Le travail décrit dans ce manuscrit est centré sur l'organocatalyse énantiosélective, tant au niveau du développement méthodologique qu'au niveau des applications en synthèse totale de produits naturels.

L'organocatalyse énantiosélective, qui implique de petites molécules organiques chirales comme catalyseurs dans des transformations énantiosélectives, est un domaine de recherche en chimie organique conceptualisé en 2000 et aujourd'hui plutôt mature. Récemment, et en capitalisant sur le savoir acquis au cours des quinze années passées, des stratégies de multi-organocatalyse, c'est à dire des stratégies impliquant des combinaisons de plusieurs organocatalyseurs au sein du même milieu réactionnel, ont été développées pour permettre la réalisation de processus réactionnels complexes, souvent très difficiles à réaliser autrement.

Par exemple, le groupe de Rovis a décrit en 2009 une cascade bi-catalytique impliquant la combinaison d'un aminocatalyseur avec un carbène N-hétérocyclique (NHC) pour la synthèse énantiosélective de cyclopentanones (Schéma 1, haut). Inspirés par ce travail, et dans la continuité des travaux de recherche de notre équipe sur les propriétés des NHCs comme bases de Brønsted organocatalytiques, nous avons imaginé une organocascade divergente à partir des même substrats pour la préparation de molécules bicycliques pontées (Schéma 1, bas).

Schéma 1. Organocascades bi-catalytiques combinant aminocatalyse et catalyse par les NHCs

Ainsi, nous avons développé une méthode bi-organocatalytique pour la synthèse énantiosélective directe de molécules bicycliques pontées, essentiellement des bicyclo[3.2.1]octanes (Schéma 2 et Chapitre 1). L'originalité de ce travail repose sur l'utilisation d'un NHC de la classe des 1,3-imidazol-2-ylidenes comme base de Brønsted organocatalytique. Une partie importante de ce travail a consisté à limiter la réversibilité des processus mis en jeu lors de la cascade réactionnelle (addition de Michael et aldolisation) pour assurer un bon contrôle de la stéréosélectivité.

Schéma 2. Organocascade bi-catalytique énantiosélective: synthèse de bicyclo[3.n.1]alcanes La méthode s'est révélée suffisamment générale et efficace pour envisager son application à la synthèse totale énantiosélective de produits naturels. Nos efforts dans le domaine se sont concentrés sur la synthèse des sesquiterpènes de la famille des quadranes, et en particulier la (+)-suberosanone et la (+)-suberosenone, deux molécules naturelles d'origine marine montrant des activités biologiques prometteuses (Schéma 3 et Chapitre 2). Nous avons obtenu la (+)-suberosanone (er > 99:1) avec un rendement global de 8% pour 15 étapes, ce qui représente la première synthèse totale énantiosélective d'un produit naturel de cette famille.

Ce travail constitue également une synthèse totale formelle de la (+)-suberosenone. La stratégie développée est suffisamment flexible pour permettre la synthèse de nombreux |analogues.

Schéma 3. Synthèse totale de la (+)-suberosanone, synthèse formelle de la (+)-suberosenone Enfin, le troisième chapitre de ce manuscrit détaille notre travail préliminaire sur une autre organocascade énantiosélective bicatalytique pour la préparation de glutarimides (Schéma 4 et Chapitre 3). Le motif glutarimide est présent dans de nombreuses molécules naturelles biologiquement actives et plusieurs médicaments, mais il n'existe que très peu de méthodes énantiosélectives pour leur préparation. Sur la base de travaux antérieurs de notre équipe, l'approche étudiée repose sur une addition de Michael organocatalytique enantiosélective à partir de cyclobutanones activées par une fonction amide secondaire suivie d'un réarrangement de cycle catalysé par une base de Lewis comme les NHCs. Nous avons obtenu la preuve du concept pour la faisabilité de cette nouvelle organocascade et identifié plusieurs systèmes catalytiques performants. Faute de temps, l'optimisation et la généralisation de la réaction restent à effectuer.

multi-catalysis

In its editorial of the 2007 thematic issue of Chemical Reviews on organocatalysis, Benjamin List defined orgacatalysis as "catalysis with small organic molecules, where an inorganic element is not part of the active principle". 1 Although well represented in Nature for centuries, 2 this field gained an identity only in 2000 with the work of List 3 and MacMillan 4 on enantioselective aminocatalysis, while examples of organocatalytic transformations can be traced back to 1859 with the work of Justus von Liebig on the catalytic properties of acetaldehyde. 5 The first enantioselective organocatalytic reaction was reported in 1971 with the Hajos & Parrish proline-catalyzed enantioselective aldol reaction, 6 but it took almost three decades before the method was regarded as a general concept rather than an isolated specific case. Nowadays, organocatalysis is firmly established as the third pillar of enantioselective catalysis, together with biocatalysis and metal catalysis. 7 Organocatalysis offers several attractive features: it generally tolerates aerobic conditions, do not require rigorous exclusion of water, and organocatalysts are usually stable and have a reduced toxicity when compared to metal-based catalytic systems. Most often, organocatalysts are obtained from naturally occurring chiral molecules (the so-called "chiral pool") but can also be prepared in their optically pure form by desymmetrization. Naturally occurring Cinchona alkaloids and amino acids have become the principal source of organocatalysts, together with synthetic trans-cyclohexane-1,2-diamine and binol derivatives. Organocatalytic transformations can be categorized according to the activation mode involved. 8 In the following, a brief summary of the main organocatalytic activation modes is presented.

Aminocatalysis

The term aminocatalysis embraces three distinct organocatalytic activation modes, namely enamine (and dienamine) activation, iminium activation, and SOMO activation (Scheme 1), all proceeding through the formation of a covalent bond between a primary or secondary amine catalyst and a carbonyl moiety in the substrate. 9 Enamine activation builds on the capacity of amines to react with enolisable carbonyl compounds to form an enamine that can in turn react with electrophiles for the -functionalization of the carbonyl compound [Highest Occupied Molecular Orbital (HOMO)-activation]. If the catalytically generated enamine is submitted to a one-electron oxidation, it produces a reactive radical cation amenable to react with nucleophiles for the -functionalization of the carbonyl compound [Single Occupied Molecular Orbital (SOMO)-activation]. With non-enolisable -unsaturated carbonyl compounds (essentially aldehydes), the situation is different. Indeed, their reactions with amine catalysts produce iminium ions amenable to react with nucleophiles for the -functionalization of the carbonyl compound via a conjugate addition [Lowest Unoccupied Molecular Orbital (LUMO)-activation]. Finally, the reaction of catalytically generated enolisable -unsaturated iminium ions with Brønsted bases produces dienamines (-deprotonation) that can in turn react with electrophiles for the functionalization of the carbonyl compound (HOMO-activation). Representative commercially available aminocatalysts are depicted in Figure 1, and the iminium activation mode is illustrated in Scheme 2. 10 8 MacMillan, D. W. C. Nature 2008, 455, 304. 9 For an excellent review on the topic, see: Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen, S.; Jørgensen, K. A. Chem. Comm. 2011, 47, 632. 10 (a) Brandau, S.; Landa, A.; Franzén, J.; Marigo, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2006, 45, 4305. For related reactions: (b) Carlone, A.; Cabrera, S.; Marigo, M.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2007, 46, 1101. (c)

Lewis base catalysis

Lewis bases such as tertiary amines, pyridines and phosphines are well known to catalyze some organic reactions. Representative Lewis base catalysts are depicted in Figure 2. In recent years, N-heterocyclic carbenes (NHCs) have also been identified as potent Lewis base organocatalysts (vide infra for NHC catalysis). Famous examples of Lewis base catalysis in the enantioselective series include the Morita-Baylis-Hillman reaction11 and acyl transfer reactions (Scheme 3). 12 The Lewis base activation involves the formation of a covalent bond between the Lewis base catalyst and an electrophilic substrate to form a zwitterionic reactive intermediate.

N-Heterocyclic carbene (NHC) catalysis

Since their isolation as stable free carbenes by Arduengo in 1991,18 N-heterocyclic carbenes (NHCs) have found a plethora of applications in organic chemistry, 19 initially in the field of organometallic chemistry 20 and more recently as a class of organocatalysts with unique properties. 21 The four most common classes of NHCs are depicted in Figure 3. On the one side, applications of NHCs in organometallic chemistry, especially 1,3-imidazol(in)-2-ylidenes, result from their excellent σdonor properties as ancillary transition metal ligands, allowing for strong metal-ligand bonds, as for example, in the late-generations Grubbs precatalysts for olefin metathesis. 22 On the other side, the applications of NHC in organocatalysis can involve three distinct activation modes depending on the nature of the NHC and the substrates: two non-ambiphilic activation modes, namely Brønsted base activation and Lewis base activation, 23 and an ambiphilic activation mode via a resonance-stabilized enaminol-type intermediate, the so-called Breslow intermediate, to trigger umpolung reactivity (Scheme 5). 24

Scheme 5. Activation modes in organocatalysis with NHCs

In the past few years, our laboratory has been actively involved in the field of NHC catalysis, especially involving the Brønsted base properties of stable (and bottleable) 22 Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010Rev. , 110, 1746. 23 . 23 Ryan, S. J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42, 4906. 24 Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511. 1,3-imidazol-2-ylidenes. The relative Brønsted basicities of NHCs follow the order shown in The work of our group in this area of research was initiated by the serendipitous discovery that the NHCs SIMes (1) and IDipp (2) are excellent catalysts for Michael additions and Michael / aldol organocascades (Scheme 6a). 26 Importantly for the following, it was demonstrated that NHC-catalyzed Michael additions performed at room temperature or below are not or slowly reversible. 26b This was also proven more recently by simple cross-experiments using methyl and tert-butyl acrylates (Scheme 6b). 27 25 (a) Amyes, T. L.; Diver, S. T.; Richard, J. P.; Rivas, F. M.; Toth, K. J. Am. Chem. Soc. 2004, 126, 4366. (b) Higgins, E. M.; Sherwood, J. A.; Lindsay, A. G.; Armstrong, J.; Massey, R. S.; Alder, R. W.; O'Donoghue, A. C. Chem. Commun. 2011, 47, 1559. (c) Contemporaneously, the groups of Scheidt and Zhang reported NHC-catalyzed oxa-Michael and aza-Michael additions, respectively, using closely related NHC catalysts (Scheme 7). 28 By analogy with the carba-series, the oxa-Michael addition was also found irreversible at 20 ºC, and slowly reversible at 70 ºC. 28a More recently, and in collaboration with Prof. Lionel Delaude from the University of Liege, our group reported the complementary NHC-catalyzed sulfa-and phospha-Michael additions using zwitterionic NHCCO 2 adducts precatalysts (Scheme 7). 29 Very recently, the group of Huang has reported some enantioselective NHC-catalyzed Michael and sulfa-Michael additions. 30 28 (a) Phillips, E. M.; Riedrich, M.; Scheidt, K. A. Jd. Am. Chem. Soc. 2010, 132, 13179. (b) Scheme 7. NHC-catalyzed hetero-Michael additions 28,29 Lately, our group reported some NHC-catalyzed hydrogen / deuterium exchange reactions between pseudo-acids (pKa DMSO = 14-19) and deuterated chloroform (Scheme 8). 31

I have been involved in this work as a side-project of my main PhD project. The excellent organocatalytic activity of the NHC IDipp (2) in these reactions was attributed to its ideal "proton shuttling" properties involving a stable azolium cation / trichloromethyl anion Brønsted pair. Surprisingly, the parent NHC SIMes (1) exhibiting a very similar Brønsted basicity than the NHC IDipp (2, pKa water = 0.2) was an incompetent catalyst in these reactions. A combined experimental and theoretical study [DFT, B3LYP 6-311++G(d,p)] allowed rationalizing this sharp difference of reactivity. It was found that the reaction of the NHC SIMes (1) with chloroform produces an unstable azolinium cation / trichloromethyl anion Brønsted pair that rapidly rearranges into the formal insertion product of the NHC 1 in the C-H bond of chloroform, resulting in a rapid loss of the catalytic activity. The recently developed chemistry of zwitterionic enolate-type intermediates is a nice example of the Lewis base activation with NHCs. The principle of these reactions is illustrated below in the case of the NHC-catalyzed reaction of a ketene with a 1-aza-diene recently reported by Ye (Scheme 9). 32a In this Lewis base-catalyzed reaction, the nucleophilic catalyst adds first to the ketene to form a zwitterionic azolium enolate intermediate. This catalytically generated species then undergoes a conjugated nucleophilic addition to the 1-aza-diene to give a zwitterionic intermediate, precursor of the δ-lactam product by nucleophilic substitution at the carbonyl group regenerating the catalyst.

Scheme 9. NHC-catalyzed formal [4 + 2] Probably the most spectacular applications of NHCs as organocatalysts involve their ambiphilic character leading to umpolung reactions of carbonyl compounds. 24 The archetypal and first developed enantioselective NHC-catalyzed umpolung transformation was the benzoin condensation (Scheme 10). 33 This reaction proceeds via the catalytic formation of an

Multi-catalysis

With the advent of organocatalysis, it has nowadays become easier to imagine multi-catalytic systems that combine several catalytic activation modes to achieve complex chemical transformations. In the last decade, a number of multi-catalytic processes have been described combining activation modes from a vast array of catalysts, including of course metal-based catalysts. 35 In an excellent Perspective article, MacMillan recently proposed a categorization of bi-catalytic processes. 36 The definitions and terminology proposed by MacMillan have been reproduced hereafter (Figure 5). In 2010, Jacobsen and co-workers reported a beautiful example of double activation catalysis in the case of the Povarov reaction between furan and N-phenyl aldimimines (Scheme 12).39 A detailed experimental and computational analysis has revealed that the two catalysts, namely triflic acid (2 mol%) and the bifunctional sulfinamido urea derivative (4 mol%), are simultaneously activating the imine substrate in a well stereodefined environment, allowing for a high stereocontrol.

Scheme 12. Double activation catalysis in the Povarov reaction

In 2009, Lathrop and Rovis reported a beautiful example of cascade catalysis. 40,[START_REF] Grondal | Reviews on cascade organocatalysis[END_REF] They described an enantioselective Michael / benzoin organocascade between 1,3-dicarbonyl compounds and -unsaturated aldehydes to give stereo-defined cyclopentanol derivatives (Scheme 13). The reaction proceeds by an initial enantioselective Michael addition under aminocatalytic iminium activation to afford the corresponding intermediate adduct 3. The latter then undergoes an intramolecular NHC-catalyzed diastereoselective benzoin condensation in the presence of a suitable achiral NHC catalyst to afford the fused bicyclic product 4 in good yield as a 4:1 mixture of diastereomers with an excellent enantioselectivity.

For comparison purpose (see below), it can be noted that the diastereo-and enantio-pure product 4 was obtained in 61 % yield. The work from the group of Rovis and other groups on the combination of aminocatalysis with NHC catalysis in cascade processes 42

Objective of the research project

As explained above, our group has a strong interest for the use of NHCs in catalysis and cascade reactions. When I joined the group in fall 2012, I have been proposed to develop an enantioselective Michael / aldol organocascade for the preparation of bicyclo[3.2.1]octane derivatives. The envisioned catalytic system was forged on an enantioselective Michael addition step under aminocatalytic iminium activation, followed by a diastereoselective NHC-catalyzed aldol ring closure reaction operating by Brønsted base activation to afford the desired bicyclic product (see Scheme 6 for the NHC-catalyzed racemic version of this reaction). Thus, the prospected organocascade would use the same substrates as in the Rovis study highlighted in Scheme 13 and the same classes of organocatalysts, namely an aminocatalyst and a NHC, but affording a different product. As illustrated below in Scheme 15, the divergence point would be due to the ability of imidazolylidene-type NHCs to operate preferentially as catalytic Brønsted bases rather than ambiphilic catalysts as it is the case with triazolylidene NHCs. This part of my work is detailed in the following of this chapter. From this series of preliminary results, it was concluded the following:

-The Michael addition works nicely under iminium activation, the most promising catalyst being the so-called Jørgensen proline derivative 12. 57 Although enantioselectivities were not determined, some previous work made us confident on this matter. This idea was tested during the laboratory internship of M. Jeremy Godemert during his Master 2. 59 In short, the proof of concept for our hypothesis was obtained with the reaction depicted in Scheme 23. In that case, the Michael addition step catalyzed by the aminocatalyst 12 introduced in 20 mol% required 2 hours at room temparature in relatively concentrated methanolic solution as determined by TLC analysis. Then, the NHC catalyst 2 (20 mol%) was added to the reaction mixture in order to achieve the aldolization step of the sequence. The desired bicyclic product 7a was obtained in 56% yield as a relatively complex and difficult to analyze mixture of four diastereomers. For simplification, the secondary alcohol in 7a was oxidized using IBX in ethyl acetate, 60 affording the diketone 16a in 77% yield, with a dr of 3:1 and an er of 11:1 for the major diastereomer. The relative configuration of the methyl group C7 in the major diastereomer of 16a was determined to be axial by 13 in the case of the diastereomer with the axial methyl substituent, the carbon at C12 is deshielded by about 10-12 ppm relative to the same carbon atom in the other diastereomer due to the absence of -effect (Scheme 24). 61 This method has largely been used in the past in our group for the determination of the relative configurations of these kinds of bicyclic systems. 62

Scheme 23. The first enantioselective Iminium / NHC Michael aldol organocascade Scheme 24. Determination of the diastereoselectivity by 13 C NMR Overall, the preliminary work exposed above allowed obtaining the proof of concept for the methodology we plan to develop. However, many problems (yields, catalysts loading, stereoselectivities) were to be solved before the method could be generalized and ultimately become a useful synthetic tool for enantioselective catalysis.

