Investigation of Cysteine as an Activator of Side-Chain N→S Acyl Transfer and Tail-to-Side-Chain Cyclization

Published as part of the Cluster Recent Advances in Protein and Peptide Synthesis

Abstract

N→S Acyl transfer is a popular method for the postsynthesis production of peptide C _α-thioesters for use in native chemical ligation and for the synthesis of head-to-tail cyclic peptides. Meanwhile thioester formation at the side chain of aspartic or glutamic acids, leading to tail-to-side-chain-cyclized species, is less common. Herein we explore the potential for cysteine to function as a latent thioester when appended to the side chain of glutamic acid. Initial insights gained through study of C-terminal β-alanine as a model for the increased chain length were ultimately applied to peptide macrocyclization. Our results emphasize the increased barrier to acyl transfer at the glutamic acid side chain and indicate how a slow reaction, facilitated by cysteine itself, may be accelerated by fine-tuning of the stereoelectronic environment.

Key words

cyclic peptides - native chemical ligation - acyl transfer

• References and Notes

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