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Title: Applications of biocatalysts in the resolution of chiral organometallic compounds
Author: Henderson, Christine Mary
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 1988
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The aim of this thesis was to resolve fully a racemic organometallic complex, using a hydrolytic enzyme as the resolving agent. This was to demonstrate the vast range of substrates that biocatalysts will react with in a specific fashion and to provide a unique example of an enzyme recognising and differentiating between the two enantiomers of a molecule showing planar chirality. Irontricarbonyl-protected 2.4-dienes were chosen as the initial target molecules. Methyl sorbate irontricarbonyl was found not to be a substrate for PLE, neither in aqueous nor in organic media. Irontricarbonyl (2,4-hexadien-1-ol) acetate was shown to be a substrate for both esterases and lipases. The biocatalyst most effectively catalysing this hydrolysis in terms of rate and enantioselectivity was PPL, which gave a maximum of 43% e.e. when the reaction was conducted in an aqueous environment of pH 7 containing 10% MeOH. 2-Carboethoxy-1,3-butadiene irontricarbonyl and its corresponding acetate derivative were both found to be suitable enzyme substrates. 2-Acetoxy-methyl-butadiene irontricarbonyl was selectively hydrolysed to give the deprotected alcohol in a maximum of 40% e.e. This was achieved using the lipase Aspergillus niger as the biocatalyst in an aqueous media of pH 7. The e.e. was determined by 31P nmr spectroscopy of a phospholane derivative of the optically active alcohol. 2-Carboethoxy-1,3- butadiene irontricarbonyl was selectively hydrolysed by PLE in aqueous media of pH 7 containing 20% MeOH to give the corresponding acid in 85% e.e. Optically active 2-carboxy-1,3-butadiene irontricarbonyl was upon one recrystallisation gained in 100% e.e. The e.e. was verified by 1H mnr spectroscopy of an amide derivative of the optically pure acid, and its absolute configuration was determined by X-Ray structure analysis and by comparison of its cd. The second type of organometallic complexes screened for enzyme-substrate feasibility were the ferrocenes. 1,1’-Ferrocenedicarboxylic acid dimethyl ester was shown to be a very non-ideal substrate, giving a mixture of mono- and di-acids as the reaction products. α-Methylferrocenecarboxylic acid methyl ester was not an enzyme substrate in either aqueous nor organic media. α -Methylferrocenemethyl acetate decomposed in aqueous conditions to give the corresponding α-methylferrocenemethyl cation, yet in organic media was proved to be an adequate lipase substrate. Studies of the comparative rates and selectivities of lipases either free in reaction media or immobilised on Biofix were carried out for the lipase- catalysed transesterification of α-methylferrocenemethyl butyrate with 1-heptanol in iso-octane at 40°C. This showed that the rate of reaction and selectivity of the lipase varied dramatically as to which condition was used. In the case of both A. niger and R. javanicus, the lipase free in solution remained inactive whereas the lipase immobilised on Biofix catalysed the reaction rapidly and non-selectively. For PPL, the act of immobilising the lipase on Biofix reversed its enantioselectivity. The exception to this was CCL, which free in solution gave the highest e.e. of 50%. The e.e. was determined by 1H nmr spectroscopy of α-methylferrocenemethyl aldehyde in the presence of chiral solvating agent 2,2,2-trifluoro-1-(9-anthryl) ethanol.
Supervisor: Not available Sponsor: Science and Engineering Research Council ; Glaxo Group Research Limited
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry