Novel class of tertiary phosphine ligands based on a phospha-adamantane framework and use in the Suzuki cross-coupling reactions of aryl halides under mild conditions

A new class of sterically hindered phosphines based on a phospha-adamantane framework is described. Arylation or alkylation of the 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phospha-adamantane system allows for the preparation of tertiary phosphines suitable for use in palladium-catalyzed cross-coupling reactions. For example, use of a catalytic system incorporating Pd2(dba)3 and 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phospha-adamantane is shown to promote the Suzuki cross-coupling of aryl iodides, bromides, and activated chlorides with a variety of aryl boronic acids at room temperature in a few hours with high yields

Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B‑Raf-Driven Tumors

Hyperactive signaling of the MAP kinase pathway resulting from the constitutively active B-Raf^V600E mutated enzyme has been observed in a number of human tumors, including melanomas. Herein we report the discovery and biological evaluation of GSK2118436, a selective inhibitor of Raf kinases with potent in vitro activity in oncogenic B-Raf-driven melanoma and colorectal carcinoma cells and robust in vivo antitumor and pharmacodynamic activity in mouse models of B-Raf^V600E human melanoma. GSK2118436 was identified as a development candidate, and early clinical results have shown significant activity in patients with B-Raf mutant melanoma