Chromatography-free asymmetric route delivers over 20 g of a TNFα small molecule inhibitor with sharply higher overall yield
- A chromatography-free, enantioselective redesign of a lead TNFα small-molecule inhibitor's synthesis delivered over 20 g, with a large overall yield gain on the original route.
- A Parham cyclization quickly builds the key dihydroisoquinolone intermediate in large quantities.
- The route also opens uncommon asymmetric access to 4-hydroxy and 4-amino tetrahydroisoquinolines and reaches the heterocycle-rich pentacyclic core without copper.
💡 Points Based on the abstract
Copper-free access to a crowded pentacyclic core is welcome, since trace metal can quietly distort biochemical readouts for trimer-disrupting chemotypes. Enantiopurity data are still missing, as is proof that the benzylic 4-stereocentre does not racemize under assay conditions. After that, the 4-hydroxy and 4-amino handles make a fast analogue sweep an obvious move.
📄 Paper · Organic Letters ↗ Asymmetric Synthesis of a Small Molecule Inhibitor of TNFα via Enantioenriched 4-Substituted Tetrahydroisoquinolines