Catalytic Asymmetric Diastereodivergent Synthesis of 2-Alkenylindoles Bearing both Axial and Central Chirality

Abstract

The catalytic asymmetric diastereodivergent synthesis of axially chiral 2-alkenylindoles was established via chiral phosphoric acid-catalyzed addition reactions of C3-unsubstituted 2-alkenylindoles with o-hydroxybenzyl alcohols under different reaction conditions. Using this strategy, two series of 2-alkenylindoles bearing both axial and central chirality were synthesized in a diastereodivergent fashion with moderate to high yields and good stereoselectivities (up to 99% yield, 95:5 er, >95:5 dr). Moreover, theoretical calculations were performed on the key transition states leading to different stereoisomers, which provided an in-depth understanding of the origin of the observed stereoselectivity and diastereodivergence of the products under different reaction conditions. More importantly, these 2-alkenylindoles were utilized in asymmetric catalysis as chiral organocatalysts and in medicinal chemistry for evaluation of their cytotoxicity, which demonstrated their potential applications. This study has not only established the catalytic atroposelective synthesis of axially chiral 2-alkenylindoles, but also provided an efficient strategy for catalytic asymmetric diastereodivergent construction of indole-based scaffolds bearing both axial and central chirality.

Scheme 1. Profile of Catalytic Asymmetric Diastereodivergent Reactions

Scheme 2. Profile of Catalytic Atroposelective Construction of Axially Chiral Indole-Based Scaffolds

Scheme 3. Our Strategy for Catalytic Asymmetric Diastereodivergent Synthesis of 2-Alkenylindoles Bearing Both Axial and Central Chirality

Scheme 4. Catalysts and Model Reaction Employed for Condition Optimization

Scheme 5. Demonstration of the Stereodivergence and Study on the Configurational Stability

Scheme 6. Synthesis (1 mmol Scale) and Application of Axially Chiral 2-Alkenylindoles in Asymmetric Catalysis

Figure 1

Chiral 2-alkenylindoles 3 and 4 with promising anticancer activity

Scheme 7. Control Experiments and Proposed Reaction Pathway

Figure 2

Key transition states to explain the enantioselectivity and diastereodivergence of the products.