Enantioselective Synthesis of Biologically Relevant Molecules Using Catalysis in Continuous Flow

Tseke, Kavnen (2022) Enantioselective Synthesis of Biologically Relevant Molecules Using Catalysis in Continuous Flow. Doctoral thesis, SETU Waterford.

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The overarching aim of this work was to engineer and develop a continuous flow process for the synthesis of 3-substituted-3-hydroxyoxindoles which are core moieties of biological importance. The first part of this work involved transferring the L-leucinol catalysed aldol reaction of isatin with acetone from batch to continuous flow for the first time. An initial batch solvent screening revealed neat acetone as the media best suited in flow. Solvents with Kamlet-Taft basicity (β)>0.6 and proticity (α) ≈ 0 had a higher solubility of isatin but poor reaction performance while solvents with β<0.2 and α< 0.6 performed excellently in the reaction albeit with poor isatin solubility. Addition of 10 equivalents of water improved the neat reaction to afford 94% yield in 93% ee at 20°C after 48 h. Having identified an ideal solvent in the batch screening, a PTFE tubing reactor was fabricated, and the identified optimal batch conditions transferred to flow and optimised. Complete conversions were obtained in 12 h residence time at 40°C without a loss in enantioselectivity. Other variants of isatin were also tested in batch and flow and in all cases, the reaction proceeded excellently with the flow reaction outperforming that in batch. Some isatin derivatives required a 4-fold dilution to achieve a solubility transferable to continuous flow, however, excellent yields and enantioselectivities were obtained in most cases. A second part of the substrate scope studies sought to examine the diastereoselective and regioselective potentials of the L-leucinol catalysed reactions of isatin with enolisable ketones for the first time. Reactions with symmetrical ketones, unsymmetrical ketones and cyclic ketones were carried out in batch and interestingly, high enantioselectivity and diastereoselectivity was observed with symmetrical ketones and cyclic ketones. Reactions with unsymmetrical ketones also proceeded smoothly but afforded two regioisomers indicating leucinol is a non-regioselective organocatalyst. Another major part of this work involved the use of aerosol jet printing and stereolithography (SLA) 3D printing for rapid prototyping of moulds which would be utilised for soft lithography fabrication of microfluidic devices. Moulds with the desired channels size (300 μm width and height) were printed using the SLA 3D printer, silanised and successfully used to fabricate PDMS based microfluidic devices. While reactions through our PDMS device were not successful, the proof of concept was demonstrated and could be extended to other replica moulding techniques which utilise polymers with better solvent and chemical resistant properties.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Enantioselective Synthesis, Biologically Relevant Molecules, Catalysis
Departments or Groups: *NONE OF THESE*
Divisions: School of Science > Department of Chemical and Life Sciences
Depositing User: Derek Langford
Date Deposited: 15 Sep 2022 10:54
Last Modified: 15 Sep 2022 10:54
URI: https://repository.wit.ie/id/eprint/3542

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