Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Northwestern University , Silverman Hall, Evanston, Illinois 60208, United States.
Department of Chemistry, Furman University , Greenville, South Carolina 29613, United States.
J Org Chem. 2017 May 5;82(9):4689-4702. doi: 10.1021/acs.joc.7b00334. Epub 2017 Apr 25.
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.
NHC 催化的不饱和醛通过有机催化的偕羟醛过程转化为饱和酯已得到深入研究。利用独特的“反转”介导的β-质子化，该过程已从偕羟醛反应性的试验台发展为更广泛的不对称催化平台。受我们成功地使用β-质子化过程从 ynals 生成 enals 并具有良好的 E/Z 选择性的启发，我们的早期研究发现，该反应的不对称变体不仅是可行的，而且可以通过 NHC 催化的酰化反应适应仲醇的动力学拆分。对该过程的深入分析确定，仔细选择催化剂和溶剂配对对于获得最佳产率和选择性至关重要；选择适当的非极性溶剂可以通过抑制氧化副反应来提高产率，而通过包含氢键供体共催化剂的协同催化方法可以显著提高对映选择性。
