Molecules (Nov 2020)

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

  • Blanca López,
  • Martí Bartra,
  • Ramon Berenguer,
  • Xavier Ariza,
  • Jordi Garcia,
  • Roberto Gómez,
  • Hèctor Torralvo

DOI
https://doi.org/10.3390/molecules25235644
Journal volume & issue
Vol. 25, no. 23
p. 5644

Abstract

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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.

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