Vitamin reductive radical addition

As a model study of methyl cobalamine (methyl transfer) in living bodies, a methyl radical, generated by the reduction of the /s(dimethylglyoximato)(pyridine)Co3+ complex to its Co1+ complex, reacts on the sulfur atom of thiolester via SH2 to generate an acyl radical and methyl sulfide. The formed methyl radical can be trapped by TEMPO or activated olefins [8-13]. As a radical character of real vitamin B12, the addition of zinc to a mixture of alkyl bromide (5) and dimethyl fumarate in the presence of real vitamin B12 at room temperature provides a C-C bonded product (6), through the initial reduction of Co3+ to Co1+ by zinc, reaction of Co1+ with alkyl bromide to form R-Co bond, its homolytic bond cleavage to form an alkyl radical, and finally the addition of the alkyl radical to diethyl fumarate, as shown in eq. 11.4 [14]. 

Inspired by Nature, hydroxocobalamine 247 (X=OH) itself or modified vitamin B12 derivatives (review [331]) were probed as catalysts for radical cyclizations. This methodology is mediated by light and electrochemical or chemical reduction to close the catalytic cycle. It was applied to total syntheses of forskolin 280 by Pattenden [325] (Fig. 67, entry 13) as well as of jasmonate 284 and prostaglandin precursors 287 by Scheffold (entry 14) [326, 327], Starting materials were bromoacetaldehyde cyclohexenyl or cyclopentenyl acetals 278, 281, or 285, which cyclized in the presence of 247 to annulated butyrolactols 279, 283, or 287. In the forskolin synthesis the cyclized radical was reduced directly, while a radical addition ensued in the presence of acetoxyacrylonitrile 282 or ynone 286 in... 

The heart has a relatively low catalase activity, which, together with the superoxide dismutase (SOD) system, acts to remove hydrogen peroxide and superoxide radicals. In addition, in man, dietary vitamin C plays an important role in the reduction of vitamin E, an intrinsic antioxidant component of biological membranes (Chen and Thacker, 1986 Niki, 1987). Both vitamins C and E can also react directly with hydroxyl and superoxide radicals (HalliwcU and Gutteridge, 1989 Meister, 1992). 

Ubiquinone functions as a carrier in the mitochondrial electron transport chain it is responsible for the proton pumping associated with complex I (Brandt, 1999) and is directly reduced by the citric acid cycle enzyme succinate dehydrogenase (Lancaster, 2002). As shown in Figure 14.8, it undergoes two single-electron reduction reactions to form the relatively stable semiquinone radical, then the fully reduced quinol. In addition to its role in the electron transport chain, it has been implicated as a coantioxidant in membranes and plasma lipoproteins, acting together with vitamin E (Section 4.3.1 Thomas etal., 1995, 1999). 

When RX is easily reduced, as in the case of allyl iodides and benzyl bromides, the competing further reduction of the intermediate radical is suppressed and radical reactions such as dimerization, addition to double bonds and aromatic compounds or reaction with anions can be favored. The radical pathway can be also promoted by catalysis with reduced forms of vitamin Bn, cobaloximes or nickel complexes. These react with the alkyl halide by oxidative addition and release the alkyl radical by homolytic cleavage. 

Single electron transfer generates radicals and although this mechanism is now more common than once thought in non-biological redox reactions, its prevalence in enzyme-catalysed reactions is limited to coenzymes with quinoid-type structures e.g. flavins, coenzyme Q, vitamins C, E and K and to enzymes containing transition metals. Of course, there is a growing interest in metabolic disorders initiated by radical reactions. Reduction by 2-electron transfer can take place by either (a) hydride, H, transfer or (b) discrete electron, e , and proton, H", addition. 

Although various mechanisms have been proposed to explain the ability of Cu(II) to promote LDL modification, the precise reactions involved in initiating the process remain a matter of contention in the literature. In a critical overview of the chemistry of copper-dependent LDL oxidation Burkitt (2001) discusses the key role of a-tocopherol. In addition to its protective, radical-scavenging action, a-tocopherol can also behave as a prooxidant via its reduction of Cu(II) to Cu(I). Generation of Cu(I) greatly faciUtates the decomposition of hpid hydroperoxides to chain carrying radicals, but the mechanisms by which the vitamin promotes LDL oxidation in the absence of preformed hydroperoxides remain more speculative. 

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