Synthesis of N α-(1-Phenyl-2-mercaptoethyl) Amino Acids, New Building Blocks for Ligation and Cyclization at Non-Cysteine Sites:  Scope and Limitations in Peptide Synthesis

• Published in: Journal of organic chemistry 2004-12, Vol.69 (26), p.9208-9214
• Main Authors: Tchertchian, Sylvie, Hartley, Oliver, Botti, Paolo
• Format: Article
• Language: English
• Subjects: Amino Acids - chemistry; Chemistry; Cysteine - chemistry; Exact sciences and technology; Magnetic Resonance Spectroscopy; Mass Spectrometry; Organic chemistry; Peptides; Peptides - chemical synthesis; Preparations and properties
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo049471k

A new and convenient method for the synthesis and incorporation of N α-(1-phenyl-2-mercaptoethyl)-derivatized amino acids applicable to chemical ligation at non-cysteine sites is presented. N α-Auxiliary derivatives of glycine and alanine were easily prepared using reductive amination approaches. Several strategies for the incorporation of these derivatives into peptide chains were investigated:  coupling without protection, with acid-labile protection, with base-labile protection, and via a novel protection strategy using the thiazolidine derivative. All amino acid derivatives were successfully coupled to various peptide resins, and with the exception of those incorporating Boc-protected derivatives, all resins yielded the desired peptide fragments. However, the coupling of the two alanine derivative diastereomers generated some epimerization. Finally, N-terminal auxiliary glycine and alanine peptides were cyclized, and the corresponding native circular peptides were obtained upon successful removal of the auxiliary.