogues of bridgehead olefins, it is obvious that the highly strained bridgehead lactams are stable enough for isolation comparing to their analogues of bridgehead olefins (Scheme 74). It is also worth noticing that prior to Schleyer olefin strain energy, Fawcett proposed an empirical parameter to predict violations of Bredt's rule. 128 This parameter was the S value which represents the sum of atoms contained in all the bridges of the bicyclic system. For example, a bicyclo[3.2.1]octane has an S value of 6. Therefore, according to Fawcett's generalization, bridged bicyclic systems with bridgehead double bonds with an S value ≥ 9 have the potential to be isolated.

While systems with S = 7 could be observed but not isolated. Whereas those with S = 6 could be entertained as fleeting intermediates. In the same period, Prelog proposed that only bicyclo[5.3.1] or larger systems (S ≥ 9) could contain a stable bridgehead double bond. 129

Synthesis of Bridgehead Lactams

The challenging synthesis of strained bicyclic bridgehead lactams attracted organic chemist since beginning of the last century. After Bredt stated his rule, Lukes tried to prepare the bridgehead lactams 275, 277 through condensation under thermal conditions, but without success. Then, he proposed that such amides with nitrogen atom at the bridgehead position would be sterically impossible to generate (Scheme 74). 130 In the same era, Woodward also tried and failed to synthesize related bicyclic 2-quinuclidones 279. 131 However, he concluded that such compounds would constitute a new type of amino-ketone.

128 Fawcett, F. S. Chem. Rev. 1950, 47, 219-274. 129 (a) Prelog, V.; Ruzicka, L.; Barman, P.;Frenkiel, L. Helv. Chim. Acta 1948, 31, 92-97;(b) Since then, many attempts to synthesize these different types of bridgehead lactams were developed. 114 Only the efforts done for the synthesis of bicyclic[3.3.1] bridgehead lactams present in Eucophylline will be presented. In 1949, Walker et al. 132 reported the formation of 1-azabicyclo[3.3.1]nonan-2-one derivative 281 during their studies on the hydrogenation reactions catalyzed by copper chromite. The reaction underwent intramolecular condensation of the cyano diester 280 to the bridgehead lactam 281, which was further reduced under the reaction conditions to 1-azabicyclo[3.3.1]nonane 282 in 39% yield (Scheme 75). Actually, this synthesis was the first to report the formation of bicyclo [3.3.1] bridgehead lactam with substitution in the bridgehead carbon.

Later in 1981, Buchanan and coworkers developed their synthesis by using a gem-dialkyl effect to facilitate the cyclization to the bridgehead amide 285 through substrate 284. Activating the carboxylic acid as an acyl chloride followed by condensation with the secondary amine or by thermal cyclization under high vacuum afforded the 1-azabicyclo[3.3.1]nonan-2-one derivative 285 but in low yield, showing the difficulties to achieve the synthesis of these strained bridgehead lactams through this approach (Scheme 76). 133 132 Badger, G. M.; Cook, J. W.; Walker, T. J. Chem. Soc.1949, 1141-1144. 133 In another synthesis of a bicyclo[3.3.1] bridgehead lactam with substituent at the bridgehead carbon, Najera showed that there was a difference in the cyclization rate between diastereoisomeric amino esters 293 to form bridgehead lactams. The endo-lactam 294 was obtained quantitatively during the removal of the benzyl group, while the amino lactam 295 did not cyclize spontaneously under this reaction conditions and the corresponding exo-lactam 294 was obtained in a separate step after treatment of the amino ester with LDA. It was also observed that the endo-lactam 294 exists in a twist boat-boat conformation due to the steric interactions between the axial methyl group and an axial hydrogen atom. Interestingly, the exo-lactam 294 adopts the common chair-boat conformation, known for this type of bridgehead lactams (Scheme 79). 137 The synthesis of simple bicyclo[3. Later, Sim used the same efficient promoter, Bu 2 SnO, in the synthesis of the closely related bridgehead lactam 303, albeit in moderate yield (Scheme 82). 140 The important information obtained from this synthesis is the distortion parameters. The X-ray structure of lactam 303 showed the following parameters: τ =16.3°; χ N = 49.1° and χ c = 5.8° while the bond lengths were N-C(O) =

1.377Å and C=O = 1.217Å. These parameters, associated with an IR stretching υ C=O at 1680 cm - Another strategy depending on Heck reaction to synthesize the bridged lactams was developed by Grigg. 141 With a catalyst system consisting of Pd(OAc) 2 and PPh 3 , the cyclization of amide substrates 304 occurred in high yield to generate a variety of bridgehead lactams 305 (Scheme 83).

To sum up this part, twisted amides have unique features that combine the ketone and amine properties depending on the degree of distortion they exhibit. As an application for this twisted amides properties, recently Szostak developed chemoselective ketone synthesis by the addition of organometallics to N-acylazetidines. 142 This reaction showed how to activate the inert amide bonds under mild reactions to give useful chemical transformations (Scheme 84).

Also bridgehead lactams and bicyclic systems with different bicyclic ring sizes are present in many natural products (Scheme 85). 112 In the following part, our efforts to access the bicyclo[3.3.1] bridgehead nitrogen system which is present in Eucophylline, will be discussed through a general strategy relaying on the recently developed free-radical carbo-oximation multicomponent reaction.

Synthesis of the Azabicyclo[3.3.1]nonane

Relying on the recently developed free-radical carbo-oximation reaction, it was reasoned that the bicyclic system in Eucophylline could be accessed through a straightforward sequence depicted below (Scheme 86). The initial retrosynthesis analysis depends on olefin 252, sulfonyloxime 233 and the xanthate ester 219, which will undergo a carbo-oximation reaction to construct the desired quaternary center. The diester benzyl oxime ether 309 will be subjected to hydrogenation under high pressure to give the free amine, which will lactamize directly to give the piperidinone 310. After chemoselective reduction of the ester and activation of the generated alcohol as a mesylate, the basemediated cyclization will eventually lead to the desired bicyclic lactam 37 (Scheme 86).

Carbo-oximation MCR with ethyl 4-methylenehexanoate 252

To start this synthesis, the starting materials sulfonyloxime 233 and olefin 252 were synthesized according the following sequences.

Sulfonyl oxime 233:

The sulfonyl oxime, the radical trap in this carbo-oximation process, is prepared according to Kim's procedure. 143 Starting from the commercially available O-benzylhydroxylamine hydrochloride 312 and through condensation with formaldehyde followed by chlorination, compound 314 was obtained in excellent yield. The introduction of the sulfonyl group was carried out through two steps via the intermediate thio-oxime ether 315, followed by oxidation to give the desired sulfonyloxime 315 in 57% overall yield and in a 15 g scale (Scheme 87).

143 Kim, S.; Lee, I. Y.; Yoon, J.-Y.; Oh, D. H. J. Am. Chem. Soc. 1996, 118, 5138-5139. As free-radical multi-component reactions are very sensitive to steric hindrance, a smaller oxime precursor could be also interesting. The easiest modification was the replacement of the benzyl group, with a methyl group. Thus, through a similar sulfonyloxime 233 synthesis pathway, the commercially available methoxyamine hydrochloride 316 was condensed with formaldehyde at 0°C.

Unfortunately, due to the volatility of the formaldehyde O-methyloxime (b.p. = 12-12.5°C/760 mmHg) 144 , the product 317 could not be isolated. Attempts at chlorinating formaldehyde Omethyloxime 317 by NCS in situ were not more successful (Scheme 88).

Olefin 252: ethyl 4-methylenehexanoate

The electron-rich olefin, the second component in this carbo-oximation process, was prepared in two steps from the cheap and commercially available propargyl alcohol 319 by reaction with EtMgBr in the presence of copper iodide as a catalyst and an active stirring. 145 The second step is a Johnson-Claisen rearrangement, proceeding through the reaction of the prepared allylic alcohol 321 with triethyl orthoacetate in the presence of catalytic amount of acetic acid in refluxing toluene, giving the desired olefin 252 in 36% overall yield and in a 5 g scale (Scheme 89). 146 144 Jensen, K. A.; Buss, L.; Holm, A. Acta. Chem. Scand. B, 1977, 31, 28-30. 145 (a) Duboudin, J. G.; Jousseaume, B. J. Organomet. Chem. 1979, 168, 1-11;(b) With these three components in hand, the first attempt of a carbo-oximation process was carried out.

The electrophilic radical, generated by the action of DTBHN/(Bu 3 Sn) 2 on the corresponding xanthate ester, added to the less substituted end of the electron-rich olefin 252 to give the nucleophilic tertiary radical, which in turn was trapped by sulfonyl oxime 233, to give the desired product 309 in 46% (Scheme 90). It also worth noticing that addition of DTBHN was repeated every 1.5 h till consumption of starting xanthate ester since DTBHN decomposes with half life time of 29 min at 65 °C. 147,148 The moderate yield prompted us to study the reaction mechanism more carefully and start a reaction optimization to increase the yield of this key reaction. Therefore, we first tried to increase the amount of olefin 252 (up to 10 eq.) since the concentration of the electron-rich olefin as compared to sulfonyloxime is crucial in this reaction. Unfortunately, the yield did not improve by increasing the olefin concentration. The byproduct 322, which results from the addition of electrophilic radical to sulfonyloxime, implies that either the olefin 252 is not electron-rich enough to attack this radical or the sulfonyloxime 233 concentration is too high allowing considerable part (15%) of the electrophilic radical to add on it (table 2).

Attempts to increase the reaction yield also included changing the olefin 252 for other olefins 325a,b having the same number of carbons. Thus, in entry (3, 4, table 2), yields of carbo-oximation reactions, with olefins bearing an alcohol protected as benzoate or silyl ether, were not improved. As in (entry 3, table 2), no trace of product was observed. Instead, the reduction product 323, resulting from the reduction of the nucleophilic radical, was the major isolable product along with many other unidentified byproducts. In entry 4, the silyl protected olefin 325b gave the expected product 326b, but in very low yield along with the byproduct 323.

Our attention was then directed to the xanthate ester part. It was reported that in some cases the xanthate part, which reacts with tin gives numerous tin residues, which complicates the separation and purification of the product. 103 It is also known that the iodine tin bond is strong and that iodine-tin residues are solids which could facilitate the isolation of the product. The proposed reaction mechanism for the formation of the product 309, byproduct 322 and reduction product 323 is shown in (Scheme 91). The expected product is formed after a sequence of two bonds formation. The first results from the addition of an electrophilic radical 326, onto the electron-rich olefin. While the second bond was formed after trapping of the nucleophilic radical 327 by sulfonyl oxime 233, ending up with the formation of the desired product. The reaction starts by the decomposition of DTBHN (half life time of 29 min at 65 °C) into tert-butoxyl radicals which react with hexabutyldistannane to give tributylstannyl radical which propagate the chain.

The byproduct 322 was formed after addition of the electrophilic radical 326 to sulfonyloxime 233, followed by β-fragmentation of the sulfonyl radical, which sustains the radical chain. This product is formed in specific cases when the second component, the olefin, is not electron-rich enough or sterically too hindered. On the other hand, the reduction product 323 may be formed when the sterically hindered tertiary nucleophilic radical abstracts hydrogen from tin residues or any other source. At this point the radical chain is broken, stopping the reaction.

Despite the rather low yield of the carbo-oximation reaction, the total synthesis of Eucophylline was pursued. So with the MCR product 309 in hand, the hydrogenation of the oxime into an amine accompanied by direct lactamization with one of the two esters would give the piperidinone ring 310. Thus, the hydrogenation of benzyl oxime ether 309 using Raney nickel under 50 atm of hydrogen pressure for 3 days afforded the desired piperidinone ring 310 in 72% yield without observation of the corresponding imide (Scheme 92). 150 The formation of the imide (through a double cyclization) under these conditions seems difficult because further ring closure in system like 310 is not favored, in good agreement with early studies of Buchanan. 135 The challenging chemoselective reduction of ethyl ester into the corresponding alcohol in the presence of an amide group led to some difficulties (Scheme 93). Soon after our work on this part of the project, Kerr et al. 152 reported the reduction of a similar system using about 40 eq. of NaBH 4 , added in portions every 10 minutes under MeOH reflux.

Carbo-oximation MCR with diethyl 4-methyleneheptanedioate 329

At this point, an olefin like 329 was found to be a promising equivalent to the olefin 252.

Interestingly, this olefin 329 will also be of interest in the context of the development of an asymmetric synthesis of Eucophylline. Consequently, a little modification in the disconnection approach was introduced. Since an extra ester group will be present in the final compound, this ester will give us a chance to desymmetrize the prochiral diester 331 by hydrolyzing it into the corresponding acid, which will then be decarboxylated later using Barton decarboxylation, 153 installing the desired all-carbon quaternary stereogenic center (Scheme 94).

151 Seyden-Penne, J.; Curran, D. P. Reductions by the alumino-and borohydrides in organic synthesis; Wiley-VCH: New York, 1997. Thus, the diester olefin 329 was prepared from the corresponding commercially available ketone 333, through a Wittig olefination reaction by methyltriphenylphosphonium bromide in nearly quantitative yield (Scheme 95). 154 With this diester olefin 329 in hand, the carbo-oximation process was carried out. Unfortunately, the yield (40%) was also modest (Scheme 96).

In a fruitful cooperation between our group and Ryu group, we tried to improve the yield of this reaction by the use of continuous flow chemistry. A visiting PhD student, Mr. Takenori Totoki, tried to perform the three-component carbo-oximation reaction under flow microreactor conditions.

154 Harada, K.; Imai, A.; Uto, K.; Carter, R. G.; Kubo, M.; Hioki, H.; Fukuyama, Y. Org. Lett. 2011, 13, 988-991. In this process, a benzene solution of xanthate ester 219, (Bu 3 Sn) 2 and DTBHN was mixed with a benzene solution of diester olefin 329 and sulfonyl oxime 233 in the first T-shaped micromixer (M1, stainless-steel made, 400 μm channel diameter). The reaction was allowed to pass through the microreactor (R1) with a residence time of 90 min at 65°C. Another addition of DTBHN was mixed with the reaction flow through (M2) and the reaction flow was allowed to pass through microreactor (R2) for another 90 min at 65°C. After collection of the reaction flow, the crude mixture was concentrated and chromatographed to afford the desired diester product in 42% yield (Scheme 97).

Since the yields being similar between the flow technique and the batch system, this process was abandoned.

At this point, a small modification of the approach was envisaged and the xanthate ester was replaced by α-bromosulfone 334 (Scheme 98). 155 The expected MCR product 335 with two esters and a sulfone group could be subjected to desulfonylation reaction, after formation of the piperidinone ring, by Al(Hg) amalgam to give the quaternary center with the desired ethyl group. 156 But again, the carbo-oximation reaction with α-bromosulfone 334 led to a modest yield (44%). The reduction product 336 was also observed in this reaction.

155 Makosza, M.; Golinski, J.; Baran, J. J. Org. Chem. 1984, 49, 1488-1494. 156 Kajiwara, Y.; Scott, A. I. Tetrahedron Lett. 2002, 43, 8795-8496.

Carbo-oxim io CR wi α-Iodothioester 337

To avoid the chemoselectivity problems that appeared during the reduction of ethyl ester in the presence of amide functional group in piperidinone like 310, our efforts were directed towards another functional group that could be reduced under milder conditions. The thioester group appeared to be a good candidate for this purpose. Again, a small modification to our original disconnection approach was added. Depending on the versatility of carbo-oximation reaction, αiodothioester 337 will be used instead of xanthate or iodide ethyl ester 219, 324 (Scheme 99)

Therefore, α-iodothioester 337 was synthesized according to the procedure described by Coltart et al. 157 from the corresponding 2-bromoacetyl bromide 339. After reaction of 339 with thiophenol, the bromide atom was exchanged by iodine under Finkelstein reaction conditions (Scheme 100).

157 Yost, J. M.; Alfie, R. J.; Tarsis, E. M.; Chong, I.; Coltart, D. M. chem. Comm. 2011, 47, 571-572.

The first carbo-oximation reaction with α-iodothioester 337 was promising. The reaction worked efficiently, under the same reaction conditions than before, in good and reproducible 67% yield (Scheme 101). It is worth noticing that, this reaction also worked well in large scale (5 g of isolated pure product) with the possibility to recover the excess of olefin 252 and oxime 233. The reaction is also clean and the product is easier to isolate as compared to the reaction with xanthate ester 219.

The key carbo-oximation step being optimized with the installation of a thioester group, a chemoselective reduction of this thioester group to alcohol was then attempted before the reduction of the oxime (with subsequent cyclization to the amide). Therefore, the reduction of thioester 338 by The hydrogenation of benzyl oxime ether 341 over Raney Nickel under 50 atm. of hydrogen for 3 days gave the free amine which cyclized directly onto the ethyl ester, affording the hydroxy-lactam 328 (Scheme 103). 159 After the quantitative activation of the free alcohol as a mesylate, the lactam 311 was submitted to sodium hydride promoting the cyclization, giving the bicyclic lactam 37 in 71% yield (Scheme 104). 160 This short sequence provides a new straightforward access to this strained bicyclic amide in four steps and 31% overall yield. This oily bicyclic lactam could not be recrystallized, but the IR stretching υ C=O at 1678 cm -1 and the 13 C NMR for the carbonyl carbon at 184.4 ppm indicate that this lactam 37 showed a moderate distortion of the amide bond, very similarly to the twisted amide 285 reported by Buchanan, 135 which suggests that the twist angle (τ) is around 20°.

Desymmetrization of Prochiral Esters

With the idea to develop an asymmetric synthesis of Eucophylline, the carbo-oximation reaction was also run between the potentially successful radical precursor, α-iodothioester 337, the symmetrical diester olefin 329 and the sulfonyl oxime 233 to afford the prochiral product 343 in a satisfactory 63% yield (Scheme 105). At this stage, the prochiral quaternary carbon could be made stereogenic by hydrolyzing one of the two esters to afford the corresponding acid ester 344, the acid chain being transformed in an ethyl group through a Barton decarboxylation. 153 This mono-hydrolysis of the diester could be done enantioselectively by the use of enzymes (bio-catalyzed desymmetrization).

The advantage of an enzymatic desymmetrization is the ability to obtain the desired enantiomer with yield up to 100% in comparison with kinetic resolution where only 50% of the initial matter is transformed into the desired enantiomer. 161 One of the most common enzymes used to desymmetrize a diester by mono-hydrolysis is the Pig Liver Esterase (PLE). PLE is one of the hydrolytic enzymes with the better synthetic potential. 162 It has been used for many desymmetrizations of diester. For example, Wender et al. 163 Based on these premises, the first desymmetrization trial was done with the prochiral diester 343.

The diester 343 was dissolved in a mixture of DMSO/phosphate buffer pH = 8 (4/1), then 45 units of PLE were added in three portions every 2 days to the reaction mixture. The temperature of the reaction was kept at 25°C and stirred for 6 days. Unfortunately, the acid ester 344 was not observed under these conditions and the only isolated product was the starting diester 343 (Scheme 107).

The anticipated difficult differentiation between the two ethyl esters and thioester groups165 prompted us to engage the chemoselective reduction of the thioester 343 into the corresponding alcohol diester 349. The enzymatic desymmetrization was repeated on the new diester under the same conditions but unfortunately, after 6 days, the only isolated product was also the starting material 343 (Scheme 108).

As this stage, we gave up our wish to develop an enantioselective route to the bicycle[3.3.1.]nonane and reported our attention to the elaboration in racemic series of the quinoline core of Eucophylline.

Synthesis of Quinoline Tetracyclic Core

One of the simplest methods to construct the quinoline ring system is the Friendländer reaction, based on an acid-or base-promoted condensation between an aromatic 2-amino-substituted carbonyl compound and an appropriately substituted carbonyl derivative containing a reactive α-methylene group. 166 The Friendländer reaction mechanism may be explained through two different possible pathways. The first one, starting from 2-amino-substituted aromatic carbonyl compound 350 and the carbonyl partner 351, involves the formation of the Schiff base 352 followed by an intramolecular aldol reaction to give the hydroxyl imine 353 (path A). The second proposed mechanism suggests that under typically acidic [H 2 SO 4 , HCl, p-TsOH] or basic (NaOH) conditions, the intermolecular aldol reaction is the first step and is followed by the formation of the Schiff base (path B). The dehydration (that may also happen before the formation of the Schiff base), then produces the expected quinoline 354 (Scheme 109).

The synthesis of a 2-amino substituted quinoline would involve, when following the path A, the formation of an intermediate amidine (Scheme 110).

But in contrast with the condensation between an amine and a ketone, the formation of an amidine cannot proceed by direct condensation of an amine with an amide. This condensation has to be triggered by a strong dehydrating agent. The coupling between the amides and anilines is known to proceed under Vilsmeier reaction conditions by the mediation of POCl 3 . 167 The preliminary coupling between the monocyclic lactam 360 with the substituted aniline 359, prepared from the commercially available nitro-benzoic acid, afforded the desired amidine 361 in 92% yield (Scheme

111).

However, an extension of this procedure to the coupling between our bicyclic lactam 37 and the same aniline 359 was disappointing. The reaction worked with a poor yield and led to a lot of degradation. The product was also difficult to isolate in a pure form (Scheme 112). This difference in reactivity may be explained by the particular reactivity of the twisted amide or by the steric hindrance.

To reduce the steric hindrance that may impede with the coupling, the methyl ester group in aniline 359 was replaced by a nitrile group. The nitrile group is very small with A value = 0.21 which will help in reducing the steric hindrance in this coupling process. 168 Consequently, the cyano aniline 363 was introduced to react with bicyclic lactam 37 in the presence of POCl 3 . Pleasingly, the reaction worked well this time to give amidine 364 in 88% yield (Scheme 113).

Mechanistic insights

The reaction between amides or lactams and POCl 3 is well-known to afford the corresponding αchloroiminiums, often called Vilsmeier intermediates, which then react efficiently with nucleophiles, including amines to form amidines (Scheme 114). 167 But in the case of highly strained bridgehead lactams, the formation of iminium species, like

Vilsmeier-Haack intermediate 366, is not favored according to Bredt's rule. This hypothesis prompted us to investigate the mechanism of this reaction.

In an attempt to try to observe the Vilsmeier-Haack intermediate, the bicyclic lactam model 297, prepared following a Steliou procedure, 138 was treated with POCl 3 in dry DCM under reflux for 3 h.

The Vilsmeier-Haack intermediate 368 could not be observed from the reaction but surprisingly, a remarkably stable bicyclic α-chloroenamine 369 could be isolated after column chromatography. In an optimized synthesis, after basic treatment of the reaction mixture with 30% NaOH till pH = 8, followed by extraction by DCM, the crude mixture is purified by column chromatography, and the bicyclic α-chloroenamine 369 could be isolated in 60% yield (Scheme 115). This result prompted us to study more in depth the chemistry of this α-chloroenamine.

The remarkable stability of this bicyclic α-chloroenamine questioned us about the general stability of chloroenamines and how these chloroenamines may be synthesized. Some answers are provided in the following lines.

Synthesis of α-chloroenamines.

In general, α-haloenamines behave as ambiphilic molecules and react as nucleophilic reagents at the β-carbon atom of the enamine function, but also show electrophilic reactivity at the α-carbon atom through the intermediate formation of a keteniminium salt (Scheme 116). By tuning the ambiphilicity of α-haloenamines through variation of the nature of the halogen atom or the amine substituents, a controllable unique reactivity of enamines could be obtained. Ghosez et.

al. pioneered the synthesis and isolation of α-haloenamines. 170 In 1969, this group was able to synthesize α-chloroenamines from the corresponding tertiary amides 370 by reacting them with phosgene followed by dehydrochlorination of the intermediate chloroiminium with triethylamine.

Later, the same group used less toxic chlorinating agents like phosphorous oxychloride or oxybromide (to obtain α-bromoenamines) (Scheme 117).

It is worth noticing that all of the reactions reported must be run under strict anhydrous conditions and that these α-haloenamines must be kept away from moisture, since they are very sensitive to any traces of water and degrade rapidly. More recently, Sarpong and coworkers reported the synthesis of α-haloeneformamides 375 from the corresponding caprolactam 374 through the reaction with POCl 3 or POBr 3 . 173 The important factor that allowed this group to isolate this enamine easily is the presence of a formyl group, an electron withdrawing substituent on the nitrogen atom. But it has also been noticed that these enamines are not stable for long time outside the fridge (Scheme 119).

Stability of α-chloroenamines.

From the previous examples, it is clear that isolation of this type of enamines in general is not an easy task. The reactivity of enamines, in general, stems from the conjugation between the olefinic πbond of the α,β-carbons and the lone pair of nitrogen (Scheme 120). Normally, an amine has a pyramidal geometry with bond angles around the nitrogen of 109.5°. The lone pair of electrons on the sp 3 -hybridized nitrogen may overlap with the p-orbitals of the π-bond, giving a high nucleophilic character to the β-carbon. 174 This reactivity is then governed by the degree of conjugation of the lone pair with the π-system and this conjugation may be influenced by electronic and steric factors. 174 Thus, the presence of an electron-withdrawing group on nitrogen will significantly alter the reactivity, exemplified by the possible isolation of α-haloeneformamides 375. Also, any variation of the coplanar conformation will have a strong effect on the system properties as it is the case in our bicyclic system where the nitrogen lone pair is forced to be quasi orthogonal to the enamine π-system (Scheme 121). This has also been observed by Doering et al. with the stable l-azabicyclo[3.2.2]non-3-en 376, in which, orthogonal enamine is forced by the bicyclic system to place the nitrogen in a pyramidal geometry with its lone pair perpendicular to the olefinic π bond, conferring the π-system a more standard olefinic character.

Coupling Reaction Mechanism

Based on these results and observations, the next question that arose was the possible involvement of this α-chloroenamine 369 as an intermediate in the coupling reaction between the bicyclic lactam 37 and aniline 363. The purified α-chloroenamine 369 was thus allowed to react with orthocyanoaniline 363 in presence of catalytic amount of TFA. The reaction worked well and the amidine 377 was isolated in 84% yield confirming that the α-chloroenamine 369 is a key reaction intermediate.

Moreover, to draw a mechanism of this reaction, the role of TFA was investigated. Therefore, the reaction was repeated under neutral condition, with just the α-chloroenamine 369 and orthocyanoaniline 363 in refluxing DCM. Surprisingly, the reaction worked well with a similar same yield (77%). The reaction was also performed under basic condition by addition of 2,6-di-tert-butyl pyridine and the same amidine was obtained with the same yield (80%) (Scheme 122). These observations showed that acid and bases are not essential, their role remaining unclear.

Treatment of α-chloroenamine 369 with TFA did not give the corresponding α-choroiminium, but led to the kinetic protonation at the nitrogen center with the formation of α-chloroenaminium salt 378 in quantitative yield (Scheme 123). A 13 C NMR analysis of this salt showed a shifting of the αcarbon of the enamine from 138 ppm to 122 ppm, due to the modification of the electronic environment around this carbon by protonation of neighboring nitrogen. When allowed to react with ortho-cyanoaniline 363, this α-chloroenaminium salt 378 afforded the amidine 377 in 59%. An in situ prototropy in 369 could provide intermediates 379 or 379′, able to react further with aniline 363.

The analogous bridgehead alkene 368, which has been isolated by Marshall et al. is reasonably stable and supports the assumption of the formation of an iminium as an intermediate in the reaction. 176 Surprisingly, when chloroenamine 369 was heated in water at 60 o C for 3 h, it was completely recovered, after extraction from DCM, without any degradation or decomposition, in sharp contrast with what is usually observed with "planar" enamines.

169,172

We also searched for the source of hydrogen that adds onto the β-carbon of enamine (C-2), using deuterated substrates or reagents. First, the use of sub-stoichiometric amount of deuterated trifluoroacetic acid in deuterated DCM catalyzed the reaction but without any change in the amidine 1 H NMR, indicating no incorporation of deuterium in the final product (Scheme 124).

This sub-stoichiometric amount being not optimal to observe a decrease in the CH 2 integration, the aniline was stirred in deuterated methanol to study the exchange of hydrogens with deuteriums.

However, the isolation of fully deuterated aniline was not successful (Scheme 125). 176 (a) Marshall, J. A.; Faubl, H. J. Am. Chem. Soc. 1967, 89, 5965-5966;(b) All of these attempts to explore the mechanism probably failed because the C-2 protons are readily exchangeable and the coupling requires an aqueous basic workup and a chromatography on silica gel, conditions that also favor deuterium-hydrogen exchanges. In an analogous fashion, these conditions were applied to our α-chloroenamine, but the reaction did not proceed and the starting material was recovered (Scheme 128).

These results confirm that our α-chloroenamine cannot form, as expected, a keteniminium intermediate and that the coupling with the aniline should follow another pathway.

To have some insight into the mechanism of the amidine formation, DFT computational studies were performed by Dr Frédéric ROBERT. Starting from the protonated α-chloroenamine 378, it appeared that the α-chloroiminium form 379 is only 1.5 kcal/mol higher, indicating that these two species should be in equilibrium. The α-cyanoaniline would then approach on the upper face to give the addition product 391. The formation of the final amidine 392, obtained after loss of HCl, was found highly exothermic, rationalizing the reaction pathway (Scheme 129). It is also worth noticing that whereas the transition state for aniline attack 390 was relatively low (+10.9 kcal/mol), the equivalent transition state with water attacking the chloroiminium was found much higher (+31.2 kcal/mol), possibly explaining the surprising stability of the α-chloroenamine in hot water.

Reactions wi α-Chloroenamine

The stability of this α-chloroenamine and its bicyclic architecture motivated us to try to functionalize them and explore their unique reactivity. In order to test if the α-chloroenamine would behave like a vinylic chloride, Pd-catalyzed reactions with boronic acids (Suzuki coupling) have been tested. 173 Thus aryl boronic acids 393a-d were allowed to react with α-chloroenamine under Pd-catalysis to afford the corresponding bicyclic aryl-enamines 394a-d in good to excellent yields.

Further functionalization of these arylenamines was performed. For instance, in order to obtain a solid enamine ready for X-ray diffraction studies, arylenamine 394a was reacted with picric acid, but the only isolated solid product was the picric acid. Arylenamine 394b was protected as a tosylate, which worked well in 93%, but unfortunately the compound 396 was also oil. When the nitro group in aryl-enamine 394c was subjected to iron reduction to give the corresponding amine, the reaction unfortunately did not work. Finally, the pyrene-enamine 394d was isolated in solid form which gave us the opportunity to start X-ray diffraction studies. Crystallographic data indicate that the bicyclic system enforces the nitrogen lone pair to be quasi orthogonal to the enamine π-system, explaining the unusual stability of such enamines and chloroenamines (Scheme 130).

Epoxidation of the enamine provides some insights into the reactivity of the enamine double bond.

Thus, arylenamine 394a was allowed to react with m-CPBA in DCM for 2 days. But our attempt to epoxide the enamine double bond was not successful and the only isolated product was the starting material (Scheme 131). The poor nucleophilicity of the double bond as compared to that of normal enamines explains this lack of reactivity.

Elaboration of Eucophylline

To complete the synthesis of Eucophylline, we needed to elaborate the last ring (noted B) in the naphthyridine core. This cyclization could be mediated by a strong base to abstract the more acidic proton, in α-position to the amidine, generating a carbanion which could attack the nitrile group to form the ring. After a work-up and tautomerization, the amino naphthyridine skeleton 402 should be obtained (Scheme 132).

Therefore, with amidine 364 in hand, the cyclization was tried by using t-BuOK. The primary results

were disappointing, as the expected product 402 was formed in only 20% along with recovered starting amidine. Extended reaction time did not improve the yield to a large extent (entry 2, table 4). The reaction was nevertheless clean with only the product and the starting material. The use of a stronger base, LDA, gave much better results (table 4). After some optimizations, the best results

were obtained by preparing very concentrated LDA and running the reaction at room temperature, conditions that gave the desired product in 70% yield (Scheme 133).

Conclusion

In summary, the first total synthesis of Eucophylline 3, the south half of Leucophyllidine

Introduction

Eburnane 2, the north fragment of Leucophyllidine 1, is a pentacyclic indole alkaloid with a skeleton present in many vinca alkaloids, mainly isolated from the plant family Apocyanaceae. 182 For example, Vincamine 407, which is known for its cerebral vasodilatory pharmacological activities, has an Eburnane pentacyclic core with an ester group in ring E. 183 The same pentacyclic core is also present in Eburnamonine 408 and Eburnamine 409 with amide or alcohol in ring E respectively, 184 and the structurally related Tacamine 414. 185 Since isolation of these Eburnane-type alkaloids, organic chemists developed numerous syntheses for constructing its pentacyclic core. Most of these syntheses were based on condensation of aldehydes with tryptamine under Pictet-Spengler reaction conditions or on Bischler-Napieralski intramolecular condensations. In the following part, a survey on the synthesis of this indole pentacyclic structures will be reviewed.

Review on the synthesis of Eburnane Pentacyclic Core

One In 1985, Takano and coworkers synthesized for the first time enantiopure (+)-Eburnamine, (-)-Eburnamenine, and (-)-Eburnamonine starting from L-glutamic acid 446. 192 Therefore, after double alkylation of lactone 447, first by allyl bromide, then by ethyl bromide, the dialkyl lactone 448 was synthesized as a single product. This lactone 448 was functionalized to access the non-tryptamine part required for the synthesis of this series of indole natural products. Therefore, hydroboration of vinylic position by dicyclohexylborane and oxidation by H 2 O 2 afforded the primary alcohol 449.

After detritylation and cleavage of the In 2000, Ghosh and coworkers developed a short synthesis of (±)-Eburnamonine through a key step involving a TiCl 4 promoted three-component coupling of dihydropyran 497, ethyl glyoxylate 498 and tryptamine. 197 Therefore, in a one-pot reaction, the ethyl glyoxylate 498 reacted with dihydropyran 497 in the presence of TiCl 4 to give the corresponding oxonium ion. The latter then reacted in situ with tryptamine to give the key imine 500 in a 1.2:1 E/Z ratio. The crude imine 500 was treated with 6 N HCl to give the amino alcohol 501 as a single diastereomer in 25% yield over two steps. It is believed that the cyclization occurred only on the E-isomer while the Z-isomer might have decomposed under the acidic reaction conditions. Treatment of amino alcohol 501 with triflic anhydride gave the tetracyclic core of Eburnane 502. Installation of the ethyl group through the reaction with EtMgBr, followed by cyclization gave the (±)-Eburnamonine 408 in 11% overall yield (Scheme 149).

197 Ghosh, A. K.; Kawahama, R. J. Org. Chem. 2000, 65, 5433-5435.

Later, Wee and coworkers developed an asymmetric synthesis of (-)-Eburnamonine and (+)-epi-Eburnamonine relying on acid 508. 198 The (S)-508 was prepared from the N-butanoyloxazolidinone 503 through a sequence of functional group transformations with a tertiary C-H insertion of a rhodium-carbene as the key step. The synthesis relied on the fact that dirhodium(II)-carbenoid insertion into configurationally defined tertiary carbon stereocenters was stereospecific and occurred with retention of configuration. Therefore the diazomalonate 506 was treated with Rh 2 (OAc) 4 to give lactone 507 in high regioselectively and excellent yield. After conversion of the protected alcohol 507 into an acid 508, the condensation of 508 with tryptamine to form amide followed by reduction of lactone into diol and protection of the less hindered alcohol gave 509. Oxidation of free alcohol in 509 gave the desired aldehyde, which underwent Pictet-Spengler reaction to give the tetracyclic lactam 510 as a 1:1 mixture of two diastereoisomers. (±)-Eburnamonine 408 was accessed, after functional group transformations, in 21 steps and 1.9% overall yield (Scheme 150).

In 2012, Westwood et al. 199 modified Schlessinger approach to access (±)-Eburnamonine. First, the acid 512 was synthesized in two steps and in 69% yield. Reduction of imine 516 was then carried out more conveniently through a transfer hydrogenation by ammonium formate instead of H 2 gas hydrogenation (Scheme 151).

199 Lancefield, C. S.; Zhou, L.; Lébl, T.; Slawin, A. M. Z.; Westwood, N. J. Org. Lett. 2012, 14, 6166-6169.

Very recently, Prasad developed a new sequence to access (+)-Eburnamonine. 200 The nontryptamine part was accessed starting from L-ethyl lactate 518 and through formation of the chiral quaternary center by a Johnson-Claisen rearrangement. After functional group transformations, aldehyde 523 underwent Pictet-Spengler reaction with tryptamine to give the desired product 524 as a 3:2 mixture of two diastereoisomers. Allylation of 524 afforded a separable mixture of two N-allyl carbolines 525, from which the major isomer was isolated in 56% yield. Construction of the tetracyclic core of eburnane 526 was achieved after treating the diene 525 with the Grubbs secondgeneration catalyst. At the end, (+)-Eburnamonine was isolated in 3.2% overall yield after 15 steps (Scheme 152).

To sum up this review, the common two pathways to access the tetracyclic core of Eburnane are either through the Pictet-Spengler reaction between an aldehyde and tryptamine or though Bischler-Napieralski intramolecular condensations between lactams and the tryptamine indole fragments. In both pathways, the challenging task is to construct the non-tryptamine part in a short and efficient sequence. As shown in the previous syntheses, construction of this non-tryptamine part took at least from 7 to 10 steps, except for a few examples. 189, 197 Nevertheless, controlling the stereochemical outcome in the Pictet-Spengler or Bischler-Napieralski intramolecular condensations cannot be achieved through theses syntheses. The most satisfactory results were observed for the synthesis of (-)-Eburnamonine 408 by Fuji through the enrichment of desired diastereoisomer through epimerization mediated by BF 3 .Et 2 O. 193 In the following part, the construction of the non-tryptamine part will be discussed relying on a short sequence using free radical processes. Furthermore, two different strategies to access eburnane 2, the north fragment of Leucophyllidine 1, will be shown in the remaining part of this chapter.

Eburnane Retrosynthesis Analysis

The retrosynthetic analysis of Eburnane proposed first the disconnection between the tryptamine and aldehyde 35. Therefore, the key reaction for constructing the tetracyclic core 36 will be a Pictet-Spengler reaction between this aldehyde and tryptamine. The challenging task is to construct this aldehyde in a short and straightforward manner. Thus, this approach will be based on the free radical carbo-oximation process between radical precursor 337, olefin 529 and sulfonyl oxime 233 to construct the quaternary center bearing the oxime function group. This oxime 528 could be hydrolysed later in one step to the desired aldehyde 35. Through this approach, the non-tryptamine part of Eburnane could be constructed in two steps only (Scheme 153).

Synthesis of the non-tryptamine part of Eburnane

Through free-radical carbo-oximation process

Similarly to the total synthesis of Eucophylline 3, the construction of the quaternary center in this non-tryptamine part 35 was based on the free-radical carbo-oximation reaction between xanthate ethyl ester 337, olefin 529 and sulfonyl oxime 233. The olefin was not commercially available but its synthesis has been reported in the literature. Thus, the first attempt at synthesizing the latter was based on Bunnelle method to convert ester 531 to allylsilane 530. 201 This allylsilane could later react with formaldehyde to give the desired alkene (Scheme 154). 202 Therefore, the commercially available ethyl propionate 531 was allowed to react with TMSCH 2 MgCl Grignard reagent, which was prepared from the corresponding TMSCH 2 Cl. The reaction is mediated by CeCl 3 , which was powdered and dried at 150°C under vacuum overnight.

