Total Synthesis and Stereochemical Assignment of Streptide

Streptide (1) is a peptide-derived
macrocyclic natural
product that has attracted considerable attention since its discovery
in 2015. It contains an unprecedented post-translational modification
that intramolecularly links the β-carbon (C3) of a residue 2
lysine with the C7 of a residue 6 tryptophan, thereby forming a 20-membered
cyclic peptide. Herein, we report the first total synthesis of streptide
that confirms the regiochemistry of the lysine-tryptophan cross-link
and provides an unambiguous assignment of the stereochemistry (3R vs 3S) of the lysine-2 C3 center. Both
the 3R and the originally assigned 3S lysine diastereomers were independently prepared by total synthesis,
and it is the former, not the latter, that was found to correlate
with the natural product. The approach enlists a powerful Pd(0)-mediated
indole annulation for the key macrocyclization of the complex core
peptide, utilizes an underdeveloped class of hypervalent iodine­(III)
aryl substrates in a palladium-catalyzed C–H activation/β-arylation
reaction conducted on a lysine derivative, and provides access to
material with which the role of streptide and related natural products
may be examined.