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Total Synthesis and Conformational Study of Callyaerin A: Anti‐Tubercular Cyclic Peptide Bearing a Rare Rigidifying ( Z )‐2,3‐ Diaminoacrylamide Moiety
Author(s) -
Zhang Shengping,
De Leon Rodriguez Luis M.,
Leung Ivanhoe K. H.,
Cook Gregory M.,
Harris Paul W. R.,
Brimble Margaret A.
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201712792
Subject(s) - moiety , chemistry , peptide , stereochemistry , cyclic peptide , amide , intramolecular force , residue (chemistry) , peptide synthesis , natural product , peptide bond , amine gas treating , organic chemistry , biochemistry
The first synthesis of the anti‐TB cyclic peptide callyaerin A ( 1 ), containing a rare ( Z )‐2,3‐diaminoacrylamide bridging motif, is reported. Fmoc‐formylglycine‐diethylacetal was used as a masked equivalent of formylglycine in the synthesis of the linear precursor to 1 . Intramolecular cyclization between the formylglycine residue and the N‐terminal amine in the linear peptide precursor afforded the macrocyclic natural product 1 . Synthetic 1 possessed potent anti‐TB activity (MIC 100 =32 μ m ) while its all‐amide congener was inactive. Variable‐temperature NMR studies of both the natural product and its all‐amide analogue revealed the extraordinary rigidity imposed by this diaminoacrylamide unit on peptide conformation. The work reported herein pinpoints the intrinsic role that the ( Z )‐2,3‐diaminoacrylamide moiety confers on peptide bioactivity.