22 March 2021

Fragment chemistry roundup part 4

Last week’s post on diversity-oriented synthesis (DOS) reminds me that it has been nearly a year since we’ve done a post on fragment chemistry. Since then, several interesting papers have appeared. These next two posts will cover them.
The point of DOS is to generate lots of analogs from a small number of starting materials in a controlled fashion. But as any chemist knows, reactions often go out of control. In ChemMedChem, John Spencer (University of Sussex) and collaborators at several institutions have decided to turn lemons into lemonade by deliberately losing control, though they are quick to emphasize “in the selectivity (not health and safety) context.”
The researchers focused on C-H bond activation, a handy class of reactions in which a carbon-hydrogen bond is broken in order to generate a new molecule. C-H bonds are of course ubiquitous in drugs, and chemists normally try to selectively activate just one. Here, the researchers focused on Ru/Pd-catalyzed photochemical arylation in the presence of alcohols, which can further react with certain substrates. For example, reacting 2-phenylpyridine with a 4-fluorophenyldiazonium salt in methanol led to five products (some of which breach the rule of three).

These products, and those of other similar reactions, were screened crystallographically against an enzyme called NUDT7, resulting in one hit.
On a related chemical subject, Quentin Lefebvre and colleagues at SpiroChem explore photoredox-nickel dual catalyzed N-arylation reactions in Beilstein J. Org. Chem. In 4 days they tested 29 combinations of amines with various aryl halides, 15 of which gave products; examples are shown to the right.
Given that SpiroChem is a chemical vendor, expect to see more of these sorts of molecules in their catalog.
Finally, in Chem Sci., Nicholas Turner (University of Manchester - corrected) and collaborators at Keele University ask whether it is “time for biocatalysis in fragment-based drug discovery.” Biocatalysis involves using enzymes to run reactions. Despite stunning advances in synthetic organic chemistry, Nature is still the master, so why not work together?
The researchers review examples where biocatalysis could be used to generate new fragments or elaborate fragment hits. Importantly, enzymes can perform selective reactions even in the presence of multiple reactive centers that would normally need to be protected in conventional synthesis. Moreover, researchers are increasingly engineering enzymes to increase their substrate scope, efficiency, or completely alter the reactions performed. Some of the products are illustrated here.
I confess I haven’t done much biocatalysis, largely due to unfamiliarity but also because enzymes for organic synthesis don’t seem to be as widely offered by vendors as – for example – transition metal catalysts. Perhaps there is a market opportunity for fragment libraries designed for enzyme-mediated elaboration?
A decade ago, the main challenge of fragment-based drug discovery was finding fragments. Now it is elaborating them. It is nice to see solutions accumulating.


Anonymous said...

FYI Nick Turner is from Manchester University and Seb Cosgrove is from Keele University

Dan Erlanson said...

Oops - sorry - corrected now!