Mechanism and Origins of Stereoselectivity in the Cinchona Thiourea- and Squaramide-Catalyzed Asymmetric Michael Addition of Nitroalkanes to Enones

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.

Bifunctional iminophosphorane catalysed enantioselective sulfa-Michael addition of alkyl thiols to alkenyl benzimidazoles

“…This mode of activation is consistent with the observed sense of enantioselectivity, and with earlier mechanistic proposals of Takemoto. Recent theoretical studies of Grayson and Houk have emphasized the importance of activation mode B in sulfa-Michael reactions promoted by Cinchona-derived catalysts 20. Our present results suggest that both activation modes may be operative, depending on catalyst and substrate, as originally hypothesized by Soós and I. Pápai 21…”

Comparison of Cinchona Catalysts Containing Ethyl or Vinyl or Ethynyl Group at Their Quinuclidine Ring

“…Since the strength of hydrogen bonding interactions plays an important role in H-bond organocatalysis [16,25,26,27], determination of p K a values could help understanding the mechanisms and catalytic activity, therefore, it can contribute the design of more efficient catalytic systems. In cases when deprotonation and/or hydrogen bonding are able to promote reactions or could increase enantioselectivity, knowing the p K a values of the corresponding groups is essential.…”

“…When bifunctional H-bond organocatalysts, such as cinchona-thioureas or squaramides were applied in Michael additions of 1,3-dioxo compounds to nitroalkenes, it was found [12,13,14,15,16] that the reaction can proceed by two mechanisms. In one of these mechanisms, the acidic NH groups (of thiourea or squaramide moieties) activate the enolate, while the protonated quinuclidine fixes the electrophile (Figure 1a).…”

Stereo‐ and Regioselective Construction of Spirooxindoles Having Continuous Spiral Rings via Asymmetric [3+2] Cyclization of 3‐Isothiocyanato Oxindoles with Thioaurone Derivatives

“…After the deprotonation of 1a by the tertiary amine moiety of the cinchona alkaloid, a hydrogen‐bonding interaction exists between 1a and the protonated tertiary amine moiety. As for substrate 2a , hydrogen bonding interactions [ 16–18 ] take place between the squaramide moiety of catalyst and the carbonyl group of 2a in transition state ( S )‐ TS1 . Thus, the energy of transition state ( S )‐ TS1 is lower than that of ( R )‐ TS1 by 5.4 kcal/mol.…”