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Studies of reductive lithiation methods for the preparation of organolithium compounds and applications of the palladium catalyzed zinc-ene cyclization

Yang, Ao (2007) Studies of reductive lithiation methods for the preparation of organolithium compounds and applications of the palladium catalyzed zinc-ene cyclization. Doctoral Dissertation, University of Pittsburgh.

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    Abstract

    There are two major methods of performing radical-anion induced reductive lithiations that result in the cleavage of carbon-heteroatom bonds to produce organolithium compounds. The conventional (PAR) method uses a stoichiometric amount of preformed aromatic radical-anion. The newer catalytic aromatic (CA) method is growing rapidly in popularity and has been claimed to be far more powerful than the PAR method. The CA method uses a large excess of lithium in the presence of a catalytic quantity of the aromatic compound, usually naphthalene or 4,4„S-di-tert-butylbiphenyl. It is revealed here that in a number of cases studied that the CA method is far inferior to the PAR method and that in at least one case the aromatic "catalyst" is not required and that in another the arene is an inhibitor rather than a catalyst. In collaboration with others, a Pd-catalyzed Zn-ene cyclization, using allyl phenyl sulfones instead of allyl acetates as precursors of allylzincs, was developed for the preparation of five-membered rings bearing adjacent cis vinyl and CH2ZnEt or CHZnEt groups. This methodology has been used for the total syntheses of the highly physiologically active prostaglandin („b)-15-deoxy-ƒ´12,14-PGJ2 and (ƒ{)-kainic acid, an alkaloid that is in great demand for medical research.The potent anti-inflammatory agent 15-deoxy-ƒ´12,14-PGJ2, was synthesized using the Zn-ene cyclization onto an alkyne as the key step in 13 linear steps in 7.7% overall yield. An important analog, 15-deoxy-9,10-2H-ƒ´12,14-PGJ2, has also been synthesized as its precursor. (ƒ{)-Kainic acid, an extremely neuroexcitatory amino acid, was synthesized through highly diastereoselective Zn-ene cyclizations of both allyl sulfone and allyl chloride substrates. The sulfone approach required 10 linear steps from commercially available D-serine methyl ester with an overall yield of 11%. The chloride strategy required 11 linear steps from the same starting material, but with a much higher overall yield of 48%, which is by far the highest of any kainic acid synthesis to date and it can be carried out on the largest scale to date. In both case, there is some loss of optical purity in the step, in which an ester is converted to an alkene.


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    Item Type: University of Pittsburgh ETD
    Creators/Authors:
    CreatorsEmailORCID
    Yang, Aoyangaocyh@gmail.com
    ETD Committee:
    ETD Committee TypeCommittee MemberEmailORCID
    Committee ChairCohen, Theodorecohen@pitt.edu
    Committee MemberDay, Billy Wbday@pitt.edu
    Committee MemberWender, Irvingwender@engr.pitt.edu
    Committee MemberBrummond, Kay Mkbrummon@pitt.edu
    Title: Studies of reductive lithiation methods for the preparation of organolithium compounds and applications of the palladium catalyzed zinc-ene cyclization
    Status: Unpublished
    Abstract: There are two major methods of performing radical-anion induced reductive lithiations that result in the cleavage of carbon-heteroatom bonds to produce organolithium compounds. The conventional (PAR) method uses a stoichiometric amount of preformed aromatic radical-anion. The newer catalytic aromatic (CA) method is growing rapidly in popularity and has been claimed to be far more powerful than the PAR method. The CA method uses a large excess of lithium in the presence of a catalytic quantity of the aromatic compound, usually naphthalene or 4,4„S-di-tert-butylbiphenyl. It is revealed here that in a number of cases studied that the CA method is far inferior to the PAR method and that in at least one case the aromatic "catalyst" is not required and that in another the arene is an inhibitor rather than a catalyst. In collaboration with others, a Pd-catalyzed Zn-ene cyclization, using allyl phenyl sulfones instead of allyl acetates as precursors of allylzincs, was developed for the preparation of five-membered rings bearing adjacent cis vinyl and CH2ZnEt or CHZnEt groups. This methodology has been used for the total syntheses of the highly physiologically active prostaglandin („b)-15-deoxy-ƒ´12,14-PGJ2 and (ƒ{)-kainic acid, an alkaloid that is in great demand for medical research.The potent anti-inflammatory agent 15-deoxy-ƒ´12,14-PGJ2, was synthesized using the Zn-ene cyclization onto an alkyne as the key step in 13 linear steps in 7.7% overall yield. An important analog, 15-deoxy-9,10-2H-ƒ´12,14-PGJ2, has also been synthesized as its precursor. (ƒ{)-Kainic acid, an extremely neuroexcitatory amino acid, was synthesized through highly diastereoselective Zn-ene cyclizations of both allyl sulfone and allyl chloride substrates. The sulfone approach required 10 linear steps from commercially available D-serine methyl ester with an overall yield of 11%. The chloride strategy required 11 linear steps from the same starting material, but with a much higher overall yield of 48%, which is by far the highest of any kainic acid synthesis to date and it can be carried out on the largest scale to date. In both case, there is some loss of optical purity in the step, in which an ester is converted to an alkene.
    Date: 26 June 2007
    Date Type: Completion
    Defense Date: 23 April 2007
    Approval Date: 26 June 2007
    Submission Date: 26 April 2007
    Access Restriction: No restriction; The work is available for access worldwide immediately.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: PhD - Doctor of Philosophy
    URN: etd-04262007-143214
    Uncontrolled Keywords: sulfones; zinc-ene cyclization; aromatic radical-anion; lithiation
    Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
    Date Deposited: 10 Nov 2011 14:42
    Last Modified: 05 Jun 2012 11:08
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-04262007-143214/, etd-04262007-143214

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