Pd-catalyzed asymmetric (6+2) dipolar cyclization for medium-sized spirooxindoles

Area of Science:

• Organic Chemistry
• Asymmetric Synthesis
• Medicinal Chemistry

Background:

• Chiral spirooxindoles are crucial structural motifs in many biologically active compounds.
• Efficient synthetic strategies for functionalizing spirooxindoles, particularly medium-sized spirocycles, are limited.

Purpose of the Study:

• To develop a novel palladium-catalyzed asymmetric (6+2) dipolar cyclization reaction.
• To synthesize enantioenriched spirooxindoles containing eight-membered lactone rings.

Main Methods:

• Employing a Pd-catalyzed asymmetric (6+2) dipolar cyclization between vinyloxetanes and 3-diazoquinoline-2,4-diones.
• Utilizing a tailored chiral phosphine ligand for high enantioselectivity.
• Generating ketene dipolarophiles *in situ* via photochemistry.

Main Results:

• Successfully synthesized enantioenriched spirooxindoles with eight-membered lactones.
• Achieved high yields (up to 90%) and excellent enantioselectivities (up to 98% ee) for 22 examples.
• Demonstrated the reaction proceeds under mild conditions.

Conclusions:

• The developed method offers an efficient and versatile route to valuable chiral spirooxindole scaffolds.
• This strategy addresses the scarcity of methods for functionalizing medium-sized spirocycles.
• The use of *in situ* generated ketenes and chiral ligands enables high stereocontrol.