Rapid Access to Chiral 3-Oxabicyclo[3.1.1]heptanes by Iridium-Catalyzed Asymmetric Hydrogenation and Sequential Cyclization

The bicyclo[3.1.1]heptanes (BCHeps) represent an essential class of three-dimensional caged scaffolds as bioisosteres of meta-substituted arenes in modern drug discovery. Despite significant achievements in the construction of chiral BCHeps, the synthetic strategies only limited to the asymmetric cycloaddition of bicycle[1.1.0]butanes (BCBs) and the innovative catalytic enantioselective protocols have rarely been exploited. Herein, we disclosed a synthetic strategy for the construction of chiral 3-oxa-BCHeps via the iridium-catalyzed asymmetric hydrogenation/cyclization of spirocyclic ketones. This protocol is a cascade procedure involving asymmetric hydrogenation to give the chiral spirocyclic alcohol intermediates and sequential acid-mediated ring opening and cyclization. Both spirocyclic azetidinyl ketones and spirocyclic oxetanyl ketones are compatible, delivering a wide range of chiral polysubstituted 3-oxa-BCHeps bearing amino and hydroxyl functional groups with high yields and enantioselectivities (up to 99% yield and 99% ee). The utility of this protocol is accentuated by diverse transformations and synthesis of a chiral analogue of the anticancer drug Sonidegib.