Stereoselective Preparation of a Cyclopentane-Based NK1 Receptor Antagonist Bearing an Unsymmetrically Substituted Sec-Sec Ether

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• 作者：Jeffrey T. Kuethe ; Jean-Francois Marcoux ; Audrey Wong ; Jimmy Wu ; Michael C. Hillier ; Peter G. Dormer ; Ian W. Davies ; David L. Hughes
• 刊名：Journal of Organic Chemistry
• 出版年：2006
• 出版时间：September 15, 2006
• 年：2006
• 卷：71
• 期：19
• 页码：7378 - 7390
• 全文大小：271K
• 年卷期：v.71,no.19(September 15, 2006)
• ISSN：1520-6904

文摘

A highly efficient synthesis of the potent and selective NK-1 receptor antagonist 1 is described. The keytransformation involved the etherification reaction between cyclopentanol 12 and chiral imidate 30 whichwas catalyzed by HBF₄ to initially give ether 14 as a 17:1 mixture of diastereomers and in 75% combinedyield. The diastereoselectivity was upgraded to 109:1 by crystallization of the triethylamine solvate 44which was isolated in 54% yield from 12. Mechanistic studies confirmed that the etherification reactionproceeds through an unprecedented S_N2 reaction pathway under typical S_N1 reaction conditions.