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Synfacts 2016; 12(07): 0657
DOI: 10.1055/s-0035-1562250
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of IPI-926

Contributor(s):
Philip Kocienski
Tremblay MR * et al. Infinity Pharmaceuticals, Cambridge and Johnson Matthey Pharma Services, Devens, USA; University of Montreal, Canada
Development of a Multi Kilogram-Scale, Tandem Cyclopropanation Ring-Expansion Reaction en Route to Hedgehog Antagonist IPI-926.

Org. Process Res. Dev. 2016;
20: 786-798
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Further Information

Publication History

Publication Date:
17 June 2016 (online)

 
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Key words

IPI-926 - cyclopamine - ring expansion - Simmons–Smith cyclopropanation - zinc carbenoids - Oppenauer oxidation

Significance

Cyclopamine (A) is a teratogenic alkaloid isolated from the corn lily (Veratrum californicum). IPI-926 is a Hedgehog signalling pathway antagonist derived from cyclopamine that was evaluated for the treatment of cancer. The key step in the synthesis depicted is the robust and scalable Simmons–Smith cyclopropanation of B followed by an acid-catalyzed carbocation rearrangement.


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Comment

For the large-scale Simmons–Smith reaction, a series of new safe and soluble iodo­methylzinc bis(aryl)phosphate reagents (e.g., C) were prepared under mild conditions that were stable during the course of the reaction. Note the rare application of an Oppenauer oxidation (I → J).


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