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Synthesis of oxetane and azetidine containing cyclic peptides
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Saunders, George J. (2020) Synthesis of oxetane and azetidine containing cyclic peptides. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3685640
Abstract
This thesis describes work towards the synthesis of small cyclic peptides by incorporation of turn-promoting 3-aminooxetane and 3-aminoazetidine units into the backbone. Functionalisation of the 3-aminoazetidine after macrocyclisation is also described.
Chapter 1 provides an introduction to cyclic peptides including their importance in medicinal chemistry, current synthetic methodologies towards the synthesis of head-to-tail cyclic peptides and an overview of work on the incorporation of oxetanes into peptides and proteins.
Chapter 2 describes the synthesis of oxetane modified cyclic peptides. The 3-aminooxetane unit was introduced into a series of tetra-, penta-, and hexapeptides using solution-phase coupling, and the macrocyclisation efficiency of these precursors assessed. Comparative studies with the parent peptides using isolated yield, product distribution and kinetic studies, including against other commonly used peptide modifications, demonstrate the value of the 3-aminooxetane as a motif to enhance the macrocyclisation of small peptides.
Chapter 3 explores the synthesis of azetidine modified cyclic peptides including late-stage functionalisation of the azetidine nitrogen after macrocyclisation. An approach exploiting conjugate addition and nitro group reduction was used to synthesise short linear peptides in solution, which showed improved cyclisation compared to the parent peptides. In contrast to the work with oxetanes, these cyclic peptides tolerated strongly acidic conditions required for side chain deprotection. A highly practical and general route towards azetidine modified cyclic peptides was demonstrated utilising Fmoc/tBu SPPS from pre-formed dipeptide building blocks.
Using Cbz for selective deprotection of the azetidine nitrogen by hydrogenation allowed for N-functionalisation by acylation, sulfonation or SNAr chemistries. In this way, biotin and fluorescent dyes could be conjugated to the cyclic peptide, as well as different azide functionalities. Insights into the structural impact of azetidine modification were gained by analysis of a crystal structure obtained from an azide functionalised derivative. Alternatively, a 2-propynyl carbamate could be installed early into the synthetic route and functionalised by CuAAC click chemistry post-cyclisation, enabling the synthesis of fluorescently conjugated cyclic peptides which could be visualised by confocal microscopy.
Chapter 4 provides detailed experimental procedures for the work carried out in Chapters 2 and 3.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QD Chemistry | ||||
Library of Congress Subject Headings (LCSH): | Cyclic peptides, Heterocyclic compounds -- Synthesis, Azides, Ring formation (Chemistry) | ||||
Official Date: | September 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 | ||||
Format of File: | |||||
Extent: | 299 leaves : illustrations | ||||
Language: | eng |
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