Visible-light-mediated Radical Dearomatization of N-(2-Phenyl)benzoyl Amino Acid Derivatives for the Construction of Spirocyclic and Bicyclic Frameworks

抄録

Spirocyclic and bridged polycyclic systems are common in bioactive molecules such as natural products and therapeutic agents. Accordingly, they have attracted attention in drug discovery as valuable “drug-like” templates. We have developed a series of visible-light-mediated radical dearomatization reactions using N-(2-phenyl)benzoyl amino acid derivatives as unified precursors for the construction of such frameworks. Mild photoredox conditions enabled radical dearomatization, leading to efficient formation of spirocyclohexadiene scaffolds. Further exploration revealed that electron-deficient biphenyl substrates underwent a radical cascade involving dearomatization, 1,4-hydrogen atom transfer, and [4+2] cycloaddition to afford bicyclo[2.2.2]octene skeletons. The spirocyclohexadiene formation strategy was successfully applied to the first total synthesis of zephycarinatines C and D, Amaryllidaceae alkaloids bearing a 6,6-spirocyclic core with multiple stereocenters. Our studies highlight the utility of visible-light-mediated radical dearomatization as a powerful and modular approach to access complex, bioactive molecular architectures from simple aromatic feedstocks.

グラフィカル アブストラクト