Zinc Catalyzed and Mediated Asymmetric Propargylation of Trifluoromethyl Ketones with a Propargyl Boronate

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• 作者：Daniel R. Fandrick ; Jonathan T. Reeves ; Johanna M. Bakonyi ; Prasanth R. Nyalapatla ; Zhulin Tan ; Oliver Niemeier ; Deniz Akalay ; Keith R. Fandrick ; Wolfgang Wohlleben ; Swetlana Ollenberger ; Jinhua J. Song ; Xiufeng Sun ; Bo Qu ; Nizar Haddad ; Sanjit Sanyal ; Sherry Shen ; Shengli Ma ; Denis Byrne ; Ashish Chitroda ; Victor Fuchs ; Bikshandarkoil A. Narayanan ; Nelu Grinberg ; Heewon Lee ; Nathan Yee ; Michael Brenner ; Chris H. Senanayake
• 刊名：The Journal of Organic Chemistry
• 出版年：2013
• 出版时间：April 19, 2013
• 年：2013
• 卷：78
• 期：8
• 页码：3592-3615
• 全文大小：1158K
• 年卷期：v.78,no.8(April 19, 2013)
• ISSN：1520-6904

文摘

The development of zinc-mediated and -catalyzed asymmetric propargylations of trifluoromethyl ketones with a propargyl borolane and the N-isopropyl-l-proline ligand is presented. The methodology provided moderate to high stereoselectivity and was successfully applied on a multikilogram scale for the synthesis of the Glucocorticoid agonist BI 653048. A mechanism for the boron鈥搝inc exchange with a propargyl borolane is proposed and supported by modeling at the density functional level of theory. A water acceleration effect on the zinc-catalyzed propargylation was discovered, which enabled a catalytic process to be achieved. Reaction progress analysis supports a predominately rate limiting exchange for the zinc-catalyzed propargylation. A catalytic amount of water is proposed to generate an intermediate that catalyzes the exchange, thereby facilitating the reaction with trifluoromethyl ketones.