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

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 a position; (2) BF3.OEt2-assisted 1,4-addition of cuprates (Ar2Cu(CN)-Li-2, Ar = aryl) followed by quenching the enolates with water; (3) reaction of the alpha-iodo-beta-aryl-cylohexanones thus formed with EtMgBr to generate magnesium enolates. The enolates thus generated in this way showed a high reactivity toward CIP(O)(OEt)(2) to furnish enol phosphates. The aforementioned procedure was also applied to a synthesis of optically active Delta(9)-tetrahydro-cannabinol. In addition, a naphthalene analogue of the latter compound was also synthesized in a similar way.