Lewis Acid/Brønsted Base-Assisted Palladium Catalysis: Stereoselective Construction of Skeletally Diverse Spiro-Ketolactams from Vinylethylene Carbonates

The diversity of spirocyclic architecture
offers a vast chemical
space and enormous potential for drug discovery, while the skeletal
diversity-oriented synthesis of spiromolecules from simple starting
materials remains a challenging task. Here, we report a divergent
stereoselective construction of [5,5] and [5,6] spiroheterocycles
from identical substrates (vinylethylene carbonates and pyrrolidone-derived
enones) through Lewis-acid-assisted and Brønsted-base-assisted
palladium catalysis, respectively. With this protocol, a broad spectrum
of enantioenriched tetrahydrofuranyl spiroketolactams was achieved via palladium/Al­(OiPr)3 cocatalyzed
asymmetric (3 + 2) annulations. A collection of cyclohexenyl spiroketolactams
was synthesized through diastereoselective (4 + 2) annulations under
a palladium/NaHCO3 catalytic system. Further synthesis
elaboration was performed using both spiroskeletons to showcase the
versatility of this methodology. In addition, density functional theory
calculations provide a rationale toward the observed different reaction
pathways with the divergently cooperative palladium catalysis.