Diversified ring expansion of saturated cyclic amines enabled by azlactone insertion

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Saturated N-heterocycles are vital in natural products and biologically active compounds.
• Developing synthetic methods for N-heterocycles is crucial for synthetic and medicinal chemistry.
• Molecular editing of N-heterocycles to alter ring sizes is highly desirable.

Purpose of the Study:

• To present a novel method for constructing synthetically challenging medium-sized azacycles.
• To enable the direct insertion of glycine derivatives as two-carbon synthons into cyclic amines.
• To establish a versatile platform for diversifying existing drug candidates.

Main Methods:

• Direct insertion of glycine derivatives into five- or six-membered saturated cyclic amines.
• Utilizing sequential Ruthenium-catalyzed C-C bond formation, retro-aza-Michael addition, and lactamization.
• Employing a homologation platform for modular insertion of one- or two-carbon units.

Main Results:

• Successful construction of medium-sized azacycles from readily available starting materials.
• Demonstration of predictable site-selective C-C bond formation.
• Conversion of a single azacycle into up to five distinct analogues.

Conclusions:

• The presented method offers a powerful toolbox for medicinal chemistry.
• This approach facilitates the diversification of drug candidates, enhancing their clinical prospects.
• The direct insertion strategy provides efficient access to synthetically challenging N-heterocyclic scaffolds.