Ligand Evolution-Enabled Enantioselective C(sp³)-H Azidation

Area of Science:

• Organic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Chiral azides are vital building blocks for pharmaceuticals and natural products.
• Direct asymmetric azidation of C-H bonds remains challenging due to azide reactivity.

Purpose of the Study:

• To develop a novel method for enantioselective α-C(sp3)-H azidation of carbonyl compounds.
• To utilize a photoinduced copper-catalyzed system with a unique chiral ligand.

Main Methods:

• Employing a photoinduced copper-catalyzed radical α-C(sp3)-H azidation.
• Utilizing a binary bisphosphine and N,N,N-tridentate anionic chiral ligand system.
• Implementing a 1,5-hydrogen atom transfer (HAT) strategy.

Main Results:

• Achieved excellent chemo-, regio-, and enantioselectivity in α-carbonyl C-H bond azidation.
• Demonstrated versatility through postazidation modifications, including synthesis of non-natural amino acids.
• Successfully installed azide groups in complex bioactive compounds for click chemistry.

Conclusions:

• The developed method offers a practical route to chiral azides from readily available carbonyl compounds.
• The ligand system acts as both a photosensitizer and chiral catalyst, crucial for enantioselectivity.
• DFT studies elucidated a remote S_H2 mechanism, guiding catalyst optimization.