Development of new biocatalytic routes to pharmaceutical intermediates: a case study on ticagrelor

UoM administered thesis: Phd

  • Authors:
  • Katharina Hugentobler

Abstract

The research carried out within this thesis was aimed at the development andimplementation of a biocatalytic route towards Ticagrelor, a platelet-aggregationinhibitor. A bio-retrosynthetic consideration of the target compound yielded differentpossible strategies, which were analysed in terms of enantioselectivity and efficiency.The ultimate goal was to generate a biocatalyst specifically tailored to the startingmaterial to yield the target compound in high optical purity and conversion. Differentapproaches to the chemoenzymatic generation of the cyclopropyl subunit (cf figure) inenantiomerically pure form were proposed and tested. The lipase from Thermomyceslanuginosus proved to be the most selective and active enzyme tested and was used asa model enzyme, initially yielding an E of 76 at a conversion of 50% after 48h. Throughboth reaction engineering and rational protein design approaches the time to attain50% conversion could be reduced to 24 h while the enantioselectivity of the processincreased to 100. Moreover, in a rational protein design approach different residues inthe lid of the lipase were identified through analysis of the resolved crystal structuresand subsequently mutated in order to investigate the influence of these residues onthe overall performance of the lipase towards the target biotransformation. Mutationson Asn88 resulted in the inactivation of the enzyme while an Asp57Asn mutationresulted in a more active enzyme. Ultimately, this research has contributed to makingthe synthetic route towards Ticagrelor more environmentally sustainable, diminishingthe need for the use of toxic, unsustainable and sterically demanding auxiliaries, aswell as the amount of waste produced. The principles of green chemistry have beenapplied to the case studied. The synthetic route towards a key fragment of Ticagrelorhas been significantly shortened using a biotransformation with an enzyme that can berecycled and employed in catalytic quantities

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Original languageEnglish
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Award date1 Aug 2015