# Evolution of a Strategy for the Unified Synthesis of Enteropeptin Sactipeptides

## TL;DR

The paper describes the development of a new method to synthesize sactipeptides, a type of antibiotic peptide, using a more efficient and unified approach.

## Contribution

The novel contribution is a modular synthesis strategy that enables unified synthesis of enteropeptin sactipeptides through early formation of the thiomorpholine ring.

## Key findings

- Late-stage hydrothiolation of an 8-mer peptide was unsuccessful.
- An annulation reaction formed the thiomorpholine ring but with low yield.
- A divergent synthesis strategy enabled unified synthesis of enteropeptin sactipeptides.

## Abstract

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.