Synthesis of enantiopure ε-oxapipecolic acid

A six-step synthesis of orthogonally-protected (S)-e-oxapipecolic acid is described, starting from a commercially available glutamate diester. The approach features an mCPBA-mediated amine oxidation and 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 e heteroatom in oxapipecolic acid exerts a strong trans substantiating effect through lone pair repulsion.