10.1021/ol2019828 r 2011 American Chemical Society Published on Web 08/25/2011 ORGANIC LETTERS 2011 Vol. 13, No. 19 5108–5111 Convergent Synthesis and Discovery of a Natural Product-Inspired Paralog- Selective Hsp90 Inhibitor Valer Jeso, † Lisa Cherry, ‡ Todd K. Macklin, † Subhas Chandra Pan, † Philip V. LoGrasso,* ,‡ and Glenn C. Micalizio* ,† Department of Chemistry, Department of Molecular Therapeutics, and the Translational Research Institute, The Scripps Research Institute, Jupiter, Florida 33458, United States micalizio@scripps.edu; lograsso@scripps.edu Received July 22, 2011 ABSTRACT 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. Benzoquinone ansamycins are polyketide-derived natural products that display a broad range of antitumor, anti- bacterial, antifungal, and antiprotozoal activities (Figure 1A). 1 While efforts in chemical synthesis have targeted this natural product class for over 30 years, with the first total synthesis appearing in 1989, 2 the discovery that benzoqui- none ansamycins are potent inhibitors of Hsp90 has led to a substantial increase in activity in this area with the goal of developing novel anticancer chemotherapeutic agents. 3 Hsp90 is widely held as a promising therapeutic target for cancer, as it plays a central role in controlling the post-translational conformational maturation and activation of a large number of oncogenic client proteins in a highly regulated and ATP-fueled manner (i.e., Bcr-Abl, Raf-1, HER2, Cdk4, Akt, ErbB2, and HIF-1R). 4 Additionally, a number of mutant oncoproteins require Hsp90 function, whereas their wild-type counterparts are either not depen- dent or only weakly dependent upon this machinery (v-SRc, EGFR, B-Raf). 5 Further enhancing the potential value of Hsp90 as a therapeutic target is the fact that it is constitutively expressed at 2- to 10-fold higher levels in tumor cells compared to their “normal” counterparts. 6 Overall, inhibition of Hsp90 results in the proteasome- mediated depletion of a number of proteins involved in cell signaling, proliferation, survival, immortalization, invasion, † Department of Chemistry. ‡ Department of Molecular Therapeutics and the Translational Research Institute. (1) For recent reviews on the biological activity of benzoquinone ansamycins, see: (a) Xu, W.; Neckers, L. Clin. Cancer Res. 2007, 13, 1625–1629. (b) Miyata, Y. Curr. Pharm. Des. 2005, 11, 1131–1138. (2) (a) Baker, R.; Castro, J. L. J. Chem. Soc., Chem. Commun. 1989, 378–381. (b) Baker, R.; Castro, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 47–65. (3) Whitesell, L.; Mimnaugh, E. G.; De Costa, B.; Myers, C. E.; Neckers, L. M. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 8324–8328. (4) Neckers, L. Trends Mol. Med. 2002, 8, S55–S61. (5) Chandarlapaty, S.; Sawai, A.; Ye, Q.; Scott, A.; Silinski, M.; Huang, K.; Fadden, P.; Partridge, J.; Hall, S.; Steed, P.; Norton, L.; Rosen, N.; Solit, D. B. Clin. Cancer Res. 2008, 14, 240–248. (6) Ferrarini, M.; Heltai, S.; Zocchi, M. R.; Rugarli, C. Int. J. Cancer 1992, 51, 613–619.