Solid-Phase Synthesis of Peptides Containing the CH₂NH Reduced Bond Surrogate

Abstract

There has been considerable interest in the past decade in the design and development of competitive peptide agonists and antagonists for numerous peptide-receptor systems. Systematic side-chain replacement is often the first step in the design process of higher-affinity ligands. Modification of the peptide backbone is another step in the design process, but requires more information about the stability and structure of the peptide. The most common types of backbone alterations are the incorporation of N-methylated amino acids and/or D amino acids into the peptide. These changes can help stabilize the peptide against proteases, disrupt or induce secondary structural elements, and eliminate hydrogen bonds. In addition to these approaches, replacement of peptide bonds by peptide bond surrogates, such as a CH₂NH reduced peptide bond, can also be performed. The initial approach to these type of compounds was exceedingly more difficult to accomplish and required considerable solution synthesis (1). In this chapter, the protected dipeptide containing the reduced bond was prepared in solution by reductive alkylation with the protected a-amino aldehyde and subsequently coupled to the peptide chain. Low coupling yields were often described when this method was attempted probably because of isosteric components present during the reaction (2).