Facile Entry to an Efficient and Practical Enantioselective Synthesis of a Polycyclic Cholesteryl Ester Transfer Protein Inhibitor

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• 作者：Zhengxu S. Han ; Yibo Xu ; Daniel R. Fandrick ; Sonia Rodriguez ; Zhibin Li ; Bo Qu ; Nina C. Gonnella ; Sanjit Sanyal ; Jonathan T. Reeves ; Shengli Ma ; Nelu Grinberg ; Nizar Haddad ; Dhileep Krishnamurthy ; Jinhua J. Song ; Nathan K. Yee ; Waldemar Pfrengle ; Markus Ostermeier ; J眉rgen Schnaubelt ; Zeno Leuter ; Sonja Steigmiller ; J眉rgen D盲ubler ; Emanuel Stehle ; Lukas Neumann ; Thomas Trieselmann ; Patrick Tielmann ; Annette Buba ; Rainer Hamm ; Gunter Koch ; Svenja Renner ; Juan R. Dehli ; Florian Schmelcher ; Christian Stange ; J眉rgen Mack ; Rainer Soyka ; Chris H. Senanayake
• 刊名：Organic Letters
• 出版年：2014
• 出版时间：August 15, 2014
• 年：2014
• 卷：16
• 期：16
• 页码：4142-4145
• 全文大小：306K
• ISSN：1523-7052

文摘

An efficient enantioselective synthesis of the chiral polycyclic cholesteryl ester transfer protein (CETP) inhibitor 1 has been developed. The synthesis was rendered practical for large scale via the development of a modified Hantzsch-type reaction to prepare the sterically hindered pyridine ring, enantioselective hydrogenation of hindered ketone 6 utilizing novel BIBOP-amino-pyridine derived Ru complex, efficient ICl promoted lactone formation, and a BF₃ mediated hydrogenation process for diastereoselective lactol reduction. This efficient route was successfully scaled to produce multikilogram quantities of challenging CETP drug candidate 1.