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
Volume141
Issue43
Pagination17361-17369
Date Published2019 10 30
ISSN1520-5126
KeywordsCatalysis, Chromatography, High Pressure Liquid, Cyclization, Iodine, Lysine, Magnetic Resonance Spectroscopy, Models, Molecular, Palladium, Peptides, Cyclic, Stereoisomerism, Tryptophan
Abstract

<p>Streptide () 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 vs 3) of the lysine-2 C3 center. Both the 3 and the originally assigned 3 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.</p>

DOI10.1021/jacs.9b09067
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