Cinchona alkaloid-derived primary amines have emerged as a privileged class of catalysts that is particularly useful for the activation of sterically encumbered carbonyl compounds. However, due to the structural complexity of these organocatalysts, it is non-trivial to explain the origin of asymmetric induction in most of the cinchona amine-catalyzed transformations reported to date. We have used quantum chemical computations to shed light on these fundamental problems, focusing on two classes of highly stereoselective enamine-activated transformations that are known, but unexplained, in the literature: (1) the a-fluorination of cyclic ketones reported by MacMillan,[1] and (2) the desymmetrizing intramolecular aldol condensation reported by List.[2] No stereochemical rationale has been proposed for any of these reactions. In this oral presentation, we present transition structure calculations and analyze the structural factors that contribute to the high levels of stereoselectivity of these reactions. We show how the origin of stereocontrol may be understood by considering well-defined cyclic transition structures comprising the substrate, the organocatalyst and the external reagent. The manner in which the ring conformations of the transition structures governs the sense and level of stereoselectivity is discussed in detail.[1] Kwiatkowski, P.; Beeson, T. D.; Conrad, J. C.; MacMillan, D. W. C., J. Am. Chem. Soc. 2011 , 133, 1738.[2] Zhou, J.; Wakchaure, V.; Kraft, P.; List, B., Angew. Chem. Int. Ed. 2008 , 47, 7656.

Theoretical modeling of stereoselective catalysis by Cinchona amines

248th National Meeting (2014)

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