Tropane and related alkaloid skeletons via a radical [3+3]-annulation process

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Catalysis

Background:

• Tropanes and related bicyclic alkaloids exhibit significant biological activity.
• Accessing N-arylated bicyclic aniline derivatives is challenging via traditional methods like the Robinson tropane synthesis.

Purpose of the Study:

• To develop a mild and efficient protocol for synthesizing N-arylated 8-azabicyclo[3.2.1]octane and 9-azabicyclo[3.3.1]nonane derivatives.
• To provide a novel route to valuable bicyclic alkaloid scaffolds for medicinal chemistry applications.

Main Methods:

• Utilized visible-light photoredox catalysis for the synthesis.
• Employed ethyl 2-(acetoxymethyl)acrylate as a 1,3-bis radical acceptor.
• Used cyclic N,N-dialkylanilines as radical 1,3-bis radical donors.

Main Results:

• Achieved synthesis of N-arylated 8-azabicyclo[3.2.1]octane and 9-azabicyclo[3.3.1]nonane derivatives in good yields.
• Demonstrated high levels of diastereoselectivity in the product formation.
• Established an unprecedented annulation process relying on electron transfer and selective deprotonation.

Conclusions:

• The developed protocol provides a facile and effective method for constructing complex bicyclic alkaloid skeletons.
• These N-arylated bicyclic aniline derivatives represent attractive scaffolds for drug discovery and medicinal chemistry.
• The photoredox-catalyzed annulation offers a significant advancement over classical synthetic approaches.