Thesis

Bridge-Substituted Bicyclo[1.1.1]pentanes

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2024
Thesis identifier
  • T18091
Person Identifier (Local)
  • 202051598
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • The saturation, conformational rigidity, and unique geometric and electronic properties of the bicyclo[1.1.1]pentane (BCP) scaffold have allowed it to emerge as a privileged bioisostere for alkynes, tert-butyl groups, and particularly aromatic rings over the past 25 years. This thesis describes new radical and polar strategies for functionalisation of the bridge positions of BCP derivatives, as potential replacements for ortho- or meta-substituted arenes. Chapter 1 introduces the importance of bioisosteres in contemporary medicinal chemistry, then outlines the ability of the BCP core to help “escape from flatland” and positively impact diverse properties of drug-like compounds. Synthetic approaches to bridge-functionalised analogues are then surveyed, with a discussion of the scope, benefits, and limitations of each method. The aims of this thesis are then presented. Chapter 2 describes the development of a photochemical decarboxylative Minisci-type reaction that allows divergent installation of nitrogen heterocycles. The scope of heterocycles and BCP partners is then exemplified, with over 30 compounds in this series synthesised. Mechanistic considerations of the reaction are briefly discussed, and the impact of the BCP core on the physicochemical properties of a representative example compared to those of its all-aromatic analogues is evaluated. An extension of the Minisci reaction to the bridge positions of the related 2-oxabicyclo[2.1.1]hexane motif is also presented. Chapter 3 describes studies towards the synthesis of BCP bridge ethers, initially through attempted photochemical decarboxylative C−O cross-coupling reactions, then subsequently through Buchwald−Hartwig/Ullmann-type cross-coupling reactions and a small range of other approaches. Chapter 4 describes the development of a lithium-halogen exchange reaction at the BCP bridge position, then examines the synthetic utility of the obtained organolithium species in enabling the installation of more than 20 functionalities previously unreported at this site. This includes the demonstration of catalytic C−C and C−N cross-coupling reactions via derived BCP organozinc reagents. A means of desymmetrising prochiral bridge-functionalised BCP derivatives, such as to control the absolute stereochemistry on the BCP core, is also presented. Chapter 5 describes the transfer of a metallaphotoredox trifluoromethylation procedure from the literature to the BCP core, then exemplifies the process on a small range of BCP partners. An initial result using similar chemistry also allows azidation of the BCP core. Chapter 6 summarises the outcomes of this study and provides a final perspective on the field. Chapter 7 provides experimental procedures and characterisation data for the synthesised compounds.
Advisor / supervisor
  • Measom, Nicholas D.
  • Murphy, John A.
  • Poole, Darren L.
Resource Type
Note
  • Previously held under moratorium in the Chemistry Department (GSK) from 24 May 2024 until 8 July 2026.
DOI
Funder
Embargo Note
  • This thesis is restricted to Strathclyde users only until 24 May 2029.

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