Haghighi, Fatemeh
(2024)
Asymmetric Allenic Pauson−Khand Reaction to Access Thapsigargin: Influence of a
Remote Stereocenter on Stereodifferentiation.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
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.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| 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 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}