Highly Enantioselective Phase-Transfer Catalytic alpha-Alkylation of alpha-tert-Butoxycarbonyllactams: Construction of beta-Quaternary Chiral Pyrrolidine and Piperidine Systems

Abstract

A new enantioselective alpha-alkylation of alpha-tert-butoxycarbonyllactams for the construction of beta-quaternary chiral pyrrolidine and piperidine core systems is reported. alpha-Alkylations of N-methyl-alpha-tert-butoxycarbonylbutyrolactam and N-diphenylmethyl-alpha-tert-butoxycarbonylvalerolactam under phase-transfer catalytic conditions (solid potassium hydroxide, toluene, -40 degrees C) in the presence of (S,S)-3,4,5-trifluorophenyl-3,3',5,5'-tetrahydro-2,6-bis(3,4,5-trifluorophenyl)-4,4'-spirobi[4H-dinaphth[2,1-c:1',2'-e]azepinium] bromide [(S,S)-NAS Br] (5 mol%) afforded the corresponding alpha-alkyl-alpha-tert-butoxycarbonyllactams in very high chemical (up to 99%) and optical yields (up to 98% ee). Our new catalytic systems provide attractive synthetic methods for pyrrolidine- and piperidine-based alkaloids and chiral intermediates with beta-quaternary carbon centers.