Revisiting N‑to‑O Acyl Shift for Synthesis of Natural Product-like Cyclic Depsipeptides

Despite the prevalence of head-to-side chain threonine linkages in natural products, their incorporation has been underexplored in synthetic cyclic peptides. Herein we investigate a cyclic peptide scaffold able to undergo an N–O acyl rearrangement. Upon acylation of the amine with diverse carboxylic...

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Bibliographic Details
Published in:Organic letters 2014-12, Vol.16 (23), p.6088-6091
Main Authors: Schwochert, Joshua, Pye, Cameron, Ahlbach, Christopher, Abdollahian, Yashar, Farley, Kathleen, Khunte, Bhagyashree, Limberakis, Chris, Kalgutkar, Amit S, Eng, Heather, Shapiro, Michael J, Mathiowetz, Alan M, Price, David A, Liras, Spiros, Lokey, R. Scott
Format: Article
Language:English
Subjects:
Acylation
Amino Acid Sequence
Biological Products - chemical synthesis
Biological Products - chemistry
Biological Products - pharmacology
Depsipeptides - chemical synthesis
Depsipeptides - chemistry
Depsipeptides - pharmacology
Molecular Conformation
Molecular Structure
Peptides - chemistry
Peptides, Cyclic
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Summary:Despite the prevalence of head-to-side chain threonine linkages in natural products, their incorporation has been underexplored in synthetic cyclic peptides. Herein we investigate a cyclic peptide scaffold able to undergo an N–O acyl rearrangement. Upon acylation of the amine with diverse carboxylic acids, the resulting cyclic depsipeptides displayed favorable cellular permeability and a conformation similar to the parent peptide. The rearrangement was found to be scaffold and conformation dependent as evidenced by molecular dynamics experiments.
ISSN:1523-7060
1523-7052
DOI:10.1021/ol503170b