Trials to prepare this allylsilane 530 under these conditions were not successful.

Another direct method was reported by Normant et al. for synthesizing this alkene. 203 In this approach, the Grignard reagent EtMgBr was added to protected alcohols 534a-b to give the desired alkene 536 in 85%. Unfortunately, this method proved to be non-reproducible in our hands, neither with TMS-protected alcohol nor with TBDPS-protected one (Scheme 156). 201 Also, another method was reported to synthesize olefin 538 through carbonyl-ene reaction between protected isopentenyl alcohol 537 and paraformaldehyde. 204 Therefore, benzoate protected isopentenyl alcohol 537 was reacted with paraformaldehyde in presence of Me 2 AlCl as a Lewis acid to give the desired olefin 538 albeit in low yield (20%) (Scheme 157).

The low yield of the previous reaction prompted us to find another procedure to circumvent the use of this olefin. Therefore, it was envisioned that thiopyran alkene 540 could be an attractive equivalent for the above olefin, as it could undergo, after carbo-oximation process, a ring opening to give the desired non-tryptamine part (as proposed in Scheme 158). Thus, dihydrothiopyranone 539 was allowed to undergo a Wittig reaction to give the corresponding alkene 540, which was isolated, albeit in low yield (24%). 205 This isolated alkene was volatile, very smelly and degraded quickly outside the fridge. As a consequence, we did not have the opportunity to run the carbo-oximation process with this olefin (Scheme 158).

Finally, olefins 546 could be synthesized based on the reported method by Kitching et al. in two steps from the corresponding protected 3-Butyn-1-ol 544a-c. 206 Therefore, the commercially available and cheap 3-butyn-1-ol 543 was protected as a p-methoxyphenylether and was allowed to undergo iodination reaction with B-iodo-9-BBN. Unfortunately, the reaction was not successful, the product being probably degraded during the workup. Therefore, the protecting group was changed to a TBDMS group, which gave better results but still with moderate yields for the iodination step and addition of EtMgBr. This moderate yield may be due to deprotection of the weak silyl ether group during isolation of the product. Finally, changing the protecting group to the more stable TBDPS silyl ether gave excellent yields in both steps (Scheme 159) With these two protected olefins 546b and 546c in hand, the first carbo-oximation process was examined, by using the optimal conditions developed during the total synthesis of Eucophylline 3 (see chapter two, Scheme 101). Therefore, α-iodothioester, sulfonyl oxime and olefin 546b or olefin 546c were allowed to undergo the free-radical carbo-oximation process to give the desired oxime 547a-b in 29% and 40% yield respectively (Scheme 160).

These modest yields with both olefins 546b-c showed that the generated nucleophilic radical intermediates in these cases are sterically quite hindered. By comparing these results with those observed with olefin 252, used in total synthesis of Eucophylline (carbo-oximation process 67%), it is assumed that with one less carbon on the side chain of the olefin, the generated nucleophilic radical could suffer from steric hindrance which may affect its approach towards the sulfonyl oxime 233. Also, the carbo-oximation process with olefin 548, with a methyl substituent in the olefinic carbon instead of ethyl, worked in 76%, 207 showing that a slight change in the steric environment might have a dramatic effect on the yields of our radical reaction.

With these two oximes in hand, the next step was the hydrolysis of the oxime functional group into an aldehyde, which could be performed according to the reported procedure on secondary oximes. 207 Therefore, oximes 547a-b were allowed to react with formaldehyde in presence of HCl.

Unfortunately, the expected aldehydes 549a-b, were not detected under these conditions.

It was reported that the hydrolysis of SEM-protected oximes is easier than for benzyloximes. 207 At this point, we however decided to change our strategy and search for another group that could be compatible with free-radical processes and easily introduced on this quaternary center with better yields. Furthermore, this group has to be convertible to aldehyde in an easy and reliable manner.

Through Carbo-alkenylation Free-radical process

According to the previous requirements, we figured out that carbo-alkenylation process could be suitable for our purpose. First, this process was demonstrated to be very successful with a wide range of olefins. 208 Second, the only modification in our retrosynthesis analysis would be the sulfonyl acceptor, which will be replaced by the commercially available vinyl bisphenylsulfone 191 or styrylsulfone 192. Third and more importantly, the installed double bond could be cleaved easily under Lemieux-Johnson oxidation209 conditions into the desired aldehyde.

Therefore, to test the viability of this approach, the carbo-alkenylation process between the xanthate ethyl ester 219, vinyl bisphenylsulfone 191 or styrylsulfone 192 and the available allylsilane 265 was performed to give the desired products 193a-b in excellent yields (Scheme 162). 208 The Lemieux-Johnson oxidation of the double bond in carbo-alkenylation product 193a, under standard conditions (OsO 4 , NaIO 4 ), was not successful. 210 This was attributed to the electronwithdrawing effect of the sulfone. In contrast, this reaction worked well in case of carboalkenylation product 193b in 54% isolated yield (Scheme 163).

With this aldehyde 550 in hand, the Pictet-Spengler reaction with tryptamine was performed in the presence of 2.0 equiv. of TFA in DCM at room temperature for 16 h. The reaction worked well, leading to the expected product 551 in 65% isolated yield as a 1:1 mixture of two diasteroisomers (Scheme 164).

With these promising results in hand, this strategy was extended to olefins 546b assigned for synthesis of Eburnane 2. Therefore, the carbo-alkenylation process between the xanthate ethyl ester 219, styrylsulfone 192 and the olefin 546b was performed. Surprisingly, only traces of the product 552 was observed and the isolation of the product in pure form was not successful (~15% yield) (Scheme 165).

Then, we tested the more reactive α-iodothioester 337 instead of xanthate ethyl ester 219.

Unfortunately, the desired product was not detected and the reaction mixture was very complex. The same result was also observed in case of olefin 546c (Scheme 166).

With these disappointing results in carbo-alkenylation approach, we began to think about different multi-component free-radical processes, which could be used to give a rapid access to Eburnane.

Use of dimethyl zinc as chain carrier

To take the advantage of multicomponent free radical processes in constructing quaternary centers in one step, our retrosynthesis was adapted to fit the idea of using methyl radicals as chain carrier.

Therefore, the modified retrosynthetic analysis proposed the use of dimethyl zinc to generate a nucleophilic methyl radical which would add onto activated olefin 554, forming an electrophilic radical, which could finally be trapped by allyl sulfone 169. After construction of the desired quaternary center, the two methyl esters could be discriminated in a later stage based on the reported method by Tello-Aburto et al. 211 Then, the acid 556 could be converted into aldehyde 418, which could undergo a Pictet-Spengler reaction with tryptamine to give the tetracyclic lactam core of Eburnane. Hopefully, Eburnane 2 could be accessed after reduction of lactam and oxidation of the double bond. Therefore, our synthetic approach started with a Rauhut-Currier reaction 212 of methyl acrylate 557, in presence of catalytic amount of tributyl phosphine, to give the desired diester olefin 554 in 23% yield. It is worth noticing that the quality of tributyl phosphine is essential here for the efficiency and yield of this reaction (Scheme 168).

With this olefin in hand, the multi-component radical approach was tested. Therefore, olefin 554, dimethyl zinc and allylsulfone 169 were allowed to react under DTBHN initiation in benzene. The starting olefin had not been consumed after 24 h, and then another addition of DTBHN was performed. Unfortunately, the reaction mixture solidified after 2 days, which likely indicates a polymerization of the starting materials. To avoid this undesired polymerization, the reaction was repeated under the same conditions, but through initiation with O 2 . After 3 day of heating at 65°C and adding O 2 through a syringe pump, the starting material had not been consumed.

Repeating the reaction by using the more stable diethyl zinc reagent did not give the expected product and the starting olefin had not been consumed after 3 days (Scheme 169).

One of the possible reasons that made this reaction difficult is the presence of two olefins in the reaction mixture (olefin 554 and allylsulfone 169). Therefore, to examine the reactivity of olefin 554 towards the addition of methyl or ethyl radicals, generated from organozinc species, a two component radical aerobic reaction between olefin 554 and diethyl zinc was performed. In this trial the starting olefin 554 was consumed, but the reaction mixture was very messy with a lot of side products. (Scheme 170).

The key idea in our approach to access eburnane is to construct the non-tryptamine aldehyde in two steps relying on the multi-component free radical processes. At that point, we were searching for a group that is compatible with free-radical processes, convertible to aldehyde in an easy and reliable manner and small enough to be installed on a quaternary center without suffering from steric hindrance. A cyano group was found to be an ideal candidate for this task. The construction of the non-tryptamine part based on the introduction of a cyano group will be discussed in the following section.

Through a Free-Radical Carbo-cyanation process

The nitrile group is a convenient equivalent the formyl functional group. Simple reduction of nitrile by using DIBAL-H could easily give the desired aldehyde ready for the Pictet-Spengler reaction.

Besides that, the nitrile group with an A-value of 0.21 represents one of the smallest functional group in synthetic organic chemistry. 213 Questions that arose were its compatibility with free-radical multi-component processes and the nature of the appropriate cyanating agent.

A literature review on the radical processes involving nitrile transfer to carbon radicals was overviewed. Hence, in 1992 Barton et al. 214 In 2002, Kim et al. 215 studied cyanation of alkyl halides through a tin-mediated radical cyanation process of primary alkyl iodides 569 with p-toluenesulfonyl cyanide 570 under radiation at 300 nm to give the desired nitrile 571 in excellent yields (Scheme 172). 213 (a) Boiadjiev, S. E.; Lightner, D. A. J. Am. Chem. Soc. 2000, 122, 11328-11339;(b) Few years later, Kim and coworkers reported a new radical approach for the synthesis of aliphatic acyl cyanides based on a tin-free radical cyanocarbonylation, using alkylallylsulfone, arylsulfonyl cyanide 572 and CO (Scheme 173). 216 Recently, Renaud and coworkers reported a cyanation process by using p-toluenesulfonyl cyanide 570. 217 Therefore, olefins 575, 576 were hydroborated with catecholborane followed by treatment with p-toluenesulfonyl cyanide in the presence of a radical initiator (DTBHN or O 2 ) to give the corresponding nitriles 577, 578 in excellent yields (Scheme 174).

From the aforementioned examples, the nitrile group proved to be compatible with free-radical processes and showed high efficacy and tolerance in these reactions. Besides that, the common cyanating agent used in these radical processes is p-toluenesulfonyl cyanide 570, which is a cheap and commercially available starting material.

Therefore, based on these premises, we decided to extend our 3-CR free radical process to include the new three component free-radical carbo-cyanation process. Thus, this new reaction, run with the same optimal reaction conditions used for carbo-oximation process, was very successful. The αiodothioester 337 was allowed to react with olefin 546c and p-toluenesulfonyl cyanide 570 to give the expected nitrile 579a in 79% (Scheme 175). This is to be compared with the 40% yield obtained with the same olefin and thioester, when using the corresponding sulfonyloxime. 216 This new and efficient reaction prompted us to study the scope and limitation of this process, which will be discussed in the following part.

Carbo-cyanation Reaction Scope & Limitations

The above efficient carbo-cyanation process suggested that this reaction could be extended to different radical precursors and olefinic partners. Therefore, with the available radical precursors and olefins present in our laboratory, an extensive study on the scope of this reaction was performed (Scheme 176).

First, different radical precursors were allowed to react with olefin 252, used in synthesis of Eucophylline. In general, yields were very good and reproducible. Therefore, α-iodothioester 337 led to the best results with this olefin as compared to those of α-iodophenol ester 580 and αiodoethyl ester 324. This comparison was extended also to olefins 546c and allylsilane 265. It is also worth noticing that the carbo-cyanation process worked with only (2.0 eq.) of olefin 546b and gave the expected product in good yield.

Secondly, the radical precursor was changed to α-bromosulfone 334 which reacted with olefins 546c and allylsilane 265 to give the expected products 579j and 579k in moderate yields. It is known that α-bromosulfone 334 is not a very reactive radical precursor; however it showed moderate yields in these carbo-cyanation processes. It is worth noticing that side-product 579l was isolated in the carbo-cyanation process between α-bromosulfone 334 and the reactive allylsilane 265. This product may be formed due to the slow addition of α-bromosulfone 334 onto allylsilane 265. This slow addition gave the opportunity to p-toluenesulfonyl cyanide 570 to add across the double bond of allylsilane 265 and form 579l in 34% yield (based on the p-toluenesulfonyl cyanide). Similar observations have been made on analogous poorly reactive radical precursors.

Third, the radical precursor was also changed to the perfluorooctyl iodide 581, which added effectively to the olefin 582 and gave the fluorinated nitrile product 579n in good yield. This reaction paved the way for the construction of pharmacologically active fluorinated structures, bearing nitrile functional group, in one step and in an efficient manner. This scope showed the generality of these multi-component free-radical processes. Radical precursors, bearing electron withdrawing groups, add onto different electron-rich olefins, the new generated radicals being trapped by sulfonyl acceptor, in good to excellent yields.

In the other side, the scope of this efficient reaction with different olefins was studied. Therefore, the more reactive radical precursor, α-iodothioester 337 was allowed to react with different olefins bearing different functional groups (Scheme 177).

The reaction showed high tolerance towards different functional groups. For instance, the reaction worked well with olefins bearing protected alcohols, nitriles, phosphates and alkyl chains to give the expected products in excellent yields. It is worth noticing that in case of O-pivalate olefin 583, the side product 579t was isolated in 48% (based on the p-toluenesulfonyl cyanide) along with the desired product 579s. This side product results from addition of the extra equivalents of ptoluenesulfonyl cyanide 570 to this electron-rich olefin 583.

In cooperation with Ms. Maren Wissig, master student in the group, the scope of the carbo-cyanation reaction with chiral allylsilanes was performed. The reaction also showed high tolerance towards chiral allylsilanes. The expected products were formed in very good yields and high diastereocontrol (Scheme 177). For instance, the products 579x, 579y with i-Pr, and phenyl groups in the terminal end of allylsilanes, showed high diastereocontrol up to (95:5). The absolute configuration of 579y was assigned by X-ray crystallography. Similarly to carbo-azidation process, the level of diastereocontrol depends on the nature of the silicon group and on the substituents at the terminal end of allylsilanes (R). This diastereocontrol could be rationalized through a Felkin-Ahn type model (Figure 9), with a pyramidalized transition state and quasi-staggered conformation to avoid gauche interactions between the most hindered groups SiR 3 and (CH 2 ) 2 C(O)SPh. According to that, the ptoluenesulfonyl cyanide 570 is believed to approach anti relative to the bulky silicon group and from the side of the smallest H substituent.

But surprisingly, with the bulky t-Bu group, at the same terminal position, the reaction did not work and the desired product 579v was not observed.

Nevertheless, when the size of the substituents on the stereogenic center was decreased as in 579u and 579w, the diastereocontrol decreased dramatically. This may be explained by the new alternative approach of the cyanide group from the side of the medium-sized phenyl group (Figure 10).

These results showed that the small size of the cyano substituent likely plays an important role in the efficacy of this reaction and in the stereocontrol achieved with chiral allylsilanes.

The extension of the scope of this carbo-cyanation process to include addition of nitrile onto double bonds in complex structures was also studied. Therefore, α-iodothioester 337 was allowed to react with different enamines, terpenes, dienes and bicyclic systems (Scheme 178).

The carbo-cyanation process with enamines did not afford the expected product. In case of 585, the desired product 584a had not been observed and instead a degradation of the starting materials was observed. Similarly, nitrile product 584b had not been observed under the carbo-cyanation process conditions. Instead, the side-product 584c was observed as a major product in this case and isolated in 48% yield (based on the p-toluenesulfonyl cyanide). This side product was probably formed through addition of p-toluenesulfonyl cyanide 570 onto the enamine double bond. Degradation of the product is believed to occur due to the presence of the amide group or the carbamate functional groups, which would favor elimination of the nitrile. This observation showed the limitation of carbo-cyanation process with enamines (Scheme 178).

In cooperation with Ms. Chahinaz Khiar, who did her internship in the group, the scope of the carbocyanation reaction with bicyclic compounds was studied. Thus, norbornene 587 reacted under carbocyanation reaction conditions and gave the expected nitrile product 584d in very good yield and two separable diastereoisomers in a 2:1 ratio. The sulfone side product 584e, resulting from the addition of p-toluenesulfonyl cyanide 570 onto the norbornene double bond, was also isolated in 52% (based on the p-toluenesulfonyl cyanide). The formation of this side product was observed when using (4.0 eq.) of norbornene 587 (Scheme 178).

Extension of this scope to include terpenes was also studied. Therefore, the carbo-cyanation process between α-iodothioester 337 and terpenes (R-Limonene 590, β-Pinene 591, R-Carvone 589 and Menthol 588 218 ) gave the expected products in moderate yields (Scheme 178).

In case of R-Limonene 590, the carbo-cyanation process gave the desired nitrile product 584h in moderate yield. The cyclization onto the endocyclic double bond is unfavoured and the carbocyanation process occurs on the more accessible 1,1-disubstituted alkene to give the expected product 584h in moderate yield.

In the case of R-Carvone 589, the presence of ketone functional group apparently altered the carbocyanation process. No traces of the expected product 584g were observed.

The carbo-cyanation process with β-Pinene 591 afforded the nitrile product 584i, after rearrangement, in moderate yield. This reaction showed that ring opening is faster than the intermolecular trapping of the nucleophilic radical (Scheme 179). 219 The carbo-cyanation reaction was extended also to dienes. Therefore, the carbo-cyanation reaction with norbornadiene 594 led to the product 597a after cyclization of the formed radical onto the second double bond. Diene 595 was also allowed to undergo carbo-cyanation process to give the bicyclo[3.3.0]octane 597b in modest yield. Besides, carbo-cyanation process with diene 596 also afforded the cyclized nitrile product 597c in modest yield. It is noteworthy that all of these nitrile products 597a-c were isolated as single diastereomers.

218 Fernandes, R. A.; Chaudhari, D. A. Eur. J. Org. Chem. 2012, 2012, 1945-1952. 219 Oldroyd, D. M.; Fisher, G. S.; Goldblatt, L. A. J. Am. Chem. Soc. 1950, 72, 2407-2410.

The reactivity observed with dienes above showed that the intramolecular cyclization of the formed nucleophilic radical onto the second double bond is faster than the intermolecular addition onto ptoluenesulfonyl cyanide 570. 220 It is also worth noticing that the transfer product 597d was observed in case of diene 596 along with the expected nitrile product 597c. The carbo-cyanation reactions with dienes were performed with equimolar ratio of the three components, in order to avoid the presence of the sulfone addition side products, generated from addition of the p-toluenesulfonyl radical onto the double bond. Although carbo-cyanation processes with dienes gave access, in one step, to complex functionalized structures, it was generally observed that the yields in these processes were quite modest.

To summarize this scope, the free-radical carbo-cyanation multicomponent process showed high tolerance to different functional groups with good to excellent yields. The small size of the cyano group plays an important role during the control of the stereochemistry in chiral allylsilanes and for the easy installation of this chemically important functional group on the most hindered olefins. The elaboration of all-carbon quaternary centers by using this carbo-cyanation process proved to be very efficient; giving access to fully functionalized quaternary centers in very good yields. However, the carbo-cyanation process showed some limitations with enamines and ketones. Nevertheless, this carbo-cyanation process gave access to different complex functionalized structures in only one step.

.Towards Tin-Free Carbo-Cyanation MCRs.

Organotin reagents showed high efficiency to mediate the radical reactions. But these reagents have perceived toxicity and it is difficult to remove their residues from the final products. 221 These disadvantages have proved to be a serious hurdle to industrial applications. Therefore, few approaches were developed to design free-radical reaction without tin mediation.

In 1997, Zard et al. 222 developed allylation reaction of olefins based on the thermal decomposition of ethyl-allylsulfones 598. The principle idea in this approach is based on the possible α-scission of alkylsulfonyl radicals with the formation of the alkyl radical and extrusion of SO 2 . The α-scission reaction is reversible and the rate of this scission depends on the stability of the formed alkyl radical (Scheme 180).

Generally, the equilibrium is shifted towards the formation of the alkylsulfonyl radical. And the more stable the alkyl radical, the higher the rate of elimination of SO 2 , shifting the equilibrium to the right. For example, the rate of α-scission in the case of benzylsulfonyl radical is 2.10 8 s -1 (295°K). 223 However, in case of an arylsulfonyl radical, the formation of the highly energetic aryl radical is not favored. Therefore, these types of aryl sulfonyl radicals do not undergo α-scission process.

Based on this, Zard and his coworkers used ethyl sulfonyl radical 600, generated from the addition of an initiator onto allylsulfone 598, which undergoes an α-scission process, thus generating an alkyl radical after elimination of SO 2 . This alkyl radical then abstracts iodine from the alkyl iodate 599 and generates radical 602. The latter then adds onto the allylsulfone 598 and liberates ethylsulfonyl radical which can propagate the radical chain (Scheme 181). 221 Kim also developed a tin-free radical cyanation process using methylallylsulfone 608. 215 In this approach, primary alkyl phenyl telluride derivatives 607 were used instead of alkyl iodides. This is due to the much faster transfer of the phenyl telluride group to the methyl radical than the corresponding iodine atom transfer. Thus, treatment of alkyl phenyl tellurides 607 with ptoluenesulfonyl cyanide 570, methylallylsulfone 608 and V-40 in t-butylbenzene gave the corresponding nitriles in excellent yields (Scheme 183).

The mechanism of this tin-free reaction involved the use of methylallylsulfone 608 as a source of methyl radical 613 for iodine or phenyl telluride transfer. The addition of p-toluenesulfonyl cyanide to methyl allyl sulfone 608 would produce methanesulfonyl radical 612 which will thermally decompose to give the desired methyl radical 613. This methyl radical would undergo the iodine atom or phenyl telluride transfer to give the alkyl radical 614, which would add to p-toluenesulfonyl cyanide 570 and give the nitrile product 609. Also, this methyl radical might add to ptoluenesulfonyl cyanide 570 to generate p-toluenesulfonyl radical 611, which propagate the chain (Scheme 184).

From the aforementioned approaches and relying on the success of 3-CR-carbo-cyanation process, we tried to synthesize the ethylsulfonyl cyanide 615 to develop a tin-free carbo-cyanation process.

In this reagent the nitrile part would act as radical acceptor and the ethyl radical, generated after extrusion of SO 2 , would propagate the radical chain.

The first reported method to synthesize this bifunctional reagent was from ethylsulfinic acid sodium salt 617 and cyanogen chloride. Therefore, ethylsulfonyl chloride 616 was treated with sodium sulfite and sodium bicarbonate to give the ethylsulfinic acid sodium salt 617, which was further reacted with cyanogen chloride to afford ethylsulfonyl cyanide 615 (Scheme 185). 225 We tried to avoid the use of the highly dangerous cyanogen chloride by using the less toxic cyanogen bromide. Therefore, the last sequence was repeated by using cyanogen bromide.

Unfortunately, the only isolated product was ethylsulfonyl bromide 618 (Scheme 186). 225 Another method was reported for the synthesis of ethylsulfonyl cyanide 615 through oxidation of ethyl thiocyanate 619 by m-CPBA. 226 The reported reaction worked only in 6% isolated yield. Our efforts to reproduce this reaction were unfortunately not successful (Scheme 187).

It was envisioned that another cyanating agent would be able to perform the same task.

( Based on these observations, our hypothesis for (Me 3 Si) 3 SiCN started by generation of the electrophilic radical 634, generated from the corresponding radical precursor 631 by action of AIBN. This electrophilic radical will add on the electron-rich olefin 632 to give the nucleophilic radical 635. The latter will then add onto the electrophilic nitrile carbon of (Me 3 Si) 3 SiCN 620 and liberate the (Me 3 Si) 3 Si radical 629, which will abstract the halide from the starting alkyl halide 631 and sustain the radical chain (Scheme 189). The problem with this approach is the much lower electrophilic character of the silylcyanide as compared to sulfonylcyanide. However, silylcyanides R 3 SiCN are in equilibrium with silylisonitriles R 3 SiNC with a large predominance (> 95%) of the cyanide form. 228 It was then being imagined that the nucleophilic alkyl radical could however react with the isonitrile form even if its concentration in the medium is likely very low. -Elimination of the (Me 3 Si) 3 Si radical would then sustain the radical chain.

Therefore, the cyanating agent (Me 3 Si) 3 SiCN 620 was synthesized according to the reported method from the corresponding cyclohexyl isocyanide 637. 229 Cyclohexyl isocyanide 637 was then refluxed in toluene with (Me 3 Si) 3 SiH 638 in presence of AIBN to give the corresponding (Me 3 Si) 3 SiCN 620 in 63% (Scheme 190).

Then, this cyanating agent was allowed to react with the more reactive α-iodothioester 337 and electron-rich allylsilane 265 in presence of AIBN as an initiator (Scheme 191). Unfortunately, the expected product 579g was not observed despite the full consumption of α-iodothioester 337. This reaction was repeated again with di-tert-butyldiazene as an initiator, but the same negative result was observed. Then, the reaction was repeated again by applying the standard condition for this carbo-cyanation process by mediation of DTBHN/(Bu 3 Sn) 2 . The reaction did not give the desired product too and only complex mixtures of by-products were observed (Scheme 191).

At this point, we gave up the tin-free radical carbo-cyanation process and reported our attention to the synthesis of Eburnane 2 relying on the carbo-cyanation under standard tin-conditions. In the following section, elaboration of Eburnane 2 through two different approaches will be introduced.

Elaboration of Eburnane

Relying on the carbo-cyanation process developed above, our efforts to elaborate eburnane started with attempts at reducing the number of equivalents of olefin used in this carbo-cyanation process.

Using equimolar amounts of this olefin will make this synthesis more efficient. Therefore, the carbocyanation process between equimolar amounts of α-iodothioester 337, olefin 546c and ptoluenesulfonyl cyanide 570 was performed. The desired product was isolated in somewhat lower yield (50%). Therefore, the reaction was repeated with 2.0 equivalents of olefin 546c and the desired product was isolated with almost the same yield observed when the reaction was performed with 4.0 equivalents (Scheme 192).

It is worth noticing that this reaction could be scaled up to 5 grams of isolated pure product in a reproducible manner.

Synthesis of Eburnane through Pictet-Spengler Approach

With nitrile product 579a in hand, our efforts were directed as to reduce the nitrile group into an aldehyde, which could be used as the non-tryptamine part for Pictet-Spengler reaction. Therefore, nitrile 579a was reduced into an aldehyde by DIBAL-H, which also reduced the thioester group into the corresponding alcohol, to form the expected lactol 639. Unfortunately, the starting material was consumed but no major product could be isolated from the reaction mixture (Scheme 193).

With the aim to access the tricyclic core of Eburnane 641 directly, a stepwise reduction sequence of thioester and nitrile was developed. First, the thioester group in 579a was reduced to alcohol by NaBH 4 . The reaction worked well and the desired alcohol 640 was isolated in very good yield (83%). Second, the nitrile group in 640 was reduced by DIBAL-H. Then, instead of hydrolyzing the formed imine by water to form aldehyde, we tried to trap this imine directly by tryptamine to form the tricyclic Pictet-Spengler product 641. This sequence failed and the lactol 639 was the only isolated product (in 70% yield). The trapping of imine by tryptamine was not successful probably due to presence of DIBAL aluminum residues in the reaction medium (Scheme 194).

The unexpected formation of 642 prompted us to investigate the possible mechanism of its formation. Therefore, different acids were used instead of AcOH to explore the role of the acid during this reaction. In parallel, the screen of acids was performed at different temperatures.

Therefore, (R)-BINOL-phosphate, TFA, AcOH were screened at 60, 90, 110 °C. Under all of these conditions, no traces of the desired product 641 or the unexpected tetracyclic product 642 were observed, except when AcOH and (R)-BINOL-phosphate were used at 110°C. In case of (R)-BINOL-phosphate at 110°C, a partial conversion of lactol towards the formation of tetracyclic core 642 was observed with formation of one diastereoisomer more than the other (Table 5). Furthermore, the reaction between benzyl protected tryptamine 644 and lactol 639 under the same conditions than those used in formation of tetracyclic product 642, did not give the Pictet-Spengler product 645 (Scheme 198).

Based on preliminary DFT studies, performed with a dimethyl lactol model 646a and methylamine, two viable routes could be possible for explaining this reactivity (Scheme 199). The first pathway would imply the expected formation of the normal iminoalchol 647b from the open form of the lactol 646b. But rather than being involved in a Pictet-Spengler reaction at C-1 (may be for steric reasons), an intramolecular hydride transfer could transform the iminoalchol into a more stable aminoaldehyde 648b which can also cyclize in an even more stable hemiaminal 648a, ready for a Pictet-Spengler reaction at C-5.

The other possible route would imply of the protonated lactol at C-5 to give the aminoaldehyde 649b and its cyclized hemiaminal form 649a (a nucleophilic substitution at the more sterically hindered C-1 would also give 647a). At this stage, the formation of the iminium would involve a Pictet-Spengler reaction at C-1. A direct thermal 1,3-hydride shift, that would transform the iminium 650a into 650b, should be antarafacial thus forbidden. But a deprotonation at the acidic C-5 position of 650a could form an azomethine ylide which would form the rearranged iminium 650b by reprotonation at C-1, 650b being the precursor the observed tetracyclic eburnane 642. Iminium migrations of this type have been extensively used by Seidel et al. in total synthesis in so-called internal-redox Mannich reactions. 231 Both routes would be energetically feasible and the process would be governed by the stability increase of the hemiaminal 648a compared to the other hemiaminal 649a, both in equilibrium with their corresponding iminiums. It was then envisioned that the reaction of tryptamine with the free aldehyde instead of lactol 639 would be more reliable. After an attempt to protect alcohol 640 with a benzyl group using benzyl bromide, the protection was performed with Dudley's benzylation reagent 232 to give the desired benzyl protected alcohol 651a in 82% yield. The free alcohol 640 was also protected as a mesylate, Again a stepwise sequence was developed to give the Pictet-Spengler products 652a-b. First, nitriles 651a-b were reduced to aldehydes by DIBAL-H. Our efforts to chromatography the formed aldehyde were not successful. But, the crude aldehyde seemed to be pure enough to undergo the next reaction. Second, aldehydes 653a-b were allowed to react with tryptamine under the acidic conditions of Pictet-Spengler reaction. The desired products were not observed neither by using TFA at room temperature nor by using AcOH at 110°C. These reactions were not successful, which may be due to the presence of DIBAL aluminum residues in the reaction medium, preventing the attack of tryptamine on the aldehyde from occurring. A solution to this problem thus had to be found.

Another pathway to access the eburnane 2 was envisioned relying on the Bischler-Napieralski intramolecular condensation. In the following section the details of this approach will be discussed.

Synthesis of Eburnane through Bischler-Napieralski Approach

In this approach, the same key carbo-cyanation reaction and product 579a were employed. The Deprotection of the alcohol, followed by oxidation to aldehyde could give a straightforward sequence to Eburnane 2 (Scheme 203).

Chapter Three: Eburnane Synthesis 166 Therefore, the thioester group in the nitrile product 579a was reduced to the corresponding aldehyde 654 either by Et 3 SiH233 or by Bu 3 SnH234 with a better yield when Et 3 SiH was used (Scheme 204).

The aldehyde 654 was then allowed to react with tryptamine under reductive conditions to give the secondary amine 655 in 92% yield (Scheme 205).

With this secondary amine 655 in hand, our first approach was to reduce the nitrile group by DIBAL-H to imine and hopefully this imine could be trapped in situ by the secondary amine. But unfortunately the desired tetracyclic product 657, resulting from the Pictet-Spengler cyclization, was not observed. Instead, only traces of the corresponding aldehyde 658 were observed (Scheme 206).

Therefore, the alternative pathway was the cyclization of this secondary amine onto the nitrile group to form the amide 656. Different reaction conditions were tested to perform this cyclization.

Refluxing the nitrile 655 in a mixture of EtOH and H 2 O was attempted first. 235 Unfortunately the desired amide 656 was not observed and the only isolated product was the starting nitrile 655.

Refluxing the nitrile 655 in mixture of MeOH/H 2 O in the presence of LiOH did not give the amide 656 either. Finally, refluxing the nitrile 655 in a mixture of HCl / MeOH (2/1) gave the desired amide group but with deprotection of the silyl ether group under these harsh acidic conditions.

Consequently, the hydroxy-lactam 659 was isolated in 65% yield (Scheme 207). 236 The reaction went probably through hydrolysis of the nitrile into a primary amide or an acid, which then reacted with secondary amine to form the amide product. 237 The cyclic amide was thus ready for the Bischler-Napieralski intramolecular condensation, which is usually mediated by POCl 3 to form a tetracyclic intermediate imine 660, followed by its reduction by NaBH 4 . Therefore hydroxyl lactam 659 was subjected to Bischler-Napieralski reaction conditions, but unfortunately, instead of isolating the tetracyclic alcohol 661, the only isolated product was hemiaminal 662 (Scheme 208).

The hemiaminal 662 was probably generated from chloroiminium 663 formed through reaction of amide 659 with POCl 3 . Chloroiminium 663 could be trapped by the free alcohol faster than the tryptamine indole (Scheme 209). After reduction of iminium 664 by NaBH 4 , the hemiaminal 662 could be formed. This side reaction has already been observed by Schultz and Pettus. 195 236 Lounasmaa, M.; Miikki, L.; Tolvanen, A. Our efforts to open hemiaminal 662 and form the hydroxyl-free tetracyclic core 661 were not successful, neither by refluxing in toluene in the presence of acetic acid, nor by using TMSOTf.

Instead, decomposition of the starting hemiaminal was observed under these conditions (Scheme

210).

Therefore, to avoid the formation of the undesired hemiaminal 662, the free alcohol 659 was protected before applying Bischler-Napieralski reaction conditions. First, the free alcohol 659 was protected as a TBDMS ether. The idea here was to protect the free alcohol temporarily during the Bischler-Napieralski reaction, this group being then removed under the harsh reaction conditions to give the desired hydroxyl-free tetracyclic core. But unfortunately, the deprotection of silyl ether group was faster than the Bischler-Napieralski cyclization and again the hemiaminal 662 was the major isolated product (Scheme 211).

It was then envisioned that the free alcohol 659 should be protected with a stronger protecting group. A benzoate protecting group was thus designed as it is quite stable under acidic conditions and most importantly, it could be removed during the reduction of Bischler-Napieralski iminium and give the desired free alcohol. Hydroxy lactam 659 was thus protected as a benzoate, and the Bischler-Napieralski reaction conditions applied to form iminium 667, the latter being then reduced by excess LiAlH 4 to remove the benzoate protecting group. Unfortunately, the reaction did not work and only degradation was observed under these conditions (Scheme 212).

Then, the standard Bischler-Napieralski reaction conditions were applied on the benzoate protected hydroxy lactam 666. Lactam 666 was thus refluxed with POCl 3 in MeCN for 16 h, followed by reduction of the generated imine by NaBH 4 to give the desired tetracyclic core of Eburnane 668 in 19%, along with hemiaminal 662 in 30% (Scheme 213).

The hemiaminal 662 was probably formed due to the partial deprotection of the benzoate under the highly acidic POCl 3 -mediated cyclization conditions. Our efforts to increase the yield of tetracyclic core 668 and avoid the formation of hemiaminal 662 were not successful. Thus, isolation of the iminium 667 by treating it with NaBF 4 then reduction of this imine by NaBH 4 in THF did not improve the yield at all (Scheme 214). 199 The protecting group was then changed for a more robust one. The benzyl protecting group was thus used instead of a benzoate. Thus, treating hydroxy lactam 659 with BnBr protected both the alcohol function and the indole NH. Bischler-Napieralski reaction conditions were applied again on the benzyl protected lactam 670, but unfortunately, the only isolated product was the hemiaminal 672 (Scheme 215).

The formation of hemiaminal 672 also resulted from the deprotection of the benzyl alcohol 670 and attack of the free alcohol on the iminium intermediate. Westwood et al. 199 performed this Bischler-Napieralski / reduction sequence with methyl ester group 515 in the position of the protected alcohol (Scheme 216). The presence of a methyl ester group in this position is likely more compatible with HCl released during POCl 3 -mediated cyclizations.

Another method was envisioned to obtain the desired tetracyclic core of eburnane. Instead of using POCl 3 , which produces a very acidic medium under high temperatures, triflic anhydride could react with amide 670 to form an iminium triflate which hopefully could be trapped by tryptamine. 238 Amide 670 was thus treated with triflic anhydride in the presence of 2-chloropyridine, followed by addition of NaBH 4 to reduce the generated iminium. Unfortunately, the only isolated product was 673 which resulted from the reduction of the iminium triflate (Scheme 217). 238 These different attempts thus showed how hard is the cyclization of this lactam. This difficulty may be attributed to the steric hindrance around the amide bond. Another approach for the cyclization was thus planed, involving the conversion of the amide 670 to a thioamide 675, followed by formation of iminium by sulfur alkylation. The tetracyclic core of Eburnane 671 could then be accessed after reduction of the final iminium (Scheme 218).

Therefore, amide 670 was refluxed with Lawesson's reagent in toluene. 239 Unfortunately, the corresponding thioamide 675 was not observed and the only isolated product was the starting material (Scheme 21).

239 Kirillova, M. S.; Muratore, M. E.; Dorel, R.; Echavarren, A. M. J. Am. Chem. Soc. 2016, 138, 3671-3674.

Conclusion

In summary, during the course of the total synthesis of the Leucophyllidine's north fragment, Eburnane 2, the key carbo-oximation reaction assigned for this total synthesis showed some limitations, mainly due to steric factors. Consequently, a novel free-radical carbo-cyanation process was developed, which showed better yields and a higher tolerance for the substitution of the different radical precursors and olefins. The small size of the nitrile helped in the development of the carbo-cyanation process with different chiral allylsilanes, bicyclic systems and terpenes. This process could also be used in the elaboration of cyclic and acyclic systems bearing fully functionalized quaternary centers in very good yields.

Relying on this carbo-cyanation process, two different approaches were developed to access the Eburnane core. The first one, through Pictet-Spengler reaction, ended up with the unexpected formation of an eburnane-like tetracyclic core with a quaternary center away from the indole ring.

While the second approach, based on the Bischler-Napieralski reaction, afforded an access to the eburnane skeleton albeit in low and non-reproducible yield.

Introduction

Since the three components Leucophyllidine 1, Eburnane 2 and Eucophylline 3 are all present in the plant, the biogenetic analysis proposed by Kam et al. 1 , then assumed that a coupling between the two monomers, Eburnane 2 and Eucophylline 3, will likely issue Leucophyllidine 1. This is the focal point in our retrosynthesis analysis of Leucophyllidine. Coupling the north fragment, Eburnane, and the south fragment, Eucophylline, will hopefully afford the unique bisindole structure of Leucophyllidine. This coupling will proceed through a Mannich type reaction between the C-7 electrophilic center of Eburnane and C-1′ electron-rich center of Eucophylline.

In general, biomimetic couplings in these types of natural products have received modest attention.

