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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. (Unpublished)

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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
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairCohen, Theodorecohen@pitt.eduCOHEN
Committee MemberDay, Billy Wbday@pitt.eduBDAY
Committee MemberWender, Irvingwender@engr.pitt.eduWENDERV
Committee MemberBrummond, Kay Mkbrummon@pitt.eduKBRUMMON
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; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: sulfones; zinc-ene cyclization; aromatic radical-anion; lithiation
Other ID:, etd-04262007-143214
Date Deposited: 10 Nov 2011 19:42
Last Modified: 15 Nov 2016 13:42


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