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(R,R,R)-alpha-Tocopherol   

21 October 2007 6,565 views 12 Comments

Breit, Rein, Demel, Outten and Netscher. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200703268. Article PDF Supporting Information Group Website

Just a short post to mention a nice little synthesis of this tocopherol by Bernhard Breit’s group at Freiburg. I first came across his work when I saw him present at OMCOS-13 in Geneva, and have been quite a fan since. This synthesis concerns his “Reagent Directing Group” (RGD) approach, which he’s been working on for a few years now (though 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 bin 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.


InChiData:

QYWNJQPTJUCKNJ-AKBASNCKBP FXNGNCULDNZDAU-QBCOQJIWBD WEYPWCVRCYRYLR-HDWAWUAVBX NYIMXAAVXUCETL-RMGZSPTMBQ MVOVBRCOOJHYGJ-PBBIAFMXBA GVJHHUAWPYXKBD-IDUGMIJRBX

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12 Comments

  • tom says:

    In the supporting information they use something called speedex to filter some reaction mixtures during work up… anyone know what the heck speedex is? I am assuming it is similar to celite?

  • DDD says:

    Think you should have an alkyl bromide, not the Grignard, for the coupling reaction.

  • TWYI says:

    Dicalite speedex is just a filter aid, so similar to Celite yes.

  • Observer says:

    This “RDG” strategy is great only as long as the “cost” of installing a stoichiometric ammount of the directing group is less than that of the chiral catalyst.

  • GZS says:

    Yeah, observer: “o-DPPB” acid costs 147$ for 5g…

  • Non-Chemist says:

    Pfaltz published a much more interesting strategy towards tocopherol in Science recently based on a hydrogenation approach with impressive results..

  • Spiro says:

    Nice work!

    Look at what’s happening in step e (scheme 2) : it looks like an SN1 reaction on a tertiary alcohol with retention of configuration!
    Solution can be found in ref 14…

  • jimbo says:

    Observer & GZS: price is usually tied to demand… if there’s enough will, a cheap way to obtain it will become available.

  • ZZZZZ says:

    zzzzz

    DPPBA can be made by quenching the dianion of benzoic acid with Ph2PCl; Breit’s postdoc advisor has done this for years…

    zzzzz

  • quickqwestion says:

    Is there a good way to perform an asymmetric epoxidation on a terminal olefin, whilst leaving an E-disubst and a trisubst olefin intact? Don’t think SAE, JAE or Shi will work right?
    Ta

  • around the corner and down the hall says:

    One of the newer variations of the Shi epoxidation might work, depending on what the terminal olefin is attached to. Kinetically, cis and terminal olefins react much faster than trans and trisubstituted olefins (although there can be some electronic factors). Can you give us any more information?

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