Convergent Synthesis and Discovery of a Natural Product-Inspired Paralog-Selective Hsp90 Inhibitor (original) (raw)

A convergent synthesis of benzoquinone ansamycin analogs is described that proceeds by a sequence of metallacycle-mediated alkyneÀalkyne coupling, followed by site-and stereoselective dihydroxylation and global carbamate formation. These studies have led to (1) validation of alkyneÀalkyne coupling to produce geldanamycin analogs that lack the problematic quinone, (2) the discovery that C6ÀC7 bis-carbamate functionality is compatible with Hsp90 inhibition, and (3) the identification of 1 as a nonquinone geldanamycin-inspired paralog-selective Hsp90 inhibitor.