The bicyclo3.1.1heptanes (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 bicycle1.1.0butanes (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.
Niu et al. (2025) studied this question.