Nitrone-cyclopropane cycloaddition

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Use of a methodology I haven't really heard about in a long time.; the nitrone-cyclopropane cycloaddition. Kerr and coworkers now use it in the synthesis of one of those indolizidine alkaloids, phyllantidine. Fairly straightforward synthesis, although again, I would always pay attention to forming an N-O bond at an early stage. One of my favourite name reactions is used- the Krapcho decarboxylation, the concomitant hydrolysis and decarboxylation of an ester using LiCl in DMSO.

I am too lazy to look up the literature, but why doesn't the nitrone add to the double bond?

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Also, the nitrone-cyclopropane addition should be nonconcerted, since we have a nicely stabilised ring opened intermediate.

The other interesting thing is the selectivity of the enolate oxidation.

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At first, I was not satisfied, but then I thought that their explanation for it sounds ok. But it looks a little crafty when you draw the vinyl group conveniently pointing in a sterically hindered direction, and make that the only structure with the group in that position! The difference between the group in that position and pointing away from that position is 2 kcal/mol by the way, at least that's what MMFF says for a model compound.

According to Eliel's latest version, the A value for OH ranges from 0.6 to 1.04 for different solvents, while that for CO2CH3 is 1.2-1.3. Also, MMFF gives a difference of 1 kcal/mol for the product with OH axial. So not much difference there, but still worth keeping in mind that the product with the CO2CH3 axial dominates. I wonder how much the reaction is product controlled here though. Such analyses depend on the thermodynamic nature of the reaction; in this case, the fact that the oxaziridine ring opens probably means that the products as a whole are lower in energy. If that is so, then the TS should resemble the reactant, but I would never place my bets on such rationalizing, as subtle effects can change things in the TS. Also there are other factors here, especially the facile nature of topside attack.

Ref: Total Synthesis of (+)-Phyllantidine, Cheryl A. Carson, Michael A. Kerr
Published Online: 13 Sep 2006
DOI: 10.1002/anie.200602569


  1. let's do some handwaving!
    please bear with me.

    this can be a curtin-hammet situation:
    1. conformer B may not be dominant but still has enough population; e.g., A value of alkyl chain is slightly more than half of that of cyclohexane ring because of oxygen lone pair in one of 1,3-position.

    2. torsional strain of confomer A in transition state is much higher than that of conformer B; i.e., actual reactive conformer is B.


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