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The chemoenzymatic preparation of optically active molecules
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Harris, Keith J. (1990) The chemoenzymatic preparation of optically active molecules. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3224705~S15
Abstract
This thesis describes the use of enzymes in organic synthesis and their application to produce optically active compounds, either by enantiospecific or enantioselective reactions.
Chapter two describes the enantioselective synthesis of a β-blocker, Betaxalol. Initial experiments to enantioselectively epoxidise a pro-chiral alkene precursor failed. However, methane monooxygenase (ex Methylococcus capsulatus (Bath)) epoxidised allyl bromide and allyl chloride, the allyl chloride produced was racemic. Microbiological reduction of α-chloroketone gave optically enriched α-chloroketone. The butanoate of the α-chloroketone was enzymatically resolved. However, other undesired hydrolysis reactions were occurring. Accordingly, a compound more closely related to Betaxalol was chosen for further investigation. A screen of ten enzymes revealed that racemic 3-[4-[2-(cyclopropylmethoxy)phcnyl]-l -chloro-2-acetoxypropane was enantioselectively hydrolysed by the lipase from Pseudomonas fluorescens (E=14). Substrate modification gave the corresponding butyrate as the optimised structure (E=35). Pseudomonas fluorescens catalysed esterification of the corresponding chlorohydrin, was attempted. The best acyl donor was vinyl acetate (E>100). Both enantiomers of
3- [4-[2-(cyclopropylmethoxy)phenyl]-l-chloro-2-acetoxypropane (>98%cc) were produced and converted in two steps into optically pure β-blocker. Reduction of the corresponding α-chloroketone was less successful.
Chapter three describes the synthesis of a protected form of 4-amino-2-oxobutanoic acid. Twenty yeasts were then screened for enantiospecific reduction of the ketone. The best yeast was Saccharomyces carlsbergensis ATCC 2345, which produced
(2S)-methyl-4-(benzyloxycarbonyloxy)-4-ami no-2-hydroxy butanoate (88%cc). The stereochemistry was determined by subsequent chemical conversion to (3S)-3-hydroxy-2-pyrrolidine.
Chapter four describes the yeast reduction of 4-(phenylthio)butan-2-onc and related ketones. Both (2R) and (2S), 4-(phenylthio)butan-2-ol (>98%ee) were produced by screening 68 yeast strains. Attempts to scale-up the yeast reduction arc described.
Chapter five describes the stereospccific hydrolysis of cis-3,6-diacetoxycyclohexene. 23 hydrolytic enzymes were screened. The Lipase P-30 (Pseudomonas sp.) produced
(+)-(3S,6R)-3-hydroxy-6-acetoxycyclohcxcne in 64% yield, 79%ec. The absolute stereochemistry was established by subsequent chemical conversion to (+)-(lS,6R)-7-oxabicyclo[4,3,0]non-2-cn-8-one.
Chapter six describes approaches to optically pure aziridine-2-carboxylates. Direct resolution of ethyl 3-phcnyl-lH-aziridine-2-carboxylate was attempted. The cis racemic pair was hydrolysed. The trans racemic pair could not be hydrolysed (9 enzymes screened). Resolution of ethyl 3-mcthyl-3-azido-2- acetoxybutanoate was more successfully. From a screen of 9 enzymes the lipase from Candida cylindracea was selected (E>100). Racemic ethyl 3-mcthyl-3-azido-2-hydroxybutanoatc was converted to ethyl 3,3,dimethyl-l H-aziridine-2-carboxylate.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QD Chemistry Q Science > QR Microbiology |
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Library of Congress Subject Headings (LCSH): | Organic compounds -- Synthesis, Ketones, Pseudomonas fluorescens, Saccharomyces carlsbergensis, Stereochemistry | ||||
Official Date: | 1990 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Department of Chemistry | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Crout, D. H. G. | ||||
Sponsors: | Science and Engineering Research Council (Great Britain) ; Smithkline Beecham ; University of Wisconsin-Madison ; University of Warwick | ||||
Extent: | xiv, 231 leaves : illustrations | ||||
Language: | eng |
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