Pyrazolidinones as templates in asymmetric catalysis

Enantioselective catalysis;Imines;Ions

Gould, Eoin ; Smith, Andrew David ; Smith, Andrew David

University:University of St Andrews

Department:Chemistry (School of)

关键词: Enantioselective catalysis;    Imines;    Ions;   

Others  :  https://research-repository.st-andrews.ac.uk/bitstream/handle/10023/3646/EoinGouldPhdThesis.pdf?sequence=3&isAllowed=y

来源: DR-NTU

【 摘 要 】

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 pyrazolidinonecatalysts 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 diastereoisomersand 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 thiscompound 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.