FLUORINATION OF (E)-BETA-(FLUOROMETHYLENE)-M-TYROSINE - REGIOSELECTIVE SYNTHESIS OF 4-FLUORO-(E)-BETA-(FLUOROMETHYLENE)-M-TYROSINE

Fluorination of (R)- and (S)-(E)-beta-(fluoromethylene)-m-tyrosine (1) by acetyl hypofluorite yielded a mixture of the corresponding 2-fluoro- (2a), 6-fluaro- (2b), 4-fluoro- (2c), and 2,6-difluoro- (2d) derivatives along with a pair of diastereomeric products of addition across the vinylic double bond. A regioselective synthesis of 4-fluoro-(E)-beta-(fluoromethylene)-m-tyrosine has also been developed based on a fluorodestannylation reaction with elemental fluorine followed by acid hydrolysis. This reaction sequence yielded minor byproducts, namely, 4-fluoro-(Z)-beta-(fluoromethylene)-m-tyrosine (II), 4,6-difluoro- and 2,4-difluoro-(E)-beta-(fluoromethylene)-m-tyrosines (12a and 12b). All these products were completely separated by semipreparative HPLC and fully characterized by NMR and mass spectroscopy. Single crystal X-ray crystallographic analyses of 2-fluoro-, 4-fluoro-, and 6-fluoro-(E)-beta-(fluoromethylene)-m-tyrosines unequivocally established the structures of these amino acids.