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

Abstract 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 be 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 .