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Durham e-Theses
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The influence of fluorine substitution on some enzyme mediated reactions

Bridge, Colin Francis (1997) The influence of fluorine substitution on some enzyme mediated reactions. Doctoral thesis, Durham University.



The replacement of a hydrogen or hydroxy group with a fluorine atom is a popular strategy to alter the activity of biologically important molecules, as their similar sizes mean that such a replacement has little steric impact. The effect of fluorine substitution in a number of enzyme mediated processes has been investigated. 3-Fluorocyclohex-l-enylcarbonyl-CoA has been synthesised and the reaction with cyclohexenylcarbonyl-CoA reductase investigated. The fluorinated substrate has a comparable K(_m) value to that of the natural substrate but a V(_max) that is five times greater. A change in the rate-determining step of the reduction was also observed upon fluorine incorporation. The enzyme showed a small but significant stereochemical preference for the production of the axial isomer, consistent with an Anh-Eisenstein model for the transformation. The 6а and 6β isomers of benzyl fluoropenicillanate were synthesised and their methoxide-mediated hydrolyses were investigated. Competitive hydrolysis, using (^19)F NMR spectroscopy, demonstrated that the β isomer was hydrolysed preferentially. A frill kinetic analysis was undertaken, which furnished the rate and equilibrium constants. Monofluorinated enamines were treated in situ with a range a Michael acceptors to afford a variety of novel substituted a-fluoro ketones. 2-Fluorohexanal was synthesised from methyl hexanoate and was demonstrated to be a substrate for the enzyme transketolase with hydroxypyruvate. The enzyme reaction was monitored by (^19)F NMR spectroscopy. The enzyme showed a diastereoselectivity of 9:1 in the condensation of the aldehyde and hydroxypyruvate, and a self-condensation product was also produced. The enzymatic oxidation of the mono- and di-fluoromethylenephosphonate analogues of glycerol-3-phosphate was investigated at neutral pH using a co-factor recycling protocol. The reactions allowed for the first time the identification of the products of oxidation and demonstrated the lability of fluoride via non-enzymatic elimination and stoichiometric defluorination.

Item Type:Thesis (Doctoral)
Award:Doctor of Philosophy
Thesis Date:1997
Copyright:Copyright of this thesis is held by the author
Deposited On:13 Sep 2012 15:52

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