Asari, Austin Haruyuki
(2022)
Tethering as a Strategy for the Re2O7-catalyzed Stereoselective Synthesis of Bis-spiroketals and Synthesis of Cyclic Dinucleotide Prodrugs for STING Activation.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The stereoselective synthesis of bis-spiroketals utilizing a tethering strategy is described. This approach was coupled with Re2O7-catalyzed allylic alcohol isomerization, spirotricyclization, and thermodynamic equilibration to provide 6,5,6-bis-spiroketals with high levels of stereocontrol. The impact of configurationally stable stereocenters on the diastereoselectivity of these reactions was evaluated in these 6,5,6-bis-spiroketal systems. This methodology enabled an enantioselective synthesis towards the bis-spiroketal core of the pinnatoxins, where a stereochemically defined alcohol dictated the formation of three new stereocenters with high levels of diastereoselectivity. Furthermore, this tethering strategy was successfully implemented towards the first stereocontrolled synthesis of the 5,5,6-bis-spiroketal in the spirolide natural products, which employed a precursor with two stereochemically defined alcohols.
Cyclic dinucleotides have emerged as potential cancer immunotherapeutics based on their ability to function as agonists for stimulator of interferon genes (STING), an adaptor protein that plays a vital role for effective innate immune signaling processes. However, the therapeutic efficacy of these small molecules is limited by several factors such as poor bioavailability due to their lack of cellular uptake and susceptibility to enzymatic hydrolysis as well as the potential for aberrant systemic STING activation, which can lead to autoimmune diseases. To address these limitations, approaches towards vinyl boronate-containing phosphotriester prodrugs of cyclic dinucleotides are described. These prodrugs are designed to specifically release the active cyclic dinucleotides in hydrogen peroxide-rich environments, a distinct biological feature observed in cancer cells as a result of oxidative stress. Efforts towards these compounds led to the successful synthesis of a cyclic dinucleotide compound containing allyl phosphotriester groups, which provides the opportunity for exploring an alternative localized release strategy employing biocompatible heterogenous transition metal catalysts.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
30 April 2022 |
| Date Type: |
Publication |
| Defense Date: |
13 January 2022 |
| Approval Date: |
25 October 2024 |
| Submission Date: |
18 January 2022 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
402 |
| 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: |
Macrocycles. Spiro compounds. Stereoselectivity. Oxygen heterocycles. STING. Cyclic dinucleotides. |
| Date Deposited: |
25 Oct 2024 19:13 |
| Last Modified: |
28 Oct 2024 12:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/42195 |
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