Sequential C–H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11β-HSD-1 Inhibitor

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• 作者：Xudong Wei ; Bo Qu ; Xingzhong Zeng ; Jolaine Savoie ; Keith R. Fandrick ; Jean-Nicolas Desrosiers ; Sergei Tcyrulnikov ; Maurice A. Marsini ; Frederic G. Buono ; Zhibin Li ; Bing-Shiou Yang ; Wenjun Tang ; Nizar Haddad ; Osvaldo Gutierrez ; Jun Wang ; Heewon Lee ; Shengli Ma ; Scot Campbell ; Jon C. Lorenz ; Matthias Eckhardt ; Frank Himmelsbach ; Stefan Peters ; Nitinchandra D. Patel ; Zhulin Tan ; Nathan K. Yee ; Jinhua J. Song ; Frank Roschangar ; Marisa C. Kozlowski ; Chris H. Senanayake
• 刊名：Journal of the American Chemical Society
• 出版年：2016
• 出版时间：November 30, 2016
• 年：2016
• 卷：138
• 期：47
• 页码：15473-15481
• 全文大小：824K
• ISSN：1520-5126

文摘

A concise asymmetric synthesis of an 11β-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C–H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl]₂.