Methyl group transfer reactions, stereochemistry

Stereochemistry of Enzyme-Catalyzed Methyl Group Transfer Reactions... 

Since 2 equiv. of Sml2 are required for the reaction, the reductive coupling process must be a two-electron process overall (Scheme 5). Cyclization appears to occur after transfer of a single electron, with Sm controlling the stereochemistry at this stage by chelation with the Lewis basic ester carbonyl. Subsequent reduction to a transient carbanion, followed by immediate protonation, accounts for the observed products. Only if a transient anion is generated can one account for >90% deuterium incorporation at the methyl group when the reaction is performed in MeOD (equation 67). ... 

A significantly more complicated situation exists in the case of the side-chain methylation leading to ergosterol, where the initial transfer of the methyl group is followed by a hydride shift from the acceptor carbon and proton loss from the methyl group to give a methylene intermediate (I), which is then reduced stereo-specifically. The stereochemistry of each of these reaction steps has been determined by Arigoni and co-workers (61, 97), with the outcome summarized in Scheme 26 (p. 285). 

Scheme III shows the experimental arrangement to study the second one-carbon transfer reaction we investigated, the formation of thymidylic acid from uridylic acid catalyzed by thymidy-late synthetase. In this reaction, the methyl group of thymidy-late is derived from the carbon and the two hydrogens of the methylene bridge plus H-6 of methylene-tetrahydrofolate. To study the stereochemistry of this reaction, we (5) synthesized serine stereospecifically labeled with tritium and deuterium at...

These systems are complicated by the fact diat they catalyze two methyl-transfer reactions, one from MeCbl to the substrate and the other from some reagent to cobalt to regenerate MeCbl. For methionine synthase, it is known that the reactions go with overall retention of the stereochemistry of the methyl group. This shows that both transfers occur either with retention or inversion. This observation, plus the absence of EPR signals indicative of Co(II) or organic radicals, suggest that these reactions do not proceed by homolysis of the Co—C bond. 

Opening to the -rr-allyl complex 9.214, which was reduced by hydride transfer from formate. Unlike most other nucleophiles (see Schemes 9.32 and 9.34), formate transfers hydrogen with retention, giving the required stereochemistry for the natural product. Completion of the synthesis included a nickel-catalysed Kumada coupling to convert the ketone, via an enol phosphate 9.216, into a methyl group and a McMurry reaction to close the seven-membered ring. 

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