Total Synthesis and Stereochemical Assignment of Enteropeptin A

Abstract

The total synthesis and structural elucidation of the antimicrobial sactipeptide enteropeptin A is reported. Enteropeptin A contains a thioaminoketal group with an unassigned stereochemical configuration that is embedded in a highly unusual thiomorpholine ring. In this synthesis, a linear peptide containing a dehydroamino acid and a pendant cysteine residue is subjected to Markovnikov hydrothiolation by a dithiophosphoric acid catalyst. This cyclization reaction forms the central thiomorpholine ring found in the enteropeptins. Both diastereomers at the unassigned thioaminoketal stereocenter of enteropeptin A were prepared, and their comparison to an authentic standard allowed for the unambiguous stereochemical assignment of the natural product to be of the D configuration. This inaugural total synthesis of enteropeptin A represents the first total synthesis of a sactipeptide reported to date. Moreover, the strategy disclosed herein serves as a general platform for the synthesis of stereochemically defined thiomorpholine-containing peptides, which may enable the discovery of new cyclic peptide antibiotics.

Figure 1.

a.) Representative sactipeptides enteropeptins A-C. b.) Retrosynthesis of enteropeptin A.

Figure 2.

LC/MS analysis of authentic and synthetic enteropeptin A. Extracted ion chromatogram for enteropeptin A (845 m/z) is shown in each trace. Authentic enteropeptin A coelutes with 1 (D-thioaminoketal) but not with epi-1 (L-thioaminoketal).

Scheme 1.

Total synthesis of enteropeptin A (1) and its thioaminoketal diastereomer (epi-1).^{a a} For details on reagents and conditions, see the supplementary information.