61 Grant, D. M.; Vernon Cheney, B. J. Am. Chem. Soc. 1967, 89, 5315. 62 Filippini, M.-H.; Faure, R.; Rodriguez, J. J. Org. Chem. 1995, 60, 6872.

Enantioselective synthesis of bicyclo[3.2.1]octanes

From the above preliminary results, we selected the reaction between tert-butyl Obviously, neutral or moderately acidic conditions are required to avoid the base-promoted epimerization of the product 7 by retro-aldol / retro-Michael processes. For this purpose, we selected pyridinium chlorochromate (PCC) as a potential oxidant candidate. We have rapidly found that in the presence of anhydrous magnesium sulfate, the desired diketone 16a could be obtained in nearly quantitative yield from the corresponding alcohol 7a (Scheme 26). Also, we have checked if the crude product 7a could be used directly in this reaction in order to save time and solvents. A comparison of the results obtained from crude and purified 7a afforded very similar results with a little preference for the reaction performed directly from crude 7a (Scheme 26).

Scheme 26. Optimization of the oxidation step

This being done, we could embark on the optimization study of the bicatalytic enantioselective reaction. We first examined the influence of the nature of the solvent on the aldolization step in the racemic series. Many common organic solvents are suitable for this NHC-catalyzed aldolization reaction, except in the challenging cases in which the aldolization is occurring at a neopentylic position as in the gem-dimethyl containing Michael adduct 17 (Scheme 27). We thus selected 17 as a model substrate. The aldehyde 17 (dr > 19:1) was treated with 20 mol% of the NHC IDipp in representative organic solvents (Scheme 27).

Unsurprisingly, this series of test showed that a protic solvent is necessary to achieve the aldolization, probably involving a Lewis acid activation of the aldehyde carbonyl group with the solvent (H-bonding).

Scheme 27. Selection of the solvent (racemic series)

Then, we examine the influence of the reaction time and temperature with both the Jørgensen and MacMillan catalysts 12 and 18, respectively, in the reaction of the -ketoester 5a and crotonaldehyde (15) (Table 1). In this case, it was rapidly confirmed that the Jørgensen catalyst 12 exhibit superior activity when compared to the MacMillan catalyst 18 (compare entries 1 with 2, and 6 with 7). A reaction performed in hexafluoroisopropanol did not improve the result (entry 3), but the reaction was found sensitive to the concentration with an optimum at 2.5 M (compare entries 1, 4 and 5). The influence of the temperature was also examined: while slightly better results were obtained at 0 o C (entry 6), longer reaction time was observed at lower temperature (compare with entry 8). Overall, the best conditions identified for the studied reaction involve a reaction in 2.5 M methanol with the Jørgensen catalyst 12 at 0 ºC (entry 6). In this case, and following oxidation, the desired diketone 16a could be obtained in 75% yield as a 4:1 mixture of diastereomers with an excellent enantiomeric ratio for the major diastereomer (er = 19:1). With good reaction conditions in hand, we embarked on the investigation of the scope of the reaction (Scheme 28). Rapidly after the beginning of this part of my work, it was clear that optimum reaction conditions identified above for the product 16a [conditions (a)] were not directly transposable to other cases, affording the desired bridged bicyclic products in low to moderate yields and/or stereoselectivities. In many cases, it was thus necessary to re-optimize the conditions (solvent, temperature, and catalyst for the Michael addition) as a function of the couple of substrates used. For example, when crotonaldehyde is replaced by hex-2-enal, conditions (a) delivered the product 16h in lower yield and stereoselectivities when compared to the product 16a. In this case, the MacMillan catalyst 18 was found much more selective although the product 16h was only obtained in 32% yield. The reaction was also found possible but not efficient with an -unsaturated aldehyde having an aromatic group at the  position, cinnamaldehyde for instance, affording the product 16i in quite low yield and stereoselectivities. In this case, a significant amount of the intermediate Michael adduct could be isolated even after prolonged reaction time using the aminocatalyst 12 (or 18), while catalyst 18 (or 12, verify) afforded the product 16i in very low stereoselectivities. The introduction of a gem-dimethyl substituent onto the starting -ketoester as in the case of the product 16b did not affect the yield of the reaction, but had a deleterious effect on the stereoselectivity. Notably, the aminocatalyst 12 was found significantly superior to 18 in this case (very slow Michael addition with 18). A rational for the observed decrease in stereoselectivity is that the aldolization step of the cascade is kinetically disfavored due to an increased steric effect, which resulted in a longer life-time of the intermediate Michael adduct

and ultimately to more NHC-catalyzed retro-Michael / Michael processes responsible for the loss of diastereoselectivity and enantioselectivity. Benzyl and methyl -ketoesters could also be used, sometimes leading to better results than tert-butyl -ketoesters as in the case of the product 16e. Also, the reaction leading to the product 16j is interesting. It uses the exact same substrates as the previously reported reaction of Rovis 40 (Scheme 13) with just a subtle difference in the structures of the NHC catalyst to afford a very different product. Other activating groups than esters could also be used. For example, the reaction with 2-acetyl cyclopentanone afforded the corresponding triketone 16k. However, in this case the reaction required a non-nucleophilic solvent to avoid the retro-Dieckmann-type fragmentation of the intermediate Michael adduct, and dichloromethane and chloroform afforded acceptable results. A -ketosulfone and a secondary -ketoamide (partially soluble in MeOH in this case)

were also productive substrates to afford the products 16g and 16f, respectively. Finally, the reaction could also be extended to six-membered -ketoester substrates to produce the bicyclo[3.3.1]nonane derivatives 16l and 16m, although with somewhat reduced efficiency and stereoselectivity. This can be explained by a relatively slow and difficult to drive to completion Michael addition, with an introduction of the NHC catalyst when some substrates are still present in the reaction mixture leading to racemic reactions (NHC-catalyzed Michael addition).

Scheme 28. Enantioselective Michael / aldol organocascade for the synthesis of bicyclo[3.n.1]alkanes. All reactions were conducted on a 0.5 mmol scale; diastereomers ratio were determined by NMR of the crude reaction mixtures; the enantiomers ratio of the major diastereomer (axial C8 substituant) was determined by HPLC on a chiral stationary phase.

Conclusion

We have developed an original organocascade for the enantioselective synthesis of bridged, essentially bicyclo[3.2.1]octanes, compounds. The reaction features an enantioselective Michael addition step under aminocatalytic iminium activation, followed by a diastereoselective NHC-catalyzed aldol ring closure reaction operating by Brønsted base activation to afford the desired bicyclic product. Very interestingly, the studied organocascade is not the first to combine iminium activation with NHC activation with these substrates (see the Rovis work in Scheme 13), and we have identified a divergence point in iminium / NHC cascade catalysis controlled by the nature of the selected NHC. One notable difference between the two studies is that we cannot introduce the two catalysts simultaneously at the beginning of the reaction as in the Rovis work.

Of course, our new methodological tool is not perfect and there is plenty of room for its improvement, but we estimated that it was good enough for applications in synthesis. In order to demonstrate the synthetic value of our method, we decided to embark on its application to a concrete case with the total synthesis of a natural product. This part of my work is the topic of the next chapter.

Chapter 2

Total synthesis of quadrane sesquiterpenes 2.1. Introduction

Quadranes natural products

Quadranes form a small class of 18 sesquiterpene natural products belonging to the larger family of polyquinanes. 63 Quadranes are also sometimes referred to as suberosanes or terrecyclanes. They generally exhibit interesting but not exceptional biological activities, especially as antimicrobial agents and anticancer agents. The structural features of this class of compounds include a diquinane ring system (cis-fused AB rings) bridged with a three carbon tether forming the bicyclo[3.2.1]octane ring system (BC rings), an axial one-carbon substituent at C8, a gem-dimethyl group at C13, and a one-carbon substituent at C5 that can exist in both relative configurations (Figure 6). Naturally occurring quadranes have been isolated from two kinds of sources, terrestrial ones in fungi, and marine ones in gorgonians. 63

Figure 6. Structural features of quadranes

The first isolated quadrane is (-)-quadrone (I), which was isolated in 1978 by Calton and Ranieri from the fermentation of broth of the fungus Aspergillus terreus (Figure 7). 64 (-)-Quadrone (I) is the only known tetracyclic quadrane. Very soon after the isolation of (-)-quadrone (I), (+)-terrecyclic acid A (II) was isolated from the same fungus by the group of Isogai (Figure 7). 65 It can already be noted that the natural products I and II are structurally closely related, and actually Isogai and co-workers were able to convert II into I (oxa-Michael addition under pyrolytic conditions). The absolute configurations of (- )-quadrone (I) and (+)-terrecyclic acid A (II) were determined in 1984 by the groups of Isoe 66

and Smith, III 67 by diastereoselective total syntheses: (+)-fenchone (terpene chiral pool) served as starting material for the synthesis of (+)-II, and (+)-I was obtained following a kinetic resolution of an advanced intermediate using (S)-O-methyl mandelic acid as the chiral auxiliary.

Figure 7: Two representative quadranes isolated from terrestrial sources

In 1996, the Boyd group reported the isolation of (+)-suberosenone (III) from the gorgonian Subergorgia suberosa (Figure 8). 68 It was the first time that a quadrane sesquiterpene could be isolated from a marine organism. Remarkably, (+)-suberosenone (III) exhibits a completely reduced carbon atom at C7 (methyl group), a feature later found in all naturally occurring quadranoids isolated from marine sources. Following this discovery, the group of Sheu reported the isolation of the closely related (-)-suberosanone (IV), 69 as well as the two bicyclic quadranes (-)-isishippuric acid A (V) and (-)-isishippuric acid B (VI) 70 from the gorgonian Isis hippuris. Interestingly, the natural products V and VI exhibit a bicyclic BC ring system biosynthetically obtained by oxidative ring fragmentation of the A ring of their biosynthetic precursors. Also, it can be noted that compound VI is actually a norquadrane with only 14 carbon atoms.

Total syntheses of quadranes

Due to their potent biological activities and challenging molecular architectures, quadrane sesquiterpenes have soon attracted great attention from the synthetic community.

This area of research was comprehensively reviewed recently, 63 and only the most important work will be highlighted here.

Danishefsky first reported the total synthesis of (±)-quadrone (I) in 1980, just two years after its isolation (Scheme 29) 72 . The synthesis started from 4,4-dimethylcyclopentenone as the precursor of ring B with a consecutive copper(I)-promoted conjugate addition of a vinyl Grignard / enolate trapping with a functionalized alkyl iodide to give intermediate 19. Five additional steps were required to prepare the AB ring system 20, notably involving a base-promoted aldolization / crotonization sequence for the construction of ring A. The quaternary carbon atom at C1 was installed by a conjugate addition of a silyl ketene acetal, and some functional groups manipulations afforded intermediate 21. The elaboration of the six-membered C ring ensued from a remarkably diastereoselective cyclization of the lithium enolate derived from 21 to give the ABC ring system of quadranes, and a deprotection step afforded intermediate 22. The -alkylation at C5 of the ketone group in 22 proved very difficult due to regioselectivity issues, the  3,4 enolate being formed preferentially. This problem was circumvented by the temporary introduction of the  2,3 unsaturation with concomitant saponification of the methyl ester at C8 to give the enone intermediate 23. Then the desired  4,5 enolate could be generated and trapped by formaldehyde, and the  2,3 double bond diastereoselectively hydrogenated from the  face to give the hydroxyacid intermediate 24. Amusingly, compound 24 was later isolated as a naturally occurring quadrane. 73 The dehydration of 24 afforded (±)-terrecyclic acid A (II), while (±)-quadrone (I) was obtained under thermolytic conditions directly from 24. Overall, this total synthesis of (±)-quadrone (I) was achieved in 19 steps and 3.1% yield from 4,4-dimethylcyclopentenone.

72 Danishefsky, S.; Vaughan, K.; Tsuzuki, K. J. Am. Chem. Soc. 1980, 102, 4262. 73 Scheme 29: Danishefsky's total synthesis of (±)-quadrone (I)

Inspired by Danishefsky's work, improved synthetic routes to quadrone (I) and other quadranes emerged. 63 Importantly, most of the existing total syntheses of quadranes are in the racemic series, and only a restricted number of non-racemic diastereoselective syntheses have been reported. These include approaches based on the chiral pool, either used as starting material or temporary chiral auxiliary, or on kinetic resolution. It must be underlined here that, to date, no enantioselective total synthesis of a quadrane sesquiterpene has been reported. In the following, two recent diastereoselective non-racemic total syntheses based on the chiral pool are highlighted. The first one uses (R)-citronellal as the starting material, while the second one exploits (R)-1-phenylethylamine as a chiral auxiliary.

In 2007, Kuwahara realized the first and only total synthesis of ()-isishippuric acid B (VI) from (R)-citronellal (Scheme 30). 74 The cycloheptadienol silyl ether 25 was obtained from (R)-citronellal in four steps including an intramolecular Horner-Wadsworth-Emmons reaction. The latter then served as an electron-rich diene in a regioselective Diels-Alder In 2015, the group of Dumas reported the total syntheses of (+)-suberosenone (III) and

(+)-suberosanone (IV) (Scheme 31). 75 This work is of importance to us because we have achieved an independent total synthesis of (+)-IV. The pivotal step of the Dumas' approach relies on a highly regio-and diastereo-selective hyperbaric Michael addition of the chiral enantiopure imine derived from the cyclopentanone 29 with methyl crotonate using (R)-1-phenylethylamine as the chiral auxiliary to afford the product 30 as a single diastereomer (dr > 39:1 as determined by NMR), thereby fixing the absolute configuration at C1. Notably, this reaction can be conducted on a gram-scale. Some functional group manipulations were then necessary to obtain the primary alcohol 31, which was converted to the corresponding iodide and engaged in a ring-closing -alkylation sequence via a silyl enol ether intermediate to give the BC ring system in 32. A Wacker-type oxidation of the olefin in 32 afforded the diketone 33. From there, the end-game strategy more or less follows previous approaches to quadranes 63 including a base-promoted aldolization / crotonization sequence, and a regio-and diastereoselective alkylation / hydrogenation sequence to afford (+)-suberosanone (VI). Overall, this total synthesis of (+)-suberosanone (VI) was achieved in 16 steps with a remarkable 18.2% yield from the -ketoester 28. In the same study, the authors were able to convert the enone 34 into (+)-suberosenone (III) in three steps (35% yield from 34, not shown). Of importance for the following, this study allowed establishing the absolute configuration of naturally occurring (+)-suberosenone (III) as (1R,2R,8R,11R). In the case of suberosanone (IV), the situation is significantly more complex. It is important to note that the synthetic products (+)-suberosenone (III) and (+)-suberosanone (IV) were obtained from the same intermediate 34 and thus have identical absolute configuration. Also, the synthetic sample of (+)-suberosanone (IV) prepared by Dumas and co-workers shows an opposite sign for its optical rotation when compared to the reported one for the isolated natural product (-)-suberosanone (IV). Providing that the sign of the optical rotation for the isolated natural product is really (-) as reported by Sheu and co-workers, 69 Scheme 31: Dumas' synthesis of (+)-suberosanone (IV).

In order to test the synthetic value of the methodology presented in Chapter 1, we decided to apply it to a concrete case through the total synthesis of a quadrane sesquiterpene.

Because of its apparent structural simplicity and resemblance with some of the products prepared during our work on the enantioselective organocascade presented in Chapter 1 (e.g. compound 16b), (-)-isishippuric acid B (VI) was selected as the target compound. As the reader will see in the following section, the realization of this project revealed a number of unforeseen difficulties and surprises.

Retrosynthetic analysis for (-)-isishippuric acid B (VI)

It was initially devised that (-)-isishippuric acid B (VI) could be obtained from the unsaturated diester 35 by a saponification / hydrogenation sequence (Scheme 32).

Intermediate 35 would be obtained directly from the ketone 36 by a Wittig-like olefination, and the ketone 36 would derive from the product 7b obtained during the methodological studies presented in Chapter 1.

