Peptide Macrocyclization Inspired by Non-Ribosomal Imine Natural Products

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 nucle...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2017-04, Vol.139 (14), p.5233-5241
Main Authors: Malins, Lara R, deGruyter, Justine N, Robbins, Kevin J, Scola, Paul M, Eastgate, Martin D, Ghadiri, M. Reza, Baran, Phil S
Format: Article
Language:English
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Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.7b01624