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Totally Synthetic by Paul H. Docherty, 21 October 2007

Total Synthesis of (R,R,R)-α-Tocopherol


C. Rein, P. Demel, R. A. Outten, T. Netscher, B. Breit, Angew. Chem. Int. Ed. 2007, 46, 8670-8673.

DOI: 10.1002/anie.200703268

A nice little synthesis of this tocopherol by Bernhard Breit’s group at Freiburg. This synthesis concerns his “Reagent Directing Group” (RGD) approach, which he’s been working on for a few years now (although he wasn’t the originator of the idea). The concept is simple - use the substrate as the chiral ligand on which a catalyst operates. In this manner, the substrate is controlling the asymmetry in the catalyst, which inself informs a reagent controlled asymmetric process. Now to see it in action:

In this case, the reaction is a rhodium catalysed hydroformylation, and the directing group is an ortho diphenylphosphine benzoate ester, resulting in a good yield and diastereomeric control. I also liked the synthesis of the vinyl silane… With that half of the molecule complete, it was time to couple to the other fragment. I haven’t covered it’s synthesis - suffice to say that it was short and efficient. The coupling, though, is rather special:

Rather than just remove the RDG, they used it as a leaving group for a copper-mediated allylic displacement, in which the stereochemistry was transferred nicely. Reductive removal of both the olefin and benzyl ether completed this short synthesis rather neatly.