Synthesis of a difluorophosphonomethyl-containing phosphatase inhibitor designed from the X-ray structure of a PTP1B-bound ligand

Article abstract of DOI:10.1016/0040-4020(96)00531-5

Protein-tyrosine phosphatase (PTP) inhibitors are potentially valuable pharmacological tools for studying cellular signal transduction and for therapeutic intervention. Small peptides containing the non-hydrolyzable phosphotyrosyl mimetic difluorophosphonomethyl phenylalanine (F₂Pmp) have been shown to be extremely potent PTP inhibitors, with the fluorines increasing inhibitory potency 1000-fold relative to the unfluorinated species. The high PTP affinity of the phosphonodifluoromethyl pharmacophore has allowed the preparation of small molecule inhibitors containing this moiety, which lack any peptide component. The X-ray structurle of one such inhibitor, 2-difluoromethylnaphthylphosphonic acid (6) complexed to the catalytic site of PTP1B has recently been solved. Computer assisted molecular modeling of this complex indicates that enhanced binding interactions may result by introduction of hydroxyl functionality onto the naphthalene ring system. Herein is reported the synthesis of one such inhibitor 1,1-difluoro-1-[2-(4-hydroxynaphthalenyl)methyl]phosphonic acid (7), which is prepared in 12 steps from commercially available 1,3-dihydroxynaphthalene. The synthetic approach relies on selective hydroxyl protection and Pd-catalyzed carbonylation to introduce functionality which is subsequently elaborated into the difluorophosphonate structure. The techniques reported herein may be applicable to the preparation of other PTP inhibitors.