Development of Enantioselective Synthetic Routes to the Hasubanan and Acutumine Alkaloids

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• 作者：Nicholas A. Calandra ; Sandra M. King ; Seth B. Herzon
• 刊名：Journal of Organic Chemistry
• 出版年：2013
• 出版时间：October 18, 2013
• 年：2013
• 卷：78
• 期：20
• 页码：10031-10057
• 全文大小：1266K
• 年卷期：v.78,no.20(October 18, 2013)
• ISSN：1520-6904

文摘

We describe a general strategy to prepare the hasubanan and acutumine alkaloids, a large family of botanical natural products that display antitumor, antiviral, and memory-enhancing effects. The absolute stereochemistry of the targets is established by an enantioselective Diels鈥揂lder reaction between 5-(trimethylsilyl)cyclopentadiene (36) and 5-(2-azidoethyl)-2,3-dimethoxybenzoquinone (24). The Diels鈥揂lder adduct 38 is transformed to the tetracyclic imine 39 by a Staudinger reduction鈥揳za-Wittig sequence. The latter serves as a universal precursor to the targets. Key carbon鈥揷arbon bond constructions include highly diastereoselective acetylide additions to the N-methyliminium ion derived from 39 and Friedel鈥揅rafts and Hosomi鈥揝akurai cyclizations to construct the carbocyclic skeleton of the targets. Initially, this strategy was applied to the syntheses of (鈭?-acutumine (4), (鈭?-dechloroacutumine (5), and four hasubanan alkaloids (1, 2, 3, and 8). Herein, the synthetic route is adapted to the syntheses of six additional hasubanan alkaloids (12, 13, 14, 15, 18, and 19). The strategic advantage of 5-(trimethylsilyl)cyclopentadiene Diels鈥揂lder adducts is demonstrated by site-selective functionalization of distal carbon鈥揷arbon 蟺-bonds in the presence of an otherwise reactive norbornene substructure. Evaluation of the antiproliferative properties of the synthetic metabolites revealed that four hasubanan alkaloids are submicromolar inhibitors of the N87 cell line.