Diastereoselective synthesis of [alpha]-tocopherol

Abstract

Vitamin E exists in eight different forms, four tocopherols and four tocotrienols. All possess a hydrophobic side chain, which allows them to penetrate into biological membranes. Their second common feature is a chromanol moiety with a hydroxyl group that can donate a hydrogen atom. These properties make vitamin E a very important radical chain-breaking antioxidant in living organisms, and therefore also an industrial product. α-Tocopherol is the member of the vitamin E family that is preferentially absorbed and accumulated in humans. There are three stereocenters in α-tocopherol, whereas RRR-α-tocopherol (1) is the natural and biologically most active form. The R-configuration at C(2) is essential in order to be recognised by the α-tocopherol transport protein and thus maintained in the plasma. The biological activity rendered RRR-α-tocopherol (1) a synthetic target. In this work two novel syntheses of RRR-α-tocopherol (1) are presented. Both syntheses involve a highly diastereoselective epoxidation of the bis-protected phytyl hydroquinone 132 as the key step followed by a cyclisation to form the chromanol ring (figure 70). In order to find suitable stereoselective epoxidation catalysts, cyclodextrin-based catalysts were prepared and tested (figure 71). However, none of these catalysts were reactive or selective enough to be applicable to the epoxidation of bis-protected phytyl hydroquinones. However, the asymmetric Shi epoxidation proved to be a suitable epoxidation method for this purpose. A number of bis-protected phytyl hydroquinones were synthesised and subsequently epoxidised under Shi epoxidation conditions. The highest diastereoslectivity could be obtained for substrate 132. By applying Shi ketone 114, which is derived from D-fructose, epoxide 148 could be obtained with 96% de, whereas if the enantiomer ent-114 (synthesised in 5 steps from L-sorbose) was used, 147 was formed with 97% de (figure 71). The epoxide function in 148 could be selectively opened with hydride. Further transformations led to the hydroquinone 155, which could be cyclised under acidic conditions to form the chromanol ring of 1 with the desired R-configuration at C(2) (figure 72). α-Tocopherol could be synthesised in 8 steps with 93% de via this route. To the best of my knowledge, this highly diasteroselective synthesis of α-tocopherol (1) is one of the shortest in terms of numbers of steps, employing a commercially available organocatalyst. In a different approach an acid supported, “anti-Baldwin” epoxide ring opening of desilylated 147 under inversion of configuration led to the 6-membered chromanol ring. α-Tocopherol could be synthesised in 10 steps and with 93% de. This synthesis was carried out in collaboration with Julien Chapelat. To the best of our knowledge this is the second application of an organocatalyst to the construction of chromanols, having a tetrasubstituted chiral carbon centre, in high diastereoselectivity.70