Benzo-Fused Medium-Sized Heterocycles with a Chiral C-N Axis from Asymmetric Cycloaddition and Skeletal Rearrangement

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Catalysis

Background:

• Benzofused heterocycles are important scaffolds in medicinal chemistry.
• Axially chiral N-aryl sulfonamides are present in pharmacologically active compounds.
• Efficient and stereoselective synthesis of complex heterocycles remains a challenge.

Purpose of the Study:

• To develop an efficient palladium-catalyzed synthesis of enantioenriched benzofused nine- and ten-membered heterocycles.
• To incorporate a stereogenic carbon and an axially chiral N-aryl sulfonamide motif.
• To explore subsequent transformations of the synthesized heterocycles.

Main Methods:

• Palladium-catalyzed formal [5 + 4] and [6 + 4] cycloadditions.
• Utilized aza-ortho-quinone methide precursors and vinyl carbonates.
• Employed sequential ring-contractive rearrangements.

Main Results:

• Efficient synthesis of diverse enantioenriched benzofused nine- and ten-membered heterocycles.
• Excellent diastereoselectivity and enantioselectivity achieved.
• Systematic access to highly functionalized nine- and eight-membered heterocycles with stereocontrol.

Conclusions:

• The developed method provides a versatile route to complex chiral heterocycles.
• The synthesized scaffolds possess significant pharmacological potential.
• The methodology allows for stereocontrolled access to various ring sizes.