Category Archives: Total synthesis

Scale-up/Scalability

The  Baran blog (see link on this page) has started a discussion about step count on their blog relating it to their recently published a scalable synthesis of thapsigargin.

However I take issue with the use of the word scalability.

Scalability is more than just making larger quantities of a particular compound. It involves a lot of careful preparation and analysis of the reaction one is about to do. Take one of the examples they give in the blog post, the selenium dioxide oxidation of a silyl ether. The reaction is reported as a 2 step 1 pot process.

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From a process chemist’s point of view this reaction is not scalable (and it should be 2 steps). Now I know it’s not the job of research to do process chemistry research, but to substantiate the claim of scalability a minimum of process work should be carried out and reported.

Inspite of using 10 equivalents of SeO2 the yield is only 52%, why? What is the rest of the material? Why is 10 equivalents required? What is the consequence of only a 90% yield of the silylation reaction? How do the side products from that reaction affect the oxidation, is this the reason for 10 equivalents of SeO2? What is the thermal profile of this reaction? What is the minimum amount of SeO2 needed? What happens to the selenium waste? Is the 52% reproducible? What about the quality of the allyl alcohol for the next step? All these questions and more need to be answered before the reaction could be called scalable.

No I am not decrying the excellent synthetic work of this group, rather I would caution the use of the word scalable. Just because you can handle 1g does not mean that you can glibly go and make  larger quantities. There comes a point where saftey becomes a serious issue and an efficient risk assessment is an absolute requirement.

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