Catalytic Activity of Novel Vitamin B12 Derivatives

Among many biologically important metals, Co, in the form of vitamin B₁₂ (cyano-cobalamin), plays a unique role. B₁₂ coenzymes are indispensable for catalyzing enzymatic rearrangements (coenzyme B₁₂, adenosylcobalamin) and methylation reactions (methylcobalamin).¹ The special ability of vitamin B₁₂ and other corrinoids to form a Co-C bond, combined with its facility in furnishing alkyl radicals via homolysis, has attracted the interest of many researchers, because corrinoids can be used as catalysts for C-C-bond forming reactions, which belong to the most challenging processes in organic synthesis. These catalytic reactions typically involve alkyl-cobalt complexes, which are formed in reactions of Co(I) species and an electrophile or a Co(II) and a radical. The most common chemical procedure utilizes the ‘supernucleophilicity’ of the Co(I) species (B₁₂s) toward alkylating agents, such as alkyl halides. Homolysis of the Co-C bond generates a carbon-centered radical, which can, in situ, disproportionate, abstract H˙, or self-couple. In these reactions, B₁₂ alkyl derivatives can be considered ‘reversible carriers’ of an alkyl radical.⁴

We have developed the synthesis of novel cobalamin derivatives possessing modified substituents at the periphery of the molecule. Our methodology presents a unique situation in which the six peripheral amide groups are transformed while leaving the bottom “f-loop” intact.² These derivatives displayed UV-Vis spectra and oxidation-reduction characteristics similar to those of vitamin B₁₂ but they differed significantly from the”incomplete” corrinoid heptamethyl cobyrinate, where the nucleotide moiety is absent, and instead, the second cyanide is coordinated. We confirmed that the intramolecular coordinating ligand plays a role in the radical reactions catalyzed by vitamin B₁₂ derivatives. For example, the microwave-assisted homocoupling of benzylbromide³ catalyzed by cobalester produced a higher yield when compared to reactions catalyzed by reduced (CN)₂Cob(OMe)_7.Furthermore, the amphiphilic character of these newly synthesized derivatives facilitates carbon insertion into the vinyl C-H bond of olefins with alkyl diazoacetates in the presence of light.

1.   Banerjee, R. Chemistry and Biochemistry of B₁₂, John Wiley & Sons, Inc, 1999

2.   Proinsias ó, K.; Giedyk, M.; Sharina, I.G.; Martin, E. and Gryko, D. ACS Med. Chem. Lett. 2012, 3, 476.

3.  Giedyk, M.; Fedosov, S.; Gryko, D. Chem. Commun. 2014, 50, 4674-4676.

4.   Shey, J.; McGinley, Ch.M.; McCauley, K.M.; Dearth, A.S.; Young, B.T. and van der Donk, W.A. J. Org. Chem. 2002, 67, 837.