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A short and efficient synthesis of the prodrug form of SC-54701A has been achieved from (trimethylsilyl)acetylene in 6 steps with an overall yield of 19%.

Cyclic or acyclic α-alkyl-α-hydroxy-β-keto esters were reduced by baker’s yeast with high stereospecificity. In the former case, one enantiomer of the racemic mixture was transformed into optically active trans-dihydroxy compounds, while the remaining α-hydroxy-β-keto ester was enantiopure.

R-(+)-Pulegone 1 is converted by several fungal strains to new regioselectively hydroxylated compounds. Epoxidation of the double bond does not seem to be responsible for the main observed hydroxylation pattern.

The conditions necessary to reduce stereoselectively aliphatic beta-ketoesters by G. candidum have been investigated. Ageing of the mycelium allowed a practical preparation of optically pure (R)-ethyl 3-hydroxybutanoate, as a result of stereoselective reduction, enantioselective metabolism and stereoisomer interconversion. The stereoconversion of 3S-hydroxybutanoate into the 3R-enantiomer via 3-oxoester formation has been demonstrated to be a determining factor in the building of the optical purity of the resulting product. Enantioselective preparations of higher homologous 3R-hydroxyesters are described.

The conditions of the reduction of racemic ethyl 2-methyi-3-oxobutanoate by the mould Geotrichum candidum have been investigated in order to produce exclusively the corresponding (2S, 3S) anti hydroxyester. The alteration of the syn/anti hydroxyester ratio previously observed is the result of an interconversion equilibrium involving the oxoester. The syn ester formation is inhibited by ageing the biomass in water before use, or by effecting the reduction in the presence of sodium chloride. Optimized conditions are described allowing the production of the anti ester in high yield and high optical purity.

The active site topology, substrate specificity, and biological roles of the human cytochrome P450 CYP2J2, which is mainly expressed in the cardiovascular system, are poorly known even though recent data suggest that it could be a novel biomarker and potential target for therapy of human cancer. This paper reports a first series of high-affinity, selective CYP2J2 inhibitors that are related to terfenadine, with Ki values as low as 160 nM, that should be useful tools to determine the biological roles of CYP2J2.

To overcome the maximum 50% yield limitation of classical resolution methods, deracemization processes involving a racemization step (dynamic resolution) or a prochiral intermediate (stereoinversion) have been developed. The use of transition metal complexes as racemizing agents, in combination with an enzymatic reaction, has been successfully extended to the deracemization of a number of simple or functionalized sec-alcohols. A two-enzyme process has been also investigated for their sequential or simultaneous deracemization. Other prominent results arise from an (apparently general) oxidoreduction process catalyzed by a single whole-cell microorganism.

1,1′-Disubstituted ferrocenyl aminoalcohols were synthesized in high enantio- and diastereomeric purities from the ketoalcohol obtained by microbial reduction of 1,1′-diacetylferrocene.

In the recent years, intensive work has been devoted to the efficient preparation of new chiral synthons by asymmetric transformation of prochiral molecules, through enzymic or microbiological catalysis. In this respect, we have developed combined chemical- microbiological reduction and oxidation (Baeyer-Villiger like) methods which allow to obtain either enantiomer of chiral substituted lactones and lactonic synthons.

A short and efficient synthesis of the prodrug form of SC-54701A has been achieved from (trimethylsilyl)acetylene in 6 steps with an overall yield of 19%.

Yeast and fungi reduce methoxy-substituted 2-cyano-1-tetralones to cis-2-cyano-1-tetralols with high enantiomeric purity, but respective opposite absolute configurations, in moderate to high yields.

Geotrichum candidum has been used for the preparative reduction of β-oxoalkanoic esters to the corresponding D-β-hydroxyesters. The stereospecificity for ethyl 3-oxobutanoate or 3-oxopentanoate is markedly increased by preincubation of the mycelium before addition of the substrate.

The Baeyer-Villiger-like oxidation of (R,S)-2,2,5,5-tetramethyl-4-hydroxy -cyclohexanone by several fungal strains was highly enantioselective, affording a rearranged (S)-hydroxy-γ-lactone. The recovery of the nearly optically pure (R)-hydroxyketone allowed its conversion to the enantiomeric (R)-hydroxylactone through a classical Baeyer-Villiger oxidation.

The reduction of racemic cyclopenta- and cyclohexanone 2-carboxyesters by various yeast and mould strains was shown to produce different amounts of isomeric beta-hydroxyesters with predominant (1 S ) stereochemistry. With several strains, only one optically pure cis or trans stereoisomer was obtained in high yield, indicating a diastereoselective and enantioselective reduction.

The reduction of alkyl aryl ketones-Cr(CO) 3 with baker's yeast has been carried out in some instances, gives complexed alcohols in high enantiomeric excesses (e.g. ( S )-Cr(CO) 3 C 6 H 5 CHOHCH 3 , ee > 99%) and in good yields. The microorganism is also able to differentiate the various metallocenic chiralities as shown with tetralone-Cr(CO) 3 .

The Reduction of 4-O-benzyl-2 -methyl-3-oxo-butyrate esters by several fungal strains produces predominantly (2S,3R)- anti -hydroxyesters in high optical purity. The corresponding (2R,3R)- syn isomer was obtained, with other strains, only in mixture with the anti isomer. These esters are useful precursors for chiral 2-methyl-3-hydroxy-butyrolactone synthons.

