A convenient approach to synthesizing peptide C-terminal N-alkyl amides

• Published in: Biopolymers 2011, Vol.96 (6), p.715-722
• Main Authors: Fang, Wei-Jie, Yakovleva, Tatyana, Aldrich, Jane V.
• Format: Article
• Language: English
• Subjects: Alkylation; Amides - chemical synthesis; Amides - chemistry; Amino Acid Sequence; Chromatography, High Pressure Liquid; Fukuyama amine synthesis; Mass Spectrometry; peptide C-terminal N-alkyl amides; Peptides - chemical synthesis; Peptides - chemistry
• ISSN: 0006-3525; 1097-0282
• DOI: 10.1002/bip.21600

Peptide C‐terminal N‐alkyl amides have gained more attention over the past decade due to their biological properties, including improved pharmacokinetic and pharmacodynamic profiles. However, the synthesis of this type of peptide on solid phase by current available methods can be challenging. Here we report a convenient method to synthesize peptide C‐terminal N‐alkyl amides using the well‐known Fukuyama N‐alkylation reaction on a standard resin commonly used for the synthesis of peptide C‐terminal primary amides, the peptide amide linker‐polyethylene glycol‐polystyrene (PAL‐PEG‐PS) resin. The alkylation and oNBS deprotection were conducted under basic conditions and were therefore compatible with this acid labile resin. The alkylation reaction was very efficient on this resin with a number of different alkyl iodides or bromides, and the synthesis of model enkephalin N‐alkyl amide analogs using this method gave consistently high yields and purities, demonstrating the applicability of this methodology. The synthesis of N‐alkyl amides was more difficult on a Rink amide resin, especially the coupling of the first amino acid to the N‐alkyl amine, resulting in lower yields for loading the first amino acid onto the resin. This method can be widely applied in the synthesis of peptide N‐alkyl amides. © 2011 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 96: 715–722, 2011.