Development of a [3+3] cycloaddition strategy toward functionalized piperidines.

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Catalysis

Background:

• Piperidines are important heterocyclic compounds found in numerous pharmaceuticals and natural products.
• Efficient and stereoselective synthesis of functionalized piperidines remains a key challenge in organic chemistry.

Purpose of the Study:

• To develop a novel and efficient synthetic route to functionalized piperidines.
• To explore the scope and limitations of a formal [3+3] cycloaddition reaction involving activated aziridines.

Main Methods:

• A formal [3+3] cycloaddition reaction between activated aziridines and palladium-trimethylenemethane (Pd-TMM) complexes was employed.
• The reaction was investigated using various N-substituted aziridines, including those with 4-toluenesulfonyl (Ts) and 4-methoxybenzenesulfonyl (PMBS) groups.
• The stereochemical outcome was examined using enantiomerically pure starting materials.

Main Results:

• The cycloaddition reaction proceeded enantioselectively, yielding enantiomerically pure 2-substituted piperidines in good to excellent yields.
• The N-substituent on the aziridine was critical, with Ts and PMBS groups enabling smooth cycloaddition.
• Spirocyclic and 2,3-disubstituted aziridines were also utilized, leading to spirocyclic and fused bicyclic piperidines, respectively.

Conclusions:

• A novel and efficient method for synthesizing functionalized piperidines has been established via a Pd-TMM catalyzed [3+3] cycloaddition.
• The reaction offers a versatile approach to enantiomerically pure piperidines and related structures.
• The choice of N-substituent on the aziridine is crucial for reaction success.