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Sulfur Based Cyclizations by Intramolecular Carbometallation and Applications to Natural Product Syntheses

Deng, Kai (2005) Sulfur Based Cyclizations by Intramolecular Carbometallation and Applications to Natural Product Syntheses. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The versatility of intramolecular carbolithiation of simple unactivated alkenes to yield cyclopentylmethyllithiums by unconjugated organolithiums is greatly increased (1) by generating the organolithiums by reductive lithiation of phenyl thioethers with aromatic radical anions and (2) by using allylic alcohol groups on the receiving alkenes. This type of reductive lithiation allows virtually any kind of organolithium to be generated, usually in a connective manner. Furthermore, the allylic lithium oxyanionic groups on the alkenes greatly accelerate the reactions and lead, in most cases, to completely stereoselective cyclization at -78 °C. Most significantly, the trans stereoselectivity is the opposite from that observed when the organometallic is allylic. A four-membered ring has also been generated by this method.Using allyl phenyl sulfones instead of using allyl acetates as precursors of Pd-catalyzed allylzinc formation greatly facilitates the efficiency of substrate preparation. The resulting allylzinc smoothly undergoes the Zn-ene cyclization onto a simple alkene or an alkyne. This methodology has been used for the most efficient of the published syntheses of the natural sesquiterpene (-)-erythrodiene in highly stereoselective fashion with an overall yield of 60% in 6 linear steps from commercially available (-)-perillyl alcohol. 15-Deoxy-delta12,14-PGJ2 (15d-PGJ2) is a potent anti-inflammatory agent that represses the expression of a number of inflammatory response genes in activated macrophages. The high-affinity binding of 15d-PGJ2 to PPARγ (peroxisome proliferator activated receptor-gamma) is believed to be responsible for the repressive effect on gene expression. The total synthesis of this natural product by using the zinc-ene cyclization as the key step has been accomplished in 13 linear steps with good overall yield. Moreover, due to our strategy of installing the double bond on the cyclopentenone ring in the late stage of the synthesis, 9,10-dihydro-15-deoxy-delta12,14-PGJ2, an analogue of PPARγ-binding prostaglandins, has been synthesized as the precursor of the natural product. The addition of a primary amine to 2-phenylsulfonyl-3-methyl-1, 3-diene is a very efficient way to construct allyl phenyl sulfones capable of undergoing the Pd-catalyzed Zn-ene cyclization. A nitrogen-containing heterocycle has been synthesized in high stereoselectivity. The total synthesis of (-)-kainic acid by utilizing this methodology is being proposed and initial studies are reported in this thesis.


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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 MemberCurran, Dennis Pcurran@pitt.eduCURRAN
Committee MemberFloreancig, Paul Eflorean@pitt.eduFLOREAN
Committee MemberMcCullough, Richard
Date: 31 January 2005
Date Type: Completion
Defense Date: 15 October 2004
Approval Date: 31 January 2005
Submission Date: 25 October 2004
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: Pd-catalyzed Zn-ene cyclization; phenylthioethers; reductive lithiation; (-)-erythrodiene; "; intramolecular carbolithiation
Other ID:, etd-10252004-171707
Date Deposited: 10 Nov 2011 20:03
Last Modified: 15 Nov 2016 13:50


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