Scheme 32. Retrosynthetic analysis for (-)-Isishippuric acid B (VI)

While the above retrosynthetic analysis is very seducing on the paper, several of its features should be highlighted:

-the ketone group at C2 is  to a quaternary center resulting in kinetically disfavored nucleophilic additions to this moiety, -a severe 1,3-diaxial interaction exists between the methyl group at C8 and the electrophilic carbon atom at C2 rendering very difficult nucleophilic additions at C2 from the  face, -a bulky gem-dimethyl is present at C13 rendering very difficult nucleophilic additions at C2 from the  face, -the bicyclic ring system in 36 is rigid and shows no conformational flexibility.

Dr. Marc Presset, a former Ph.D. student in our group, has extensively studied the synthetic route presented in Scheme 32 in the racemic series. 56 For the reasons mentioned above, all attempts to perform a Wittig-type olefination at C2 on intermediate 36 and its analogs failed, leaving the starting material unchanged in most cases. After considerable efforts several analogs of the unsaturated intermediate 35 could be prepared. Again, the reduction of the  2,3 double bond in 35 and its analogs proved extremely challenging, and no conditions could be identified at the time to perform this reaction. Some nucleophilic substitutions at C2 were also examined from the activated alcohol (e.g. the corresponding mesylate) derived from 36, and in this case again, no suitable conditions could be identified.

From this accumulated knowledge, and despite the many unsuccessful attempts, it was decided to push forward our work on the total synthesis of (-)-isishippuric acid B (VI) taking advantage of some recently described methods for the manipulation of the sterically hindered double bonds as the  2,3 double bond in 35 and its analogs. Our efforts in this direction are detailed in the next section. with the previously developed conditions, we were able to obtain compound 7b in 90% yield from the -ketoester 5b and crotonaldehyde using a combination of catalyst 12 and the NHC IDipp 2 in methanol (Scheme 33). The determination of the diastereoselectivity and enantioselectivity of the reaction was realized as before on the diketone product 16b obtained in 89% from 7b (80% over the two steps). Surprisingly, the diketone 16b was obtained as a mixture of two diastereomers with a reverse diastereoselectivity (dr = 1:4.4 Me ax :Me eq ), the diastereomer with the equatorial methyl group being largely major. Moreover, the desired diastereomer with the axial methyl group (the minor one in this case) proved almost racemic (er = 1.6:1). This unexpected difference between the results obtained on a 50-100 mg scale and on a 10 g scale forced us to look deeper to the reaction conditions, especially the evolution of the internal temperature during the reaction. It was rapidly found that the Michael addition step is relatively exothermic, and the observed loss of stereoselectivity was attributed to the uncontrolled elevation of the temperature during the early stages of the reaction producing less stereoselective Michael additions and probably some NHC-catalyzed retro-Michael / Michael processes leading to racemization. Accordingly, we modified our protocol as follow:

Synthetic approach to (-)-isishippuric acid B (VI)

-the reaction mixture containing 5b and catalyst 12 was diluted to 0.5 M instead of 2.5 M, cooled down to -30 o C, and vigorously stirred to dissipate efficiently the evolved heat, -the crotonaldehyde was added dropwise over 1h at -30 ºC and the resulting reaction mixture was kept at that temperature for 4 h and then allowed to warm slowly to 0 ºC.

Functionalization at C2

As mentioned above, Dr. Marc Presset has already accomplished a large body of work on these transformations in the racemic series, 56 and my work builds up on his findings.

Notably, it was previously found that the ketone group at C2 in 36 could undergo diastereoselective nucleophilic additions with vinyl Grignard reagents from the  face to give the corresponding adduct 38 (Scheme 35, top). Surprisingly, and in apparent contradiction with earlier results (see for example the hydrogenation step in Scheme 29), this reaction indicates that the gem-dimethyl group at C13 induces less steric effect than the axial methyl group at C8. The reaction however required some thermal activation to proceed efficiently.

Next, an allylic transposition from 38 allowed installing the desired double bond  2,3 as in the products 39 and 40 (Scheme 35, bottom). A number of conditions were then tested to perform the diastereoselective hydrogenation, or more generally the reduction, of the double bond in 39 and its derivatives. A few attempts were also performed for the rhodium-catalyzed isomerization of the allylic alcohol moiety in 40 into the corresponding saturated aldehyde.

Regrettably, no suitable conditions could be identified, compound 39 and its derivatives being extremely stable. This chemical inertness of these compounds toward hydrogenation and isomerization reactions was attributed, again, to the very crowded environment of the  2,3 double bond. hydrogenation product be detected after 24 hours. However, forcing a little the conditions, that is in toluene under 50 bars of H 2 at 100 ºC, allowed for the first time the hydrogenation of the  2,3 double bond in 42 to afford 43 (Scheme 37). These conditions were also suitable for the hydrogenation of the parent unsaturated hydroxyacid 41 to give the products 44 and 45. In both cases the isolated yield was excellent, producing three diastereomers, and in the case of the acid-containing product some spontaneous lactonization was observed as in 45. We were very happy with this result, but were unable to determine the relative configurations of the various diastereomers at this stage.

Scheme 37. Hydrogenation of the  2,3 double bond

In order to do so, it was decided to convert a 1:1:1 mixture of the three diastereomers present in 43 (sample obtained by silica gel chromatography from the crude product) into the corresponding diacid 48 (1:1:1 dr) and compare the spectroscopic data of this material with those of the natural product VI. Thus, the primary alcohol group in 43 was converted into a carboxylic acid moiety in two steps, 80 and the methyl ester was saponified to afford the expected diacid 48 as a 1:1:1 mixture of diastereomers (Scheme 38). It was a great disappointment when we realized that none of the three diastereomers of 48 show comparable NMR data with the natural product VI. Actually, our sample of 48 contains all the possible non-natural diastereomers of the natural product. proton would be able to do so. However, the C2 position in 35 is electrophilic, and an umpolung at C2 would be necessary in order to achieve such a transformation. As mentioned in Chapter 1, NHCs are capable of catalyzing umpolung reactions of aldehydes via the Breslow intermediate. With -unsaturated aldehydes, conjugated Breslow intermediates are formed, and these species are at the core of the chemistry of homoenolates. 82 More specifically, the groups of Scheidt and Bode simultaneously reported that catalytically generated homoenolates react with alcohols to afford the corresponding saturated esters, thereby providing a method for the NHC-catalyzed conversion of -unsaturated aldehydes into saturated esters (Scheme 41). 83 The main side-product observed during these reactions is the oxidized -unsaturated ester. The latter is believed to result from a Cannizzaro-like generation of a hydride equivalent from the aldehyde. beneficial effect was observed in our case with the best base identified (N,N-diisopropylethylamine [DIPEA]). After these trials, the strategy was abandoned.

Scheme 42. NHC-catalyzed redox reactions of 50

Ultimately, we explored some radical-mediated transformations for the reduction at C2.

Dr. Marc Presser already explored some related routes during his thesis. 56 In 1993, Sir Barton reported a study on the stability and radical deoxygenation of tertiary xanthates. 84 Following the described conditions, we tried to prepare the tertiary xanthate 52 from the tertiary alcohol 51 derived from the nucleophilic addition of allyl magnesium bromide to the ketone 36 of products (degradation) from which we could not identify the desired allylated product.

However, ca. 15-30% of the allyl ether product 59 (not isolated) could be identified. A plausible explanation for this unexpected outcome would involve the formation of an alkoxyl (and not alkyl as desired) radical from the precursor 58.

Scheme 48. Generation of a radical at C2 via a N-(alkoxyoxalyloxy)pyridine-2-thione From all the above, it was concluded that our retrosynthetic analysis for (-)-isishippuric acid B (VI) presented in Scheme 32 has very few chances to be correct. Indeed, and after considerable efforts, the diastereoselective manipulation of the retrosynthetic intermediates 35

and 36 at C2 was found very difficult, and when possible, it afforded the wrong relative configuration. For example, we could prepare all the non-natural diastereomers of the natural product VI by this approach, but not the only desired naturally occurring one. At this stage of my work, it was decided to change the natural product synthetic target from (-)-isishippuric acid B (VI) to (+)-suberosenone (III) and/or (-)-suberosanone (IV). This part of my work is detailed in the next section.

Total synthesis of (-)-suberosanone (IV) and formal

synthesis of (+)-suberosenone (III)

Retrosynthetic analysis

Based on the work of Danishefsky 72 and others 63 on the total synthesis of quadrone (I), it was postulated that a diastereoselective hydrogenation of the cyclopentenone 60 would be possible from the  face to afford the tricyclic ring system of (+)-suberosenone (III) and (-

)

The Arndt-Eistert homologation

The synthesis started with the ketone 36 obtained as described above (Scheme 34 Regrettably, we were not able to prepare the required diazoketone in the presence of the free alcohol under the same conditions as above (Scheme 51).

Scheme 51. Toward the Arndt-Eistert homologation with a free alcohol

As demonstrated above, the nucleophilic addition to the ketone group at C2 in substrate 36 is very difficult, meaning that its protection, for example as an acetal, would also be very challenging. So we decided to mask this ketone group as a benzyl ether. Although this strategy is step-demanding (4 steps are required to protect/deprotect the ketone), we finally got a little lucky with this idea. As mentioned above, the two diastereomers of 57 cannot be separated by silica gel chromatography. When 57 (dr Me ax :Me eq = 2:1, er Me ax = 8:1) was treated with sodium hydride (2.5 equiv) / benzyl bromide (2.2 equiv) in order to prepare the corresponding benzyl ether as a mixture of diastereomers, we had a good surprise to observe that the diastereomer with the equatorial methyl group was totally etherified to give the product 65b, and that only a fraction of the diastereomer with the axial methyl group was converted into the corresponding benzyl ether. However, when the same reaction was conducted with 10 equiv of sodium hydride, most of the two diastereomers of 57 were converted into the corresponding benzyl ethers 65. We saw here an opportunity to separate the two diastereomers of 57 taking advantage of this difference of kinetic. And indeed, after several trials, we have found some good conditions to achieve the selective etherification of the diastereomer of 57 with the equatorial methyl group, allowing for the quantitative recovery of the diastereochemically pure product 57a having an axial methyl group (Scheme 52).

Scheme 52. Separation of 57

The above kinetically driven separation was a big step further and a great relief for us.

Indeed, it may not have been realized yet that all the work described above was conducted using mixtures of diastereomers (moreover in various amounts depending on batches), which complicated a lot the purification, analysis and structural determination of our products. In the following, only diastereomerically pure compounds will be used.

In order to make sure that no racemization occurred during the Barton-McCombie deoxygenation (Scheme 34), the enantiomeric ratio of 57a was measured. As expected, we have found 8:1 er, a value identical to the one measured on compound 16b (see Scheme 33) before the Barton-McCombie deoxygenation, thereby attesting that no racemization occurred.

Luckily, compound 57a was obtained as a white solid after its chromatographic separation from the benzyl ether 65b. At this stage we attempted a recrystallization of 57a (8:1 er) with the idea to obtain some material with higher er for the completion of the syntheses. The compound 57a was found soluble in all the tested organic solvents, going from non-polar hydrocarbons (e.g. pentane) to polar and/or protic solvents (e.g. THF, MeOH).

After some unsuccessful trials and optimization, it was found that 0.16 M solution of 57a in acetonitrile stored at 0 ºC for 10 days reproducibly afforded beautiful large colorless needles.

The analysis of these crystals by HPLC on chiral stationary phase showed that this material is enantiopure (>99:1 er), the minor enantiomer being undetectable (Figure 9). Also, we examined the er of the mother liquor and we had the good surprise to find that it was racemic (1.02:1 er) after a single recrystallization. We have thus identified extremely efficient conditions for the enantiomeric enrichment of compound 57a by recrystallisation, allowing obtaining crystalline enantiopure material and racemic mother liquor in a single operation.

The enantiopure crystalline 57a was analyzed by X-ray diffraction technique, which allowed confirming its structure, but also its absolute configuration to be as depicted [Flack parameter = 0.05 (6), see Supporting Information] and as desired for the projected synthetic applications (Figure 9).

Figure 9. Enantiomeric enrichment and X-ray diffraction analysis of 57a

With the diastereo-and enantio-pure product 57a in hand, we moved on its homologation by the planned Arndt-Eistert homologation. As shown above, the free hydroxyl group is not compatible with the projected chemistry, and it was converted into the corresponding benzyl ether using KH as a base in the presence of benzyl bromide (Scheme 53). The reaction afforded the protected product 65a in good yield. It can be noted that a simple switch from sodium hydride to potassium hydride dramatically changed the reactivity of the alcoholate corresponding to 57a (compare with Scheme 52).

Scheme 53. Protection of the free hydroxyl group in 57a

As before, the tert-butyl ester moiety in 65a was quantitatively hydrolyzed under acidic conditions, and this time, the resulting carboxylic acid 66 could successfully be converted into the desired diazoketone 67 in good yield (Scheme 54). Under silver(I) catalysis conditions, the Wolff rearrangement proceeded smoothly, affording the expected homologated carboxylic acid 68 in 72% yield (Scheme 54).

Scheme 54. Arndt-Eistert homologation of 66

Completion of the syntheses

Following our synthetic plan, the carboxylic acid moiety in 68 was converted into the corresponding methylketone by treatment with an excess of methyllithium to afford compound 69 (Scheme 55). 92 Then, the hydrogenolysis of the benzyl ether group followed by the oxidation of the resulting secondary alcohol 60 in 70 afforded the targeted diketone 61 in good overall yield (Scheme 55).

Scheme 55. Synthesis of the diketone 61

The projected formation of ring A by an aldolization / crotonization sequence paralleling the work of Kende, 88 Smith, 89 and others 63 was next attempted. Potassium tert-butoxide being identified as the best base in the previously reported closely related transformations, we logically focused our efforts in this direction. The optimization studies were performed on the undesired diastereomer 61b (obtained from 65b), which required 2.1 equiv of t-BuOK in THF at 25 ºC for 3 hours to reach full conversion, and the enone 71b was isolated in 91% yield (Scheme 56). When the same conditions were employed with the correct diastereomer 61 having an axial methyl group, no reaction occurred, demonstrating, again if necessary, the strong steric effect induced by the axial methyl substituent at C8. Finally, increasing the temperature to 69 ºC and using 3. Based on the work of Danishefsky 72 (and others 63 ) illustrated in Scheme 29 (see 23  24), we planned to rely on a diastereoselective -methylation of the enolate derived from the enone 71 followed by a diastereoselective hydrogenation of the double bond to complete the total synthesis of (-)-suberosanone (IV) (Scheme 57). Indeed, the steric effect from the axial methyl at C8 should induced a methylation of the enolate derived from 71 from the  face, and with this additional methyl group on the  face, the hydrogenation should then occur from the  face.

Scheme 57. End-game stereoselectivities

In practice, the treatment of a THF solution of enone 71 with LDA and then iodomethane in the presence of HMPA at low temperature afforded the alkylated product 60 in good yield as the only observable diastereomer in the 1 H NMR spectrum of the crude reaction product (> 25:1 dr) (Scheme 58). Ultimately, a palladium-catalyzed hydrogenation of 60 afforded the target compound (+)-IV quantitatively, again as the only detectable diastereomer by NMR spectroscopy (> 25:1 dr), which completed the total synthesis.

Scheme 58. Completion of the total synthesis of (+)-suberosanone (IV)

In order to ascertain the identity of our synthetic sample of (+)-IV, its spectroscopic data were carefully compared with the data reported by Sheu and co-workers at the time of the isolation and structural identification of (-)-IV from the gorgonian Isis hippuris. 69 Two notable differences were found: 1) in the 1 H NMR data, the chemical shift for the C14 methyl As to the 1 H NMR chemical shift of the C14 methyl group, Dumas and co-workers have reported a signal at 1.13 ppm for their synthetic sample of IV, a value nicely comparable with the one we observed on our own synthetic sample ( = 1.14 ppm). This was reassuring but not enough. On March 5, 2015, we contacted Prof. Sheu, who isolated naturally occurring IV, and informed him on the different chemical shift values reported and/or measured for the hydrogen atoms at C14 for natural and synthetic IV. Very kindly, Prof. Sheu has send to us a copy of the original 1 H NMR spectrum obtained for the natural sample of IV, on which the signal for the hydrogen atoms at C14 is clearly visible at 1.14 ppm, and not at 1.04 ppm as reported in the original paper due to a simple typographical error (Figure 10). We would like to express here our deepest gratitude to Prof. Sheu for making that information available to us. for quadrane sesquiterpenes in the gorgonian Isis hippuris. As shown in Scheme 30, the Kuwahara group reported in 2007 the total synthesis of the natural product (-)-isishippuric 93 The biogenesis of terrecyclene, the generally accepted biosynthetic precursor for quadranes (see ref. 63), has recently been examined computationally: Barquera-Lozada, J. E.; Cuevas, G. J. Org. Chem. 2011, 76, 1572. acid B (VI) from (R)-citronellal, thereby establishing its absolute configuration as (1R). 74 In a follow-up article, the absolute configuration of naturally occurring (-)-isishippuric acid A (V) could also be confirmed as (1R). 94 And it should be noted that the three natural products (- This being said, the discrepancies observed in the absolute value of our synthetic sample of (+)-IV with the two other known samples cannot be ignored (Figure 11). The different HPLC traces obtained from our sample of (+)-IV are reproduced in Figure 12. As can be seen from the bottom DAD-recorded trace at 290 nm, our sample of (+)-suberosanone (IV), although obtained on a 20 mg scale after silica gel chromatography, is not free from impurities, especially some chiral species detected at ca. 10.5 minutes on the chromatograms.

