Catalytic Asymmetric Tandem Reaction of Tertiary Enamides: Expeditious Synthesis of Pyrrolo[2,1-a]isoquinoline Alkaloid Derivatives

• Published in: Angewandte Chemie International Edition 2016-03, Vol.55 (11), p.3799-3803
• Main Authors: Xu, Xin-Ming, Zhao, Liang, Zhu, Jieping, Wang, Mei-Xiang
• Format: Article
• Language: English
• Subjects: Alkaloids; Alkaloids - chemical synthesis; Amides - chemistry; Aromatic compounds; asymmetric catalysis; Asymmetry; Biocompatibility; Biomedical materials; Carbonyl compounds; Carbonyls; Cascade chemical reactions; Catalysis; Chemical synthesis; Construction; copper; cyclizations; Derivatives; Diastereoisomers; Enantiomers; Interception; Isoquinolines - chemical synthesis; Pyrroles - chemical synthesis; Surgical implants; synthetic methods; Transformations
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201600119

Reported is a new and efficient strategy for rapid construction of the chiral tetrahydropyrrolo[2,1‐a]isoquinolin‐3(2H)‐one structure from unique tertiary enamide synthons. A Cu(OTf)2/chiral Pybox complex catalyzes the intramolecular enantioselective addition of tertiary enamides to ketonic carbonyls with subsequent diastereoselective interception of the resulting acyliminium by tethered electron‐rich aryl moiety. The tandem reaction produces diverse tetrahydropyrrolo[2,1‐a]isoquinolin‐3(2H)‐one derivatives as the sole diastereoisomers in good to excellent yields with up to 98.5 % ee. The transformations of the resulting heterocycles into various hexahydropyrrolo[2,1‐a]isoquinoline derivatives were also demonstrated. The cyclization products, which are difficult to obtain by other synthetic means, are structural motifs found in many bioactive alkaloids. 'Soul' isomer: The title reaction proceeds under mild reaction conditions to produce tetrahydropyrrolo[2,1‐a]isoquinolin‐3(2H)‐one derivatives, which contain two tetrasubstituted stereogenic centers, as the sole diastereoisomers in high yields and excellent enantioselectivity. These products can be easily transformed into various hexahydropyrrolo[2,1‐a]isoquinoline derivatives.