Integrated Catalysis Opens New C-C Bond Formation Selectivity

  • Jonathan Latham

Student thesis: Phd

Abstract

The combination of multiple catalytic events into chemical transformations can allow a significant amount of molecular complexity to be introduced in an efficient manner. Of particular interest is the combination of biocatalysis with chemocatalysis, since such combinations can allow the selectivity inherent to enzymes to be exploited beyond the repertoire of reactions which enzymes can directly catalyse. Although an attractive prospect, differences in operating conditions and mutual deactivation often preclude the efficient combination of bioand chemo-catalysts. This thesis focuses on the combination of biocatalytic halogenation reactions with palladium-catalysed cross-coupling reactions. Aryl halides are useful compounds in their own right, with a significant number of pharmaceuticals and agrochemicals containing halogen atoms, as well as being versatile synthetic intermediates for Pd-catalysed cross-coupling reactions. Traditional halogenation methods are typically fraught with poor regioselectivity, often affording mixtures, and require deleterious reagents. The flavin-dependent halogenase (FlHal) enzymes have been demonstrated to be a viable alternative - catalysing the regioselective halogenation of a range of substrates using benign inorganic halide sources. It was therefore envisioned that combination of these enzymes with Pd-catalysed reactions could allow regioselective cross-coupling reactions. The utility of FlHals in synthesis is currently limited by poor enzyme productivity, thought to result from slow halogenation reactions combined with low enzyme stability. To address these issues, this thesis characterised a proposed FlHal from a thermophilic Streptomyces strain in the hope of finding more productive biocatalysts. In addition to exploring the stability and substrate scope of this enzyme, its crystal structure was also obtained and studied to rationalise the structural features which contribute to increased stability. A number of FlHals were also combined with Pd-catalysis to allow the regioselective arylation, vinylation and heteroarylation of several aromatic scaffolds. To overcome the mutual deactivation of each of the catalytic systems, a number of compartmentalisation strategies were explored to allow efficient combination of the two reactions into single pot transformations. Notably, halogenases of different regioselectivity were used to allow the selective activation of the indole C7, C6 and C5 positions - reactions which were beyond the scope of traditional CH activation approaches at the time. This rationale was subsequently extended to allow the regioselective cyanation of the indole nucleus and, by introduction of additional catalysts, the selective amidation of the indole C7 position. A number of attempts were also made to combine nitrile-hydrating enzymes with Cu- and Pd-catalysed C-N bond formation reactions to allow the atom economic synthesis of secondary amides and enamides.
Date of Award31 Dec 2017
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorJason Micklefield (Supervisor) & Michael Greaney (Supervisor)

Keywords

  • Monooxygenase
  • Integrated Catalysis
  • Flavin
  • One-pot
  • Enzyme
  • Chemocatalysis
  • Biocatalysis
  • Halogenase

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