Synthetic and mechanistic insight into nosylation of glycine residues?

Organic & Biomolecular Chemistry Pub Date: 2013-02-19 DOI: 10.1039/C3OB00014A

Abstract

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 SO2 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.

Graphical abstract: Synthetic and mechanistic insight into nosylation of glycine residues
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