10.1021/ol201464m r 2011 American Chemical Society Published on Web 06/27/2011 ORGANIC LETTERS 2011 Vol. 13, No. 15 3940–3943 Synthesis of a Pladienolide B Analogue with the Fully Functionalized Core Structure Sarah M € uller, † Timo Mayer, † Florenz Sasse, ‡ and Martin E. Maier* ,† Institut f € ur Organische Chemie, Universit € at T€ ubingen, Auf der Morgenstelle 18, 72076 T€ ubingen, Germany, and Abteilung Chemische Biologie Helmholtz-Zentrum f € ur Infektionsforschung, Inhoffenstrasse 7, 38124 Braunschweig, Germany martin.e.maier@uni-tuebingen.de Received May 31, 2011 ABSTRACT Starting from (R)-(À)-linalool (6), terminus differentiation and chain extension via aldol type reactions led to ketophosphonate 16 (C1ÀC8 building block). In a HornerÀWadsworthÀEmmons reaction, 16 reacted with aldehyde 22, which contained the vicinal anti-MeÀOH pattern and a vinyl iodide function, to provide the C1ÀC13 part of pladienolide B. After Shiina macrolactonization, reduction of the enone 26 gave the core structure 27. A Stille cross-coupling of vinyl iodide 27 with tributylphenylstannane eventually furnished analogue 30. A living cell can be considered as a very complex factory. While there might be many menial tasks, most of the cellular processes are highly complex. Disfunctions in key processes cause diseases, like cancer. In deciphering biological processes, natural products are still an impor- tant tool and the discovery of natural products often identifies new biological targets to treat diseases. Illustra- tive examples in this regard are the pladienolides and FR901464 (Figure 1). Appropriately labeled and modified derivatives of pladienolide B 1À3 (1) and FR901464 4,5 (4) showed that the strong antitumor activities of these natural products are connected with interference of the splicing process. 6À8 Protein production in eukaryotic cells requires removal of introns from the initial transcript, the pre- mRNA, by the spliceosome before the mature mRNA is released to the cytosol. The splicing process involves well organized binding and release of several small nuclear ribonucleoproteins (snRNPs), like U1, U2, U4/U6ÀU5 † Institut f€ ur Organische Chemie, Universit € at T€ ubingen. ‡ Abteilung Chemische Biologie Helmholtz-Zentrum f€ ur Infektionsforschung. (1) (a) Sakai, T.; Sameshima, T.; Matsufuji, M.; Kawamura, N.; Dobashi, K.; Mizui, Y. J. Antibiot. 2004, 57, 173–179. (b) Sakai, T.; Asai, N.; Okuda, A.; Kawamura, N.; Mizui, Y. J. Antibiot. 2004, 57, 180–187. (2) Stereochemistry: Asai, N.; Kotake, Y.; Niijima, J.; Fukuda, Y.; Uehara, T.; Sakai, T. J. Antibiot. 2007, 60, 364–369. (3) Biological activity: Mizui, Y.; Sakai, T.; Iwata, M.; Uenaka, T.; Okamoto, K.; Shimizu, H.; Yamori, T.; Yoshimatsu, K.; Asada, M. J. Antibiot. 2004, 57, 188–196. (4) Isolation and structure: (a) Nakajima, H.; Sato, B.; Fujita, T.; Takase, S.; Terano, H.; Okuhara, M. J. Antibiot. 1996, 49, 1196–1203. (b) Nakajima, H.; Hori, Y.; Terano, H.; Okuhara, M.; Manda, T.; Matsumoto, S.; Shimomura, K. J. Antibiot. 1996, 49, 1204–1211. (c) Nakajima, H.; Takase, S.; Terano, H.; Tanaka, H. J. Antibiot. 1997, 50, 96–99. (5) For recent total syntheses and synthetic studies, see: (a) Thompson, C. F.; Jamison, T. F.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 9974–9983. (b) Motoyoshi, H.; Horigome, M.; Ishigami, K.; Yoshida, T.; Horinouchi, S.; Yoshida, M.; Watanabe, H.; Kitahara, T. Biosci. Biotechnol. Biochem. 2004, 68, 2178–2182. (c) Motoyoshi, H.; Horigome, M.; Watanabe, H.; Kitahara, T. Tetrahedron 2006, 62, 1378–1389. (d) Albert, B. J.; Sivaramakrishnan, A.; Naka, T.; Czaicki, N. L.; Koide, K. J. Am. Chem. Soc. 2007, 129, 2648–2659. (e) Osman, S.; Albert, B. J.; Wang, Y.; Li, M.; Czaicki, N. L.; Koide, K. Chem.;Eur. J. 2011, 17, 895–904. (6) Pladienolide study: Kotake, Y.; Sagane, K.; Owa, T.; Mimori- Kiyosue, Y.; Shimizu, H.; Uesugi, M.; Ishihama, Y.; Iwata, M.; Mizui, Y. Nat. Chem. Biol. 2007, 3, 570–575. (7) FR901464 (spliceostatin A) study: Kaida, D.; Motoyoshi, H.; Tashiro, E.; Nojima, T.; Hagiwara, M.; Ishigami, K.; Watanabe, H.; Kitahara, T.; Yoshida, T.; Nakajima, H.; Tani, T.; Horinouchi, S.; Yoshida, M. Nat. Chem. Biol. 2007, 3, 576–583. (8) For a summary, see: Rymond, B. Nat. Chem. Biol. 2007, 3, 533– 535. (9) (a) van Alphen, R. J.; Wiemer, E. A. C.; Burger, H.; Eskens, F. A. L. M. Br. J. Cancer 2009, 100, 228–232. (b) House, A. E.; Lynch, K. W. J. Biol. Chem. 2008, 283, 1217–1221.