Intramolecular Anti-Markovnikov Alkene Hydroaminative Cyclization to cis-2,3-Disubstituted Piperidines

Area of Science:

• Organic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Multisubstituted piperidines are crucial scaffolds in pharmaceutical development.
• Efficient synthesis of stereochemically defined piperidine derivatives remains a significant challenge.

Purpose of the Study:

• To develop a novel photodriven anti-Markovnikov hydroaminative cyclization for synthesizing cis-2,3-disubstituted piperidines and azepanes.
• To achieve high diastereoselectivity and yield in the synthesis of these valuable heterocyclic compounds.

Main Methods:

• Utilized a lactate-derived C2-symmetric arylthiol catalyst for a photodriven reaction.
• Employed a (Z)/(E)-isomeric mixture of trisubstituted alkenes as starting materials.
• Conducted experimental and computational investigations to understand reaction mechanisms.

Main Results:

• Successfully synthesized cis-2,3-disubstituted piperidines and azepanes with high diastereoselectivity.
• Achieved good overall yields for the target piperidine and azepane products.
• Elucidated the origin of diastereoselectivity and factors influencing hydroamination rates through mechanistic studies.

Conclusions:

• The developed photodriven hydroaminative cyclization offers an efficient route to complex piperidine and azepane structures.
• The chiral catalyst enables precise stereochemical control, crucial for pharmaceutical applications.
• Mechanistic insights provide a foundation for further optimization and development of related synthetic methodologies.