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Chemistry. 2019 Jul 2;25(37):8780-8789. doi: 10.1002/chem.201900087. Epub 2019 Jun 5.

Stereoselective Cascade Cyclizations with Samarium Diiodide to Tetracyclic Indolines: Precursors of Fluorostrychnines and Brucine.

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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.


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.


alkaloids; cascade reaction; dearomatization; fluorinated heterocycles; lactones; samarium diiodide


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