)
These impurities are not visible of the 1 H and 13 C NMR spectra of our sample of (+)-IV (see Supporting Information). Because of the strong absorption observed for the impurities @ 290 nm and the apparent purity of the sample by NMR, it was hypothesized that the impurities exhibit a high molar extinction coefficient  @ 290 nm, indicating a conjugated system as, for example, in the enone 71. The observed variation in the absolute value of the [] D in our sample of (+)-IV was attributed to these impurities. The preparative HPLC purification of our synthetic sample of (+)-IV is on going in order to solve this issue.

94 Torihata, M.; Kuwahara, S. Biosci. Biotechnol. Biochem. 2008, 72, 1628.

Summary and conclusion

Quadranes are sesquiterpene natural products belonging to the larger family of polyquinanes, the biological properties and total syntheses of which have been long studied. 63 In this section of the manuscript, and after considerable difficulties, we are pleased to report the first enantioselective total and formal syntheses of two quadranes, namely (+)-suberosanone (IV) and (+)-suberosenone (III), respectively (Scheme 59). Among the difficulties we faced, we have notably learned what steric effect means to kinetics, and how risky it is to embark on a total synthesis project.

The work described confirmed the recent findings of Dumas and co-workers that (+)-suberosanone-(IV) is (1R)-configured, questioning the occurrence for two enantiodivergent biosynthetic routes to quadranes. In our eyes, further investigations are required to ascertain this point, including the confirmation of the optical rotation of naturally occurring IV and the determination of the absolute configuration of the other quadranes present in the studied sample of Isis hippuris.

Introduction

The results summarized in this Chapter are preliminary, and accordingly, briefly introduced and presented. I actually ran out of time to complete this study.

Glutarimides in drugs and natural products

Glutarimides, that is to say piperidine-2,6-dione derivatives, can be found in numerous biologically active natural products and drugs (Figure 13). Famous examples include cycloheximide (72, a strong protein synthesis inhibition agent) and migrastatin (73, an antimetastatic drug lead) for the natural products, 96 and pomalidomide (74, a thalidomide analog with immunomodulator and anti-angiogenic properties), 97 and aminoglutethimide (75, an anti-steroid synthesis drug) 98 for the synthetic compounds.

Enantioselective routes to glutarimides

As illustrated above, some structurally simple chiral glutarimides have important biological applications, and of course, the control of their absolute configuration is crucial.

The well-known case of thalidomide is a perfect illustration for this. 99 In sharp contrast with the importance of non-racemic glutarimides in chemistry, biology and medicine, there are only a very limited number of studies available on the enantioselective synthesis of glutarimides.

In 2002, Simpkins has reported the desymmetrization of prochiral

Our approach

A few years ago, our group reported some enantioselective organocatalytic Michael additions of activated cyclobutanones to nitroalkenes using bifunctional organocatalysts (Scheme 11). 37 The reaction performed best with cyclobutanone substrates activated by a secondary amide moiety, and a variety of cyclobutanone Michael adducts were obtained with high to excellent yields and stereoselectivities.

From these results, and because of the ring strain energy in cyclobutanones, 104 it was hypothesized that some Lewis base-catalyzed ring-rearrangement of the cyclobutanone products would be possible to afford glutarimides as depicted in Scheme 64. The Lewis base catalyst would first undergo a sp 2 -centered nucleophilic substitution at the cyclobutanone carbonyl group via a retro-Dieckmann-type ring opening to produce the zwitterionic intermediates 78 and then 79 (tautomers), and the latter would then cyclize back by a sp 2 -centered nucleophilic substitution of the nucleophilic nitrogen atom of the secondary amide to the carbonyl group bearing the positively charged Lewis base catalyst, affording both the glutarimide product and liberating the catalyst. As one can see from Scheme 64, some diastereoselectivity issues are anticipated due to a possible loss of chiral information during the process (78  79 should proceed with poor diastereoselectivity).

Scheme 64. Proposed stepwise approach to glutarimides

Ideally, both the enantioselective Michael addition and the ring rearrangement steps should be performed in a bi-organocatalytic cascade process comparable with the methodology detailed in Chapter 1, allowing for a de novo enantioselective synthesis of 104 Reviews: (a) Bellus, D.; Ernst, B. Angew. Chem. Int. Ed. Engl. 1988, 27, 797. (b)

The optically active series

With in hand a method for the preparation of racemic glutarimides via the proposed cascade process, we turned our attention to its development in the enantioselective series. And before going into the overall cascade process, we examined the NHC-catalyzed ring rearrangement step individually. For this purpose, the enantiopure cyclobutanone Michael adduct 82 (11:1 dr, er > 99:1) was allowed to react with a catalytic amount of the NHC IDipp (2) in dichloromethane (Scheme 68). The desired glutarimide product 83 was obtained in 59% yield, but disappointingly, as a 1.6:1 mixture of two almost racemic diastereomers (er = 1:1 and 1.5:1, respectively). While the preparation of 83 as a mixture of two diastereomers was anticipated, its almost complete racemization was not.

Scheme 68. NHC-catalyzed ring rearrangement

In order to determine at what stage the racemization occurred, two control cross-experiments were performed in the racemic series. In the first one (Scheme 69, top), the glutarimide 84 was allowed to react with the NHC IDipp 2 in the presence of the nitroalkene 85 having an extra methyl group. No cross-product 86 could be detected from this reaction, leading to the conclusion that no retro-Michael / Michael process is occurring on the glutarimide product under these conditions. Analogously, the second control experiment (Scheme 69, bottom) was performed from the cyclobutanone adduct 87, still in the presence of the nitroalkene 85. In this case, the glutarimide 84 was obtained in 43% together with the cross-product glutarimide 86 (12%), demonstrating the some retro-Michael / Michael processes occurred before the ring rearrangement.

Conclusion

The preliminary work detailed in this Chapter has allowed obtaining the proof of concept for an enantioselective bi-organocatalytic cascade to convert prochiral cyclobutanones into glutarimides. Some good, but probably not yet best, catalysts have been identified, and the full enantioselective cascade remains to be demonstrated. This and related work is ongoing in our laboratory.

The work described in this manuscript is centered on enantioselective organocatalysis, including methodological developments and their application in the total synthesis of natural products.

Enantioselective organocatalysis, which involves small chiral organic molecules as catalysts in enantioselective transformations, is a very acting field of research in organic chemistry. It has been conceptualized back to 2000, and is now relatively mature. In recent years, the maturity of the field has translated into the emergence of the concept of multi-organocatalysis, involving combination of several organocatalysts in the same reaction mixture for the realization of complex transformations that would be difficult, if not impossible, to realize otherwise.

For example, the group of Rovis described in 2009 a bi-catalytic organocascade involving the combination of an aminocatalyst with a N-heterocyclic carbene (NHC) for the enantioselective synthesis of cyclopentanones (Scheme 72, top). Inspired by this work, and in the continuation of the research program of our group on the properties of NHCs as organocatalytic Brønsted bases, we have imagined a divergent organocascade from the same substrates for the preparation of bridged bicyclic compounds (Scheme 72, bottom).

Scheme 72. Bi-catalytic organocascades combining aminocatalysis and NHC catalysis

We have thus developed an original bi-organocatalytic methodology for the direct and enantioselective synthesis of bridged bicyclic compounds, essentially bicyclo[3.2.1]octane derivatives (Scheme 73 and Chapter 1). The originality of the work lies on the use of a 1,3-imidazol-2-ylidene NHC as an organocatalytic Brønsted base (proton shuttle). A large part of the work has been directed at the optimization of the reaction to minimize the reversibility of the processes at hand (Michael addition & aldolization) in order to maintain a good control of the stereoselectivity.

Scheme 73. Enantioselective bi-catalytic organocascade: synthesis of bicyclo[3.n.1]alkanes

The method was found general and efficient enough for its application to the enantioselective total synthesis of natural products. For this part of the work, we have focused on the synthesis of quadrane sesquiterpenes, and more specifically on the marine natural products (+)-suberosanone and (+)-suberosenone, two compounds with a promising biological profile (Scheme 74 and Chapter 2). Using our methodology as the key step, we could obtain (+)-suberosanone (ee > 99%) with an overall yield of 8% for 15 steps. Notably, this work represents the first enantioselective total synthesis of a quadrane sesquiterpene. A formal synthesis of (+)-suberosenone could also be achieved, and the overall synthetic strategy is believed to be flexible enough for the preparation of many analogs. Through this work, we have notably learned what steric effect means to kinetics, and how challenging it is to embark on a total synthesis project.

Finally, the third and last Chapter of this manuscript details our preliminary work on another enantioselective bi-catalytic organocascade for the preparation of glutarimides. The glutarimide moiety, i.e. the piperidine-2,6-dione moiety, can be found in biologically active natural products and synthetic drugs, but very few methods are available for their enantioselective synthesis. Capitalizing on earlier work from our group, we have examined a bi-catalytic approach based on an enantioselective Michael addition of cyclobutanones activated by a secondary amide moiety using a bifunctional catalyst, combined with a Lewis base catalyst, e.g. a NHC, capable of promoting a ring rearrangement of the intermediate Michael adduct into the desired glutarimide (Scheme 75 and Chapter 3). We have obtained the proof of concept for this original organocascade and identified several promising catalytic systems. This reaction should now be optimized and generalized.

Scheme 75. Enantioselective bi-catalytic organocascade: synthesis of glutarimides

In conclusion, the basic research work presented herein is anchored at the core of modern synthetic organic chemistry, and more specifically in the field of enantioselective multi-organocatalysis. During this work, we have identified two original organocascades and demonstrated the synthetic relevance of one of these through applications in total synthesis. More generally, our work adds to the arsenal of enantioselective multi-catalytic processes for the time-efficient synthesis of complex small molecules. It is the author's view that such modern synthetic processes are keys to unlock the availability of truly complex functional molecules.

ES.0. General experimental information

•All of commercial available reagents were used without further purification unless otherwise stated. Oxygen and/or moisture sensitive reactions and manipulations were performed under argon atmosphere, using syringes, cannula, oven-dried glassware, and dry solvents obtained from a solvent purification system. Anhydrous methanol was prepared by refluxing for 2 hours in the presence of magnesium turnings and distilled under argon.

•Reactions were monitored by TLC visualized by ultraviolet light (254 nm) and/or using an acidic p-anisaldehyde ethanolic solution. Flash chromatography was performed on 40-63 µm silica gel, generally eluted with EtOAc / petroleum ether (herein abbreviated PE, bp 40-60°C) or EtOAc / Et 2 O.

• 1 H NMR data were generally recorded in CDCl 3 at 294 K at 300 MHz or 400 MHz using the residual nondeuterated solvent as an internal standard (δ = 7.26 ppm). 13 C{ 1 H} NMR spectra were generally recorded in CDCl 3 at 294 K at 75 MHz or 100 MHz using the deuterated solvent as an internal standard (δ = 77.16 ppm). In some cases, CD 2 Cl 2 or (CD 3 ) 2 CO were used to record the NMR data, again using the residual nondeuterated solvent as an internal standards. Coupling constants (J) are in Hertz (Hz) and the classical abbreviations are used to describe the signal multiplicities.

•Melting points were measured with a Büchi B-540 apparatus.

•Specific rotations were recorded on an Anton Paar MCP 200 Polarimeter at 589 nm and at 25 o C or 20 o C and specific rotations are reported as follows: specific rotation (concentration in grams/100 mL of solution, solvent).

•Low resolution mass spectra (MS) were recorded on ion trap Brucker Esquire 6000, equipped with an electrospray source (ESI), methanol is used as solvent (Sigma Aldrich/HPLC grade). High resolution mass spectra (HRMS) were recorded at the spectropole (http://fr-chimie.univ-amu.fr/spectropole/) on a Waters Synapt G2 HDMS apparatus using a positive electrospray (ESI) ionization source.

•HPLC analyses for the determination of enantiomeric ratio were performed on a Merck-Hitachi system equipped with Chiralpak AD-H, Chiralcel OD-3, Chiralcel IF,

ES.1. Chemistry of bicyclo[3.n.1]octanes

General procedure: To a solution of α-activated cycloalkanone 5 (0. To a solution of α-carbonylated-cyclopentanone 5 (1.0 equiv) in dry solvent (0.1 M) under an argon atmosphere was added the appropriate base (1.5 equiv) and the mixture was stirred for 5 min at room temperature. ,-unsaturated aldehyde (1.5 equiv) was then added dropwise and the reaction was stirred at room. After full conversion, when K 2 CO 3 was used, simple filtration through a pad of Celite and concentration of the filtrate in vacuum gave the crude bicyclic compounds 7, which were purified by flash chromatography. In the case of DBU, the reaction mixture was poured into saturated aqueous NH 4 Cl and extracted twice with EtOAc.

The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuum to afford the crude bicyclic compounds which were purified by flash chromatography.

▪oxidation of compound 7:

To a solution of compound 7 in dichloromethane was added pyridinium chlorochromate (PCC) (2.0 equiv) and magnesium sulfate (2.0 equiv), the reaction mixture was stirred at room temperature overnight. The resulting crude was filtered, then concentrated in vacuum and purified by flash chromatography to afford compound 16.

Compound 16a

Following the general procedure, the reaction between 5a (92.1 mg, 0. 7.34 -7.27 (m, 2H), 7.25 -7.16 (m, 2H), 7.05 -6.95 (m, 1H), 3.76 -3.58 (m, 1H), 3.44 (d, J = 6.8 Hz, 1H), 3.40 -3.24 (m, 1H), 2.94 -2.39 (m, 3H), 2.37 -2.19 (m, 1H), 2.14 -2.00 (m, 1H), 1.33 (s, 9H). equatorial-Ph: 7. 34 -7.27 (m, 2H), 7.25 -7.16 (m, 2H), 7.05 -6.95 (m, 1H), 3.76 -3.58 (m, 1H), 3.40 -3.24 (m, 1H), 3.03 (dd, J = 16.7, 13.4 Hz, 1H), 2.94 -2.39 (m, 3H), 2.37 -2.19 (m, 1H), 2.14 -2.00 (m, 1H), 1.30 (s, 9H)

Compound 16b

Following the general procedure, the reaction between 5b (106.1 mg, 0.

Compound 16e

Following the general procedure, the reaction between 5e (109.

Compound 16n

Following the general procedure, the reaction between 5e (109.

Compound 16c

The reaction between 5c (123.2 mg, 0. = 16.2, 7.5 Hz, 1H), 2.48 (ddd, J = 22.5, 15.1, 3.9 Hz, 3H), 2.33 -2.16 (m, 2H), 2.04 -1.94 (m, 1H), 1.44 -1.31 (m, 2H), 1.24 (td, J = 13.4, 4.9 Hz, 2H), 0.85 (t, J = 6.9 Hz, 3H).

Compound 16k

Following the general procedure, the reaction between 2-acetylcyclopentanone (61.7, µL (98% purity), 0.5 mmol) and trans-crotonaldehyde (83 µL, 1.0

Compound 16d

Following the general procedure, in the presence of catalyst 12, the reaction between 5d (85.0 mg, 0.

Compound 16g

Following the general procedure, the reaction between 5g (112.

Compound 16f

Following the general procedure, the reaction between 5f (124.

Compound 16m

Following the general procedure, in the presence of catalyst 18, the reaction between methyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride (neutralized with NaOH before using) (141.9 mg, 0. dias), 2.47 (p, J = 6.8 Hz, 1H, dia 1), 2.28 (tt, J = 12.0, 6.1 Hz, 1H, dia 1), 2.12 -1.43 (m, 6H×4, 4 dias), 1.33 -1.19 (m, 1H×4, 4 dias), 1.15 (s, 3H, dia 1), 1.12 (s, 3H, dia 2), 0.95 (s, 3H, dia 1), 0.94 (s, 3H, dia 2), 0.89 (d, J = 6.9 Hz, 3H, dia 1), 0.77 (d, J = 6.5 Hz, 3H, dia 2), 0.68 (d, J = 6.5 Hz, 3H, dia 3), 0.67 (d, J = 6.4 Hz, 3H, dia 4). Crude acid 62 was subjected to benzene (5 mL, 0.05 M), and then oxalyl chloride (197.3 µL, 2.3 mmol) was injected to the benzene solution. The reaction mixture was stirred under reflux and argon atmosphere overnight. After completion, benzene and excess oxalyl chloride was removed by vacuum to afford an acyl chloride which was used directly. To a solution of generating acyl chloride in mixture solvents of THF and acetonitrile (5 mL, v : v = 1:1) was added trimethylsilyldiazomethane (230 µL, 2.0 M in hexane) at 0 o C, then the reaction solution was allowed to warm to room temperature and stirred for 10h to give diazoketone 63 (40.4 13.3, 9.7, 6.5, 3.2 Hz, 1H), 1.62-1.58 (m, 1H), 1.48-1.41 (m, 1H), 1.35 (s, 9H), 1.26 -1.11 (m, 2H), 0.98 (s, 3H), 0.96 (s, 3H), 0.84-0.75 (m, 1H), 0.68 (d, J = 6.5 Hz, 3H).

