Biocatalysis in organic synthesis

Foley, Aoife M.

Restricted to everyone for five years. Restriction lift date: 2024-02-04T09:55:59Z

Biocatalysis in organic synthesis

dc.check.chapterOfThesis	1, 5
dc.check.date	2024-02-04T09:55:59Z
dc.check.embargoformat	Apply the embargo to the e-thesis on CORA (If you have submitted an e-thesis and want to embargo it on CORA)	en
dc.check.info	Restricted to everyone for five years	en
dc.check.opt-out	No	en
dc.check.reason	This thesis is due for publication or the author is actively seeking to publish this material	en
dc.contributor.advisor	Maguire, Anita R.	en
dc.contributor.author	Foley, Aoife M.
dc.contributor.funder	Science Foundation Ireland	en
dc.date.accessioned	2019-02-05T09:55:59Z
dc.date.issued	2019
dc.date.submitted	2018
dc.description.abstract	The first chapter provides an overview of the use of biocatalysis for the synthesis of pharmaceutical intermediates and natural products. This review focuses, in particular, on the impact of recent developments in technologies which enable the increased use of biocatalysts. These developments include: • the immobilisation of biocatalysts to enhance stability and ease of use, and enabling use in combination with metal and organocatalysts leading to dynamic kinetic resolution, as well as in continuous flow. • discovery and development of novel enzymes using molecular biology for enzyme engineering and metagenomics. The second chapter describes the lipase-mediated kinetic resolution of 2-phenylalkanols by tuning the steric properties of the acyl group to control the efficiency and selectivity of the resolution. In contrast to literature reports, efficient resolution was achieved using short-chain acyl groups through careful process control and substrate modification. The effect of increased steric demand at the stereocentre was also explored. Chapter three describes proof of concept that a hydrolase-catalysed dynamic kinetic resolution of a lactol is possible. By taking advantage of the spontaneous racemisation of the unreacted starting material, the dynamic kinetic resolution was carried out without the need for a separate racemisation catalyst. While the kinetic resolution was effective in a model system, the biotransformation was inhibited by the introduction of a second, remote stereocentre. Chapter four describes a dynamic kinetic resolution of synthetically versatile nitroalcohols by combination of a lipase-mediated resolution and the reversible intramolecular nitroaldol (Henry) reaction. Significant challenges in effecting the combination of the base-mediated racemisation step and the lipase-mediated resolution step were encountered. Reaction engineering allowed design of a sequential one-pot reaction system which furnished the products with excellent enantioselectivity, and good diastereoselectivity. Chapter five describes the use of novel transaminases in the kinetic resolution of model amine substrates and pharmaceutical intermediates by oxidative deamination, including exploration of the substrate scope of these novel biocatalysts. While transaminase-mediated reductive amination is an attractive method for asymmetric synthesis of chiral amines, the reductive amination is generally thermodynamically disfavoured. Preliminary investigation of approaches to favour the reductive amination is described. The final chapter contains the full experimental details, including spectroscopic and analytical data of all the compounds synthesised in this project; details of chiral phase HPLC analysis are included in the appendix.	en
dc.description.status	Not peer reviewed	en
dc.description.version	Accepted Version
dc.format.mimetype	application/pdf	en
dc.identifier.citation	Foley, A. M. 2019. Biocatalysis in organic synthesis. PhD Thesis, University College Cork.	en
dc.identifier.endpage	234	en
dc.identifier.uri	https://hdl.handle.net/10468/7431
dc.language.iso	en	en
dc.publisher	University College Cork	en
dc.relation.project	info:eu-repo/grantAgreement/SFI/SFI Research Centres/12/RC/2275/IE/Synthesis and Solid State Pharmaceutical Centre (SSPC)/	en
dc.rights	© 2019, Aoife M. Foley.	en
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/3.0/	en
dc.subject	Biocatalysis	en
dc.subject	Enantioselective synthesis	en
dc.thesis.opt-out	false
dc.title	Biocatalysis in organic synthesis	en
dc.type	Doctoral thesis	en
dc.type.qualificationlevel	Doctoral	en
dc.type.qualificationname	PhD	en
ucc.workflow.supervisor	a.maguire@ucc.ie