Late-Stage Formation of a Sactionine Linkage Enabled by Lossen Rearrangement of Glycyl Hydroxamic Acid

Org Lett. 2024 Jun 21;26(24):5167-5171. doi: 10.1021/acs.orglett.4c01685. Epub 2024 Jun 7.

Abstract

Late-stage formation of a sactionine thioether bond connecting a Gly α-carbon and Cys thiol was achieved by Lossen rearrangement of a glycyl hydroxamic acid (GlyHA) residue in a peptide. Lossen rearrangement allowed conversion of GlyHA within a peptide to an N-acyl iminium equivalent, which subsequently reacted with S-acetamidomethyl Cys (Cys(Acm)) in TFA in the presence of guanidine hydrochloride (Gn·HCl) to yield the desired thioether linkage in the final stage.