Vitamin E is the most important lipid-soluble antioxidant in biological systems. (R,R,R)-α-tocopherol, the naturally occurring stereoisomer, exhibits the highest antioxidant activity, but still lacks an economic total synthesis. Commercial vitamin E is mostly the all-rac material, a mixture of all 8 stereoisomers. Thus, an enantioselective industrial synthesis is highly desirable. Our synthesis relies on a 3-way disconnection approach to a key chiral tertiary alcohol precursor, formed via direct asymmetric 1,2-addition of a Grignard reagent to a ketone. This methodology involves the use of an inexpensive chiral tridentate phenol/diamine type ligand, which can be easily recovered and reused. Vatiquinone, a product currently in phase 2/3 clinical trials for multiple indications, is structurally analogous to vitamin E. This allows our asymmetric methodology to applied in its total synthesis. This work describes the optimisation of the work of Bieszczad and Gilheany, towards the total synthesis of (R,R,R)-α-tocopherol, whereby two separate routes were developed to the key chiral tertiary alcohol precursor. Significant improvements to cost and time were made to the scaled-up synthesis after studies were performed on the asymmetric Grignard step. The methodology was also applied in the total synthesis of the tertiary alcohol precursor to vatiquinone in 7 steps.

Application of asymmetric Grignard strategies in total synthesis

ACS Spring 2022

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