Stereoselectivity in (Acyloxy)borane-Catalyzed Mukaiyama Aldol Reactions

The origin of diastereo- and enantioselectivity in a Lewis acid catalyzed Mukaiyama aldol reaction is investigated using a combination of dispersion corrected DFT calculations and transition state force fields (TSFF) developed using the quantum guided molecular mechanics (Q2MM) method. The reaction proceeds via a closed transition structure involving a nontraditional hydrogen bond that is 3.3 kJ/mol lower in energy than the corresponding open transition structure. The correct prediction of the diastereoselectivity of a Mukaiyama aldol reaction catalyzed by the conformationally flexible Yamamoto chiral (acyloxy) borane (CAB) requires extensive conformational sampling at the transition structure, which is achieved using a Q2MM-derived TSFF, followed by DFT calculations of the low energy conformational clusters. Finally, a conceptual model for the rationalization of the observed diastereo-and enantioselectivity of the reaction using a closed transition state model is proposed.U.S. National Science Foundation [NSF CHE1058075]; Shenzhen Peacock Program [JCYJ20140509093817689]; National Research Council of Sweden [2010-4856]; Astra-Zeneca; NIH [T32GM075762]SCI(E)EIPubMedARTICLEphelquis@nd.edu; Olaf.G.Wiest.1@nd.edu135314-53218