Our current poll (please vote on the right-hand side of the page!) asks about commercial fragment libraries. However, there is much to be said about making your own fragments: you have total control over the quality, and it is easier to get into novel chemical space. We highlighted one example of custom fragments in 2016; here are a few more. Please feel free to share others in the comments.
James Bull and collaborators at Imperial College London and Eli Lilly describe a nice divergent approach to cyclopropane-containing compounds in a Eur. J. Org. Chem. paper published last year. As they note, cyclopropane is the tenth most common ring found in small-molecule drugs: common enough to be validated, but sufficiently rare as to quickly yield novel compounds. They start with an efficient cobalt-catalyzed cyclopropanation that can be conducted on gram-scale to produce scaffolds A1 and A2. The sulfur atoms can be oxidized to sulfoxides or sulfones, and the esters can be converted to amides. Perhaps more interestingly, the sulfoxides can be converted to Grignard reagents that can be reacted with electrophiles or used in cross coupling reactions, ultimately generating diverse molecules such as A24 and A25.
The researchers also calculated various parameters of the 56 molecules they synthesized, and found that many of them were quite “shapely” as assessed by calculating principal moments of inertia.
A more recent paper, by Adam Nelson and colleagues at the University of Leeds and published in Bioorg. Med. Chem., also looked at more “three-dimensional” fragments based on bridged bicyclic lactams found in certain alkaloids. Intermediates such as compound B11 could be rapidly assembled and diversified at multiple points to generate very different molecules such as B17b and B19. All in all, 22 fragments with < 17 non-hydrogen atoms and clogP < 2.5 were generated.
Finally, Nicola Luise and Paul Wyatt at the University of Dundee describe the synthesis of semi-saturated bicyclic pyrazoles in Chem. Eur. J. As the researchers point out, at least five fragment-derived drugs that have gone into the clinic contain pyrazole moieties, and 4-bromopyrazole seems to be a universal fragment. Although many pyrazoles are commercially available, the number drops considerably with partially aliphatic bicycles, and these may also have improved physicochemical properties.
As we noted in 2016, Paul Wyatt is having students build libraries of novel fragments. Given the range of chemistries explored in this paper, this seems like good training. Starting from 3-bromopyrazole, the researchers generated 25 different molecules, all conforming roughly to the rule of three, and also characterized whether they met criteria for purity, stability, and solubility at 2 mM in phosphate buffer. Only a single molecule dropped out, supporting the design criteria, and the molecules have been added to the Dundee fragment library.
Papers like these do not get as much attention as they deserve, in part because the biological properties of new molecules are by definition unknown. Still, it is refreshing to see chemists coming up with creative new classes of fragments. Hopefully we will revisit some of them as hits in future posts!