Optimisation of chemoenzymatic processes in asymmetric synthesis

Deasy, Rebecca E.

Optimisation of chemoenzymatic processes in asymmetric synthesis

dc.contributor.advisor	Maguire, Anita R.
dc.contributor.author	Deasy, Rebecca E.
dc.contributor.funder	Irish Research Council for Science Engineering and Technology	en
dc.contributor.funder	Eli Lilly and Company, United States	en
dc.date.accessioned	2013-02-26T13:00:04Z
dc.date.available	2015-12-19T05:00:05Z
dc.date.issued	2012-09
dc.date.submitted	2013-01-11
dc.description.abstract	This thesis describes the optimisation of chemoenzymatic methods in asymmetric synthesis. Modern synthetic organic chemistry has experienced an enormous growth in biocatalytic methodologies; enzymatic transformations and whole cell bioconversions have become generally accepted synthetic tools for asymmetric synthesis. Biocatalysts are exceptional catalysts, combining broad substrate scope with high regio-, enantio- and chemoselectivities enabling the resolution of organic substrates with superb efficiency and selectivity. In this study three biocatalytic applications in enantioselective synthesis were explored and perhaps the most significant outcome of this work is the excellent enantioselectivity achieved through optimisation of reaction conditions improving the synthetic utility of the biotransformations. In the first chapter a summary of literature discussing the stereochemical control of baker’s yeast (Saccharomyces Cerevisae) mediated reduction of ketones by the introduction of sulfur moieties is presented, and sets the work of Chapter 2 in context. The focus of the second chapter was the synthesis and biocatalytic resolution of (±)-trans-2-benzenesulfonyl-3-n-butylcyclopentanone. For the first time the practical limitations of this resolution have been addressed providing synthetically useful quantities of enantiopure synthons for application in the total synthesis of both enantiomers of 4-methyloctanoic acid, the aggregation pheromone of the rhinoceros beetles of the genus Oryctes. The unique aspect of this enantioselective synthesis was the overall regio- and enantioselective introduction of the methyl group to the octanoic acid chain. This work is part of an ongoing research programme in our group focussed on baker’s yeast mediated kinetic resolution of 2-keto sulfones. The third chapter describes hydrolase-catalysed kinetic resolutions leading to a series of 3-aryl alkanoic acids. Hydrolysis of the ethyl esters with a series of hydrolases was undertaken to identify biocatalysts that yield the corresponding acids in highly enantioenriched form. Contrary to literature reports where a complete disappearance of efficiency and, accordingly enantioselection, was described upon kinetic resolution of sterically demanding 3-arylalkanoic acids, the highest reported enantiopurities of these acids was achieved (up to >98% ee) in this study through optimisation of reaction conditions. Steric and electronic effects on the efficiency and enantioselectivity of the biocatalytic transformation were also explored. Furthermore, a novel approach to determine the absolute stereochemistry of the enantiopure 3-aryl alkanoic acids was investigated through combination of co-crystallisation and X-ray diffraction linked with chiral HPLC analysis. The fourth chapter was focused on the development of a biocatalytic protocol for the asymmetric Henry reaction. Efficient kinetic resolution in hydrolase-mediated transesterification of cis- and trans- β-nitrocyclohexanol derivatives was achieved. Combination of a base-catalysed intramolecular Henry reaction coupled with the hydrolase-mediated kinetic resolution with the view to selective acetylation of a single stereoisomer was investigated. While dynamic kinetic resolution in the intramolecular Henry was not achieved, significant progress in each of the individual elements was made and significantly the feasibility of this process has been demonstrated. The final chapter contains the full experimental details, including spectroscopic and analytical data of all compounds synthesised in this project, while details of chiral HPLC analysis are included in the appendix. The data for the crystal structures are contained in the attached CD.	en
dc.description.status	Not peer reviewed	en
dc.description.version	Accepted Version	en
dc.format.mimetype	application/pdf	en
dc.identifier.citation	Deasy, R. E. 2012. Optimisation of chemoenzymatic processes in asymmetric synthesis. PhD Thesis, University College Cork.	en
dc.identifier.uri	https://hdl.handle.net/10468/993
dc.language.iso	en	en
dc.publisher	University College Cork	en
dc.relation.uri	http://www.sciencedirect.com/science/article/pii/S0957416610008608
dc.relation.uri	http://pubs.acs.org/doi/abs/10.1021/jo102148p
dc.relation.uri	http://pubs.rsc.org/en/content/articlelanding/2011/CE/c1ce06320k
dc.rights	© 2012, Rebecca E. Deasy	en
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/3.0/	en
dc.subject	Biocatalysis	en
dc.subject	3-arylalkanoic acids	en
dc.subject	Baker's yeast	en
dc.subject	Nitroaldol reaction	en
dc.subject.lcsh	Asymmetric synthesis	en
dc.title	Optimisation of chemoenzymatic processes in asymmetric synthesis	en
dc.type	Doctoral thesis	en
dc.type.qualificationlevel	Doctoral	en
dc.type.qualificationname	PhD (Science)	en