Synthesis of tetrahydrocannabinols based on an indirect 1,4-addition strategy

Article abstract of DOI:10.1021/jo020457m

The synthetic procedure presented for the preparation of the title compounds requires 1,4-addition of bulky cuprates to cyclohexenones and subsequent reaction with electrophiles. However, the enolates generated by BF₃·OEt₂-assistance suffer from lack of nucleophilicity. To circumvent this problem, we developed an indirect method consisting of the following three steps: (1) iodination of the cyclohexenones at the α position; (2) BF₃·OEt₂-assisted 1,4-addition of cuprates (Ar₂Cu(CN)-Li₂, Ar = aryl) followed by quenching the enolates with water; (3) reaction of the α-iodo-β-arylcylohexanones thus formed with EtMgBr to generate magnesium enolates. The enolates thus generated in this way showed a high reactivity toward ClP(O)(OEt)₂ to furnish enol phosphates. The aforementioned procedure was also applied to a synthesis of optically active Δ⁹-tetrahydrocannabinol. In addition, a naphthalene analogue of the latter compound was also synthesized in a similar way.