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Asymmetric Allenic Pauson−Khand Reaction to Access Thapsigargin: Influence of a Remote Stereocenter on Stereodifferentiation

Haghighi, Fatemeh (2024) Asymmetric Allenic Pauson−Khand Reaction to Access Thapsigargin: Influence of a Remote Stereocenter on Stereodifferentiation. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Thapsigargin is a potent histamine liberator, a subnanomolar inhibitor of sarco/endoplasmic reticulum calcium ATPase, and a potent inhibitor of major human respiratory viruses including RSV, OC43, SARS-COV-2, and influenza A virus. G202, G115, MAD, and JQ- FT are prodrugs of thapsigargin with anticancer and antileukemic properties. Among more than a hundred synthesized thapsigargin analogs, there are only two reports on a stereochemical change which puts a limit on the SAR studies. To fill this gap, herein we report an asymmetric synthesis of thapsigarin analogs with the potential of accessing different stereoisomers. We initiated the synthesis of thapsigargin using an achiral starting material, 3-furaldehyde, which is a key feature of our approach compared to the three previous total synthesis reports. We synthesized the 5,7,5- ring system of thapsigargin through an asymmetric catalysis approach giving access to a stereochemical array of thapsigargin analogs. The C8 stereocenter was set via an organocatalyzed asymmetric aldol reaction of a heteroarenyl aldehyde and acetone. The C2 stereocenter was set via an asymmetric allenic Pauson–Khand reaction through a catalyst-controlled stereodifferentiative dynamic kinetic asymmetric transformation process. The molecular configuration for all stereoisomers was assigned using VCD and 13C NMR. DFT computed transition state structures were predictive of enantioselectivity and aligned with the stereochemical assignments.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Haghighi, Fatemehfah27@pitt.edufah270000-0002-5883-7802
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBrummond, Kay M.kbrummon@pitt.edukbrummon
Committee MemberFloreancig, Paul E.florean@pitt.eduflorean
Committee MemberLiu, Pengpengliu@pitt.edupenguin
Committee MemberXie, Xiang Qun Seansean.xie@pitt.edusean.xie
Date: 20 December 2024
Date Type: Publication
Defense Date: 24 October 2024
Approval Date: 20 December 2024
Submission Date: 18 October 2024
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 273
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, Asymmetric Catalysis, Stereodifferentiation, Pauson–Khand Reaction, Vibrational Circular Dichroism, Computated Transition States
Date Deposited: 20 Dec 2024 14:16
Last Modified: 20 Dec 2024 14:16
URI: http://d-scholarship.pitt.edu/id/eprint/47019

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