Enantioselective Total Synthesis of (−)-Δ⁹-Tetrahydrocannabinol via N-Heterocyclic Carbene Catalysis

Abstract

Enantioselective syntheses of (-)-Δ⁸-tetrahydrocannabinol ((-)-Δ⁸-THC) and (-)-Δ⁹-THC have been achieved in eight and 10 steps, respectively, from a known cinnamic acid. The syntheses take advantage of an enantioselective N-heterocyclic carbene (NHC)-catalyzed (4 + 2) annulation between donor-acceptor cyclobutanes and cinnamoyl fluorides to construct the highly enantioenriched cycloxyl β-lactone shown. Having constructed this A-ring precursor, elaboration to (-)-Δ⁸-THC is achieved through β-lactone alcoholysis followed by oxidation, dual decarboxylation, trimethylation, and cationic cyclization. Finally, the conversion to (-)-Δ⁹-THC is achieved with established chemistry.