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Expanding the Scope of the Asymmetric Allenic Pauson–Khand Reaction Towards the Synthesis of Thapsigargin and Analogues

deihl, eric (2022) Expanding the Scope of the Asymmetric Allenic Pauson–Khand Reaction Towards the Synthesis of Thapsigargin and Analogues. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Thapsigargin is a potent inhibitor of sarco/endoplasmic reticulum calcium ATPase. A prodrug of thapsigargin called mipsagargin has been investigated in clinical trials for treating several types of cancer. The ability to synthesize thapsigargin analogues would further the structure activity relationship studies of this biologically important compound. The asymmetric allenic Pauson–Khand reaction affords enantioenriched cyclopentenones in a dynamic kinetic asymmetric transformation process. Herein we report the use of the asymmetric allenic Pauson–Khand reaction of furanyl tethered allene-ynes to rapidly form the carbocyclic core ring system of thapsigargin with good yields and enantioselectivities. The highest enantioselectivities observed in the asymmetric allenic Pauson–Khand reaction were with an allene-yne having a chloroacetate group. Computational results show the good enantioselectivity is due to a high activation barrier for the competing racemic background reaction. Expanding the substrate scope to include a benzene tethered allene-yne resulted in low enantioselectivities. The products of the allenic Pauson–Khand reaction were further functionalized via hydrolysis and hydrogenation reactions. The asymmetric allenic Pauson–Khand reaction of an allene-yne having a butanoyl group on the tether afforded products containing this important C8 group present in thapsigargin. The asymmetric allenic Pauson–Khand reaction is poised to be used in the synthesis of thapsigargin and thapsigargin analogues.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
deihl, ericedd25@pitt.eduedd25
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBrummond,
Committee MemberFloreancig,
Committee MemberWang,
Committee MemberBrodsky, Jeffrey
Date: 30 September 2022
Date Type: Publication
Defense Date: 13 June 2022
Approval Date: 30 September 2022
Submission Date: 15 July 2022
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 198
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: thapsigargin allenic pauson khand reaction asymmetric catalysis enantioselective
Date Deposited: 30 Sep 2022 18:08
Last Modified: 15 Mar 2023 15:06


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