Jean-Luc Vasse

A Direct Stereoselective Approach to trans-2,3-Disubstituted Piperidines: Application in the Synthesis of 2-Epi-CP-99,994 and (+)-Epilupinine

A simple synthesis of enantiomerically pure piperidine esters is described, offering a straightforward access to the trans-2,3-disubstituted piperidine skeleton which is present in a broad range of biologically active compounds.

Diastereoselective access to nonracemic 2-cis-substituted and 2,6-cis-disubstituted piperidines.

Access to nonracemic amino ketones via a hydrozirconation/transmetalation/acylation sequence applied to Boc-protected 1-aminobut-3-enes is presented. This method was applied to the stereoselective synthesis of cyclic imines (or iminiums) which were diastereoselectively converted into 2-cis-substituted and 2,6-cis-disubstituted piperidines. The potential of this approach in the field of alkaloid synthesis was illustrated by the synthesis of (-)-coniine and (-)-indolizidine 209D. Furthermore, access to indolizidines bearing a quaternary center could also be envisioned through this strategy.

Highly stereoselective Friedel-Crafts type cyclization. Facile access to enantiopure 1,4-dihydro-4-phenyl isoquinolinones

Abstract The present report describes a stereoselective synthesis of 1,4-dihydro-4-phenyl isoquinolinones 5 based on a stereoselective Friedel–Crafts type cyclization. Cyclization precursors 1 were prepared in two steps, from the readily available (S)-mandelic acid, in 60–80% overall yield. The stereoselective electrophilic cyclization was accomplished in 20–86% yield and with 20–97% ee. In the course of this work, the presence of the amide carbonyl was found to be particularly important to guarantee a stereospecific process during the electrophilic aromatic substitution.

Chiral biomimetic NADH models in the benzo[b]-1,6-naphthyridine series. A novel class of stable, reactive and highly enantioselective NADH mimics

Abstract The preparation of a new class of tricyclic models 1 based on a Friedlander reaction between chiral piperidine-2,4-diones 2 and azomethine 3 is reported. Alkylation of the lactam allowed to install various pendant arms on the chiral cyclic inducer. The so-obtained mimics 1a,d,f,g,h,k were involved in the reduction of methyl benzoylformate to furnish methyl mandelate in 4–87% ee (R). The presence of a coordinating pendant arm proved to be essential to reach optimum results in terms of enantioinduction. Asymmetric reduction of 2-benzoylpyridine with mimics 1d,f,g produced α-phenyl-2-pyridinemethanol in 30–84% ee (R).

Diastereoselective Access to trans-2-Substituted Cyclopentylamines

A highly diastereoselective synthesis of trans-2-substituted cyclopentylamines via a tandem hydrozirconation/Lewis acid-mediated cyclization sequence applied to butenyl oxazolidines is described. The method allows an easy preparation of diversely substituted cyclopentylamines which appear to be useful synthetic intermediates. This was further illustrated by the syntheses of (±)-Rodocaine, (±)-trans-pentacin, and enantiomerically enriched trans-cyclopentane-1,2-diamine.

Stable annelated chiral NADH models with a rigidified amide part in the quinoline series: synthesis, reactivity and grafting on a Merrifield resin

Abstract The synthesis of new chiral nicotinamide adenine dinucleotide hydrogenated models derived from quinoline is described. Using a biomimetic approach, the out-of-plane positioning of the amide carbonyl was obtained by involving the chiral auxiliary in a lactam structure. It is shown that electron-donating groups on the benzene ring of the quinoline structure are necessary to obtain high chemical yields during the reduction of methyl benzoylformate. An interesting variation of the enantioselectivity as a function of magnesium ion concentration has been observed. Under the best conditions, methyl mandelate was obtained in up to 95% ee ( R ). To facilitate the recycling of these models, grafting of reagent 4 on a Merrifield resin has been developed. The resulting polymer-supported reagent 4 was tested in the asymmetric reduction of methyl benzoylformate.

Titanium‐Catalyzed Hydroalumination of Conjugated Dienes: Access to Fulvene‐Derived Allylaluminium Reagents and Their Diastereoselective Reactions with Carbonyl Compounds

The described titanium-catalyzed hydroalumination of conjugated dienes opens up a new way to allylaluminium reagents. The reaction is carried out by using diisobutylaluminium hydride (DIBAL-H) and a catalytic amount of [Cp2TiCl2] (Cp = cyclopentadienyl). When applied to mono- and disubstitued pentafulvenes, this reaction proceeds in a highly endocyclic manner. The formed allylaluminium compounds react regio- and stereoselectively with both aldehydes and ketones to afford homoallylic alcohols that are suitable synthons for functionalized cyclopentanones. An extension of this methodology to simple dienes was also investigated. In the proposed mechanism, the initially formed bimetallic species (Ti/Al) are involved in the two possible catalytic cycles with a direct hydroalumination or/and a hydrotitanation followed by a titanium to aluminium transmetallation.

Switching Regioselectivity in the Allylation of Imines by N-Side Chain Tuning

A spectacular inversion of α- to γ-regioselectivity in the allylzincation of imines can be achieved by fine-tuning of the N-side chain. This approach allows easy preparation of regioisomeric amines, in racemic as well as enantiopure forms. The usefulness of the method is illustrated by the parallel asymmetric syntheses of 2,3- and 2,5-diphenylpyrrolidines.

Access to enantiomerically enriched cis-2,3-disubstituted azetidines via diastereoselective hydrozirconation.

An asymmetric variant of the hydrozirconation reaction has been established starting from Boc-protected chiral allylic amines. The resulting diastereoselectively formed N-functionalized organozirconiums can be considered as promising chirons. In this case, they have been transformed into enantiomerically enriched cis-2,3-disubstituted azetidines through a iodination/cyclization sequence.

Atropoisomeric quinolinium salt promoting the access to both enantiomeric forms of methyl mandelate: a versatile NADH mimicElectronic supplementary information (ESI) available: experimental. See http://www.rsc.org/suppdata/cc/b2/b207434f/

Asymmetric reduction of methyl benzoylformate by a new NADH mimic is reported; depending on the hydride source used to reduce the NAD+ precursor, NADH mimics so obtained lead to an inversion of enantioselectivity, affording either (R)-methyl mandelate in 88% ee or (S)-methyl mandelate in 78% ee.