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.