Development of Organocatalyzed Enantioselective Conjugate Addition and Application to the Total Synthesis of Cannabinoids



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(–)-detla9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) were synthesized via an organocatalyzed tandem enantioselective conjugate addition/enolate alkylation annulation with a novel ambiphilic trifluoroborate in 7 steps (longest linear steps; 10 steps overall with 23% yield for THC and 18% yield for CBD) from inexpensive commercially available starting materials. Both vinyl and aryl ambiphilic trifluoroborates were synthesized and showed great compatibility with various functional group, high yields, and excellent stereoselectivity. To demonstrate how these qualities will facilitate synthesizing THC and CBD analogs that were previously difficult to access with existing methods, we completed the synthesis of a novel benzo-fused A-ring analog of THC. Tandem reaction product containing all-carbon quaternary centers were also obtained with good to excellent enantioselectivity.



Ambiphilic organoboronates, Conjugate addition, Enantioselective organocatalysis, Cannabinoids