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.