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.