Only few syntheses were designed relying on the biomimetic couplings in synthesis of bisindole-like structures. In the following part a literature survey about biomimetic couplings in synthesis of natural products will be highlighted.

Biomimetic Coupling in Synthesis of Natural Products

The synthesis of Vinblastine 5 constitutes one of the most well-known syntheses, relying on a biomimetic coupling between two monomeric alkaloids. Boger et al. 240 Since the introduction of this coupling reaction by Potier and Kutney, 241 some features of the mechanism were not well understood. For instance, The Fe(III)-promoted coupling reaction displays high stereochemical selectivity, producing exclusively the natural diastereomer, which could not be rationalized based on the traditional Polonovski fragmentation (Scheme 225). 242 The initial studies on the mechanism of this coupling revealed that it is a free-radical oxidation reaction. The reaction is initiated by generation of an electrophilic radical in catharanthine 13 fragment. This radical is generated by a single electron oxidation of the indole ring by the Fe(III)

salt. An intramolecular one-electron-two center bonding interaction between the radical site α to the carbomethoxy group and the iminium carbon may stabilize a conformation in which the upper face of the radical is sterically blocked. Hence, addition of this radical to electron-rich vindoline will lead exclusively to the formation of the natural stereoisomer. This proposal suggests that the initial indole radical cation 677 and its fragmented cation radical 678 possess a unique stability, persistence, electrophilic character, and conformational properties to effectively react selectively with vindoline (Scheme 226). 243 This mechanism was built based on initial results obtained from the mechanistic model study on simplified indoles 680. In Catharanthine 13, the free indole NH would be required. Despite the apparent complexity of these biomimetic couplings, they may be very easy in some cases. For example, Vobparicine 32 results from the union of the two monoterpenic indole alkaloids, Apparicine 33 and Vobasinol 34. Thus, treatment of Vobasinol with an excess of Apparicine under acidic conditions effectively led to Vobparicine (Scheme 232). 247 The coupling was speculated to occur through the reaction between the C-3′ electrophilic center of Vobasinol and the C-22 electronrich center of Apparicine.

In the course of the total synthesis of Haplophytine 696, Corey and his coworkers investigated coupling models between electron-rich arenes and Canthiphytine derivatives (Scheme 233). 248 Several trials finally showed that biomimetic coupling is not operative to generate the benzylic quaternary center under the studied conditions, pointing out the difficulties in finding proper conditions to initiate this sterically unfavorable coupling.

From the aforementioned examples and based on the retrosynthesis analysis of Leucophyllidine, the final step in the total synthesis of this bisindole alkaloid 1 will be the biomimetic coupling between the Eburnane 2 and Eucophylline 3, which would involve a direct Mannich-type coupling between the ortho-phenol moiety of Eucophylline 3 and a putative iminium generated from the north Eburnane 2 (Scheme 234).

The regioselectivity of the process should be governed both by the ortho-phenol group, and by the strongly donating ability of the aminoquinoline moiety (Scheme 234). The stereocontrol arising during the biomimetic coupling will be studied carefully. It is believed that the stereochemistry of the newly created stereogenic center should be governed by the torsional effects generated at the transition state through the CH 2 moiety adjacent to the iminium. Approach of the Eucophylline 3 from the top face of the iminium intermediate, syn to the ethyl group on the quaternary center, leads to a staggered conformation, providing the new stereocenter with the desired configuration. A priori, this approach is similar to what is observed during the biosynthesis of these alkaloids. In contrast, the approach from the bottom face suffers from torsional strain.

Therefore, to save the available and valuable amounts of Eburnane and Eucophylline, the feasibility of this biomimetic coupling approach will be investigated firstly through models 697, 698 which are very similar to the north fragment, Eburnane, and south fragment, Eucophylline, respectively (Scheme 235). These models will be tested under several reaction conditions, for which exist some precedents in the literature. These preliminary experiments should provide further insight into the regio-and stereoselectivity of the final coupling. These studies will also provide information on the stability of the Eucophylline vinyl moiety under the coupling reaction conditions (and ultimately indicate if this group must be installed before or after the coupling). Based on these results, the coupling between Eburnane 2 and Eucophylline 3 will be performed to furnish the natural Leucophyllidine 1.

In the following section, synthesis of the north fragment model 697 and the south one 698 will be discussed firstly, before presentation of preliminary results on the biomimetic coupling approach.

Synthesis of North Fragment Model.

Through Pictet-Spengler Reaction.

The north model 697 was designed to be very similar to the Eburnane 2 and could be accessed in a short and straightforward sequence. Therefore, the retrosynthesis analysis of this model will not differ so much from the one proposed for Eburnane 2. Thus, the tetracyclic model 697 could be accessed through a base-mediated cyclization of the tricyclic Pictet-Spengler product 700, which in turn could be accessed from Pictet-Spengler reaction between benzyl protected tryptamine 644 and aldehyde 699. This aldehyde 699 could be accessed from the corresponding commercially available diol 698 (Scheme 236).

The starting point was the synthesis of aldehyde 699. Commercially available diol 698 was monoprotected as TBDMS or TBDPS groups, followed by Swern oxidation of the free alcohol to give aldehydes 699a-b (Scheme 237). 249 It is worth noticing that, the purification of these aldehydes through column chromatography was not successful, however the crude product is pure enough to be used in the next step without further purifications.

In the meantime, the tryptamine NH 2 was protected by a benzyl group under reductive conditions to give the benzylated tryptamine 644 (Scheme 238). 250 The latter was allowed to react with aldehydes 699a-b under Pictet-Spengler reaction conditions to give the tetrahydro-β-carboline 700a-b (scheme 236). 251 It was noticed that in case of R = TBDMS, the yield was quite modest. This was attributed to degradation of the silyl ether group during the silica chromatography of the product.

Then, to elaborate the tetracyclic model 697, the removal of silyl ether group from 700b was performed with TBAF, followed by oxidation of the so-formed free alcohol 702 to aldehyde through a Swern reaction. Unfortunately, the oxidation step was not successful and instead a degradation of the product 703 was observed (Scheme 239).

At that point, and to save time and materials, another easier and shorter pathway to access this tetracyclic model 697 was envisioned. In the following section the synthesis of model 697 though Bischler-Napieralski reaction will be discussed.

Through Bischler-Napieralski Reaction

In this approach, the tetracyclic Model 697 was accessed based on the Bischler-Napieralski condensation between the amide group and the tryptamine indole in compound 705. This amide could be accessed through the reaction between the benzyl protected tryptamine 644 and the commercially available acid chloride 704. After construction of the tricyclic core 706, the base mediated cyclization of indole NH into the methyl ester group will afford the tetracyclic lactam 707

which should be easily reduced to the corresponding tetracyclic amino-alcohol 697 (Scheme 240).

Acid chloride 704 was condensed with benzyl protected tryptamine 644 in the presence of Et 3 N to afford amide 705 in excellent yield (94% With this indole tricycle in hand, the cyclization between indole NH and the methyl ester group was performed in the presence of DBU to form the tetracyclic lactam 707 in 80% yield.248 This lactam was then reduced into the corresponding amino-alcohol by using LiAlH 4 , to give the desired product 697a,b in 82% yield as a 2:1 mixture of two separable diastereoisomers (Scheme 242).

Synthesis of the South Fragment Model.

Similarly to the north fragment, the south model was designed to be very similar to Eucophylline 3 and to be accessed in a short and straightforward manner. Therefore, the bicyclic lactam, used in the synthesis of Eucophylline, will be replaced with the commercially available monocyclic lactam 360.

This lactam will be coupled with the trisubstituted aniline 359 to give amidine 361, which will undergo the same steps, followed in the elaboration of Eucophylline, to give the tricyclic model 698 (Scheme 243).

The starting point was the synthesis of the trisubstituted aniline 359. Commercially available pmethoxy-2-nitrobenzoic acid 710 was esterified first, by using thionyl chloride in refluxing methanol to give methyl ester derivative 711 in nearly quantitative yield. Subsequently, the nitro group was reduced into an amino-group under hydrogen pressure in the presence of palladium on charcoal to give the desired trisubstituted aniline 359 in 96% yield (Scheme 244). 254The trisubstituted aniline was then coupled with monocyclic lactam 360 in the presence of POCl 3 to give the desired amidine 361 in 92% yield (Scheme 245). 255 It is worth noticing that the reaction was clean and the product isolated in very pure form after a simple basic work-up and no chromatography.

With this amidine in hand, the base-mediated cyclization to elaborate the tricyclic model was performed in the presence of different bases. The first attempt was made by using t-BuOK as a base.

Unfortunately, the product was not formed and instead degradation of the starting material was observed. By changing the base to LiHDMS, the desired product was isolated, albeit in modest yield. Finally, an excess of LDA in THF gave the desired product 708 in 90% yield (Scheme 246).

The next step was the installation of the vinyl moiety. The hydroxyl group in tricyclic 708 was converted to a more reactive leaving group. Thus, our first attempts were directed as to avoid the use of the expensive Comins' reagent, as in the synthesis of Eucophylline. So the hydroxyl group in 708 was converted to a nosylate, by reacting 708 with nosyl chloride in the presence of Et 3 N, which gave the desired nosylate in 81% yield. Then, the installation of the vinyl moiety was tested by reacting nosylate 712 with the vinyl trifluoroborate 405 under Suzuki coupling conditions. 256 Unfortunately, the vinyl quinoline 698 was not observed under these conditions (Scheme 247).

The installation of the vinyl moiety was thus performed following the procedure already designed for the synthesis of Eucophylline. Thus, the hydroxyl group in 708 was converted to a triflate, by reacting 708 with Comins' reagent to give the desired triflate in 91% yield. The vinyl group was then installed through a Suzuki coupling with vinyl trifluoroborate 405 to give the desired vinyl quinoline 698 in 79% yield (Scheme 248). 257

Biomimetic Coupling

With these two models in hand, the biomimetic coupling between was studied. Since the idea was to generate the imine in the north model and trap it with electron-rich arenes, our first attempt was carried out with commercially available electron-rich quinolinol 714, which will be used as a south fragment model. Therefore, the north model 697a was allowed to react with quinolinol 714 under different acidic conditions ( Firstly, the major diastereoisomer of the north model 697a was reacted with quinolinol 714 in the presence of BF 3 -etherate as a Lewis acid. Unfortunately, the coupling product 715 was not observed under these conditions (entry 1, Table 6), and instead the minor diastereoisomer of the north fragment 697b and quinolinol 714 were the only isolated products. 258 Repeating the reaction with addition of TFAA (trifluoroacetic anhydride) (entry 2, Table 6) to enhance the formation of imine, did not improve the situation and the same result was observed.

Then, the Lewis acid was changed to FeCl 3 but unfortunately also the result did not change at all and the only isolated products were the minor diastereoisomer 697b of the north fragment and quinolinol 258 Kitamura, T.; Harano, K.; Hisano, T. Chem. pharm. Bull. 1992Bull. , 40, 2255Bull. -2261. . 714 (entry 3, Table 6). The Lewis acid was changed to TiCl 4 but, again also the same negative results were observed (entry 5, Table 6).

As illustrated above with the reported couplings from the literature, the coupling was also performed in HCl acidified solutions. 259 Our coupling conditions were thus performed in methanolic solution of HCl under reflux for several days (entry 7, Table 6). Unfortunately, the desired coupling product 715 was not observed and instead degradation of the starting north Model was observed, beside the isolation of quinolinol 714. Changing the acid to be TFAA, did not also lead to the desired product and again the only isolated products were the minor diastereoisomer of the north fragment 697b and quinolinol 714 (entry 8, Table 6).

A recently reported method showed that imines could be trapped by electron-rich arenes just by heating them in a mixture of THF and H 2 O.260 Therefore, the major diastereoisomer of the north model 697a was heated with quinolinol 714 in a 2:1 THF/H 2 O mixture. Unfortunately, the same negative results were observed (entry 9, Table 6). Starting with the minor diastereoisomer of the north model 697b, the only isolated product was the major diastereoisomer of the same model 697a.

Another electron-rich arene was used instead of quinolinol 714. Anisole 716 was thus allowed to react with the major diastereoisomer of the north model 697a under acidic conditions.

Unfortunately, no traces of the desired product 717 was observed and the north model was decomposed under HCl/MeOH reaction conditions or in TFAA/TMSOTf medium (Scheme 249).

The coupling between the major diastereoisomer of the north model 697a and the south model 698 was also tested. In this trial, the most common and frequently cited procedure that described this type of couplings was followed. 259 The coupling reaction was performed in a methanoic HCl solution at 65°C for 6 days. Unfortunately, no traces of the desired coupling product 718 were observed and instead degradation of the north model 697a was observed along with isolation of the south model 698. Repeating the reaction under dry conditions using TMSOTf in anhydrous DCM did not lead to the formation of the desired coupling product 718 (Scheme 250).

After these disappointing results, our attention was directed towards the reactivity of the north model 697a,b under these acidic conditions. The careful analysis of this model showed that the absence of gem-dimethyl effect at C-14 (as in natural Eburnamine) probably led ring D to stand essentially in its opened form under acidic conditions, the concentration of the real cyclic iminium 719, essential for the coupling, being thus very low. This hypothesis was reinforced by the formation, in some cases, of the other diastereoisomer of the north model which showed that cyclic and opened forms are in equilibrium. The comparison between this model 697 and Eburnamine 409

showed that in Eburnamine 409 there is an ethyl group at C-14 beside fused rings D and E, likely forcing closure of ring D and formation of iminium 721. This gem-dimethyl effect facilitates the coupling with Eburnamine 409, a feature that is absent in model 697 (Scheme 251).

At that point, it was thus essential to use the real Eburnane 2 to test this biomimetic coupling. To access Eburnane 2 in a short sequence, it was envisioned to follow Harley-Mason sequence which represents one of the shortest pathways to access Eburnane from inexpensive and available starting materials. 261 In the following section, synthesis of Eburnane 2 through Harley-Mason sequence will be discussed.

Elaboration of Eburnane through Stork Reaction

Relying on the Stork reaction between commercially available butanal 722 and methyl acrylate 557, the non-tryptamine part of Eburnane could be accessed in two steps from inexpensive starting materials. Following to the literature procedure,262 the pyrrolidine enamine of butanal 723 was prepared in 56% yield by the reaction of butanal 722 with pyrrolidine in the presence of potassium carbonate. This enamine was then allowed to undergo Michael addition with methyl acrylate 557 to give the aldehyde ester 417 in 54% yield (Scheme 252).

By repeating the same steps than before, aldehyde ester 417 reacted with pyrrolidine to form the intermediate enamine 724. This enamine 724 was allowed to undergo a nucleophilic addition with either allyl bromide 127 or nitroethene 725, generated in situ by thermolysis of nitroethyl acetate. 263 Both reactions worked, but unfortunately, the methyl ester part of the formed aldehydes was transesterified by pyrrolidine to give aldehyde amides 726 and 727 in 30% and 28% yields respectively (Scheme 253). It is worth noticing that, the isolated aldehyde amide 726 was not described in the Harley-Mason synthesis, who obtained the aldehyde-ester 418. 261 Since the aim was just to test the biomimetic coupling with easily prepared Eburnane 2, we proceeded directly to the following step. Therefore, Pictet-Spengler reactions between tryptamine and aldehydes 727 and 726 were performed in the presence of TFA in DCM at room temperature.

With the aldehyde 727, the Pictet-Spengler product 728 was not observed, while with aldehyde 726, the cyclized product 729 was isolated in 79% yield as a 1:1 mixture of diastereomers (Scheme 254).

With the Pictet-Spengler product 729 in hand, the intramolecular transamidation reaction between the secondary amine and the amide was tried under different acidic and basic conditions. First, 729

was treated with DBU for 2 days, but the desired tetracyclic lactam 419 was not observed. The same result was also observed when treating 729 with sodium methoxide. Changing to acidic conditions, did not change the outcome. For instance, treating 729 with boric acid in water or in DCE under reflux did not lead to the desired product 419. 264 Similarly, using aluminum chloride as a Lewis acid according to a reported method, did not give the tetracyclic lactam 419 (Scheme 255). At this stage and due to time constrains, we abandoned this route to access Eburnane 2. A recently appointed PhD student in the group will continue investigating this biomimetic coupling.

Conclusion

In this chapter, we initiated preliminary studies on the proposed biomimetic coupling, leading to Leucophyllidine. North and south models were designed with structures as close as possible to the Eburnane and Eucophylline skeletons. These models were accessed easily through short sequences of reactions from commercially available and inexpensive starting materials. The north model 697ab led to some disappointing results under acidic conditions due to the absence of gem-dimethyl in its skeleton, which disfavor the formation of the cyclic imine required in the coupling. Interestingly, the south fragment model 698 showed high stability under harsh acidic conditions and the vinyl moiety incorporated in this model was not affected by these reaction conditions, suggesting that the future coupling might be realized after its incorporation.

Our efforts to elaborate Eburnan 2 fragment through Stork reaction, which was guided by Harley-Mason precedent, could not be reproduced according to the literature report. The final transamidation reaction proved to be impossible under the reaction conditions tested, thus preventing us from obtaining the desired eburnane fragment.

Conclusion

Along this dissertation, we described the first total synthesis of Eucophylline, a unique vinyl quinoline alkaloid incorporating a bicyclic system, which was recently isolated from Leuconotis eugenifolius. We also described an approach towards the total synthesis of cytotoxic Leucophyllidine, a new bisindole alkaloid isolated from Leuconotis griffithii exhibiting a promising and selective anti-cancer activity. In both syntheses, we relied on new free-radical multi-component reactions, showing through them the utility and effectiveness of free-radical reactions in accessing complex structures and constructing quaternary centers through short sequences.

The In the course of our investigations on the reactivity of bridgehead bicyclic lactams under Vilsmeiertype conditions, we observed that these reactions went through the intermediacy of a remarkably stable α-chloroenamines. The unique reactivity of these twisted amides allowed us to isolate and functionalize the stable bicyclic α-chloroenamine intermediate 369, illustrating the absence of conjugation between the nitrogen's lone-pair and the enamine double bond (Scheme 257).

In the synthesis of Eburnane 2, the north fragment of Leucophyllidine, the carbo-oximation process, which showed its efficiency in synthesis of Eucophylline, did not display the same efficiency during the construction of the non-tryptamine part of Eburnane, likely as a result of an increased steric hindrance around the generated nucleophilic radical that complicated the trapping of this radical by sulfonyl oxime. Furthermore, the conversion of the oxime 547b to aldehyde 549b was not reliable under the used conditions (Scheme 258).

In search for a functional group equivalent to an aldehyde and compatible with free-radical multicomponent processes, we came out with the new three-component carbo-cyanation free-radical reaction. This reaction showed high tolerance towards different radical precursors, different olefins and structures containing double bonds. Besides that, the p-toluenesulfonyl cyanide 570, the sulfonyl acceptor, is commercially available, which is not the case for other sulfonyl acceptors. The small A-value of the nitrile group (0.21) allowed the nucleophilic radical, generated after the first step of the multi-component radical process, to attack easily the small nitrile acceptor to afford the desired MCR product. This process provides easy and efficient way to construct fully functionalized quaternary centers in very good yields and in only one step (Scheme 259).

Conclusion & Perspectives

200

Relying on this efficient carbo-cyanation reaction, two approaches were developed to access Eburnane 2, the north fragment of Leucophyllidine 1. The first one was based on a Pictet-Spengler reaction between tryptamine and a fully functionalized aldehyde 653a-b, obtained from the corresponding nitrile product 579a. The reaction was not successful with real aldehydes due to the difficulties encountered to isolate them in pure form (Scheme 260).

However, the masked aldehyde, lactol 639, gave a Pictet-Spengler product 642, after refluxing at high temperature with tryptamine, having an unexpected structure. The formation of this tetracyclic product was rationalized based on a redox-Mannich process (Scheme 261).

The second approach was based on the Bischler-Napieralski condensation. Therefore, the same carbo-cyanation product 579a, used before, was the key precursor in this approach. Playing with the reactivity of the thioester group allowed us to get access to aldehyde 654, which reacted under reductive conditions with tryptamine to give the secondary amine 655. Cyclization of this secondary amine onto the nitrile group gave the lactam 659, designed for Bischler-Napieralski condensation.

Unfortunately, the presence of a free alcohol in lactam 659 gave the hemiaminal 662 instead of the expected tetracyclic alcohol. Protection of this free alcohol and applying Bischler-Napieralski reaction conditions gave the desired tetracyclic product 668 albeit in low and non-reproducible yield (Scheme 262).

The biomimetic coupling between the Eburnane 2 and Eucophylline 3 was finally studied using structurally similar models. The latter were accessed very easily in a limited number of steps from commercially available starting materials. Preliminary results on this model study showed that absence of gem-dimethyl effect in the north model 697 probably prevents the formation of the cyclic imine, crucial intermediate in the desired coupling (Scheme 263).

Perspectives

The new free-radical carbo-cyanation reaction, which showed high tolerance to different functional groups, provided an efficient procedure to install the nitrile group in complex structures and formation of quaternary centers. This opens the door to the use of this reaction widely in synthetic organic chemistry. The nitrile group is a C-1 equivalent and could be easily converted to a wide range of functional groups (aldehyde, amine, carboxylic acid, carboxylic amide, and ketone), through well-known reactions.

To increase the impact of this reaction and avoid using equimolar amounts of tin species, the development of a tin-free version of this reaction would deserve considerable interest. Synthesizing the key ethylsulfonyl cyanide and tuning the right conditions will hopefully lead to an environmental more benign reaction.

The enantioselective synthesis of Eucophylline could also be accessed relying on this carbocyanation reaction and on the nitrile product 597d. Reduction of prochiral nitrile 549d to amine and "desymmetrizing" cyclization of this amine onto one of the two esters could possible give an access to the desired chiral center in the bicyclic system of Eucophylline.

compatible for the Bischler-Napieralski reaction, leading to better and reproducible yields (Scheme

268). 267

Finally, after elaboration of Eburnane 2, the biomimetic coupling could hopefully be performed in moderately acidic medium taking in the consideration the possible protonation of the Eucophylline nitrogens which could alter the nucleophilicity of Eucophylline and abort the coupling.

General information

All reactions were carried out under an argon atmosphere with dry solvents under anhydrous conditions unless otherwise noted. Dichloromethane, MeOH, THF and toluene were dried over activated alumina columns on MBraun Solvent Purification System (SPS-800). Benzene was distilled from Na/benzophenone, 1,2-dichloroethane and acetonitrile was distilled from CaH 2 . All commercial reagents were used as received without further purification unless otherwise stated.

Diisopropylamine, Et 3 N, isopropylcyclohexylamine, TMEDA were distilled from KOH. nBuLi was titrated using N-benzylbenzamide. 268 Yields refer to chromatographically and spectroscopically ( 1 H and 13 C NMR) homogeneous materials unless otherwise stated.

Experimental Part for Chapter Two

4-Hydroxy-3-iodo-1-methylquinolin-2(1H)-one (268)

To a solution of quinolinone 267 (50 mg, 0.28 mmol) in dry CH 3 CN (10 mL), TFA (0.02 mL, 0.314 mmol, 1.1 eq.) was added. The reaction mixture was stirred at room temperature for 5 min after that NIS (70.64 mg, 0.314 mmol, 1.1 eq.) was added. The reaction was stirred at room temperature for 24 h. After that, the reaction was stopped and the solvent was removed under reduced pressure. The residue was treated with 10 % sodium thiosulfate solution (10 mL) and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na 2 SO 4 and the solvent was removed under reduced pressure to afford dark brown oil which was purified by chromatography on silica gel (PE/EtOAc 95/5). The desired compound 268 was obtained as yellow solid (57 mg, 66%

Ethyl 4-methylenehexanoate (252)

In two necked round bottom flask equipped with Dean Stark apparatus connected with a reflux condenser, a solution of alcohol 321 (2.65 g, 30.84 mmol, 1 eq.), triethyl-orthoacetate (6.21 mL, 33.92 mmol, 1.1 eq.) and acetic acid (0.17 mL, 3.084 mmol, 0.1 eq.) were added. The reaction mixture was refluxed at 170°C for 12h.

The solvent was evaporated under vacuum then the crude material was purified by chromatography on silica gel using (PE/EtOAc 98/2). The olefin 252 was obtained as colorless oil (3.360 g, 70%). R f = 0.52 (Pentane/Et 2 O 98/2). IR (ATR) ν max (cm -1 ) = 3253,2976,2928,2856,1730,1621,1457,1261,1091.

H NMR (CDCl 3 , 300 MHz): δ (ppm) = 4.74-4.68 (m, 2H, H-1), 4.11 (q, 2H, J = 7.2 Hz, H-8), 2.46-2.30 (m, 4H, H-5 and H-6), 2.02 (q, 2H, J = 7.5 Hz, H-3), 1.24 (t, 3H, J = 7.2 Hz, H-9), 1.02 (t, 3H, J = 7.5 Hz, H-4).

4-Methylenehexyl benzoate (352a)

To a solution of suspended LiAlH 4 (134 mg; 3.52 mmol, 1.1 eq.) in dry Et 2 O (30 mL), olefin 252 (500 mg, 3.20 mmol, 1.0 eq.) was diluted in dry Et 2 O (10 mL) and added dropwise to the reaction mixture at 0°C. The reaction was stirred at this temperature for 30 min. After that, the reaction was quenched by addition of drops of concentrated solution of NH 4 Cl at 0°C. The formed solids were filtered off and the filtrate was concentrated under reduced pressure to afforded alcohol 325 which is used directly in the next step without further purification.

To a solution of alcohol 325 (250 mg, 2.18 mmol, 1.0 eq.) in dry DCM (5 mL), benzoyl chloride (0.50 mL, 4.37 mmol, 2.0 eq.) and pyridine (0.35 mL, 4.37 mmol, 2.0 eq.) were added. The reaction was stirred at room temperature for 3 h. After that, the reaction was diluted by H 2 O (5 mL) and the organic layer was separated and washed with solution of 5% HCl followed by saturated aqueous solution of NaHCO 3 . The combined organic layers were dried over Na 2 SO 4 and concentrated under vacuum to afford faint yellow oil which was purified by chromatography on silica gel (PE/EtOAc 95/5). The desired protected alcohol 325a was obtained as colorless oil (434 mg, 91%). R f = 0.72 (PE/EtOAc 95/5). IR (ATR) ν max (cm -1 ) = 3067, 2964,2928,1716,1645,1601,1452,1268,1113

Tert-butyldimethyl((4-methylenehexyl)oxy)silane (325b)

To a solution of alcohol 325 (250 mg, 2.18 mmol, 1.0 eq.) in dry DCM (10 mL), TBDMSCl (0.41 mL, 2.40 mmol, 1.1 eq.) and DIPEA (0.39 mL, 2.40 mmol, 1.1 eq.) were added. The reaction was stirred at room temperature for 3 h. After that, the reaction was diluted by saturated solution of NH 4 CL (10 mL) and the organic layer was separated and dried over Na 2 SO 4 and concentrated under vacuum to afford faint yellow oil which was purified by chromatography on silica gel (pentane/ Et 2 O 95/5). The desired protected alcohol 325b was obtained as colorless oil (419 mg, 84%). R f = 0.81(pentane/Et 2 O 95/5). IR (ATR) ν max (cm -1 ) = 2933,2854,1613,1584,1535,1461,1349.

H NMR (CDCl 3 , 300 MHz): δ (ppm) = 4.71-4.70 (m, 2H, H-4), 3.61 (t, 2H, J = 6.3 Hz, H-7), 2.09-1.99 (m, 4H, H-5 and H-6), 1.68-1.63 (m, 2H, H-2), 1.03 (t, 3H, J = 7.5 Hz, H-1), 0.90 (s, 9H, H-9), 0.05 (s, 6H, H-8).

13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 151.2 (C-3), 107.5 (C-4), 62.9 (C-7), 32.3 (C-5), 31.0 (C-6), 28.8 (C-2), 25.9 (C-9), 18.3 (C-10), 12.3 (C-1), -5.2 (C-8).

HRMS (ESI):

[M+H] + C 13 H 28 OSiNa: calcd. 228.1909OSiNa: calcd. 228. , found 228.1923.

(E)-Diethyl 4-(((benzyloxy)imino)methyl)-4-ethylheptanedioate (309)

To a solution of xanthate 219 (243.3 mg, 1.16 mmol, 1 eq.) in dry degassed benzene (11.6 mL), olefin 252 (730 mg, 4.67 mmol, 4 eq.), oxime 269 233 (804.1 mg, 2.33 mmol, 2.5 eq.), di(tributyl)tin (1.01g, 0.1.75 mmol, 1.5 eq.) and 20 mol% of DTBHN (40.7 mg, 0.23 mmol) were added. The reaction mixture was stirred for 1.5 h at 65°C. The reaction progress was monitored by TLC and further additions of DTBHN (20 mol%, 40.7 mg, 0.23 mmol) were done. The yellow reaction mixture was concentrated under reduced pressure and the residue purified by chromatography on silica gel (PE/EtOAc 95/5). The desired compound 309 was obtained as colorless oil (205 mg, 46%). R f = 0.5 (PE/EtOAc 90/10). IR (ATR) ν max (cm -1 ) = 2965, 1733, 1260, 1182, 1027, 800.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.45-7.29 (m, 5H, H-16), 7.21 (s, 1H, H-4), 5.09 (s, 2H, H-15), 4.15 (q, 4H, J = 6.9 Hz, H-13 and H-10), 2.29-2.17 (m, 4H, H-1 and H-8), 1.86-1.74 (m, 4H, H-2 and H-7), 1.47 (q, 2H, J = 7.5 Hz, H-5), 1.29 (t, 6H, J = 7.2 Hz, H-11 and H-14), 0.84 (t, 3H, J = 7.2 Hz, H-6).

13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 173.6 (C-9 and C-12), 155.5 (C-4), 137.8 (C-16), 128.5 (C-16), 128.4 (C-16), 127.9 (C-16), 75.9 (C-15), 60.6 (C-10 and C-13), 41.9 (C-1 and C-8), 29.4 (C-2 and C-7), 28.9(C-5), 27.3 (C-3), 14.3(C-11 and C-14)

Ethyl 3-(3-ethyl-6-oxopiperidin-3-yl)propanoate (310)

To a solution of MCR product 309 (200 mg, 0.960 mmol, 1 eq.) in EtOAc (10 mL), a pinch of Raney nickel catalyst (slurry in water) was added. The reaction mixture was subjected to high pressure of hydrogen (50 atm.) with stirring for 2 days at room temperature. The reaction mixture was then filtered through a short pad of celite and the solvent was concentrated under reduced pressure to give the crude product which was purified by chromatography on silica gel (DCM/MeOH 95/5). The desired piperidinone 310 was obtained as a white solid (157 mg, 72%). Mp = 62-64°C (DCM). R f = 0.4 (DCM/ MeOH 95/5). IR (KBr) ν max (cm -1 ) = 3219, 2939, 1731, 1661, 1308, 1185.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.12 (br, 1H, NH), 4.06 (q, 2H, J = 10.8 Hz, H-12), 2.96 (d, 2H, J = 3.3 Hz, H-5), 2.36-2.07 (m, 4H, H-2 ,H-8), 1.76-1.48 (m, 4H, H-3, H-7), 1.44-1.26 (m, 2H, H-9), 1.19 (t, 3H, J = 7.2 Hz, H-13), 0.78 (t, 3H, J = 7.2 Hz, H-10).

(Z)-diethyl 4-(((benzyloxy)imino)methyl)-4-(3-ethoxy-3-oxopropyl)heptanedioate (330)

To a solution of xanthate 219 (100 mg, 0.425 mmol, 1 eq.) in dry degassed benzene (4.2 mL), olefin 329 (388.4 mg, 1.70 mmol, 4 eq.), oxime 233 (292.8 mg, 1.06 mmol, 2.5 eq.), di(tributyl)tin (370.1 mg, 0.63 mmol, 1.5 eq.) and 20 mol% of DTBHN (14.8 mg, 0.08 mmol) were added. The reaction mixture was stirred for 1.5 h at 65°C. The reaction progress was monitored by TLC and further additions of DTBHN (20 mol%, 14.8 mg, 0.08 mmol) were made. The yellow reaction mixture was concentrated under reduced pressure and the residue purified by chromatography on silica gel (PE/EtOAc 80/20). The desired compound 330 was obtained as colorless oil (88.0 mg, 40%). R f = 0.53 (PE/EtOAc 80/20). IR (ATR) ν max (cm -1 ) = 2987, 1730, 1468, 1326, 1179, 1038, 1027 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.42-7.22 (m, 5H, H-16), 7.17 (s, 1H, H-4), 5.06 (s, 2H, H-15), 4.12 (qd, 6H, J = 1.2, 7.2 Hz, H10, H13 and H18), 2.22 (t, 6H, J = 7.8, 8.7 Hz, H-1, H-8, and H-6), 1.76 (t, 6H, J = 8.7, 7.8 Hz, H-2, H-5 and H-7), 1.26 (td, 9H, J = 1.2, 7.2 Hz, H-11, H-14 and H-19). To a solution of bromosulfone 334 (341.6 mg, 1.45 mmol, 1 eq.) in dry degassed benzene (14.5 mL), olefin 329 (1.32 g, 5.81 mmol, 4 eq.), oxime 233 (1.0 g, 3.6 mmol, 2.5 eq.), di(tributyl)tin (1.26 g, 2.17 mmol, 1.5 eq.) and 20 mol% of DTBHN (50.6 mg, 0.29 mmol) were added. The reaction mixture was stirred for 1.5 h at 65°C. The reaction progress was monitored by TLC and further additions of DTBHN (20 mol%, 50.6 mg, 0.29 mmol) were made. The yellow reaction mixture was concentrated under reduced pressure and the residue purified by chromatography on silica gel (PE/EtOAc 80/20). The desired compound 335 was obtained as colorless oil (322 mg, 44%). R f = 0.39 (PE/EtOAc 80/20). IR (ATR) ν max (cm -1 ) = 2928, 2869,1726,1587,1448,1377,1306,1177. 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 172.7 (C-9, C-12), 153.2 (C-4), (138.9, 137.3, 133.7, 129.3, 128.4

(E)-Ethyl 4-(((benzyloxy)imino)methyl)-4-ethyl-7-oxo-7-(phenylthio)heptanoate (338)

To a solution of α-iodothioester270 337 (108 mg, 0.388 mmol, 1 eq.) in dry benzene (3.8 mL), olefin 252 (242 mg, 1.55 mmol, 4 eq.), oxime 233 (267 mg, 0.97 mmol, 2.5 eq.), di(tributyl)tin (338 mg, 0.58 mmol, 1.5 eq.)

were added, the reaction mixture was degassed for 20 min. The reaction was initiated by adding 20 mol% of DTBHN (13.5 mg, 0.07 mmol). The reaction mixture was then stirred for 1.5 h at 65°C. The reaction progress was monitored by TLC and another addition of DTBHN (20 mol%, 13.5 mg, 0.07 mmol) was done then the reaction mixture was stirred for another 1.5 h at 65 °C. During the reaction progress a white precipitate was formed in the reaction medium. After 3h, the mixture was concentrated under reduced pressure and the residue purified by chromatography on silica gel with (PE/EtOAc 95/5). The desired compound 338 was obtained as colorless oil (115 mg, 67%). R f = 0.27 (PE/EtOAc 90/10). IR (ATR) ν max (cm -1 ) = 2956,2928,2861,1732,1708,1605,1581,1536,1454, 1440 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.40-7.35 (m, 10H, H-10, H-15), 7.18 (s, 1H, H-4), 5.07 (s, 2H, H-14), 4.12 (q, 2H, J = 7.0 Hz, H-12), 2.61-2.53 (m, 2H, H-1), 2.22-2.17 (m, 2H, H-8), 1.88-1.77 (m, 4H, H-2, H-7), 1.46 (q, 2H, J = 7.4 Hz, H-5), 1.26 (t, 3H, J = 7.2 Hz, H-13), 0.82 (t, 3H, J = 7.6 Hz, H-6). To a solution of compound 338 (95 mg, 0.21 mmol) in dry THF (3 mL), was added at 0 °C NaBH 4 (24 mg, 0.63 mmol, 5.0 eq.). The reaction was stirred at r.t. for 2 days. After removal of THF under reduced pressure, the residue was quenched by adding NH 4 Cl and extracted 3 times with EtOAc. The combined organic layer was washed by brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the crude yellow oil was purified by chromatography on silica gel (PE/EtOAc 70/30). The desired compound 341 was obtained as colorless oil (34 mg, 80%). R f = 0.58 (PE/EtOAc 70/30). IR (ATR) ν max (cm -1 ) = 3408,3083,3063,3031,2932,2869,1732,1611,1538,1496,1454,1373. 1988, found 358.1979.

(E)-1-Ethyl 7-methyl 4-(((benzyloxy)imino)methyl)-4-ethylheptanedioate (342)

Isolated as a trans-esterification by-product during the reduction of 338 by NaBH 4 in MeOH. IR (ATR) ν max (cm -1 ) = 3063,3031,2928,2876,1734,1605,1496,1496,1452,1438 1375.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.35-7.28 (m, 5H, H-14), 7.17 (s, 1H, H-7), 5.05 (s, 2H, H-8), 4.11 (q, 2H, J = 7.2 Hz, H-12), 3.66 (s, 3H, H-14), 2.24-2.16 (m, 4H, H-10, H-4), 1.78-1.72 (m, 4H, H-3, H-9), 1.43 (q, 2H, J = 7.2 Hz, H-1), 1.25 (t, 3H, J = 7.2 Hz, H-13), 0.80 (t, 3H, J= 7.5 Hz, H-6).

13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 173.9 (C-11), 173.5 (C-5) 155.3 (C-7), (137.7, 128.3, 127.8 (C-14)), 75.8 (C-8), 60.4 (C-12), 51.6 (C-14), 41.9 (C-2), 29.3 (C-4), 29.2 (C-10), 28.7 (C-3), 28.5 (C-9), 27.7 (C-1), 14.2 (C-13), 7.6 (C-6).

HRMS (ESI):

[M+Na] + C 20 H 29 NO 5 Na : calcd. 386.1937Na : calcd. 386. , found 386.1929.

5-Ethyl-5-(3-hydroxypropyl)piperidin-2-one (328).

To a solution of alcohol 328 (100 mg, 0.29 mmol, 1 eq.) in EtOAc (5 mL), a pinch of Raney nickel catalyst (slurry in water) was added. The reaction mixture was subjected to high pressure of hydrogen (50 atm.) with stirring for 2 days at room temperature. The reaction mixture was filtered through a short pad of celite and the solvent was concentrated under reduced pressure to give the crude product which was purified by chromatography on silica gel (DCM/MeOH 95/5). The desired compound 341 was obtained as a white solid (46 mg, 83%). Mp = 110-111°C (DCM). R f = 0.31 (DCM/ MeOH 95/5). IR (KBr) ν max (cm -1 ) = 3321, 2960,2924,2865,1655,1538,1496,1450,1407,1383. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 6.49 (br s, 1H, NH), 3.63-3.58 (m, 2H, H-10), 3.01 (d, 2H, J = 2.7 Hz, H-5), 2.35-2.28 (m, 2H, H-2), 1.60 (t, 2H, J = 6.9 Hz, H-3), 1.46-1.36 (m, 6H, H-8, H-9, H-6), 0.82 (t, 3H, J = 7.5 Hz, H-7). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 173.0 (C-1), 62.8 (C-10), 50.9 (C-5), 33.7 (C-2), 33.6 (C-9), 29.6 (C-3), 27.7 (C-4), 26.9 (C-8), 26.3 (C-6), 7.4 (C-7). HRMS (ESI): [M+Na] + C 10 H 19 NO 2 Na : calcd. 208.1308, found 208.1316.

