Photosensitization enables Pauson-Khand-type reactions with nitrenes

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• The Pauson-Khand reaction is a widely used cycloaddition reaction, typically employing carbon monoxide (CO) as a C1 building block.
• Existing cycloaddition methods are limited in their ability to incorporate nitrogen atoms as N1 units.

Purpose of the Study:

• To develop analogous cycloaddition reactions using nitrenes as N1 building blocks.
• To synthesize novel bicyclic compounds and explore their potential as bioisosteres of common saturated heterocycles.

Main Methods:

• Utilized a novel cycloaddition reaction involving nonconjugated dienes and nitrene precursors.
• Conducted experimental and computational mechanistic studies to elucidate the reaction pathway.
• Applied the developed methodology for late-stage functionalization of drug compounds.

Main Results:

• Successfully demonstrated cycloaddition reactions with nitrenes as N1 units, analogous to the Pauson-Khand reaction.
• Synthesized bicyclic bioisosteres of saturated heterocycles like piperidine, morpholine, and piperazine.
• Mechanistic studies confirmed the relay of triplet nitrene's diradical character into the π-system.

Conclusions:

• The developed nitrene-based cycloaddition offers a new route for synthesizing nitrogen-containing heterocycles.
• The reaction is valuable for late-stage functionalization in drug discovery and development.
• Identified potential soluble epoxide hydrolase inhibitors using this novel synthetic approach.