Counteranion-Controlled Unprecedented Diastereo- and Enantioselective Tandem Formal Povarov Reaction for Construction of Bioactive Octahydro-Dipyrroloquinolines

The asymmetric inverse-electron-demand hetero-Diels–Alder (IEHDA) reactions of imines and dienophiles have emerged as an attractive tool for derivatizing optically active complex azaheterocycles. In comparison, such reactions involving iminium ions remain great challenges because of low association of iminium ions with neutral catalytic centers. To overcome this, we report a metal-phosphate-catalyzed asymmetric tandem hydroamination/formal Povarov reaction of secondary aminoalkynes via a chiral counteranion-controlled iminium ion intermediate strategy. Critical to the success of this challenging strategy was chiral phosphate as an ion pair to achieve counteranion-controlled asymmetric reaction of in situ-generated iminium ions. This method enables a convenient, powerful, and atom-economical access to tetracyclic octahydro-dipyrroloquinoline frameworks bearing multiple contiguous stereogenic centers in good yields with diastereo- and enantioselectivities, from acyclic starting materials, and the catalyst loadings could be as low as 1 mol %. The asymmetric cross-coupling reaction of different aminoalkynes has further been demonstrated with good results. Furthermore, this methodology was applied to enantioselective synthesis of incargranine B aglycone epimer in only two steps. The reaction is demonstrated to proceed through a stepwise process for formal Povarov reaction.

亚胺与亲双烯体的不对称反电子需求杂Diels-Alder（IEHDA）反应，已成为衍生制备具有光学活性的复杂氮杂环化合物的极具吸引力的合成工具。相较而言，涉及亚胺鎓离子（iminium ions）的此类反应仍存在巨大挑战，根源在于亚胺鎓离子与中性催化中心的结合亲和力较低。为攻克这一难题，我们报道了一种基于手性反离子控制的亚胺鎓离子中间体策略的反应：由金属磷酸酯催化的仲氨基炔烃的不对称串联氢胺化/形式Povarov反应（formal Povarov reaction）。该挑战性策略的核心在于以手性磷酸酯作为离子对，实现原位生成的亚胺鎓离子的反离子控制不对称转化。该方法可从非环起始原料出发，以良好收率、优异的非对映选择性与对映选择性，便捷高效且原子经济性地构建带有多个连续手性中心的四环八氢二吡咯并喹啉骨架，且催化剂负载量可低至1 mol%。我们还进一步实现了不同仲氨基炔烃的不对称交叉偶联反应，取得了良好的反应结果。此外，该合成策略仅需两步即可完成incargranine B苷元差向异构体的对映选择性合成。研究证实，该形式Povarov反应通过分步过程进行。