Asymmetric Synthesis of a Small Molecule Inhibitor of TNFα via Enantioenriched 4-Substituted Tetrahydroisoquinolines

An improved decagram-scale enabling asymmetric synthesis of a lead small molecule inhibitor of TNFα is described. An overall >15-fold improvement in yield compared to the original route was accomplished through the development of a new chromatography-free enantioselective sequence that delivered >20 g of the target compound. Highlights of the new route include an efficient Parham cyclization that rapidly afforded hectagram quantities of a key dihydroisoquinolone, an uncommon asymmetric synthesis of 4-hydroxy and 4-amino tetrahydroisoquinoline intermediates, and improved Cu-free access to the unique heterocycle-rich pentacyclic scaffold.