One step retrosynthesis of drugs from commercially available chemical building blocks and conceivable coupling reactions

Babak Mahjour, Felix Katzenburg, Emil Lammi, and Tim Cernak (2025)
Highlighted by Jan Jensen

What are important reactions that we currently can't perform? I asked myself this a few years ago and found that there were very few papers in the literature that addressed this. It turns out that I possessed the skills to figure it out for myself if I had only had the idea. The idea being that "the most valuable couplings would utilize the most abundant building blocks to form the most common types of bonds found in [a] target dataset."

As an example, the authors took a list of 9028 known drugs and asked how many could potentially be made in a single step from molecules in the MilliporeSigma catalog by hypothetical coupling reactions. The answer turns out to be 2573 (28%), which is a surprisingly large number. The most common reaction was the coupling of alkyl alcohols and alkyl amines, followed by alkyl acid-alkyl amine and alkyl acid-alkyl alcohols. All reaction for which there's no robust and generally applicable synthetic protocol, although AFAIK, although Zhang and Cernak took a stab at the alkyl acid-alkyl amine coupling. 

I really wish there were more papers like this. Identifying important questions to work on is just as important as solving them, and the latter is almost always a communal effort.


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