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    Research Statement 05

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    ram6025
    The document discusses three student research projects involving the use of quinine derivatives as chiral catalysts or auxiliaries. The first project explores using an esterified quinine derivative to catalyze asymmetric Michael additions with improved selectivity. The second examines quinine-borohydride complexes for the chiral reduction of ketones. The third project involves synthesizing a crotyl ester of quinine to use as a chiral auxiliary in Diels-Alder reactions. Preliminary results have been obtained for each project, but further work is still needed, including purification, characterization, and optimization of reaction conditions.

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    Research Statement 05

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    ram6025
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    The document discusses three student research projects involving the use of quinine derivatives as chiral catalysts or auxiliaries. The first project explores using an esterified quinine derivative to catalyze asymmetric Michael additions with improved selectivity. The second examines quinine-borohydride complexes for the chiral reduction of ketones. The third project involves synthesizing a crotyl ester of quinine to use as a chiral auxiliary in Diels-Alder reactions. Preliminary results have been obtained for each project, but further work is still needed, including purification, characterization, and optimization of reaction conditions.

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    The document discusses three student research projects involving the use of quinine derivatives as chiral catalysts or auxiliaries. The first project explores using an esterified quinine derivative to catalyze asymmetric Michael additions with improved selectivity. The second examines quinine-borohydride complexes for the chiral reduction of ketones. The third project involves synthesizing a crotyl ester of quinine to use as a chiral auxiliary in Diels-Alder reactions. Preliminary results have been obtained for each project, but further work is still needed, including purification, characterization, and optimization of reaction conditions.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    53 views4 pages

    Research Statement 05

    Uploaded by

    ram6025
    The document discusses three student research projects involving the use of quinine derivatives as chiral catalysts or auxiliaries. The first project explores using an esterified quinine derivative to catalyze asymmetric Michael additions with improved selectivity. The second examines quinine-borohydride complexes for the chiral reduction of ketones. The third project involves synthesizing a crotyl ester of quinine to use as a chiral auxiliary in Diels-Alder reactions. Preliminary results have been obtained for each project, but further work is still needed, including purification, characterization, and optimization of reaction conditions.

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    Student Research Projects

    William Dasher Department of Chemistry University of Puget Sound Quaternary amines have been used as phase-transfer catalysts (PTC) allowing many reactions to occur under milder conditions and greater yields than other techniques. The pharmaceutical industry has pioneered and continues to use phase-transfer reactions extensively. Recent applications involve use of a chiral PTC reagent (APTC) to induce asymmetry in a reaction. One of the most successful series of asymmetric PTC reagents are those derived from quinine, an alkaloid found in the bark of the cinchona tree. Quinine is best known historically for use in treating malaria. Several groups, most notably from Merck Pharmaceuticals and the labs E. J. Corey at Harvard and B. Lygo at University of Nottingham, have developed highly efficient quinine derived PTC reagents for the production of chiral amino acids and other medicinally useful molecules. To date, modifications on quinine have been to quarternize the 3 amine group with large, flat, substituents such as the anthracene derivative, shown below, and possibly adding a substituent to the 2 hydroxy group.

    OH N N Br

    OMe Figure 1. A modified cinchonium salt - third generation.

    Our focus on the use of quinine in asymmetric reactions is on modifications of the secondary alcohol rather than the tertiary nitrogen. Currently we have three related projects which utilize quinine (or related molecules) which have been esterified to form new reagents for use as a chiral catalyst or chiral ancillary.

    The first project derives from earlier work in our lab which explored the use of underivatized quinine as a catalyst for the Michael reaction between malonates and cyclic enones. The yields were high with modest stereoenhancement. By esterifying with 4-hydroxy phenyl acetic acid we hope to change the nonbonding interactions responsible for creating a tighter chiral environment for the reaction to occur in. This is illustrated in Scheme 1.

    O RedAl RO2 C CO2 R +


    HO MeO N N

    CO2 R CO2 R

    RO MeO N

    N R= HO CO2

    Scheme 1. Chiral Michael Reaction and modified quinine The second project is to explore the use of a quinine-borohydride complex to effect chiral reduction of ketones. To this end we are making sodiumborohydride complexes with underivatized quinine and evaluating the degree of stereoselectivity in the reduction of bulky ketones. We have also esterified with several anhydrides to give a free acid which we hope will, once again, create a tighter chiral complex and thus lead to greater asymmetric induction. (see scheme 2).

    OH N N NaBH4 "Complex

    OMe NaBH4

    OR N N R= or OMe CO2 O C OH CO2 CO2 H

    Scheme 2. Quinine - sodium borohydride complex and modified quinine. And lastly, we have synthesized the crotyl ester of quinine and are exploring its use in the DielsAlder reaction. Here quinine is being used as a chiral auxiliary rather than a catalyst. Much of the early work on this project is focusing on finding an appropriate diene and conditions to effect a thermal reaction. Later we hope to look at a Lewis acid catalyzed DA reaction as well. (See Scheme 3). O O N + N RO RO CO2

    OMe Scheme 3. Quinine as an ancillary agent in the chiral Diels-Alder reaction

    All of these projects have generated some preliminary results but much remains to be done. These projects involve performing reactions, including purification and complete spectral characterization. You will be expected to research reaction conditions and background material in the library (or with an on-line database) and to run and maintain a research laboratory including any purification of reagents. Expertise in spectral methods and in handling (sometimes) complex mixtures will be part of your legacy. General References The Quest for Quinine, T.S. Kaufman adn E.A. Ruveda, Angewandte Chemie Int. Ed, 2005, 44, 845-885 Dolling, Ulf-H; Davis, Paul; Grabowski, Edward J. J. JACS. 1984, 106, 446. Lygo, Barry; Andrews, Benjamin I. Acc. Chem. Res. 2004, 37, 518-525. ODonnel, M. J. Acc. Chem. Res. 2004, 37, 506-517. Jah, S.C.; Joshi, N.N. Tetrahedron: Asymmetry, 2001, 12. Hanson, Kelsey. Sr. Thesis, University of Puget Sound, 2004. Gang, Zhao; Jian-Bing, Hu. Chinese Journal of Chemistry, 2003, 21, 819-823. Aldriciica Acta, M.J. ODonnel, 2001, 44, 3-15.

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