Open AccessPeptide Macrocyclization Inspired by Non-Ribosomal Imine Natural Products
Author(s) -
Lara R. Malins,
Justine N. deGruyter,
Kevin J. Robbins,
Paul M. Scola,
Martin D. Eastgate,
Mojtaba Ghadiri,
Phil S. Baran
Publication year - 2017
Publication title -
journal of the american chemical society
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.7b01624
Subject(s) - chemistry , imine , circular dichroism , intramolecular force , peptide , combinatorial chemistry , bioorthogonal chemistry , cyclic peptide , stereochemistry , reactivity (psychology) , peptide conformation , organic chemistry , click chemistry , biochemistry , medicine , alternative medicine , pathology , catalysis
A thermodynamic approach to peptide macrocyclization inspired by the cyclization of non-ribosomal peptide aldehydes is presented. The method provides access to structurally diverse macrocycles by exploiting the reactivity of transient macrocyclic peptide imines toward inter- and intramolecular nucleophiles. Reactions are performed in aqueous media, in the absence of side chain protecting groups, and are tolerant of all proteinogenic functional groups. Macrocyclic products bearing non-native and rigidifying structural motifs, isotopic labels, and a variety of bioorthogonal handles are prepared, along with analogues of four distinct natural products. Structural interrogation of the linear and macrocyclic peptides using variable-temperature NMR and circular dichroism suggests that preorganization of linear substrates is not a prerequisite for macrocyclization.