1 research outputs found
Development of a Multi Kilogram-Scale, Tandem Cyclopropanation Ring-Expansion Reaction en Route to Hedgehog Antagonist IPI-926
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 EtZnCH<sub>2</sub>I. Herein,
we describe the process optimization studies that led to successful
large-scale production of the d-homocyclopamine core necessary
for IPI-926