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Enantioenriched Piperidinyl Allylic Boronates: From Mechanism to Drug Discovery
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- Author / Creator
- Estaitie, Mohamad
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Functionalized piperidine rings are frequently found in a variety of alkaloids and pharmaceuticals attesting to the importance of this class of heterocycles in drug discovery. According to recent data, the piperidine ring is the most abundant heterocycle found in FDA approved drugs. Thus, gaining access towards enantioenriched piperidines through convenient and cost-effective methods is highly desirable. One approach to access such heterocycles is the use of enantioenriched alkyl boronic esters. Alkyl boronic esters have gained attention as versatile building blocks in organic transformations and drug discovery due to their low toxicity and configurational stability. This thesis focuses on the development and optimization of synthetic methodologies towards the synthesis of functionalized enantioenriched piperidines using chiral boronic ester intermediates. In addition, this thesis also focuses on the application of such intermediates in drug discovery. Chapter 2 describes a collaborative effort of a mechanistic study on the borylative migration reaction, which is a robust methodology previously reported by our group to access enantioenriched tetrahydropyran and piperidine derivatives. The study uses a combination of experimental and computational approaches to decipher the mechanistic pathway of this reaction. The aim of this project is gain insights about the reaction, which would be useful in expanding the scope of the borylative migration towards other heterocyclic systems. Since its discovery of the borylative migration, the synthetic applications of obtained products were limited to allylboration on aldehydes and Csp3–Csp2 Suzuki–Miyaura cross-coupling reactions. Chapter 3 of this thesis describes our recent efforts to expand the application of the piperidinyl allylic boronic intermediates towards a stereospecific Csp3–Csp3 cross-coupling reactions. This gives access to novel enantioenriched 2-substitued piperidines bearing a cinnamyl moiety. iii Chapter 4 focuses on a collaborative project for the application of the borylative migration reaction in drug discovery. The synthesis of vacquinol-1 analogs, potential drugs in the treatment of glioblastoma multiforme (GBM) is described. In addition, in vitro biological testing of these analogs against GBM cell lines is also presented.
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- Graduation date
- Fall 2022
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
- This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.