Enantioselective Hydroarylation via Chiral Transient Directing Groups: Access to Chiral Benzo-Fused Heterocycles with Collaborative Enantiomeric Control

A general and practical enantioselective C-H activation/hydroarylation enabled by chiral transient directing groups (cTDGs) and ruthenium η-arene catalysts is reported, providing efficient access to benzo-fused six-membered heterocycles, including chiral chromanes, xanthenes, and related frameworks. It represents a rare and stereochemically distinct application of cTDG-enabled asymmetric C-H activation in d-metal catalysis, which operates a sequential hydroarylation, in contrast to the well-established Pd(II)-based cTDG systems that primarily mediate other classes of C-H functionalization pathways. Notably, this method enables streamlined access to bioactive xanthene scaffolds, including dendrafaconrol-type frameworks, while being equally applicable to chromane derivatives. The catalytic system employs readily available and structurally tunable Ru(II) arene complexes in combination with simple α-branched chiral amines for cooperative enantiomeric control. Arising from the interplay between the cTDG and the η-arene ligand, modular combinations of chiral amines and Ru-arene catalysts enabled efficient optimization of both reactivity and enantioselectivity across diverse substrates. Mechanistic studies, including H/D scrambling, kinetic isotope effect experiments, and density functional theory (DFT) computations, reveal a dynamic catalytic landscape in which the turnover-determining transition state (TDTS) is condition-dependent, and the two enantiomeric pathways proceed through distinct rate-determining steps, providing insight into asymmetric induction in conformationally flexible d-metal systems. The retained aldehyde functionality enables diverse downstream transformations, affording rapid access to biorelevant polycyclic scaffolds and previously unreported architectures. Collectively, this work establishes a modular and tunable platform for asymmetric C-H hydroarylation and expands the synthetic utility of cTDG-enabled catalysis.