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The total synthesis of vitamin B-12 by Robert Burns Woodward and Albert Eschenmoser, is over 30 years old. At its time, it was considered a landmark in the field.

With current developments (e.g. olefin metathesis, palladium catalysis, etc.) is it possible to optimize this synthesis?

By "optimize" I mean reduce the number of steps in the synthesis.

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Almost certainly, yes. Applications of modern organic synthesis methods have drastically shortened the synthetic routes for such previously "daunting" targets such as strychnine see Vanderwal, tetracyclines Myers and pyrroloindole alkaloids Movassaghi, to name but a few - and recent efforts by Baran and White on C-H activation of alkanes have already yielded more efficient syntheses of many complex polycyclic terpenes. There is no reason to think that significant improvement could not occur for chlorophyll or B12. In fact, the absence of chlorophyll or Vitamin B12 from modern synthetic efforts represents a bit of a blind spot; it could well be that new chemistry could be discovered in the process. Although that 1,16 hydride shift by Eschenmoser will be hard to beat :-)

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  • $\begingroup$ I would not call that a blind spot. The synthesis was done, looking for a better route would be done if there were some interest in synthesis industrially. Just being the second one for fun is not promising. Do You know the second man to climb Mt Everest? $\endgroup$ – Georg Jul 12 '12 at 9:05
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    $\begingroup$ Total synthesis works this way: be first or be best. Sometimes (often!), the first synthesis is not always the most efficient. Academic organic chemists use total synthesis as a "sharpening stone" for the development of new methods. Strychnine has been synthesized >15 different ways; morphine likewise. What I'm saying is that methods development & total synthesis research is not directly tied to industrial synthesis needs. Indirectly, however, it is basic research that furthers the field. $\endgroup$ – james_ash Jul 12 '12 at 15:52
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A bibliographic for total syntheses of Vitamin B12 or any other cobalamin turns out to be fruitless. In fact, all references turn out to be to the famous historical synthesis, but I could not find much work (any work, in fact) on total syntheses, or even proposals for new synthesis routes. Not much was achieved since then.

This is partly due to lack of practical need. There are many molecules out there that are challenging to synthesize, and Vitamin B12 is currently produced at the industrial level by bacterial fermentation. From Wikipedia:

The species Pseudomonas denitrificans and Propionibacterium shermanii are more commonly used today. These are frequently grown under special conditions to enhance yield, and at least one company […] used genetically engineered versions of one or both of these species. Since a number of species of Propionibacterium produce no exotoxins or endotoxins and are generally regarded as safe (have been granted GRAS status) by the Food and Drug Administration of the United States, they are presently the FDA-preferred bacterial fermentation organisms for vitamin B12 production.


A good recent reference on the subject of its synthesis would be: K. C. Nicolaou and E. J. Sorensen, “Vitamin B12” in Classics in Total Synthesis, VCH: New York, 2003.

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  • $\begingroup$ This is good to know, but it does not answer the question directly. At the same time, I don't think there can be a definite answer to this question. You'd have to focus on a particular series of steps in the synthesis to find out if they can be done better/faster with current methods. To me, the question is not too localized but actually too broad. $\endgroup$ – CHM Apr 25 '12 at 22:54

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