▪benzylation of 57a to 65a

To a solution of 57a (192.5 mg, 0.72 mmol) To a solution of ketone 60 (42.7 mg, 0.196 mmol) in ethyl acetate was added Pd/C (20.9 mg, 0.02 mmol, 10 % loading on carbon), then bubbled H 2 for 2 minutes. The reaction was stirred vigorously with a hydrogen balloon (1 atm.) at room temperature. After 1 hour, the reaction completed. Pd/C was filtered, and the filtrate was concentrated in vacuum to afford IV (42.8 mg, >99 %) without purification as a colorless oil which is not UV active and is not visible even though soaked by stains.

Schéma 4 .

 4 Organocascade bi-catalytique énantiosélective : synthèse de glutarimides

Figure 2 .Scheme 4 .

 24 Figure 2. Representative popular chiral Lewis base organocatalysts

Figure 3 .

 3 Figure 3. The four common classes of NHCs

Figure 4

 4 Figure 4. 25

Figure 4 .

 4 Figure 4. Relative Brønsted basicities of NHCs. The pKa values are for the corresponding azolium salts, and are of course highly dependent on the nature of the R i substituents.

Scheme 6 .

 6 Scheme 6. (a) Examples of NHC-catalyzed Michael addition and Michael / aldol cascade. 26 (b) Cross-experiments probing the non-reversibility of the NHC-catalyzed Michael addition.

Figure 5 .

 5 Figure 5. Classification of catalytic systems involving two catalysts. Reproduced from ref 36.

  Scheme 13. Michael / benzoin organocascade under iminium / NHC activation

( a )

 a The reaction was carried out in 2.5 mol/L MeOH, the reaction time of aldolization is 2-10 h;(b) The reaction was carried out in 2.5 mol/L (CF 3 ) 2 CHOH, the reaction time of aldolization is 5 h;(c) The reaction was carried out in 10.0 mol/L MeOH, the reaction time of aldolization is 5 h.;(d) The reaction was carried out in 0.5 mol/L MeOH, the reaction time of aldolization is 5 h; (e) The enantiomeric ratio was determined by HPLC on a chiral stationary phase for the major diastereomer having the axial methyl group (see experimental section).

Figure 8 :

 8 Figure 8: Four representative quadranes isolated from marine sources

Scheme 35 .

 35 Scheme 35. Early results in the racemic series (from the PhD thesis of Dr.Marc Presset)

Scheme 41 .

 41 Scheme 41. Homoenolate generation and protonation by Scheidt and Bode

  group of natural IV was reported at 1.04 ppm while our synthetic sample of IV showed a signal at1.14 ppm; and 2) the [] D value of natural IV was reported at [] D 25 = -60 (c = 0.1, CHCl 3 ), while we measured [] D 25 = +17 (c = 0.1, CHCl 3 ) for our synthetic sample. Two puzzling and anxiety-provoking observations! Research programs aiming at the total synthesis of never-prepared natural products are a risky activity. Indeed, one may, for example, end up with the finding that the proposed structure is actually wrong, turning down most of the synthetic efforts. Or eventually, just a few days before you obtain the long-desired first milligram of the targeted product, one may discover in the literature that another group was working on the same synthesis and published before you. And this is exactly what happened to us one morning of January 2015 when we saw the Dumas paper in the asap of Chemical Communications. 75 The story could have been sad, but actually, the contribution from Dumas and co-workers was more a blessing than a problem to us.

Figure 10 .

 10 Figure 10. The 1 H NMR spectrum of naturally occurring (-)-IV (courtesy of Prof. J.-H. Sheu)

Figure 11 .

 11 Figure 11. The different [] D values reported for IV

Figure 12 .

 12 Figure 12. HPLC traces of our sample of (+)-IV. Top: detector = circular dichroism @ 290 nm; Middle = on line polarimeter equipped with a Hg(Xe) lamp; Bottom: detector = UV detector @ 290 nm. For details see ref 95 .

Figure 13 .

 13 Figure 13. Naturally occurring and synthetic drugs with a glutarimide moiety

Scheme 61 .

 61 Scheme 61. Dixon alkylation with cyclic sulfamidates

  5 mmol) and α,β-unsaturated aldehyde(1.0 mmol) in dry solvent (0.2 mL) under argon atmosphere was added (S)-α,α-bis[3,5-bis(trifluoromethyl) phenyl]-2-pyrrolidinemethanol trimethylsilyl ether tert-Butyl-3-methyl-5-benzyl-4-imidazolidinone (MacMillan catalyst 18) (15 mol%).Then the mixture was stirred at 0 o C or room temperature, the reaction was monitored bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene (IDipp) (20 mol%) was added. The reaction mixture was concentrated in vacuum to afford compound 7 (purify or not depend on the followed reaction) ▪preparation of racemate:

  5 mmol) and trans-crotonaldehyde (83 µL, 1.0 mmol) at 0 o C using catalyst 12 in MeOH (2.5 M) afforded compound 16a (94.6 mg, 75 %, 4:1 dr, 19:1 er) as a white solid after silica gel purification. R f (PE/EtOAc: 4/1) = 0.26; M.p. = 111-119 o C; HRMS (ESI+) for C 14 H 21 O 4 + : calcd. [M+H] + : 253.1434, found: 253.1428; HPLC (Lux-Amylose-2, Heptane/ethanol 80/20, 1.0 mL/min, UV 220 nm): τ axial-Me = 6.85 min and 7.29 min 13 C NMR (100 MHz,  ppm/CDCl 3 ): axial-Me: 205.1 (C), 200.4 (C), 169.6 (C), 82.1 (C), 65.7 (CH), 60.7 (C), 42.

Table 1 :

 1 comparison of 1 H chemical shifts of (-)-isishippuric acid B and compound 48(d, J = 14.0 Hz, 1H) 2.45(d, J = 14.0 Hz, 1H) To a solution of 36 (479.5 mg, 1.80 mmol, 2:1) in ethanol was added NaBH 4 (170.2 mg, 4.5 mmol). The reaction mixture was heated to 78 o C for 10h. The reaction mixture was then poured into saturated aqueous NH 4 Cl, extracted with diethyl ether, dried over Na 2 SO 4 and concentrated in vacuum. Purification by flash chromatography afforded compound 57 (57a and 57b: 372.0 mg, 77 %, 2:1 dr). R f = 0.53 (PE:EtOAc/9:1).

25. 3 (

 3 CH 2 ), 25.0 (CH 3 ), 19.8 (CH 3 ), 18.3 (CH 2 ); 1 H NMR (300 MHz,  ppm/CDCl 3 ): 7.29-7.13 (m, 5H), 4.53 (d, J = 12.0 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.33 (d, J = 4.6 Hz, 1H), 2.09 (p, J = 7.1 Hz, 1H), 2.01 -1.79 (m, 2H), 1.63 (br. s, 1H), 1.53(d, J = 13.7 Hz, 1H), 1.47(d, J = 13.7 Hz, 1H), 1.37 (s, 9H), 1.32 -1.16 (m, 2H), 1.12 (d, J = 7.3 Hz, 3H), 1.02 (s, 3H),0.98 (s, 3H).▪saponification of t-butyl ester 65a to acid 66To a solution of 65a (232.3 mg, 0.65 mmol) in dichloromethane (12.9 mL, 0.05 M) was added trifluoroacetic acid (995 µL, 13.0 mmol) at 0 o C, then the reaction solution was warmed to room temperature, stirred for 2 hours, concentrated in vacuum. Purification by flash chromatography afforded compound 66(193.5 mg, 99 %) as a white solid. R f = 0.27 (PE:EtOAc/4:1). Mp = 134 -135 o C. HRMS (ESI+) for C 19 H 27 O 3 + : calcd. [M+H] + : 303.1955, found: 303.1960; C 19 H 30 NO 3 + : calcd. [M+NH 4 ] + : 320.2226, found: 320.2220; [ ] = +10.3 (c 1.0, EtOH absolute ). 13 C NMR (75 MHz,  ppm/(CD 3 ) 2 CO): 177.6 (C), 140.4 (C), 128.9 (CH×2), 128.0 (CH×2), 127.9 (CH), 83.0 (CH), 73.0 (CH 2 ), 54.9 (C), 50.0 (CH 2 ), 46.9 (CH),

  (ddd, J = 20.9, 14.1, 7.2 Hz, 1H) 10α 10β1.62 (ddd, J = 13.5, 6.5, 2.5 Hz, 1H) 1.68 (m, 1H)1.70 -1.55 (m, 2H)ES.3. Chemistry of glurarimides ▪preparation of catalyst 3 and α-substituted-β-oxocyclobutanecarboxamidesThe preparation of squaramide catalyst 80 was according to Rawal 109 and He'and nitrostyrenes under the catalysis of squaramide catalyst80. 111 ▪preparation of racemic glutarimidesTo a solution of α-substituted-β-oxocyclobutanecarboxamides (1.0 equiv) in DCM (0.05 M) was added nitrostyrene (2.0 equiv) and IDipp 2 (0.2 equiv). The reaction mixture was stirred at room temperature under an argon atmosphere for 20h. The reaction solution was then concentrated in vacuum, purified by flash chromatography to afford glutarimides.▪enantioselective synthesis of glutarimide 83

  enaminol intermediate, the so-called Breslow intermediate, from benzaldehyde and the NHC catalyst. As illustrated above in Scheme 5, both the nucleophilic  and electrophilic  orbitals of the carbene atom are involved in the formation of the Breslow intermediate. This nucleophilic species (equivalent to a d 1 -synthon in the terminology of Seebach for umpolung reactions 34 ) can add to a second molecule of benzaldehyde to finally produce benzoin and liberate the NHC catalyst.

	Scheme 10. The enantioselective NHC-catalyzed benzoin condensation

33

(a)

Enders, D.; Kallfass, U. Angew. Chem. Int. Ed. 2002, 41, 1743.

For the current state of the art catalyst for the benzoin condensation of benzaldehyde: (b) Baragwanath, L.; Rose, C. A.; Zeitler, K.; Connon, S. J. J.

Org. Chem. 2009, 74, 9214. 34 Seebach, D. Angew. Chem. Int. Ed. 1979, 18, 239.

1.2. Original enantioselective bi-organocatalytic synthesis of bicyclo[3.2.1]octanes 1.2.1. Preparation of substrates

	1.1.3. The recent work summarized above for the single step synthesis of optically active Single step enantioselective construction of
	bicyclo[3.2.1]octane derivatives highlights, if necessary, the advantages of enantioselective bicyclo[3.2.1]octanes metallic or organic catalysis over the chiral auxiliary and chiral pool approaches. However,
	A highlight-type article from our group has recently appeared in the literature on this and despite the recent progresses in the field, a general efficient enantioselective catalytic
	topic, 44 and only a synopsis of the work described therein, together with the most recent work approach is still highly desirable, especially for applications in the synthesis of natural
	products. Our own approach is detailed in the next section of this manuscript. will be described here. Most of the substrates, reagents and catalysts used for the work were obtained by
	Although several approaches to optically active bicyclo[3.2.1]octane derivatives have been described from the chiral pool or by multi-step synthesis, 45 only a few approaches are available for their single-step enantioselective synthesis. Among these, we can mention the early work of Engler and co-workers, who achieved enantioselective 6 (5+2) cycloadditions of 1,4-benzoquinones with aromatic olefins using a titanium-TADDOLate complex catalyst The same year, the Rueping group developed a different clever approach based on a Michael / aldol organocascade from cyclohexane-1,2-dione and -unsaturated aldehydes using the Hayashi-Jørgensen aminocatalyst (Scheme 18, top). 48 A remarkable feature of the Scheme 18. Enantioselective Michael / aldol organocascades for the synthesis of commercial sources. The non-commercially available cyclic -ketoesters and -ketoamides of type 5 were easily prepared from the corresponding 2-diazo-cyclopentan-1,3-diones 53 and one equivalent of alcohols or amines (Scheme 20). 54 The method involves a microwave-assisted Wolff rearrangement of the diazo substrate to produce an -oxo-ketene intermediate, which is trapped by the nucleophilic alcohol or amine substrate to give the (Scheme 16). Scheme 17. Enantioselective Michael / elimination / Michael organocascade reaction is that cyclohexane-1,2-dione reacts successively as a nucleophile and an electrophile bicyclo[3.2.1]octanes product 5.
	involving an iminium / enamine cascade activation with the same aminocatalyst. Shortly after,
	and contemporaneously with Zhao and coworkers, 49 the Rueping group reported a Finally, the Alexakis group recently reported an approach to the bicyclo[3.2.1] ring
	conceptually similar enantioselective organocatalytic Michael-Henry cascade from system based on a distinct Michael / aldol cascade, also using a bifunctional Brønsted
	cyclohexan-1,2-dione and nitrostyrene derivatives, using a bifunctional Brønsted base/H-bond base/H-bond donor bifunctional catalyst (Scheme 19). 52 In this work, and in analogy with the
	donor catalyst. 50 In a closely related study, Zhong and coworkers used 2-carbomethoxy work we plan to develop, a 2-oxo-cyclopentane carboxylic acid derivative is used as
	cyclohexan-1,4-dione for the efficient construction of the bridged products and more recently bis-pronucleophile in combination with an activated -unsaturated ketone acting as a
	Kokotos and co-workers developed a complementary sequence with simple bis-electrophile. Although the method was found relatively general and efficient in terms of
	cyclohexan-1,4-dione (Scheme 18, bottom). 51 isolated yields of the product, it suffers from stereoselectivity issues.
	Scheme 15. A divergence point in dual iminium / NHC organocatalytic activation Scheme 20. Microwave-assisted synthesis of -ketoesters and -ketoamides
	The -ketosulfone 5g was previously prepared in the laboratory and was obtained by
	oxidation of the corresponding sulfide using described methods (Scheme 21). 55
	Scheme 19. Enantioselective Michael / aldol organocascade for the synthesis of
	bicyclo[3.2.1]octanes
	48 Rueping, M.; Kuenkel, A.; Bats, J. W. Angew. Chem. Int. Ed. 2009, 48, 3699. Scheme 21. Synthesis of the -ketosulfone 1g
	49 Ding, D.; Zhao, C.-G.; Guo, Q.; Arman, H. Tetrahedron 2010, 66, 4423.
	50 Rueping, M.; Kuenkel, A.; Fröhlich, R. Chem. Eur. J. 2010, 16, 4173.
	51 (a) Tan, B.; Lu, Y.; Zeng, X.; Chua, P. J., Zhong, G. Org. Lett. 2010, 12, 2682 (erratum: ibid Org. Lett. 2010, 52 (a) Lefranc, A.; Gremaud, L.; Alexakis, A. Org. Lett. 2014, 16, 5242. For an early comparable approach: (b)
	12, 2892). (b) Tsakos, M.; Elsegood, M. R. J.; Kokotos, C. G. Chem. Commun. 2013, 49, 2219. Cao, C.-L.; Sun, X.-L.; Kang, Y.-B.; Tang, Y. Org. Lett. 2007, 9, 4151.

46

A few other metal-catalyzed transformations were also developed. 44

Scheme 16. Titanium(IV)-catalyzed enantioselective 6 (5+2) cycloaddition

As to organocatalytic approaches, a few systems were described early on over the 2000-2007 period, but none of these were found both general and efficient. A significant step further was accomplished in 2009 with the work of Tang, Li and their co-workers who described a general approach to bicyclo[3.n.1] derivatives involving an interesting Michael / elimination / Michael cascade sequence catalyzed by a bifunctional aminocatalyst operating by enamine / H-bonding activation (Scheme 17). 47 Although a single example of a bicyclo[3.2.1]octane product was reported in the study, it was obtained in high yield, diastereo-and enantio-selectivity.

44

Presset, M.; Coquerel, Y.; Rodriguez, J. ChemCatChem 2012, 4, 172. 45 Presset, M.; Coquerel, Y.; Rodriguez, J. Chem. Rev. 2013, 113, 525. 46 Enders, T. A.; Letavic, M. A. J. Org. Chem. 1999, 64, 2391. 47 Cao, C.-L.; Zhou, Y.-Y.; Zhou, J.; Sun, X.-L.; Tang, Y.; Li, Y.-X.; Li, G.-Y.; Sun, J. Chem. Eur. J. 2009, 15, 11384.

