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Readily accessible sp3-rich cyclic hydrazine frameworks exploiting nitrogen fluxionality
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Dean, Conor (2020) Readily accessible sp3-rich cyclic hydrazine frameworks exploiting nitrogen fluxionality. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3518286~S15
Abstract
This thesis describes work on the asymmetric synthesis of orthogonally protected cyclic hydrazines, their subsequent functionalization and the study of their structure, to examine their potential as drug-like scaffolds.
Chapter 1 is an introduction to cyclic hydrazines, including a discussion of their relevance to medicinal chemistry as sp3 -rich scaffolds. It includes a summary of previous synthetic methodologies that have been developed to access cyclic hydrazines.
Chapter 2 describes the synthesis of orthogonally protected cyclic hydrazines. Initially a synthetic methodology is developed for the synthesis of orthogonally protected diazetidines. The first method explored ring opening of epoxides with hydrazine nucleophiles. The second, more general method, is based on the Asymmetric Transfer Hydrogenation of aryl ketones, which was successful across a range of ring sizes and substitution patterns. Twenty-eight examples were synthesised, including 4- to 7-membered rings in up to 99% ee.
Chapter 3 is focused on the deprotection and subsequent functionalization of these cyclic hydrazine scaffolds. Initially the functionalisation of pyrazolidines was explored, and suitable conditions for Buchwald-Hartwig couplings were developed using high throughput screening. Derivatisation was subsequently expanded to include acylation and reductive amination reactions and was also shown to be effective across all the ring sizes synthesised in chapter 2.
Chapter 4 describes the study of the 3D structure of the cyclic hydrazine scaffolds. XRD, PMI plots and NMR indicated a preference for the anti, anti conformation in the solid state and in solution. VT NMR was used to determine if interconversion to other conformational isomers was possible through N-inversion, analysis of one system provided evidence this was possible.
Chapter 5 details possible future directions for this work and chapter 6 contains the experimental procedures and characterisation for the novel compounds synthesised in chapters 2 and 3.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QD Chemistry | ||||
Library of Congress Subject Headings (LCSH): | Hydrazines, Molecular crystals, Nuclear magnetic resonance, Pharmaceutical chemistry | ||||
Official Date: | May 2020 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Department of Chemistry | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Shipman, Michael | ||||
Sponsors: | University of Warwick ; Eli Lilly and Company | ||||
Format of File: | |||||
Extent: | 241 leaves : illustrations (some colour) | ||||
Language: | eng |
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