Complementary Strategies for Installation of Thioimidates into Peptide Backbones

Abstract

Thioimidates are a precursor and synthetic branch point to access either thioamide or amidine isosteres of the native amide (peptide bond). Previous syntheses of thioimidatecontaining peptides were prone to side reactivity and required slow, cumbersome steps that were difficult to monitor. We describe a more efficient approach to directly couple thioimidates onto the growing peptide chain. This work also outlines optimal conditions for thioimidate formation on solid support and identifies potential off-target sites for alkylation that impact the choice of protecting group.