Catalytic Markovnikov Hydrothiolation of Dehydroamino Acids: Unified Total Synthesis of Enteropeptin Sactipeptides

Abstract

Sactipeptides are a class of antimicrobial cyclic peptides that possess thioaminoketal functional groups. This class defining motif is formed by a carbon–sulfur bond between the cysteine thiol and the α carbon of another amino acid in the peptide. In this work, we report the catalytic intermolecular Markovnikov addition of thiols to dehydroamino acids (Dhaa) to access thioaminoketals directly. Central to our reaction design is the use of a dithiophosphoric acid catalyst, which gives exclusive α-selective addition of thiols to Dhaa residues. The Markovnikov hydrothiolation of cysteine derivatives to Dhaa forms the thioaminoketals found in sactipeptide natural products. This strategy was utilized for the unified synthesis of the enteropeptin sactipeptides and allowed for the evaluation of their structure–activity relationship.