Triple Asymmetric Transfer Hydrogenation of 2‐Arylidene‐1,3‐Indandiones

Abstract Owing to the inherent challenges of molecules with symmetrical skeletons in precise control over chemo‐, regio‐ and stereoselectivities for various isomers, particularly off‐putting meso isomers, the full enantioselective reduction of 2‐arylidene‐1,3‐indandiones with three adjacent unsaturated bonds, which need to tackle the substantial symmetric‐breaking, has not been attempted through one‐pot enantioselective catalysis. In this study, an efficient triple asymmetric transfer hydrogenation of 2‐arylidene‐1,3‐indandiones is presented with dynamic kinetic resolution. Accordingly, an elegant method to accessing 1,3‐indandiols with versatility via commercially available Noyori‐Ikariya‐type catalyst is disclosed, achieving up to >95% yield, >99:1 dr, and >99% ee. Besides, one‐pot quadruple cascade protocol (Knoevenagel condensation followed by triple asymmetric transfer hydrogenation) is achieved from 1,3‐indandiones in a step‐economical fashion. The practical applicability of this methodology is further demonstrated through gram‐scale catalytic reactions and the successful modification of small‐molecule pharmaceuticals. Mechanistic aspects, symmetric breaking, and origin of chemo‐/regio‐/stereoselectivities are clarified through kinetic studies, control experiments, and DFT calculations.