Total Synthesis and Stereochemical Assignment of Streptide

Abstract

Streptide (<b>1</b>) 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 (3<i>R</i> vs 3<i>S</i>) of the lysine-2 C3 center. Both the 3<i>R</i> and the originally assigned 3<i>S</i> 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.