Preparation of 2'-(13)C-L-Histidine Starting from (13)C-Thiocyanate: Synthetic Access to Any Site-Directed Stable Isotope Enriched L-Histidine

1-Benzyl-2-(methylthio)-imidazole-5-ketone is obtained in a few simple steps starting from thiocyanate and glycine amide (glycin). Subsequent treatment with diethyl phosphorocyanidate and functional group manipulations gives 1-benzyl-5-chloromethyl-imidazolium chloride. This compound is converted under mild O’Donnell conditions into the corresponding L-histidine derivative. After deprotection L-histidine is obtained in good yield and 99% enantiomeric excess. 2'-(13)C-L-Histidine has been obtained via this new scheme with high (99%) (13)C incorporation starting with commercially available (13)C- thiocyanate. This synthetic scheme allows access to any isotopomer of L-histidine and many other biologically important imidazole derivatives.