1.2.2. Early work

	In our group, the first trial for enantioselective organocatalytic Michael / aldol
	organocascades leading to optically active bicyclo[3.2.1]octane derivatives dates back to 2008
	with the PhD thesis of Dr. Marc Presset. 56 At that time, a series of organocatalysts known to
	catalyze Michael addition reactions were tested in the model reaction depicted below (Scheme
	22). Regrettably, and despite the fact that some Michael / aldol cascades were found to be
	catalyzed by a single organocatalyst (iminium then enamine activation), 10d none of the tested
	catalysts was able to promote the desired organocascade, and only the Michael adducts were
	obtained in moderate yields (24-59%) with poor to excellent diastereoselectivites. The
	enantioselectivity of the reactions was not examined during this work.
	Scheme 22. Evaluation of catalysts for Michael-Aldol reaction
	56 Dr. Marc Presset, PhD thesis Aix-Marseille Université 2010, DOI: 2010AIX30033

Table 1 .

 1 Optimization of reaction time and temperature with catalysts 12 and 18

	entry	cat	T.( o C)	reaction time of MA (h)	product (%)	dr (ax : eq.)	er e
	1 a	12	25	18	74	4:1	17.2:1
	2 a	18	25	72	60	4:1	9.5:1
	3 b	12	25	72	55	4:1	7.3:1
	4 c	12	25	120	20	3:1	4:1
	5 d	12	25	72	70	3:1	7:1
	6 a	12	0	22	75	4:1	19:1
	7 a	18	0	96	_	_	_
	8 a	12	-10	64	72	4:1	19:1

  reaction with methyl acrylate to afford the bicyclic intermediate 26. After some chemical manipulations, the key diester intermediate 27 could be obtained. The bicyclo[3.2.1]octane ring system of the natural product was next elaborated by an elegant intramolecular Michael addition, regrettably performing with a moderate diastereoselectivity (dr = 2.3:1), and the

	Scheme 30: Kuwahara's synthesis of (-)-isishippuric acid B (VI)

saponification of the resulting material afforded ()-isishippuric acid B (VI). Overall, this total synthesis of ()-isishippuric acid B (VI) was achieved in 16 steps and 6.9% yield from (R)-citronellal, which allowed establishing the absolute configuration of naturally occurring (-)-VI as (1R).

74 Torihata, M.; Nakahata, T.; Kuwahara, S. Org.

Lett. 2007, 9, 2557.

2.2.1. Construction of the bicyclo[3.2.1]octane The bicatalytic Michael / aldol organocascade

	As detailed in Chapter 1, we have developed a method to prepare optically active
	bicyclo[3.2.1]octane derivatives based on a bicatalytic enantioselective organocascade
	combining iminium activation with NHC activation. Using this method on a 10-gram scale

  combined together, these results indicate that the diastereoselective hydrogenation of the retrosynthetic intermediate 35 and/or its analogs from the  face is very unlikely to occur.Aware of the recent work of Prof. Clément Mazet in Geneva on the iridium-catalyzed isomerization of allylic alcohols into aldehydes, 81 we initiated collaboration with him to test his method on our challenging substrates. We selected the representative substrates 41 and 42 for these tests, which were sent to Prof. Mazet in Geneva. M. Hou-hua Li, a PhD student in the Mazet group performed the isomerization reactions. It was found that the acid-containing substrate 41 is inert under the reaction conditions, probably due to chemical incompatibility of the carboxylic acid moiety with the cationic iridium catalyst (Scheme 40). However, substrate 42 (1:2 Me ax :Me eq dr) did undergo some isomerization reaction, but only the undesired diastereomer with the equatorial methyl group could be converted into the corresponding aldehyde, moreover with the wrong relative configuration at C2 (Scheme 40). The unreacted diastereomer with the axial methyl group in 42 was recovered (in part), and the rest of the material could not be identified.

	Scheme 40. Iridium-catalyzed isomerization reactions (performed in the Mazet group)
	At that stage of our studies, it was decided to stop the hydrogenation strategy to obtain
	the targeted natural product (-)-isishippuric acid B (VI). As demonstrated above, the severe
	steric effect observed on the retrosynthetic intermediate 35 and its analogs precludes the

80

For the Lindgren-Pinnick oxidation: (a) Lindgren, B. O.; Nilsson, T. Acta Chem.

Scand. 1973, 27, 888. (b)

Kraus, G. A.; Taschner, M. J. J.

Org. Chem. 1980, 45, 1175. (c)

Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091. All approach of large entities to C2 from the  face. It was hypothesized that may be a simple 81 (a) Mantilli, L.; Mazet, C. Angew. Chem. Int. Ed. 2009, 48, 5143. (b) Mantilli, L.; Mazet, C. Eur. J. Inorg. Chem. 2012, 3320. (c) Mazet, C. CHIMIA, 2011, 65, 802.

  Scheme 43). Using the previously developed conditions (see above), we could prepare the desired tertiary alcohol 51 in 60% yield. However, the corresponding xanthate 52 could not be obtained under the conditions described by Barton using KH as the base and CS 2 /MeI as the trapping agent, leaving the substrate 51 unreacted. Practically, 57cshowing an equatorial hydroxyl group could be separated from the two other diastereomers by silica gel chromatography, but 57a and 57b could not be separated at this stage. Reduction at C2 with sodium borohydride (from Dr. Marc Presset PhD thesis)Based on the work of Oshima on the radical-mediated allylation of primary, secondary and tertiary alkyl halides, 86 we tried to generate the secondary alkyl bromide or iodide from the mixture of diastereomer alcohols 57a and 57b (Scheme 47). Several halogen sources were tested, including iodine, bromine, phosphorus tribromide, and carbon tetrabromide in Appel-like reactions, but in no case a reaction was observed and the starting alcohols were recovered in full.

	Scheme 45. Attempts for the preparation of a tertiary thiocarbamate From the above, it was concluded that the desired tertiary radical would be very difficult to generate. It was then decided to study the generation of the corresponding secondary radical at C2. During his thesis, Dr. Marc Presset identified that sodium borohydride could add to the ketone group at C2 in 36 to afford the corresponding secondary alcohol (Scheme Finally, we also attempted the generation of the desired secondary radical at C2 using the remote system developed by Barton, Newcomb and Crich via a N-(alkoxyoxalyloxy)pyridine-2-thione. 87 The reaction must be conducted in a one-pot manner without isolating any intermediate. After some optimization on model compounds, we succeeded in preparing the desired radical precursor 58 (not isolated because unstable), but its 46). Scheme 46. Scheme 47. Attempts for Appel-type reactions at C2 reaction in the presence of a radical initiator and allyltributyltin only led to complex mixtures

84

Barton, D. H.; Tse, C. H. Tetrahedron Lett. 1993, 34, 2733.

(Scheme 43. Attempts for the radical deoxygenation of a tertiary xanthate Alternatively, we tried to prepare the corresponding tertiary thiocarbamate from 53, which should be reductible under radical conditions.

85

Two different electrophiles were tested in these reactions, namely di(1H-imidazol-1-yl)methanethione 54 and phenyl isothiocyanate 56, using two sets of conditions (Scheme 44). In most cases, no reaction occurred. And when something happened, the reaction led to degradation, or in the best case, to the isolation of the undesired diastereomer with the equatorial methyl group as in 55 (the diastereomer of 53 with the axial methyl group was recovered unchanged). 85 (a) Yadav, J. S.; Sridhar, B. Org. Lett., 2013, 15, 3782. (b) Yamashita, S.; Hirama, M. Tetrahedron Lett. 2009, 50, 3277. (c) Yamashita, S.; Hirama, M. J. Org. Chem. 2011, 76, 2408.

Scheme 44. Attempts for the radical deoxygenation of a tertiary thiocarbamate

We also tried to trap the magnesium tertiary alcoholate intermediate obtained after the nucleophilic addition of the Grignard reagent with 36 without more success, the tertiary alcohol 51 being isolated in 46% yield under these conditions (Scheme 45).

56

Interestingly, it was found that the diastereomer of 36 with the axial methyl group diastereoselectively underwent hydride addition from the  face affording the axial alcohol 57a, while the diastereomer of 36 with the equatorial methyl group underwent a much less diastereoselective reaction to afford the diastereomer alcohols 57b and 57c.

86 Tsuji, T.; Yorimitsu, H.; Oshima, K. Angew.

Chem. Int. Ed. 2002, 41, 4137. 87

(a) Simakov, P.; Newcomb. M. J. Org. Chem. 1998, 63, 1226. (b) Barton, D.; Zard, S. Tetrahedron 1985, 41, 5507. (c) Crich, D.; Fortt, S. Synthesis 1987, 1, 35.

  -suberosanone (IV, Scheme 49). Similarly, based on the approach of Kende, 88 Smith, 89 and others63 to quadrone (I), the cyclopentenone 60 would be obtained from the diketone 33, the latter being available from the product 7b obtained during the methodological studies presented in Chapter 1. It can already be noted that our retrosynthetic plan shows some similarities with the recent work of Dumas and co-workers.75

	Scheme 49. Retrosynthetic analysis for (+)-suberosenone (III) and (-)-suberosanone
	(IV)

88 Kende, A. S.; Roth, B.; Sanfilippo, P. J.; Blacklock, T. J. J. Am.

Chem. Soc. 1982, 104, 5808. 89

Smith, III, A.; Slade, J. Tetrahedron

Lett. 1982, 23, 1631.

. Enantioselective synthesis of glutarimides 3.2.1. The racemic series

  (Scheme 65). More specifically, it was anticipated that NHCs could be suitable Lewis base catalysts for this purpose.Of course, we needed a racemic synthesis of the targeted glutarimides. Because the NHC IDipp 2 is 1) a very good Brønsted base catalyst to perform Michael additions, and 2) a very good Lewis base (N parameter  22 105 ), we surmised that both elemental steps of the cascade could be catalyzed by the NHC IDipp (2) acting successively as a Brønsted base and then as a Lewis base. In practice, this idea was evaluated in two model reactions, which indeed afforded the expected glutarimide products 81 but in somewhat low yields at full conversion, and virtually no diastereoselectivity (Scheme 66). The efficiency issue is probably due to the instability of the cyclobutanone substrates in the presence of the NHC IDipp (2).

	Scheme 65. Proposed enantioselective bicatalytic organocascade for the synthesis of glutarimides 3.2Scheme 67. Bi-organocatalytic racemic organocascade

Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449. (c) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485. (d)

The Chemistry of Cyclobutanes, (Eds.: Z. Rappoport, J.F. Liebman), John

Wiley & Sons, Chichester, 2005

. (e) Seiser, T.; Saget, T.; Tran, D. N.; Cramer, N. Angew.

Chem. Int. Ed. 2011, 50, 7740.

glutarimides Nevertheless, these first examples validated the strategy.

Scheme 66. Early attempts for the racemic organocascade

In another version of the racemic Michael reaction, two distinct catalysts were used, namely the polystyrene-supported phosphazene base P-BEMP 106 and the NHC IDipp

(2)

, in order to reach an acceptable degree of efficiency (Scheme 67).

105

The nucleophilicity parameter N of the closely related NHC IMes was measured at 21.72. For comparison, the N parameter of triphenylphosphine is 13.59, and the one of DABCO is 18.80 See: (a) Maji, B.; Breugst, M.; Mayr, H. Angew. Chem. Int. Ed. 2011, 50, 6915. (b) Baidya, M.; Kobayashi, S.; Brotzel, F.; Schmidhammer, U.; Riedle, E.; Mayr, H. Angew. Chem. Int. Ed. 2007, 46, 6176. 106 Bensa, D.; Constantieux, T.; Rodriguez, J. Synthesis 2004, 923.

-allylic transposition to 10 and acid 11 poured

  To a suspension ofNaH (52.94 mmol, 1270.6 mg) in THF(0.2 M, 203.6 mL) was added CS 2(24.5 mL, 407.2 mmol) under an argon atmosphere and the mixture was cooled down to 0 o C. 7b(40.72 mmol, 11.5 g, 5.3:4.6:4:1 dr) in THF was added and stirred for 45 min at 0 o C.Then, MeI (81.44 mmol, 5.1 mL) was added and the reaction solution was stirred for 15 h. into 5% aqueous HCl and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na 2 SO 4 , then concentrated in vacuum and purified by flash chromatography to afford acid 41 (154.9 mg, 65%, 1:1 dr). R f = 0.17 (PE:EtOAc/ 6:4); MS

