Total Synthesis and Stereochemical Assignment of Enteropeptin A

• Published in: Journal of the American Chemical Society Vol. 146; no. 26; pp. 17629 - 17635
• Main Authors: Zhang, Yiwei, Saha, Shuvendu, Esser, Yannik C. C., Ting, Chi P.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 03.07.2024
• Subjects: Cyclization; Morpholines - chemical synthesis; Morpholines - chemistry; Stereoisomerism
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.4c06126

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.