title: Synthetic and mechanistic insight into nosylation of glycine residues.
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 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.
authors: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. nsh@sund.ku.dk
authors: Nicolai
authors: N
authors: Stuhr-Hansen
authors: Theis Ivan
authors: TI
authors: Sølling
authors: Kristian
authors: K
authors: Strømgaard
mesh_terms: D003198:Computer Simulation; D005998:Glycine / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D009578:Nitrobenzenes / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry
chemical_list: D009578:Nitrobenzenes; D010455:Peptides; C002732:2-nitrobenzenesulfenyl chloride; D005998:Glycine