Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel鈥揅rafts Alkylation of Indole with Chiral 伪-Phenyl Benzyl Cation

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• 作者：John Y. L. Chung ; Dietrich Steinhuebel ; Shane W. Krska ; Fred W. Hartner ; Chaoxian Cai ; Jonathan Rosen ; Danny E. Mancheno ; Tao Pei ; Lisa DiMichele ; Richard G. Ball ; Cheng-yi Chen ; Lushi Tan ; Antony D. Alorati ; Sarah E. Brewer ; Jeremy P. Scott
• 刊名：Organic Process Research & Development
• 出版年：2012
• 出版时间：November 16, 2012
• 年：2012
• 卷：16
• 期：11
• 页码：1832-1845
• 全文大小：545K
• 年卷期：v.16,no.11(November 16, 2012)
• ISSN：1520-586X

文摘

Development of a practical asymmetric synthesis of a glucagon receptor antagonist drug candidate for the treatment of type 2 diabetes is described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane core substituted with a propyl and three aryl groups including a fluoro-indole. The key steps to construct the ethane core and the two stereogenic centers involved a ketone arylation, an asymmetric hydrogenation via dynamic kinetic resolution, and an anti-selective Friedel鈥揅rafts alkylation of a fluoro-indole with a chiral 伪-phenyl benzyl cation. We also developed two new efficient syntheses of the fluoro-indole, including an unusual Larock-type indole synthesis and a Sugasawa-heteroannulation route. The described convergent synthesis was used to prepare drug substance in 52% overall yield and 99% ee on multikilogram scales.