Chorismate Mutase Inhibitors: Synthesis and Evaluation of Some Potential Transition-State Analogues

Article abstract of DOI:10.1021/jo00249a013

A number of bicyclic diacids have been synthesized as potential transition state analogue inhibitors of chorismate mutase, including the oxa- and carbabicyclic diacids 5, 8, 9, and 13.An unsuccessful attempt was made to generate the oxabicyclic nitronate 10, which proved to be very labile toward hydrolysis; instead, the oximinolactone 11 and carbabicyclic nitronate 12 were prepared as potentially more accurate mimics of the postulated transition state 1.The oxabicyclic diacids were prepared from the Diels-Alder adduct of butadiene and dimethyl itaconate, via selenocyclization of cyanohydrin 17, elimination of the selenoxide and epoxidation of the olefin 18, isomerization of epoxide 19 to the allylic alcohol 20, hydrolysis of the nitrile, and stereochemical manipulation of the bridge carboxyl group.The carbabicyclic compounds were similarly accessible by electrophilic cyclization of β-keto ester 37, affording ketone 43 via the cyclopropane 40 and selenide 41.Methylenation of 43 and formation and selective rearrangement of the diepoxide 49 were key steps in further elaboration to the diester 36.A shorter route to diene 48 was also developed, involving the one pot bismethylenation of lactone 45 with an excess of Cp2Ti(Cl)CH2AlMe2. The oximinolactone 11 and nitronate 12 were prepared by nitrosation or nitration of the protected diesters 30 and 53, respectively, followed by hydrolysis and decarboxylation.The endo isomer of oxabicyclic diacid 5 proved to be the most potent inhibitor known for a chorismate mutase, with a K_i value of 0.12 μM against the chorismate mutase-prephenate dehydrogenase from Escherichia coli.The related isomeric and carbabicyclic analogues 8, 9, and 13 are less tightly bound (13μM < I₅₀ < 100 μM), and oximinolactone 11 and nitronate 12 are poor inhibitors (I₅₀ > 4 mM).