General Synthesis of Conformationally Constrained Noncanonical Amino Acids with C(sp3)-Rich Benzene Bioisosteres

J Org Chem. 2024 Apr 5;89(7):5010-5018. doi: 10.1021/acs.joc.4c00225. Epub 2024 Mar 26.

Abstract

Recent years have seen novel modalities emerge for the treatment of human diseases resulting in an increase in beyond rule of 5 (bRo5) chemical matter. As a result, synthetic innovations aiming to enable rapid access to complex bRo5 molecular entities have become increasingly valuable for medicinal chemists' toolkits. Herein, we report the general synthesis of a new class of noncanonical amino acids (ncAA) with a cyclopropyl backbone to achieve conformational constraint and bearing C(sp3)-rich benzene bioisosteres. We also demonstrate preliminary studies toward utilities of these ncAA as building blocks for medicinal chemistry research.

MeSH terms

  • Amines
  • Amino Acids* / chemistry
  • Benzene*
  • Humans
  • Molecular Conformation

Substances

  • Amino Acids
  • Benzene
  • Amines