Beemelmanns Christine, Nitsch Dominik, Bentz Christoph, Reissig Hans-Ulrich
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustraße 3, 14195, Berlin, Germany.
Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie, Beutenbergstraße 11a, 07745, Jena, Germany.
Chemistry. 2019 Jul 2;25(37):8780-8789. doi: 10.1002/chem.201900087. Epub 2019 Jun 5.
A series of γ-indolylketones with fluorine, cyano or alkoxy substituents at the benzene moiety was prepared and subjected to samarium diiodide-promoted cyclization reactions. The desired dearomatizing ketyl cascade reaction forming two new rings proceeded in all cases with high diastereoselectivity, but with differing product distribution. In most cases, the desired annulated tetracyclic compounds were obtained in moderate to good yields, but as second product tetracyclic spirolactones were isolated in up to 29 % yield. The reaction rate was influenced by the substituents at the benzene moiety of the substrate as expected, with electron-accepting groups accelerating and electron-donating groups decelerating the cyclization process. In case of a difluoro-substituted γ-indolylketone a partial defluorination was observed. The intermediate samarium enolate of the tetracyclic products could be trapped by adding reactive alkylating agents as electrophiles delivering products with quarternary carbons. In the case of a dimethoxy-substituted tetracyclic cyclization product a subsequent reductive amination stereoselectively provided a pentacyclic compound that was subsequently N-protected and subjected to a regioselective elimination. The obtained functionalized pentacyclic product should be convertible into the alkaloid brucine by four well-established steps. Overall, the presented report shows that functionalized tetracyclic compounds with different substituents are rapidly available with the samarium diiodide cascade cyclization as crucial step. Hence, analogues of the landmark alkaloid strychnine, for example, with specific fluorine substitutions, should be easily accessible.
制备了一系列在苯环部分带有氟、氰基或烷氧基取代基的γ-吲哚基酮，并将其用于二碘化钐促进的环化反应。在所有情况下，形成两个新环的所需去芳构化酮基级联反应都以高非对映选择性进行，但产物分布不同。在大多数情况下，所需的稠合四环化合物以中等至良好的产率获得，但作为次要产物，四环螺内酯的分离产率高达29%。正如预期的那样，反应速率受底物苯环部分取代基的影响，吸电子基团加速环化过程，供电子基团则使其减速。在二氟取代的γ-吲哚基酮的情况下，观察到了部分脱氟现象。通过加入作为亲电试剂的活性烷基化剂，可以捕获四环产物的中间体钐烯醇化物，从而得到带有季碳的产物。对于二甲氧基取代的四环环化产物，随后的还原胺化反应立体选择性地提供了一种五环化合物，该化合物随后进行了N-保护并进行了区域选择性消除。通过四个成熟的步骤，所得到的官能化五环产物应该可以转化为生物碱马钱子碱。总体而言，本报告表明，以二碘化钐级联环化作为关键步骤，可以快速获得具有不同取代基的官能化四环化合物。因此，例如具有特定氟取代的标志性生物碱士的宁类似物应该很容易获得。
