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Catalytic, Enantioselective β-Protonation through a Cooperative Activation Strategy

Author:
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.
Source:
Journal of organic chemistry 2017 v.82 no.9 pp. 4689-4702
ISSN:
1520-6904
Subject:
acylation, alcohols, aldehydes, catalysts, catalytic activity, chemical structure, enantioselectivity, esters, hydrogen bonding, organic chemistry, solvents
Abstract:
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.
Agid:
5683097