Abstract
Enantiomerically enriched indole-containing heterocycles play a vital role in bioscience, medicine, and chemistry. As one of the most attractive subtypes of indole alkaloids, highly substituted tetrahydro-γ-carbolines are the basic structural unit in many natural products and pharmaceuticals. However, the syntheses of tetrahydro-γ-carbolines with high functionalities from readily available reagents are significant challenging. In particular, the stereodivergent syntheses of tetrahydro-γ-carbolines containing multi-stereogenic centers remain quite difficult. Herein, we report an expedient and stereodivergent assembly of tetrahydro-γ-carbolines with remarkably high levels of stereoselective control in an efficient cascade process from aldimine esters and indolyl allylic carbonates via a synergistic Cu/Ir catalyst system. Control experiments-guided optimization of synergistic catalysts and mechanistic investigations reveal that a stereodivergent allylation reaction and a subsequent highly stereoselective iso-Pictet-Spengler cyclization are the key elements to success.
Highlights
Enriched indole-containing heterocycles play a vital role in bioscience, medicine, and chemistry
The indole-containing heterocycles hold a vital role in modern organic chemistry owing to their widely distribution in nature[10,11,12,13,14], and the tetrahydro-γ-carboline scaffolds are one of the most attractive subtypes of indole alkaloids since they have long been identified as structural cores in many bioactive natural products and pharmaceuticals[15,16,17,18,19,20,21]
We reported the development of stereodivergent assembly of tetrahydro-γ-carbolines via a synergistic Cu/Ir catalyst system to achieve a stereodivergent allylation of aldimine esters and indolyl allylic carbonates followed by a spontaneous intramolecular iso-Pictet-Spengler cyclization
Summary
Enriched indole-containing heterocycles play a vital role in bioscience, medicine, and chemistry. The indole-containing heterocycles hold a vital role in modern organic chemistry owing to their widely distribution in nature[10,11,12,13,14], and the tetrahydro-γ-carboline scaffolds are one of the most attractive subtypes of indole alkaloids since they have long been identified as structural cores in many bioactive natural products and pharmaceuticals[15,16,17,18,19,20,21]. Lewis acid-catalyzed cycloadditions for the elegant construction of highly substituted tetrahydro-γ-carbolines with good to high diastereoselectivity and excellent enantioselectivity[33,34,35,36] All those reported catalytic asymmetric cyclization methods have focused on the preparation of only one stereoisomer or its enantiomer, which was rendered by selecting switch between a pair of enantiomeric catalysts. The cascade strategy that combines asymmetric allylation with subsequent intramolecular nucleophilic cyclization imparts three stereogenic centers to the overall two carbon–carbon bond-forming processes and constitutes an intriguing protocol to rapidly build complex molecular architectures from readily available reagents (Fig. 2)
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