Construction of Thioamide Peptides from Chiral Amino Acids

Thioamide peptides were synthesized via a straightforward one-pot process via the linkage of diverse natural amino acids in the presence of thiolphosphonate and trichlorosilane, wherein carbonyl groups were replaced with thiono compounds with minimal racemization. Experimental and computational mechanistic studies demonstrated that trichlorosilane enabled the activation of carboxylic acids via intense interactions with the Si–O bond, followed by coupling of the carboxylic acids with thiolphosphonate to obtain the key intermediate S-acyl dithiophosphate. Silyl-activated quadrangular metathesis transition states afforded thioamide peptides. The potential applications for thioamide peptides were further highlighted via late-stage linkages of diverse natural products and pharmaceutical drugs and the thioamide moiety.