Synthesis of Enantiopure ε-Oxapipecolic Acid

J Org Chem. 2020 Feb 7;85(3):1680-1686. doi: 10.1021/acs.joc.9b02382. Epub 2019 Nov 8.

Abstract

A six-step synthesis of orthogonally protected (S)-ε-oxapipecolic acid is described, starting from a commercially available glutamate diester. The approach features mCPBA-mediated amine oxidation and an intramolecular Mitsunobu reaction to form the tetrahydrooxazine ring. The enantiopure building block was employed in the synthesis of a short model peptide to determine the amide rotamer preference N-terminal to the cyclic residue. In contrast to pipecolic acid, which exhibits a high cis amide population, the ε heteroatom in oxapipecolic acid exerts a strong trans substantiating effect through lone pair repulsion.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.