Integration of C-Acylation in the Solid-Phase Synthesis of Peptides and Peptidomimetics Employing Meldrum’s Acid, Phosphorus, and Sulfur Ylides

Abstract

The modification of native peptides to peptidomimetics is an important goal in medicinal chemistry and requires, in many cases, the integration of C-acylation steps involving amino acids with classical peptide synthesis. Many classical C-acylation protocols involving Claisen condensations and the use of ylides are not compatible with peptide synthesis, mostly due to the requirements for strong bases leading to epimerization or deprotection of peptides. Meldrum’s acid as well as several specific phosphorus and sulfur ylides, however, are acidic enough to provide reactive C-nucleophiles under mildly basic conditions tolerated during peptide synthesis. This review provides an overview of peptide-compatible C-acylations using Meldrum’s acid and phosphorus and sulfur ylides, and their application in the medicinal chemistry of peptides.

1 Introduction

2 C-Acylation of Meldrum’s Acid

2.1 C-Acylation of Meldrum’s Acid on Solid Phase

3 Ylides as Substrates for C-Acylation

3.1 C-Acylation of Phosphorus Ylides in Solution Phase

3.2 C-Acylation of Solid-Supported Phosphorus Ylides

3.3 C-Acylation of Sulfur Ylides

3.4 C-Acylation of Solid-Supported Sulfur Ylides

4 Miscellaneous Ylides as Acyl Anion Equivalents

5 Summary

Key words

C-acylation - peptidomimetics - Meldrum’s acid - phosphorus ylides - sulfur ylides - peptides

Publication History

Received: 22 June 2021

Accepted after revision: 12 October 2021

Accepted Manuscript online:
12 October 2021

Article published online:
18 January 2022

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