Multistep One-Pot Synthesis of Enantioenriched Polysubstituted Cyclopentabindoles

摘要

The development of asymmetric methodologies for the synthesis of chiral indoles has been a long-standing project in organic synthesis. Indole skeletons are heterocyclic systems and are present in numerous alkaloid products, pharmaceuticals, and agrochemicals. Cyclopentabindole skeletons can be found in a number of indole alkaloids, but have not been extensively reported. Compounds that contain such a unit exhibit a wide range of biological activities. For example, 2-aminocyclopentabindoles, cyclopentabindole-substi-tuted acetic acids, and a series of yuehchukene analogues have been successfully synthesized and used in medicinal chemistry. Although a number of methods have been developed for the synthesis of cyclopentabindoles, only few of them are asymmetric and especially catalytic asymmetric methods. To the best of our knowledge, there is only one example of the synthesis of chiral cyclopentabindoles by asymmetric catalysis with acceptable enantioselectivities. The development of efficient methods for the construction of cyclopentabindole units is therefore highly desirable. As a continuation of the work of our research group toward the catalytic asymmetric α-alkylation of carbonyl compounds, we rationally designed a one-pot three-step reaction, which consisted of the oc-alkylation of an aldehyde, catalyzed by a primary-amine-substituted thiourea, and two consecutive Bronsted acid catalyzed Friedel-Crafts reactions of an indole, to construct chiral polysubstituted cyclopentabin-doles (Scheme 1). Herein, we report these consecutive organocatalyzed reactions, which gave structurally diverse cyclopentabindoles in high yields (up to 85), and with excellent diastereoselectivities (up to >99:1) and enantioselectivities (up to 99 ee).