A novel tandem Michael addition/Meerwein-Ponndorf-Verley reduction:: Asymmetric reduction of acyclic α,β-unsaturated ketones using a chiral mercapto alcohol

The introduction of a thiol group into a chiral alcohol reagent for asymmetric Meerwein-Ponndorf-Verley (MPV) reductions allows asymmetric reduction of alpha,beta-unsaturated ketones to secondary alcohols and allylic alcohols via a novel tandem Michael addition/MPV reduction. The reaction of acyclic alpha,beta-unsaturated ketones 1 and an optically active 1,3-mercapto alcohol (-)-2 using dimethylaluminum chloride afforded the MPV reduction products 3 diastereoselectively in very high yields (up to 96%). Mechanistic studies elucidated (1) the structure of the chelation complex D with (-)-2 and Me2AlCl, (2) an asymmetric 1,7-hydride shift (intramolecular MPV reduction), and (3) dynamic kinetic resolution via reversible Michael addition. Subsequent reductive desulfurization of the MPV products 3 with a modified Raney nickel system led to the highly enantioselective reduction of alpha,beta-unsaturated ketones to saturated secondary alcohols in 96-98% ee. beta-Elimination of the corresponding sulfoxides gave the allylic alcohols in 86-98% ee. Applications to the asymmetric reduction of a synthetic intermediate 1m of prostaglandins and to a new asymmetric synthesis of the (+)-Rove beetle pheromone 11 are described.