Vitamin B12 total synthesis

The total synthesis of vitamin B12 (cobalamin) was accomplished in 1972 by two different approaches between the collaborating research groups of Robert Burns Woodward at Harvard and Albert Eschenmoser at ETH. The synthetic endeavor required the effort of 91 postdoctoral researchers (77 from Harvard, 14 from ETH), and 12 PhD students (from ETH) over a period of almost 12 years. The synthesis project induced and involved a major paradigm shift in the field of natural product synthesis.

The target molecule

The biomolecule vitamin B12 (molecular formula C63H88CoN14O14P), is the most complex of all known vitamins. Its chemical structure was previously elucidated by X-ray crystallography in 1956 by the research group of Dorothy Hodgkin (Oxford), in collaboration with Kenneth N. Trueblood (UCLA) and John G. White (Princeton). At the core of this molecule is the corrin structure, a nitrogenous tetradentate ligand system. The corrin system is biogenetically related to porphyrins and chlorophylls, yet differs from them structurally. Its carbon skeleton lacks a meso carbon atom “bridge” otherwise linking the five-membered pyrrole-like rings; two of these rings (A and D, Figure 1) are directly fused by a C–C single bond. Lined up along the periphery of the B12 corrin ring are eight methyl groups, three propanamide, and three acetamide side chains. The periphery also contains nine stereocenters. The monobasic corrin ligand is equatorially coordinated with a trivalent Co3+ cobalt ion, which bears two additional axial ligands. Several natural variants of the B12 structure exist that differ in the identity of these axial ligands.

In vitamin B12 itself, the cobalt is coordinated to a cyano group on the top side of the corrin plane (cyanocobalamin), and a nucleotide loop on the opposite side. This nucleotide loop is connected on its other end to the peripheral propanamide group located at ring D (Figure 1) and consists of structural elements derived from aminopropanol, phosphate, ribose, and 5,6-dimethylbenzimidazole. The imidazole derivative is axially coordinated to the cobalt, closing the loop. Cobyric acid, one of the natural derivatives of vitamin B12, lacks this nucleotide loop. Depending on the nature of the two axial ligands at the cobalt center, it instead displays propionic acid function at ring D as a carboxylate (as shown in Figure 1), or as the carboxylic acid, in the case of two cyanide ligands at cobalt.

The two syntheses The structure of vitamin B12 was the first low-molecular weight natural product to be determined by X-ray analysis rather than by chemical degradation. As a result, though the structure of this novel type of complex biomolecule was established, its chemistry remained essentially unknown. Exploration of this chemistry became one of the tasks of the vitamin's chemical synthesis. In its time, the synthesis of such an exceptionally complex and unique structure presented a major challenge at the frontier of research in organic natural product synthesis.

In 1960, the research group of biochemist Konrad Bernhauer in Stuttgart had reconstituted vitamin B12 from one of its naturally occurring derivatives, cobyric acid. This was achieved by stepwise construction of the vitamin's nucleotide loop. This particular work amounted to a partial synthesis of vitamin B12 from a natural product containing all the structural elements of vitamin B12, except the nucleotide loop. As a result, cobyric acid was chosen as the target molecule for a total synthesis of vitamin B12. Collaborative work between research groups at Harvard and at ETH resulted in two cobyric acid syntheses (Figure 3), concomitantly accomplished in 1972, one by Harvard and the other by ETH. The described "competitive collaboration" of that size (totaling 103 graduate students and postdoctoral researchers for a time of almost 177 person-years) was then unheard of in the history of organic synthesis. The two syntheses are intricately intertwined chemically, though differ in the way the central macrocyclic corrin ligand system is constructed. Both strategies are patterned after two model corrin syntheses developed at ETH. The first of these syntheses, published in 1964, achieved the construction of the corrin chromophore by combining an A–D component with a B–C component via iminoester/enamine C–C condensations; the final ring closure was attained between rings A and B. The second model synthesis, published in 1969, explored a novel photochemical cycloisomerization process to create the direct A/D ring junction, with final ring closure occurring between rings A and D. The A/B approach to the cobyric acid syntheses was collaboratively pursued and accomplished in 1972 at Harvard. It combined a bicyclic Harvard A–D component with an ETH B–C component, and closed the macrocyclic corrin ring between rings A and B. The A/D approach to the synthesis, accomplished at ETH and finished at the same time as the Harvard A/B approach, successively adds rings D and A to the B–C component of the A/B approach and attains the corrin ring closure between rings A and D. The paths of the two syntheses met in a common corrinoid intermediate. The final steps from this intermediate to the cobyric acid target were also carried out collaboratively; each group working with material prepared via their own respective approach.

Synopsis of the Harvard/ETH collaboration

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