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