King, Alexandra Clare;
(2021)
Biocatalytic Molecular Assembly Utilising Ene-Reductases and Transaminases.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
With a growing interest in the pharmaceutical, fine chemical and agrochemical industry for environmentally benign and sustainable syntheses, biocatalysis has emerged as a forerunner in the field of green chemistry. Significant advantages over traditional chemical routes have been demonstrated, including high regio- and stereoselectivity under mild conditions. Ene-reductases (ERs) perform the asymmetric reduction of activated alkene substrates. Operating via a stereospecific [2H] trans-reduction mechanism with high regio-, and stereospecificity, they are a powerful tool in the design of asymmetric synthetic pathways. Transaminases (TAms) mediate the enantioselective transfer of an amino group from an amine donor to a keto acceptor, generating an optically active amine. As enantiopure amines are valuable synthons, TAms present an efficient means for their preparation. In this PhD, the application of ERs and TAm in a biocatalytic cascade towards the molecular assembly of amino alcohols from unsaturated α-hydroxyketones was investigated. Chiral amino alcohols are an important and prevalent structural motif in value-added synthons and bioactive pharmaceuticals. Therefore, the development of an ER-TAm biocatalytic cascade for their molecular assembly represents a significant advancement in the field of green chemistry. Moreover, this work represents the first biocatalytic means of furnishing diastereomerically enriched amino alcohols. In this PhD the potential of ERs was explored via substrate walking strategies using aromatic aldehyde, ketone and α-hydroxyketone substrates, with the systematic optimisation of assay parameters. The application of TAms with α-hydroxyketone derivatives was subsequently investigated for the molecular assembly of optically pure amino alcohols on a preparative scale via a one-pot ER-TAm cascade. Chiral amino alcohols were afforded in 30% and 32% isolated yields with further reaction providing chiral 2-aminooxazoles in 93:7 and 97:3 dr. Finally, to further demonstrate the use of ERs in synthesis, their use in the production of chiral fluorinated compounds was explored. With an efficient means for the production of chiral fluorinated compounds new classes of pharmaceuticals may be discovered.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Biocatalytic Molecular Assembly Utilising Ene-Reductases and Transaminases |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10138496 |
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