Ionic-Liquid-Catalyzed Access to CTr: An Antitumor Agent

CTr (5,6,11,12,17,18-hexahydrocyclononal[1,2-b:4,5-b′:7,8-b″]triindole) is a unique 9-membered indole-fused cycloalkane alkaloid with improved druglike privilege and therapeutic potential, but its supply issue remains unsolved, which thus restrains its further exploration. Here, using [EMIm][HSO4] as catalyst and solvent, we present an efficient synthesis of CTr from 3-[(phenylmethoxy)methyl]-1H-indole (O-Bn-I3C) which is readily prepared from indole-3-carbinol (I3C). The multiple H-bonding interactions of O-Bn-I3C with [EMIm][HSO4] were evidenced to play decisive roles in the selective construction of CTr. The approach is selective, sustainable, scalable, and easy-to-handle, thereby serving as a reliable access to the alkaloid. The amply afforded CTr sample allowed us to investigate its solvent-dependent conformational preference and its spectrum of antitumor activity, pinpointing that CTr is also active against human osteosarcoma cell line H2OS with an IC50 value of 1.0 μM. In aggregation, the work uncovers the catalytic feature and prowess of [EMIm][HSO4] and establishes the efficient synthesis of CTr, thereby extending the application of the multiple H-bonding catalysis over ionic liquid and facilitating further development of this structurally intriguing therapeutic candidate.