Castillo-Pazos, DJ; Macmillan, D; (2017) Investigation of Cysteine as an Activator of Side-Chain N -> S Acyl Transfer and Tail-to-Side-Chain Cyclization. Synlett , 28 (15) pp. 1923-1928. 10.1055/s-0036-1590797.

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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.

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