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Title: Biotransformations with yeasts and their applications in organic synthesis
Author: Christen, Markus
ISNI:       0000 0001 3548 9430
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 1988
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This thesis describes the synthesis of a new chiral synthon via biotransformation and the applications of this chiron in organic synthesis. It was possible to reduce a variety of β-ketoesters with a range of yeast species to the corresponding β -hydroxyesters. We selected from these screening results methyl 4-(p-chlorophenylthio)-3-oxobutanoate as the substrate of choice and the two yeast strains Saccharomyces cerevisiae and Candida guilliermondii as the biocatalysts. Immobilisation of the yeasts proved to be a successful method for improving the yield and enantiomeric excess in the biotransformation, and we obtained the product methyl 4-(p-chlorophenylthio)-3-hydroxybutanoate in both enantiomeric forms, depending on the choice of the biocatalyst. S.cerevisiae, immobilised on alginate, gave the L-product in 60% yield and 80% ee, whilst C.guilliermondii afforded the D-product in 60% yield and 87% ee. Both enantiomers could be recrystallised to an optical purity of ee > 95%. We then proceeded to explore the reactivity pattern of our new chiron. We found that it was possible to protect the hydroxyl group with a variety of protecting groups under acid or base catalysed reaction conditions. We chose the tert-butyldimethylsilyl group as the most suitable one for our purposes. Hydrolysis of the protected ester, followed by conversion into the imidazolide and treatment with methyl magnesium malonate resulted in the formation of a new β-ketoester, which in turn could be deprotected with an overall yield of 68% to methyl 4-(p-chorophenylthio)-5-hydroxy-3-oxohexanoate. This ester was subsequently reduced with tetramethylammonium triacetoxyborohydride to the anti diastereomer and with methoxydiethylborane / sodium borohydride to the syn diastereomer. We succeeded therefore in synthesizing all four stereoisomers of methyl 6-(p-chlorophenylthio)-3,5-dihydroxyhexanoate in enantiomerically pure form. Additionally we found that it was possible to chlorinate the original β-hydroxyester at C-4 under radical reaction conditions. This allowed us to form a new carbon-carbon bond by treatment of the chlorinated product with a silylenolether under Lewis acid catalysis. Further manipulation of this addition product allowed the synthesis of 3-hydroxytetradecanoic acid with high enantiomeric excess. The alkylation at C-2 was easily achieved via the corresponding dioxanone by deprotonation and diastereoselective methylation.
Supervisor: Not available Sponsor: GlaxoSmithKline
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry