Development of a Multi Kilogram-Scale, Tandem Cyclopropanation Ring-Expansion Reaction en Route to Hedgehog Antagonist IPI-926

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• 作者：Brian C. Austad ; Andrew B. Hague ; Priscilla White ; Stéphane Peluso ; Somarajan J. Nair ; Kristopher M. Depew ; Michael J. Grogan ; André B. Charette ; Lin-Chen Yu ; Caroline D. Lory ; Louis Grenier ; André Lescarbeau ; Benjamin S. Lane ; Richard Lombardy ; Mark L. Behnke ; Nii Koney ; James R. Porter ; Matthew J. Campbell ; Jeanne Shaffer ; Jimin Xiong ; Joseph C. Helble ; Michael A. Foley ; Julian Adams ; Alfredo C. Castro ; Martin R. Tremblay
• 刊名：Organic Process Research & Development
• 出版年：2016
• 出版时间：April 15, 2016
• 年：2016
• 卷：20
• 期：4
• 页码：786-798
• 全文大小：634K
• 年卷期：0
• ISSN：1520-586X

文摘

The formation of the d-homocyclopamine ring system in IPI-926 is the key step in its semisynthesis and proceeds via a chemoselective cyclopropanation followed by a stereoselective acid-catalyzed carbocation rearrangement. In order to perform large-scale cyclopropanation reactions, we developed new iodomethylzinc bis(aryl)phosphate reagents that were found to be both effective and safe. These soluble reagents can be prepared under mild conditions and are stable during the course of the reaction. Importantly, they have favorable energetics relative to other cyclopropanating agents such as EtZnCH₂I. Herein, we describe the process optimization studies that led to successful large-scale production of the d-homocyclopamine core necessary for IPI-926.