Vitamin B12: How the Problem of Its Biosynthesis Was Solved

Vitamin B12 is an essential vitamin for human health, and lack of it leads to pernicious anemia. This biological activity has attracted intense interest for some time; in addition, the complex architecture of the B12 molecule has fascinated chemists and biochemists since its discovery as the first natural organocobalt complex and the establishment of its structure by X‐ray analysis. The organic ligand surrounding the cobalt displays many stereogenic centers along its periphery carrying reactive functional groups. This complexity led vitamin B12 to be rightly regarded as an extreme challenge to the synthetic chemist. Yet microorganisms achieve this synthesis in vivo with complete control of regio‐ and stereochemistry. How do they do it? This review tells the full remarkable story. Success in unraveling this biosynthetic puzzle resulted from a collaborative effort by biologists and chemists using the full range of methods available from their disciplines–from genetics at one end of the spectrum to synthesis and NMR spectroscopy at the other. This work can act as a guide for future research on the biosynthesis of yet more complex natural substances. To discover how the complex molecule vitamin B12 (shown on the right) was formed in living systems was one of the greatest challenges in bioorganic chemistry. Since its structure determination and total synthesis, vitamin B12 has held a special fascination for chemists. But the tremendous achievement chronicled here is also of broader interest as an example of the productive interplay of modern methods in biology and chemistry.