	M.p. = 84-100 o C (s, 9H, dia 3), 1.16 (d, J = 7.2 Hz, 3H, dia 1), 1.33 (s, 3H, dia 1), 1.13 (s, 6H, dia 3), 0.97 (s,
	HRMS (ESI+) for C 18 H 22 NO 4 3H, dia 1), 0.95 (d, J = 7.0 Hz, 3H, dia 3); 13 C NMR (75 MHz,  ppm/CDCl 3 ): + : calcd. [M+H] + : 316.1543, found: 316.1543
	HPLC (Chiralpak IC, Heptane/Ethanol 80/20, 1.0 mL/min, DAD): τ axial-Me = 7.96min and equatorial-Me (equatorial-OH and axial-OH): 212.3 (C), 212.3 (C), 169.0 (C), 169.0 (C),
	8.61 min 13 C NMR (75 MHz,  ppm/CDCl 3 ): axial-Me: 207.2 (C), 202.4 (C), 169.6 (C), 136.8 (C), 128.8 (CH×2), 128.8 (CH×2), 127.9 (CH), 64.8 (CH), 62.8 (CH 2 ), 62.4 (C), 61.2 (CH 2 ), 59.3 (CH 2 ), 52.3 (CH 3 ), 48.9 (CH 2 ), 32.8 (CH), 19.6 (CH 3 ); equatorial-Me: 206.2 (C), 203.4 (C), 170.1 (C), 137.1 (C), 129.2 (CH×2), 128.8 (CH×2), 128.0 (CH), 66.1 (CH), 62.6 (C), 61.5 (CH 2 ), 59.6 (CH 2 ), 56.4 (CH 2 ), 52.7 (CH 3 ), 47.9 (CH 2 ), 31.2 (CH), 16.4 (CH 3 ); 1 H NMR (300 MHz,  ppm/CDCl 3 ): axial-Me: 7.28 -7.13 (m, 5H), 3.71 (s, 3H), 3.50 -3.09 (m, 6H), 2.85 -2.61 (m, 3H), 2.28 (dd, J = 16.0, 6.2 Hz, 1H), 0.92 (d, J = 7.1 Hz, 3H); equatorial-Me: 7.28 -7.13 (m, 5H), 3.70 (s, 3H), 3.50 -3.09 (m, 6H), 2.85 -2.61 (m, 3H), 2.28 (dd, J = 16.0, 6.2 Hz, 1H), 0.87 (d, J = 6.2 Hz, 3H) ▪Cross experiment between a and b To a solution of methyl-2-oxo-cyclopentanecarboxylate (65 µL, 0.5 mmol, 95% purity) in DCM was added methyl acylate (45µL, 0.5 mmol) and P-BEMP (11.4 mg, 10 mmol%, 2.2 mmol/g base loading on polystyrene). The reaction was stirred at room temperature for 24 h. 81.4 (C), 81.4 (C), 72.8 (CH), 72.8 (CH), 64.5 (CH), 64.4 (C), 63.9 (CH), 63.8 (CH), 38.0 (CH 3 ), 37.3 (CH 2 ), 36.6 (CH 2 ), 35.9 (CH 2 ), 35.4 (CH), 35.2 (CH 2 ), 33.8 (C), 33.5 (C), 33.0 (CH 3 ), 32.0 (C), 28.2 (CH 3 ×3, t-Bu), 28.2 (CH 3 ×3, t-Bu), 25.1 (CH 3 ), 24.8 (CH 3 ), 16.6 (CH 3 ), 16.1 (CH 3 ); 1 H NMR (300 MHz,  ppm/CDCl 3 ): equatorial-Me (equatorial-OH and axial-OH): 4.28 -4.24 (m, 1H, dia 2), 4.06 -3.94 (m, 1H, dia 4), 2.88 -2.35 (m, 2H, dia 2), 2.88 -2.35 (m, 2H, dia 4), 2.22 -2.13 (m, 1H, dia 2), 2.22 -2.13 (m, 1H, dia 4), 2.06 -1.93 (m, 2H, dia 2), 2.06 -1.93 (m, 2H, dia 4), 1.79 -1.49 (m, 2H, dia 2), 1.79 -1.49 (m, 2H, dia 4), 1.42 (s, 9H, dia 2), 1.41 (s, 9H, dia 4), 1.00 (s, 3H, dia 2), 1.00 (s, 3H, dia 4), 0.99 (s, 3H, dia 2), 0.99 (s, 3H, dia 4), 0.92 (d, J = 6.7 Hz, 3H, dia 2), 0.88 (d, J = 6.4 Hz, 3H, dia 4) ▪preparation of racemate 7b To a solution of α-carbonylated-cyclopentanone 5b (10.0 grams, 47.1 mmol ) in dry toluene (471 mL, 0.1 M) under an argon atmosphere was added 1,8-diazabicyclo[5.4.0]undec-7-ene (10.6 mL, 70.7 mmol), the mixture was stirred for 10 min at room temperature. Crotonaldehyde 15 (5.9 mL, 70.7 mmol) was then added dropwise and the reaction was stirred at room temperature for 12 h. After full conversion, the reaction mixture was poured into saturated aqueous NH 4 Cl and extracted twice with EtOAc. The combined organic layers The reaction mixture was poured into saturated NaCl, extracted with diethyl ether, dried over NaSO 4 , and then concentrated in vacuum to afford xanthate 37 which was used without further purification. To a solution of 37 in dry toluene under an argon atmosphere were successively added tributyltin hydride (13.1 mL, 48.86 mmol) and azobisisobutyronitrile (AIBN, 668.7 mg, 4.07 mmol). The reaction mixture was heated to 110 o C for 2 h in toluene (200 mL, 0.2M), which then was cooled down to room temperature, concentrated in vacuum. Purification by flash chromatography afforded compound 36 (9219.9 mg, 85%, 2:1 dr) as colorless oil. R f (average) = 0.50 (PE:EtOAc/9:1); HRMS (ESI+) for C 16 H 26 NaO 3 + : calcd. 289.1774 [M+Na] (C), 80.7 (C), 62.5 (C), 58.3 (CH), 46.8 (CH 2 ), 42.2 (CH), 32.5 (C), 31.8 (CH 3 ), 28.5 (CH 2 ), 28.0 (CH 3 ×3, t-Bu), 25.2 (CH 2 ), 22.8 (CH 3 ), 16.3 (CH 3 ); equatorial-Me: 215.6 (C), 169.2 (C), 81.0 (C), 64.5 (C), 56.9 (CH), 42.4 (CH), 37.0 (CH 2 ), 32.7 (C), 32.0 (CH 3 ), 29.9 (CH 2 ), 28.2 (CH 3 ×3, t-Bu), 27.1 (CH 2 ), 23.0 (CH 3 ), 17.0 (CH 3 ); 1 H NMR (300 MHz,  ppm/CDCl 3 ): axial-Me: 2.50 -2.35 (m, 1H), 2.11 -1.44 (m, 6H), 1.32 (s, 9H), 1.24 -1.16 (m, 1H), 1.08 (s, 3H), 1.02 (d, J = 7.1 Hz, 3H), 0.91 (s, 3H); equatorial-Me: 2.50 -2.35 (m, 1H), 2.11 -1.44 (m, 6H), 1.35 (s, 9H), 1.24 -1.16 (m, 1H), 1.07 (s, 3H), 0.88 (s, 3H), 0.77 (d, J = 6.9 Hz, 3H) (C), 120.2 (CH), 60.1 (CH 2 ), 58.3 (C), 50.0 (CH 2 ), 49.4 (CH), 38.9 (CH), 36.6 (C), 32.8 (CH), 29.6 (CH 2 ), 26.4 (CH 2 ), 22.9 (CH 3 ), 17.1 (CH 3 ). Equatorial-Me:178.3 (C), 153.7 (C), 115.2 (CH), 60.2 (C), 60.0 (CH 2 ), 39.3 (CH 2 ), 48.4 (CH), 41.4 (CH), 37.3 (C), 32.7 (CH), 28.0 (CH 2 ), 25.7 (CH 2 ), 23.0 (CH 3 ), 17.6 (CH 3 ); 1 H NMR (300 MHz,  ppm/CDCl 3 ): Axial-Me: 7.37 (br. s, 1H), 5.65 (t, J = 6.9 Hz, 1H), 4.27 -4.07 (m, 2H), 2.30(m, 1H), 2.24 -2.15 (m, 1H), 2.04 -1.76 (m, 3H), 1.63 -1.40 (m, 3H), 1.32 -1.13 (m, 1H), 1.10 (s, 3H), 0.94 (s, 3H), 0.91(d, 3H, estimated: covered by the dimethyl group). Equatorial-Me: 7.36 (br. s, 1H), 5.54 (t, J = 6.8 Hz, 1H), 4.27 -4.07 (m, 2H), 2.30(m, 1H), 2.24 -2.15 (m, 1H), 2.04 -1.76 (m, 3H), 1.63 -1.40 (m, 3H), 1.32 -1.13 (m, 1H), 1.07 (s, 3H), 0.93 (s, 3H), 0.79 (d, J = 6.4 Hz, 3H) ▪methylation of 41 to 42 To a solution of acid 41 (238.3 mg, 1 mmol, 1:2 dr Me ax :Me eq ) in dichloromethane and methanol (v:v = 9:1, 3.0 mL) was added (trimethylsilyl)diazomethane (0.5 mL, 2.0 M in hexane) under argon atmosphere. The reaction mixture was stirred under room temperature ▪1,3(ESI-, m/z): 237 [M-H] ; 13 C NMR (75 MHz,  ppm/CDCl 3 ): axial-Me: 180.3 (C), 147.2 overnight, then, concentrated in vacuum and purified by flash chromatography to afford
	P-bemp was removed by filtration, and the filtrate was concentrated in vaccum to afford pure were washed with brine, dried over Na 2 SO 4 and concentrated in vacuum, purified by flash methyl ester 42 (214.5 mg, 85%, 1:2 dr, yellow solid). R f = 0.43 (PE:EtOAc/ 6:4); MS (ESI+,
	Michael adduct (111.8 mg, 98%) without any purification. chromatography to afford bicyclic compound 7b (12.0 grams, 90 %, 4 dias, 1:1:1:1 dr). m/z): 275 [M+Na] + ; 13 C NMR (75 MHz,  ppm/CDCl 3 ): axial-Me:175.5(C), 147.4 (C), 120.5
	To a 20 mL round bottom flask with screwed cap was charged the generated Michael adduct ▪deoxygenation of 7b to carboxylate 36 (CH), 60.2 (CH 2 ), 58.4 (C), 51.7 (CH 3 ), 49.8 (CH 2 ), 49.3 (CH), 39.1 (CH), 36.5 (C), 32.8
	(111.8 (CH 3 ), 26.5 (CH 2 ), 25.7 (CH 2 ), 22.9 (CH 3 ), 17.1 (CH 3 ). Equatorial-Me: 173.8 (C), 154.1 (C), mg, 0.49 mmol) in CD 2 Cl 2 , and then was added
	5 mmol) and tert-butyl-2-oxo-cyclopentanecarboxylate (72µL, 0.49 mmol) and IDipp (19 mg, 0.05 mmol) 115.4 (CH), 60.3 (C), 60.1 (CH 2 ), 51.7 (CH 3 ), 48.4 (CH), 41.6 (CH), 39.4 (CH 2 ), 37.2 (C),
	trans-crotonaldehyde (83 µL, 1.0 mmol), at 25 o C in CDCl 3 (2.5 M) afforded to the solution. the reaction was stirred for 1 h, 24 h at room temperature, 1 h and 24 h at 50 32.8 (CH 3 ), 29.6 (CH 2 ), 28.1 (CH 2 ), 23.0 (CH 3 ), 17.6 (CH 3 ); 1 H NMR (300 MHz, 
	compound 16m (71.0 mg, 45%, 2:1 dr, 7.3:1 er) as a yellow solid after flash C in order to track the cross behaviour. o ppm/CDCl
	chromatography.
	R f (PE/EtOAc: 6/4) = 0.59

+ :, found: 289.1774; 13 C NMR (75 MHz,  ppm/CDCl 3 ): axial-Me: 213.8 (C), 171.1 3 ): Axial-Me: 5.60 (t, J = 7.0 Hz, 1H), 4.23 -4.02 (m, 2H), 3.63 (s, 3H), 2.28 -2.13 (m, 2H), 2.06 -1.71 (m, 3H),

1.62 -1.49 (m, 3H), 1.31 -1.14 (m, 1H)

, 1.08 (s, 3H), 0.91 (s, 3H), 0.87

(d, J = 6.8 Hz, 3H)

. Equatorial-Me: 5.38 (t, J = 6.9 Hz, 1H),

4.23 -4.02

▪Pinnick oxidation from 46 to 47

	To a solution of 46 (33 mg, 0.13 mmol, 1:1:1 dr) in a mixture solvent (5 mL,
	t-BuOH/THF/H 2 O with v:v:v = 6:3:1) was added monosodium phosphate (20.3 mg, 0.17
	mmol), sodium chlorite (7.1 mg, 0.078 mmol) and 2-methyl-2-butene (16.5 µL, 0.16 mmol),
	the reaction was stirred at room temperature overnight. Then, the reaction mixture was poured
	into 5% aqueous chloric acid, extracted with ethyl acetate, dried over NaSO 4, concentrated in
	vacuum to afford 47 (30 mg, 86%, crude) without purification. R f = 0.40 (PE:EtOAc/6:4).
	MS (ESI+, m/z): 267 [M-H] -. 13 C NMR (75 MHz,  ppm/CDCl 3 ): 3 dias: 179.5 (C), 179.5
	(C), 178.9 (C), 176.3 (C), 175.8 (C), 175.8 (C), 60.6 (C), 55.9 (C), 55.1 (C), 53.0 (CH), 51.7
	(CH 3 ), 51.7 (CH 2 ), 51.5 (CH 3 ), 51.5 (CH 3 ), 49.9 (CH), 47.7 (CH), 46.7 (CH), 43.1 (CH), 40.7
	(CH 2 ), 40.5 (CH), 40.0 (CH), 39.5 (CH 2 ), 39.0 (C), 38.0 (CH 2 ), 37.4 (C), 36.8 (C), 36.0 (CH),
	34.5 (CH), 33.4 (CH 3 ), 33.2 (CH 3 ), 32.8 (CH 2 ), 31.3 (CH 2 ), 30.3 (CH 2 ), 30.0 (CH 3 ), 28.3
	(CH 2 ), 27.3 (CH 2 ), 26.3 (CH 3 ), 24.9 (CH 2 ), 24.7 (CH 3 ), 24.6 (CH 3 ), 20.4 (CH 3 ), 21.3 (CH 2 ),
	18.3 (CH 2 ), 17.7 (CH 3 ), 17.5 (CH 3 ); 1 H NMR (300 MHz,  ppm/CDCl 3 ): 3 dias: 9.24 (s,
	1H×3), 3.67 (s, 3H), 3.63 (s, 3H), 3.62 (s, 3H), 2.93 -2.54 (m, 2H×3), 2.22 -1.96 (m, 3H×3),
	1.75 -1.45 (m, 6H×3), 1.16 (s, 3H), 1.14 (s, 3H), 1.13 (s, 3H), 1.10 (s, 3H), 1.07 (s, 3H), 1.07
	(s, 3H), 0.94 (d, J = 7.4 Hz, 3H), 0.69 (d, J = 6.3 Hz, 3H), 0.67 (d, J = 6.1 Hz, 3H).

▪saponification of 47 to the undesired dias of (+)-isishippuric acid B

  To allylic alcohol42 (252.3 mg, 1.0 mmol, 3:1 dr) in dichloromethane (10.0 mL, 0.1 M) was added manganese oxide (1022.8 mg, 10.0 equiv, activated 85%). The reaction was stirred at room temperature for 10h. When the reaction reached full conversion, MnO 2 was removed by filtration. The filtrate was concentrated in vacuum to afford 49(225.3 mg, 90 %, 3:1 dr)

	without purification. R f = 0.71 (PE:EtOAc/3:1); MS (ESI+, m/z): 273 [M+Na] + ; 13 C NMR
	(75 MHz,  ppm/CDCl 3 ): axial-Me: 191.0 (CH), 173.6 (C), 172.3 (C), 124.6 (CH), 60.0 (C),
	51.9 (CH 3 ), 49.7 (CH), 48.7 (CH 2 ), 41.1 (CH), 36.6 (C), 32.7 (CH 3 ), 28.5 (CH 2 ), 25.0 (CH 2 ),
	22.6 (CH 3 ), 16.8 (CH 3 ); Equatorial-Me: 191.5 (CH), 177.7 (C), 172.1 (C), 119.9 (CH), 61.8
	(C), 52.0 (CH 3 ), 48.9 (CH), 38.6 (CH 2 ), 43.2 (CH), 37.4 (C), 32.6 (CH 3 ), 31.1 (CH 2 ), 27.4
	(CH 2 ), 22.7 (CH 3 ), 17.4 (CH 3 ); 1 H NMR (300 MHz,  ppm/CDCl 3 ): axial-Me: 9.85 (d, J =
	8.1 Hz, 1H), 6.10 (d, J = 8.1 Hz, 1H), 3.64 (s, 3H), 3.00 -3.29 (m, 1H), 2.48 (p, J = 6.8 Hz,
	1H), 2.12 -1.57 (m, 5H), 1.23 (dd, J = 14.2, 5.7 Hz, 1H), 1.14 (s, 3H), 0.94 (s, 3H), 0.85 (d, J
	= 6.9 Hz, 3H); Equatorial-Me: 9.80 (d, J = 7.9 Hz, 1H), 5.94 (d, J = 8.0 Hz, 1H), 3.70 (s,
	3H), 3.00 -3.29 (m, 1H), 2.31 (td, J = 12.0, 5.9 Hz, 1H), 2.12 -1.57 (m, 5H), 1.23 (dd, J =
	14.2, 5.7 Hz, 1H), 1.12 (s, 3H), 0.92 (s, 3H), 0.75 (d, J = 6.5 Hz, 3H)
	▪redox reaction from
	To a solution of acid 47 (30 mg, crude,  0.11 mmol, 1:1:1 dr) in THF/H 2 O (v:v = 2:1) was
	added lithium hydroxide (26.8 mg, 1.12 mmol). The reaction was stirred for 10h. Then, the

reaction mixture was poured into 5% aqueous chloric acid, extracted with ethyl acetate, dried over NaSO 4, concentrated in vacuum to afford 48 (27 mg, 99%, crude) without purification.

aldehyde 49 to undesired ester 50

  (CH 2 ), 62.0 (C), 52.1 (CH 3 ), 49.6 (CH), 43.7 (CH), 38.7 (CH 2 ), 37.4 (C), 32.9 (CH 3 ), 30.0 (CH 2 ), 27.7 (CH 2 ), 22.9 (CH 3 ), 17.5 (CH 3 ); 1 H NMR (400 MHz,  ppm/CDCl 3 ): four dias (not all of the diastereomers are obvious sometimes): 7.41 -7.32 (m, 5H×4, 4 dias), 6.00 (s, 1H, dia 1), 5.81 (s, 1H, dia 2 ), 5.37 (s, 1H, dia 3), 5.20 -5.09 (m, 2H×4, 4 dias), 3.74 (s, 3H, dia 1), 3.69 (s, 3H, dia 2), 3.60 (s, 3H, dia 3), 3.56 (s, 3H, dia 4), 3.46 -3.43 (m, 1H×4, for 4

	To a mixture of aldehyde 49 (47.9 mg, 0.25 mmol, 3:1 dr) and benzyl aldehyde (81.1 mg,
	0.75 mmol) in toluene (1.0 mL, 0.25 M) was added 1,3-Dimethyl-1H-benzimidazolium iodide
	(13.7 mg, 0.05 mmol) and N,N-diisopropylethylamine (22 µL, 0.125 mmol). The reaction
	mixture was stirred under argon atmosphere at 110 o C for 10h, then concentrated in vacuum
	and purified by flash chromatography to afford 50 (40.9 mg, 55%, 4 dias, 17:5:2:1 dr). MS
	(ESI+, m/z): 379 [M+Na] + ; 13 C NMR (75 MHz,  ppm/CDCl 3 ): only two diastereomers were
	observed. major dia: 174.4 (C), 167.5 (C), 166.5 (C), 136.5 (C), 128.6 (CH), 128.3 (CH),
	128.2 (CH), 112.6 (CH), 65.8 (CH 2 ), 60.2 (C), 51.9 (CH 3 ), 50.4 (CH), 49.0 (CH 2 ), 41.2 (CH),
	36.6 (C), 32.9 (CH 3 ), 27.3 (CH

2 ), 25.2 (CH 2 ), 22.8 (CH 3 ), 17.0 (CH 3 ); minor dia: 173.4 (C), 162.5 (C), 156.0 (C), 136.4 (C), 128.7 (CH), 128.3 (CH), 128.2 (CH), 108.1 (CH), 65.9

▪saponification of ester 36 to carboxylic acid 62 and Arndt-Ester reaction toward undesired diketone 64

