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

• Published in: Precision Chemistry Vol. 2; no. 5; pp. 208 - 220
• Main Authors: Yang, Shuang, Huang, Jia-Bo, Wang, Da-Hua, Wang, Ning-Yi, Chen, Yu-Yu, Ke, Xin-Yan, Chen, Hao, Ni, Shao-Fei, Zhang, Yu-Chen, Shi, Feng
• Format: Journal Article
• Language: English
• Published: United States University of Science and Technology of China and American Chemical Society 27.05.2024; American Chemical Society
• Subjects: Diastereodivergent synthesis; 2-Alkenylindole; Axial chirality; Central chirality; Chiral phosphoric acid
• ISSN: 2771-9316; 2771-9316
• DOI: 10.1021/prechem.4c00008

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.