Synthesis of the CETP Inhibitor Torcetrapib: The Resolution Route and Origin of Stereoselectivity in the Iminium Ion Cyclization

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• 作者：David B. Damon ; Robert W. Dugger ; George Magnus-Aryitey ; Roger B. Ruggeri ; Ronald T. Wester ; Meihua Tu ; and Yuriy Abramov
• 刊名：Organic Process Research & Development
• 出版年：2006
• 出版时间：May 2006
• 年：2006
• 卷：10
• 期：3
• 页码：464 - 471
• 全文大小：286K
• 年卷期：v.10,no.3(May 2006)
• ISSN：1520-586X

文摘

A practical, efficient synthesis of (-)-(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)methoxycarbonylamino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethylester (1), a cholesteryl ester transfer protein (CETP) inhibitor,is described. The key reaction in the synthesis, addition of anN-vinylcarbamate to an iminium ion rapidly followed by animinium ion cyclization onto the aryl ring, sets up the cisrelationship of the two subsituents of the tetrahydoquinolinering of 6. The origin of the high cis stereoselectivity in thecyclization was explored using high-level quantum chemistrycalculations.