Catalytic, Enantioselective Beta-Protonation through a Cooperative Activation Strategy
Wang, M. H.; Barsoum, D.; Schwamb, B.; Cohen, D. T.; Goess, B. C.; Riedrich, M.; Chen, A.; Maki, B. E.; Mishra, R. K.; Scheidt, K. A. Catalytic, Enantioselective Beta-Protonation through a Cooperative Activation Strategy. J. Org. Chem., 2017, 82, 4689-4702.
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.
Journal of Organic Chemistry