Concise Six-Step Asymmetric Approach to Ramelteon from an Acetophenone Derivative Using Ir, Rh, Cu, and Ni Catalysis

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• Ramelteon is a melatonin receptor agonist used for treating insomnia.
• The synthesis of ramelteon's complex tricyclic core presents significant challenges.
• Developing efficient and enantioselective synthetic routes is crucial for pharmaceutical development.

Purpose of the Study:

• To develop a concise and highly enantioselective synthesis of ramelteon.
• To establish the shortest synthetic pathway to date for ramelteon.
• To demonstrate novel catalytic methods for constructing the ramelteon core structure.

Main Methods:

• A six-step asymmetric synthesis starting from a monocyclic precursor.
• Utilized Iridium-catalyzed O-vinylation and Rhodium-catalyzed vinyl ether annulation via C-H activation for core assembly.
• Introduced chirality through enantioselective reduction of an α,β-unsaturated nitrile using a copper(II)/Walphos catalyst under hydrosilylation conditions.

Main Results:

• Achieved a 17% overall yield for the synthesis.
• Obtained nearly enantiomerically pure ramelteon with 97% enantiomeric excess (ee) in the key asymmetric step.
• The developed methodology represents the shortest synthetic route to ramelteon reported.

Conclusions:

• The presented six-step synthesis is the most concise approach to ramelteon.
• The methodology efficiently constructs the challenging tricyclic indeno[5,4-b]furan core.
• This route offers a practical and enantioselective pathway for ramelteon production.