Organocatalytic Asymmetric Tandem Michael Addition−Hemiacetalization: A Route to Chiral Dihydrocoumarins, Chromanes, and 4<i>H</i>-Chromenes

Asymmetric tandem Michael addition−hemiacetalization between aliphatic aldehydes and (E)-2-(2-nitrovinyl)phenols was investigated for constructing benzopyran backbones. Interestingly, the diastereo- and enantioselectivities changed markedly when the reaction was mediated by different types of secondary amine catalysts. The diphenylprolinol silyl ether 7 promoted the reaction with excellent enantioselectivities (up to 99% ee) but with moderate diastereoselectivities (2.8:1 to 10:1). Prolylprolinols are another type of efficient catalyst. Among them, l,l-prolylprolinol 5c is identified as the optimal species, showing high catalytic activity, good enantioselectivities (up to 89% ee), and excellent diasereoselectivities (up to 50:1 dr). Various aliphatic aldehydes and substituted (E)-2-(2-nitrovinyl)phenols were proven to be well tolerated in this tandem reaction. In addition, the chroman-2-ols 3 yielded in the above reactions could be conveniently transformed to synthetically and biologically significant chiral dihydrocoumarin, chroman, and 4H-chromene derivatives.本研究针对脂肪族醛与(E)-2-(2-硝基乙烯基)苯酚之间的不对称串联迈克尔加成-半缩醛化反应展开探究，以构建苯并吡喃骨架。值得注意的是，当采用不同类型的二级胺催化剂介导该反应时，其非对映选择性与对映选择性会发生显著变化。二苯基脯氨醇硅醚7可催化该反应，展现出优异的对映选择性（最高可达99% ee），但非对映选择性中等（2.8:1至10:1）。脯氨酰脯氨醇是另一类高效催化剂，其中L,L-脯氨酰脯氨醇5c被确定为最优催化剂，表现出较高的催化活性、良好的对映选择性（最高可达89% ee）以及优异的非对映选择性（最高可达50:1 dr）。各类脂肪族醛与取代(E)-2-(2-硝基乙烯基)苯酚在该串联反应中均表现出良好的底物耐受性。此外，上述反应生成的色满-2-醇类化合物3可便捷地转化为在合成与生物学领域具有重要价值的手性二氢香豆素、色满及4H-色烯衍生物。