Protecting-Group-Controlled Radical Cascade to Quaternary α,β'-Diamino Ketones

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Catalysis

Background:

• The 1,4-diamino-2-hydroxy motif is crucial for HIV protease inhibitors.
• Classical synthesis of α,β'-diamino ketones is hampered by a polarity mismatch in C-N bond formation, necessitating stepwise approaches.

Purpose of the Study:

• To develop a novel, single-step method for accessing quaternary α,β'-diamino ketones.
• To overcome the inherent polarity mismatch in C-N bond formation using a radical cascade approach.

Main Methods:

• A protecting-group-controlled radical cascade reaction was developed.
• Dirhodium(II) catalysis and N-fluorobenzenesulfonimide (NFSI) were employed as a unified nitrogen source.
• The influence of different hydroxyl protecting groups on the reaction outcome was investigated.

Main Results:

• The radical cascade successfully generated an aminyl radical, initiating a 1,2-carbon shift to an oxocarbenium intermediate.
• Benzyl ether protecting groups selectively promoted β-elimination, leading to vinyl ether formation, subsequent amination, and in situ deprotection.
• Alternative protecting groups resulted in premature cleavage or required separate deprotection steps, highlighting the importance of protecting group selection.

Conclusions:

• Protecting group control is a critical design element in this radical cascade strategy.
• The developed method provides a step-economical route to quaternary α,β'-diamino ketones and related diamino scaffolds.
• This approach offers significant advantages over traditional stepwise synthesis for accessing complex diamino structures.