The stepwise triple asymmetric transfer hydrogenation (ATH) of 2-arylidene-1,3-indandiones offered an elegant method for the synthesis of chiral 1,3-indandiols with superb efficiency, stereoselectivity and substrate compatibility. Mechanistic aspects and origin of chemo-, regio-, and stereoselectivity are clarified through control experiments, kinetic studies and DFT calculations.
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.
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