Mitsunobu mischief: neighbor-directed histidine N(τ)-alkylation provides access to peptides containing selectively functionalized imidazolium heterocyclesElectronic supplementary information (ESI) available: Experimental details and NMR data for select compounds. See DOI: 10.1039/c5ob00171d

• Main Authors: Qian, Wen-Jian, Burke, Terrence R
• Format: Journal Article
• Language: English
• Published: 24.03.2015
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c5ob00171d

There are few methodologies that yield peptides containing His residues with selective N(τ), N(π)-bis-alkylated imidazole rings. We have found that, under certain conditions, on-resin Mitsunobu coupling of alcohols with peptides having a N(π)-alkylated His residue results in selective and high-yield alkylation of the imidazole N(τ) nitrogen. The reaction requires the presence of a proximal phosphoric, carboxylic or sulfonic acid, and proceeds through an apparent intramolecular mechanism involving Mitsunobu intermediates. These transformations have particular application to phosphopeptides, where "charge masking" of one phosphoryl anionic charge by the cationic histidine imidazolium ion is now possible. This chemistry opens selective access to peptides containing differentially functionalized imidazolium heterocycles, which provide access to new classes of peptides and peptide mimetics. Selective on-resin histidine N(τ)-alkylation under Mitsunobu conditions is achieved by the coordinated participation of a proximal acidic residue.