Synthesis of novel cyclobutylphosphonic acids as inhibitors of imidazole glycerol phosphate dehydratase

Article abstract of DOI:10.1016/S0040-4020(97)00682-0

Diethyl 3-oxocyclobutylphosphonate (5) has been synthesised via a novel one-pot cyclisation reaction of the α-phenylsulphonyl-γ,δ-epoxyphosphonate 8. Addition of 5-lithio-1-trityl-1,2,4-triazole to ketone 5 and deprotection then afforded cis-3-hydroxy-3-(1,2,4-triazol-3-yl])cyclobutylphosphonic acid (cis-4) which showed modest in vitro inhibition of the enzyme imidazole glycerol phosphate dehydratase. In an attempt to obtain the corresponding trans isomer (trans-4), whose inhibitory activity was anticipated to he higher, an efficient three-step synthesis was developed employing base-mediated cyclisation of the γ,δ-epoxy-γ-(1,2,4-triazol-5-yl)phosphonate 35. Although this latter route stereoselectively afforded cis-36, an efficient epimerisation reaction could be subsequently used to obtain the desired trans stereochemistry. However, all attempts at deprotection of trans-36 proceeded with simultaneous re-epimerisation to give the previously prepared cis-4. High level ab initio calculations have been used to rationalise the relative thermodynamic stability of cis-4 and trans-4.