PC-Phos Enabled Catalytic Palladium-heteroallyl Asymmetric Cycloaddition

Area of Science:

• Organic Chemistry
• Asymmetric Catalysis
• Synthetic Methodology

Background:

• Asymmetric cycloadditions are crucial for synthesizing enantioenriched cyclic compounds.
• Hetero (3+2) cycloadditions using heteroallyl cations are rare and challenging due to their thermally forbidden nature.
• No asymmetric versions yielding enantioenriched heterocycles have been previously reported.

Purpose of the Study:

• To develop the first catalytic asymmetric (3+2) cycloaddition reaction involving electrophilic palladium-heteroallyl zwitterion intermediates.
• To synthesize highly substituted or fused pyrrolidine and tetrahydrofuran rings with high stereocontrol.

Main Methods:

• Utilized electrophilic palladium-heteroallyl zwitterion intermediates (Pd-OTMM or Pd-NTMM).
• Employed cyclic and acyclic 1,3-dienes as reaction partners.
• Engineered chiral sulfinamide phosphine (Sadphos) type ligands, specifically PC-Phos, with di-tert-butyl and/or 3,5-difluorophenyl groups.

Main Results:

• Achieved the first catalytic asymmetric (3+2) cycloaddition of palladium-heteroallyl zwitterions with 1,3-dienes.
• Delivered highly substituted or fused pyrrolidine and tetrahydrofuran rings in high yields.
• Demonstrated excellent regio-, diastereeo-, and enantioselectivity through ligand engineering.

Conclusions:

• Successfully established a novel asymmetric cycloaddition pathway via palladium-heteroallyl zwitterions.
• Ligand design, particularly with PC-Phos variants, is critical for achieving high catalytic performance and enantioselectivity.
• This methodology provides a powerful new tool for constructing enantioenriched heterocyclic compounds.