3-(3-Ethyl-6-oxopiperidin-3-yl)propyl methanesulfonate (311).

To a solution of hydroxy-lactam 328 (26 mg, 0.14 mmol) in dry DCM (3 mL), were added at 0 °C, MsCl (17.7 mg, 0.154 mmol, 1.1 eq.) and Et 3 N (0.02 mL, 0.154 mmol, 1.1 eq.). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was then treated with a concentrated solution of NH 4 Cl and extracted by DCM. The combined organic layers were dried over Na 2 SO 4 and the solvent was removed under reduced pressure. The crude white solid was purified by chromatography on silica gel (DCM/MeOH 95/5). The desired compound 311 was obtained as a white solid (37 mg, 100%). Mp = 105-106°C (DCM). R f = 0.54 (DCM/ MeOH 95/5). IR (KBr) ν max (cm -1 ) = 3416,3293,3190,3047,2992,2960,2932,2869,1668,1506,1474,1437,1409. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 6.19 (br s, 1H, NH), 4.22 (t, 2H, J= 6.3 Hz, H-10), 3.04 (d, 2H, J= 3 Hz, H-5), 3.01 (s, 3H, H-11), 2.33 (t, 2H, J= 7.2 Hz, H-2), 1.68-1.63 (m, 4H, H-9, H-3), 1.46-1.39 (m, 4H, H-8, H-6), 0.84 (t, 3H, J= 7.5 Hz, H-7).

5-Ethyl-1-azabicyclo[3.3.1]nonan-2-one (37).

To a solution of NaH (31.4 mg, 0.78 mmol, 1.5 eq.) in dry DMF (10 mL), was added dropwise at 0°C, mesylate 311 (138 mg, 0.52 mmol). The reaction mixture was stirred at room temperature for 3 h, and then quenched through addition of a saturated solution of NH 4 Cl. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na 2 SO 4 and the solvent removed under reduced pressure.

The crude yellow oil was purified by chromatography on silica gel (PE/EtOAc 50/50). The desired compound 37 was obtained as colorless oil (62 mg, 71%). R f = 0.79 (PE/EtOAc 50/50). IR (KBr) ν max (cm -1 ) = 3400, 2928,2853,1678,1540,1492,1456,1375,1341. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 4.11 (ddd, 1H, J = 1.2, 5.4, 13.8 Hz, H-6a), 3.19 (d,1H,J = 15 Hz,2.74 (dt,1H,J = 3.3,12.3 Hz, H-6b), 2.66 (d, 1H, J = 13.5 Hz, H-5b), 2.52-2.41 (m, 1H, H-8a), 2.31 (ddd, 1H, J = 1.2, 5.7, 14.4 Hz, H-8b), 1.88 (ddd, 1H, J = 1.2, 8.1, 13.8 Hz, H-2a), 1. 75-160 (m, 1H, H-7a), 1.43-125 (m, 6H, H-2b, H-7b, H-3, H-9), 0.89 (t, 3H, J = 7.2 Hz, H-10). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 184.4 (C-1), 57.3 (C-5), 50.9 (C-6), 36.9 (C-4), 36.1 (C-3), 33.5 (C-8), 33.3 (C-9), 29.4 (C-2), 21.5 (C-7), 7.7 (C-10). HRMS (ESI): [M+Na] + C 10 H 17 NONa: calcd. 190.1202NONa: calcd. 190. , found 190.1209.

(Z)-diethyl 4-(((benzyloxy)imino)methyl)-4-(3-oxo-3-(phenylthio)propyl)heptanedioate (343)

To a solution of α-iodothioester 337 (100 mg, 0.35 mmol, 1 eq.) in dry benzene (3.5 mL), olefin 329 (328.3 mg, 1.43 mmol, 4 eq.), oxime 233 (247.5 mg, 0.89 mmol, 2.5 eq.), di(tributyl)tin (312.9 mg, 0.53 mmol, 1.5 eq.) were added, the reaction mixture was degassed for 20 min. The reaction was initiated by adding 20 mol% of DTBHN (12.53 mg, 0.07 mmol). The reaction mixture was then stirred for 1.5 h at 65°C. The reaction progress was monitored by TLC and another addition of DTBHN (20 mol%, 12.53 mg, 0.07 mmol) was done then the reaction mixture was stirred for another 1.5 h at 65 °C. During the reaction progress a white precipitate was formed in the reaction medium. After 3h, the mixture was concentrated under reduced pressure and the residue purified by chromatography on silica gel with (PE/EtOAc 95/5). The desired compound 343 was obtained as colorless oil (116 mg, 63%). R f = 0.24 (PE/EtOAc 90/10). IR (ATR) ν max (cm -1 ) = 3003,2956,2928,2873,1730,1607,1583,1496,1452,1440,1419,1375. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.44-7.39 (m, 10H, H-10, H-15), 7.21 (s, 1H, H-4), 5.11 (s, 2H, H-14), 4.12 (q, 4H, J = 7.0 Hz, H-12, H-17), 2.64-2.59 (m, 2H, H-1), 2.29-2.13 (m, 4H, H-8, H-6), 1.89-1.78 (m, 6H, H-2, H-5, H-7), 1.30 (t, 6H, J = 7.2 Hz, H-13). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 196.8 (C-9), 173.0 (C-11), 154.1(C-4), (137.7, 134.5, 129.4, 129.2, 128.5, 128.4, 127.9, 127.8 (C-10, C-15)), 75.9 (C-14), 60.5 (C-12, C-17), 41.9 (C-8), 38.3 (C-3), 29.7 (C-7), 29.7(C-1, C-6), 28.5 (C-2, C-5), 14.3 (C-13, C-18). HRMS (ESI): [M+Na] + C 28 H 35 NO 6 NaS : calcd. 536.2077, found 536.2083.

(E)-Ethyl 4-(((benzyloxy)imino)methyl)-4-ethyl-7-hydroxyheptanoate (344)

To a solution of compound 343 (100 mg, 0.19 mmol) in dry THF (9 mL), was added at 0 °C NaBH 4 (36.8 mg, 0.95 mmol, 5.0 eq.). The reaction was stirred at r.t. for 3 days. After removal of THF under reduced pressure, the residue was quenched by adding NH 4 Cl and extracted 3 times with EtOAc. The combined organic layer was washed by brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the crude yellow oil was purified by chromatography on silica gel (PE/EtOAc 50/50). The desired compound 344 was obtained as colorless oil (57 mg, 72%). R f = 0.51 (PE/EtOAc 50/50). IR (ATR) ν max (cm -1 ) = 3465,3030,2926,2873,1731,1496,1455,1420,1370. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7. 34-7.29 (m, 5H, H-14), 7.17 (s, 1H, H-7), 5.03 (s, 2H, H-8), 4.11 (q, 4H, J = 7.2 Hz, H-12, H-14), 3.56 (br t, 2H, H-5), 2.22-2.17 (m, 4H, H-6, H-10), 1.78-1.72 (m, 4H, H-1, H9), 1.45-1.44 (m, 4H, H-4, H-3), 1.24 (t, 6H, J = 7.2 Hz, H-13, H-15). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 173.4 (C-11), 155.3 (C-7), (137.5, 128.4, 128.83, 127.8 (C-14)), 75.8 (C-8), 62.8 (C-5), 60.55 (C-12, C-14), 41.4 (C-2), 30.1 (C-4), 29.8 (C-10, C-6), 28.7 (C-9, C-1), 26.4 (C-3), 14.2 (C-13, C-15). HRMS (ESI): [M+Na] + C 22 H 33 NO 6 Na : calcd. 430.2200, found 430.2194.

(E)-2-((5-Ethyl-1-azabicyclo[3.3.1]nonan-2-ylidene)amino)-4-methoxybenzonitrile (364).

To a solution of bicyclic lacatam 37 (50 mg, 0.29 mmol, 1.0 eq.) in dry DCM (3.0 mL), POCl 3 (0.030 mL, 0.328 mmol, 1.1 eq.) was added. The mixture was refluxed at 60°C for 3 h till consumption of the bicyclic lactam (checked by TLC). Then the reaction was cooled down to room temperature and a solution of aniline 363 (66.4 mg, 0.448 mmol, 1.5 eq.) in DCM (2.0 mL) was added dropwise. The reaction mixture was heated under reflux for 12 h. Then the solvent was evaporated under reduced pressure and the yellow oily residue was treated by an ice-cold H 2 O and basified with a 30% NaOH solution up to pH = 8. The aqueous layer was extracted by DCM and the combined organic layers were washed with brine and dried over Na 2 SO 4 . The solvents were removed under reduced pressure and the crude yellow oil was purified by chromatography on silica gel (DCM/MeOH 99/01). The desired amidine 364 was obtained as yellow oil (78 mg, 88%). R f = 0.62 (DCM/MeOH 99/01). IR (ATR) ν max (cm -1 ) = 3361, 2959,2928,2853,2214,1627,1593,1563,1488,1456,1375. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.41 (d, 1H, J = 8.7 Hz, H-13), 6.53 (dd, 1H, J = 2.4, 8.7 Hz, H-14), 6.26 (d, 1H, J = 1.8 Hz, H-16), 4.25 (dd, 1H, J = 4.8, 12.9 Hz, H-6a), 3.75 (s, 3H, H-17), 3.12-2.80 (m, 2H, H-6b, H-5a), 2.60 (d, 1H, J = 13.5 Hz, H-5a), 2.28-2.12 (m, 3H, H-3, H-8a), 1.70 (dd, 1H, J = 7.2, 13.8 Hz, H-8b), 1.57-1.30 (m, 4H, H-2, H-7), 1.23 (q, 2H, J = 6.9 Hz, H-9), 0.82 (t, 3H, J = 7.2 Hz, H-10).

2-Chloro-1-azabicyclo[3.3.1]non-2-ene (369)

In a 10 mL two-necked round bottom flask equipped with a reflux condenser, bicyclic piperidinone 267 (60 mg, 0.43 mmol) was dissolved in dry DCM (3 mL). POCl 3 (0.044 mL, 0.47 mmol, 1.1 eq.) was introduced dropwise to the reaction mixture, which was then heated under reflux for 3 h. POCl 3 (0.044 mL; 0.47 mmol; 1.1 eq.) was then added again and the reaction mixture refluxed for another 3h, until complete consumption of piperidinone. The heating was stopped and the reaction mixture allowed to cool to room temperature. The solvent was removed under vacuum and the remaining yellow oil was dissolved in an ice. The mixture was then treated with a 30% solution of NaOH until pH = 8. Then the aqueous layer was extracted by DCM (3x). The combined organic layers were washed with brine and dried over Na 2 SO 4 . The solvent was removed and the crude yellow oil was purified through column chromatography (PE/EtOAc 95/5) to afford chloroenamine 369 as faint yellow oil with characteristic menthol like smell (40 mg, 60%). R f = 0.71 (PE/EtOAc 95/5). IR (ATR) ν max (cm 2865,1641,1444,1363,1339,1330,1308,1266,1238,1218. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 5.58 (t, 1H, J = 3.6 Hz, H-2), 3.30 (dd, 1H, J = 3, 14.1 Hz, H-6a), 3.13 (dd, 1H, J = 1.2, 12.6 Hz, H-5a), 3.04 (dd, 1H, J = 1.8, 12.6 Hz, H-5a), 2. 84-2.74 (m, 1H, H-6b), 2.41-2.31 (m, 1H, H-8a), 1.95-1.61 (m, 5H, H-4, H-3, H-7a, H-8b ), 1.33-1.24 (m, 1H, H-7a). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 138.6 (C-1), 116.4 (C-2), 55.6 (C-5), 48.5 (C-6), 31.5 (C-4), 31.1 (C-8), 26.0 (C-3), 17.6 (C-7). 13 C NMR (CD 2 Cl 2 , 75 MHz): δ (ppm) = 138.9 (C-1), 116.2 (C-2), 55.5 (C-5), 48.4 (C-6), 31.4 (C-4), 31.0 (C-8), 26.2 (C-3), 17.6 (C-7). HRMS (EI): [M] + C 8 H 12 ClN : calcd. 157.06583, found 157.06618.

Reactions of chloroenamine with aromatic anilines a. Under acidic conditions.

To a solution of chloroenamine 369 (30 mg, 0.19 mmol, 1.0 eq.) in dry DCM (2.5 mL), methoxyaminobenzonitrile 363 (42.2 mg, 0.285 mmol, 1.5 eq.) and TFA (1.4 µL, 0.019 mmol, 0.1 eq.) were added. The reaction mixture was heated under reflux for 12 h. Then the solvent was evaporated under reduced pressure and the yellow oily residue was treated by an ice-cold H 2 O and basified with a 30% NaOH solution up to pH = 8. The aqueous layer was extracted by DCM and the combined organic layers were washed with brine and dried over Na 2 SO 4 . The solvents were removed under reduced pressure and the crude yellow oil was purified by chromatography on silica gel (DCM/MeOH 99/1) to afford amidine 363 as yellow oil (43 mg, 84%).

b. Under basic conditions.

To a solution of chloroenamine 369 (25 mg, 0.158 mmol, 1.0 eq.) in dry DCM (2 mL), methoxyaminobenzonitrile 363 (35.2 mg, 0.237 mmol, 1.5 eq.) and 2,6-di-tert-butyl pyridine (3.5 µL, 0.015 mmol, 0.1 eq.) were added. The reaction mixture was heated under reflux for 12 h. Then the solvent was evaporated under reduced pressure and the yellow oily residue was treated by an ice-cold H 2 O and basified with a 30% NaOH solution up to pH = 8. The aqueous layer was extracted by DCM and the combined organic layers were washed with brine and dried over Na 2 SO 4 . The solvents were removed under reduced pressure and the crude yellow oil was purified by chromatography on silica gel (DCM/MeOH 99/1) to afford amidine 377 as yellow oil (34 mg, 80%).

c. Under neutral conditions.

To a solution of chloroenamine 369 (25 mg, 0.158 mmol, 1.0 eq.) in dry DCM (2 mL), methoxyaminobenzonitrile 363 (35.2 mg, 0.237 mmol, 1.5 eq.) was added. The reaction mixture was heated under reflux for 12 h. Then the solvent was evaporated under reduced pressure and the yellow oily residue was treated by an ice-cold H 2 O and basified with a 30% NaOH solution up to pH = 8. The aqueous layer was extracted by DCM and the combined organic layers were washed with brine and dried over Na 2 SO 4 . The solvents were removed under reduced pressure and the crude yellow oil was purified by chromatography on silica gel (DCM/MeOH 99/1) to afford amidine 377 as a yellow oil (33 mg, 77%).

Kinetic protonation of chloroenamine 2-Chloro-1-azabicyclo[3.3.1]non-2-en-1-ium 2,2,2-trifluoroacetate (378)

In a NMR tube, bicyclic chloroenamine 369 (10 mg, 0.06 mmol, 1.0 eq.) was dissolved in dry CD 2 Cl 2 (0.5 mL). Deuterated trifluoroacetic acid (TFA-d) (4.8 µL, 0.06 mmol, 1.0 eq.) was then introduced dropwise to the reaction mixture to provide the desired enamine salt which was directly subjected to NMR studies. The solvent was then removed under reduced pressure and the crude reaction product submitted to high resolution mass spectroscopy. 1 H NMR (CD 2 Cl 2 , 300 MHz): δ (ppm) = 11.7 (s, 1H, CF 3 COOH), 6.36 (t, 1H, J = 4.2 Hz, H-2), 3.62-3.58 (m, 1H, H-6a), 3.61 (m, 3H, H-6b, H-5), 3.49-3.39 (m, 1H, H-4), 2.70 (ddd, 1H, J = 3.3, 7.2, 19.8 Hz H-8a), 2.47-2.41 (m, 1H, H-8b), 2.24-2.22 (m, 1H, H-7a), 2.00-1.82 (m, 3H H-7b, H-3). 13 C NMR (CD 2 Cl 2 , 75 MHz): δ (ppm) = 159.8 (q, CF 3 CO, J = 39.75 Hz), 128.4 (C-2), 122.8 (C-1) 115.1(q, CF 3 , J = 285 Hz), 54.7 (C-5), 50.6 (C-6), 29.7 (C-4), 28.6 (C-8), 22.9 (C-3), 15.5 (C-7). HRMS (ESI): [M] + C 8 H 13 ClN + : calcd. 158.0731, found 158.0724.

Reaction of bicyclic enamine 369 with aniline-d 7

To a solution of chloroenamine 369 (50 mg, 0.31 mmol, 1.0 eq.) in dry CD 2 Cl 2 (2.5 mL), aniline-d 7 381 (31.77 mg, 0.317 mmol, 1.0 eq.) and TFA-d (2.4 µL, 0.031 mmol, 0.1 eq.) were added. The reaction mixture was heated under reflux for 48 h. Then the solvent was evaporated under reduced pressure and the yellow oily residue was treated by an ice-cold H 2 O and basified with a 30% NaOH solution up to pH = 8. The aqueous layer was extracted by DCM and the combined organic layers were washed with brine and dried over Na 2 SO 4 . The solvents were removed under reduced pressure and the crude yellow oil was purified by chromatography on silica gel (DCM/MeOH 99/1) to afford amidine 382 as a faint yellow oil (40 mg, 57%). R f = 0.27 (DCM/MeOH 99/1). IR (ATR) ν max (cm -1 ) = 2929, 2854, 1633, 1563, 1456m 161, 1351, 1339, 1253, 1170. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 4. 26-4.20 (dd, 1H, J = 4.2, 12.9 Hz, H-3), 3.37-3.32 (m, 1H, H-3), 3.00-2.95 (m, 2H, H-4), 2.57-2.51 (m, 1H, H-6), 2.17-1.92 (m, 5H, H-8, H-6, H-5), 1.89-1.77 (m, 1H, H-7), 1.59-1.54 (m, 2H, H-1). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 169.5 (C-2), 150.5 (C-9), (128.6, 128.3, 128.0, 122.0, 121.4, 121.1, 120.8 C-Ar.), 54.2 (C-3), 51.9 (C-4), 31.2 (C-7), 28.3(C-6), 25.1(C-8), 24.4(C-5), 19.5(C-1) HRMS (CI): [M+H] + C 14 H 14 D 5-N 2 : calcd. 220.1707, found 220.1710.

General procedure for Suzuki coupling with α-chloroenamine

To a solution of the chloroenamine 369 (1 eq.) in freshly distillated DME (0.019 M) and H 2 O (0.054 M), were added the boronic acid derivative (1.5 eq.) and K 2 CO 3 (1 eq.). The flask containing the reaction mixture was flashed with argon for 30 min, then Pd(PPh 3 ) 4 (0.1 eq.) was added. The reaction mixture was heated at 95°C for 3 h, then cooled down to room temperature and the solvent was evaporated under vacuum. The residue was diluted with DCM and water and the aqueous layer was extracted with DCM. The combined extracts were dried over Na 2 SO 4 and solvents were evaporated under vacuum. The crude product was purified by flash chromatography on silica gel.

2-(4-Methoxyphenyl)-1-azabicyclo[3.3.1]non-2-ene (394a)

Synthesized according to the general procedure above, from a mixture of chloroenamine 369 (30 mg, 0.190 mmol, 1 eq.) in DME (10 mL) and H 2 O (3.5 mL), 4-methoxyphenylboronic acid 393a (43.3 mg, 0.28 mmol, 1.5 eq.), K 2 CO 3 (26.3 mg, 0.190 mmol, 1 eq.) and Pd(PPh 3 ) 4 (22 mg, 0.019 mmol, 0.1 eq.). The crude product was purified by chromatography on silica gel (PE/EtOAc 95/5) to give the enamine 394a as yellow oil (40 mg, 92%). R f = 0.42 (PE/EtOAc 95/5).

IR (ATR) ν max (cm -1 ) = 2997,2921,2900,2855,1630,1607,1575,1507,1461,1441,1369,1354,1321,1298,1269,1254.

3-(1-Azabicyclo[3.3.1]non-2-en-2-yl)phenol (394b)

Synthesized according to the general procedure above, from a mixture of chloroenamine 369 (30 mg, 0.190 mmol, 1 eq.) in DME (10 mL) and H 2 O (3.5 mL), 3-hydroxyphenylboronic acid 393b (39.4 mg, 0.28 mmol, 1.5 eq.), K 2 CO 3 (26.3 mg, 0.19 mmol, 1 eq.) and Pd(PPh 3 ) 4 (22 mg, 0.019 mmol, 0.1 eq.). The crude product was purified by chromatography on silica gel (PE/EtOAc 80/20) to give the enamine 394b as yellow oil (24.5 mg, 60%). R f = 0.40 (PE/EtOAc 80/20).

IR (ATR) ν max (cm -1 ) = 3354,2927,2855,2825,1631,1579,1480,1445,1369,1355,1323,1281,1245,1218.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.17-7.07 (m, 3H, Ar), 6. 1H,Ar), 5.99 (t, 1H, J = 3.9 Hz, H-2), 5.12 (br s, 1H, OH), 3.18 (dd, 1H, J = 1.2, 12.3 Hz, H-6a), 2.99 (d,1H,J = 12.6 Hz,3H,1H,2H,3H,. 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 155.8 (C-1), (149.9,139.8,129.3,118.4,117.0,), 112.9 (C-2), 54.2 (C-5), 49.4 (C-6), 31.7(C-4), 31.0 (C-8), 26.3 (C-3), 18.0 (C-7). HRMS (ESI): [M+H] + C 14 H 18 NO : calcd. 216.1382, found 216.1375.

2-(2-nitrophenyl)-1-azabicyclo[3.3.1]non-2-ene (394c)

Synthesized according to the general procedure above, from a mixture of chloroenamine 369 (34 mg, 0.21 mmol, 1 eq.) in DME (11.3 mL) and H 2 O (3.8 mL), 2-nitrophenylboronic acid 393c (54 mg, 0.32 mmol, 1.5 eq.), K 2 CO 3 (29.8 mg, 0.21 mmol, 1 eq.) and Pd(PPh 3 ) 4 (24.9 mg, 0.021 mmol, 0.1 eq.). The crude product was purified by chromatography on silica gel (PE/EtOAc 80/20) to give the enamine 394c as deep yellow oil (50 mg, 95%). R f = 0.52 (PE/EtOAc 95/05). IR (ATR) ν max (cm -1 ) = 3057,3035,2927,2857,1637,1604,1574,1529,1459,1445,1366,1332,1322. (144.3, 134.2, 131.4, 130.7, 128.2, 123.5

2-(Pyren-1-yl)-1-azabicyclo[3.3.1]non-2-ene (394d)

Synthesized according to the general procedure above, from a mixture of chloroenamine 369 (35 mg, 0.22 mmol, 1 eq.) in DME (11 mL) and H 2 O (4 mL), pyrene-1-boronic acid 393d (82 mg, 0.33 mmol, 1.5 eq.), K 2 CO 3 (30.6 mg, 0.22 mmol, 1 eq.) and Pd(PPh 3 ) 4 (25.6 mg, 0.022 mmol, 0.1 eq.). The crude product was purified by chromatography on silica gel (PE/EtOAc 95/5) to give the desired enamine 394c as a yellow solid (60 mg, 84%). Mp = 55°C (DCM/Hexane) R f = 0.40 (PE/EtOAc 95/5). IR (KBr) ν max (cm -1 ) = 3040,2923,2855,2824,1630,1601,1583,1504,1488,1457,1444,1415.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 8.66 (d,1H,J= 9.3 Hz,Ar),8H,Ar),5.92 (t,1H,J= 3.6 Hz,2H,, 2.83-2.75 (m, 2H, H-5), 2. 73-2.63 (m, 1H, H-4), 2.25 (dd, 1H, J= 3.9, 18.9 Hz, H-8a), 2.18-2.06 (m, 2H, H-8b, H-7a), 2.00-1.88 (m, 2H, H-7b, H-3a), 1.33-1.29 (m, 1H, H-3b). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 146.9 (C-2), (135.4, 131.3, 131.0, 130.8, 129.8, 127.6, 127.4, 127.2, 126.9, 125.8, 124.8, 127.7, 124.3 (C-Ar)), 121.8 (C-2), 54.4 (C-5), 49.2 (C-6), 31.9 (C-4), 31.3 (C-8), 26.4 (C-3), 18.5 (C-7). HRMS (ESI): [M+H] + C 24 H 22 N : calcd. 324.1746, found 324.1746.

3-(1-Azabicyclo[3.3.1]non-2-en-2-yl)phenyl 4-methylbenzenesulfonate (396)

To a solution of enamine 394b (10 mg, 0.46 mmol, 1.0 eq.) in dry DCM (2.5 mL), were added at 0 °C, TsCl (9.74 mg, 0.051 mmol, 1.1 eq.), Et 3 N (0.6 μL, 0.04 mmol, 1.0 eq.) and DMAP (0.5 mg, 0.004 mmol, 0.1 eq.).

The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was then treated with a concentrated solution of NH 4 Cl and extracted by DCM. The combined organic layers were dried over Na 2 SO 4 and the solvent was removed under reduced pressure. The crude white solid was purified by chromatography on silica gel (PE/EtOAc 9/1). The desired compound 396 was obtained as a colorless oil (16 mg, 93%). R f = 0.62 (PE/EtOAc 9/1). IR (ATR) ν max (cm -1 ) = 2927,2856,1631,1598,1575,1444,1372,1190, 1178 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7. 2H,1H,2H,1H,5.89 (t,1H,J= 3.6 Hz,1H,1H,3H,2.43 (s,3H,4H,H7),2H,. 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 149.9 (C-1), (140.2, 129.8, 129.6, 129.1, 128.6, 128.4. 124.3, 121.0, 119.9 In a 25 mL two necked round bottom flask (flame-dried and equipped with an inlet for argon) was added n-BuLi (0.39 mL, 0.72 mmol, 3.0 eq.), then freshly distilled diisopropylamine (DIPA) (0.10 mL, 0.75 mmol, 3.1 eq.) at r.t. During addition of DIPA, the reaction mixture forms a colorless gel. The reaction mixture was then diluted with dry THF (0.5 mL) and stirred for 30 min at r.t. Amidine 364 (72 mg, 0.24 mmol, 1.0 eq.) was dissolved in dry THF (2.5 mL) and introduced dropwise to the reaction mixture (which became clear deep yellow). The reaction mixture was allowed to react overnight at r.t., then was quenched with a few drops of a NH 4 Cl solution. THF was then evaporated under reduced pressure. The residue was diluted with a NH 4 Cl solution and extracted with DCM. The combined organic layers were washed with brine and dried over Na 2 SO 4 . The solvent was concentrated under reduced pressure and the residue purified by chromatography on silica gel (DCM/MeOH/NH 4 OH 95/4/1) to give 402 as a faint brown solid (50 mg, 70%). Mp = 212°C (DCM). R f = 0.45 (DCM/MeOH/NH 4 OH 95/4/1). IR (KBr) ν max (cm -1 ) = 3325,2964,2924,2857,1661,1639,1597,1540,1496,1452,1405,1387,1260. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.66 (d,1H,J = 9 Hz,7.26 (d,1H,6.94 (dd,1H,J = 2.4,9 Hz,5.03 (br s,2H,NH),3.86 (s,3H,1H,3.12 (dt,1H,J = 3.6,13.2 Hz, H-1), 3.01 (d, 1H, J = 13.5 Hz, H-7a), 2.86 (d, 1H, J = 13.2 Hz, H-7b), 2.47 (d, 1H, J = 16.5 Hz, H-3a), 2.28 (d,1H,J = 16.2 Hz,4H,1.36 (q,2H,J = 7.8 Hz, H-5), 0.95 (t, 3H, J = 7.2 Hz, H-6). To a solution of the amine 402 (78 mg, 0.262 mmol, 1 eq.) and H 2 SO 4 (0.07 mL, 1.31 mmol, 5 eq.), NaNO 2 (90 mg, 1.31 mmol, 5 eq.) in H 2 O (2 mL) was added dropwise at 0°C. Stirring was then continued for 12 h at room temperature. A 20% NaOH solution was added dropwise at 0°C until pH = 9. The aqueous layer was then extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na 2 SO 4 and the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel (DCM/MeOH/NH 4 OH 96/3/1) to give 403 as a white solid (60 mg, 77% yield). Mp = >300°C (DCM). R f = 0.47 (DCM / MeOH / NH 4 OH 95/4/1). IR (KBr) ν max (cm -1 ) = 3435,3225,3003,3063,2933,2850,2797,1629,1605,1558,1500,1480,1422. 1 H NMR (CD 3 OD, 300 MHz): δ (ppm) = 8.12 (d, 1H, J = 9 Hz, H-17), 6.93 (dd, 1H, J = 2.4,9 Hz, H-14), 6.88 (d,1H,J = 2.4 Hz,3.90 (s,3H,1H,1H,, 2.99 (d, 1H, J = 12.9 Hz, H-7a), 2.85 (d,1H,J = 14.1 Hz,2.55 (d,2H,J = 17.4 Hz,2.44 (d,1H,J = 17.4 Hz,1H,2H, H-H-2), 1.38 (q, 2H, J = 7.5 Hz, H-5), 1.30 (s, 1H, H-10b), 1.00 (t, 3H, J = 7.5 Hz, H-6). 13 C NMR (CD 3 OD, 75 MHz): δ (ppm) = (162.7,126.2,113.2,111.3,97.4 (Ar)), 57.8 (C-7), 54.6 (C-18), 53.8 (C-1), 35.7 (C-5), 34.5 (C-3), 31.6, 31.5, 30.3, 29.3, 22.4, 18.9 (C-2), 13.0, 5.9 (C-6). HRMS (ESI): [M+Na] + C 18 H 22 N 2 O 2 Na: calcd. 321.1573, found 321.1578. To a solution of phenol 403 (44 mg, 0.14 mmol, 1 eq.) in dry DCM (7 mL), triethylamine (0.030 mL, 0.22 mmol, 1.5 eq.) and DMAP (9 mg, 0.073 mmol, 0.5 eq.) were added at 0°C and the reaction mixture was stirred for 30 min. The color during this period changed from colorless to deep yellow. Comins' reagent (115.8 mg, 0.29 mmol, 2 eq.) was added and the reaction mixture was stirred for 16 h at r.t. A 30% ammonium hydroxide solution was added until pH = 13 and the organic solvents were evaporated under vacuum. The residue was then diluted with EtOAc and saturated NaCl solution, the organic layer was separated and dried over Na 2 SO 4 . The solvent was concentrated under reduced pressure and the crude material purified by chromatography on silica gel (DCM/MeOH 98/2) to give triflate 404 as a white solid (63 mg, 99%). Mp = 112-113°C (DCM). R f = 0.53 (DCM/MeOH 98/2). IR (KBr) ν max (cm -1 ) = 2963,2935,2857,1625,1562,1524,1497,1449,1410,1372,1333,1233,1208. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.83 (d,1H,J = 9.3 Hz,7.30 (d,1H,J = 2.4 Hz,7.17 (dd,1H,J = 2.4,9.3 Hz,3.91 (s,3H,3.76 (d,1H,J= 12.9 Hz,1H,3.12 (dd,1H,J = 1.5,13.5 Hz, H-7a), 2.97 (br s, 1H, H-7b), 2.89 (d, 1H, J = 18.6 Hz, H-3a), 2.78 (d,1H,J = 19.2 Hz,1.80 (d,1H,J = 13.2 Hz, H-10a), 1.61-1.56 (m, 1H, H-2a), 1.38 (q, 2H, J = 7.5 Hz, H-5), 2H,0.96 (t,3H,J = 7.5 Hz,. To a solution of the triflate 404 (63 mg, 0.146 mmol, 1 eq.) in freshly distillated DME (7 mL) and H 2 O (2.5 mL), vinyl potassium trifluoroborate 405 (31 mg, 0.21mmol, 1.5 eq.) and K 2 CO 3 (20 mg, 0.186 mmol, 1 eq.) were added. The flask containing the reaction mixture was flashed with argon for 30 min, then Pd(PPh 3 ) 4 (17 mg, 0.014 mmol, 0.1 eq.) was added. The reaction mixture was heated at 95°C for 3 h. The reaction mixture was then cooled down to room temperature and the solvent evaporated under vacuum. The product was purified by chromatography on silica gel (EtOAc 100%) to give 406 as yellow oil (36 mg, 80%). R f = 0.3 (EtOAc 100%). IR (ATR) ν max (cm -1 ) = 3054,2925,2855,1621,1561,1501,1451,1424,1269,1264,1228,1160. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.91 (d,1H,J = 9.3 Hz,7.27 ( d,1H ,J = 2.7 Hz,7.02 (dd,1H ,J = 2.7,9.3 Hz,6.83 (dd,1H,J = 11.7,18 Hz,5.83 (dd,1H,J = 1.8,11.7 Hz,5.53 (dd,1H,J = 1.8,18 Hz,3.90 (s,3H,1H,1H,3.06 (dd,1H,J = 1.8,13.2 Hz,2.93 (dd,1H,J = 1.5,13.2 Hz, H-7b), 2.71 (d,1H,J = 17.7 Hz,2.54 (dd,1H,J = 1.5,17.7 Hz,4H,1.35 (q,2H,J = 7.5 Hz, H-5), 0.94 (t, 3H, J = 7.5 Hz, H-6). To a cold (0 °C) stirred solution of compound 406 (26 mg, 0.083 mmol) in dry DCM (1 mL) under argon, was added a 1M solution of BBr 3 in DCM (0.126 mL, 0.126 mmol)). The cooling bath was then removed and the resulting solution was stirred at room temperature for 16 h. The reaction mixture was then cooled to 0°C, quenched and neutralized with saturated aqueous Na 2 CO 3 (1 mL). The organic layer was separated and dried over Na 2 SO 4 . The resulting crude product was purified through column chromatography (DCM/MeOH 98/2) to afford Eucophylline 3 as a faint yellow solid (21.5 mg, 87%). Spectroscopic data are in good agreement with those of the natural product described by Morita et al. 2 Mp = 159-160°C. R f = 0.60 (DCM/MeOH 98/2). IR (KBr) ν max (cm -1 ) = 3353,3058,2925,2857,1618,1575,1496,1449,1368,1343,1264,1236,1162. 1 H NMR (CD 3 OD, 400 MHz): δ (ppm) = 7.90 (d,1H,J = 9.2 Hz,7.08 ( d,1H,J = 2.0 Hz,6.98 (dd,1H ,J = 2,9.2 Hz,6.90 (dd,1H,J = 11.6,18 Hz,5.87 (d,1H,J = 11.6 Hz,5.51 (dd,1H,J = 18 Hz,3.62 (d,1H,J = 12.8 Hz,1H,3.04 (d,1H,J = 12.8 Hz, H-7a), 2.86 (d, 1H, J = 13.2 Hz, H-7b), 2.74 (d, 1H, J = 17.6 Hz, H-3a), 2.58 (d,1H,J = 18 Hz,1H,, 1.33 (q, 2H, J = 7.2 Hz, H-5), 1.22 (m, 2H, H-10b, H-2b), 0.94 (t, 3H, J = 7.2 Hz, H-6). To a solution of 3-butyn-1-ol 543 (3.0 g, 42.8 mmol, 1.0 eq.) and i-Pr 2 NEt (7.78 mL, 47.08 mmol, 1.1 eq.) in DCM (65 mL), was added TBDMSCl (8.15 mL, 47.08 mmol, 1.1 eq.) to The resulting slurry at 0 °C. The reaction mixture was allowed to warm up 25 °C and stirred at that temperature for 3 h. Then, the reaction was quenched with a saturated aqueous solution of NH 4 Cl (10 mL) and the separated aqueous layer was extracted with CH 2 Cl 2 (3×20 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude protected alcohol 544b (7.71 g, 91%, brown oil) was used directly in the next step without further purifications.

5-Ethyl

(But-3-yn-1-yloxy)(tert-butyl)diphenylsilane (544b)

To a solution of 3-butyn-1-ol 543 (2.5 g, 35.7 mmol, 1.0 eq.) and imidazole (2.55 g, 35.7 mmol, 1.05 eq.) in DCM (200 mL), was added TBDPSCl (9.27 mL, 35.7 mmol, 1.1 eq.) to The resulting slurry at 0 °C. The reaction mixture was allowed to warm up 25 °C and stirred at that temperature for 16 h. Then, the reaction mixture was filtered through a plug of silica gel eluting with DCM. The solvent was concentrated under reduced pressure. The crude protected alcohol 544c (11 g, quant., colorless oil) was used directly in the next step without further purifications.

General Procedure:

To a stirred solution of alkyne 544b or 544c (1.0 eq.) in dry hexane, B-iodo-9-BBN (1.2 eq., 1.0 M in hexane) was added at 0 °C. The reaction mixture was allowed to slowly warm to room temperature and stirred for 16 h. the boron adduct was hydrolysed by the addition of NaOAc (1.2 eq.), followed by AcOH (3.5 eq.) and the reaction was stirred for 1 h. Then, the solution was diluted with hexane and washed with water, saturated NaHCO 3 and water respectively. The organic layer was dried over MgSO 4 and the solvent was removed under reduced pressure. The crude oil was purified by chromatography on silica gel.

Tert-butyl((3-iodobut-3-en-1-yl)oxy)dimethylsilane (545b)

Synthesized according to the general procedure above from alkyne 544b (1000 mg, 5.42 mmol, 1.0 eq.) in dry hexane (40 mL) and B-iodo-9-BBN (6.5 mL, 6.50 mmol, 1.2 eq., 1.0 M in hexane). The hydrolysed was performed by NaOAc (534 mg, 6.50 mmol, 1.2 eq.), followed by AcOH (1.1 mL, 18.99 mmol, 3.5 eq.). The crude brownish oil was purified by chromatography on silica gel (Pentane/Et 2 O 95/5). The desired compound 545b was obtained as colorless oil (765 mg, 45%). R f = 0.99 (Pentane/Et 2 O 95/5). IR (ATR) ν max (cm -1 ) = 3413,3064,2931,1456,1427,1258,1107.

Tert-butyl((3-iodobut-3-en-1-yl)oxy)diphenylsilane (545c)

Synthesized according to the general procedure above from alkyne 544c (3000 mg, 9.72 mmol, 1.0 eq.) in dry hexane (120 mL) and B-iodo-9-BBN (11.67 mL, 11.67 mmol, 1.2 eq., 1.0 M in hexane). The hydrolysed was performed by NaOAc (11.67 mg, 6.50 mmol, 1.2 eq.), followed by AcOH (0.67 mL, 11.67 mmol, 3.5 eq.).

The crude brownish oil was purified by chromatography on silica gel (Pentane/Et 2 O 95/5). The desired alkene 545c was obtained as colorless oil (3.98 g, 94%). R f = 0.79 (PE/EtOAc 98/2). IR (ATR) ν max (cm -1 ) = 3071,3049,2999,2921,2858,1615,1589,1471,1462,1471,1428.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.77-7. 74 (m,4H,Ar),6H,Ar). 6.17-6.16 (m, 1H, H-1a), 5.85 (m, 1H, H-1b), 3.85 (t, 2H, J = 6.3 Hz, H-4), 2.69 (td, 2H, J = 0.9, 6.0 Hz, H-3), 1.12 (s, 9H, H-7).

