Vitamin B12S-promoted model rearrangement of methylmalonate to succinate is not a free radical reaction.

Abstract

To probe for free radical intermediates in the model methylmalonate to succinate rearrangements promoted by vitamin B12., a model series with a pentenyl side chain radical trap has been devised. The control free radical, generated by tri-n-butyltin hydride treatment of bromomethylpentenylmalonate thioester, undergoes rapid cyclization to the six-membered ring, and, as anticipated, no succinate rearrangement product is detected. By contrast when the bromide is treated with vitamin B12., little cyclized product is observed;

Understanding the Mechanism of B12-Dependent Methylmalonyl-CoA Mutase: Partial Proton Transfer in Action

“…The mechanism of the rearrangement has been investigated since 1960, when Eggerer and co-workers farsightedly proposed a pathway via intermediate free radicals. Subsequent investigations, aided by model studies, have led to a number of other proposals for intermediates, including radicals, carbanions, and organometallic species . Support for a pathway involving organometallic intermediates comes from recent model studies whose results led to the rejection of the involvement of protein-bound free radicals in preference for a mechanism in which a crucial role is played by cobalt .…”

A new model compound for vitamin B12 coenzyme: synthesis and crystal structure of a tetraazamacrocyclic alkylcobalt(III) compound with a pendant coordinating alkyl arm

“…1 Recently, radicals were detected upon addition of ( R , S)-methylmalonyl-CoA to a solution of methyl-malonyl-CoA mutase and coenzyme B It is widely believed that homolysis of the cobalt-carbon bond of coenzyme B generating a 5'-deoxyadenosyl radical and cob(ir)alamin, is an essential step in enzymatic 1,2-rearrangements catalysed by coenzyme B12.1 However, a recent study using a model substrate containing a pentenyl group as an alkene radical trap indicates that a free radical pathway is unlikely in the methylmalonate to succinate rearrangement. 3 Attempts to mimic the mechanism of coenzyme BIZ dependent enzymatic reactions have involved the synthesis of model compounds containing an intramolecular cobalt(n1)-carbon bond.4.5 These permit a study of the properties of carbon-centred radicals which are forced to stay in close proximity to the cobalt(i1) complex formed on homolysis of the cobalt(i1r)-carbon bond. Intramolecularly bound alkylcobalt( 111) compounds derived from the open-chain ligands dimethylglyoximate5 and bis( salicyla1dehydato)ethane-1 2diimines have been reported.…”

Mechanism of Action of Vitamin B12. Ultrafast Radical Clocks Provide No Evidence for Radical Intermediates in Cyclopropane Models for the Methylmalonyl-CoA to Succinyl-CoA Carbon Skeleton Rearrangement

“…The rearranged succinate 24 was obtained in 70% yield, with the cyclopropane ring intact (eq 1) . The product 24 is a diethyl ester, reasonably presumed to arise from exchange of the thioester with solvent ethanol following the rearrangement . In a related reaction conducted in water (see Supporting Information), hydrolysis did not occur and the rearranged thioester was isolated.…”

“…Experiments to probe the existence of radicals such as 11 have already been reported, and two key observations are summarized in Figure …”