Kinetic Study and Development of Ligand-Accelerated Clip Reactions and Synthesis of a Tetrahydrofuran Analog of FR901464

Pohorilets, Ivanna (2022) Kinetic Study and Development of Ligand-Accelerated Clip Reactions and Synthesis of a Tetrahydrofuran Analog of FR901464. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Fluorescence has found many uses in the areas of analytical, organic, biological, and physical chemistry. Herein, fluorescence was used to study the kinetics of Tsuji-Trost reaction under biologically relevant conditions. The Tsuji-Trost reaction was studied using a fluorogenic substrate, which allowed for high throughput, accurate data collection and revealed three kinetic regimes. The turnover limiting step was found to depend on the substrate concentration and reaction temperature.
Florescence was also used to develop and optimize palladium-catalyzed clip reaction. Currently, deallylation is deemed to be too slow to be viable uncaging reaction and more rapid, palladium-catalyzed propargylic C-O or C-N bond cleavage is typically used. These studies avoid using phosphine ligands, known to accelerate the reaction. Here, new phosphine ligands were synthesized and tested under biological conditions. This palladium-catalyzed deallylation with phosphine as an added ligand was found to be 35 times faster than previously reported phosphine-free palladium-catalyzed depropargylation.
Next, the synthesis of tetrahydrofuran FR901464 analog is discussed. FR901464, a natural product splicing regulator with low nanomolar activity against various cancer cell lines. FR901464 analogs regulate the alternative splicing of the myeloid cell leukemia 1 pre-mRNA. We describe the synthesis of the first tetrahydrofuran FR901464 analog. The key step in the synthesis is electrophilic, N-bromosuccinimide-mediated cyclization. The new analog was shown to inhibit cancer cell growth with low micromolar potency, indicating the importance of the tetrahydropyran ring.

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Details

Item Type:	University of Pittsburgh ETD
Status:	Unpublished
Creators/Authors:	Creators Email Pitt Username ORCID Pohorilets, Ivanna IVP2@PITT.EDU ivp2
ETD Committee:	Title Member Email Address Pitt Username ORCID Committee Chair Koide, Kazunori koide@pitt.edu Committee Member Floreancig, Paul florean@pitt.edu Committee Member Liu, Peng pengliu@pitt.edu Committee Member Zhang, Lin zhanglx@upmc.edu
Date:	24 February 2022
Date Type:	Publication
Defense Date:	25 August 2021
Approval Date:	24 February 2022
Submission Date:	15 September 2021
Access Restriction:	2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages:	300
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:	Tsuji-Trost, deallylation, palladium, allyl, kinetics, FR901464
Date Deposited:	24 Feb 2023 06:00
Last Modified:	24 Feb 2023 06:00
URI:	http://d-scholarship.pitt.edu/id/eprint/41816

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• Kinetic Study and Development of Ligand-Accelerated Clip Reactions and Synthesis of a Tetrahydrofuran Analog of FR901464. (deposited 24 Feb 2023 06:00) [Currently Displayed]

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