Olefins (546b-c)

General Procedure: To a solution containing 546b or 546c (1.0 eq.), Fe(acac) 3 (3% mol), in a mixture NMP and dry THF was added dropwise a solution of EtMgBr (1 M in THF) over 5 min. The temperature was maintained in between -5°C and 0°C during the addition. Stirring was continued for 15 min, and the reaction mixture was hydrolyzed at -10°C with aqueous HCl (10%). The reaction was diluted by ether, and then the organic layer was separated washed with saturated NaHCO 3 and water respectively. The combined organic layer was dried over MgSO 4 and the solvent was removed under reduced pressure. The crude faint yellow oil was purified by chromatography on silica gel.

Tert-butyldimethyl((3-methylenepentyl)oxy)silane (546b)

Synthesized according to the general procedure above from a solution containing 545b (730 mg, 2.338 mmol, 1.0 eq.), Fe(acac) 3 (25 mg, 0.069 mmol, 3% mol), in a mixture NMP (0.632 mL) and dry THF (22 mL) and by addition of EtMgBr ( 2.57 mL, 2.57 mmol, 1.1 eq., 1 M in THF).The reaction mixture was hydrolyzed at -10°C with aqueous (80 ml) HCl (10%). The crude faint yellow oil was purified by chromatography on silica gel (Pentane/Et 2 O 95/5). The desired alkene 546b was obtained as colorless oil (272 mg, 54%). R f = 0.85 (PE/EtOAc 98/2). IR (ATR) ν max (cm -1 ) = 3073,2960,1645,1595,1471,1259,1097. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 4. 77-4.75 (m, 1H, H1a), 4.72-4.71 (m, 1H, H1b), 3.70 (t, 2H, J = 7.2 Hz, H-4), 2.25 (t, 2H, J = 7.5 Hz, H-3), 2.04 (q, 2H, J = 7.2 Hz, H-8), 1.02 (t, 3H, , J = 7.5 Hz H-9), 0.89 (s, 9H, H-7). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 148.5 (C-2), 109.1 (C-1), 62.5 (C-4), 39.6 (C-3), 29.25 (C-6), 25.8 (C-7), 18.3 (C-8), 12.3 (C-9), -5.2 (C-5). HRMS (CI): [M-H] + C 12 H 26 IOSi :found 213.14.

Tert-butyl((3-methylenepentyl)oxy)diphenylsilane (546c)

Synthesized according to the general procedure above from a solution containing 545c (3.85g, 8.82 mmol, 1.0 eq.), Fe(acac) 3 (93.02 mg, 0.263 mmol, 3% mol), in a mixture NMP (2.38 mL) and dry THF (82 mL) and by addition of EtMgBr (9.70 mL, 9.70 mmol, 1.1 eq., 1 M in THF).The reaction mixture was hydrolyzed at -10°C with aqueous (80 ml) HCl (10%). The crude faint yellow oil was purified by chromatography on silica gel (Pentane/Et 2 O 95/5). The desired alkene 546c was obtained as colorless oil (2.59 g, 87%). R f = 0.77 (PE/EtOAc 98/2). IR (ATR) ν max (cm -1 ) = 3051,3072,2962,2932,2858,1645,1590,1463,1472,1428,1390.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7. 4H,Ar),6H,Ar),1H,H1a),1H,H1b), 3.81 (t, 2H, J = 7.2 Hz, H-4), 2.36 (t, 2H, J = 6.9 Hz, H-3), 2.04 (q, 2H, J = 7.5 Hz, H-8), 1.11 (s, 9H, H-7), 1.03 (t, 3H, , J = 7.5 Hz H-9). ONaSi: calcd. 361.1962ONaSi: calcd. 361. , found 361.1958.

S-Phenyl 4-(((benzyloxy)imino)methyl)-6-((tert-butyldimethylsilyl)oxy)-4-ethylhexanethioate (547a)

To a solution of α-iodothioester 337 (81.06 mg, 0.29 mmol, 1 eq.) in dry benzene (2.9 mL), olefin 546b (250 mg, 1.16 mmol, 4 eq.), oxime 233 (200.6 mg, 0.72 mmol, 2.5 eq.), di(tributyl)tin (253.6 mg, 0.43 mmol, 1.5 eq.) were added, the reaction mixture was degassed for 20 min. The reaction was initiated by adding 20 mol% of DTBHN (10.16 mg, 0.05 mmol). The reaction mixture was then stirred for 1.5 h at 65°C. The reaction progress was monitored by TLC and another addition of DTBHN (20 mol%, 10.16 mg, 0.05 mmol) was done then the reaction mixture was stirred for another 1.5 h at 65 °C. During the reaction progress a white precipitate was formed in the reaction medium. After 3h, the mixture was concentrated under reduced pressure and the residue purified by chromatography on silica gel with (PE/EtOAc 95/5). The desired compound 547a was obtained as colorless oil (42 mg, 29%). R f = 0.61 (PE/EtOAc 95/05). IR (ATR) ν max (cm -1 ) = 2923,2869,1708,1613,1566,1501,1432, 1415 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7. 10H,Ar),7.27 (s,1H,5.09 (s,2H,3.64 (t,2H,J = 10.5 Hz,2H,2H,, 1.70 (t, 2H, J = 10.2 Hz, H-2), 1.53-1.44 (m, 2H, H-5), 0.91 (s, 9H, H-15), 0.84 (t, 3H, J = 11.1 Hz H-6), 0.06 (s, 6H). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 197.1 (C-9), 156.0 (C-4), (137.7, 134.5, 129.3, 129.1, 128.3, 128.8, 127.8 (C-Ar)), 75.7 (C-11), 41.5 (C-1), 38.5 (C-8), 37.3 (C-7), 30.2 (C-2), , 27.9 (C-3), 25.9 (C-15), 18.3 (C-5), 7.7 (C-6), -5.3 (C-13). HRMS (ESI): [M+Na] + C 28 H 41 NO 3 NaSSi : calcd. 522.2474, found 522.2466.

S-Phenyl 4-(((benzyloxy)imino)methyl)-6-((tert-butyldimethylsilyl)oxy)-4-ethylhexanethioate (547b)

To a solution of α-iodothioester 337 (81.06 mg, 0.29 mmol, 1 eq.) in dry benzene (2.9 mL), olefin 546c (394.7 mg, 1.16 mmol, 4 eq.), oxime 233 (200.6 mg, 0.72 mmol, 2.5 eq.), di(tributyl)tin (253.6 mg, 0.43 mmol, 1.5 eq.) were added, the reaction mixture was degassed for 20 min. The reaction was initiated by adding 20 mol% of DTBHN (10.16 mg, 0.05 mmol). The reaction mixture was then stirred for 1.5 h at 65°C. The reaction progress was monitored by TLC and another addition of DTBHN (20 mol%, 10.16 mg, 0.05 mmol) was done then the reaction mixture was stirred for another 1.5 h at 65 °C. During the reaction progress a white precipitate was formed in the reaction medium. After 3h, the mixture was concentrated under reduced pressure and the residue purified by chromatography on silica gel with (PE/EtOAc 95/5). The desired compound 547b was obtained as colorless oil (72 mg, 40%). R f = 0.59 (PE/EtOAc 95/05). IR (ATR) ν max (cm -1 ) = 3070,3032,2960,2931,2880,2857,1711,1588,1472,1454,1441,1428. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7. 4H,Ar),16H,Ar),7.11 (s,1H,4.95 (s,2H,, 3.57 (t, 2H, J = 6.9 Hz, H-1), 2. 43-2.37 (m, 2H, H-8), 1.75-1.68 (m, 2H, H-7), 1.63 (t, 2H, J = 7.2 Hz, H-2), 1.34 (q, 2H, J = 6.3 Hz, H-5), 0.96 (s, 9H, H-15), 0.64 (t, 3H, J = 7.5 Hz H-6). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 197.2 (C-9), 155.9 (C-4), (137.7, 135.6, 134.5, 133.6, 129.7, 129.3, 129.1, 128.3, 127.8, 127.7 (C-Ar)), 75.7 (C-11), 59.9 (C-1), 41.5(C-8), 38.4 (C-7), 37.0 (C-2), 30.1 (C-3), 27.7 (C-15), 26.8 (C-15), 7.7 (C-6). HRMS (ESI): [M+Na] + C 38 H 45 NO 3 NaSSi : calcd. 646.2781, found 646.2798.

Ethyl 5-(dimethyl(phenyl)silyl)-4-formylpentanoate (550)

To a solution of 193b (100 mg, 0.272 mmol, 1.0 eq.) in (3:1) mixture of dioxane and water (2.0 mL) was added 2,6-lutidine (0.063 mL, 0.54 mmol, 2.0 eq.), sodium periodate (233 mg, 1.09 mmol, 4.0 eq.) and osmium tetroxide solution in t-butanol (0.0039 mL, 0.371 mmol, 0.2 eq., 2.5 Wt %) sequentially. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted by DCM (5 mL) and the organic layer was separated. The combined organic layer was dried over MgSO 4 and the solvent was removed under reduced pressure. The crude faint yellow oil was purified by chromatography on silica gel with (PE/EtOAc 95/5). The desired aldehyde 550 was obtained as colorless oil (43 mg, 54%). R f = 0.37 (PE/EtOAc 95/05). IR (ATR) ν max (cm -1 ) = 3068, 2961, 1732, 1427, 1375, 1250. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 9.50 (d,1H,J = 2.7 Hz,2H,Ar),3H),4.13 (q,2H,J = 7.2 Hz,3H,2H,1.26 (t,3H,J = 7.2 Hz,1H,1H,, 0.37 (s, 6H, H-4) 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 203.7 (C-1), 172.9 (C-8), (133.5,129.2,128.0,127.9,, 15.2 (C-3), 14.2 (C-10), -2.3 (C-4) HRMS (ESI): [M+Na] + C 16 H 24 O 3 NaSi : calcd. 315.1386, found 315.1399.

Diethyl 4-cyano-4-ethylheptanedioate (579d) Synthesized according to the general procedure from α-iodoethylester 324 (72 mg, 0.33 mmol, 1.0 eq.), olefin 252 (210.2 mg, 1.34 mmol, 4.0 eq.), p-toluenesulfonyl cyanide 570 (119.5 mg, 0.66 mmol, 2.0 eq.), di(tributyl)tin (292.8 mg, 0.50 mmol, 1.5 eq.) and DTBHN (11.7 mg,0.06 mmol). The crude faint green oil was purified by chromatography on silica gel (PE/EtOAc 80/20). The desired nitrile product 579d was obtained as faint green oil (48 mg, 53%). R f = 0.66 (PE/EtOAc 80/20). IR (ATR) ν max (cm -1 ) = 3452,2979,2943,2887,2232,1739,1732,1463,1455,1422,1379,1304,1256.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 4.08 (q, 4H, J = 7.2 Hz, H-6, H-13), 2. 42-2.36 (m, 4H, H-4, H-11), 1.88-1.82 (m, 4H, H-3, H-10), 1.57 (q, 2H, J = 5.1 Hz, H-8), 1.20 (t, 6H, J = 7.2 Hz, H-7, H-14), 0.97 (t, 3H, J = 7.2 Hz, H-9).

S-Phenyl 6-((tert-butyldiphenylsilyl)oxy)-4-cyano-4-ethylhexanethioate (579a)

Synthesized according to the general procedure from α-iodothioester 337 (200 mg, 0.71 mmol, 1.0 eq.), olefin 546c (973.9 mg, 2.87 mmol, 4.0 eq.), p-toluenesulfonyl cyanide 570 (257.3 mg, 1.42 mmol, 2.0 eq.), di(tributyl)tin (625.8 mg, 1.07 mmol, 1.5 eq.) and DTBHN (25.0 mg, 0.14 mmol). The crude faint yellow oil was purified by chromatography on silica gel (PE/EtOAc 95/05). The desired nitrile product 579a was obtained as colorless oil (292 mg, 79%). R f = 0.31 (PE/EtOAc 95/05). IR (ATR) ν max (cm -1 ) = 3071,2932,2879,2858,2233,1713,1589,1471,1443,1425,1391,1361.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.68-7.65 (m, 3H, Ar), 7.45-7.37 (m, 12H, Ar), 3.81 (t, 2H, J = 6.6 Hz, H-6), 2.80-2.74 (m, 2H, H-10), 2.02-1.97 (m, 2H, H-9), 1.83 (t, 2H, J = 6.9 Hz, H-5), 1.64 (q, 2H, J = 7.5 Hz, H-3), 1.06 (s, 9H, H-8), 0.97 (t, 2H, J = 7.5 Hz, H-4) 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 196.0 (C-11), (135.5, 134.8, 134.4, 133.1, 129.8, 129.5, 129.2, 127.8 (C-Ar)), 122.6 (CN), 60.0 (C-6), 39.4 (C-1), 38.9 (C-10), 37.3 (C-5), 31.2 (C-9), 29.7 (C-7), 29.3 (C-3), 26.8 (C-3), 8.70 (C-4). HRMS (ESI): [M+Na] + C 31 H 37 NO 2 NaSiS : calcd. 538.2206, found 538.2203.

Phenyl 6-((tert-butyldiphenylsilyl)oxy)-4-cyano-4-ethylhexanoate (579e)

Synthesized according to the general procedure from α-iodophenylester 580 (38.7 mg, 0.14 mmol, 1.0 eq.), olefin 546c (200 mg, 0.59 mmol, 4.0 eq.), p-toluenesulfonyl cyanide 570 (50.7 mg, 0.28 mmol, 2.0 eq.), di(tributyl)tin (128.5 mg, 0.22 mmol, 1.5 eq.) and DTBHN (5.1 mg, 0.02 mmol). The crude faint yellow oil was purified by chromatography on silica gel (PE/EtOAc 95/05). The desired nitrile product 579e was obtained as colorless oil (55 mg, 75%). R f = 0.48 (PE/EtOAc 95/05). IR (ATR) ν max (cm -1 ) = 3072,3048,2965,2932,2884,2858,2233,1760,1593,1494,1471,1428,1391,1306. -11), (150.5, 135.5, 129.8, 129.4, 127.8, 125.9, 121.4, 115.2 (C-Ar)), 122.7 (CN), 60.0 (C-6), 39.5 (C-1), 37.3 (C-5), 30.9 (C-9), 29.8 (C-10), 29.7 (C-7), 29.4 (C-3), 26.8 (C-3), 8.70 (C-4). HRMS (ESI): [M+Na] + C 31 H 37 NO 3 NaSi : calcd. 522.2434, found 522.2423.

Ethyl 6-((tert-butyldiphenylsilyl)oxy)-4-cyano-4-ethylhexanoate (579f)

Synthesized according to the general procedure from α-iodoethylester 324 (31.6 mg, 0.14 mmol, 1.0 eq.), olefin 546c (200 mg, 0.59 mmol, 4.0 eq.), p-toluenesulfonyl cyanide 570 (50.7 mg, 0.28 mmol, 2.0 eq.), di(tributyl)tin (128.5 mg, 0.22 mmol, 1.5 eq.) and DTBHN (5.1 mg, 0.02 mmol). The crude faint yellow oil was purified by chromatography on silica gel (PE/EtOAc 90/10). The desired nitrile product 579f was obtained as colorless oil (52 mg, 78%). R f = 0.63 (PE/EtOAc 90/10). IR (ATR) ν max (cm -1 ) = 3047,3068,2961,2932,2892,2857,2232,1736,1471,1460,1472,1390.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.68-7.65. (m, 3H, Ar), 7.47-7.36 (m, 7H), 4.14 (q, 2H, J = 7.2 Hz, H-12), 3.81 (t, 2H, J = 6.6 Hz, H-6), 2.44-2.39 (m, 2H, H-10), 1.96-1.91 (m, 2H, H-9), 1.83 (t, 2H, J = 6.6 Hz, H-5), 1.63 (q, 2H, J = 7.5 Hz, H-3), 1.25 (t, 3H, J = 6.9 Hz, H-13), 1.05 (s, 9H, H-8), 0.97 (t, 3H, J = 7.5 Hz, H-4).

S-Phenyl 4-cyano-5-(dimethyl(phenyl)silyl)pentanethioate (579g)

Synthesized according to the general procedure from α-iodothioester 337 (100 mg, 0.35 mmol, 1.0 eq.), allylsilane 265 (253.6 mg, 1.43 mmol, 4.0 eq.), p-toluenesulfonyl cyanide 570 (126.8 mg, 0.70 mmol, 2.0 eq.), di(tributyl)tin (312.9 mg, 0.53 mmol, 1.5 eq.) and DTBHN (12.5 mg, 0.07 mmol). The crude faint yellow oil was purified by chromatography on silica gel (PE/EtOAc 95/05). The desired nitrile product 579g was obtained as colorless oil (111 mg, 87%). R f = 0.33 (PE/EtOAc 95/05). IR (ATR) ν max (cm -1 ) = 3069,3056,3022,2929,2956,2236,1704,1585,1478,1441,1427,1410,1362,1327. (137.1, 134.5, 133.5, 129.64, 129.61, 129.3, 128.1, 127. Phenyl 4-cyano-5-(dimethyl(phenyl)silyl)pentanoate (579h) Synthesized according to the general procedure from α-iodophenylester 580 (37.1 mg, 0.14 mmol, 1.0 eq.), allylsilane 265 (100 mg, 0.56 mmol, 4.0 eq.), p-toluenesulfonyl cyanide 570 (50.7 mg, 0.28 mmol, 2.0 eq.), di(tributyl)tin (123.4 mg, 0.21 mmol, 1.5 eq.) and DTBHN (4.9 mg, 0.02 mmol). The crude faint yellow oil was purified by chromatography on silica gel (PE/EtOAc 95/05). The desired nitrile product 579h was obtained as colorless oil (38 mg, 79%). R f = 0.28 (PE/EtOAc 95/05). IR (ATR) ν max (cm -1 ) = 3070,3047,3017,2957,2926,2236,1760,1593,1493,1455,1427,1378,1317. .34-1.06 (dd, 1H, J = 5.7, 14.7 Hz, H-3b) 0.45-0.41 (d, 6H, J = 12.0 Hz, H-4) 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 170.8 (C-7), (150.4, 137.0, 133.5, 129.5, 129.4, 128.1, 126.0, 121.4 (C-Ar)), 122.4 (CN), 31.5 (C-6), 30.6 (C-5), 26.5 (C-1), 20.0 (C-3), (-2.3, -3.0 (C-4). HRMS (ESI): [M+Na] + C 20 H 23 NO 2 NaSi : calcd. 360.1390, found 360.1406.

Ethyl 4-cyano-5-(dimethyl(phenyl)silyl)pentanoate (579i) Synthesized according to the general procedure from α-iodoehtylester 324 (55 mg, 0.25 mmol, 1.0 eq.), allylsilane 265 (181.1 mg, 1.02 mmol, 4.0 eq.), p-toluenesulfonyl cyanide 570 (90.6 mg, 0.5 mmol, 2.0 eq.), di(tributyl)tin (223.6 mg, 0.38 mmol, 1.5 eq.) and DTBHN (8.9 mg, 0.05 mmol). The crude faint yellow oil was purified by chromatography on silica gel (PE/EtOAc 95/05). The desired nitrile product 579i was obtained as colorless oil (71 mg, 95%). R f = 0.56 (PE/EtOAc 95/05). IR (ATR) ν max (cm -1 ) = 3070,3070,3958,2939,2236,1739,1590,1449,1427,1395,1377,1317,1252.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7. 2H,Ar),3H,Ar), 3.91 (q, 2H, J = 7.2 Hz, H-8), 2.46-2.39 (m, 3H, H-1, H-1), 2.34-2.18 (m, 2H, H-6), 1.76-1.61 (m, 2H, H-5), 1.06-0.98 (m, 4H, H-3a, H-9), 0.88-0.82 (dd, 1H, J = 5.7, 14.7 Hz, H-3b), 0.23-0.20 (d,6H,J = 11.1 Hz, 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 172.1 (C-7), (137.1, 133.5, 129.5, 128.0 (C-Ar)), 122.5 (CN), 60.6 (C-8), 31.4 (C-6), 30.8 (C-5), 26.5 (C-1), 19.9 (C-3), 14.1 (C-9), (-2.3, -3.1 (C-4). HRMS (ESI): [M+Na] + C 16 H 23 NO 2 NaSi : calcd. 312.1390, found 312.1396.

S-Phenyl 6-((tert-butyldimethylsilyl)oxy)-4-cyano-4-ethylhexanethioate (579m)

Synthesized according to the general procedure from α-iodothioester 337 (291.8 mg, 1.04 mmol, 1.0 eq.), olefin 546b (450 mg, 2.09 mmol, 4.0 eq.), p-toluenesulfonyl cyanide 570 (376.9 mg, 2.08 mmol, 2.0 eq.), di(tributyl)tin (913.1 mg, 1.57 mmol, 1.5 eq.) and DTBHN (36.5 mg, 0.20 mmol). The crude faint yellow oil was purified by chromatography on silica gel (PE/EtOAc 95/05). The desired nitrile product 579m was obtained as colorless oil (244 mg, 60%). R f = 0.45 (PE/EtOAc 95/05). IR (ATR) ν max (cm -1 ) = 3062, 2954,2930,2883,2857,2232,1709,1584,1471,1463,1441,1410,1389,1361.

4-((tert-Butyldiphenylsilyl)oxy)-2-ethyl-2-(2-(phenylsulfonyl)ethyl)butanenitrile (579j)

Synthesized according to the general procedure from α-bromosulfone 334 (34.72 mg, 0.14 mmol, 1.0 eq.), olefin 546c (200 mg, 0.59 mmol, 4.0 eq.), p-toluenesulfonyl cyanide 570 (53.52 mg, 0.29 mmol, 2.0 eq.), di(tributyl)tin (128.5 mg, 0.22 mmol, 1.5 eq.) and DTBHN (5.1 mg, 0.02 mmol). The crude faint yellow oil was purified by chromatography on silica gel (PE/EtOAc 80/20). The desired nitrile product 579j was obtained as colorless oil (38 mg, 50%). R f = 0.37 (PE/EtOAc 80/20).

IR (ATR) ν max (cm -1 ) = 3071, 2959,2932,2883,2858,2234,1462,1447,1428,1308,1149. (138.6, 135.5, 134.0, 133.0, 129.9, 129.4, 128.0, 127.8 (C-Ar)), 121.9 (CN), 59.8 (C-6), 52.0 (C-10), 39.0 (C-1), 37.4 (C-5), 29.3 (C-3), 28.7 (C-9), 26.7 (C-8), 19.0 (C-7), 8.5 (C-4) HRMS (ESI): [M+Na] + C 30 H 37 NO 3 NaSiS : calcd. 542.2155, found 542.2135.

2-((Dimethyl(phenyl)silyl)methyl)-4-(phenylsulfonyl)butanenitrile (579k)

Synthesized according to the general procedure from α-bromosulfone 334 (60.4 mg, 0.25 mmol, 1.0 eq.), allylsilane 265 (181.3 mg, 1.02 mmol, 4.0 eq.), p-toluenesulfonyl cyanide 570 (93.15 mg, 0.51 mmol, 1.2 eq.), di(tributyl)tin (223.6 mg, 0.38 mmol, 1.5 eq.) and DTBHN (8.9 mg, 0.05 mmol). Three additions of DTBHN were added in this reaction. The crude faint yellow oil was purified by chromatography on silica gel (PE/EtOAc 80/20). The desired nitrile product 579k was obtained as colorless oil (47 mg, 51%).

2-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)-2-ethyl-5-hydroxypentanenitrile (640)

To a solution of nitrile 579a (555 mg, 1.07 mmol) in dry THF (36.8 mL), was added at 0 °C NaBH 4 (203 mg, 5.38 mmol, 5.0 eq.). The reaction was stirred at r.t. for 3 h. After removal of THF under reduced pressure, the residue was quenched by adding NH 4 Cl and extracted 3 times with EtOAc. The combined organic layer was washed by brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the crude yellow oil was purified by chromatography on silica gel (PE/EtOAc 70/30). The desired compound 640 was obtained as colorless oil (367 mg, 83%). R f = 0.66 (PE/EtOAc 70/30). IR (ATR) ν max (cm -1 ) = 3452,3068,3047,2939,3883,3853,2232,1591,1471,1458,1430,1391,1363,1309.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7. 4 H,Ar),6H,Ar), 3.83 (t, 2H, J = 6.9 Hz, H-7), 3.61 (t, 2H, J = 4.5 Hz. H-9), 1.84 (t, 2H, J = 6.6 Hz, H-8), 1.66-1.59 (m, 7H, H-3, H-5, H-6, OH), 1.05 (s, 9H, H-11), 0.96 (t, 3H, J = 7.2 Hz).

3-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)-3-ethyltetrahydro-2H-pyran-2-ol (639)

To a solution of nitrile 579a (150 mg, 0.366 mmol, 1.0 eq.) in dry DCM (18 mL) under inert conditions, DIBAL-H (1.46 mL, 1.46 mmol, 4.0 eq., 1 M in DCM) was added dropwise to the reaction mixture at -78 °C. The reaction was stirred for 1 h at room temperature. Then, the reaction was quenched with 1 M HCl (3 mL) at 0 °C. The mixture was then stirred for 15 min at room temperature then Na 2 SO 4 was added to the reaction mixture and the stirred for another 15 min. Then solids were filtered through celite and the residue was concentrated under reduced pressure. The resulting crude colorless oil was purified by chromatography on silica gel (PE/EtOAc 80/20) to give lactol 639 as colorless oil (111.7 mg, 74%, d.r. 3:1). R f = 0.63 (PE/EtOAc 80/20). IR (ATR) ν max (cm -1 ) = 3370,3071,3049,3017,1471,1460,1428,1390,1361,1261,1111,1085. 1 H NMR (CDCl 3 , 200 MHz): δ (ppm) = 7.76-7.68 (m, 4H, Ar), 7.47-7.37 (m, 6H, Ar), 5.44-5.39 (d, 1H, J = 9 Hz, OH), 4.63 (d, 0.25H, J = 3.2 Hz, m H-1), 4.44 (d, 0.75H, J = 3.2 Hz, M H-1), 4.12-4.02 (m, 1H, H-9a), 3. 75-3.46 (m, 3H, H-9b, H-5), 2.24 (ddd, 1H, J = 4.8, 9.8, 15 Hz, H-8a), 1.69-1.17 (m, 7H, H-3, H-4, H-8b, H-6), 1.07 (s, 9H, H-11), 0.77 (t, 3H, J = 7.6 Hz). 13 C NMR (CDCl 3 , 50 MHz): δ (ppm) = (135.7, 135.6, 133.4, 132.6, 132.5, 129.9, 129.7, 127.8, 127.7, (C-Ar)), 100.3, 99.6 (C-1), 65.4, 63.6 (C-9), 40.0, 38.9 (C-5), 36.1 (C-2), 33.0, 32.59 (C-8), 29.6 (C-10), 26.8, 26.6 (C-11) To a solution of tryptamine (45.19 mg; 0.28 mmol, 1.2 eq.) in dry toluene (5 mL), lactol 639 (97 mg; 0.23 mmol, 1.0 eq.) was dissolved in dry toluene (4 mL) and added to the reaction mixture. The reaction was stirred at room temperature for 30 min. At the end of 30 min. AcOH (0.026 ml; 0.47 mmol; 2.0 eq.) was added. Then the reaction was refluxed at 110 °C overnight. Then, the solvent was removed and the residue was diluted with sat. NaHCO 3 solution (to neutralize AcOH monitored by pH paper), and EtOAc. The organic layer was separated and washed with and brine solution (~5 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by silica gel (60 Å) flash column (PE/EtOAc 90/10) to give tetracyclic product 642 as brown oil (120 mg, 95%, d.r. 1:1). The first diastereoisomer (642a): R f = 0.58 (PE/EtOAc 90/10). IR (ATR) ν max (cm -1 ) = 3241,3070,2961,2930,2856,1632,1589,1460,1427,1389,1327,1265. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7. 4H,Ar),8H,Ar), 7.12-7.06 (m, 2H, Ar), 3.73 (t, 2H, J = 10.8 Hz, H-9), 3.10-3.05 (br d, 1H, J = 15.3 Hz, H-1), 2.93-2.86 (m, 2H, H-13a, H-14a), 2.71-2.50 (m, 3H, H-13b, H-14b, H-5a), 2.12-2.07 (m, 1H, H-5b), 1.86-1.43 (m, 7H, H-2, H-3, H-8, NH), 1.26-1.17 (m, 2H, H-6), 1.07 (s, 9H, H-11), 0.69 (t, 3H, J = 11.1 Hz). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (135.9, 315.6, 135.4, 135.9, 129.6, 127.6, 127.4, 121.1, 119.3, 118.0, 110.7, 108. , 2962, 2935, 2905, 2801, 1619, 1587, 1260, 1088, 1026. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7. 5H,Ar),7H,Ar),2H,Ar),2H,1H,J = 10.5 Hz,2H,1H,),4H,3H,NH),4H,9H,, 0.78 (t, 3H, J = 7.5 Hz). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (135.9, 135.6, 1333.9, 129.9, 129.4, 127.8, 127.5, 121.1, 119.3, 118.0, 110.7, 108. To a solution of the second diastereoisomer of tetracyclic protected alcohol 642b (50 mg; 0.093 mmol) in dry THF (7 mL) was added TBAF (0.139 mL; 0.139, 1.5 eq., 1 M in THF) at 0 °C, The reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was diluted with EtOAc and saturated solution of NaHCO 3 . The organic layer was separated and washed with and brine solution (~5 mL). The combined organic layers were dried over MgSO 4 and the solvent was removed under reduced pressure.

The crude product was purified by silica gel (60 Å) column (DCM/MeOH 95/5) to give tetracyclic product 643 as white solid (19.8 mg, 71%). R f = 0.58 (PE/EtOAc 90/10). Mp = 167 °C (DCM). IR (ATR) ν max (cm -1 ) = 3234,3054,2956,2918,2854,1624,1592,1432. 1 H NMR (CDCl 3 , 600 MHz): δ (ppm) = 8.04 (br s, 1H, NH), 7.43 (d,1H,J = 7.8 Hz,7.35 (d,1H,J = 3.9 Hz,1H,1H,, 3.62 (br s, 2H, H-9), 3.26 (d, 1H, J = 11.4 Hz, H-1), 3.08-3.05 (m, 1H, H-11a), 2.99-2.96 (m, 1H. H-10a), 2.84 (d,1H,1H,J = 4.2,15 Hz,1H,J = 4.2,11.4 Hz, H-10), 2.21 (d, 1H, J = 11.4 Hz, H-5b), 2.11 (br d, 1H, J = 13.2 Hz, H-2a), 1.19 (br s, 1H, OH), 1.65-1.60 (m, 3H, H-2b, H-8), 1.38-1.25 (m, 4H, H-3, H-6), 0.85 (t, 3H, J = 3.6 Hz, H-7). 13 C NMR (CDCl 3 , 150 MHz): δ (ppm) = (136. 1, 133.9, 127.1, 121.5, 119.5, 118.1, 111.

5-(Benzyloxy)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-ethylpentanenitrile (651a)

A solution of alcohol 640 (159 mg; 0.388 mmol, 0.1 eq.), Dudley reagent (271.2 mg, 0.77 mmol, 2.0 eq.) and MgO (31.29 mg, 0.77 mmol, 2.0 eq.) in dry DCE (4 mL) was refluxed at 80 °C for 24 h. Then, the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel (60 Å) flash column (PE/EtOAc 95/5) to give tetracyclic product 651a as yellow oil (160 mg, 72%). R f = 0.51 (PE/EtOAc 95/05). IR (ATR) ν max (cm -1 ) = 3070,3051,3025,2230,1589,1472,1455,1427,1390,1361,1308,1262. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7. 4H,Ar),11H,Ar), 4.53 (s, 2H, H-6), 3.57 (t, 2H, J = 6.9 Hz, H-10), 3.50 (t, 2H, J = 5.4 Hz, H-5), 1.90 (t, 2H, J = 6.6 Hz, H-9), 1.72-1.66 (m, 6H, H-3, H-4, H-7), 1.11 (s, 9H, H12), 1.01 (t, 3H, , J = 7.2 Hz, H-8). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (138.3, 135.5, 134.8, 133.3, 129.8, 129.6, 128.4, 127.7, 127.6 (C-Ar)),123.5 (CN), 72.9 (C-6), 60.8 (C-5), 60.2 (C-10), 39.5 (C-9), 37.5 (C-4), 32.8 (C-3), 29.3 (C-11)

6-((tert-Butyldiphenylsilyl)oxy)-4-cyano-4-ethylhexyl methanesulfonate (651b)

To a solution of alcohol 640 (150 mg, 0.366 mmol, 1.0 eq.) in dry DCM (7.5 mL), were added at 0 °C, MsCl (0.034 mL, 0.439 mmol, 1.2 eq.) and Et 3 N (0.076 mL, 0.549 mmol, 1.5 eq.). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was then treated with a concentrated solution of NH 4 Cl and extracted by DCM. The combined organic layers were dried over Na 2 SO 4 and the solvent was removed under reduced pressure. The crude yellow oil was purified by chromatography on silica gel (PE/EtOAc 70/30). The desired compound 651b was obtained as a yellow oil (178 mg, quant.). R f = 0.69 (PE/EtOAc 70/30). IR (ATR) ν max (cm -1 ) = 3068,2956,2934,2858,2232,1472,1428,1357,1176.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7. 4H,Ar),6H,Ar),4.19 (t,2H,J = 5.7 Hz, H-5), 3.80 (t, 2H, J = 6.9 Hz, H-10), 2.98 (s, 3H, H-6), 1.83 (t, 2H, J = 6.9 Hz, H-9), 1.70-1.66 (m, 6H, H-3, H-4, H-7), 1.05 (s, 9H, H12), 0.96 (t, 3H, , J = 7.5 Hz, H-8). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (135.5, 1333.1, 129.8, 127.8 (C-Ar)), 123.0 (CN), 69.0 (C-5), 60.9 (C-10), 39.4 (C-9), 37.4 (C-6), 37.3 (C-4) 32.8 (C-3), 29.3 (C-11), 26.8 (C-12)

5-(Benzyloxy)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-ethylpentanal (653a)

To a solution of nitrile 651a (011 mg, 0.011 mmol, 1.0 eq.) in dry DCM (01 mL) under inert conditions, DIBAL-H (18.1 mL, 18.1 mmol, 4.0 eq., 1 M in DCM) was added dropwise to the reaction mixture at -78 °C. The reaction was stirred for 1 h at room temperature. Then, the reaction was quenched with 1M HCl (3 mL) at 0 °C. The mixture was then stirred for 15 min at room temperature then Na 2 SO 4 was added to the reaction mixture and the stirred for another 15 min. Then solids were filtered through celite and the residue was concentrated under reduced pressure. The resulting crude colorless oil 653a (100 mg) was used directly in the next step without further purification. IR (ATR) ν max (cm -1 ) = 3069,3047,3030,1724,1664,1471,1455,1427,1361,1111. HRMS (ESI): [M+Na] + C 32 H 42 O 3 NaSi : calcd. 525.2795, found 525.2778.

2-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)-2-ethyl-5-oxopentanenitrile (654)

Under very dry conditions and Argon atmosphere, place 10% Pd on carbon (15.49 mg; 0.05 eq.) and evacuate the system and flash it with Argon gas. Then thio-ester 579a (1.5 g; 2.9) was dissolved in acetone (37.5 mL) and added to the reaction flask. The mixture was stirred for 5 minutes and then freshly distilled Et 3 SiH (1.40, 8.72mmol, 3.0 eq.) was added. After 5 minutes of addition of Et 3 SiH, hydrogen bubbles start to appear in the reaction mixture, it is an indicator that the reaction worked. The stirring was continued for 1 h. Then, the reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude colorless oil was purified by chromatography on silica gel (PE/EtOAc 80/20). The desired aldehyde 654 was obtained as a colorless oil (190 mg, 75%). R f = 0.30(PE/EtOAc 90/10). IR (ATR) ν max (cm -1 ) = 3071,3051,2933,2858,2726,2231,1726,1589,1473,1462,1428,1390. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 9.7 (br t, 1H, H-1), 7. 4H,Ar),6H,Ar),2H,2H,2H,2H,2H,1.05 (s,9H,, 0.97 (t, 3H, J = 6.9 Hz, H-8).

5-((2-(1H-Indol-3-yl)ethyl)amino)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-ethylpentanenitrile (655)

To a solution of tryptamine (236.2 mg; 1.47 mmol, 1.1 eq.) on dry MeOH (3 mL), aldehyde 654 (545 mg; 1.33 mmol, 1.0 eq) was dissolved in dry MeOH (15 ml) and added to the reaction mixture. The reaction was allowed to react overnight. Then, the reaction was cooled to 0°C and NaBH 4 (101 mg, 2.67 mmol, 2.0 eq.) was added to the reaction mixture in two portions. Then the reaction was allowed to warm to room temperature and stirred for another 4 h. The solvent was removed and the residue was diluted with EtOAc and quenched with saturated aqueous NaHCO 3 .The organic layer was separated, washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the crude product was purified by silica gel (60 Å) flash column (DCM/MeOH 90/10) to give 655 as yellow heavy oil (679 mg, 92%). R f = 0.55(DCM/MeOH 90/10). IR (ATR) ν max (cm -1 ) = 3413,3122,2938,2232,1590,1455,1265,1107. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 8.14 (br s, 1H, NH-indole), 7. 5H,Ar),7H,Ar),2H,Ar), 7.02-7.01 (m, 1H, Ar), 3.78 (t, 2H, J = 6.9 Hz, H-7), 3.00-2.95 (m, 4H, H-1, H-12), 2.60-2.59 (m, 2H, H-13), 2.30 (br s, 1H, NH), 1.79 (t, 2H, J = 6.9 Hz, H-6), 1.58-1.52 (m, 6H, H-2, H3, H-10), 1.05 (s, 9H, H-9), 0.92 (t, 3H, J = 7.2 Hz, H-11). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (136.4, 135.5, 1333.3, 129.8, 127.7, 127.3, 122.1, 122.0, 119.3, 118.8, 113.4, 111.

1-(2-(1H-Indol-3-yl)ethyl)-3-ethyl-3-(2-hydroxyethyl)piperidin-2-one (659)

A solution of nitrile 655 (366 mg; 0.66 mmol, 1.0 eq.) in a (2/1) mixture of HCl (37%) / MeOH (21 mL) was refluxed for 16h. Then, MeOH was removed under reduced pressure, and the residue was basified to pH = 10 by a solution of NaOH (50%). The aqueous layer was extracted by EtOAc and the combined organic layers were washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the crude product was purified by silica gel (60 Å) flash column (DCM/MeOH 90/10) to give 659 as brown oil (136 mg, 65%). R f = 0.52 (DCM/MeOH 90/10). IR (ATR) ν max (cm -1 ) = 3280,3055,2937,2862,1755,1607,1493,1457,1358,1264,1231,1201. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 8.67 (br s, 1H, NH), 7.65-7.62 (d,1H,J = 7.5 Hz,1H,3H,1H,3H,, 3.17-3.14 (m, 2H, H-2), 3.00 (t, 2H, J = 7.2 Hz, H-11), 9H,OH), 0.82 (t, 3H, J = 7.5 Hz, H-9). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 176.2 (C-5), (136.3, 127.4, 122.4, 121.7, 119.1, 118.6, 112.5, 111.3 (C-Ar)), 58.9 (C-7), 49.2 (C-10), 48.9 (C-1), 43.9 (C-4), 40.

