Scalable synthesis and coupling of quaternary α-arylated amino acids: α-aryl substituents are tolerated in α-helical peptides.

Daniel J Leonard,John W Ward,Isabelle Wellhöfer,Jonathan Clayden,Francis Zieleniewski,Emily G Baker,Derek N Woolfson

doi:10.1039/d1sc01378e

Daniel J Leonard, John W Ward + Show 5 more

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https://doi.org/10.1039/d1sc01378e

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Abstract

Quaternary amino acids are important tools for the modification and stabilisation of peptide secondary structures. Here we describe a practical and scalable synthesis applicable to quaternary alpha-arylated amino acids (Q4As), and the development of solid-phase synthesis conditions for their incorporation into peptides. Monomeric and dimeric α-helical peptides are synthesised with varying degrees of Q4A substitution and their structures examined using biophysical methods. Both enantiomers of the Q4As are tolerated in folded monomeric and oligomeric α-helical peptides, with the (R)-enantiomer slightly more so than the (S).

Highlights

Advances in automated synthesis and better understanding of peptide and peptidomimetic structural properties have allowed rapid development in the eld of peptide-based therapeutics
In uence conformations adopted by peptides, which plays a major role in determining their biological activities.[4] a-Arylated amino acids do not occur naturally and their incorporation into peptide structures could allow exploration of new chemical space beyond that tested through traditional peptide design
Whilst phenylglycine and related residues are prone to racemisation during Fmoc solid-phase peptide synthesis (SPPS),[5] quaternary a-arylated amino acids, which lack an enolisable proton, are fully con gurationally stable

Summary

Introduction

Advances in automated synthesis and better understanding of peptide and peptidomimetic structural properties have allowed rapid development in the eld of peptide-based therapeutics. Whilst phenylglycine and related residues are prone to racemisation during Fmoc solid-phase peptide synthesis (SPPS),[5] quaternary a-arylated amino acids, which lack an enolisable proton, are fully con gurationally stable.

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