Diastereoselective synthesis of [alpha]-tocopherol

Buss, Axel Wolfgang. Diastereoselective synthesis of [alpha]-tocopherol. 2008, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_8515

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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
Advisors:Woggon, Wolf-Dietrich
Committee Members:Mayor, Marcel
Faculties and Departments:05 Faculty of Science > Departement Chemie > Former Organization Units Chemistry > Organische Chemie (Gademann)
UniBasel Contributors:Woggon, Wolf-Dietrich and Mayor, Marcel
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:8515
Thesis status:Complete
Number of Pages:125
Identification Number:
edoc DOI:
Last Modified:05 Apr 2018 17:32
Deposited On:13 Feb 2009 16:50

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