10.1021/ol202515x r 2011 American Chemical Society Published on Web 10/25/2011 ORGANIC LETTERS 2011 Vol. 13, No. 22 6038–6041 A Kiyooka Aldol Approach for the Synthesis of the C(14)ÀC(23) Segment of the Diastereomeric Analog of Tedanolide C Leila B € ulow, Arun Naini, J € org Fohrer, and Markus Kalesse* Centre for Biomolecular Drug Research, Leibniz Universit € at Hannover, 30167 Hannover, Germany Markus.Kalesse@oci.uni-hannover.de Received September 16, 2011 ABSTRACT The challenging synthesis of a quaternary center within the highly oxygenated setting of tedanolide C can be performed via a Kiyooka aldol reaction. Here, the diastereomeric analog of tedanolide C with the configurations between C10 and C20 opposite compared to the proposed structure was chosen as the synthetic target. The tetra-substituted silyl ketene acetal provides the southern hemisphere of tedanolide C in useful selectivities, and the absolute configuration of the newly generated quaternary center was determined by NOE experiments of the corresponding acetonide. In 2005 Ireland and co-workers isolated tedanolide C (1) from the marine sponge Ircinia sp. 1 It belongs to the family of the tedanolides which includes, up to now, five members 2À4 which have attracted considerable synthetic interest. 5 Tedanolide C (1) exhibits potent cytotoxicity against HCT-116 cells in vitro with an IC 50 of 57 ng/mL. Subsequent cell cycle analysis showed that treatment of HCT-cells with 0.2 μg/mL tedanolide C (1) resulted in a strong accumulation of cells in the S-phase. These results indicate that tedanolide C (1) could be a promising lead compound for the inhibition of protein biosynthesis. 6 Tedanolide C (1) contains a highly functionalized 18- membered macrolactone displaying 12 stereogenic centers (Figure 1). The side chain, which bears an epoxide, is characteristic for all members of the tedanolide family. 7 (1) Ireland, C. M.; Aalbersberg, W.; Andersen, R. J.; Ayral-Kaloustian, S.; Berlinck, R.; Bernan, V.; Carter, G.; Churchill, A. C. L.; Clardy, J.; Concepcion, G. P.; Dilip De Silva, E.; Discafani, C.; Fojo, T.; Frost, P.; Gibson, D.; Greenberger, L. M.; Greenstein, M.; Harper, M. K.; Mallon, R.; Loganzo, R.; Nunes, M.; Poruchynsky, M. S.; Zask, A. Pharm Biol. 2003, 41, 15. (2) Tedanolide: Schmitz, F. J.; Gunasekera, S. P.; Yalamanchili, G.; Hossain, M. B.; van der Helm, D. J. Am. Chem. Soc. 1984, 106, 7251. (3) 13-Deoxytedanolide: Fusetani, N.; Sugawara, T.; Matsunaga, S. J. Org. Chem. 1991, 56, 4971. (4) Candidaspongiolide: Meragelman, T. L.; Willis, R. H.; Woldemichael, C. M.; Heaton, A.; Murphy, P. T.; Snader, K. M.; Newman, D. J.; van Soest, R.; Boyd, M. R.; Cardellina, J. H.; McKee, T. C. J. Am. Prod. 2007, 70, 1133. (b) Whitson, E. L.; Pluchino, K. M.; Hall, M. D.; McMahon, J. B.; McKee, T. C. Org. Lett. 2011, 13, 3518. (5) (a) Smith, A. B.; Adams, C. M.; Barbosa, S. A. L.; Degnan, P. J. Am. Chem. Soc. 2003, 125, 350. (b) Smith, A. B.; Adams, C. M.; Barbosa, S. A. L.; Degnan, P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12042. (c) Julian, L. D.; Newcom, J. S.; Roush, W. R. J. Am. Chem. Soc. 2005, 127. (d) Ehrlich, G.; Hassfeld, J.; Eggert, U.; Kalesse, M. J. Am. Chem. Soc. 2006, 128, 14038. (e) Ehrlich, G.; Hassfeld, J.; Eggert, U.; Kalesse, M. Chem.;Eur. J. 2008, 14, 2232. (f) Dunetz, J. R.; Julian, L. D.; Newcom, J. S.; Roush, W. R. J. Am. Chem. Soc. 2008, 130, 16407. (6) Tedanolide, C; Chevallier, C.; Bugni, T. S.; Feng, X.; Harper, M. K.; Orendt, A. M.; Ireland, C. M. J. Org. Chem. 2006, 71, 2510. (7) (a) Taylor, R. E. Nat. Prod. Rep. 2008, 25, 854. (b) Roy, M.; Kalesse, M. Nat. Prod. Rep. 2008, 25, 862.