An Enantioselective Approach to 4-Substituted Proline Scaffolds: Synthesis of (<i>S</i>)-5-(<i>tert</i>-Butoxy carbonyl)-5-azaspiro[2.4]heptane-6-carboxylic Acid

Abstract

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.

Keywords

• phase-transfer catalysis
• stereoselective synthesis
• antiviral agent
• proline analogue