Total Synthesis and Stereochemical Assignment of Enteropeptin A

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Chemical Biology

Background:

• Sactipeptides are a class of antimicrobial cyclic peptides with unique structural features.
• Enteropeptin A, a sactipeptide, possesses a challenging thioaminoketal group within a thiomorpholine ring.
• The stereochemistry of the thioaminoketal in enteropeptin A was previously unassigned.

Purpose of the Study:

• To achieve the total synthesis of the antimicrobial sactipeptide enteropeptin A.
• To elucidate the structure and stereochemistry of enteropeptin A.
• To develop a general synthetic strategy for stereochemically defined thiomorpholine-containing peptides.

Main Methods:

• A linear peptide precursor containing a dehydroamino acid and cysteine was synthesized.
• Markovnikov hydrothiolation using a dithiophosphoric acid catalyst facilitated thiomorpholine ring formation.
• Synthesis of both diastereomers at the thioaminoketal stereocenter allowed for stereochemical assignment.

Main Results:

• The first total synthesis of enteropeptin A was successfully accomplished.
• The stereochemical configuration of the thioaminoketal group was unambiguously assigned as D.
• The synthetic strategy provides a versatile platform for related cyclic peptide antibiotics.

Conclusions:

• This study reports the inaugural total synthesis of a sactipeptide, enteropeptin A.
• The developed synthetic methodology enables the preparation of stereochemically defined thiomorpholine peptides.
• This work may facilitate the discovery and development of new cyclic peptide antibiotics.