It’s a common problem: you find a fragment that binds to your target and want to grow it to improve affinity. A search for commercial analogs comes up empty, so you look into modifying the hit, only to discover that you’ve got a six-step synthesis on your hands. Or worse; perhaps there is no precedent at all. The chemical literature is replete with total syntheses of complicated natural products, but seemingly simple fragments are often not well-represented. Last year, researchers from Astex exhorted chemists to develop synthetic routes for attractive fragments, and in a recent paper in Org. Biomol. Chem. David Rees and colleagues take up their own challenge in the case of dihydroisoquinolones.
Dihydroisoquinolone itself is a nifty little fragment. It has just 11 atoms, cLogP = 1.0, and its solubility is > 5 mM in aqueous buffer. Its cis-amide moiety can serve as a hydrogen bond donor and acceptor, and the adjacent phenyl ring provides a bit of grease for interacting with hydrophobic protein residues.
The researchers built on existing methodology using a rhodium catalyst to introduce polar groups (such as hydroxymethyl and dimethylamino) at the R position. Depending on the nature of the R group, regioisomers in which the substituent ends up at the 4-position could sometimes also be isolated.
The methodology is robust and tolerates air, moisture, and various substituents. The alkene starting material is easy to come by, and the aromatic starting material is easy to make. By varying this, the researchers could generate 6- or 7- substituted dihydroisoquinolones, though 5- and 8- substituted versions seem harder to access. The team was also able to use other aromatics as starting materials, including thiophene, thiazole, and pyridine.
Thus, if dihydroisoquinolone comes up as a hit, this paper will allow you to quickly explore most of the vectors. So how often does this fragment show up? It is not clear why some fragments, such as 7-azaindole and 4-bromopyrazole, show up again and again, while others languish so lazily in the library that they might as well not even be there. We’ve highlighted at least one case where a dihydroisoquinolone was a useful hit.
Practical Fragments would love to know your experience. Do you have dihydroisoquinolones in your library? How often do they show up as hits? And what other fragments do you find that are in need of better synthetic routes for further exploration?