Backbone-Enabled and Ester Groups Switched δ-C(sp²)-H Amination/Fluorination: Cyclic Dipeptides Synthesis

Area of Science:

• Organic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Cyclic dipeptides are important structural motifs in natural products and pharmaceuticals.
• Existing methods for synthesizing cyclic dipeptides can be lengthy or lack efficiency.
• Developing novel synthetic strategies is crucial for accessing diverse cyclodipeptide libraries.

Purpose of the Study:

• To develop an efficient and site-selective method for synthesizing cyclic dipeptides.
• To explore the use of palladium catalysis in C-H functionalization for cyclodipeptide construction.
• To demonstrate the versatility of the method by switching products using the C-terminal ester group.

Main Methods:

• Palladium-catalyzed site-selective δ-C(sp2)-H amination/fluorination.
• Utilizing backbone amides as endogenous directing groups.
• Employing N-to-C cyclization strategy.

Main Results:

• Successful synthesis of cyclic dipeptides via a novel Pd-catalyzed pathway.
• Demonstration of site-selectivity in C-H amination and fluorination.
• Control over product formation by varying the C-terminal ester group.

Conclusions:

• The disclosed strategy provides an efficient and concise route to cyclic dipeptides.
• This novel chemistry offers a robust alternative for constructing cyclodipeptide fragments.
• The method holds potential for the synthesis of diverse and complex cyclodipeptide structures.