Construction of Thioamide Peptides from Chiral Amino Acids

Thioamide peptides were synthesized in 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 the trichlorosilane enables 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 the thioamide peptides. The potential applications of these thioamide peptides were further highlighted via late-stage linkages of diverse natural products and pharmaceutical drugs and the thioamide moiety.

Automated summary

Thioamide peptides were synthesized in a one-pot process by linking natural amino acids in the presence of thiolphosphonate and trichlorosilane, with minimal racemization. Experimental and computational studies showed that trichlorosilane enables the activation of carboxylic acids and coupling with thiolphosphonate to obtain the intermediate S-acyl dithiophosphate. Silyl-activated quadrangular metathesis transition states resulted in the formation of thioamide peptides.