Couple-close construction of polycyclic rings from diradicals

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Methodology

Background:

• Heteroarenes are vital in bioactive molecules, offering improved properties over arenes.
• Semisaturated heterocycles enhance solubility and binding affinity but are synthetically challenging.
• Current methods for semisaturated heterocycles are often non-modular, limiting diversity and throughput.

Purpose of the Study:

• To develop a modular and efficient synthetic strategy for constructing semisaturated heterocycles.
• To overcome limitations in current synthetic methods for accessing these important molecular scaffolds.
• To enable rapid assembly of diverse spirocyclic, bridged, and substituted saturated ring systems.

Main Methods:

• A novel couple-close approach merging metallaphotoredox C(sp2)-C(sp3) cross-coupling with intramolecular Minisci-type radical cyclization.
• Utilizing dual radical precursors derived from abundant heteroaryl halides and simple bifunctional feedstocks.
• Employing reagent-controlled radical generation for regioselective and stereospecific annulation.

Main Results:

• Rapid assembly of a variety of spirocyclic, bridged, and substituted saturated ring types.
• Successful fusion of heteroaryl halides with bifunctional feedstocks to create complex structures.
• Demonstration of late-stage functionalization of pharmaceutical scaffolds.

Conclusions:

• The developed platform provides an intuitive and modular route to valuable semisaturated heterocycles.
• This method significantly expands access to underexplored chemical space for drug discovery.
• The approach offers a powerful alternative to lengthy de novo syntheses for pharmaceutical development.