Institute of Microbial Chemistry (BIKAKEN), Tokyo , 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan.
J Am Chem Soc. 2017 Jun 21;139(24):8295-8301. doi: 10.1021/jacs.7b03291. Epub 2017 Jun 9.
α-Halogenated carbonyl compounds are susceptible to dehalogenation and thus largely neglected as enolate precursors in catalytic enantioselective C-C bond-forming reactions. By merging the increased stability of the α-C-halogen bond of amides and the direct enolization methodology of the designed amide, we explored a direct catalytic asymmetric Mannich-type reaction of α-halo 7-azaindoline amides with N-carbamoyl imines. All α-halo substituents, α-F, -Cl, -Br, -I amides, were tolerated to provide the Mannich-adducts in a highly stereoselective manner without undesirable dehalogenation. The diastereoselectivity switched intriguingly depending on the substitution pattern of the aromatic imines, which is ascribed to stereochemical differentiation based on the open transition-state model. Functional group interconversion of the 7-azaindoline amide moiety of the Mannich-adducts and further elaboration into a diamide without dehalogenation highlight the synthetic utility of the present protocol for accessing enantioenriched halogenated chemical entities.
α-卤代羰基化合物容易发生脱卤反应，因此在催化对映选择性 C-C 键形成反应中，它们作为烯醇化物前体的应用受到了很大的限制。通过结合酰胺中α-C-卤键的稳定性增加和设计的酰胺的直接烯醇化方法，我们探索了α-卤代 7-氮杂吲哚酰胺与 N-碳酰亚胺的直接催化不对称曼尼希型反应。所有的α-卤取代基，α-F、-Cl、-Br、-I 酰胺，都被容忍，以高度对映选择性的方式提供曼尼希加成产物，而没有不希望的脱卤。立体选择性令人惊讶地取决于芳族亚胺的取代模式，这归因于基于开放过渡态模型的立体化学差异。曼尼希加成物的 7-氮杂吲哚酰胺部分的官能团转化以及进一步转化为无脱卤的二酰胺突出了本方案在获得对映富集卤代化学实体方面的合成实用性。
