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Photoflow Preparation of PTP4A3 Inhibitors, and Concise Total Syntheses of Ergot and Clavine Alkaloids

Tasker, Nikhil R. (2023) Photoflow Preparation of PTP4A3 Inhibitors, and Concise Total Syntheses of Ergot and Clavine Alkaloids. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The first section of this thesis describes the photooxygenation of a thienopyridone to generate a potent, novel PTP4A3 inhibitor bearing an iminopyridinedione pharmacophore. A scalable flow process was developed to facilitate throughput of the lead inhibitor JMS-053 and to enable structure-activity-relationship studies in collaboration with a fellow researcher, and a convergent imination was implemented to simplify purification of final products. Several analogs were synthesized and are described, and a preliminary binding pose is proposed.

The second section describes the total syntheses of several ergot, clavine, and unnatural alkaloids and a C(3) indole alkylation methodology. The methyl lysergates, which are direct precursors to tetracyclic ergot and clavine alkaloids, are synthesized in four steps (28% overall yield). An expedited synthesis delivers methyl lysergates with only one chromatographic purification. A transition metal-free Hydrogen Autotransfer (HA) reaction to alkylate C(3) of indole was discovered, developed, and implemented in the synthesis, and the mechanism of this transformation was investigated. The rapid synthesis was expanded to several alkaloids, including lysergic acid, lysergol, isolysergol, lysergene, lysergine, isolysergine, and festuclavine. Structural isomers of the clavine alkaloids were discovered during these efforts, and the scaffolds were expanded to lysergic acid diethylamide and lysergol analogs. Studies toward developing an asymmetric synthesis of the methyl lysergates are detailed. Finally, several alkaloids and unnatural products were evaluated for their ability to bind and activate 5-HT receptors.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Tasker, Nikhil R.nrt22@pitt.edunrt220000-0002-9293-979X
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWipf,
Committee MemberCurran,
Committee MemberDeiters,
Committee MemberLazo,
Date: 11 May 2023
Date Type: Publication
Defense Date: 20 March 2023
Approval Date: 11 May 2023
Submission Date: 10 April 2023
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 351
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: PTP4A3, phosphatase, SMI, photooxygenation, flow, ergot, clavine, alkaloid, 5-HT, serotonin
Date Deposited: 11 May 2023 19:45
Last Modified: 11 May 2023 19:45

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