  13 C NMR (75 MHz,  ppm/CDCl 3 ): axial-Me: 177.0 (C), 80.1 (C), 74.2 (CH), 54.7 (C), 47.9 (CH), 47.8 (CH 2 ), 36.9 (CH), 33.8 (CH 3 ), 33.5 (C), 28.0 (CH 3 ×3, t-Bu), 25.0 (CH 2 ), 24.8 (CH 3 ), 19.4 (CH 3 ), 17.4 (CH 2 ); equatorial-Me: 176.1 (C), 80.8 (C), 74.3 (CH), 56.5 (C), 47.4 (CH), 38.4 (CH 2 ), 34.3 (C), 33.5 (CH), 29.5 (CH 3 ), 28.1 (CH 3 ×3, t-Bu), 27.2 (CH 2 ), 24.8 (CH 3 ), 20.3 (CH 2 ), 16.6 (CH 3 ); 1 H NMR (300 MHz,  ppm/CDCl 3 ): axial-Me: 4.43 (dd, J = 5.0, 2.3 Hz, 1H), 2.55 (d, J = 2.3 Hz, 1H), 2.38 -1.84 (m, 3H), 1.72-1.42 (m, 3H), 1.36 (s, 9H), 1.32 -1.19 (m, 2H), 1.08 (d, J = 7.0, 3H), 1.02 (s, 3H), 0.97 (s, 3H); equatorial-Me: 4.20 (d, J = 4.7 Hz, 1H), 2.82 (d, J = 1.4 Hz, 1H), 2.38 -1.84 (m, 3H), 1.72 -1.42 (m, 3H), 1.38 (s, 9H), 1.32 -1.19 (m, 2H), 0.99 (s, 3H), 0.96 (s, 3H), 0.62 (d, J = 6.7 Hz, 3H)To a solution of t-butyl ester 36 (60 mg, 0.23 mmol, 1:2 dr Me ax :Me eq ) in dichloromethane was added trifluoroacetic acid(345 µL, 4.6 mmol), the reaction was stirred under room temperature for 2h. The reaction mixture was poured into saturated aqueous NH 4 Cl, extracted by ethyl acetate, dried over NaSO 4 . Then, the organic solution was concentrated in vacuum to afford acid 62 (crude) without purification. R

f = 0.31 (PE:EtOAc/6:4).

benzylic compound 65b: R f =

  mg, 75%). R f = 0.56 (PE:EtOAc/4:1). MS (ESI+, m/z): 257 [M+Na] + . 13 C NMR (75 MHz,  ppm/ CDCl 3 ): axial-Me: 217.3 (C), 194.1 (C), 64.1 (C), 58.5 (CH), 54.8 (CH), 46.4(CH 2 ), 44.6 (CH), 32.7 (CH 3 ), 31.9 (C), 28.9 (CH 2 ), 24.9 (CH 2 ), 22.8 (CH 3 ),16.2 (CH 3 ); equatorial-Me: 218.1 (C), 191.6 (C), 66.5 (C), 57.8 (CH), 55.4 (CH), 46.1 (CH), 35.9 (CH 2 ), 32.5 (CH 3 ), 32.3 (C), 30.7 (CH 2 ), 27.3 (CH 2 ), 22.9 (CH 3 ), 16.6 (CH 3 ); 1 H NMR (300 MHz,  ppm/CDCl 3 ): axial-Me: 6.06 (s, 1H), 2.84 -2.76 (m, 1H), 2.25 (d, J = 14.1 Hz, 1H), 2.03 -1.80 (m, 3H), 1.71 (d, J = 14.4 Hz, 1H), 1.63 -1.22 (m, 2H), 1.16 (s, 3H), 0.91 (s, 3H), 0.88 (d, J = 7.1 Hz, 3H); equatorial-Me: 5.86 (s, 1H), 2.25 (d, J = 14.1 Hz, 1H), 2.15 -2.05 (m, 1H), 2.03 -1.80 (m, 3H), 1.71(d, J = 14.4 Hz, 1H), 1.63 -1.22 (m, 2H), 1.13 (s, 3H), 0.90 (s, 3H), 0.81(d, J = 6.5 Hz, 3H).To a solution of diazoketone 63(40.4 mg, 0.17 mmol) in dioxane (3.5 mL, 0.05 M) was added H 2 O (61 µL, 3.4 mmol) and silver benzoate (7.8 mg, 0.034 mmol). The reaction mixture was stirred at 80 o C for 10h. Then, the reaction solution was extracted with diethyl ether, dried over Na 2 SO 4 and concentrated in vacuum. Purification by flash chromatography afforded compound 64 (27.5 mg, 72 %, 1:2 dr) as a white solid. R f = 0.23 (PE : EtOAc = 5:1). MS (ESI+, m/z): 247 [M+Na] + . 13 C NMR (75 MHz,  ppm/ CDCl 3 ): axial-Me: 215.6 (C), 209.2 (C), 66.7 (CH 2 ), 64.9 (C), 58.1 (CH), 45.6 (CH 2 ), 42.9 (CH), 32.6 (CH 3 ), 32.6 (C), 28.7 (CH 2 ), 24.7 (CH 2 ), 22.8 (CH 3 ), 16.2 (CH 3 ); equatorial-Me: 216.1 (C), 206.8 (C), 67.7 (C), 67.4 (CH 2 ), 56.9 (CH), 44.6 (CH), 35.4 (CH 2 ), 32.6 (C), 32.5 (CH 3 ), 30.3 (CH 2 ), 27.1 (CH 2 ), 22.9 (CH 3 ), 16.8 (CH 3 ); 1 H NMR (300 MHz,  ppm/CDCl 3 ): axial-Me: 4.76 -4.58 (m, 1H), To a solution of 57 (57a, 57b) (372.0 mg, 1.39 mmol, 2:1 dr) in THF was added benzyl bromide (198 µL, 1.67 mmol) and sodium hydride (36.7 mg, 1.53 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction solution was poured into saturated aqueous NH 4 Cl, extracted with diethyl ether, dried over Na 2 SO 4 and concentrated in vacuum. Purification by flash chromatography afforded compound 57a (white solid, 250.0 mg, 67%, 77 % ee) and 42b as white solid. R f = 0.38 (PE:Et 2 O/ 5:1). Mp = 108 -109 o C; HRMS (ESI+) for C 16 H 29 O 3 + : calcd. [M+H] + : 269.2111, found: 269.2117. After recrystallization, the enantiomeric excess was increased to >99 %, 192.5 mg 57a was obtained. HPLC (chiralpak AZ-H, heptane/ethanol 80/20, 1.0 mL/min, UV 220 nm): τ axial-Me = 6.30 min; [ ] = -32.0 (c 0.8, EtOH absolute ).13 C NMR (75 MHz,  ppm/CDCl3): 177.2 (C), 80.3 (C), 74.4 (CH), 54.8 (C), 47.9 (CH), 47.9 (CH 2 ), 37.1 (CH), 34.0 (CH 3 ), 33.6 (C), 28.2 (CH 3 ×3, t-Bu), 25.1 (CH 2 ), 24.9 (CH 3 ), 19.5 (CH 3 ), 17.5 (CH 2 ); 1 H NMR (300 MHz,  0.65 (PE:EtOAc/ 20:1). 13 C NMR (75 MHz,  ppm/CDCl 3 ): 175.4 (C), 139.1 (C), 128.2 (CH×2), 127.4 (CH×2), 127.4 (CH), 83.9 (CH), 79.8 (C), 71.9 (CH 2 ), 57.3 (C), 46.5 (CH), 39.0 (CH 2 ), 34.6 (C), 33.3 (CH), 28.9 (CH 3 ), 28.2 (CH 3 ×3, t-Bu), 27.8 (CH 2 ), 25.1 (CH 3 ), 21.0 (CH 2 ), 17.0 (CH 3 ); 1 H NMR (300 MHz,  ppm/CDCl 3 ): 7.30 -7.15 (m, 5H), 4.45 (s, 2H), 3.96 (d, J = 4.6 Hz, 1H), 2.54 (p, 6.4 Hz, 1H), 1.89 (d, J = 14.1 Hz, 1H), 1.77 (dddd, J =

	▪separation of 57a
	ppm/CDCl3): 4.49 (d, J = 4.3 Hz, 1H), 2.44 (br. s, 1H), 2.05-1.98 (m, 3H), 1.64-1.49 (m, 3H),
	1.43 (s, 9H), 1.38 -1.22 (m, 2H), 1.15 (d, J = 6.9 Hz, 3H), 1.09 (s, 3H), 1.04 (s, 3H).
	4.37 -4.25 (m, 1H), 3.14 (br. s, 1H), 2.89 -2.80 (m, 1H), 2.13 -1.96 (m, 3H), 1.94 -1.89
	(m, 1H), 1.75 (d, J = 14.0 Hz, 1H), 1.73 -1.38 (m, 2H), 1.18 (s, 3H), 0.98 (s, 3H), 0.85 (d, J =
	7.1 Hz, 3H); equatorial-Me: 4.76 -4.58 (m, 1H), 4.37 -4.25 (m, 1H), 3.21 (br. s, 1H), 2.52
	3H)

(dp, J = 12.2, 6.3 Hz, 1H), 2.23 (d, J = 14.3 Hz, 1H), 2.13 -1.96 (m, 2H)

,1.94 -1.89 (m, 1H), 1.74

(d, J = 14.3 Hz, 1H), 1.73 -1.38 (m, 2H)

, 1.15 (s, 3H), 0.91 (s, 3H), 0.76

(d, J = 6.5 Hz,

  in THF (7.2 mL, 0.1 M) was added benzyl bromide (103 µL, 0.86 mmol) and potassium hydride (43.3 mg, 1.08 mmol). The reaction mixture was stirred at room temperature for 7 h. The reaction solution was poured into saturated NH 4 Cl, extracted with diethyl ether, dried over Na 2 SO 4 and concentrated in vacuum. Purification by flash chromatography afforded compound 65a (232.3 mg, 90 %) as colorless oil. R f = 0.63 (PE:Et 2 O/15:1). HRMS (ESI+) for C 23 H 34 NaO 3 + : calcd. [M+Na] + : 381.2400, found: 381.2400. [ ] = +15.1 (c 1.0, EtOH absolute ). 13 C NMR (75 MHz,  ppm/CDCl 3 ): 175.8 (C), 139.7 (C), 128.2 (CH×2), 127.1 (CH×2), 127.1 (CH), 82.3 (CH), 79.7 (C), 72.6 (CH 2 ), 55.1 (C), 49.5 (CH 2 ), 46.5 (CH), 36.4 (CH), 33.9 (C), 33.7 (CH 3 ), 28.2 (CH 3 ×3, t-Bu),

  HRMS (ESI+) for C 15 H 24 NaO + : calcd. [M+Na] + : 243.1719, found: 243.1719; [ ] = +17.0 (c 0.1, EtOH absolute ). HPLC (Lux-Cellulose-2, heptane/tertiobutanol (98/2), 1.0 mL/min, CD 290 nm): τ axial-Me = 8.56 min. 13 C NMR (100 MHz,  ppm/ CDCl 3 ): 220.4 (C), 57.0 (C), 50.1 (CH), 49.8 (CH), 47.9 (CH 2 ), 44.0 (CH), 40.8 (CH 2 ), 39.3 (C), 35.8 (CH), 34.4 (CH 3 ), 28.4 (CH 2 ), 27.1 (CH 2 ), 27.1 (CH 3 ), 17.1 (CH 3 ), 8.2 (CH 3 ); 1 H NMR (400 MHz,  ppm/CDCl 3 ): 2.51 -2.32 (m, 4H), 2.05 (ddd, J = 20.9, 14.1, 7.2 Hz, 1H), 1.88 (p, J = 7.2 Hz, 1H), 1.75 (br. t, J = 3.1 Hz, 1H), 1.70 -1.55 (m, 2H), 1.40 (d, J = 14.5 Hz, 1H), 1.33 (d, J = 14.5 Hz, 1H), 1.32 (dd, J = 14.5, 6.0 Hz, 1H), 1.13 (s, 3H), 1.08 (s, 3H), 1.03 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H).

Table 3 :

 3 the comparison of 1 H chemical shifts of (+)-suberosanone

	proton	literature 69 500 MHz / CDCl 3	compound IV 400 MHz / CDCl 3
	2	2.38 (m, 1H)
	3α		2.51 -2.32 (m, 4H)

List, B. Chem. Rev.

2007, 107, 5413. 2 (a) March, J. J.; Lebherz, H. G. TIBS 1992, 17, 110. (b) Rutter, W. J.Fed. Proc. Am. Soc. Exp. Biol. 1964, 23,

(a) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem Rev. 2010, 110, 5447. (b) Wei, Y.; Shi, M. Chem. Rev.2013, 113, 6659.

Phosphine catalysis: (a) Marinetti, A.; Voituriez, A. Synlett 2010, 174. Pyridine catalysis: (b) Roux, C.; Chuzel, O.; Bressy, C. Angew. Chem. Int. Ed. 2014, 53, 766. (c) Yunmi Lee, S.; Murphy, J. M.; Ukai, A.; Fu, G. C. J. Am. Chem. Soc. 2012,

134, 15149 and references therein.

Arduengo, A. J., III; Harlow, R. L.; Kline, M. J. Am. Chem. Soc.

1991, 113, 361. 19 Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature 2014, 510, 485. 20 Select reviews: (a) Hahn, F. E.; Jahnke, M. C. Angew. Chem. Int. Ed. 2008, 47, 3122. (b) Díez-González, S.; Marion, N.; Nolan, S. P. Chem. Rev. 2009, 109, 3612. 21 Select reviews: (a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606. (b) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307.

Mailhol, D.; Sanchez Duque, M. M.; Raimondi, W.; Bonne, D.; Constantieux, T.; Coquerel, Y.; Rodriguez, J Adv.Synth. Catal. 2012, 354, 3523.

For benchmark work on this type of bifunctional organocatalysis: (a) Tomotaka, O.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. For reviews: (b) Marcelli, T.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem. Int. Ed. 2006, 45, 7496. (c) Connon, S. J. Chem. Eur. J. 2006, 12, 5418. (d) Serdyuk, O.V.; Heckel, C. M.; Tsogoeva, S. B. Org. Biomol. Chem. 2013, 11, 7051. (e) Fang, X; Wang, C. -J. Chem.Commun. 2015Commun. , 51, 1185. .

Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N. Science 2010, 327, 986.

[START_REF] Presset | comparison of 13 C chemical shifts of (-)-isishippuric acid B and compound 48 carbon (-)-isishippuric acid B 70 125.7 MHz / Pyridine-d 5 compound 48 (3 dias) 75 MHz / Pyridine-d 5 60[END_REF] Mailhol, D.; Coquerel, Y.;[START_REF] Presset | comparison of 13 C chemical shifts of (-)-isishippuric acid B and compound 48 carbon (-)-isishippuric acid B 70 125.7 MHz / Pyridine-d 5 compound 48 (3 dias) 75 MHz / Pyridine-d 5 60[END_REF], 16, 2549.

[START_REF] Presset | comparison of 13 C chemical shifts of (-)-isishippuric acid B and compound 48 carbon (-)-isishippuric acid B 70 125.7 MHz / Pyridine-d 5 compound 48 (3 dias) 75 MHz / Pyridine-d 5 60[END_REF] Coquerel, Y.; Rodriguez, J. J. Org. Chem. 2009, 74, 415.

Trost, B.M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 1287

Deoxygenation at C10

With in hand a protocol for the preparation of compound 7b on a multi-gram scale, we examined its deoxygenation using the conditions found earlier by Dr. Marc Presset in the racemic series. 56 To do so, the Barton-McCombie reduction 76 proved very useful.

The clean crude xanthate 37 was obtained following classic conditions and directly used for the next step (Scheme 34). In the presence of small amount of the radical initiator AIBN (5 mol%) and a stoichiometric amount of tributyltin hydride (1.1 equiv) in refluxing toluene for 2 hours, the xanthate 37 could be converted into the corresponding deoxygenated product 36 in 85% yield over the two steps. 76 (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574. (b) Barrett, A. G. M.; Barton, D. H. R. Chem. Soc.Chem. Commun. 1979, 24, 1175. (c)

General conclusion

Scheme 74. Total synthesis of (+)-suberosanone, and formal synthesis of (+)-suberosenone

Experimental part

Compound 16h

Following the general procedure, the reaction between 5a (92.

Compound 16i

Following the general procedure, the reaction between 5a (92. To a solution of 53 (25 mg, 0.09 mmol, 1:2 dr Me ax :Me eq ) in THF (1.9 mL, 0.05 M) was added N,N'-thiocarbonyldiimidazole (80.2 mg, 0.45 mmol) and potassium hydride (36.1 mg, 0.9 mmol). The reaction was stirred under reflux and argon atmosphere. After 12h, the reaction mixture was poured into saturated aqueous NH 4 Cl, and then dried over Na 2 SO 4 , concentrated in vacuum, purified by flash chromatography to afford the undesired 55 (15.9 mg, 47 %). R f = 0.46 (PE:EtOAc = 7:3). MS (ESI+, m/z): 399 [M+Na] + . Mots-clés: énantiosélectivité, multi-organocatalyse, synthèse totale, NHC, base de Brønsted, base de Lewis