DFT studies of asymmetric synthesis of axially chiral indazole substituted pyrrole compounds from 3-aminoindazole and 1,4-diketone

A range of axially chiral indazole-substituted pyrrole compounds were successfully synthesized through a chiral phosphoric acid (CPA)-catalyzed cyclization between 3-aminoindazole and 1,4 - diketones, affording products in moderate to high yields (up to 92%) and excellent enantioselectivities (ee up to 96%). The stereochemical outcome was influenced by both the steric hindrance and electronic properties of the substituents on the 1,4 - diketone and indazole components.

The rotational barrier of the resulting axially chiral framework was investigated through DFT calculation at the r2SCAN-3c//WB97X-D4REV level. Two different reaction pathways were evaluated, revealing that the energy barriers for interconversion between atropisomers are strongly dependent on the steric hindrance around the chiral axis. The chiral phosphoric acid catalyst plays the role in controlling the enantioselectivity by stabilizing key transition states through hydrogen bond. This Project provides a practical route to synthesize axially chiral indazole-substituted pyrrole compounds and demonstrates how the synergy effect between catalytic asymmetric cyclization reaction and rotational barrier control enables the construction of stable chiral molecules.