Enantioselective synthesis of alpha-benzoxy-alpha-alkylmalonate via Phase-transfer Catalytic alkylation

Abstract

Chiral alpha-hydroxy malonates and their equivalents are potentially valuable intermediates for the synthesis of natural products and pharmaceuticals. alpha-Hydroxy malonate itself can be easily modified to chiral glycerols or alpha,alpha-dihydroxy esters according to the chemical conversion of two esters. There have been a lot of enantioselective synthetic methods of alpha-hydroxy-β-ketoesters. However, they have been mostly achieved by the enzymatic desymmetrization of prochiral malonates. Recently, our research team reported a new synthetic method of chiral alpha,alpha-dialkylmalonates in high chemical yields and enantioselectivities by phase-transfer catalytic (PTC) desymmetrization of malonates in the presence of chiral quaternary ammonium salts, and successfully proved its usefulness by applications to the synthesis of various chiral building blocks bearing quaternary carbon center. Based on this study, highly enantioselective alkylation of tert-butyl diphenylmethyl alpha-benzoxymalonate could be accomplished under phase-transfer catalysis in the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide as PTC catalyst to afford the corresponding alpha-benzoxy-alpha-alkylmalonates in high chemical (up to 99%) and optical yields (up to 93% ee) which could be readily converted to versatile chiral intermediates.