SYNTHESIS OF NOVEL CYCLOBUTYLPHOSPHONIC ACIDS AS INHIBITORS OF IMIDAZOLE GLYCEROL PHOSPHATE DEHYDRATASE

Diethyl 3-oxocyclobutylphosphonate (5) has been synthesised via a nove l one-pot cyclisation reaction of the alpha-phenylsulphonyl-gamma,delt a-epoxyphosphonate 8. Addition of 5-lithio-1-trityl-1,2,4-triazole to ketone 5 and deprotection then afforded hydroxy-3-(1,2,4-triazol-3-yl) cyclobutylphosphonic acid (cis-4) which showed modest in vitro inhibit ion of the enzyme imidazole glycerol phosphate dehydratase. In an atte mpt to obtain the corresponding trans isomer (trans-4), whose inhibito ry activity was anticipated to be higher, an efficient three-step synt hesis was developed employing base-mediated cyclisation of the ,delta- epoxy-gamma-(1,2,4-triazol-5-yl)phosphonate 35. Although this latter r oute stereoselectively afforded cis-36, an efficient epimerisation rea ction could be subsequently used to obtain the desired ira,ls stereoch emistry. However, all attempts at deprotection of trans-36 proceeded w ith 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. (C) 1997 Elsev ier Science Ltd.