5526 J. Org. Chem. 2010, 75, 5526–5532 Published on Web 07/22/2010 DOI: 10.1021/jo100696w r 2010 American Chemical Society pubs.acs.org/joc Chiral Sulfur Ylides for the Synthesis of Bengamide E and Analogues Francisco Sarabia,* Francisca Martı´n-G alvez, Samy Chammaa, Laura Martı´n-Ortiz, and Antonio S anchez-Ruiz Department of Organic Chemistry, Faculty of Sciences, University of Malaga, Campus de Teatinos s/n 29071, Malaga, Spain frsarabia@uma.es Received April 10, 2010 A new synthetic methodology of asymmetric epoxidation developed in our laboratories has been employed for the stereoselective synthesis of bengamide E (16) and analogues at the terminal olefinic position. In the event, the chiral sulfonium salt 30 was transformed into its corresponding sulfur ylide and reacted with aldehydes 21 and 44 to efficiently provide epoxy amides 31 and 45, respectively. To access the bengamides from these epoxy amides, we combined a synthetic strategy previously reported by us, using an olefin cross metathesis reaction to introduce various alkyl substituents at the terminal olefinic position of amide 33, with reactions mediated by palladium (Negishi or Suzuki couplings) from amide 49. This latter route of introduction of alkyl groups proved to be more efficient than the metathesis approach and allowed access to the generation of a wide array of new bengamide analogues. Introduction The bengamides A-F were discovered and isolated between 1986 1 and 1989 2 by the research group of Professor Crews from an undescribed member of an orange sponge belonging to the Jaspidae family. Following these discoveries, the isolation of new members, such as the bengamides G-J, 3 L, 4 and M-R 5 (Figure 1), together with bengamides Z and Y, 6 K 3 and isobengamide E, 2 were described. Rapidly, these natural pro- ducts were recognized as interesting bioactive compounds possessing potent cytotoxic activity against larynx epithelial carcinoma (1.0 μg/mL) as well as prominent antibiotic and antihelmintic properties. 7 More recently, the biological mode of action of the bengamides has been disclosed, 8 revealing an intriguing mechanism characterized by their binding to either methionine aminopeptidase type 1 (MetAp1) or type 2 (Met- Ap2), 9 enzymes involved in the cell cycle of endothelial cells and angiogenesis. 10 Interestingly, this is a mode of action similar to (1) Quı´ ~ no a, E.; Adamczeski, M.; Crews, P.; Bakus, G. J. J. Org. Chem. 1986, 51, 4494–4497. (2) (a) Adamczeski, M.; Quı´ ~ no a, E.; Crews, P. J. Am. Chem. Soc. 1989, 111, 647–654. (b) Adamczeski, M.; Quı´ ~ no a, E.; Crews, P. J. Org. Chem. 1990, 55, 240–242. (3) D’Auria, M. V.; Giannini, C.; Minale, L.; Zampella, A.; Debitus, C.; Frostin, M. J. Nat. Prod. 1997, 60, 814–816. (4) Fern andez, R.; Dherbomez, M.; Letourneux, Y.; Nabil, M.; Verbist, J. F.; Biard, J. F. J. Nat. Prod. 1999, 62, 678–680. (5) Thale, Z.; Kinder, F. R.; Bair, K. W.; Bontempo, J.; Czuchta, A. M.; Versace, R. W.; Phillips, P. E.; Sanders, M. L.; Wattanasin, S.; Crews, P. J. Org. Chem. 2001, 66, 1733–1741. (6) Groweiss, A.; Newcomer, J. J.; O’Keefe, B. R.; Blackman, A.; Boyd, M. R. J. Nat. Prod. 1999, 62, 1691–1693. (7) (a) Crews, P.; Matthews, T. R.; Quı´ ~ no a, E.; Adamczeski, M. U.S. Patent, 4,831,135, 1989. (b) Kinder, F. R.; Bair, K. W.; Bontempo, J.; Crews, P.; Czuchta, A. M.; Nemzek, R.; Thale, Z.; Vattay, A.; Versace, R. W.; Weltchek, S.; Wood, A.; Zabludoff, S. D.; Phillips, P. E. Proc. Am. Assoc. Cancer Res. 2000, 41, 600. (c) Phillips, P. E.; Bair, K. W.; Bontempo, J.; Crews, P.; Czuchta, A. M.; Kinder, F. R.; Vattay, A.; Versace, R. W.; Wang, B.; Wang, J.; Wood, A.; Zabludoff, S. Proc. Am. Assoc. Cancer Res. 2000, 41, 59. (8) (a) Towbin, H.; Bair, K. W.; DeCaprio, J. A.; Eck, M. J.; Kim, S.; Kinder, F. R.; Morollo, A.; Mueller, D. R.; Schindler, P.; Song, H. K.; van Oostrum, J.; Versace, R. W.; Voshol, H.; Wood, J.; Zabludoff, S.; Phillips, P. E. J. Biol. Chem. 2003, 278, 52964–52971. (b) Kim, S.; LaMontagne, K.; Sabio, M.; Sharma, S.; Versace, R. W.; Yusuff, N.; Phillips, P. E. Cancer Res. 2004, 64, 2984–2987. (c) Hu, X.; Dang, Y.; Tenney, K.; Crews, P.; Tsai, C. W.; Sixt, K. M.; Cole, P. A.; Liu, J. O. Chem. Biol. 2007, 14, 764–774. (9) (a) Lowther, W. T.; Orville, A. M.; Madden, D. T.; Lim, S.; Rich, D. H.; Matthews, B. W. Biochemistry 1999, 38, 7678–7688. (b) Sashidhara, K. V.; White, K. N.; Crews, P. J. Nat. Prod. 2009, 72, 588–603. (10) (a) Folkman, J.; Klagsburn, M. Science 1987, 235, 442–447. (b) Brooks, P. C.; Montgomery, A. M. P.; Rosenfeld, M.; Reisfled, R. A.; Hu, T.; Klier, G.; Cherest, D. A. Cell 1994, 79, 1157–1164. (c) Hu, X.; Addlagatta, A.; Lu, J.; Matthews, B. W.; Liu, J. O. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 18148–18153.