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

作者：Bai, Leiyang; Li, Jiayi; Jiang, Xuefeng^*

来源：Chem, 2023, 9(2): 483-496.

DOI：10.1016/j.chempr.2022.10.021

• CONCISE TOTAL-SYNTHESIS
• ATOM-TRANSFER
• CONSTRUCTION
• ALKENES
• 2-(IODOMETHYL)CYCLOPROPANE-1,1-DICARBOXYLATE
• (+)-PESTALAZINE
• ALKALOIDS
• PYRROLOINDOLINE
• STRATEGY
• REVISION

The concise total synthesis of (+)-asperazine A, bearing unsymmet-rical C3-N1' linkage, was achieved stereoselectively via an unprece-dented 4N-based cascade linkage. Umpolung from nucleophilic an-iline (N1) to electrophilic N-iodoaniline was implemented via oxidant iodine cation, released steadily by Ni-catalyzed keto/enol-tautom-erism ring-opening of 1,3-dicarbonyl iodomethylcyclopropane. It triggered the condensation via endo-attack by enamine (N2) fol-lowed 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 addi-tion 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-isom-erization, efficiently establishing a 22-membered library of aspera-zine A scaffolds. Control experiments and density functional theory calculations supported the electrophilic N-iodoaniline pathway and elucidated the highly endo-selective preference.

• 单位
  中国科学院; 南开大学; 上海交通大学