2-Oxa-5-azabicyclo[2.2.1]heptane as a Platform for Functional Diversity: Synthesis of Backbone-Constrained γ-Amino Acid Analogues

J Org Chem. 2022 Aug 19;87(16):11261-11273. doi: 10.1021/acs.joc.2c01338. Epub 2022 Jul 28.

Abstract

We communicate a versatile synthetic approach to C-3 disubstituted 2-oxa-5-azabicyclo[2.2.1]heptanes as carbon-atom bridged morpholines, starting with 4R-hydroxy-l-proline as a chiron. Attaching an acetic acid moiety on the C-3 carbon of the 2-oxa-5-azabicyclo[2.2.1]heptane core reveals the framework of an embedded γ-amino butyric acid (GABA). Variations in the nature of the substituent on the tertiary C-3 atom with different alkyls or aryls led to backbone-constrained analogues of the U.S. Food and Drug Administration-approved drugs baclofen and pregabalin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids*
  • Carbon
  • Heptanes* / chemistry
  • Proline
  • Stereoisomerism

Substances

  • Amino Acids
  • Heptanes
  • Carbon
  • Proline