7-(2-(1H-Indol-3-yl)ethyl)-3a-ethyloctahydrofuro[2,3-b]pyridine (662)

To solution of hydroxy-lactam 659 (60 mg; 0.19 mmol, 1.0 eq.) in dry benzene (4 ml), POCl 3 (0.10 ml; 1.14 mmol; 6 eq.) was added dropwise. The reaction mixture was refluxed at 90 °C for 24h. Then, the solvent was removed reduced pressure and the residue was placed under high vacuum for 15 min. then, dry MeOH (5 ml) was added to the reaction mixture under Argon atmosphere and the reaction mixture was cooled to 0 °C in ice bath. NaBH 4 (36.1 mg; 0.95 mmol; 5.0 eq.) was added to the reaction mixture in two portions. The reaction was stirred at room temperature for 1 h. Then, the solvent was removed under reduced pressure and the residue was diluted with EtOAc (5 mL) and saturated solution of NaHCO 3 (5 ml) till pH = 9. The aqueous layer was extracted with EtOAc (3x5 mL). The combined organic layers were washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the crude product was purified by silica gel (60 Å) flash column (DCM/MeOH 98/2) to give hemiaminal 662 as brown oil (35 mg, 60%). R f = 0.38 (DCM/MeOH 98/2). IR (ATR) ν max (cm -1 ) = 3417,3281,3056,2932,2875,2858,1755,1620,1455,1355,1265,1225. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 8.17 (br s, 1H, NH), 7.68-7.65 (d,1H,J = 7.8 Hz,1H,3H,7.05 (d,1H,J = 2.1 Hz,4.31 (s,1H,2H,4H,1H,1H,8H,, 0.92 (t, 3H, J = 7.5 Hz, H-9). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (136. 1, 127.7, 121.7, 121.5, 119.0, 118.9, 114.7, 110.

2-(1-(2-(1H-Indol-3-yl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)ethyl benzoate (666)

To a solution of alcohol 659 (135 mg, 0.42 mmol, 1.0 eq.) in dry DCM (10 mL), pyridine (0.069 mL, 0.85 mmol, 2.0 eq.) was added at 0 °C. After that, BzCl (0.099 mL, 0.85mmol, 2.0 eq.) was added to the resulting slurry at 0 °C. The reaction mixture was allowed to warm up to room temperature and stirred at that temperature for 3 h. Then, the reaction mixture was diluted by water (5 mL) and the aqueous layer was separated and washed with DCM. The combined organic layers were washed with 5% HCI, saturated solution of NaHCO 3 and brine respectively. The combined organic layers were dried over Na 2 SO 4 and the solvent was removed under reduced pressure. The crude product was purified by silica gel (60 Å) flash column (PE/ EtOAc 70/30) to give protected product 666 as brown oil (131 mg, 73%). R f = 0.53 (PE/EtOAc 98/2). IR (ATR) ν max (cm -1 ) = 3272,3058,2939,2870,1714,1614,1493,1455,1357,1240,1315,1275. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 8.48 (br s, 1H, NH), 8. 2H,Ar),1H,Ar),1H,Ar),3H,Ar),2H,Ar),1H,J = 2.1 Hz,Ar),2H,2H,2H,, 3.02 (t, 2H, J = 7.2 Hz, H-11), 2.26 (m, 1H, H-6a), 1.96-1.71 (m, 7H, H-2, H-3, H-6b, H-8), 0.89 (t, 3H, J = 7.5 Hz, H-9). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 173.7 (C-5), 166.7 (C-20), (136.3, 132.9, 130.3, 129.5, 128.3, 127.4, 122.3, 121.8, 119.1, 118.7, 112.8, 111. To solution lactam 666 (43 mg; 0.10 mmol, 1.0 eq.) in dry MeCN (3 ml), POCl 3 (0.29 ml; 3.12 mmol; 30.4 eq.) was added dropwise. The reaction mixture was refluxed at 90 °C for 24h. Then, the solvent was removed reduced pressure and the residue was placed under high vacuum for 15 min. then, dry MeOH (5 ml) was added to the reaction mixture under Argon atmosphere and the reaction mixture was cooled to 0 °C in ice bath. NaBH 4 (19.4 mg; 0.51 mmol; 5.0 eq.) was added to the reaction mixture in two portions. The reaction was stirred at room temperature for 1 h. Then, the solvent was removed under reduced pressure and the residue was diluted with EtOAc (5 mL) and saturated solution of NaHCO 3 (5 ml) till pH = 9. The aqueous layer was extracted with EtOAc (3x5 mL). The combined organic layers were washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the crude product was purified by silica gel (60 Å) flash column (PE/EA 80/20) to give Eburnan 668 as brown oil (8 mg, 19%) and hemiaminal 662 (13 mg, 30%). R f = 0.68 (PE/EA 80/20). IR (ATR) ν max (cm -1 ) = 3344,3064,2926,2857,2750,1702,1621,1602,1582,1524,1462,1451. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 10.1 (br s, 1H, NH), 8.16-8.13 (m, 2H, Ar), 7.76-7.46 (m, 8H, Ar), 7.37-7.32 (m, 1H, Ar), 7.17-7.08 (m, 3H, Ar), 5.12 (m, 1H, H-7a), 4.43-4.34 (m, 1H, H-7b), 3.84-3.61 (m, 1H, H-10a), 3.39 (s, 1H, H-5), 3.00-2.87 (m, 4H, H-10b, H1, H11a), 2.68-2.60 (m, 2H, H-11b, H-6a), 2.43-2.33 (m, 2H, H-6b, H3a), 1.87-1.61 (m, 5H, H2, H-3b, H-8), 0.67 (t, 3H, J = 7.8 Hz, H-9). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 176.2 (C-20), (144.5, 1333.4, 129.8, 129.5, 128.5, 128.2, 126.5, 121.0, 118.8, 117.5, 115.4, 111.4, 111.3 (C-Ar)), 66.8 (C-5), 62.9 (C-7), 56.9 (C-10), 54.0 (C-1), 39. To a suspension of NaH (30.5 mg; 0.76 mmol, 4.0 eq.) in dry THF (2.0 mL), hydroxy-lactam 659 (60 mg; 0.19 mmol, 1.0 eq.) was dissolved in dry THF (1.2 mL) and added to the reaction mixture at 0 °C. The reaction mixture was stirred at this temperature for 30 min and then BnBr (0.09 mL, 0.76 mmol, 4.0 eq.) was added to the reaction mixture. The reaction was stirred for 16h at room temperature. Then, the solvent was removed under reduced pressure and the residue was diluted by EtOAc and quenched by saturated solution of NaHCO 3 . The organic layer was separated and washed with brine then dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the crude product was purified by silica gel (60 Å) flash column (PE/EA 70/30) to give protected alcohol 670 as brown oil (67 mg, 71%). R f = 0.61 (PE/EA 70/30). IR (ATR) ν max (cm -1 ) = 2962,2909,2857,1626,1488,1462,1445,1413,1260. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) 7. 1H,Ar),13H,Ar),6.93(s,1H,Ar),5.25 (s,2H,4.46 (d,2H,J = 1.2 Hz,4H,, 3.16-3.13 m, 2H, J-1), 2.98 (t, 2H, J = 7.5 Hz, H-12), 2.11-2.01 (m, 2H, H-6), 1.83-1.69 (m, 5H, H-2, H-3, H-9a), 1.57-1.48 (m, 1H, H-9b), 0.84 (t, 3H, J = 7.2 Hz, H-10).

13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 174.0 (C-5), (138.5, 137.6, 136.6, 128.7, 128.3, 128.1, 127.6, 127.5, 127.4, 126.8, 126.1, 121.7, 119.1, 119.0, 112.6, 109.6 (C-Ar)),72.9 (C-8), 67.5 (C-7), 49.8 (C-11), 49.0 (C-21), 48.8(C-1), 43.9(C-4), 37.8 (C-6), 31.5 (C-3), 23.1(C-12), 19.8 (C-9), 8.6 (C-10). HRMS (ESI): [M+Na] + C 33 H 38 N 2 O 2 Na : calcd. 517.2825, found 517.2805.

7-(2-(1-Benzyl-1H-indol-3-yl)ethyl)-3a-ethyloctahydrofuro[2,3-b]pyridine (672)

To solution of lactam 670 (15 mg; 0.03 mmol, 1.0 eq.) in dry MeCN (1 ml), POCl 3 (0.08 ml; 0.9 mmol; 30.4 eq.) was added dropwise. The reaction mixture was refluxed at 90 °C for 24h. Then, the solvent was removed reduced pressure and the residue was placed under high vacuum for 15 min. then, dry MeOH (1 ml) was added to the reaction mixture under Argon atmosphere and the reaction mixture was cooled to 0 °C in ice bath. NaBH 4 (5.7 mg; 0.15 mmol; 5.0 eq.) was added to the reaction mixture in two portions. The reaction was stirred at room temperature for 1 h. Then, the solvent was removed under reduced pressure and the residue was diluted with EtOAc (5 mL) and saturated solution of NaHCO 3 (5 ml) till pH = 9. The aqueous layer was extracted with EtOAc (3x5 mL). The combined organic layers were washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the crude product was purified by silica gel (60 Å) flash column (PE/EtOAc 80/20) to give hemiaminal 672 as brown oil (8 mg, 60%). R f = 0.60 (PE/EtOAc 80/20). IR (ATR) ν max (cm -1 ) = 3060,2962,2926,2857,1726,1673,1617,1454,1413,1378,1331. 1 H NMR (CDCl 3 , 600 MHz): δ (ppm) = 7.65-7.64 (d,1H,J = 4.2 Hz,Ar),2H,Ar),2H,Ar),4H,Ar),1H,Ar),5.28 (s,2H,4.25 (s,1H,1H,1H,4H,1H,1H,, 2.09-2.06 (m, 2H, H-6), 1.67-1.59 (m, 6H, H-2, H-3, H-8), 0.90-0.85 (m, 3H, H-9). 13 C NMR (CDCl 3 , 150 MHz): δ (ppm) = (135.2, 128.6, 127.4, 126.8, 125.7, 127.0, 125.0, 124.7, 121.5, 119.1, 118.7, 114.1, 109.

1-Benzyl-3-(2-(3-(2-(benzyloxy)ethyl)-3-ethylpiperidin-1-yl)ethyl)-1H-indole (673)

To a stirred solution of amide 670 (36 mg, 0.07 mmol, 1.0 eq.) and 2-Cl-pyridine (8.2 μL, 0.08 mmol, 1.2 eq.) in dry DCM (3 mL) at -20 °C was added Tf 2 O (13.29 μL, 0.08 mmol, 1.1 eq.). The reaction mixture was stirred for 10 min at -20 °C and 1.5 h at room temperature by which time a deep brown color had formed. The mixture was cooled to -20 °C again, and the solution of NaBH 4 (5.5 mg, 0.14mmol, 2.0 eq.) in MeOH (1.4 mL) was then added dropwise over 5 min. The color rapidly disappeared, and the reaction mixture was stirred for further 1 h. the reaction mixture was quenched with saturated Na 2 CO 3 solution (5 mL) and diluted with DCM (10 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were washed with brine and dried over Na 2 SO 4 . Then, the solvent was removed under reduced pressure and the crude product was purified by silica gel (60 Å) flash column (DCM/MeOH 95/05) to give compound 673 as yellow oil (23 mg, 68%). R f = 0.61 (DCM/MeOH 95/05). IR (ATR) ν max (cm -1 ) = 3054,3029,2963,2929,2854,2802,1661,1627,1614,1495,1467,1454.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7. 1H,Ar),61h,Ar),Ar),1H,Ar),5.26 (s,2H,4.48 (s,2H,, 3.52 (t, 2H, J = 6.9 Hz, H-7), 3. 01-2.95 (m, 2H, H-11), 2.78-2.69 (m, 2H, H-1), 1.75-136 (m, 12H, H-12, H-2, H-3, H-5, H-6 ,H-9), 0.85 (t, 3H, J = 7.5 Hz, H-10). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (138.5, 137.6, 136.5, 128.7, 128.4, 128.3, 127.9, 127.7, 127.6, 127.5, 126.8, 126.0, 121.7, 118.9, 117.2, 109.6 A solution of N-benzyltryptamine 644 (200 mg; 0.79 mmol; 1.0eq.) in dry benzene (9 mL) was refluxed at 90 °C. After 5 min, aldehyde 699a (485 mg; 0.239 mmol; 3 eq.) was added to the reaction mixture. After 30 min, acetic acid (0.5 mL; 8.72 mmol; 10.9 eq.) was added to the reaction mixture. The reaction was stirred under reflux over nigh at 90 °C. After that, the reaction was allowed to cool to room temperature and the solvent was removed under reduced pressure. After that NaHCO 3 (2 % solution) was add to the residue dark brown oil, then the mixture was extracted with DCM (3 x 10 ml). The combined organic layers were dried over Na 2 SO 4 , and the solvent was removed under reduced pressure to afford dark brown oil. The crude brown oil was purified by chromatography on silica gel (PE/EtOAc 90/10). The desired compound 770a was obtained as yellow oil (60 mg, 16%). R f = 0.47 (PE/EtOAc 95/05). IR (ATR) ν max (cm -1 ) = 3408,3060,3029,2926,2739,1682,1636,1622,1604,1587,1544,1494,1470, 1387 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 8.37 (br s, 1H, NH), 7.55 (d,1H,J = 7.5 Hz,Ar.),6H,Ar.),2H,Ar.),4H,),1H,2H,1H,5H,, 0.91 (s, 9H, H-7), 0.07 (s, 6H, H-5). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (139.9,135.7,135.5,128.8,128.3,127.4,126.9,121.2,119.1,118.0,110.7,), 63.7 (C-1), 57.3 (C-4), 55.9 (C-18), 45.0 (C-8), 31.8 (C-2), 29.0 (C-6), 26.0 (C-7), 18.4 (C-9), -5.2 (C-5). HRMS (ESI): [M+H] + C 27 H 39 N 2 OSi : calcd. 435.2826, found 435.2824.

2-Benzyl-1-(3-((tert-butyldiphenylsilyl)oxy)propyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (700b)

A solution of N-benzyltryptamine 644 (200 mg; 0.79 mmol; 1.0eq.) in dry benzene (9 mL) was refluxed at 90 °C. After 5 min, aldehyde 699b (326.1 mg; 0.99 mmol; 1.25 eq.) was added to the reaction mixture. After 30 min, acetic acid (0.09 mL; 1.58 mmol; 2.0 eq.) was added to the reaction mixture. The reaction was stirred under reflux over nigh at 90 °C. After that, the reaction was allowed to cool to room temperature and the solvent was removed under reduced pressure. After that NaHCO 3 (2 % solution) was add to the residue dark brown oil, then the mixture was extracted with DCM (3 x 10 ml). The combined organic layers were dried over Na 2 SO 4 , and the solvent was removed under reduced pressure to afford dark brown oil. The crude brown oil was purified by chromatography on silica gel (PE/EtOAc 90/10). The desired compound 700b was obtained as yellow oil (330 mg, 74%). R f = 0.62 (PE/EtOAc 95/05). IR (ATR) ν max (cm -1 ) = 3408,3063,2928,2853,1607,1587,1538,1429,1325. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.77 (br s, 1H, NH), 7. 19 H,Ar.),4H,1H,2H,1H,2H,3H,1.05 (s,9H,. 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (139.9, 135.8, 135.6, 135.4, 133.9, 133.8, 129.7, 128.9, 128.2, 127.4, 126.9, 121.3, 119.2, 118.0, 110.7, 107. To a solution of tricycle 700b (1,210 g; 2.16 mmol) in dry THF (25 mL), TBAF (2.82 ml; 2.815 mmol; 1.3 eq., 1M in THF) was added. The reaction was stirred at room temperature for 24h. After that, the reaction was quenched by drops of saturated aqueous NH 4 Cl and the solvent was removed under vacuum. The residue was diluted with EtOAc and saturated aqueous NH 4 Cl. Then the organic layer was separated and the aqueous layer was washed three times with EtoAc. The combined organic layers were dried over Na 2 SO 4 , and the solvent was removed under reduced pressure to afford brown oil. The crude brown oil was purified by chromatography on silica gel (DCM/MeOH 95/05). The desired compound 702 was obtained as brown oil (331 mg, 92%). R f = 0.38 (DCM/MeOH 95/05). IR (ATR) ν max (cm -1 ) = 3272,3059,2930,1683,1621,1585,1495,1454. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 8. 26 (br s,1H,NH),9H,Ar.),3H,1H,1H,1H,2H,1H,1H,2H,1H, 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (137.4, 136.0, 133.9, 129.7, 128.4, 127.5, 127.0, 121.6, 119.4, 118.1, 110.8, 107.2 (C-Ar)), 62.7 (C-4), 57.7 (C-1), 57.3(C-15), 43.2 (C-5), 33.2 (C-2), 30.2 (C-3), 17.2 (C-6) HRMS (ESI): [M+Na] + C 21 H 24 N 2 ONa : calcd. 343.1780, found 343.1788.

Methyl 4-((2-(1H-indol-3-yl)ethyl)(benzyl)amino)-4-oxobutanoate (705)

To a solution of N-benzyltryptamine 644 (9.88 g; 39.47 mmol; 1.0 eq.) in dry DCM (130 mL), Et 3 N (6.46 mL; 46.5 mmol; 1.1 eq.) was added. Then Methyl-4-chloro-4-oxobutyrate 704 (6. 73 g; 43.41 mmol; 1.1 eq.) was dissolved in DCM (3 mL) and cautiously dropped into the reaction mixture under vigorous stirring. The reaction mixture was heated under reflux for 2 h. After that, the reaction was allowed to cool to room temperature and treated with 1% HCl. The organic layer was separated, washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure to afford white solid. The crude white solid was purified by chromatography on silica gel (PE/EtOAc 50/50). The desired compound 705 was obtained as white needles (13.5 g, 94%). R f = 0.48 (DCM/MeOH 95/05). Mp = 102-103 °C (DCM) IR (KBr) ν max (cm -1 ) = 3439,3263,3056,2953,1728,1627,1486,1435,1412,1384,1263,1230. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 8.37 (br d,1H,J = 27.6 Hz,NH),1H,8H,Ar),1H,Ar),4.67 (s,1H,4.48 (s,1H,3.74 (d,3H,J = 7.8 Hz,1H,1H,2H,4H,H6,H7). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 173.6 (C-4), 171.6 (C-1), (137.7,136.8,136.3,128.9,128.6,128.1,127.6,127.3,126.4,122.2,113.1,112.1,111.5,(51.8 ,47.8,, (29.4, 29.2 (C-3)), (28.3, 27.8 (C-2)), (24.4, 23.5 (C-7)). To a solution of amide 705 (11.245 g; 30.86 mmol) in 300 ml dry benzene under Ar-atmosphere, POCl 3 (20 ml; 216 mmol; 7 eq.) was added dropwise to the reaction mixture. The reaction mixture was refluxed at 90 °C. The reaction was mentored by TLC and after consumption of the starting material, the solvent was removed and placed under vacuum for 15 min. Dry MeOH (400 ml) was added to the reaction mixture under Ar-atmosphere. The reaction was cooled to 0 °C in ice bath. (5.8 g; 154.3 mmol; 5 eq) of NaBH 4 was added in two portions to the reaction mixture. After that the solvent was removed and the residue was diluted with 50 ml DCM. The reactive materials were quenched by adding (50 ml) saturated solution of NH 4 Cl. The aqueous layer was extracted with DCM (3x50 ml). The combined organic layers were washed with NaHCO 3 , dried over Na 2 SO 4 and concentrated under reduced pressure to afford dark green oil. The crude oil was purified by chromatography on silica gel (PE/EtOAc 80/20). The desired compound 706 was obtained as faint yellow oil (6.95 g, 65%). R f = 0.70 (PE/EtOAc 8/2). IR (ATR) ν max (cm -1 ) = 3392,3097,2916,2853,1726,1619,1601,1494,1452. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 8.06 (br s, 1H, NH), 7. 1H,Ar),8H,Ar),3.75 (s,2H,1H,3.60 (s,3H,1H,2H,3H,, 2.13-2.00 (m, 2H, H-2). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 174.6 (C-4), (139.6,136.0,134.4,129.1,128.2,127.2,127.0,121.5,119.3,118.1,110.9,, 55.4 (C-1), 51.6 (C-5), 44.7 (C-7), 30.5 (C-2), 29.3 (C-3), 17.9 (C-8). HRMS (ESI): [M+Na] + C 22 H 24 N 2 O 2 Na : calcd. 371.1729, found 371.1721.

3-Benzyl-3,3a,4,5-tetrahydro-1H-indolo[3,2,1-de][1,5]naphthyridin-6(2H)-one (707)

To a solution of ester 706 (6.65 g; 19.09 mmol; 1.0 eq.) in dry DCM (230 mL), DBU (8.55 ml; 57.26 mmol; 3 eq.) was added at r.t. The reaction was stirred at r.t. for 2 days. After that, the solvent was removed under reduced pressure. The residue was treated by 10 % CuCO 4 solution and then extracted with DCM. The combined organic layer was dried over Na 2 SO 4 and concentrated under vacuum to afford dark green oil. The crude oil was purified by chromatography on silica gel (PE/EtOAc 70/30). The desired compound 707 was obtained as gray green solid (4.83 g, 80%). R f = 0.78 (PE/EtOAc 7/7). Mp = 173-175 °C (EtOAc) IR (KBr) ν max (cm -1 ) = 3390,3082,2964,2920,2886,2808,1701,1640,1601,1495,1474,1457,1383. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 8. 1H,(m,8H,Ar),4.23 (d,1H,J = 13.5 Hz,1H,3.40 (d,1H,J = 13.5 Hz,3.21 (dd,1H,J = 5.7,11.4 Hz,1H,2H,1H,2H,1.90 (qd,1H,J = 4.5,12.9 Hz,. 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 168.1 (C-4), (138.5, 135.0, 134.6, 129.4, 128.8, 128.4, 127.2, 124.4, 123.9, 118.1, 116. To a solution of LiAlH 4 (26.39 mg; 0.69 mmol; 1.1 eq.) in dry THF (3 mL) under inert conditions, amide 1 (200 mg; 0.63 mmol; 1.0 eq.) in dry THF (7 mL) was added dropwise at 0 °C. The reaction was stirred for 30 min at 0 °C. After 30 min, the excess LiAlH 4 in the reaction mixture was quenched by adding H 2 O (2 mL) carefully and dropwise. After that the formed solid was filtered and washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was treated with DCM and washed with brine. The organic layer was dried over Na 2 SO 4 and concentrated under vacuum to afforded foamy light faint brown solid. The crude solid was purified by chromatography on silica gel (pentane/Et 2 O 50/50). The desired compound 71 was obtained as faint yellow solid in two diastereoisomers (d.r. 2:1) (166 mg, 85%). First diastereoisomer (697a): R f = 0.62 (PE/EtOAc 50/50). Mp =149-150 °C (EtOAc) IR (KBr) ν max (cm -1 ) = 3416,3039,2956,2892,2841,2924,1645,1605,1494,1454,1427,1401,1383,1310. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.67 (d,1H,J = 6.9 Hz,6H,Ar),2H,Ar),1H,4.15 (d,1H,J = 13.5 Hz,1H,3.14 (dd,1H,J = 5.7,11.7 Hz,2H,1H,2H,1H,1H,1H,1H,. 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (138.6, 137.9, 129.0, 126.4, 128.1, 127.2, 121.6, 120.3, 118.2, 115.5, 111.9, 107.3 3432,3079,3059,3023,2956,2920,2853,2825,1617,1492,1460,1440,1337,1236. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.46-7.29 (m, 7H, Ar), 7.22-7.10 (m, 2H, Ar), 6.00 (s, 1H, H-4), 4.23 (d, 1H, J = 13.5 Hz, H-5a), 3.54 (br d, 1H, J = 9 Hz, H-1), 3.38 (d,1H,J = 13.2 Hz,3.22 (dd,1H,J = 5.7,11.7 Hz,1H,2H,H),3H,H7b,1H,. 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (136. 1, 129.2, 128.7, 128.4, 121.7, 121.6, 120.4, 118.6 (C-Ar)), 110.2 (C-11), 66.0 (C-4), 58.9 (C-5), 56.9 (C-1), 49.4 (C-6), 30.2 (C-3), 21.2 (C-2), 19.7 (C-7). HRMS (ESI): [M+NA] + C 21 H 23 N 2 ONa : calcd. 319.1804, found 319.1813.

(E)-Methyl 4-methoxy-2-((1-methylpiperidin-2-ylidene)amino)benzoate (361)

To a solution of 1-methylpiperidin-2-one 360 (563 mg; 4.97 mmol) in dry DCM (29 mL), POCl 3 (0.46mL; 4.97 mmol) was add dropwise. The reaction was stirred for 3 h. at room temperature. After that, trisubstituted aniline 359 (820 mg, 4.52 mmol) was dissolved in dry DCM (20 mL) and introduced to the reaction mixture. The reaction was refluxed for 12 h. After that, the reaction was allowed to cool to room temperature and the solvent was removed under reduced pressure. Then the remaining yellow oil was dissolved in 3M HCl. and extracted with DCM (3 x 50 ml). The DCM layers were concentrated under vacuum and the resulting faint yellow oil was carried through the above procedure for more three times. The combined aqueous layers were basified with 1 M NaOH till pH = 8. After that the aqueous layer was extracted with Ethyl acetate (3 x 100 ml). The combined ethyl acetate layers were dried over Na 2 SO 4 and the solvent was removed under vacuum. The desired compound 361 was obtained as faint yellow solid (1.14 g, 78%). R f = 0.58 (DCM/MeOH 95/05). Mp = 64-66 °C (DCM) IR (KBr) ν max (cm -1 ) = 301,2982,2949,2837,1717,1671,1625,1596,1557,1488,1460,1320. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) 7.80 (d, J = 6 Hz, 1H, H-3), 7.48 (dd, J = 3, 9 Hz, 1H, H-1), 6.26 (d,J = 3 Hz,1H,3.79 (s,3H,3.75 (s,3H,, 3.27 (t, J = 6 Hz, 2H, H-11), 3.02 (s, 3H, H-16), 2.14 (t, 2H, J = 6 Hz, H-13); 1.79 (m, 2H, H-12); 1.62 (m, 2H, H-14). In 25 mL dry round bottom two-necked flask, n-BuLi (0.514 mL; 0.9047 mmol, 2.5 eq., 1.7 M in THF) was placed. After that freshly distilled diisopropylamine (0.135 mL; 0.95 mmol, 2.65 eq.) was added very drop wisely to reaction mixture. (LDA begin to form as a gel). After that, dry THF (2 mL) was added to the reaction mixture. The reaction mixture was cooled to -78°C. Amidine 361 (100 mg; 0.361 mmol) was dissolved in dry THF (2 ml) and introduced drop wisely to the reaction mixture. The reaction was allowed to react for 3h at -78°C and then was allowed to warm up to room temperature overnight. Then, the reaction was quenched with a few drops of a NH 4 Cl solution. THF was then evaporated under reduced pressure. The residue was diluted with a NH 4 Cl saturated solution and extracted with DCM. The combined organic layers were washed with brine and dried over Na 2 SO 4 . The solvent was concentrated under reduced pressure and the residue purified by chromatography on silica gel (DCM/MeOH 95/5) to give 708 as a faint pink solid (79.5 mg, 90%). Mp = > 300°C (DCM). R f = 0.50 (DCM/MeOH 95/5). IR (KBr) ν max (cm -1 ) = 3071,2943,2848,1632,1591,1548,1500,1469,1390,1338,1314,1278. 1 H NMR (MeOH, 300 MHz): δ (ppm) = 8.03-8.00 (d, 1H, J = 8.7 Hz, H-5), 7.07 (d,1H,J = 2.1 Hz,1H,J = 2.4,8.7 Hz,3.88 (s,3H,3.44 (t,2H,J = 5.4 Hz,3.20 (s,3H,2.69 (t,2H,J = 6.3 Hz,2H,. 13 C NMR (MeOH, 75 MHz): δ (ppm) = (161.3, 155.7, 150.0, 121.9, 125.6, 111.5, 105.4, 98. To a solution of phenol 708 (100 mg, 0.40 mmol, 1 eq.) in dry DCM / DMF (15 mL 2/1), triethylamine (0.073 mL, 0.532 mmol, 1.3 eq.) was added and the reaction mixture was stirred for 30 min. The color during this period changed from colorless to deep yellow. NsCl (117.9 mg, 0.532 mmol, 1.3 eq.) was added and the reaction mixture was stirred for 3 h at r.t. The solvents were removed under reduced pressure and the crude material purified by chromatography on silica gel (PE/EtOAc 50/50) to give nosylate 712 as orange solid (143 mg, 81%). R f = 0.31 (PE/EtOAc 50/50). Mp = 202-203°C (DCM). IR (KBr) ν max (cm -1 ) = 3440,3111,2956,2936,2849,1631,1617,1555,1534,1464,1448,1395,1365. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 8.42 (d, 2H, J = 1.8 Hz, Ar), 8.17 (d, 1H, J = 1.8 Hz, Ar), 7.06 (br s, 1H, Ar), 6.96 (d, 1H, J = 9.0 Hz, H-2), 6.59-6.55 (dd, 1H, J = 2.4, 9.0 Hz, H-6), 3.89 (s, 3H, H-7), 3.50 (t, 2H, J = 5.7 Hz, H-13), 3. 32 (s,3H,2.89 (t,2H,J = 6.3 Hz,2H,. 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (160.9, 151.0, 142.0, 129.7, 124.5, 122.1, 113.7, 111.5, 105. To a solution of phenol 708 (400 mg, 0.286 mmol, 1 eq.) in dry DCM / DMF (30 mL 2/1), triethylamine (0.35 mL, 0.429 mmol, 1.5 eq.) and DMAP (14.7 mg, 0.81 mmol, 0.5 eq.) were added at 0°C and the reaction mixture was stirred for 30 min. The color during this period changed from colorless to deep yellow. Comins' reagent (224.6 mg, 0.572 mmol, 1.5 eq.) was added and the reaction mixture was stirred for 16 h at r.t. A 30% ammonium hydroxide solution was added until pH = 13 and the organic solvents were evaporated under vacuum. The residue was then diluted with EtOAc and saturated NaCl solution, the organic layer was separated and dried over Na 2 SO 4 . The solvent was concentrated under reduced pressure and the crude material purified by chromatography on silica gel (PE/EtOAc 7/3) to give triflate 713 as brown oil (535 mg, 87%). R f = 0.76 (PE/EtOAc 7/3). IR (ATR) ν max (cm -1 ) = 3090,2901,2853,1613,1511,1483,1443,1372. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.66-7.63 (d, 1H, J = 9.0 Hz, H-5), 7.09 (d, 1H, J = 2.4 Hz, H-2), 6.93-6.89 (dd, 1H, J = 2.4, 9.0 Hz, H-6), 3.94 (s, 3H, H-7), 3.52 (t, 2H, J = 5.7 Hz, H-13), 3.33 (s, 3H, H-14), 2.98 (t, 2H, J = 6.0 Hz, H-11), 2.04-2.00 (m, 2H, H-12). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (161.3,155.7,150.0,148.6,128.8,121.9,(114.5,111.1,110.7,105.4(C-Ar)), 55.4 (C-7), 49.6 (C-14), 37.2 (C-13), 22.8 (C-11), 20.5(C-12). HRMS (ESI): [M+H] + C 15 H 16-N 2 O 4 F 3 S : calcd. 377.0777, found 377.0784.

8-Methoxy-1-methyl-5-vinyl-1,2,3,4-tetrahydrobenzo[b][1,8]naphthyridine (698)

To a solution of the triflate 713 (140 mg, 0.37 mmol, 1 eq.) in freshly distillated DME (14 mL) and H 2 O (7 mL), vinyl potassium trifluoroborate (55.07 mg, 0.39 mmol, 1.05 eq.) and K 2 CO 3 (51.4 mg, 0.372 mmol, 1 eq.) were added. The flask containing the reaction mixture was flashed with argon for 30 min, then Pd(PPh 3 ) 4 (4.9 mg, 0.01 mmol, 0.1 eq.) was added. The reaction mixture was heated at 95°C for 3 h. The reaction mixture was then cooled down to room temperature and the solvent evaporated under vacuum. The product was purified by chromatography on silica gel (PE/EtOAc 80/20) to give 698 as yellow oil (75 mg, 79%). R f = 0.45 (PE/EtOAc 80/20). IR (ATR) ν max (cm -1 ) = 3079,2939,2839,1615,1584,1562,1509,1463,1449,1423,1401,1343. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.66-7.63 (d, 1H, J = 9.0 Hz, H-5), 7.06 (d,1H,J = 2.4 Hz,2H,1H,J = 1.8,11.4 Hz,1H,J = 2.1,18.0 Hz,3.90 (s,3H,3.43 (t,2H,J = 5.7 Hz,3.28 (s,3H,2.82 (t,2H,J = 6.3 Hz,2H,. 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (160.0, 155.3, 148.6, 141.2, 132.4, 125.9 (C-Ar)),121.8 (C-15), (116.4, 144.7, 105.6

Preparation of 2-nitroethyl acetate:

A solution of (0.5 g) of NaOAc in (2.4 mL, 25.55 mmol) of Ac 2 O was maintained at a temperature of 35 °C using a cold H 2 O bath, as 2 g (1.1 mol) of 2-nitroethanol was added over a period of 30 min. (Caution:The temperature of this reaction must be carefully controlled. If allowed to exceed 60 °C, a violent decomposition may occur). When the reaction temperature no longer tended to rise, the bath was removed and the solution was allowed to stir overnight. The solution was then poured into a large volume of cold H 2 O and extracted with three portions of DCM. The extracts were washed with NaCl solution and dried over Na 2 SO 4 . Evaporation of the solvent under reduced pressure afforded yellow oil (3.052 g, quant. yield). The crude oil was used directly in the next step.

Preparation of enamine:

To a solution of pyrrolidine (0.15 mL, 1.89 mmol, 1.0 eq.), aldehyde 417 (300 mg, 1.89 mmol, 1.0 eq.) in dry toluene (42 mL) p-toluene sulfonic acid (0.6 mL, 0.4 mol%.) was added. The reaction mixture was refluxed at 110°C for 5h using dean's stark apparatus. Then solvent was removed with a rotary evaporator, and the resulting crude product was used directly in the next step.

Preparation of aldehyde 727:

A solution of 2-nitroethyl acetate (315 mg, 2.36 mmol, 1.25 eq.), in CH 3 CN (2 mL) was added to a crude solution of the enamine of 417 (400 mg, 1.89 mmol, 1.0 eq.) in CH 3 CN (6 mL). The reaction was maintained at room temperature for 2 h. After 2 h, HCl (5% aqueous solution, 8 mL) was added and the resulting mixture was extracted with EtOAc (3 x 5mL). The combined organic extracts were washed with saturated NaHCO 3 solution and then brine, dried over MgSO4. The solvent was concentrated under reduced pressure and the crude material purified by chromatography on silica gel (EtOAc 100%) to give aldehyde 727 as colorless oil (144 mg, 28%).

4-Ethyl-1-(pyrrolidin-1-yl)-4-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)hept-6-en-1-one (729)

To a solution of tryptamine (44.5 mg; 0.27 mmol, 1.1 eq.) in dry DCM (7.5 mL), aldehyde 726 (60 mg; 0.25 mmol, 1.0 eq.) was dissolved in dry DCM (2.0 mL) and introduced to the reaction mixture. The reaction was stirred at room temperature for 2 h. At the end of 2.0 h, the reaction mixture was cooled to 0 °C in an ice bath and TFA (0.04 ml; 0.50 mmol; 2.0 eq.) was added. The reaction mixture was stirred for about 30 min at 0 °C. The ice bath was removed after 30 min and the reaction mixture was stirred at room temperature for about 16 hours. Then, the reaction was quenched with sat. NaHCO 3 solution, to neutralize TFA (monitored by pH paper). The reaction mass was diluted with methylene chloride and the organic layer was washed with water (~5 mL) and brine solution (~5 mL). the combined organic layer was dried over MgSO 4 and the solvent was concentrated under reduced pressure and the crude material purified by chromatography on silica gel (EtOAc 100%) to give Pictet-Spengler product 729 as brown solid (76 mg, 79%, d.r. (1:1)). R f = 0.39 (DCM/MeOH 95/5). Mp = 135°C (DCM). IR (KBr) ν max (cm -1 ) = 3185,3071,2970,2877,1608,1473,1444,1340. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 9.89 (br s, 2H, NH), 7. 3H,Ar),3H,Ar),1H,1H,2H,2H,4.16 (s,2H,9H,6H), 2.58-2.09 (m, 12H), 1.97-1.81 (m, 10H), 1.67-1.50 (m, 4H, H-3), 1.01 (t, 3H, J = 7.2 Hz, H-4), 0.79 (t, 3H, J = 7.2 Hz, H-4). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (172.7, 172.4, (C-10)), (136.1,135.5,135.4,134.1,133.9,126.9,126.8,121.1,118.7,117.6,117.5,117.4,111.5,111.3,), (58.4 , 58.0 (C-1)), 46.8, 46.7, 45.8, 43.9, 43.8, 43.3, 43.2, 40.9, 39.6, 29.9, 29.7, 28.7, 28.7, 28.1, 27.2, 25.9, 24.45, 24.40, (23.3, 23.2 (C-3)), (8.5, 8.3 (C-4)

Figure 4 .

 4 Figure 4. Space filling model of the fluorovinblastine binding site (R = F, left), (R = H, middle). X-ray structure of vinblastine bound to tubulin highlighting the region surrounding vinblastine C20′ site (right image).

  involved the addition of nucleophilic radical 42 to the electron poor olefin 41 to form a C-C bond. Radical 42 was generated from the corresponding alkyl iodide by the abstraction of iodine with Bu 3 Sn • . As a result, the newly generated electrophilic radical 43 could be trapped by the electron rich allylstannane 44 to form another C-C bond, followed by a β-elimination and regeneration of tin radical, which in turn propagates the radical chain. The reaction ended up successfully with the desired product 45 in excellent yields (Scheme 22). In 1995 Porter and coworkers 48 developed the first asymmetric radical carbo-allylation (also the first asymmetric MCR) by the addition of an alkyl radical, generated from the corresponding iodide 46, on an oxazolidinone derived from an acrylate 47 (Evans' oxazolidinone) in the presence of a Lewis acid and a chiral ligand, a bisoxazoline (BOX) 50. The generated intermediate radical was trapped by an allylstannane 48 to form the desired products 49 in very good yields and enantiomeric excesses (Scheme 23).

  to α-amino acids or amides after hydrolysis of α-aminonitriles. Recently, Porta et al. 61 developed the radical version of this reaction. The reaction starts by the formation of a hydroxyl radical through the reduction of hydrogen peroxide by Ti III . This highly reactive radical then abstracts a hydrogen from amide 99 to form the nucleophilic formamidyl radical 102 which in turn adds to the in situ 60 (a) Kim, S.; Sub Yoon, K.; Suk Kim, Y. Tetrahedron 1997, 53, 73-80 ; (b) Kim, S.; Kim, Y.; Yoon, K. S.

