Enantioselective Pd-Catalyzed α-Arylation of N-Boc-Pyrrolidine: The Key to an Efficient and Practical Synthesis of a Glucokinase Activator

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• 作者：Artis Klapars ; Kevin R. Campos ; Jacob H. Waldman ; Daniel Zewge ; Peter G. Dormer ; Cheng-yi Chen
• 刊名：Journal of Organic Chemistry
• 出版年：2008
• 出版时间：July 4, 2008
• 年：2008
• 卷：73
• 期：13
• 页码：4986 - 4993
• 全文大小：251K
• 年卷期：v.73,no.13(July 4, 2008)
• ISSN：1520-6904

文摘

A short and practical synthesis of glucokinase activator 1 was achieved utilizing a convergent strategy involving S_NAr coupling of activated aryl fluoride 11 with hydroxypyridine 9. The key to the success of the synthesis was the development of a novel method for enantioselective formation of α-arylpyrrolidines during the course of the project. In this method, (−)-sparteine-mediated enantioselective lithiation of N-Boc-pyrrolidine was followed by in situ transmetalation to zinc and Pd-catalyzed coupling with aryl bromide 3, proceeding in 92% ee. This transformation allowed the preparation of compound 1 in a 31% overall yield over six steps.