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Chan Rearrangement

  • Page ID
    92181
  • Chan rearrangement is an organic reaction whereby an alpha-acyloxyester can be converted to a alpha-hydoxy-beta-ketoester in presence of a strong base. It was developed by Tak-Hang Chan and in the seminal publication the authors proposed the following plausible mechanism:

    Chan rearrangement.jpg

    Mechanistic insights

    Hamada and co-workers developed a very similar reaction involving a rearrangement of acyclic imides to alpha-aminoketone. A crossover experiment with two different imides produced no crossover products which indicated that this reaction solely goes through an intramolecular fashion.

    Hamada crossover.jpg

    Hamada's group also reported that choice of appropriate solvent can have a dramatic effect on stereoselectivity of this reaction. While THF proved detrimental for the stereointegrity, ether was found suitable to retain high enantioselectivity in the product.

    Hamada stereo.jpg

    Peter Wipf and co-workers found out that benzyl pivaloates were not a good substrate for this rearrangement as compared to a similar imide (reported by Hamada). Wipf's computational studies showed that the required s-cis conformation for this reaction was significantly disfavored (>16 kcal/mol) in the case of ester while for the imide s-trans conformation had a little preference over s-cis (1.4 kcal/mol).

    Wipf calculations.jpg

    Applications:

    1. James D. White and co-workers applied this rearrangement enroute to the total synthesis of (+)-Aplasmomycin. This elegant synthetic strategy applied "double Chan rearrangement" on an advanced intermediate.

    aplasmomycin_white.jpg

    2. White again used this reaction in his synthetic studies towards Rapamycin.

    White rapamycin.jpg

    3. Holton's total synthesis of Taxol elegantly used Chan-like rearrangement of an alpha-carbonatoketone into an alpha-hydroxy-beta-ketoster. This is the first report of such rearrangement in a cyclic system and produces product with high diastereoselectivity.

    Holton.jpg

    4. Dewynter and co-workers used the same idea for transannular rearrangement of activated lactams where the authors observed high diastereoselectivity possibly due to the bulky alkyl (iPr in the figure) group preventing the formation of the aziridine ring in the same side.

    Dewynter example.jpg

    References:

    1. Lee, S. D.; Chan, T. H.; Kwon, K. S. Tetrahedron Lett. 1984, 25, 3399. (seminal publication)
    2. White, J. D.; Vedananda, T. R.; Kang, M. -C.; Choudhry, S. C. J. Am. Chem. Soc. 1986, 108, 8105. (Total synthesis of Aplasmomycin)
    3. White, J. D.; Jeffrey, S. C. J. Org. Chem. 1996, 61, 2600. (synthetic studies on Rapamycin)
    4. Holton, R. A. et. al. J. Am. Chem. Soc. 1994, 116, 1597. (First total synthesis of Taxol)
    5. Hara, O.; Ito, M.; Hamada, Y. Tetrahedron Lett 1998, 39, 5537. (often called Chan-Hamada reaction)
    6. Wipf, P.; Methot, J. -L. Org. Lett. 2001, 3, 1261. (conformational studies)
    7. Farran, D.; Parrot, I.; Toupet, L.; Martinez, J.; Dewynter, G. Org. Biomol. Chem., 2008, 6, 3989.

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