Alternative casdatifan route uses stereospecific copper-catalyzed cyclopropane opening
- Chiral diols are converted into an enantioenriched 2-aryl cyclopropane diester, the starting point for a formal synthesis of the HIF-2α inhibitor casdatifan.
- The new step is a copper(I)-catalyzed, stereospecific ring opening by a functionalized aryl Grignard reagent, installing a stereocenter described as hard to reach.
- A late Friedel–Crafts cyclization builds the tetralin and delivers the diketone intermediate used in the existing manufacturing route, supporting a lower-cost supply option.
💡 Points
Setting an aryl-bearing stereocenter by stereospecific Cu/Grignard opening of a chiral cyclopropane is a tidy way to transfer chirality from cheap diols, and it should carry over to analogs with different aryl Grignards. Landing on the existing diketone is the smart part: no requalifying downstream steps. Still, functionalized Grignards and a late Friedel–Crafts need real scale-up testing before the cost claim holds.