150

  or by Ir(III)* to give an N-acyliminium cation 154 that was trapped by the alcohol to form αamidoethers 155 (Scheme 40).

  Winkler and Dunitz introduced three independent parameters to measure and quantify the distortion degree of amide bonds. 118 These parameters are: (i) twist angle (τ) which describes the magnitude of rotation around the N-C(O) bond, (ii) pyramidalization at nitrogen (χ N ), and (iii) pyramidalization at carbon (χ C ). The last two parameters, describe the tetrahedral character of the nitrogen and carbon atoms respectively (Figure 7).

Figure 7 .

 7 Figure 7. Winkler-Dunitz Distortion Parameters of Amide Bonds.

  Moreover, Yamada proposed a qualitative description of the distorted amides based on the twist angle and pyramidalization of the nitrogen atom. 113 Therefore, he classified the twisted amides into three classes: (i) Type A amides: which have perpendicularly twisted N-C(O) bonds and nonpyramidalized nitrogen atoms, (ii) Type B amides: which have planar N-C(O) bonds and sp 3 nitrogen atoms, and (iii) Type C amides: which have perpendicularly twisted N-C(O) bonds and pyramidalized nitrogen atoms. b) Bond Lengths in Bridgehead Lactams.

  (a) Buchanan, G. L. J.Chem. Soc. Chem. Commun. 1981, 814-815;(b) Buchanan, G. L. J.Chem. Soc. Perkin Trans. 1, 1984, 2669-2670. Buchanan showed that a bridgehead lactam like 285 exists in a chair-boat conformation, like the anti-Bredt olefin bicyclo[3.3.1]non-1-ene 286. These compounds favor a trans double bond in the larger ring (Scheme 77).134 The X-ray of lactam 285 reported by Buchanan showed τ =20.8°; χ N = 48.8° and χ c = 5.9° while the bond lengths were N-C(O) = 1.374Å; C=O = 1.201Å. All of these parameters beside the IR stretching υ C=O = 1695 cm -1 indicate that this lactam showed a moderate distortion of the amide bond.135 More recently, an exploratory unit in Sanofi Aventis R&D developed a sequence to access 1azabicyclo[3.3.1]nonane derivative 292 with a pyridinyl substituent at the bridgehead carbon.136 Starting from the pyridinyl acetonitrile 297 and after deprotonation αto the nitrile group and alkylation by ethyl acrylate, the cyano diester 288 was obtained in excellent yield. The cyano diester 288 was then hydrogenated into an amine, which lactamized directly with one of the two esters to give the first lactam cycle 290. The reduction of both the ester and amide followed by the conversion of the free alcohol into a bromide allowed the final cyclization to give the azabicyclo[3.3.

  3.1] bridgehead lactams without substituent at the bridgehead carbon was developed by Steliou in 1983 by promoting the difficult lactamization by di-n-butyltin oxide under high dilution to afford the desired bridgehead lactam 297 in 77% yield (Scheme 80). 138 137 Alonso, D. A.; Costa, A.; Mancheno, B.; Najera, C. Tetrahedron 1997, 53, 4791-4814. 138 Steliou, K.; Poupart, M. A. J. Am. Chem. Soc. 1983, 105, 7130-7138.This tin-mediated lactamization has been used by Gerlach to prepare the enantiomerically enriched bridged lactam (+)-297.139 After reaction of piperidine alcohol 298 with bromocamphorsulfonic acid, the enantiomerically enriched alcohol (+)-298 was obtained. A homologation reaction, via the replacement of an activated alcohol by a cyano group, was used to prepare the desired piperidine carboxylic acid (+)-299. The di-n-butyltin oxide reagent could then facilitate the lactamization giving the enantiomerically enriched bridged lactam (+)-297 in good yield (Scheme 81).

  NaBH 4 to the corresponding alcohol 341 in MeOH gave the expected product in moderate yield (42%) in combination with the trans-esterification byproduct 342. To avoid the formation of the undesired trans-esterification byproduct 342 the solvent was changed to THF. The reaction worked better (80%) but slower due to the low solubility of NaBH 4 in THF. Attempts to increase the solubility of NaBH 4 by cation exchange with n-tetrabutylammonium chloride decreased the yield significantly to 47% (Scheme 102).158 158 Nagao, Y.; Ikeda, T.; Inoue, T.; Yagi, M.; Shiro, M.; Fujita, E. J.Org. Chem. 1985, 50, 4072-4080.

  Ghosez and coworkers described the α,β-dehydration of tertiary carboxyamides 383 by pyridine Noxide though the α-chloroenamine intermediate 384. The reaction probably involved ionization of αchloroenamine 384 to the corresponding ketene-iminium chloride 385 followed by the addition of pyridine N-oxide. A base mediated 1,4-elimination produced finally an α,β-unsaturated amide 387 (Scheme 127).177

Figure 8 .

 8 Figure 8. The 1 H NMR spectra of both natural and synthesized Eucophylline.

  of the first syntheses of Eburnamine 409 has been done in 1960 by Taylor.188 In this synthesis, the condensation of β-ethyl-β-formyladipic acid 415, prepared from p-ethyl phenol 414 under Reimer-Tiemann reaction conditions, with tryptamine afforded the eburnamonine lactam 416. This lactam 416 was reduced to the corresponding eburnamine 409 in poor yields for the ring closure (25%) and Reimer-Tiemann reaction (8%) (Scheme 139).In 1965, Harley-Mason developed a synthesis for (±)-Eburnamine.189 The synthesis of the nontryptamine part of this indole alkaloid was based on alkylation of the pyrrolidine enamine intermediate, derived from methyl 4-formyl-hexanoate 417, with allyl bromide 127 (Stork reaction conditions) to afford the desired aldehyde 418. This aldehyde was condensed with tryptamine under Pictet-Spengler reaction conditions to give (±)-Eburnamine lactam 420 that was reduced later to give the (±)-Eburnamine 409 (Scheme 140).188 Bartlett, M. F.; Taylor, W. I. J. Am.Chem. Soc. 1960, 82, 5941-5946. 189 Barton, J. E. D.; Harley-Mason, J. Chem. Commun. 1965, 298-299.In 1979, Schlessinger et al. 191 developed another pathway to access dl-Eburnamonine 408 and (±)-Eburnamine 409 through Bischler-Napieralski intramolecular condensation. The construction of the first quaternary center was achieved by deprotonation of amide 432 α-carbon followed by alkylation with methylbromoacetate to afford a single product in 95%. The Bischler cyclization of lactam 433 to the corresponding tetracyclic salt, followed by the reduction of the imine by a hydride source gave the tetracyclic product 445. Base-mediated cyclization, followed by reduction of this Eburnamonine 408 by LiAlH 4 afforded the corresponding (±)-Eburnamine 409 (Scheme 142).

  aldehyde underwent spontaneous reaction to furnish the bicyclo[3.2.1]nonane acetal 451. This bicyclic compound 451 was treated with propane-1,3-dithiol to give the key dithiane-lactone 452 (Scheme 143).Condensation of lactone 452 with tryptamine at 160°C afforded the amide 454 and δ-lactam 453 in 81 and 14% yields respectively. The amide 454 was then allowed to cyclize under Bischler-Napieralski reaction conditions to afford the iminium salt 455, which was reduced by LiAl(OtBu) 3 H to give the tetracyclic core 456 in 62% overall yield and with the desired configuration. After hydrolysis of the dithiane group, the aldehyde 457 formed underwent spontaneous cyclization to afford (+)-Eburnamine 409 and (-)-Eburnamenine 458 in 27 and 3% yields respectively. Further transformation of (+)-eburnamine 409 to (-)-Eburnamonine 408 could be achieved by oxidation with pyridinium dichromate (Scheme 144). Five year later, Fuji et al. 193 developed an enantioselective synthesis of (-)-Eburnamonine 408 from the chiral (S)-lactone 459. Therefore, the reductive denitration of 459 in DME afforded hemiacetal 460. Reduction of 460 followed by refluxing in HCl/MeOH gave γ-lactone 461 in 75% overall yield. The desired non-tryptamine unit was obtained after three steps from lactone 461. γ-Lactone 461 was thus subjected to Jones oxidation, DIBAL-H reduction and acid treatment in MeOH to afford the desired lactone 462. Refluxing the latter with tryptamine in AcOH under Pictet-Spengler reaction conditions proceeded smoothly to afford an approximately 1:1 mixture of the two diastereoisomers 463a and 463b. After enrichment of the desired diastereoisomer 463b by recrystallization, the dilactam 464 was obtained by Sarett oxidation. Reduction of this dilactam and oxidation of eburnamine afforded (-)-Eburnamonine 408 in 74% yield. The other diastereoisomer 463a formed from Pictet-Spengler reaction could serve as an intermediate for the synthesis of (-)-Eburnamonine 408, as the 463a and 463b were showed to establish an equilibrium with an approximate 1:1 ratio in the presence of BF 3 -OEt 2 (equation 1) Therefore, an alternative synthesis of (-)-Eburnamonine 408 was developed through oxidation of 465a by Hg(OAc) 2 followed by reduction of the iminium with In a unique approach to access (±)-Eburnamonine, Grieco et al. 196 developed a [4+2] intramolecular imino Diels-Alder reaction of vinyl indole into imine to give the tetracyclic core of Eburnamonine, which was then rapidly converted into (±)-Eburnamonine. Lactam 487 was doubly alkylated, first on the α-carbon to lactam by ethyl iodide and then on the lactam's nitrogen by a 2-(trimethylsilyl)ethyl-4-nitrophenyl carbonate 487i. This alkylated lactam 488 was reduced and dehydrogenated to give enamine 489, which underwent cyclopropanation with ethyl diazoacetate to give exo and endo cyclopropanes 490 in a 1.1:1 ratio. Saponification of the endo-cyclopropane and coupling with indole 492 gave the amide 493. Methylenation of aldehyde 493 and liberation of imine through reaction with Bn(Me) 3 NF gave the key vinyl-imine 495 in 81%. The imino Diels-Alder reaction was performed in the presence of Florisil at 50°C in EtOAc to give the desired tetracyclic core of Eburnamonine 496 in 82%. Dehydration of 496 with H 2 SO 4 in EtOH gave (±)-Eburnamonine 408 in 11 steps from δ-valerolactam 487 and 16% overall yield (Scheme 148).196 Grieco, P. A.; Kaufman, M. D. J. Org. Chem. 1999, 64, 7586-7593.

  reported the decarboxylative cyanation of Barton's ester and addition of sulfonyl cyanide 561 onto olefins. The reaction started by photolysis of Barton's ester 559 to generate the corresponding carbon radicals 563 through the primarily formed carboxyl radicals 562. These carbon radicals 562 could be trapped by sulfonyl cyanides 561 to give nitriles 566 and sulfonyl radicals 564. These sulfonyl radicals may also add onto olefins 560 to give intermediate radical 565 which was trapped again with another molecule of sulfonyl cyanides 561 (Scheme 171).

  For example, diene 595 underwent 5-exo-trig cyclization onto the second double bond to give the bicyclo[3.3.0]octane 597b. Similarly, diene 596 underwent 5-exotrig cyclization to give the trisubstituted cyclopentane 597c. While diene 594 underwent 3-exo-trig to give disubstituted tricyclo[2.2.1.0]heptane 597a.

  More recently, Renaud et al.224 relied on the same α-scission process to develop azidation reactions of iodate or xanthate derivatives 604 by using ethylsulfonylazide 605. The azide part of this reagent 605 acts as a radical acceptor and the ethyl radical, generated after extrusion of SO 2 , propagate the radical chain (Scheme 182).

  (a) M. S. A. Vrijland, Org. Synth. 1977, 57, 88; (b) Kim, S.; Lim, K.-C.; Kim, S. Chem. Asian J. 2008, 3, 1692-1701

  231 (a)Ma, L.; Seidel, D. Chem. Eur. J. 2015, 21, 12908-12913; (b) Seidel, D. Acc. Chem. Res. 2015, 48, 317-328.

  which might be useful for a potent cyclization with the secondary amine resulting from the Pictet-Spengler reaction (Scheme 200). With these protected alcohols in hand and similarly to the previous idea of nitrile reduction / Pictet-Spengler cyclization sequence, the nitrile group in 651a-b was reduced by DIBAL-H. Then, instead of hydrolyzing the formed imine by water to form aldehyde, this imine was trapped directly by tryptamine to form the tricyclic Pictet-Spengler product 652a-b. Unfortunately, the desired Pictet-Spengler products 652a-b were not observed, and only traces of the corresponding aldehydes 653ab were detected (Scheme 201).

  nitrile product 579a bearing a thioester group could undergo a chemoselective reduction of the thioester into the aldehyde 654. This aldehyde 654 could react with tryptamine under reductive conditions to give the secondary amine 655, which could cyclize onto the nitrile to give the key amide intermediate 656. The Bischler-Napieralski intramolecular condensation between this amide and tryptamine indole should hopefully give the desired tetracyclic core of Eburnane 657.

  The minor diastereoisomer of the north fragment 697b and the starting quinolinol 714. major diastereoisomer of the north fragment 697a and the starting quinolinol 714.

  first total synthesis of Eucophylline was achieved in 10 steps and 10% overall yield based on the recently developed free-radical multi-component carbo-oximation reaction between radical precursor α-iodothioester 337, the electron-rich olefin 252 and sulfonyl oxime 233. This key reaction allowed us to construct the quaternary center in Eucophylline and devise a new straightforward access to the azabicyclo[3.3.1]nonane skeleton with an efficient and short sequence of reactions (Scheme 256).

1 H

 1 NMR and 13 C NMR were recorded on a Brüker DPX 200 ( 1 H: 200 MHz, 13 C: 50 MHz), a Brüker Avance 300 ( 1 H: 300 MHz, 13 C: 75.46 MHz) using CDCl 3 as internal reference unless otherwise indicated. The chemical shifts (δ) and coupling constants (J) are expressed in ppm and Hz respectively. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, quint = quintuplet, hex = hexuplet. FT-IR spectra were recorded on a Perkin-Elmer Spectrum 100 using a ZnSe crystal ATR accessory. HRMS were recorded with a Waters Q-TOF 2 spectrometer in the electrospray ionization (ESI) mode. Analytical thin layer chromatography was performed using silica gel 60 F254 pre-coated plates (Merck) with visualization by ultraviolet light, potassium permanganate. Fluka silica gel 60 (230-400 mesh) was used for flash chromatography.268 Burchat, A. F.; Chong, J. M.; Nielsen, N. J.Organomet. Chem. 1997, 542, 281-283.

  13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 177.4 (C-9), 160.4 (C-7), 139.3 (C-4), 132.0 (C-2), 124.1(C-3), 122.2 (C-1), 114.1 (C-6), 113.9 (C-5), 77.7 (C-8), 31.4 (C-10). HRMS (ESI): [M+Na] + C 10 H 8 NO 2 NaI : calcd. 323.9492, found 323.9481.

  ): [M+H] + C 9 H 16 O 2 : calcd. 156.11503, found 156.11532.

  ): [M+Na] + C 12 H 21 NO 3 Na : calcd. 250.1413, found 250.1420.

  13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 173.2 (C-9, C-12, C-17), 154.4 (C-4), 137.5 (C-16), 128.5 (C-16), 128.4 (C-16), 127.9 (C-16), 75.9 (C-15), 60.5 (C-10, C-13, C-18), 41.3 (C-3), 29.5 (C-1, C-6, C-8), 28.6 (C-2, C-5, C-7), 14.2 (C-11, C-14,C-19). HRMS (ESI): [M+Na] + C 24 H 35 NO 7 Na : calcd. 472.2311, found 472.2317.

  ): [M+Na] + C 27 H 35 NO 7 NaS : calcd. 540.2026, found 540.2017.

  13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 197.1 (C-9), 173.4 (C-11), 155.1(C-4),(137.7, 134.5, 129.4, 129.2, 128.5, 128.4, 127.9, 127.8 (C-10, C-15)), 75.9 (C-14), 60.5 (C-12), 41.9 (C-1), 38.3 (C-3), 29.6 (C-8), 29.4 (C-2), 28.8 (C-7), 27.4 (C-5), 14.3 (C-13), 7.6 (C-6). HRMS (ESI): [M+Na] + C 25 H 31 NO 4 SNa : calcd. 464.1866, found 464.1874. (E)-Ethyl 4-(((benzyloxy)imino)methyl)-4-ethyl-7-hydroxyheptanoate (341)

  13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 172.5 (C-1), 70.1 (C-10), 50.7 (C-5), 37.3 (C-11), 33.6 (C-4), 29.6 (C-2), 29.4 (C-3), 27.7 (C-9), 26.6 (C-6), 23.2 (C-8), 7.4 (C-7). HRMS (ESI): [M+Na] + C 11 H 21 NO 4 NaS: calcd. 286.1083, found 286.1082.

  13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 170.1 (C-1), 163.4 (C-11), 156.4 (C-15), 134.2 (C-13), 118.8 (CN), 109.2 (C-14), 107.1 (C-16), 97.1 (C-12), 56.7 (C-5), 55.4 (C-17), 53.5 (C-6), 36.3 (C-3), 35.5 (C-9), 33.6 (C-8), 29.1 (C-4), 26.2 (C-7), 20.6 (C-2), 7.5 (C-10). HRMS (ESI): [M+H] + C 18 H 24 N 3 O: calcd. 298.1913, found 298.1910.

  13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 159.1 (C-1), 146.3 (C-1), (130.0, 127.1, 114.3, 113.5 (C-Ar)), (C-2), 55.2 (C-9), 54.3 (C-5), 49.3 (C-6), 31.9 (C-4), 31.0 (C-8), 26.5 (C-3), 18.1 (C-7). HRMS (ESI): [M+H] + C 15 H 20 NO : calcd. 230.1539, found 230.1543.

  (C-Ar)), 121.0 (C-2), 53.7 (C-5), 49.4 (C-6), 31.7 (C-4), 30.9 (C-8), 26.2 (C-3), 18.0 (C-7). HRMS (ESI): [M+H] + C 14 H 16 N 2 O 2 : calcd. 245.1284, found 245.1286.

  (C-Ar)), 117.4 (C-2), 54.2 (C-5), 49.3 (C-6), 31.8 (C-4), 31.0 (C-8), 26.4 (C-3), 21.7 (C-11), 18.0 (C-7). HRMS (ESI): [M+H] + C 21 H 24 NO 3 S: calcd. 370.1471, found 370.1474.

  13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 162.1 (C-8), 160.1 (C-11), 148.4 (C-13), 146.8 (C-15), 120.8 (C-17), 115.7 (C-16), 111.0 (C-12), 106.9 (C-14), 105.2 (C-9), 57.8 (C-7), 55.3 (C-18), 55.0 (C-1), 36.3 (C-10), 35.2 (C-5), 33.3 (C-3), 30.3 (C-4), 19.4 (C-2), 7.2 (C-6). HRMS (ESI): [M+H] + C 18 H 24-N 3 O : calcd. 298.1919, found 298.1916. 5-Ethyl-10-methoxy-3,4,5,6-tetrahydro-2H-1,5-methanoazocino[2,3-b]quinolin-7-ol (403)

  13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 163.6 (C-8), 161.3 (C-11), 150.1 (C-13), 147.5 (C-15), 121.8 (C-17), 119.7(C-16), 118.1 (C-19), 115.4 (C-12), 114.6 (C-14), 106.4 (C-9), 57.4 (C-7), 56.2 (C-18), 55.6 (C-1), 35.6 (C-10), 34.9 (C-5), 32.8 (C-3), 29.9 (C-4), 19.5 (C-2), 7.0 (C-6). HRMS (ESI): [M+H] + C 19 H 22 F 3 N 2 O 4 S: calcd. 431.1246, found 431.1232. 5-Ethyl-10-methoxy-7-vinyl-3,4,5,6-tetrahydro-2H-1,5-methanoazocino[2,3-b]quinolone (406)

  13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 161.6 (C-8), 160.0 (C-11), 148.4 (C-13), 143.6 (C-15), 131.9 (C-19), 126.0 (C-20), 122.6 (C-17), 121.8 (C-16), 119.2 (C-12), 117.5 (C-14), 106.5 (C-9), 57.6 (C-7), 55.7 (C-18), 55.4 (C-1), 36.6 (C-10), 36.1 (C-5), 35.1 (C-3), 30.6 (C-4), 19.5 (C-2), 7.2 (C-6). HRMS (ESI): [M+H] + C 20 H 24 N 2 ONa : calcd. 331.1780, found 331.1774.

  13 C NMR (CD 3 OD, 75 MHz): δ (ppm) = 160.9 (C-8), 158.4 (C-11), 147.7 (C-13), 144.8 (C-15), 131.7 (C-18), 126.1 (C-19), 122.0 (C-17), 121.1 (C-16), 118.6 (C-12), 117.3 (C-17), 107.9 (C-9), 57.1 (C-7), 55.3 (C-1), 36.2 (C-10), 35.6 (C-5), 34.6 (C-3), 30.2 (C-4), 19.0 (C-2), 5.97 (C-6). HRMS (ESI): [M+H] + C 19 H 23 N 2 O : calcd. 295.1804, found 295.1814.

  13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (135.6, 133.6, 129.7, 127.7 (C-Ar)), 127.5 (C-1), 107.6 (C-2), 62.3 (C-4), 48.2 (C-3), 41.9 (C-6), 26.8 (C-7). HRMS (ESI): [M+Na] + C 20 H 25 ONaSiI: calcd. 459.0611, found 459.0611.

  13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 148.5 (C-2), (135.6, 134.0, 129.5, 127.6 (C-Ar)), 109.1 (C-1), 63.1 (C-4), 39.3 (C-3), 29.0 (C-6), 26.8 (C-7), 19.2 (C-8), 12.2 (C-9). HRMS (ESI): [M+Na] + C 22 H 30

  13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 172.2 (C-5, C-12), 122.3 (CN), 60.8 (C-6, C-13), 40.2 (C-1), 30.3 (C-4, C-11), 29.5 (C-3, C-10), 28.8 (C-8), 14.1 (C-7, C-14), 8.5 (C-9). HRMS (ESI): [M+Na] + C 14 H 23 NO 4 Na : calcd. 292.1519, found 292.1526.

  13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 172.3 (C-11), (135.5, 133.1, 129.8 J = 6.9 Hz, 127.8 (C-Ar)), 122.8 (CN), 60.7 (C-12), 60.0 (C-6), 39.4 (C-1), 37.3 (C-5), 31.0 (C-9), 29.7 (C-10), 29.3 (C-3), 26.7 (C-8), 19.0 (C-7), 14.1 (C-13), 8.6 (C-4) HRMS (ESI): [M+Na] + C 27 H 37 NO 3 NaSi : calcd. 474.2434, found 474.2428.

  2 (C-Ar)), 122.3 (CN), 40.5 (C-6), 31.1 (C-5), 26.5 (C-1), 20.0 (C-3), (-2.3, -3.0 (C-4). HRMS (ESI): [M+Na] + C 20 H 23NONaSiS : calcd. 376.1161NONaSiS : calcd. 376. , found 376.1168. .

  13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 196.1 (C-11), (136.5, 134.5, 129.5, 129.2 (C-Ar)), 122.7 (CN), 59.3 (C-6), 39.6 (C-1), 38.9 (C-10), 37.6 (C-5), 31.2 (C-9), 29.4 (C-3), 28.9 (C-7), 25.9 (C-8), 8.70 (C-4), -5.4 (C-12) HRMS (ESI): [M+Na] + C 21 H 33 NO 2 NaSiS : calcd. 414.1893, found 414.1892.

  13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (135.5, 133.3, 129.8, 127.7(C-Ar)), 123.4 (CN), 62.4 (C-7), 60.1 (C-9), 39.5 (C-8), 37.4 (C-2), 32.3 (C-6), 29.3 (C-10), 27.5 (C-5), 26.8 (C-11), 19.1 (C-3), 8.7 (C-4). HRMS (ESI): [M+Na] + C 25 H 35 NO 2 NaSi : calcd. 432.2329, found 432.2321.

  , 26.2 (C-3), 21.5 (C-4), 19.1, 19.0 (C-6), 7.0, 6.9 (C-7). HRMS (ESI): [M+Na] + C 25 H 36 O 3 NaSi : calcd. 435.2325, found 435.2317.

  2 (C-Ar)), 64.7 (C-5), 60.3 (C-1), 60.0 (C-9), 53.6 (C-13), 40.5 (C-8), 35.4 (C-4), 33.5 (C-3), 29.2 (C-10), 26.8 (C-11), 26.2 (C-2), 25.3 (C-6) , 21.7 (C-14), 7.6 (C-7) HRMS (ESI): [M+H] + C 35 H 45 N 2 OSi : calcd. 537.3285, found 537.3295. The second diastereoisomer (642b): R f = 0.45 (PE/EtOAc 90/10). IR (ATR) ν max (cm -1 ) = 3051

  3 (C-Ar)), 65.07 (C-5), 60.6 (C-9), 60.3 (C-1), 53.6 (C-13), 35.3 (C-8), 34.3 (C-4), 34.1 (C-3), 31.5 (C-6), 29.2 (C-10), 26.8 (C-11), 26.2 (C-2), , 21.7 (C-14), 7.4 (C-7). HRMS (ESI): [M+Na] + C 35 H 44 N 2 ONaSi : calcd. 559.3115, found 559.3110.

  0, 108.0 (C-Ar)), 64.8 (C-5), 59.9 (C-1), 59.2 (C-9), 53.3 (C-10), 40.2 (C-8), 36.1 (C-6), 35.9 (C-4), 33.4 (C-3), 27.6 (C-2), 21.2 (C-11), 7.5 (C-7) HRMS (ESI): [M+Na] + C 19 H 26 N 2ONa : calcd. 321.1937ONa : calcd. 321. , found 321.1941. .

  13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 200.0 (C-1), (135.5, 133.1, 129.8, 127.8 (C-Ar), 122.8 (CN), 60.0 (C-6), 39.3(C-5), 37.3 (C-2), 29.4 (C-10), 28.0 (C-3), 26.7 (C-11), 24.5(C-4), 19.0 (C-7), 8.7 (C-8) HRMS (ESI): [M+Na] + C 25 H 33 NO 2 NaSi : calcd. 430.2172, found 430.2177.

  2 (C-Ar)), 123.5 (CN), 60.2 (C-7), 49.6 (C-12), 49.3 (C-1), 39.5 (C-6), 37.4 (C-3), 33.6 (C-2), 29.2 (C-8), 26.8 (C-9), 25.4 (C-13), 24.5 (C-4), 19.1 (C-10), 8.7 (C-11) HRMS (ESI): [M+H] + C 35 H 46 N 3 OSi : calcd. 552.3404, found 552.3393.

  9 (C-Ar)), 97.7 (C-5), 63.2 (C-7), 55.5 (C-10), 45.1 (C-1), 41.3 (C-4), 36.2 (C-6), 27.1 (C-3), 26.7 (C-2), 23.9 (C-11), 21.3 (C-8), 9.1 (C-9). HRMS (ESI): [M+H] + C 19 H 27 N 2 O : calcd. 229.2117, found 299.2117.

  2 (C-Ar)), 62.3 (C-7), 48.8 (C-10), 48.5(C-1), 43.8 (C-4), 36.7 (C-6), 31.7 (C-3), 29.6 (C-2), 23.9 (C-11), 19.8 (C-8), 8.6 (C-9). HRMS (ESI): [M+Na] + C 26 H 30 N 2 O 3 Na : calcd. 441.2148, found 411.2137.

  3 (C-4), 36.1 (C-6), 31.1 (C-3), 29.7 (C-2), 25.2 (C-11), 22.2 (C-8), 7.03 (C-9). HRMS (ESI): [M+H] + C 26 H 31 N 2 O 2 : calcd. 403.2380, found 403.2395.

  4 (C-Ar)), 94.6 (C-5), 63.2 (C-7), 55.5 (C-10), 49.8 (C-20), 45.1 (C-1), 41.2 (C-4), 36.2 (C-6), 27.1 (C-3), 26.7 (C-2), 23.6 (C-11), 21.3 (C-8), 9.1 (C-9). HRMS (ESI): [M+Na] + C 26 H 32 N 2 ONa: calcd. 411.2406, found 411.2408.

  (C-Ar)), 93.0 (C-8), 67.5 (C-7), 66.5 (C-5), 59.5 (C-11), 54.8 (C-1), 49.8 (C-21), 41.2 (C-4), 35.5 (C-6), 27.0 (C-3), 23.4 (C-2), 22.6 (C-11), 19.5 (C-8), 7.46 (C-9). HRMS (ESI): [M+Na] + C 33 H 40 N 2 ONa: calcd. 503.3032, found 503.3027.

  9 (C-Ar)), 64.0 (C-1), 57.3 (C-4), 56.2 (C-9), 45.1 (C-10), 30.8 (C-2), 28.8 (C-5), 27.0 (C-6), 19.3 (C-11). HRMS (ESI): [M+Na] + C 37 H 42 N 2 OSiNa : calcd. 558.3061, found 558.3058.

  HRMS (ESI): [M+Na] + C 22 H 24 N 2 O 3 Na : calcd. 387.1679, found 387.1675.

  2 (C-Ar)), 113.5 (C-11), 57.7 (C-5), 57.2 (C-1), 50.1 (C-6), 32.9 (C-3), 27.5 (C-2), 21.3 (C-7). HRMS (ESI): [M+H] + C 21 H 21 N 2 ONa : calcd. 317.1653, found 317.1662.

  (C-Ar)), 78.7 (C-4), 58.4 (C-5), 57.4 (C-1), 50.2 (C-6), 33.1 (C-3), 26.2 (C-2), 21.3 (C-7). HRMS (ESI): [M+Na] + C 21 H 22 N 2 ONa : calcd. 341.1624, found 341.1637. Second diastereoisomer (697b): R f = 0.5 (PE/EtOAc 50/50). Mp = 136-138 °C (EtOAc) IR (KBr) ν max (cm -1 ) =

  13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 166.8 (C-10), 163.10 (C-17), 156.9 (C-2), 155.7 (C-4), 132.9 (C-6), 114.6 (C-1), 108.2 (C-3), 107.9 (C-5), 55.2 (C-20), 51.2 (C-16), 50.6 (C-11), 37.3 (C-15), 26.9 (C-14), 23.7 (C-13), 21.2 (C-12). HRMS (ESI): [M+Na] + C 15 H 0 N 2 O 3 Na : calcd. 299.1366 found 299.1359.

  2 (C-Ar)), 54.5 (C-7), 49.3 (C-14), 43.2 (C-13), 21.9 (C-11) 20.7(C-12). HRMS (ESI): [M+Na] + C 14 H 16-N 2 O 2 Na : calcd. 267.1103, found 267.1113.

  3 (C-Ar)), 55.3 (C-7), 49.8 (C-14), 37.2 (C-13), 23.2 (C-11), 20.6 (C-12). HRMS (ESI): [M+H] + C 20 H 20-N 3 O 6 S : calcd. 430.1067, found 430.1075.

  (C-Ar)), 112.9 (C-16) 55.3 (C-7), 50.0 (C-14), 37.0 (C-13), 26.0 (C-11), 21.6 (C-12). HRMS (ESI): [M+H] + C 16 H 19-N 2 O : calcd. 255.1491, found 255.1490.

  The history of MCRs returns back over 150 years with the Strecker (1850), 39 Hantzsch (1882), 40 Biginelli (1891),41

(

  ArN 2 X) to an electron-poor alkene, paved the way towards the development of aryl radical reactions. 55 More recently, Heinrich et al. 56 were able to develop successfully carbo-diazenylation reactions of olefins. Starting from aryl diazonium salts 73, which were reduced by TiCl 3 to aryl radical 75 with evolution of N 2 , the aryl radicals could add onto olefins 74 to form the nucleophilic intermediate radical 76, which was trapped directly by another molecule of aryl diazonium salts 73.

  58 Recently, Studer et al.59 were able to

57 Jasch, H.; Landais, Y.; Heinrich, M. R. Chem.

Eur. J. 2013, 19, 8411-8416. 58

(a)

[START_REF] Barton | Half a Century of Radical Chemistry[END_REF] Bridon, D.; Zard, S. Tetrahedron Lett. 1986, 27, 4309-4312;(b)

Ding, B.; Bentrude, W. G. J. Am. Chem. Soc. 2003, 125, 3248-3259; (c) Sato, A.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2006, 128, 4240-4241; (d) Wada, T.; Kondoh, A.; Yorimitsu, H.; Oshima, K. Org. Lett. 2008, 10, 1155-1157; (e) Shirai, T.; Kawaguchi, S.-I.; Nomoto, A.; Ogawa, A. Tetrahedron Lett. 2008, 49, 4043-4046; (f) Cossairt, B. M.; Cummins, C. C. New J. Chem. 2010, 34, 1533-1536; (g) Leca, D.; Fensterbank, L.; Lacôte E.; Malacria, M. Chem. Soc. Rev. 2005, 34, 858-865. 59 (a) Vaillard, S. E.; Mück-Lichtenfeld, C.; Grimme, S.; Studer, A. Angew. Chem. Int. Ed. 2007, 46, 6533-6539; (b) Lamas, M.-C.; Studer, A. Org. Lett. 2011, 13, 2236-2239.

  develop a 3CR-carbo-phosphorylation reaction, through addition of alkyl radicals 95, generated from the corresponding iodide 93, to unactivated olefins 94. The generated nucleophilic radical was trapped later by Me 3 SiPPh 2 or Me 3 SnPPh 2 to liberate silyl or stannyl radicals, which then propagate the radical chain. The phosphane product thus obtained was oxidized in situ by H 2 O 2 to form phosphinyl oxide product 98 (Scheme 31).

  Porta et al. 64 developed another radical version of the Mannich reaction using the system Ti III /Ti IV described above. The tert-butyl hydroperoxide (TBHP) was used as a source of tert-butoxy radical, which can abstract hydrogens in α-position of heteroatoms. The nucleophilic α-alkoxyalkyl radical thus generated can attack the generated in situ iminium to form aminoalcohols or

; Greco, C.; Clerici, A.; Punta, C.; Porta, O. Org. Lett. 2010, 12, 3898-3901. 63 Yamada, K.-I.; Yamamoto, Y.; Tomioka, K. Org. Lett. 2003, 5, 1797-1799. Chapter one: Free Radical Multi-Component Chemistry 55 Later, aminoethers (Scheme 34).

  Another radical anionic MCR mediated Cr II was described by Takai group.72 It relies on the fact that single electron transfers (SET) in the presence of Cr II salts are much faster with allylic radicals than with secondary or tertiary alkyl radicals. Thus, they developed 3-CR radical anionic reactions involving CrCl 2 , which reduces isopropyl iodide 129 through a one-electron reduction with Cr II ion,

One of the leading

examples in this type of reactions is the one developed by Mukaiyama in 1973 using (nBu) 3 B.

70

The reaction starts with the decomposition of (nBu) 3 B in the presence of O 2 to give the butyl radical which adds onto the Michael acceptor 118 to generate the enoyl radical 120. The latter then reacts with another molecule of Bu 3 B to give a boron enolate and a butyl radical, which propagate the radical chain. This enolate 121 reacts finally with benzaldehyde to give the aldol adduct 122 in good yield and moderate diastereoselectivity (Scheme 35).

More recently, Chemla et al.

71

exploited rate differences to design MCR cascade reaction. First, an alkyl radical, formed from the decomposition of dialkylzinc with oxygen was shown to add onto the double bond system of 123. This triggered a 5-exo-trig radical cyclization which is faster than the reduction of the enolate radical. Finally, homolytic substitution at the zinc center forms a zincate derivative 126 and an alkyl radical, which propagate the radical chain. A transmetallation of zinc with copper eventually initiates a S N 2 displacement of an allyl bromide 127 to give substituted pyrrolidines 128 in good yields and moderate diastereoselectivity (Scheme 36).

to form the isopropyl radical 132 which may then add regioselectively to 1,3-diene 130. Finally, SET from Cr II salt to the resulting allylic radical 133 forms allylchromium species 134 which add to 71 (a) Denes, F.; Chemla, F.; Normant, J. F. Angew.

Chem. Int. Ed. 2003, 42, 4043-4046;(b)

Denes, F.; Cutri, A.; Perez-Luna, A.; Chemla, F. Chem. Eur. J. 2006, 12, 6506-6513; (c) Perez-Luna, A.; Botuha, C.; Ferreira, F.; Chemla, F. Chem. Eur. J. 2008, 14, 8784-8788. 72 Takai, K.; Matsukawa, N.; Takahashi, A.; Fujii, T. Angew. Chem. Int. Ed. 1998, 37, 152-155.

1.5.2. Carbo-allylation depending on Sulfonyl Radical Renaud

  et al.88 provide recently a nice example of the utility of allylsulfones, using organoboranes derivatives as radical precursors. The reaction starts by the addition of nucleophilic alkyl radical, resulting from the corresponding catecholborane 167, to the electron poor olefin to give the electrophilic radical intermediate 171 which is trapped by the allylsulfone 169 to give the allylated product 173 and phenylsulfonyl radical that sustains the radical chain by reacting with the starting

borane 167 (Scheme 45).

Zard et al.

89

also developed allylthiophenemethylsulfone 174, which undergoes α-scission to give the nucleophilic radical 177. This radical adds onto the electron poor olefin 175 to give the electrophilic radical 178, which is finally trapped by another molecule of sulfone 174 to give the allylated product 179 (Scheme 46). 88 Schaffner, A. P.; Sarkunam, K.; Renaud, P. Helv. Chim. Acta 2006, 89, 2450-2461. 89 Bertrand, F.; Le Guyader, F.; Liguori, L.; Ouvry, G.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. C. R. Acad. Sci., Ser. IIC: Chem. 2001, 4, 547-555.

1.5.3. Carbo-alkenylation and alkynylation

  Addition of alkenyl or alkylnyl groups across olefin backbones remained for a long time a difficult task. Pioneering studies in this direction came from Fuchs et al.87 who incorporated alkenyl or alkynyl groups to ethers or alkanes 181 using vinyl-and alkynyltriflone derivatives 180.

	The radical
	process starts by a C-H abstraction by the very electrophilic trifluoromethyl radical 182. The
	resulting nucleophilic alkyl radical 183 then adds onto the alkenyl-or alkynyltriflone 180, followed
	by the β-elimination of the unstable trifluoromethanesulfonyl radical, which decomposes into SO 2
	and the trifluoromethyl radical 182 that sustains the radical chain (Scheme 47).
	More recently, Renaud et al. 90 developed a carbo-alkenylation and alkynylation of various olefins
	using organoboranes as a source of alkyl radicals. The reaction starts with the hydroboration of the
	corresponding olefins and formation of intermediates 186. The alkyl radicals, generated by addition
	of sulfonyl radical or t-butoxide radical (from DTBHN initiator) onto the borane, then add onto the

sulfone derivatives 187 to give, after β-elimination of the phenylsulfonyl moiety, the alkenylated or alkynylated products 188 in good yields (Scheme 48).

