Photoinduced Copper-Catalyzed Stereoselective C(sp³)-H Amination Enabled by Preorganized Multiple Noncovalent...

Area of Science:

• Organic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Chiral α-amino cyclic amines are vital bioactive scaffolds in drug discovery.
• Asymmetric C(sp3)-H amination of saturated cyclic amines remains a significant synthetic challenge.

Purpose of the Study:

• To develop a highly enantioselective α-C(sp3)-H amination of cyclic amines.
• To utilize readily available nitrogen sources like amides and N-heterocycles.

Main Methods:

• Photoinduced copper-catalyzed asymmetric C-H amination.
• Utilized pharmaceutically relevant aromatic and α,β-unsaturated amides, N-heterocycles, and imines as coupling partners.
• Employed mechanistic studies and DFT calculations to elucidate the reaction pathway.

Main Results:

• Achieved highly enantioselective α-C(sp3)-H amination of cyclic amines.
• Demonstrated successful amination with diverse substrates including amides, N-heterocycles, and imines, yielding functionalized α-amino cyclic amines with high diastereoselectivity.
• Identified radical addition to Cu(II)-amide species followed by reductive elimination as the key C-N bond formation mechanism.

Conclusions:

• Developed a unique reaction model combining photoredox catalysis, radical cross-coupling, and noncovalent interactions for efficient synthesis.
• The preassembly strategy involving (R)-BINOL and BOPA-copper(II) benzamide enhances stereoselectivity via specific noncovalent interactions.
• This methodology provides a powerful new route to synthesize chiral α-amino cyclic amines, expanding synthetic capabilities in medicinal chemistry.