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Synfacts 2017; 13(12): 1229
DOI: 10.1055/s-0036-1591619
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Synthesis of Ipatasertib

Contributor(s):
Philip Kocienski
Gosselin F. * et al. Genentech, Inc., South San Francisco, USA and F. Hoffmann-La Roche AG, Basel, Switzerland
Asymmetric Synthesis of Akt Kinase Inhibitor Ipatasertib.

Org. Lett. 2017;
19: 4806-4809
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Further Information

Publication History

Publication Date:
17 November 2017 (online)

 
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Key words

Ipatasertib - Akt kinase inhibitor - biotransformation - nitrilase-catalyzed resolution - ketoreductase reduction - asymmetric hydrogenation

Significance

Ipatasertib (GDC-0068) is an Akt kinase inhibitor that that is of interest for the treatment of cancer. The stereogenic centers in fragment F were installed using a nitrilase-catalyzed resolution of nitrile (rac)-A and a ketoreductase-catalyzed reduction of ketone D. For a related large-scale synthesis of Ipatasertib, see: T. Remarchuk et al. Org. Process Res. Dev. 2014, 18, 1652.


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Comment

The stereogenic center in fragment L was installed by asymmetric hydrogenation. Using [Ru(TFA)2((S)-BINAP)] with catalyst activation by NaBr as an additive, allowed for S/C = 10,000. The optimal ratio to ensure reaction robustness was Ru/NaBr = 1:20 and thus afforded >99% conversion and 98.8:1.2 er.


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