	The last two examples showed the progress in the alkenylation and alkynylation of olefins. But these
	methods showed some limitations either for using CF 3 group in the first example or using
	catecholboranes in the second one. Recently our group developed new free-radical three-component
	carbo-alkenylation and alkynylation of olefins in which two functional groups could be added across
	the π-system of unactivated olefins. 91
	90 Schaffner, A. P.; Darmency, V.; Renaud, P. Angew. Chem. Int. Ed. 2006, 45, 5847-5849.

91

Liautard, V.; Robert, F.; Landais, Y. Org.

Lett. 2011Lett. , 13, 2658Lett. -2661. .

1 224 was established. 96 Based on the stereocontrolled carbo-azidation reaction of chiral allylsilane 222 as key step, the authors established their synthesis (Scheme 55).

96 Chabaud, L.; Landais, Y.; Renaud, P.Org. Lett. 2005, 7, 2587-2590.

1.5.5. Carbo-oximation Kim

  et al.97 first showed that sulfonyloximes are good radical traps. They demonstrated that the addition of alkyl radical 228, generated from the corresponding alkyl halide 225, onto sulfonyloxime 226 affords, after β-elimination of the phenylsulfonyl radical, the alkylated oxime 227 (Scheme 56).

	These oximes are very useful intermediates for the synthesis of the corresponding carbonyls.
	Actually Kim's first trials 97 were to develop radical mediated acylation reactions. But due to the
	reversible addition of alkyl radicals to C=O as a consequence of the higher π-bond strength of the
	C=O bond, these trials were unsuccessful. Therefore, sulfonyloximes, are excellent surrogates of
	carbonyl radical acceptors. Based on this methodology, the hydrolysis of oxime 227 in
	formaldehyde and HCl gave access to the corresponding aldehyde or ketone 230 depending on the
	R 2 substituent (Scheme 56).

prepare xanthate quinoline derivative 270, either from the corresponding iodoquinoline 268 or from quinoline derivative 267, by reaction with bi-xanthate 110 were unfortunately not successful (Scheme 69).

	Unfortunately, the reaction was not successful; the starting iodoquinoline 264 was consumed, but no
	major product could be isolated. The presence of a benzyl group which could generate benzyl
	radical and lead to undesired products may have caused this failure.
	In order to save time and efforts, we turned our attention to the commercially available methyl
	protected quinoline 267. Iodination of methyl quinoline derivative 267 by NIS in MeCN worked
	well with yield up to 66%, in good agreement with the previously reported product. 109a With this
	iodinated quinoline 268, the carbo-oximation reaction was tested again with allylsilane 265 and
	sulfonyl oxime 233 (Scheme 68), but again, the reaction was not successful.
	Sheibani, H.; Mosslemin, M. H.; Behzadi, S.; Islami, M. R.; Saidi, K. Synthesis 2006, 3, 435-438. 109 (a) Barr, S. A.; Neville, C. F.; Grundon, M. F.; Boyd, D. R.; Malone, J. F.; Evans, T. A. J. Chem. Soc. Perkin Trans. 1 1995, 445-452; (b) Reisch, J.; Nordhaus, P. Monatshefte für Chemie,1994, 125, 225-231; Further trials to 110 (a) Shi, L.; Chapman, T. M.; Beckman, E. J. Macromolecules 2003, 36, 2563-2567; (b) Gagosz, F.; Zard,
	(c) Bossharth, E.; Desbordes, P.; Monteiro, N.; Balme, G. Tetrahedron Lett. 2009, 50, 614-616. S. Z. Synlett 2003, 3, 387-389.

Table 2 .

 2

	Entry	X	R 1	Olefin	Yield
				N. of. Eq.	(%)
	1 2 3 4	SC(S)OEt SC(S)OEt SC(S)OEt SC(S)OEt CH 2 OTBDMS CO 2 Et CO 2 Et CH 2 OBz	4.0 10.0 4.0 4.0	46 a 35 a 0 b 10 a
	5	I	CO 2 Et	4.0	26

149

Based on this premises, α-iodoethylester 324 was used instead of xanthate ester (entry 5, table 2). Surprisingly, despite of the formation of the expected iodine-tin solid residues that gave cleaner reaction, the yield decreased dramatically to 26% (entry 5, table 2). a with formation of the byproduct 322 in 15%. b formation of reduction product 323

Table 3 .

 3 degraded.151 Milder conditions were tried, but unfortunately, all of them failed. The typical reducing agents for ethyl ester group are LiAlH 4 or DIBAL-H, but these agents will also reduce the amide functional group, a reaction we wanted to avoid. Screening of reduction solvents and temperature.

	Entry	Solvent	Temp.	Yield
			°C	(%)
	1	THF/MeOH (1:1)	65	0
	2	THF/MeOH (1:1)	r.t.	0
	3	MeOH	r.t.	0
	4	THF	r.t.	0
	5	THF	65	0

By using NaBH 4 in different combinations of solvent (table 3), no trace of the desired product was observed. The described condition for reduction of ethyl ester into the corresponding alcohol in the presence of amide is NaBH 4 in mixture of THF/MeOH (1:1) at 65 °C was not successful and starting piperidinone ester 150 Gualtierotti, J.-B.; Pasche, D.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2014, 53, 9926-9930.

was

  169

169 Ghosez, L.; George-Koch, I.; Patiny, L.; Houtekie, M.; Bovy, P.; Nshimyumukiza, P.; Phan, T.

Tetrahedron 1998, 54, 9207-9222.

  175

173 Beng, T. K.; Wilkerson-Hill, S. M.; Sarpong, R. Org.

Lett. 2014, 16, 916-919. 174

Enamines: Synthesis, Structure and Reactions; Cook, A. G., Ed.; Marcel Dekker: New-York and London, 1969. 175 Doering, W. v. E.; Birladeanu, L.; Andrews, D. W.; Pagnotta, M. J. Am. Chem.

Soc. 1985, 107, 428-435.

  369 and a catalytic amount of TFA-d in CD 2 Cl 2 . The amidine 382 was isolated in lower yield (57%) but without any incorporation of deuterium at C-2 (Scheme 126), the structure of this amidine being established though extensive 1 H and 13 C NMR studies and confirmed by HRMS.

Wiseman, J. R. J. Am.

Chem. Soc. 1967, 89, 5966-5968.

chloroenamine

Table 4 .

 4 Optimization of Amidine Cyclization. (a) brsm Chapter two: Total Synthesis of Eucophylline 115With this amino naphthyridine 402 in hand, the installation of vinylic fragment was planned relaying on a Suzuki coupling with diazonium salts derived from this amino naphthyridine 402.178 Due to the modest yields obtained with model compounds, an alternative strategy using triflate was developed.Therefore, the diazotation of the amino naphthyridine 402 was performed in sodium nitrite and sulfuric acid, followed by hydrolysis to give the corresponding alcohol 403. After reaction of the latter with Comins' reagent, 179 the corresponding triflate 404 was obtained in quantitative yield Also the 13 C NMR is in good agreement with the one reported for natural Eucophylline. HRMS of the synthesized Eucophylline is [M+H] + = 295.1814 in good agreement with that reported for natural Eucophylline 295.1816.

	Entry	base	Base Eq.	Temp.	time Yield% (a)
				°C
	1	t-BuOK	2.65	25	3	20(59)
	2	t-BuOK	2.65	25	16	21(53)
	3	LDA	2.65	-78	3	44(79)
	4	LDA	3	-78	3	35(64)
	5	LDA(neat)	3	25	3	56(88)
	6	LDA(neat)	3	25	16	70

(Scheme 134).

With this triflate 404 in hand, the installation of vinylic moiety was carried out through the Suzuki coupling with commercially available vinyl trifluoroborate 405 in the presence of potassium carbonate to afford the desired vinyl naphthyridine 406 in 80% yield (Scheme 135).

180

To achieve the synthesis of Eucophylline 3, O-demethylation of vinyl naphthyridine 406 was performed with BBr 3 which worked in an excellent 87% yield (Scheme 136).

The synthesized (±)-Eucophylline analytical data are in good agreement with those found for the natural product isolated by Morita et al.102 The 1 H NMR spectra of both natural and synthesized Eucophylline showed good agreement (Figure

8

).

  1, has been reported in 10 steps from α-iodothioester 337 and in a 10% overall yield relying on the recently developed carbo-oximation free radical reaction. This total synthesis also includes a new straightforward method to access the azabicyclo[3.3.1]nonane skeleton. The unique reactivity of twisted amides, present in the bicyclic lactams, allowed us to isolate and functionalize a remarkably stable bicyclic α-chloroenamine intermediate, illustrating again the importance of the conjugation of the nitrogen's lone-pair electron position in the reactivity of amides and enamines. This total synthesis, the study on the bridgehead bicyclic lactam and α-chloroenamine intermediate were the topic of a recently published article in Organic Letters in 2015.181

181 Hassan, H.; Mohammed, S.; Robert, F.; Landais, Y. Org.

Lett. 2015, 17, 4518-4521.

  Eburnane skeleton also constitutes the half part of several pharmacologically active bisindole alkaloids like Pleiomutine 411, Kopsoffine 412 and

	Leuconoline 413 (Scheme 138). 186,187
	182 England, D. B.; Padwa A. J. Org. Chem. 2008, 73, 2792-2802.
	183 Hava, M. The Pharmacology of Vinca species and their Alkaloids, The Vinca Alkaloids; Taylor, W. I.,
	Farnsworth, N. R., Eds.; Marcel Dekker: New York, 1973; Chapter 6, p 305.

184

Ho, T-L.; Chen, C-K Helv.

Chim. Acta 2005, 88, 2764-2770. 185

Van Beek, T. A.; Verpoorte, R.; Baerheim, Svendsen, A. Tetrahedron 1984, 40, 737-748. 186 Lounasmaa, M.; Tolvanen, A. The alkaloids; Cordell G. A., Ed.; Academic press, New York, 1992, Vol. 42, chapter 1. 187 (a) Feng, X. Z.; Kan, C.; Husson, H.-P., Potier, P.; Kan, S.-K.; Lounasmaa, M. J. Nat. Prod. 1984, 47, 117-122; (b) Gan, C.-Y.; Low, Y.-Y.; Robinson, W. T.; Komiyama, K.; Kam, T.-S. Phytochemistry 2010, 71, 1365-1370.

  Narayanan, B. A.; Bunnelle, W. H. Tetrahedron Lett. 1987, 28, 6261-6264.

202

Paterson, I.; Cumming, J. G.; Smith, J. D.; Ward, R. A. Tetrahedron

Lett. 1994, 35, 441-444. 203

Alexakis, A.; Normant, J. F. J. Organometallic

Chem. 1975, 96, 471-485.

  Me 3 Si) 3 SiCN 620 could be a source of electrophilic nitrile and the (Me 3 Si) 3 Si part could propagate the radical chain. This hypothesis is based on the results obtained in the group with

allyl(tristrimethylsilyl)silane 621 which was used to propagate the radical chain in 2-CR carbooximation, alkenylation, and allylation process.

227

The mechanism of this TTMS propagation starts with generation of TTMS radical from the corresponding allyl(tristrimethylsilyl)silane 621 followed by halogen abstraction from alkyl halide 622 by the (Me 3 Si) 3 Si radical 629. The generated nucleophilic alkyl radical 626 adds onto the sulfonyl acceptor 623 to afford the desired product 624 and release of phenylsulfonyl radical 630. The latter can then react with the electron-rich allyl(tristrimethylsilyl)silane 621 to generate the allylsulfone 628 and regenerate TTMS radical 629, which sustains the radical chain (Scheme 188).

226

Pews, R. G.; Corson, F. P. J.

Chem. Soc. D., Chem. Comm. 1969, 1187. 227

Rouquet, G.; Robert, F.; Méreau, R.; Castet, F.; Landais, Y. Chem. Eur. J. 2011, 17, 13904-13911.

Table 5 .

 5 Acid and temperature Screen for reaction between lactol 639 and tryptamine

	Entry	Acid (eq.)	Temperature	Product 642	Product 641
			(°C)	(%)	(%)
	1	AcOH (2.0 eq.)	60	N/A	N/A
	2	AcOH (2.0 eq.)	90	N/A	N/A
	3	AcOH (2.0 eq.)	110	95 (d.r. 1:1)	N/A
	4	AcOH (0.2 eq.)	110	N/A	N/A
	5	TFA (0.2 eq.)	60	N/A	N/A
	6	TFA (0.2 eq.)	90	N/A	N/A
	7	TFA (0.2 eq.)	110	N/A	N/A
	8	(R)-BINOL-phosphate (0.2 eq.)	60	N/A	N/A
	9	(R)-BINOL-phosphate (0.2 eq.)	90	N/A	N/A
	10	(R)-BINOL-phosphate (0.2 eq.)	110	Partial	N/A
				conversion

  through a neutral azabenzofulvene. The protonation of the tertiary amino group may stop its competitive single electron oxidation. In contrast, in the case of simplified indoles 680, the coupling with electron-rich aromatics, or with Vindoline, afforded the expected coupling products in good yields, which indicates that removal of the tertiary amino group as well as N-methylation did not preclude coupling with Vindoline 12 (Scheme 227). All of these observations indicate that Fe(III)-mediated oxidation is sufficient for the coupling reaction to occur and reveal that the reaction does not require the presence of the indole free NH or the participation of Catharanthine tertiary amino group. Therefore, since the reaction no longer requires the reduction of catharanthine-derived iminium ion in the reaction product, NaBH 4 is no longer required for the reductive workup of this reaction. For sure, in the case of simplified indoles 680, the reaction provided a mixture of

	In 1994, Passarella et al. 246 developed a biomimetic coupling between eburnamine 409 and 11-
	diastereomer, which confirms that the C16′ stereochemistry set in vinblastine Fe(III)-promoted methoxytabersonin 691 in the course of a model study to access modified Vinblastine-type
	coupling reaction is principally controlled by Catharanthine. antitumor alkaloids. The coupling was performed in 3% HCl / MeOH solution to give the binary
	alkaloid 692 in 65% yield (Scheme 231).
	Moreover, it was confirmed that Vindoline 12 is susceptible to aromatic substitution by electrophilic
	carbon radicals. Treatment of Vindoline 12 with the radical generated from radical precursor
	ICH 2 CO 2 Et or BrCH(CO 2 Et) 2 gave the aromatic substitution products 687, arising from the addition
	of the electrophilic radical to vindoline aromatic ring, followed by rearomatization through air
	oxidation (Scheme 228). The electrophilic radical substitution reaction of Vindoline 12 in protic
	solvents supported the fact that Fe(III)-promoted reactions with Catharanthine in water follow a
	radical pathway rather than a route involving an azabenzofulvene intermediate, as previously (Scheme 230). In this example, the authors showed the possibility to couple two different alkaloidal
	suggested. monomers to form a non-natural bisindole structure, which suggests a generality for this type of
	biomimetic couplings.

The reaction is 241 Vukovic, J.; Goodbody, A. E.; Kutney, J. P.;

Misawa, M. Tetrahedron 1988, 44, 325-331. 242

Langlois, N.; Gueritte, F.; Langlois, Y.; Potier, P. J. Am.

Chem. Soc. 1976, 98, 7017-7024. 243

Gotoh, H.; Sears, J. E.; Eschenmoser, A.; Boger, D. L. J. Am. Chem. Soc.

2012, 134, 13240-13243

. proceeding In 1985, Magnus and Brown developed a biomimetic coupling reaction between Eburnamine 409 and (-)-Kopsinine 688 by refluxing the two fragments in 2% aqueous HCl to afford the bisindole alkaloid, (-)-norpleiomutine 689 (Scheme 229). 244 In 1993, Szántay et al. 245 also developed a biomimetic coupling between Eburnamine 409 and Vindoline 12 in a mixture of HCl / MeOH to give the Aspidosperma-Eburnane Bisindole 690 244 Magnus, P.; Brown, P. J. Chem. Soc., Chem. Commun. 1985, 184-186 245 Honty, K.; Szántay, C. Jr.; Kolonits, P.; Demeter, Á.; Szántay, C. Tetrahedron 1993, 49, 10421-10426.

Table 6

 6

	Entry	Reagent	Additives	Solvent	Temperature	Time	Results
		/ (eq.)	/ (eq.)		°C
	1	BF 3 . Et 2 O	---	THF	r.t.	24 h The minor diastereoisomer of the north
		(1.5 eq.)					fragment 697b and the starting quinolinol 714.
	2	BF 3 . Et 2 O	TFAA	MeOH	r.t.	40 h The minor diastereoisomer of the north
		(5.0 eq.)	(1.0 eq.)				fragment 697b and the starting quinolinol 714.
	3	FeCl 3	---	MeOH	r.t.	24 h The minor diastereoisomer of the north
		(5.0 eq.)					fragment 697b and the starting quinolinol 714.

). 256 Cheval, N. P.; Dikova, A.; Blanc, A.; Weibel, J.-M.; Pale, P. Chem. Eur. J. 2013, 19, 8765-8768. 257 (a) Molander, G. A.; Rodriguez Rivero, M. Org. Lett. 2002, 4, 107-109; (b) Darses, S.; Michaud, G.; Gene t, J. P. Tetrahedron Lett. 1998, 39, 5045-5048.

Table 6 .

 6 Screening Different Acidic Conditions for Biomimetic Coupling between North Model 697a-b and Quinolinol 714.

a using the minor diastereoisomer of the North Model.

  265

264 Nguyen, T. B.; Sorres, J.; Tran, M. Q.; Ermolenko, L.; Al-Mourabit, A. Org.

Lett. 2012, 14, 3202-3205. 265

Bon, E.; Bigg, D. C. H.; Bertrand, G. J.

Org. Chem. 1994, 59, 4035-4036.

  ).

	Mp = 170°C (DCM).
	R f = 0.45 (PE/EtOAc 50/50). IR (KBr) ν max (cm -1 ) = 3349, 2976, 2928, 1647, 1540, 1088, 1044.
	H NMR (CDCl 3 , 300 MHz): δ (ppm) = 8.05-8.02 (dd, 1H, J = 12, 15, 78 Hz, H-1), 7.66-7.61 (m, 1H, H-2),
	7.39-7.36 (d, 1H, J = 9 Hz, H-6), 7.28-7.23 (dd, 1H, J = 9.9, .0.9, 15.3 Hz, H-3), 3.78 (s, 3H, H-10).

  M+Na] + C 12 H 15 NO 3 Na : calcd. 244.0944, found 244.0954.

	, 7.7(C-6).
	HRMS (ESI): [M+Na] + C 21 H 31 NO 5 Na : calcd. 400.2094, found 400.2104.
	Ethyl 3-((benzyloxy)imino)propanoate (322)
	(E/Z ration 65/35)
	R f = 0.71 (PE/EtOAc 90/10). IR (ATR) ν max (cm -1 ) = 3087, 3063, 3031, 2924, 2869, 1738, 1631, 1454, 1396, 1181, 1094. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.61(t, 1H, J = 6.3 Hz, H-5, Z-isomer), 7.43-7.31 (m, 5H, H-7), 7.7
	(t, 1H, J = 4.8 Hz, H-5, E-isomer), 5.18, 5.13 (s, 2H, H-6, E/Z), 4.21 (qd, 2H, J = 7.2 Hz, H-2), 3.45, 3.29 (d,
	2H, J = 4.8, 6.3 Hz, H-4, E/Z), 1.30 (td, 3H, J = 7.2 Hz, H-1, E/Z).
	13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 169.2 (C-3E), 144.3 (C-5Z), 143.8 (C-5E), 137.5 (C-7), 128.4 (C-7),
	128.2 (C-7), 128.0 (C-7), 127.9 (C-7), 76.1 (C-6E), 75.9 (C-6Z), 61.2 (C-2Z), 61.1 (C-2E), 35.2 (C-4Z), 31.6
	(C-4E), 14.2 (C-1EZ).
	HRMS (ESI): [

  M+Na] + C 32 H 41 NO 2 NaSi : calcd. 522.2798, found 522.2783.

	, 26.8 (C-
	12), 24.7 (C-2), 19.1 (C-7), 8.7 (C-8).
	HRMS (ESI): [

  , 24.7 (C-2), 19.1 (C-7), 8.7 (C-8). HRMS (ESI): [M+Na] + C 26 H 37 NO 4 NaSiS: calcd. 510.2104, found 510.2095.

  M+Na] + C 19 H 26 N 2 O 2 Na : calcd. 337.1886, found 337.1895.

	3 (C-6), 31.2 (C-3), 29.7 (C-2), 22.9 (C-11), 19.3
	(C-8), 8.2 (C-9)
	HRMS (ESI): [

  ). HRMS (ESI): [M+H] + C 24 H 34-N 3 O : calcd. 380.2696, found 380.2695.

Sur la base de cette réaction de carbo-cyanation, deux approches ont été développées afin d'accéder au motif éburnane 2, le fragment nord de la Leucophyllidine 1. La première met en jeu une réaction de Pictet-Spengler entre la tryptamine et l'aldéhyde 653a-b entièrement fonctionnalisé, et obtenu à partir du nitrile 579a correspondant. Malheureusement, la réaction n'a pas conduit au produit attendu, les aldéhydes étant difficiles à isoler sous forme pure (Schéma VI).

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Conclusion & PerspectivesConclusion & Perspectives

Conclusion & Perspectives

This carbo-cyanation reaction and the new straightforward sequence, used in construction ofazabicyclo[3.3.1]nonane 37, open the door for constructing and functionalizing nitrogen bridgehead bicycles with different sizes relying on versatility of the carbo-cyanation MCR. Moreover, taking benefit from the reactivity of twisted amides present in these bicyclic systems, their functionalization should give rise to bicyclic enamines, generated by reaction with POCl 3 .266 The stability of these enamines will depend on the ring size of bicyclic systems (Scheme 267).On the Eburnane side, the use of olefin 732 in the carbo-cyanation process will hopefully lead to a product bearing a methyl ester in the side chain of lactam 515, which will be more reliable and 266 (a) Bassler, D. P.; Spence, L.; Alwali, A.; Beale, O.; Beng, T. K. Org.Biomol. Chem., 2015, 13, 2285- 2292;(b) Beng, T. K.; Wilkerson-Hill, S. M.; Sarpong, R. Org. Lett. 2014, 16, 916-919; (c) Haveaux, B.; Dekoker, A.; Rens, M.; Sidani, A. R.; Toye, J.; Ghosez, L. Org. Synth. 1979, 59, 26.

(a) Herrmann, J. L.; Cregge, R. J.; Richman, J. E.; Kieczykowski, G. R.; Normandin, S. N.; Quesada, M. L.; Semmelhack, C. L.; Poss, A. J.; Schlessinger, R. H. J. Am. Chem.Soc. 1979Soc. , 101, 1540Soc. -1544;;(b) Lancefield, C. S.; Zhou, L.; Lébl, T.; Slawin, A. M. Z.; Westwood, N. J. Org. Lett. 2012, 14, 6166-6169.

Kim, S.; Lee, I. Y.; Yoon, J. Y.; Oh, D. H. J. Am. Chem.Soc. 1996, 118, 5138.

Yost, J. M.; Alfie, R. J.; Tarsis, E. M.; Chong, I.; Coltart, D. M., Chem. Commun. 2011, 47, 571.

Acknowledgements

Chapter Three

Eburnane Synthesis

PCC, after treating by BF 3 -OEt 2 , to afford the desired (-)-Eburnamonine 408 (Scheme 145). In 1994, Plamisano et al. 194 accessed (-)-eburnamonine 408 through a [3,3]-allyl vinyl ether-type rearrangement (Claisen rearrangement) of the enantiopure β-alkoxy acrylate 470. Preparation of βalkoxy acrylate 470 started from achiral hydroxyl compound 469, which underwent enzyme kinetic resolution by immobilized Pseudomonas cepacia lipase in neat vinyl acetate to give (S)-469. The latter then reacted with methyl propiolate to give 470. After tandem decarboxylation-rearrangement sequence of 470, the aldehyde 471 was obtained. Reduction of this aldehyde to alcohol 472 and protection of this alcohol as a 4-methoxybenzyl ether (PMB), followed by allylic oxidation by Cr(CO) 6 / t-BuOOH gave enone 474. Osmylation of this enone by OsO 4 and N-methylmorpholine N-oxide (NMO) followed by glycol cleavage with Pb(OAc) 4 gave the expected aldehyde 475 in 72%. Refluxing this aldehyde with tryptamine in AcOH gave the tetracyclic lactam 463a,b in (d.r. When then performed separately the DIBAL-H reduction of nitrile into aldehyde, followed by in situ cyclization, which gave the lactol 639 in 74% yield and a 3:1 diastereomeric ratio (Scheme 195).

With lactol 639 in hand, the Pictet-Spengler reaction between this masked aldehyde and tryptamine was attempted. Therefore, lactol 639 was treated with tryptamine under acidic conditions in DCM at room temperature. Unfortunately, the Pictet-Spengler product 641 was not observed neither in presence of TFA nor AcOH. But surprisingly, when the reaction was performed in toluene under reflux at 110°C for 16 h and in the presence of AcOH, 230 the tetracyclic core of an Eburnane-type compound 642 was isolated in 95% yield as a 1:1 mixture of two separable diastereoisomers.

However, as shown later by X-ray diffraction studies, this cyclization had placed the quaternary center away from the indole ring (Scheme 196).

The formation of this isomer of Eburnane 642 was not expected. To confirm the structure of the tetracyclic core of 642, one of the two diastereoisomers was allowed to undergo deprotection of the silyl ether group by TBAF to give the hydroxyl-free tetracyclic core of eburnane 643, with inverted quaternary center, in 71% yield. The structure of this tetracyclic core was confirmed by X-ray diffraction studies (Scheme 197).

Chapter Four Preliminary Results on Biomimetic Coupling

Experimental Part

Carbo-Cyanation Reaction

General Procedure:

To a solution of radical precursor (1.0 eq.) in dry benzene (1.0 M), olefin (4.0 or 2.0 eq.), p-toluenesulfonyl cyanide 570 (2.0 eq.), di(tributyl)tin (1.5 eq.) were added, the reaction mixture was degassed for 20 min. Then, the reaction was initiated by adding DTBHN (20 mol%). The reaction mixture was then stirred for 1.5 h at 65°C. The reaction progress was monitored by TLC and another addition of DTBHN (20 mol%) was done then the reaction mixture was stirred for another 1.5 h at 65 °C. After 3h, the mixture was concentrated under reduced pressure and the residue purified by chromatography on silica gel.

Ethyl 4-cyano-4-ethyl-7-oxo-7-(phenylthio)heptanoate (579b) Synthesized according to the general procedure from α-iodophenylester 337 (133.5 mg, 0.48 mmol, 1.0 eq.), olefin 252 (300 mg, 1.92 mmol, 4.0 eq.), p-toluenesulfonyl cyanide 570 (173.9 mg, 0.96 mmol, 2.0 eq.), di(tributyl)tin (417 mg, 0.72 mmol, 1.5 eq.) and DTBHN (16.7 mg, 0.09 mmol). The crude faint yellow oil was purified by chromatography on silica gel (PE/EtOAc 90/10). The desired nitrile product 579b was obtained as yellow oil (112 mg, 70%). R f = 0.25 (PE/EtOAc 90/10). IR (ATR) ν max (cm -1 ) = 3062, 2974,2939,2233,1731,1714,1584,1478,1422,1379,1304.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.40-7.34 (m, 5H, Ar), 4.14 (q, 2H, J = 6.9 Hz, H-6), 2.83-2.78 (m, 2H, H-4), 2.47-2.42 (m, 2H, H-11), 1.99-1.91 (m, 4H, H-3, H-10), 1.63 (q, 2H, J = 7.5 Hz, H-8), 1.25 (t, 3H, J = 7.2 Hz, H-7), 1.03 (t, 3H, J = 7.5 Hz, H-9).

1-Ethyl 7-phenyl 4-cyano-4-ethylheptanedioate (579c)

Synthesized according to the general procedure from α-iodophenylester 580 (62 mg, 0.33 mmol, 1.0 eq.), olefin 252 (150 mg, 0.96 mmol, 4.0 eq.), p-toluenesulfonyl cyanide 570 (119.5 mg, 0.66 mmol, 2.0 eq.), di(tributyl)tin (208.9 mg, 0.36 mmol, 1.5 eq.) and DTBHN (8.3 mg, 0.04 mmol). The crude faint green oil was purified by chromatography on silica gel (PE/EtOAc 90/10). The desired nitrile product 579c was obtained as faint green oil (46 mg, 60%). R f = 0.29 (PE/EtOAc 90/10). 2960,2232,1757,1732,1593,1493,1456,1420,1379.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.41-7.07 (m, 5H, Ar), 4.16 (q, 2H, J = 6.9 Hz, H-6), 2.77-2.72 (m, 2H, H-4), 2.52-2.47 (m, 2H, H-11), 2.03-1.97 (m, 4H, H-3, H-10), 1.66 (q, 2H, J = 7.5 Hz, H-8), 1.27 (t, 3H, J = 7.2 Hz, H-7), 1.07 (t, 3H, J = 7.5 Hz, H-9). R f = 0.37 (PE/EtOAc 80/20). IR (ATR) ν max (cm -1 ) = 3069,2956,2924,2871,2854,2237,1586,1447,1427,1377,1308,1377,1308. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.88-7.85 (m, 2H, Ar), 7.60-7.38 (m, 8H, Ar), 3.29-3.08 (m, 2H, H-6), 2.68-2.63 (m, 1H, H-1), 2.07-1.93 (m, 2H, H-5), 1.21-1.16 (m, 1H, H-3a), 1.05-0.98 (dd, 1H, J = 5.4, 14.7 Hz, H-3b), 0.42-0.38 (d, 6H, J = 12 Hz, H-4). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (138.7, 136.6, 134.0, 133.5, 129.7, 128.5, 128.2, 127.9 (C-Ar)), 121.5 (CN), 53.5 (C-6), 28.7 (C-5), 26.2 (C-1), 19.9 (C-3), (-2.4, -3.2 (C-4) (145.6, 136.3, 135.2, 133.6, 130.2, 129.7, 129.3, 128. 2,2-Diethyl-4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundecanenitrile (579n) Synthesized according to the general procedure from perfluorooctyl iodide 581 (80 mg, 0.146 mmol, 1.0 eq.), olefin 582 (49.33 mg, 0.586 mmol, 4.0 eq.), p-toluenesulfonyl cyanide 570 (31.86 mg, 0.175 mmol, 1.2 eq.), di(tributyl)tin (127.5 mg, 0.21 mmol, 1.5 eq.) and DTBHN (5.1 mg, 0.02 mmol). The crude faint yellow oil was purified by chromatography on silica gel (PE/EtOAc 98/02). The desired nitrile product 579n was obtained as colorless oil (45 mg, 58%). R f = 0.32 (PE/EtOAc 98/02). IR (ATR) ν max (cm -1 ) = 2956, 2924,2857,2237,1720,1582,1479,1460,1441,1374,1290.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 2.36 (t, 2H, J = 19.2 Hz, H-5), 1.84 (q, 4H, J = 7.5 Hz H-3, H-6), 1.08 (t, 6H, J = 7.5 Hz, H-4, H-7).

13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = (129.4, 129.1, 126.9, 124.9 (C-F)), 121.6 (CN), 38.5 (C-1), (34.7, 34.4, 34.1 (C-5)), 29.2 (C-3, C-6), 8.5 (C-4, C-7). HRMS (ESI): [M+Na] + C 15 H 12 NF 17 Na: calcd. 552.0590, found 552.0609.

S-Phenyl 4-cyano-4-methoxypentanethioate (579o)

Synthesized according to the general procedure from α-iodothioester 337 (80 mg, 0.287 mmol, 1.0 eq.), olefin 730 (82.9 mg, 1.15 mmol, 4.0 eq.), p-toluenesulfonyl cyanide 570 (104.3 mg, 0.57 mmol, 2.0 eq.), di(tributyl)tin (250.3 mg, 0.43 mmol, 1.5 eq.) and DTBHN (10.0 mg, 0.05 mmol). The crude faint yellow oil was purified by chromatography on silica gel (PE/EtOAc 95/05). The desired nitrile product 579o was obtained as colorless oil (51 mg, 72%

S-Phenyl 4,5-dicyanopentanethioate (579p)

Synthesized according to the general procedure from α-iodothioester 337 (80 mg, 0.287 mmol, 1.0 eq.), allyl cyanide 731 (77.19 mg, 1.15 mmol, 4.0 eq.), p-toluenesulfonyl cyanide 570 (104.3 mg, 0.57 mmol, 2.0 eq.), di(tributyl)tin (250.3 mg, 0.43 mmol, 1.5 eq.) and DTBHN (10.0 mg, 0.05 mmol). The crude faint yellow oil was purified by chromatography on silica gel (PE/EtOAc 70/30). The desired nitrile product 579p was obtained as colorless oil (57 mg, 81%). R f = 0.5 (PE/EtOAc 70/30). IR (ATR) ν max (cm -1 ) = 3060,2930,2875,0857,2247,1701,1478,1440,1419.

S-Phenyl 3-((2S,5R)-1-cyano-2-isopropyl-5-methylcyclohexyl)propanethioate (584f)

Synthesized according to the general procedure from α-iodothioester 337 (91.3 mg, 0.328 mmol, 1.0 eq.), terpene 588 (200 mg, 1.31 mmol, 4.0 eq.), p-toluenesulfonyl cyanide 570 (119 mg, 0.65 mmol, 2.0 eq.), di(tributyl)tin (285.7 mg, 0.492 mmol, 1.5 eq.) and DTBHN (11.4 mg, 0.06 mmol). The crude faint yellow oil was purified by chromatography on silica gel (PE/EtOAc 98/02). The desired nitrile product 584f was obtained as colorless oil (52 mg, 48%). R f = 0.23 (PE/EtOAc 98/02). IR (ATR) ν max (cm -1 ) = 3061, 2955,2929,2870,2228,1709,1478,1456,1441,1414,1390.

Ethanesulfonyl bromide (618)

A mixture of Na 2 SO 3 (1.260 g, 10 mmol, 1.0 eq.), and NaHCO 3 (1.680 g, 20 mmol, 2.0 eq.) in H 2 O (40 mL) was stirred and degased before addition of ethylsulfonyl chloride 616 (1.28 g, 10 mmol, 1.0 eq.). The reaction was stirred at room temperature for 26 h. After that, cyanogen bromide (2.183 g, 20 mmol, 2.0 eq.) was added to the reaction mixture in one portion with vigorous stirring at 0 °C and then the reaction mixture was stirred for 1 h at this temperature. The mixture was extracted with DCM (40 mL) and the aqueous layer was extracted again with EtOAc, then the organic extracts were washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the crude yellow oil was purified by chromatography on silica gel (PE/EtOAc 90/10). Ethanesulfonyl bromide 618 was obtained as colorless oil (917 mg, 53%) instead of the desired ethanesulfonyl cyanide. R f = 0.70 (PE/EtOAc 90/10). IR (ATR) νmax (cm-1) = 2985,2944,2924,2878,1455,1400. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 3.73 (q, 2H, J = 6.9 Hz, H-1), 1.45 (t, 3H, J = 7.5 Hz, H-2). 13 C NMR (CDCl3, 75 MHz): δ (ppm) = 64.2 (C-1), 9.6 (C-2). HRMS (CI): [M+H] + C 2 H 5 O 2 SBr : calcd. 172.92, found 172.9, 174.9 two isotopes of bromine. R f = 0.42 (EtOAc 100%)., IR (ATR) ν max (cm -1 ) = 3420,2968,2932,2876,1718,1629,1550,1440,1383,1383,1363. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 9.36 (s, 1H, H-6), 4.38-4.28 (m, 2H, H-1), 3.40-3.30 (m, 4H, H-10, H-13), 2.26-2.07 (m, 4H, H-2, H-8), 1.97-1.75 (m, 6H, H-7, H-11, H-12), 1.63-1.47 (m, 2H, H-4), 0.83 (t, 3H, J = 7.5 Hz, H-5).

Preparation of enamine:

To a solution of pyrrolidine (0.15 mL, 1.89 mmol, 1.0 eq.), aldehyde 417 (300 mg, 1.89 mmol, 1.0 eq.) in dry toluene (42 mL) p-toluene sulfonic acid (0.6 mL, 0.4 mol%.) was added. The reaction mixture was refluxed at 110°C for 5h using dean's stark apparatus. Then solvent was removed with a rotary evaporator, and the resulting crude product was used directly in the next step.

Preparation of aldehyde 726:

A solution of allyl bromide 127 (1.11 mL, 12.7 mmol, 3.55 eq.), in dry CH 3 CN (2 mL) was added to a crude solution of the enamine of 417 (900 mg, 3.59 mmol, 1.0 eq.) in dry CH 3 CN (6 mL). The reaction was maintained at room temperature for 2 h. After 2 h, HCl (5% aqueous solution, 8 mL) was added and the resulting mixture was extracted with EtOAc (3 x 5mL). The combined organic extracts were washed with saturated NaHCO 3 solution and then brine, dried over MgSO4. The solvent was concentrated under reduced pressure and the crude material purified by chromatography on silica gel (EtOAc 100%) to give aldehyde 726 as colorless oil (154 mg, 30%) and aldehyde 726′ (112 mg, 8%). R f = 0.62 (EtOAc 100%). IR (ATR) ν max (cm -1 ) = 3077,2964,2878,2703,1722,1634,1446,1344,1260. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 9.44 (s, 1H, H-7), 5. 73-5.59 (m, 1H, H-2), 5.12-5.05 (m. 1H, H-1), 3.43 (t, 2H, J = 6.9 Hz, H-11), 3.34 (t, 2H, J = 6.6 Hz, H-14), 2. 28-2.23 (m, 2H, H-9), 2.12-2.07 (m, 2H, H-3), 1.94-1.79 (m, 6H, H-8, H12, H13),1.63-1.48 (m. 2H, H-5), 0.81(t, 3H, J = 7.5 Hz, H-6). 13 C NMR (CDCl 3 , 75 MHz): δ (ppm) = 206.3 (C-7), 170.6 (C-10), 132.7 (C-2), 118.5 (C-1), 51.7 (C-4), 46.5 (C-11), 45.7 (C-14), 35.1 (C-3), 28.9 (C-9) , 27.1 (C-8), 26.0 (C-5), 24.7 (C-11), 24.3 (C-14), 7.8 (C-6). HRMS (ESI): [M+Na] + C 14 H 23-NO 2 Na : calcd. 260.1621, found 260.1623.

2-Ethyl-5-oxo-5-(pyrrolidin-1-yl)pentanal (726′)

R f = 0.62 (EtOAc 100%). IR (ATR) ν max (cm -1 ) = 3048,2964,2874,1721,1631,1441,1343,1267. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 9.54 (m, 1H, H-4), 3.41-3.31 (m, 4H, H-8, H-11), 2.25-2.17 (m, 3H, H-6, H-9), 1.99-1.74 (m, 6H, H-9, H-10, H-5), 1.71-1.59 (m, 1H, H-2a), 1.56-1.44 (m, 1H, H-2b), 0.89(t, 3H, J = 7.2 Hz, H-1).