Thesis

Investigation of electrochemical methods for applications in pharmaceutical synthesis

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2022
Thesis identifier
  • T17271
Person Identifier (Local)
  • 201878322
Qualification Level
Department, School or Faculty
Abstract
  • In recent years, electrochemistry has re-emerged as a valuable method of organic synthesis. Replacing the need for chemical reagents, with electrons supplied directly from the electrodes of an electric circuit, can prevent the production of stoichiometric quantities of reaction waste and, in some cases, completely avoid the use of toxic reagents. Additionally, the ability of an electrical circuit to apply a precise oxidative or reductive potential directly to an organic substrate can provide new and innovative reaction manifolds that are inaccessible via traditional chemical means. Benzylic oxidation was initially targeted as an area where electrochemistry could overcome the need for super-stoichiometric quantities of transition metal oxidants. Investigation of direct and indirect methods of benzylic oxidation was carried out to find a method that could be used to conduct a ‘robustness screen’ of electrochemical oxidation. During this study, an unusual observation concerning a change in chemoselectivity upon the application of an alternating potential led to further investigation of the alternating potential function of the popular IKA ElectraSyn 2.0 device. This study showed the selectivity switch to be the result of an unexpected increase in the anodic potential during the negative phase of the alternating potential cycle. This behaviour was also shown to be general to the ElectraSyn, with publication of these findings enabling the manufacturer to develop a software update to allow the precise application of a constant and alternating potential, preventing possible erroneous experimental work by other users. The prevalence of nitrogen atoms in bioactive compounds makes their synthetic incorporation into drug molecules critically important during pharmaceutical research. As a result, the second part of this study has been focused on the development of novel electrochemical methods of nitrogen incorporation. Initial investigation in this area involved the development of a method to electrochemically reduce an imine to the corresponding amine followed by application to the electrochemical synthesis of α-deuterated amines. This work was further developed by utilising the α-amino radical intermediate derived from the cathodic reduction of imine species to perform a Minisci-type aminoalkylation of quinolines. The method was optimised and exemplified on a number of substrates, showing several distinct advantages over existing chemical approaches and multi-step routes. Finally, the method was applied to the aminoalkylation of a drug-like natural product to demonstrate its suitability for use as a method of late stage functionalisation during drug development.
Advisor / supervisor
  • Alder, Catherine M.
  • Kerr, William J.
  • Poole, Darren L.
Resource Type
Note
  • Previously held under moratorium in the Chemistry department (GSK) from 7th December 2022 until 20th March 2025.
DOI
Funder
Embargo Note
  • The digital version of this thesis is restricted to Strathclyde users only until 7th December 2027.

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