Total Synthesis of (2RS)-α-Tocopherol through Ni-Catalyzed 1,4-Addition to a Chromenone Intermediate

A novel strategy for the total synthesis of a-tocopherol (vitamin E) was elaborated on the basis of the conjugate addition of AlMe3 (as a methyl anion equivalent) to a 2-substituted chromenone. Starting from trimethylhydroquinone and (R,R)-hexahydrofarnesol, the required chromenone substrate was efficiently prepared in a short sequence exploiting a TiCl4-mediated Fries rearrangement and a KOtBu-induced Baker-Venkatamaran rearrangement. The envisioned key step, which sets up the quaternary center at C2, was performed in virtually quantitative yield through Ni-catalyzed conjugate addition of AlMe3. However, this transformation, which likely proceeds through a radical mechanism, could not be rendered stereoselective by means of chiral ligands. Nevertheless, the elaborated synthesis of (2RS,4'R,8'R)-alpha-tocopherol (2-ambo-alpha-tocopherol) is efficient and challenges the future development of suitable protocols for the asymmetric 1,4-addition.