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

Abstract

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'-13C-L-Histidine has been obtained via this new scheme with high (99%) 13C incorporation starting with commercially available 13C- thiocyanate. This synthetic scheme allows access to any isotopomer of L-histidine and many other biologically important imidazole derivatives.

Keywords

• 1-benzyl-2-(methylthio)-5-imidazole carbonitrile
• ethyl-1-benzyl-5-imidazol-carboxylate
• N-diphenylmethylene glycine tert-butyl ester
• O’Donnell method