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

The 1,4-diamino-2-hydroxy motif found in HIV protease inhibitors motivates efficient access to quaternary α,β'-diamino ketones, yet classical C-N bond formation at the α- and β'-positions requires nitrogen sources of opposite polarity, a fundamental mismatch that forces stepwise synthesis. Here we report a protecting-group-controlled radical cascade that overcomes this polarity mismatch in a single operation. Under dirhodium(II) catalysis, N-fluorobenzenesulfonimide (NFSI) serves as a unified nitrogen source to generate an aminyl radical, which initiates a 1,2-carbon shift to a transient oxocarbenium intermediate. The subsequent course of this intermediate is governed by the hydroxyl protecting group. Benzyl ethers selectively promote β-elimination to form a vinyl ether, enabling a second amination and in situ deprotection, whereas other protecting groups either undergo premature cleavage or remain intact, requiring a separate deprotection step. These results identify protecting group control as a key design element in this radical cascade and provide step-economical access to quaternary α,β'-diamino ketones and related diamino scaffolds.