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Synfacts 2013; 9(5): 0463
DOI: 10.1055/s-0032-1316882
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Commercial Manufacture of Halaven®

Contributor(s):
Philip Kocienski
Fang FG * et al. Eisai, Inc., Andover, USA and Eisai Co., Ltd., Ibaraki, Japan
Commercial Manufacture of Halaven®: Chemoselective Transformations En Route to Structurally Complex Macrocyclic Ketones.

Synlett 2013;
24: 333-337
Article in Thieme ConnectGoogle Scholar
Further Information

Publication History

Publication Date:
17 April 2013 (online)

 
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Key words

halaven - eribulin mesylate - Nozaki–Hiyama–Kishi reaction - macrocyclization

Significance

Eribulin mesylate (Halaven®) was approved by the FDA in 2010 for the treatment of metastatic breast cancer. It triggers apoptosis in cancer cells following prolonged and irreversible mitotic blockade. Workers at the Eisai company report a multigram-scale synthesis of eribulin that is a tour de force of synthetic strategy and tactics. The closing stages are shown in the scheme. Two accompanying papers describe the synthesis of the key fragments from d-(–)-gulono-1,4-lactone (B. M. Lewis et al. Synlett 2013, 24, 323) and d-glucurono-3,6-lactone (C. E. Chase et al. Synlett 2013, 24, 327).


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Comment

The Eisai synthesis of eribulin underscores the power of the Nozaki–Hiyama–Kishi (NHK) reaction in the construction of complex frail molecules. It was twice deployed in the construction of the bonds indicated in structure A; however, the most spectacular achievement was the forging of the macrocycle C under high dilution conditions using a ligand-accelerated asymmetric variant of the NHK reaction – a process that has been implemented on kilogram scale.


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