Ein synthetisches Modell für die Aktivstelle der Coenzym-B12-abhängigen Methylmalonyl-CoA-Mutase

A synthetic model of the active site of the coenzyme B₁₂ dependent methylmalonyl-CoA mutase The synthesis of a bridged cobaloxime with a built-in methylmalonic ester moiety is described. 2-Brommethyl-2-methylmalonic acid dichloride ( 5 ) afforded upon reaction with 5-heptin-1-ol ( 4 ) the corresponding diester 6 . Subsequent treatment of 6 with ozone, dimethylsulfide and hydroxylamine hydrochloride led to the pentadentate ligand: 10-brommethyl-10-methyl-9, 11-dioxo-8, 12-dioxa-nonadecane-2, 3, 17, 18-tetraone tetraoxime ( 8 ). Reaction of 8 with cobalt (II) chloride, pyridine and sodium borohydride furnished in 7% yield the bridged cobaloxime 10 , which was spectroscopically characterized. Short term irradiation of 10 in methanol caused the exchange of the axial pyridine ligand by a solvent molecule affording 10a , the structure of which has been determined by X-ray crystallography. Long term irradiation of 10 in methanol or ethanol led to irreversible cleavage of the Co, C-bond. Upon alkaline hydrolysis the degradation product afforded methylsuccinic acid in 82–95% yield. No incorporation of solvent protons into this product could be observed. Implications of these findings for the mechanism of the coenzyme-B₁₂ catalysed rearrangement of methylmalonyl-CoA are discussed.