Building C(sp³)-rich complexity by combining cycloaddition and C-C cross-coupling reactions

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• Cycloaddition reactions rapidly build molecular complexity, forming new ring systems and stereocenters, crucial in synthesis and education.
• Carbon-carbon cross-coupling methods are vital for synthesis due to their programmability and reliability.
• Overreliance on cross-coupling in drug discovery has led to an excess of flat, sp2-hybridized carbon-rich molecular architectures.

Purpose of the Study:

• To develop a strategy that merges the strengths of cycloaddition and cross-coupling reactions.
• To enable the modular, enantioselective, and scalable preparation of valuable chemical building blocks.
• To facilitate the synthesis of natural products and lead scaffolds for drug discovery.

Main Methods:

• A novel synthetic sequence combining cycloaddition and carbon-carbon cross-coupling reactions was developed.
• The strategy focuses on overcoming the limitations of traditional cycloadditions, such as lack of modularity.
• The method allows for programmable synthesis of complex molecular scaffolds.

Main Results:

• Demonstrated a strategy for combining cycloaddition and cross-coupling reactions into a single sequence.
• Enabled modular, enantioselective, and scalable preparation of diverse chemical structures.
• Facilitated the synthesis of useful building blocks, natural products, and drug lead scaffolds.

Conclusions:

• The developed strategy effectively integrates cycloaddition and cross-coupling, addressing limitations of each.
• This approach provides a programmable and scalable route to complex molecules relevant to drug discovery.
• The method enhances the synthesis of sp3-rich architectures, diversifying molecular scaffolds in medicinal chemistry.