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

Abstract

AbstractA novel strategy for the total synthesis of α‐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)‐α‐tocopherol (2‐ambo‐α‐tocopherol) is efficient and challenges the future development of suitable protocols for the asymmetric 1,4‐addition.