Synergetic Tandem Enantiomeric Enrichment in Catalytic Asymmetric Multi-Component Reactions (AMCRs): Highly Enantioselective Construction of Tetracyclic Indolines with Four Continuous Stereocenters

Tetracyclic indolines are ubiquitous skeletons in bioactive natural products and pharmaceuticals, and efficient methods for their enantioselective synthesis are highly desired. Here, we report an efficient three-component formal [2 + 2 + 2] cycloaddition reaction between indoles, 2,3-dihydropyran, and methylene malonates for rapid construction of optically active tetracyclic indolines bearing four continuous stereocenters. Although the optimal catalyst Cu(II)/BOX displays only moderate enantioselectivities in either formal cyclobutanation or [4 + 2] cycloaddition reaction with donor-acceptor cyclobutanes bearing a nonracemizable stereocenter, the collaborative tandem enantiomeric enrichment in the one-pot asymmetric multicomponent reaction is highly effective, thereby affording a wide range of tetracyclic indoline derivatives with excellent diastereo- and enantioselectivities in high yields.