On the Mechanism of the Acid-Catalyzed Stereoselective Chroman Cyclization Reaction

Naturally occurring tocopherols and tocotrienols are single-isomer vitamin E compounds. (2R,4’R,8’R)-alpha-Tocopherol as a prominent example is of high commercial interest due to its biological and antioxidant properties.^[1] Although the stereospecific cyclization reaction of hydroquinone intermediates and precursors to chromans under carefully controlled acidic conditions is known for a long time^[2] and has been used as a key step in many total syntheses,^[3] the mechanism of this transformation is unknown.

We investigated the course of the acid catalyzed ring closure reaction by starting from doubly ¹⁸O-labelled hydroquinone derivatives obtained by applying standard literature procedures showed complete (>95%) chirality transfer as well as ¹⁸O-incorporation. The mechanism proposed will be discussed in comparison to findings documented in previous research papers.

References:

[1] T. Netscher, Vitamins Hormones 2007, 76, 155-202.
[2] H. Mayer, W. Vetter, J. Metzger, R. Rüegg, O. Isler, Helv. Chim. Acta 1963, 50, 1168-1178; N. Cohen, R. J. Lopresti, C. Neukom, J. Org. Chem. 1981, 46, 2445-2450.
[3] See e.g. C. Rein, P. Demel, R. A. Outten, T. Netscher, B. Breit, Angew. Chem. Int. Ed. 2007, 46, 8670-8673, and references cited therein.