Regio- and Enantioselective Aza-Diels-Alder Reactions of 3-Vinylindoles: A Concise Synthesis of the Antimalarial Spiroindolone NITD609

• Published in: Angewandte Chemie International Edition Vol. 54; no. 37; pp. 10958 - 10962
• Main Authors: Zheng, Haifeng, Liu, Xiaohua, Xu, Chaoran, Xia, Yong, Lin, Lili, Feng, Xiaoming
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 07.09.2015; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Antimalarials - chemistry; asymmetric catalysis; Asymmetry; aza-Diels-Alder reactions; Chemistry; Chemistry, Multidisciplinary; Derivatives; Heterocyclic aromatic compounds; Imines; indoles; Indoles - chemistry; ketimines; Ligands; nickel catalysis; Pathways; Physical Sciences; Science & Technology; Stereoisomerism; Stereoselectivity; Synthesis (chemistry); CATALYSIS; ASYMMETRIC-SYNTHESIS; CASCADE; asymmetric catalysis; PICTET-SPENGLER REACTIONS; DISCOVERY; nickel catalysis; MANNICH REACTION; indoles; POTENT; ketimines; LIGANDS; ISATINS; aza-Diels-Alder reactions
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201505717

An asymmetric aza‐Diels–Alder reaction of 3‐vinylindoles with isatin‐derived ketimines has been developed. A series of spiroindolone derivatives were thus obtained in good to excellent yields with excellent enantioselectivity (up to 96 % yield and 99 % ee). Furthermore, the antimalarial compound NITD609 could be obtained in three steps with an overall yield of 40.6 %. Control experiments and operando IR experiments imply a concerted reaction pathway. The regioselectivity and exo selectivity result from π–π interactions between the two indoline rings of the two reactants. An asymmetric aza‐Diels–Alder reaction of 3‐vinylindoles with isatin‐derived ketimines leads to spiroindolone derivatives with high regio‐, diastereo‐, and enantioselectivity and also provides facile access to the valuable antimalarial drug NITD609. The stereoselectivity is thought to arise from π–π interactions between the two reactants and the chiral N,N′‐dioxide ligand.