Asymmetric Synthesis of (−)-Cannabidiol (CBD), (−)-Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) and Their cis Analogs Using an Enantioselective Organocatalyzed Diels–Alder Reaction

Abstract

Herein we describe an asymmetric synthesis of the pharmacologically relevant natural (−)-trans-CBD and psychoactive (−)-trans-Δ 9 -THC, as well as their synthetic cis diastereomers. The key step is an enantioselective Diels−Alder reaction catalyzed by a prolinol-based catalyst, which provides the cyclohexene carbaldehyde intermediate in good yield and high enantiomeric excess. Optimization of the substituted resorcinol protecting groups to avoid harsh and low-yield deprotection of the acid sensitive resorcinol moiety is also described.