Total synthesis of (+)-asperazine A: A stereoselective domino dimerization

The concise total synthesis of (+)-asperazine A, bearing unsymmetrical C3–N1′ linkage, was achieved stereoselectively via an unprecedented 4N-based cascade linkage. Umpolung from nucleophilic aniline (N¹) to electrophilic N-iodoaniline was implemented via oxidant iodine cation, released steadily by Ni-catalyzed keto/enol-tautomerism ring-opening of 1,3-dicarbonyl iodomethylcyclopropane. It triggered the condensation via endo-attack by enamine (N²) followed by the addition of aniline (N³) for the key quaternization at C3 position. The proton generated in the first cyclization initiates the isomerism from enamine (N⁴) to iminium, followed by the addition from aniline (N¹). The unsymmetrical dimer 4 was acquired via ring-reopening (N⁴) driven by the thermodynamic stability of indole aromatization. This domino process assembles four distinct “N”s in sequence to achieve the aniline-dihydro-pyrrole dimerization-isomerization, efficiently establishing a 22-membered library of asperazine A scaffolds. Control experiments and density functional theory calculations supported the electrophilic N-iodoaniline pathway and elucidated the highly endo-selective preference.