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Utility of the Catalytic, Asymmetric Acyl Halide-Aldehyde Cyclocondensation Reaction in Natural Product Synthesis

Wasmuth, Andrew Stephen (2007) Utility of the Catalytic, Asymmetric Acyl Halide-Aldehyde Cyclocondensation Reaction in Natural Product Synthesis. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The ability of the catalytic, asymmetric acyl halide-aldehyde cyclocondensation (AAC) reaction to produce stereoenriched beta-lactone products has found extensive utility in natural product synthesis. The asymmetric Al(III)-catalyzed AAC-SN2' ring opening sequence was exploited in synthetic efforts towards the enantioselective total synthesis of the aspidospermane alkaloid (-)-rhazinilam. The synthetic sequence features an enantioselective cyclization of a tethered pyrrole moiety onto an optically-active allene to set the quaternary carbon stereocenter while concomitantly forming rhazinilam's tetrahydroindolizine core. In addition, attempts at forming the requisite biaryl bond via a Pd-catalyzed cross-coupling reaction are also discussed. Recently, it was found that the Cinchona alkaloids quinine and quinidine can catalyze the AAC reaction to produce disubstituted beta-lactones in high yield and in essentially enantiomerically and diastereomerically pure form. Reaction conditions were developed which allowed for the effective formation of masked polypropionate units by employing the Cinchona alkaloid-catalyzed AAC reaction. Based on the pseudoenantiomer of the Cinchona alkaloid used, different stereoarrays of polypropionate units are obtained. A variety of optically active aldehydes are viable in this transformation as reaction conditions can be optimized for a specific substrate. A matched/mismatched phenomenon was observed where the matched case produced the desired polypropionate unit in good yield and high diastereoselectivity and the mismatched case afforded an unexpected beta-lactone product in diminished yield and diastereoselectivity. (+)-Discodermolide is a marine, microtubule-stabilizing polyketide that can only be isolated in scarce amounts from nature. Due to our inability to harvest it in supple amounts, the total synthesis of (+)-discodermolide has been the focus of many research groups. Application of the cinchona alkaloid-catalyzed AAC reaction towards the catalytic, asymmetric total synthesis of an analogue of (+)-discodermolide is discussed.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Wasmuth, Andrew
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairNelson, Scott Gsgnelson@pitt.eduSGNELSON
Committee MemberDay, Billy Wbday@pitt.eduBDAY
Committee MemberWilcox, Craig Sdaylite@pitt.eduDAYLITE
Committee MemberWipf, Peterpwipf@pitt.eduPWIPF
Date: 30 January 2007
Date Type: Completion
Defense Date: 6 September 2006
Approval Date: 30 January 2007
Submission Date: 9 November 2006
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: Chemistry; Nelson; Wasmuth
Other ID:, etd-11092006-082910
Date Deposited: 10 Nov 2011 20:04
Last Modified: 15 Nov 2016 13:51


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