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Combinatorial organocatalyst development and screening of conjugate additions

Fleischer, Ivana. Combinatorial organocatalyst development and screening of conjugate additions. 2010, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_9119

Abstract

Diverse approaches to the discovery of new organocatalysts were examined. A novel screening method based on mass-spectrometric detection of catalytic intermediates was applied to the organocatalyzed Michael reaction of malonates to enals. Based on the principle of microscopic reversibility, it is possible to determine the enantioselectivity of a catalyst by screening the intermediates in the retro-Michael reaction of a pair of quasienantiomeric Michael adducts.
After establishing the appropriate conditions for the retro-reaction and for the mass-spectrometric measurement, the ESI-MS (electrospray ionization mass spectrometry) screening of different organocatalysts was conducted. The selectivity of the catalysts was determined without time-consuming purification and analysis of the products. The results obtained by the screening correlated to the enantioselectivities in the preparative reaction.
The method was successfully extended to the screening of catalyst mixtures. A crude mixture of six catalysts synthesized in one batch was subjected to mass-spectrometric screening. The most selective catalyst was easily identified and used for the optimization of the preparative Michael addition. In addition, mechanistic studies provided insights into the action mode of secondary amines as catalysts.
An alternative approach towards the development of new catalysts was based on self-assembled catalyst constituting of two parts connected by hydrogen bonds. The structure comprised a proline-derived unit for the activation of a carbonyl compound and a pyridine derivative as an additive, which can provide steric hindrance or activate the other reaction partner. The enamine-catalyzed 1,4-addition of ketones to nitroolefins was chosen as a test reaction. The first generation proline amide-derived catalyst displayed poor activity and selectivity. However, the formation of self-assembled species was indicated by enhanced or reversed selectivity and by their detection with ESI-MS. Improvements in both activity and selectivity were achieved with the second generation catalyst. In principle, it was shown that the additives affect the outcome of the reaction.
Furthermore, ESI-MS was also used for mechanistic investigations of the Michael addition of aldehydes to enones and of the Morita-Baylis-Hillman reaction.
Advisors:Pfaltz, Andreas
Committee Members:Wennemers, Helma
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Synthetische organische Chemie (Pfaltz)
Item Type:Thesis
Thesis no:9119
Bibsysno:Link to catalogue
Number of Pages:230 S.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:41
Deposited On:04 Aug 2010 13:37

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