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

Overview

MeSH Major

  • Biomedical Research
  • Genetic Association Studies
  • Lymphoma
  • Translational Medical Research

abstract

  • © 2016 American Chemical Society.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.

publication date

  • April 15, 2016

Research

keywords

  • Academic Article

Identity

Digital Object Identifier (DOI)

  • 10.1021/acs.oprd.6b00048

Additional Document Info

start page

  • 786

end page

  • 798

volume

  • 20

number

  • 4