Total Synthesis and Stereochemical Assignment of Enteropeptin A

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.