Evolution of a Strategy for the Unified Synthesis of Enteropeptin Sactipeptides

Sactipeptides are a class of natural product peptides with remarkable antibiotic properties that are defined by the presence of thioaminoketals in their structure. Recently, we reported the first total synthesis of a sactipeptide in our synthesis of enteropeptin A. The key to our synthesis involved the use of a dithiophosphoric acid catalyzed Markovnikov hydrothiolation of dehydroamino acids. With this reaction, thioaminoketals found in sactipeptides can be prepared directly from a dehydroamino acid and a cysteine residue. This article summarizes our initial approach toward enteropeptin synthesis and the evolution of our strategy that ultimately enabled the synthesis of these peptide natural products. Our first strategy involved late-stage Markovnikov hydrothiolation of an 8-mer peptide containing a dehydroamino acid and a cysteine residue that was unsuccessful. The second strategy involved an annulation reaction between a methyl ester of a dehydroamino acid and a cysteine with an unprotected amine that forged the central thiomorpholine ring albeit in low yield. The third strategy involved a divergent synthesis of the enteropeptins by early stage formation of the thiomorpholine ring by Markovnikov hydrothiolation followed by amidative coupling of the N- and C-terminal peptide fragments. This modular strategy enabled the unified synthesis of the enteropeptin sactipeptides.