Highly Regio- and Enantioselective Synthesis of 4-Substituted Dihydroisoquinolones Catalyzed by a Planar-Chiral Rhodium(III) Catalyst Bearing a Penta-Substituted Prochiral Cyclopentadienyl Ligand

A class of rationally designed planar-chiral rhodium(III) catalysts featuring prochiral 1,3,4-triaryl-2,5-dialkyl cyclopentadienyl ligands has been developed. By a modular synthetic strategy that enables rapid diversification, the prochiral cyclopentadienyl ligands can be readily prepared in only three steps. Resolution of the planar-chiral complexes is efficiently achieved by flash column chromatography assisted by a chiral diene ligand. The catalyst could enable highly regio- and enantioselective asymmetric C-H activation of phenylhydroxamic acids with unactivated terminal alkenes, affording 4-substituted dihydroisoquinolones with high efficiency (55 examples, >20:1 rr, up to 98% yield, up to 99% ee). This transformation well addressed a long-standing and notoriously challenging problem in asymmetric synthesis. This reaction tolerates a wide range of functional groups in reactants, such as halogen, hydroxy, acetyl, alkoxy, amido, and cyano groups. Synthetic utilities of this methodology are showcased, such as the concise syntheses of 4-<i>n</i>-butyl and 4-benzyl tetrahydroisoquinolines. Mechanistic studies have been conducted, including H/D exchange, kinetic isotope effect (KIE), and capture of the metallacyclic intermediate. The 1,3,4-triaryl-2,5-dialkyl cyclopentadienyl moiety proves to be the key structural feature for achieving high regioselectivity. The cyclopentadienyl ligand adopts a well-defined conformation in the metallacycle intermediate formed during C-H activation. Density functional theory (DFT) calculations revealed that the migratory insertion of olefin was irreversible, constituting the stereo- and regioselectivity-determining event.