Diversity-Generating Skeletal Editing Transformations | JoVE Visualize

Area of Science:

Organic Synthesis
Medicinal Chemistry
Photocatalysis

Background:

Skeletal editing enables late-stage modification of molecules, crucial for exploring chemical space around lead compounds.
Traditional skeletal editing often yields a single product, limiting diversification essential for structure-activity relationship (SAR) studies.
Developing skeletal editing strategies that allow for rapid diversification is key to accelerating drug discovery.

Purpose of the Study:

To develop novel skeletal editing transformations that enable simultaneous skeletal modification and functional group incorporation.
To create methods for rapid diversification of molecular scaffolds, thereby expediting SAR investigations.
To explore photocatalytic approaches for skeletal editing and diversity generation.

Main Methods:

Development of an α-iodonium diazo-based carbynyl radical equivalent reagent for photoredox-catalyzed ring-expansion of indenes.
Design of an atomic carbon equivalent reagent for Ciamician-Dennstedt-type indole ring-expansion.
Photocatalyzed De Mayo reaction for cyclic ketone ring-expansion and dearomative ring-expansion of thiophenes.
Development of a nitrogen-to-carbon atom transmutation via pyridine ring-opening, olefination, and ring-closure.

Main Results:

Facilitated ring-expansion of indenes with insertion of over ten functionalized carbon atoms.
Achieved mild and selective indole ring-expansion with simultaneous installation of a functionalizable oxime ester handle.
Demonstrated photocatalyzed ring-expansion of cyclic ketones and thiophenes via small-ring insertion, allowing multiple product access.
Successfully converted pyridine to benzene rings, enabling diverse functional group installation via Horner-Wadsworth-Emmons olefination.

Conclusions:

Novel skeletal editing strategies have been developed that allow for simultaneous skeletal modification and diversity generation.
These methods enable rapid exploration of chemical space and can significantly expedite SAR investigations.
The developed transformations offer versatile tools for accessing diverse molecular architectures through late-stage functionalization.