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    The Stork Synthesis of

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    Chandra Reddy
    The document summarizes Gilbert Stork's total synthesis of the alkaloid reserpine published in 2005. It describes the key steps in Stork's synthesis, which began with the enantioselective addition of acrylate to butadiene to set the stereochemistry. The central step was the addition of a lithium enolate to a silyl acrylate, creating two stereocenters through a concerted Diels-Alder-like reaction. After further transformations, this intermediate was converted to the crucial aldehyde tosylate. Condensation with tryptamine initially gave the wrong stereoisomer, but stirring the product in aqueous HCl provided reserpine with the correct stereochemistry.

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    The Stork Synthesis of

    Uploaded by

    Chandra Reddy
    55 views2 pages
    The document summarizes Gilbert Stork's total synthesis of the alkaloid reserpine published in 2005. It describes the key steps in Stork's synthesis, which began with the enantioselective addition of acrylate to butadiene to set the stereochemistry. The central step was the addition of a lithium enolate to a silyl acrylate, creating two stereocenters through a concerted Diels-Alder-like reaction. After further transformations, this intermediate was converted to the crucial aldehyde tosylate. Condensation with tryptamine initially gave the wrong stereoisomer, but stirring the product in aqueous HCl provided reserpine with the correct stereochemistry.

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    Alkaloid Material for Students-2

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    The Stork Synthesis Of

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    The document summarizes Gilbert Stork's total synthesis of the alkaloid reserpine published in 2005. It describes the key steps in Stork's synthesis, which began with the enantioselective addition of acrylate to butadiene to set the stereochemistry. The central step was the addition of a lithium enolate to a silyl acrylate, creating two stereocenters through a concerted Diels-Alder-like reaction. After further transformations, this intermediate was converted to the crucial aldehyde tosylate. Condensation with tryptamine initially gave the wrong stereoisomer, but stirring the product in aqueous HCl provided reserpine with the correct stereochemistry.

    Copyright:

    © All Rights Reserved
    Download as DOCX, PDF, TXT or read online from Scribd
    Download as docx, pdf, or txt
    55 views2 pages

    The Stork Synthesis of

    Uploaded by

    Chandra Reddy
    The document summarizes Gilbert Stork's total synthesis of the alkaloid reserpine published in 2005. It describes the key steps in Stork's synthesis, which began with the enantioselective addition of acrylate to butadiene to set the stereochemistry. The central step was the addition of a lithium enolate to a silyl acrylate, creating two stereocenters through a concerted Diels-Alder-like reaction. After further transformations, this intermediate was converted to the crucial aldehyde tosylate. Condensation with tryptamine initially gave the wrong stereoisomer, but stirring the product in aqueous HCl provided reserpine with the correct stereochemistry.

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    © All Rights Reserved
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    of 2

    The Stork Synthesis of (-)-Reserpine

    The history of reserpine (3), isolated from the Indian shrub Rauwolfia serpentina, is storied. The
    anxiolytic activity of reserpine, the first tranquilizer, pointed the way to the development by HoffmannLaRoche of the blockbuster drugs Librium and Valium.
    The spectacular first total synthesis of reserpine was achieved by R.B. Woodward in 1956. Several
    alternative approaches have been been published since that time. The most recent (J. Am. Chem.
    Soc. 2005, 127, 16255. DOI: 10.1021/ja055744x), by Gilbert Stork of Columbia University, centering
    on the aldehyde tosylate 2, illustrates the power of chiral induction for the kinetic establishment of
    distal stereocenters. Condensation of 2 with 6-methoxytryptamine (1) led to reserpine (3).

    The preparation of 2 started with the previously-reported enantioselective addition of acrylate to


    butadiene, to give the acid 6. Iodolactone formation followed by reduction gave the diol 7. Under the
    conditions of benzyl ether formation, the iodohydrin cyclized to the epoxide, giving 8. Phenyl
    selenide added to 8 to give the expected diaxial product 9, which on oxidation gave 10 in high
    enantiomeric excess.

    The key reaction in the assembly of 2 was the addition of the kinetic lithium enolate of 10 to the silyl
    acrylate 11 to give 12. This reaction is seen as involving two sequential Michael additions, but the
    stereochemical outcome is the same as would be expected from a concerted Diels-Alder
    cycloaddition. Exposure to TBAF converted the furyl silane to the fluorosilane, which was
    debenzylated and carried on to the tosylate 13. On exposure to two equivalents of hydrogen
    peroxide, the ketone underwent Baeyer-Villiger oxidation with high regioselectivity. The silane was
    also oxidized, delivering 14. Methylation followed by Dibal reduction then gave 2.

    An additional stereogenic center is created when 1 and 2 are combined. Initial attempts to carry out
    the condensation gave the wrong stereochemical outcome, as Pictet-Spengler condensation
    preceded tosylate displacement. To work around this problem, 1 and 2 were combined in the
    presence of cyanide ion, to give 15. Heating of 15 gave cyclization, but again to the wrong
    diastereomer, perhaps because in the intermediate ion pair from cyanide ionization, the cyanide ion
    was blocking one face of the intermediate cation. Fortunately, on stirring at room temperature in
    aqueous HCl, 15 did cyclize to the correct diastereomer, providing, after acylation, reserpine (3).

    D. F. Taber, Org. Chem. Highlights 2006, May 1.


    URL: http://www.organic-chemistry.org/Highlights/2006/01May.shtm
    Corrections needed? Please send an email to the author of a specific Highlight column and to
    [email protected]!
    Subscribing to Org. Highlights (third party offer - for more options and information click here)

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