Synthetic and mechanistic insight into nosylation of glycine residuesElectronic supplementary information (ESI) available. See DOI: 10.1039/c3ob00014a

• Main Authors: Stuhr-Hansen, Nicolai, Sølling, Theis Ivan, Strømgaard, Kristian
• Format: Journal Article
• Language: English
• Published: 13.03.2013
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c3ob00014a

The Fukuyama-Mitsunobu alkylation procedure is widely used to introduce alkyl substituents to amino groups in general and N -alkylation of peptides in particular. Here we have investigated the procedure in detail for N -alkylation of peptides with N-terminal glycine residues, based on the observation that standard conditions lead to substantial bis-nosylation of the glycine amino group. A systematic evaluation of this observation was carried out and it was demonstrated that for peptides with alanine, β-alanine or γ-aminobutyric acid (GABA) as N-terminal residues mono-nosylation was observed under the same conditions. Moreover, bis-nosylation was independent of the type of resin, neighboring amino acid and nature of the peptide. Calculations suggest that the reason for the bis-nosylation is the fact that the deprotonated mono-nosyl species is particularly stable in the case of the terminal Gly residue because the N − residue can become closer to the SO 2 unit. Finally, the mono-nosylated N-terminal glycine could be obtained by careful optimization of the procedure, adding only one equivalent of 2-nitrobenzenesulfonyl chloride. The glycine residue is the only primary amine moiety undergoing bis-nosylation upon reaction with an excess of nosyl chloride.