2015 Beckman Symposium   

Alexander Yeh

Presentation Date:

Alexander Yeh

18 - Origins of Stereoselectivity in Cinchona Alkaloid-Primary Amine-Catalyzed Intermolecular Aldol Reactions

University of California, Los Angeles

Chemistry and Biochemistry

Organocatalysis, or the use of small organic compounds to accelerate reactions, has recently exploded in popularity. Organocatalysts are able to perform reactions with a high degree of stereocontrol and can provide an alternative to transition-metal-mediated chemistry. Cinchona alkaloid derivatives form a privileged class of organocatalysts for a wide variety of reactions, especially derivatives containing a primary amine which readily perform covalent catalysis. Unfortunately the origins of stereocontrol in many of these reactions are yet to be elucidated, even in such well studied mechanisms as the Aldol reaction. Here the origins of stereoselectivity in an organocatalyzed intermolecular aldol reaction are computationally explored using density functional theory. Specifically we model the cinchona alkaloid-derived primary amine-catalyzed aldol condensation of substituted benzaldehydes and cyclic ketones, first reported by Zheng et al. (Org. Biomol. Chem. 2007, 5, 2913-2915.). The stereodetermining transition state features concerted C-C bond formation and proton transfer from the quinuclidinium N+_H bond of the catalyst moiety to the acceptor carbonyl oxygen, thus forming a hydrogen-bonded nine-membered ring. The conformations of this ring resemble the conformations of eight membered rings, and we elucidate the relationship between stereocontrol and conformations of the cyclic transition state.

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