Open AccessTotal Synthesis and Stereochemical Assignment of Streptide
Author(s) -
Nicholas A. Isley,
Yusuke Endo,
Zhi Chen Wu,
Brett C. Covington,
Leah B. Bushin,
Mohammad R. Seyedsayamdost,
Dale L. Boger
Publication year - 2019
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.9b09067
Subject(s) - chemistry , total synthesis , natural product , lysine , annulation , residue (chemistry) , peptide , stereochemistry , diastereomer , indole test , tryptophan , regioselectivity , hypervalent molecule , combinatorial chemistry , cyclic peptide , amino acid , catalysis , iodine , organic chemistry , biochemistry
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 (3 R vs 3 S ) of the lysine-2 C3 center. Both the 3 R and the originally assigned 3 S 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.