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

Abstract

Cu^I/(S,R)-rev-Josiphos-catalyzed asymmetric 1,4-conjugate addition of alkyl Grignard reagents to 2-methyl-substituted chromone derivatives by Lewis acid activation is reported, enabling the construction of a chiral tetrasubstituted carbon center and affording a series of 2-methyl chromanone derivatives with 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 a 9-step longest linear sequence with an overall yield of 12%.