Mitsunobu mischief: neighbor-directed histidine N(τ)-alkylation provides access to peptides containing selectively functionalized imidazolium heterocycles

Organic & Biomolecular Chemistry
Wenjian Qian, Terrence R Burke

Abstract

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.

References

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Jul 3, 2013·Bioorganic & Medicinal Chemistry Letters·Ravichandran N MuruganJeong Kyu Bang

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Citations

Oct 20, 2015·Trends in Pharmacological Sciences·Kyung S LeeEunhye Lee
Jun 9, 2016·The Journal of Organic Chemistry·Li-Rong WenMing Li
Sep 4, 2018·Bioorganic & Medicinal Chemistry Letters·David HymelTerrence R Burke

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