Asymmetric Synthesis of Conformationally Constrained <i>trans</i>-2,3-Piperidinedicarboxylic Acid Derivatives

Abstract

An efficient asymmetric synthesis of conformationally constrained (2S,3S)-piperidinedicarboxylic acid derivatives starting from l-aspartic acid β-tert-butyl ester and 3-chloro-2-(chloromethyl)-1-propene is described. The key steps involve N-alkylation of the aspartic acid ester followed by a stereoselective enolate intra­molecular cyclization (>95:5 dr). Various synthetic strategies were explored to achieve the cyclopropanation of the resulting olefin, ­including the Simmons-Smith reaction and palladium-catalyzed cyclopropanation.