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

Abstract

AbstractThe 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 Introduction2 C-Acylation of Meldrum’s Acid2.1 C-Acylation of Meldrum’s Acid on Solid Phase3 Ylides as Substrates for C-Acylation3.1 C-Acylation of Phosphorus Ylides in Solution Phase3.2 C-Acylation of Solid-Supported Phosphorus Ylides3.3 C-Acylation of Sulfur Ylides3.4 C-Acylation of Solid-Supported Sulfur Ylides4 Miscellaneous Ylides as Acyl Anion Equivalents5 Summary