Organic Process Research and Development p. 786 - 798 (2016)
Update date:2022-08-03
Topics:
Austad, Brian C.
Hague, Andrew B.
White, Priscilla
Peluso, Stéphane
Nair, Somarajan J.
Depew, Kristopher M.
Grogan, Michael J.
Charette, André B.
Yu, Lin-Chen
Lory, Caroline D.
Grenier, Louis
Lescarbeau, André
Lane, Benjamin S.
Lombardy, Richard
Behnke, Mark L.
Koney, Nii
Porter, James R.
Campbell, Matthew J.
Shaffer, Jeanne
Xiong, Jimin
Helble, Joseph C.
Foley, Michael A.
Adams, Julian
Castro, Alfredo C.
Tremblay, Martin R.
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.
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