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Development of new cyclobutenone rearrangements and their application in target syntheses

Development of new cyclobutenone rearrangements and their application in target syntheses
Development of new cyclobutenone rearrangements and their application in target syntheses
Cribrostatin 6, is a natural product that has been shown to be active against cancers as well as being an antimicrobial agent. The mode of action is via reactive oxygen species generation, which cancer cells are particularly susceptible to. Cribrostatin 6, has been synthesised many times with the synthesis improving and simplifying with each iteration. We sought to use the approach developed by the Harrowven group to synthesise a series of analogues to understand and improve the activity of the ROS generating cribrostatin 6 analogues by adding substituents such as phenyl, 2-furanyl, 4-(tert-butyl)phenyl and 4-(trimethylsilyl)phenyl groups.

A second theme relates to an unusual thermal rearrangement of aminocyclobutenones. It was observed that aminocyclobutenones form 5H-furanones on thermolysis due to a previously unknown steric buttressing effect. Furthermore these aminocyclobutenones can undergo an unprecedented rearrangement that involves a metal free CH activation that leads to dihydrofuropyridinones. Use of an adjacent bulky substituent allows the reaction to proceed to the dihydrofuropyridinones in a concerted fashion at lower temperatures. Detailed herein is a study using silyl substituents as a bulky surrogate to allow further functionalisation of these interesting products in a protodesilyation, halodesilylation and palladium coupling reaction.

A third theme relates to the first total synthesis of alpkinidine. In an attempt to generate the key quinone function in this molecule, a colleague unexpectedly formed a 5H-furanone halting their planned synthesis. With the newly understood steric buttressing effect in mind we describe how we achieved the formation of the desired quinone by reducing the steric interaction of adjacent substituents. We then attempted to add the other two rings using well documented manganese(III) acetate mediated free radical chemistry.
University of Southampton
Wilson, Dharyl Charles
a64ee73e-0685-4aee-b96d-a43ec736fe33
Wilson, Dharyl Charles
a64ee73e-0685-4aee-b96d-a43ec736fe33
Harrowven, David C.
bddcfab6-dbde-49df-aec2-42abbcf5d10b

Wilson, Dharyl Charles (2018) Development of new cyclobutenone rearrangements and their application in target syntheses. University of Southampton, Doctoral Thesis, 296pp.

Record type: Thesis (Doctoral)

Abstract

Cribrostatin 6, is a natural product that has been shown to be active against cancers as well as being an antimicrobial agent. The mode of action is via reactive oxygen species generation, which cancer cells are particularly susceptible to. Cribrostatin 6, has been synthesised many times with the synthesis improving and simplifying with each iteration. We sought to use the approach developed by the Harrowven group to synthesise a series of analogues to understand and improve the activity of the ROS generating cribrostatin 6 analogues by adding substituents such as phenyl, 2-furanyl, 4-(tert-butyl)phenyl and 4-(trimethylsilyl)phenyl groups.

A second theme relates to an unusual thermal rearrangement of aminocyclobutenones. It was observed that aminocyclobutenones form 5H-furanones on thermolysis due to a previously unknown steric buttressing effect. Furthermore these aminocyclobutenones can undergo an unprecedented rearrangement that involves a metal free CH activation that leads to dihydrofuropyridinones. Use of an adjacent bulky substituent allows the reaction to proceed to the dihydrofuropyridinones in a concerted fashion at lower temperatures. Detailed herein is a study using silyl substituents as a bulky surrogate to allow further functionalisation of these interesting products in a protodesilyation, halodesilylation and palladium coupling reaction.

A third theme relates to the first total synthesis of alpkinidine. In an attempt to generate the key quinone function in this molecule, a colleague unexpectedly formed a 5H-furanone halting their planned synthesis. With the newly understood steric buttressing effect in mind we describe how we achieved the formation of the desired quinone by reducing the steric interaction of adjacent substituents. We then attempted to add the other two rings using well documented manganese(III) acetate mediated free radical chemistry.

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Dharyl Wilson Thesis - Development of New Cyclobutenone Rearrangements and their Application in Target Syntheses - Version of Record
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Published date: January 2018

Identifiers

Local EPrints ID: 422132
URI: http://eprints.soton.ac.uk/id/eprint/422132
PURE UUID: fd88dbcf-d8c5-4640-8941-b83ccd6fcb82
ORCID for David C. Harrowven: ORCID iD orcid.org/0000-0001-6730-3573

Catalogue record

Date deposited: 17 Jul 2018 16:30
Last modified: 29 Apr 2021 04:01

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Contributors

Author: Dharyl Charles Wilson
Thesis advisor: David C. Harrowven ORCID iD

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