Precision Synthesis of Chimeric Peptides through Site-Specific Azomethine Ylide–Dehydroalanine Cycloaddition

13 May 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Site-selective conjugation of peptides is crucial for constructing structurally uniform peptide chimeras for applications such as drug discovery and drug delivery. Nevertheless, the site-specific late-stage transformation of peptides is challenging due to the presence of multiple nucleophilic sites, such as lysine ε-amine. In this work, we developed a three-component assembly method involving N-terminus/dehydroalanine (Dha)-selective peptide–peptide connections via a 1,3-dipolar cycloaddition reaction, resulting in the formation of peptide chimeras with complete endo-diastereoselectivity. Tolerating a broad range of functional groups, including the ɛ-amine of a lysine residue, the present method offers an opportunity for the expedient and modular assembly of readily accessible aldehyde, N-terminus-unprotected peptides, and peptide-based dehydroalanines into the chemically robust pyrrolidine ring.

Keywords

Peptides
Peptide modification
Azomethine ylides
Cycloaddition
Multicomponent reactions

Supplementary materials

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Description
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Supporting Information
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Data of conditions study.
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