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Pyrazolidinones as templates in asymmetric catalysis
|Smith, Andrew David
|This thesis principally focuses on the development of a novel series of asymmetric iminium ion organocatalysts, based on the pyrazolidin-3-one template. Also described is the development of a novel asymmetric Steglich rearrangement with pyrazolyl carbonates. The pyrazolidin-3-one framework has been identified as a potentially effective new scaffold for iminium ion organocatalysis. The development of a synthetic route to racemic pyrazolidinone catalysts is outlined which allows for systematic variation of key substituents. The influence of these groups on reactivity and diastereoselectivity in the Diels-Alder reaction of (E)-cinnamaldehyde and cyclopentadiene is described and an optimised catalyst identified. A method for the resolution of a simple pyrazolidinone precursor was then investigated in order to access an enantioenriched catalyst for asymmetric reaction. Resolution was achieved by amide coupling to a chiral acid, chromatography to separate the subsequent diastereoisomers and acid cleavage. The initial enantioenriched catalyst gave modest enantioselectivity in the Diels-Alder reaction. The diastereoisomeric intermediates in the resolution process were themselves identified as active and enantioselective iminium ion organocatalysts. In general, one diastereoisomer was superior in terms of enantioselectivity, indicating a ‘matching’ of the two catalyst stereocentres. An optimised asymmetric diastereoisomeric catalyst derived from a trifluoromethyl-substituted pyrazolidinone and Cbz-protected proline gave good diastereo- and enantioselectivities in Diels-Alder reactions with a range of aryl aldehydes. Mechanistic investigations with this compound then found that fast ring-opening occurs under catalysis conditions creating a new chiral hydrazide which was catalytically active at catalyst loadings as low as 1 mol%. Also explored was the Steglich rearrangement of structurally related pyrazolyl carbonates. Rearrangement was observed with a range of Lewis base organocatalysts, with N-heterocyclic carbenes (NHCs) generally superior. Chiral NHCs were also effective in an asymmetric reaction, particularly with methyl substituted pyrazolyl carbonates.
|University of St Andrews
|Pyrazolidinones as templates in asymmetric catalysis
|PhD Doctor of Philosophy
|The University of St Andrews
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