Potential Inhibitors of Phosphoenolpyruvate Carboxylase. II. Phosphonic Acid Substrate Analogs Derived From Reaction of Trialkyl Phosphites With Halomethacrylates

Abstract

Analogues of phosphoenolpyruvate (PEP), the substrate of PEP carboxylase , were synthesized as potential inhibitors of the enzyme. Esterified analogue precursors were obtained by nucleophilic substitution of various halomethacrylate derivatives with trialkyl phosphites. Substitution of the halomethacrylates can occur either α to the leaving halogen or in the γ position with subsequent allylic shift of the double bond. The course of the reaction was influenced both by reaction conditions and the nature of the substituents on the reactants. The phosphonomethacrylates obtained were hydrolysed to PEP analogues that were found to be moderate to good inhibitors of PEP carboxylase. Phosphonomethacrylic acid derivatives bearing two halogen substituents in the γ position were found to be the most potent inhibitors of this enzyme.