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Synfacts 2019; 15(07): 0717
DOI: 10.1055/s-0039-1689867
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of GDC-0908

Contributor(s):
Philip Kocienski
Zhang H. * Li BX, Wong B, Stumpf A, Sowell CG, Gosselin F. Genentech, Inc., South San Francisco, USA
Convergent Synthesis of PI3K Inhibitor GDC-0908 Featuring Palladium-Catalyzed Direct C–H Arylation toward Dihydrobenzothienooxepines.

J. Org. Chem. 2019;
84: 4796-4802
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Further Information

Publication History

Publication Date:
17 June 2019 (online)

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Key words

GDC-0908 - phosphoinositide 3-kinase inhibitor - C–H arylation - Negishi reaction - Boulton–Katritzky rearrangement - 1,2,4-triazoles - 1,2,4-oxadiazoles

Significance

GDC-0908 is a phosphoinositide 3-kinase (PI3K) inhibitor that is of interest for the treatment of cancer. The convergent synthesis ­depicted features (1) a palladium-catalyzed direct C–H arylation to construct 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine L, (2) a Boulton–Katritzky rearrangement of 1,2,4-oxadiazole F to the 1,2,4-triazole G, and (3) a palladium-catalyzed Negishi reaction to forge the heterobiaryl linkage.


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Comment

In order to deploy the Negishi coupling to forge heterobiaryl I, chemoselective metalation of the C3–H in triazole G was accomplished using the hindered Knochel base TMPZnCl•LiCl (see Review below). An excess of the base (3.3 equiv) was required because of competing metallation of amide functionalities in G and H.


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Review

B. Haag, M. Mosrin, H. Ila, V. Malakhov, P. Knochel Angew. Chem. Int. Ed. 2011, 50, 9794–9824.


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