Total synthesis of γ-Tocopherol via asymmetric 1,4-conjugate addition of alkyl Grignard reagents to 2-methyl chromone

Abstract

CuI/(S,R)-rev-Josiphos-catalyzed asymmetric 1,4-conjugate addition of alkyl Grignard reagents to C2-methyl-substituted chromone derivatives by Lewis acid activation is reported. This reaction enables the construction of chiral quaternary carbon centers and affords a series of 2-methyl chromanone derivatives with a broad substrate scope, excellent regioselectivities, and good to excellent enantioselectivities (75–97% ee). Furthermore, this methodology has been successfully applied to the total synthesis of γ-tocopherol in 9 steps with overall yield of 12%.