All stereomers of cyclohexane and cyclopentane-derived analogues of glutamic acid have been synthesized from the corresponding 3-keto-cycloalkyl carboxylic acid esters by a combination of microbial steps and standard chemical methods.

The double reduction of benzil by different yeast strains is carried out with varying enantio- and diastereoselectivity. With selected strains, it is possible to obtain in reasonable yields nearly optically pure (R,R) or (S,S) hydrobenzoin.

Reduction of 2-methyl 3-oxobutanoate or pentanoate by several fungal strains gave essentially the corresponding and anti (2S,3S)-hydroxyesters in high optical purity.

An efficient, highly stereoselective synthesis of (1 R ,3 S )- cis -chrysanthemic acid 6 is described. The crucial step of this synthesis was the microbiological reduction of dione 1 into ( S )-ketol 2.

Biomimetic synthesis, inspired by direct and fast biosynthetic processes, is an efficient way to produce complex natural products. This thesis doctoral work focused on the development of collective strategies, from biomimetic intermediates, to get a quick access to three families of diketopiperazines: gliocladrides (functionalized DKPs), quinazolino-DKPs and oxepino-DKPs. The late-stage chemical oxidation reactions and microbial transformations on the two first intermediates were envisaged to synthesize gliocladrid A and oxepino-DKPs. A regioselective late-stage oxidation operated by DDQ was discovered, bringing new synthetic possibilities to make aurantiomides in a collective manner. An alternative methodology to synthesize oxepino-DKPs was investigated in the meantime. A temperature-controlled tandem cyclopropanation/oxa-Cope rearrangement was developed successfully to prepare 2,5-dihydrooxepines. This method was afterwards elucidated by experimental and computational (DFT) studies and further applied as the key step to finish the intractable total synthesis of radulanins. This oxa-Cope rearrangement approach also led to achieve the installation of 2,5-dihydrooxepine DKP, getting close to the accomplishment of the total synthesis of cinereain.; La synthèse biomimétique, inspirée par des voies de biosynthèse directes et rapides, est un moyen efficace pour produire des produits complexes. Le travail de cette thèse a porté sur le développement de stratégies collectives à partir d’intermédiaires biomimétiques pour accéder rapidement à trois familles de dikétopipérazines : les gliocladrides (DKPs fonctionnalisés), les quinazolino-DKPs et les oxépino-DKPs. Les fonctionnalisations oxydantes tardives par voies chimiques et biologiques des deux premiers intermédiaires ont été envisagées dans le but d’accéder directement au gliocladride A et aux oxépino-DKPs. Une fonctionnalisation oxydante régiosélective par la DDQ a pu être découverte et offre un accès à la synthèse totale des aurantiomides. Alternativement, pour synthétiser des oxépino-DKPs : une méthodologie de synthèse, via une réaction cascade de cyclopropanation/réarrangement oxa-Cope vers des 2,5-dihydrooxepines, a été développée. Cette méthode a bien été explorée par des études expérimentales et théoriques (DFT) et a été appliquée aux synthèses totales des radulanines. De plus, nous avons démontré que l’utilisation de cette stratégie était possible dans une synthèse totale à finaliser des produits naturels de type cinéreain.

Biomimetic synthesis, inspired by direct and fast biosynthetic processes, is an efficient way to produce complex natural products. This thesis doctoral work focused on the development of collective strategies, from biomimetic intermediates, to get a quick access to three families of diketopiperazines: gliocladrides (functionalized DKPs), quinazolino-DKPs and oxepino-DKPs. The late-stage chemical oxidation reactions and microbial transformations on the two first intermediates were envisaged to synthesize gliocladrid A and oxepino-DKPs. A regioselective late-stage oxidation operated by DDQ was discovered, bringing new synthetic possibilities to make aurantiomides in a collective manner. An alternative methodology to synthesize oxepino-DKPs was investigated in the meantime. A temperature-controlled tandem cyclopropanation/oxa-Cope rearrangement was developed successfully to prepare 2,5-dihydrooxepines. This method was afterwards elucidated by experimental and computational (DFT) studies and further applied as the key step to finish the intractable total synthesis of radulanins. This oxa-Cope rearrangement approach also led to achieve the installation of 2,5-dihydrooxepine DKP, getting close to the accomplishment of the total synthesis of cinereain.; La synthèse biomimétique, inspirée par des voies de biosynthèse directes et rapides, est un moyen efficace pour produire des produits complexes. Le travail de cette thèse a porté sur le développement de stratégies collectives à partir d’intermédiaires biomimétiques pour accéder rapidement à trois familles de dikétopipérazines : les gliocladrides (DKPs fonctionnalisés), les quinazolino-DKPs et les oxépino-DKPs. Les fonctionnalisations oxydantes tardives par voies chimiques et biologiques des deux premiers intermédiaires ont été envisagées dans le but d’accéder directement au gliocladride A et aux oxépino-DKPs. Une fonctionnalisation oxydante régiosélective par la DDQ a pu être découverte et offre un accès à la synthèse totale des aurantiomides. Alternativement, pour synthétiser des oxépino-DKPs : une méthodologie de synthèse, via une réaction cascade de cyclopropanation/réarrangement oxa-Cope vers des 2,5-dihydrooxepines, a été développée. Cette méthode a bien été explorée par des études expérimentales et théoriques (DFT) et a été appliquée aux synthèses totales des radulanines. De plus, nous avons démontré que l’utilisation de cette stratégie était possible dans une synthèse totale à finaliser des produits naturels de type cinéreain.