ISBN 9783843917803

978-3-8439-1780-3, Reihe Organische Chemie

Florian Bächle
Determining the Enantioselectivity of Chiral Catalysts – Mass Spectrometry as a Mechanistic and Screening Tool

299 Seiten, Dissertation Universität Basel (2014), Softcover, A5

Zusammenfassung / Abstract

This thesis is focused on the application of ESI-MS as a screening method and mechanistic tool for organocatalyzed reactions. In previous studies cationic metal complexes or iminium ions were the key intermediates to be detected by ESI-MS analysis. Due to the high sensitivity of ESI-MS for ionic species these intermediates were easily detected even at the very low concentrations commonly present in a catalytic cycle. However, processes with neutral intermediates are of course very common, especially in organocatalysis, and therefore we started to focus on such reactions to further broaden the scope of the screening method. The organocatalyzed aldol reaction represents a very interesting process in this context, as this transformation proceeds via neutral enamine intermediates in the selectivity-determining step. These intermediates could be protonated in solution to allow for ESI-MS monitoring. Within this thesis, the synthesis of suitable mass-labeled, quasienantiomeric aldol products is shown in Chapter 2. Unforeseen complications, encountered with the ESI-MS screening of neutral intermediates are discussed in detail. Though, a general ESI-MS screening protocol for the organocatalyzed aldol reaction was still successfully developed. For the first time, additives were applied to the screening to overcome certain limitations. Moreover, screening of additive effects was elaborated, which further extends the reaction portfolio. Another transformation for the ESI-MS screening of enantiopure catalysts is the phosphine-catalyzed Morita-Baylis-Hillman reaction. For this process, not only are new selective catalysts still required, the reaction also proceeds via zwitterionic phosphorus intermediates, which were not investigated by ESI-MS thus far. The preliminary ESI-MS results and the identification of potential mass-labeled Morita-Baylis-Hillman products are presented in Chapter 3. The potential of the ESI-MS back reaction screening to answer mechanistic questions is highlighted in Chapter 4. Catalytic intermediates and the enantioselectivity-determining step were identified in the secondary amine-catalyzed conjugate addition of aldehydes to form nitroolefins. The ESI-MS-based determination of the enantioselectivity of racemic catalysts is further elaborated in Chapter 5. A screening protocol and a straightforward synthesis of racemic pyrrolidine and isoindoline-based organocatalysts were developed and applied to organocatalyzed Michael additions.