Thesis

Iridium-catalysed hydrogen isotope exchange of pharmaceutically-relevant sulfoximines and selective fragment coupling of two unactivated alcohols

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2025
Thesis identifier
  • T17217
Person Identifier (Local)
  • 202065419
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Chapter 1 Deuterium- and tritium-labelled pharmaceutical candidates have become invaluable for in vivo and in vitro studies conducted in both a preclinical and clinical context. The preparation of these deuterium, or tritium, containing molecular architectures has been largely enabled by transition metal-catalysed hydrogen isotope exchange. Within this field, work in our laboratory has led to the design of a suite of iridium(I) Nheterocyclic carbene complexes tailored towards the late-stage functionalisation of C(sp2 )–H sites located within aromatic and heteroaromatic systems ortho to a Lewis basic directing group. Within this chapter, we describe the expansion of our ortho-directed labelling strategy to the sulfoximine functional group. Extending from this, a method for the straightforward prediction of the outcome of the arene functionalisation process was developed. Moreover, we have uncovered a novel C–H activation pathway at challenging to label S-methyl C(sp3 )–H centres. The generality of our catalytic systems is demonstrated through the successful delivery of isotopic substituents into high-complexity substrates. Chapter 2 Metal-catalysed allylic substitution has emerged as a leading technology for the construction of carbon–carbon and carbon–heteroatoms bonds at C(sp3 )-centres of allylic electrophiles. However, within this arena highly substituted allylic frameworks are seldom used. In recognition of this, this section of this thesis describes development of a method to directly couple unactivated highly substituted allylic electrophiles and alcohols, to form ether products. Through use of a catalyst design plan an optimal pre-catalyst was identified for an iridium-catalysed etherification protocol that operates under hydrogen activation. Following this, mechanistic understanding of this transformation was used to develop another etherification system which utilises an acid additive, in place of the hydrogen atmosphere. To accelerate the discovery and development of the acid additive system, a highthroughput screening approach was utilised to enable the rapid identification of promising acid additives. Preface Research within modern medicinal chemistry has been devoted to the generation and diversification of novel frameworks in the pursuit of previously elusive molecular solutions for high value targets. Among these motifs, sulfoximines have risen to prominence within the pharmaceutical industry. We therefore envisioned that our range of iridium(I) carbene precatalysts could be programmed to permit access to an unprecedented collection of isotopically-enriched pharmaceutically relevant free and N-functionalised sulfoximine architectures, through a synergistic experimentally and computationally guided approach. Through this approach existing pre-catalysts that our group have previously developed were computationally screened to identify an appropriate hydrogen isotope exchange catalyst for our targeted transformation. From this, an ortho-directed labelling strategy mediated via the sulfoximine functional group and a complementary system capable of labelling C(sp3 )–H centres located at S-methyl position were established. Following completion of the first project focus was placed on showcasing the versatile nature of our iridium(I) pre-catalyst range through expansion of their use to other areas of transitionmetal catalysis. Accordingly, we targeted the direct functionalisation of highly substituted unactivated allylic alcohols to provide access to a range of products substituted at C(sp3 )- centres, given the statistical correlation between the degree of carbon saturation and the presence of stereogenic centres featured in medicinal candidates with clinical success. More specifically, the establishment of a system that can directly couple allylic electrophiles and alcohols, to form ether products was pursued. To achieve this, we used a catalyst design plan to tune our pre-catalyst range to promote this allylic substitution type transformation, where we moved away from the electron rich variants of our pre-catalysts that are used in the hydrogen isotope exchange of various molecules. Collectively, the second chapter of this report outlines the broadening of the utility of our laboratories iridium(I) pre-catalyst range through the development of an iridium-catalysed fragment coupling protocol.
Advisor / supervisor
  • Kerr, William
Resource Type
DOI
Date Created
  • 2024
Funder
Embargo Note
  • This thesis is restricted to Strathclyde users only until 12th February 2030.

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