Late-stage diversification of indole skeletons through nitrogen atom insertion

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Drug Discovery

Background:

• Direct skeletal editing of pharmaceutical lead compounds remains a significant challenge.
• Current late-stage functionalization strategies primarily focus on carbon-hydrogen bonds.

Purpose of the Study:

• To develop a reliable method for the direct skeletal editing of indole-based compounds.
• To access quinazoline and quinoxaline bioisosteres through nitrogen atom insertion.

Main Methods:

• Generation of an electrophilic nitrene species from ammonium carbamate and hypervalent iodine.
• Utilizing a silyl group as a labile protecting group for product release.
• Application of the methodology to late-stage skeletal editing of commercial drugs.

Main Results:

• Successful skeletal editing of indoles via nitrogen atom insertion.
• Formation of quinazoline and quinoxaline bioisosteres.
• Demonstration of high functional group compatibility in late-stage drug modification.

Conclusions:

• The developed method provides a novel route for skeletal diversification of indole scaffolds.
• This approach facilitates the late-stage modification of drug molecules, offering new possibilities in medicinal chemistry.
• The strategy is applicable to complex pharmaceutical lead compounds and commercial drugs.