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Catalytic, Enantioselective β-Protonation through a Cooperative Activation Strategy

Wang, Michael H., Barsoum, David, Schwamb, C. Benjamin, Cohen, Daniel T., Goess, Brian C., Riedrich, Matthias, Chan, Audrey, Maki, Brooks E., Mishra, Rama K., Scheidt, Karl A.
Journal of organic chemistry 2017 v.82 no.9 pp. 4689-4702
acylation, alcohols, aldehydes, catalysts, catalytic activity, chemical structure, enantioselectivity, esters, hydrogen bonding, organic chemistry, solvents
The NHC-catalyzed transformation of unsaturated aldehydes into saturated esters through an organocatalytic homoenolate process has been thoroughly studied. Leveraging a unique “Umpolung”-mediated β-protonation, this process has evolved from a test bed for homoenolate reactivity to a broader platform for asymmetric catalysis. Inspired by our success in using the β-protonation process to generate enals from ynals with good E/Z selectivity, our early studies found that an asymmetric variation of this reaction was not only feasible, but also adaptable to a kinetic resolution of secondary alcohols through NHC-catalyzed acylation. In-depth analysis of this process determined that careful catalyst and solvent pairing is critical for optimal yield and selectivity; proper choice of nonpolar solvent provided improved yield through suppression of an oxidative side reaction, while employment of a cooperative catalytic approach through inclusion of a hydrogen bond donor cocatalyst significantly improved enantioselectivity.