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Our Friend and advisor Prof Baran from Scripps published the following in JOC: Aiming for the Ideal Synthesis, doi: 10.1021/jo1006812. In which he makes the following statement "Finally, scalable syntheses of complex natural products help debunk the myth that such compounds are not economically viable targets in the pharmaceutical industry". With this statement he is so far from the mark it is not true. A 50 step synthesis with an overall yield of 5 - 10% is just not realistic, 0.05% may be better. This means tons of SM must be converted down the line. I know, I have done it!

I think he has absolutely no idea what development of a drug substance entails. Does anyone here have an opinion? I would be glad to hear it

Baran gives many examples of "ideal synthesis" here is one he quotes from Heathcock: alt text

He tries to redefine an idea from Hendrickson %ideality = (no. of construction reactions) + (no. of strategic redox reactions) all divided by the total number of steps, the result multiplied by 100.

I should add that each purification step, chromatography, crystallisation, distillation also counts as a "reaction step"

From an industrial standpoint this synthesis from Heathcock has several "faults"

1 low temperature reactions at least 4

2 DIBAL-H in my experience reduces esters directly to the alcohols unless you do it at -90 - -100°C 3 MsCl is a big no no due to toxicity issues (MAC in air 1ppb) especially in the GMP step thus very careful analysis is required to ensure none is carried through to the final compound.

4 two compounds containing sensitive aldehyde groups.

5 Methylamine, toxicity problems, sensitiser, waste disposal etc

6 The compound must be an acetic acid salt although this is not discussed. This would be an expensive synthesis. I don't know how many compounds are crystalline, I would guess not many, making handling difficult.

I could go on and on.

So my point still remains: has absolutely no idea what development of a drug substance entails.

I can send a copy of the paper if anyone wants it.

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@quintus, no answers here, but a question. What specific examples of "scalable syntheses of complex natural products" does Baran cite in his paper to support his case? – Rich Apodaca Jun 29 at 15:08
I should add that he has no examples of scalable synthesis in this paper,most of all the other examples are from his work. – quintus Jun 29 at 16:44
The Baran paper has appeared in the pipeline.corante.com – quintus Jun 30 at 11:56

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My thought is that lab synthesis will never be as efficient as nature and thus after 50 or so steps, if we manage a 5-10% yield then good! We are using primitive techniques in comparison with nature. Our synthetic techniques compared to nature are like using a chisel and stone to collaborate with a research group across the globe where as nature is using e-mail and Skype. Sure we are loosing large amounts of SM but we are also using reactions designed to be general, where as nature is using enzymes designed to do one reaction very, very well.

I feel that his statement about scalable synthesis is pretty general, meaning that it's been shown possible in a few molecules so given time and money, it should be possible for any other synthesis to scale. He very well could be getting carried away in a dream world but I agree that as the science of organic chemistry evolves and depending on how bad a streamlined synthesis is wanted, chemist will be able to develop reactions/techniques that will at least be able to match nature. However, this won't happen over night.

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Thanks for the answer. Of course we will never be as efficient as nature. But you did not respond to Baran's comment about the "myth" A published synthesis of 50 steps with an overall yield of between 5 - 10% is rubbish and there are lots in the literature. – quintus Jun 18 at 8:31

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