An Enantioselective Approach to 4-Substituted Proline Scaffolds: Synthesis of (S)-5-(Tert-Butoxy Carbonyl)-5-Azaspiro[2.4]heptane-6-Carboxylic Acid.

A catalytic and enantioselective preparation of the (S)-4-methyleneproline scaffold is described. The key reaction is a one-pot double allylic alkylation of an imine analogue of glycine in the presence of a chinchonidine-derived catalyst under phase transfer conditions. These 4-methylene substituted proline derivatives are versatile starting materials often used in medicinal chemistry. In particular, we have transformed tert-butyl (S)-4-methyleneprolinate (12) into the N-Boc-protected 5-azaspiro[2.4]heptane-6-carboxylic acid (1), a key element in the industrial synthesis of antiviral ledipasvir.

Total synthesis of entecavir.

Entecavir (BMS-200475) was synthesized from 4-trimethylsilyl-3-butyn-2-one and acrolein. The key features of its preparation are: (i) a stereoselective boron-aldol reaction to afford the acyclic carbon skeleton of the methylenecylopentane moiety; (ii) its cyclization by a Cp2TiCl-catalyzed intramolecular radical addition of an epoxide to an alkyne; and (iii) the coupling with a purine derivative by a Mitsunobu reaction.

Highly stereoselective approach to alk-2-yne-1,4-diols by oxazaborolidine-mediated reduction of alk-2-yne-1,4-diones.

We performed the borane-mediated reduction of a series of symmetrical alk-2-yne-1,4-diones (5) in the presence of the oxazaborolidine (R)-6 to afford (R,R)-alk-2-yne-1,4-diols ((R,R)-1) in good yields and high stereoselectivities (up to 99.9% ee). In some cases, the stereochemical purity of 1 was improved by a two-step process: (i) temporary transformation of 1 into its vic-dibromo derivatives 9, which allowed us to remove the minor meso isomer by chromatography, and (ii) regeneration of the enantioenriched diols 1 with SmI2. Reduction of the hexacarbonyldicobalt complexes 8 derived from 5 was also successful.