Stereodivergent Inverse Electron-Demand Diels–Alder Reactions Enabled by Modification of Prolinol-Derived Catalysts

Access to the full array of stereoisomers of molecules bearing multiple stereocenters from the same substrates is an enduring challenge in asymmetric synthesis. In the ideal scenario, stereodivergence is achieved using a single-catalyst system, where a minimal modification of the catalyst enables access to both diastereoisomers, while exploiting identical activation modes. Here, we applied this strategy by a simple modification of a prolinol-derived catalyst in fully stereodivergent, enamine-mediated inverse electron-demand Diels-Alder reactions of aldehydes with electron-deficient dienes. Modulation of the bulkiness of the β'-substituent of the prolinol catalyst proved key to achieving diastereodivergence, allowing for the formation of both diastereoisomers with excellent enantioselectivity. First, it is shown by using enantiomers of the catalysts that all four stereoisomers of the cycloadduct can be obtained, followed by extending the reaction to optically active aldehydes, thereby allowing for the selective formation of all eight stereoisomers. The general scope of the inverse electron-demand Diels-Alder reaction proceeds in high to excellent yields and diastereoselectivity, and enantioselectivities up to >99% ee. Computational and experimental studies revealed that stereodivergence originates from a catalyst-dependent mechanistic dichotomy. Surprisingly, DFT calculations reveal that one catalytic system enforces diastereocontrol during the initial C-C bond-forming event, while the other, having increased steric bulk, perturbs the elimination kinetics, rendering downstream catalyst elimination stereodetermining under Curtin-Hammett control. The role of the catalyst for controlling the stereochemical outcome of the computationally proposed mechanisms for the inverse electron-demand Diels-Alder reaction was supported by a series of experiments and the isolation of a catalyst-bound adduct.