Total Synthesis and Stereochemical Assignment of Streptide.

TitleTotal Synthesis and Stereochemical Assignment of Streptide.
Publication TypeJournal Article
Year of Publication2019
AuthorsIsley, NA, Endo, Y, Wu, Z-C, Covington, BC, Bushin, LB, Seyedsayamdost, MR, Boger, DL
JournalJ Am Chem Soc
Date Published2019 10 30
KeywordsCatalysis, Chromatography, High Pressure Liquid, Cyclization, Iodine, Lysine, Magnetic Resonance Spectroscopy, Models, Molecular, Palladium, Peptides, Cyclic, Stereoisomerism, Tryptophan

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.

Alternate JournalJ Am Chem Soc
PubMed ID31577142
PubMed Central IDPMC6821584
Grant ListF32 GM114948 / GM / NIGMS NIH HHS / United States
R01 CA041101 / CA / NCI NIH HHS / United States