Stereoselective synthesis of δ-fluorinated isoleucines exploiting consecutive C(sp3)-H bond activations

Abstract

Fluorinated α-amino acids are important building blocks for pharmaceutical and agrochemical industries, as well as in protein NMR and material science. We optimized a synthetic route to generate 5-fluoro-l-isoleucine (1) and 5,5-difluoro-l-isoleucine (2) from l-alanine by leveraging two consecutive C(sp3)-H bond functionalization reactions and developed a new oxidation protocol to facilitate directing and protecting group removal without α-epimerization of the amino acid or trigger other side reactions.