The truth about total synthesis

17 December 2015 - TotSynth

An interesting comment in the latest issue of Nature by Philip Ball titled "Chemistry: Why synthesize?". His take on total synthesis is of particular interest. The pros and cons of total synthesis are continuously debated in the blogs and on twitter with consensus definitely heading towards "utterly pointless" but mainstream chemistry thus far has been silent. Total synthesis top gun K. C. Nicolaou has many a review and essay on the topic to his name but none of them stand out for intellectual content. Reads more like an erupting database.

So what is Ball's take on total synthesis? "Today, most wholly synthetic routes to complex natural products are too complicated to be useful in themselves to the pharmaceutical industry" but the efforts at least serve "to equip students with the practical skills that industry requires". Also "some chemists feel that total synthesis of large and complicated natural products has now become a scaling of peaks just because they are there ? with, moreover, a meaningless race to the summit that is often won by brute force" To make things worse "If you want to make a complicated molecule, do you really need an army of dedicated graduate students working through the night? Or could it be done by machine?" According to Ball there is no need to worry that automation will kill total synthesis as an art form. It is a done deal, the same thing has already happened to the art of playing chess.

One strong argument in favour of total synthesis I find lacking in Ball's comment. The importance of reliable reagents. Hundreds of reagents for the same purpose (oxidation, reduction) exist and new ones get invented every week. But which one to choose for your next project? You can be sure a researcher contemplating a reagent for step 101 of a 102 step total synthesis with just 1 milligram left will pick the most reliable one in terms of conversion, selectivity and ease of work-up. The fancy new reagent recommended by the supervisor or a best friend will be ignored, even plain bribery will not help. If the reagent does not perform who wants to spend months repeating step 1 to 100?