Abstract
We report density functional theory calculations that examine the mechanism and origins of stereoselectivity of Soós' landmark discovery from 2005 that cinchona thioureas catalyze the asymmetric Michael addition of nitroalkanes to enones. We show that the electrophile is activated by the catalyst's protonated amine and that the nucleophile binds to the thiourea moiety by hydrogen bonding. These results lead to the correction of published mechanistic work which did not consider this activation mode. We have also investigated the corresponding cinchona squaramide-catalyzed reaction and found that it proceeds by the same mechanism despite the differences in the geometry of the two catalysts' hydrogen-bond-donating groups, which demonstrates the generality of this mechanistic model.
Highlights
Cinchona alkaloids and their derivatives have been used extensively in organic synthesis.[1−4] The cinchona alkaloidderived thiourea catalysts, independently reported by the Chen,[5] Sooś,6 Connon,[7] and Dixon[8] groups in 2005, represent one of the most important discoveries in this field of catalysis
We have previously studied the cinchona urea-catalyzed asymmetric conjugate addition of aromatic thiols to cycloalkenones using density functional theory (DFT) and found that the electrophile was activated by a protonated amine and that the urea binds the nucleophile by hydrogen bonding.[15]
We have investigated the cinchona squaramide-catalyzed asymmetric Michael addition of nitroalkanes to enones (Scheme 2)[21] to examine the generality of this mechanistic model and to see if the differences in the geometry of the thiourea and squaramide hydrogen-bond-donating groups (Figure 1) changes the preferred mechanism
Summary
Cinchona alkaloids and their derivatives have been used extensively in organic synthesis.[1−4] The cinchona alkaloidderived thiourea catalysts, independently reported by the Chen,[5] Sooś ,6 Connon,[7] and Dixon[8] groups in 2005, represent one of the most important discoveries in this field of catalysis. Sooś ’ landmark reaction from 2005, the cinchona thioureacatalyzed asymmetric Michael addition of nitroalkanes to enones (Scheme 1),[6] has been the focus of computational studies.[12,13] the mechanism of this important reaction remains unclear. We have explored the mechanism and origins of stereoselectivity of Sooś ’ cinchona thiourea-catalyzed asymmetric Michael addition of nitroalkanes to enones using DFT calculations. Since the pioneering work by Rawal in 2008,17 chiral squaramides have been reported to catalyze many highly asymmetric reactions.[18−20] We report DFT calculations that examine the asymmetric Michael addition of nitroalkanes to enones but catalyzed by the corresponding cinchona squaramide reported by Yang and Du in 2010 (Scheme 2).[21] A common mechanism was found between these two cinchona-catalyzed reactions (mode B) despite the differences in the geometry of their hydrogen-bond-. Donating groups (Figure 1), demonstrating the generality of this mechanistic model
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