A Divergent Enantioselective Total Synthesis of Post‐Iboga Indole Alkaloids

• Published in: Angewandte Chemie Vol. 132; no. 42; pp. 18890 - 18899
• Main Authors: Zhou, Jie, Tan, Dong‐Xing, Han, Fu‐She
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 12.10.2020
• Subjects: Aldehydes; Alkaloids; Cascade chemical reactions; cascade reactions; Catalysts; Chemistry; Coupling (molecular); Divergence; divergent synthesis; Enantiomers; indole alkaloids; Indoles; Natural products; Stereoselectivity; Stille coupling; total synthesis
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202008242

Divergent enantioselective total syntheses of five naturally occurring post‐iboga indole alkaloids, dippinine B and C, 10,11‐demethoxychippiine, 3‐O‐methyl‐10,11‐demethoxychippiine, and 3‐hydroxy‐3,4‐secocoronaridine, as well as the two analogues 11‐demethoxydippinine A and D, are presented for the first time. The enantioenriched aza[3.3.1]‐bridged cycle, a common core intermediate to the target molecules, was constructed through an asymmetric phase‐transfer‐catalyzed Michael/aldol cascade reaction. The challenging azepane ring fused around the indole ring and the [3.3.1]‐bridged cycle were installed through an intramolecular SN2′‐type reaction. These cyclization strategies enabled rapid construction of the [6.5.6.6.7]‐pentacyclic core at an early stage. Highlights of the late‐stage synthetic steps include a Pd‐catalyzed Stille coupling and a highly stereoselective catalyst‐controlled hydrogenation to incorporate the side chain at C20 with both R and S configurations in the natural products. Enantioselective total syntheses of post‐iboga indole alkaloids were achieved in a divergent manner. The construction of the [6.5.6.6.7]‐pentacyclic core included an asymmetric Michael/aldol cascade reaction for installing the aza[3.3.1]‐bridged cycle and an intramolecular SN2′‐type reaction for assembling the azepane ring. The stereoselective incorporation of the side chain involved a Pd‐catalyzed Stille coupling and a catalyst‐controlled hydrogenation.