Total Synthesis of the Marine Alkaloid Halichlorine: Development and Use of a General Route to Chiral Piperidines

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• 作者：Dazhan Liu ; Hukum P. Acharya ; Maolin Yu ; Jian Wang ; Vince S. C. Yeh ; Shunzhen Kang ; Chandramouli Chiruta ; Santosh M. Jachak ; Derrick L. J. Clive
• 刊名：Journal of Organic Chemistry
• 出版年：2009
• 出版时间：October 2, 2009
• 年：2009
• 卷：74
• 期：19
• 页码：7417-7428
• 全文大小：1293K
• 年卷期：v.74,no.19(October 2, 2009)
• ISSN：1520-6904

文摘

The total synthesis of the marine alkaloid halichlorine is described, based on an approach that involves constructing the fully substituted asymmetric center at an early stage. The five-membered ring is formed by 5-exo-trig radical cyclization and the unsaturated six-membered ring by a process that formally represents a sequential combination of conjugate addition and Sb>Nb>2′ displacement—a method that is general for making bicyclic compounds with nitrogen at a ring fusion position. A formal synthesis of (+)-halichlorine is also reported, based on the development of a general method for preparing optically pure piperidines. The key step of this method, which was used to make one of our intermediates, is the Claisen rearrangement of a 4-vinyloxy-3,4-dihydro-2H-pyridine-1-carboxylic acid benzyl ester. Such O-vinyl compounds are easily generated in situ from the corresponding alcohols, which are themselves readily assembled from serine and terminal acetylenes.