1973

B₁₂ Synthesis

Robert Burns Woodward (1917–1979), Albert Eschenmoser (b. 1925), Dorothy Crowfoot Hodgkin (1910–1994)

The chemical structures of the different vitamins are all over the map. There aren’t many similarities, since they serve completely different purposes in biochemistry. The only thing that they have in common is that they are vital for human health and that our cells don’t have the ability to make them.

Vitamin B₁₂ is used to treat cyanide poisoning and pernicious anemia, but you’ll find it in your daily multivitamin, too. Its structure is an outlier even by the standards of the other vitamins, since it alone contains a metal—a cobalt atom in the middle of a large cyclic complex, broadly similar to the one that holds iron inside hemoglobin. This framework has nine chiral centers, a formidable synthetic challenge. Coming off this framework is a “tail” region, joined to the complex part of the molecule by an amide linker. British biochemist Dorothy Crowfoot Hodgkin, whose work was instrumental in understanding penicillin and in protein crystallography, identified these features in 1956 with yet another high-profile X-ray crystallography structure.

Then American chemist Robert Burns Woodward and Swiss chemist Albert Eschenmoser joined forces in a ten-year effort for one of the most difficult organic syntheses yet attempted. B₁₂ has four linked nitrogen-containing rings circling the cobalt atom, and all four are chiral. Rings A and B were made via “resolution” (physically separating the left- and right-hand isomers), while C and D were made from chiral starting materials. The A and D rings were joined and then coupled to the B-C piece through an intricate series of reactions. The cobalt atom was then introduced, and it helped hold the ends of the molecule close to each other for the final cyclization.

Seemingly every major reaction type of the day found its way into Woodward and Eschenmoser’s lengthy route (seventy-two total steps), including the Birch reduction, the Grignard reaction, diazomethane, ozonolysis, and a Diels-Alder reaction whose details helped pave the way for the Woodward-Hoffman rules. The synthesis of vitamin B₁₂, reported in 1973, is a landmark in the field.

SEE ALSO Ozone (1840), Chirality (1848), Asymmetric Induction (1894), Diazomethane (1894), Grignard Reaction (1900), X-Ray Crystallography (1912), Diels-Alder Reaction (1928), Birch Reduction (1944), Woodward-Hoffman Rules (1965)

R. B. Woodward holds a model of a difficult section of the vitamin B₁₂ molecule, 1973. The light-colored atom in the center is the cobalt discussed above.