Eckhard Claus

The chemistry and biology of ratjadone.

Ratjadone (1), a remarkably cytotoxic secondary metabolite, was isolated in 1994 by Höfle et al. from Sorangium cellulosum collected as a soil sample at Cala Ratjada (Mallorca, Spain). It belongs to a family of so-called orphan ligands which include polyketides like leptomycin, callystatin A, and other related compounds. In initial biological evaluations, it was found that ratjadone exhibits high cytotoxicity in cultured mouse cell lines (L929) with an IC50 value of 50 pg mLÿ1. Additionally, it was found that this compound inhibits the growth of the HeLa cell line (KB3.1) at remarkably low concentrations (40 pg mLÿ1).[5] We initiated the total synthesis of ratjadone in order to provide molecular tools that can be used to investigate the biological effects of individual substructures and to contribute to a better understanding of its mode of action. Our total synthesis of ratjadone was therefore set up to allow the rapid assembly of various ratjadone diastereomers and derivatives from three fragments (Scheme 1). During our manuscript preparation, Williams et al. reported the synthesis of (ÿ)-ratjadone.[6e] The pivotal steps in the synthesis are a Wittig reaction for the junction of the fragments B and C followed by a Heck reaction for the attachment to the A fragment. For the synthesis of diastereomers, the enantiomeric fragments A, B, and C were synthesized according to our original strategy (Scheme 1). From these different fragments, diastereomeric ratjadone frameworks could be assembled in just two steps, with only three further transformations remaining to obtain ratjadone or any of its diastereomers. By using this strategy, we were able to generate the diastereomeric compounds (2 ± 5) and analogues (6 ± 9) shown in Scheme 2. Magae, K. Nagai, Immunology 2000, 99, 243 ± 248; g) T. Kataoka, M. Muroi, S. Ohkuma, T. Waritani, J. Magae, A. Takatsuki, S. Kondo, M. Yamasaki, K. Nagai, FEBS Lett. 1995, 359, 53 ± 59; h) T. Kataoka, K. Takaku, J. Magae, N. Shinohara, H. Takayama, S. Kondo, K. Nagai, J. Immunol. 1994, 153, 3938 ± 3947; i) A. Nakamura, J. Magae, R. F. Tsuji, M. Yamasaki, K. Nagai, Transplantation 1989, 47, 1013 ± 1016. [10] A. Fürstner, J. Grabowski, C. W. Lehmann, T. Kataoka, K. Nagai, ChemBioChem 2001, 2, 60 ± 68. [11] A. Fürstner, Synlett 1999, 1523 ± 1533. [12] a) M. S. Melvin, J. T. Tomlinson, G. R. Saluta, G. L. Kucera, N. Lindquist, R. A. Manderville, J. Am. Chem. Soc. 2000, 122, 6333 ± 6334; b) M. S. Melvin, D. C. Ferguson, N. Lindquist, R. A. Manderville, J. Org. Chem. 1999, 64, 6861 ± 6869. The investigations summarized in this paper strongly suggest an intercalative binding mode for prodigiosin, with preferences for AT sites. [13] Many DNA-cleaving agents use metal ions and O2 to cause oxidative damage. Most important among them is bleomycin, an anticancer agent in clinical use. For reviews see: a) W. K. Pogozelski, T. D. Tullius, Chem. Rev. 1998, 98, 1089 ± 1107; b) G. Pratviel, J. Bernadou, B. Meunier, Angew. Chem. 1995, 107, 819 ± 845; Angew. Chem. Int. Ed. Engl. 1995, 34, 746 ± 769; c) S. M. Hecht, J. Nat. Prod. 2000, 63, 158 ± 168; d) J. Stubbe, J. W. Kozarich, W. Wu, D. E. Vanderwall, Acc. Chem. Res. 1996, 29, 322 ± 330; e) R. M. Burger, Chem. Rev. 1998, 98, 1153 ± 1169; f) R. B. Hertzberg, P. Dervan, Biochemistry 1984, 23, 3934 ± 3945. [14] F. Sanger, G. M. Air, B. G. Barrell, N. L. Brown, A. R. Coulson, J. C. Fiddes, C. A. Hutchinson, P. M. Slocombe, M. Smith, Nature 1977, 265, 687 ± 695. [15] For a discussion of the assay and the assignment of the bands see: J. Drak, N. Iwasaka, S. Danishefsky, D. M. Crothers, Proc. Natl. Acad. Sci. USA 1991, 88, 7464 ± 7468. [16] The activity of compound 6 to induce strand cleavage in combination with Cu has been examined at various concentrations, setting the incubation time to 1 h. The minimum concentration found to be effective was 10 ± 15 mM. Therefore, the comparative investigation of different prodigiosin analogues shown in Figure 2 as well as the kinetic experiment depicted in Figure 1 have been carried out with 30 mM concentrations of the individual compounds, which is well above this threshold. [17] a) D. Eichinger, H. Falk, Monatsh. Chem. 1987, 118, 255 ± 260; b) H. Falk, The Chemistry of Linear Oligopyrroles and Bile Pigments, Springer, Wien, 1989. [18] The equilibrium is dependent on the pH of the medium, see: V. Rizzo, A. Morelli, V. Pinciroli, D. Sciangula, R. DAlessio, J. Pharm. Sci. 1999, 88, 73 ± 78.

Synthesis of the C1C9 segment of epothilons

Abstract The C1ue5f8C9 segment of epothilons was generated by an aldol reaction between chiral aldehyde 3 and ethyl ketone 4. Removal of the TBS protecting groups and debenzylation generated spiro ketal 13 which was analyzed by X-ray crystallography.

The Formal Total Synthesis of Epothilone A

The formal total synthesis of epothilone A is described. The key steps in the synthesis of the northern hemisphere are a Z-selective ten-membered ring-closing metathesis reaction (RCM) and the diastereoselective alkylation at C8. Aldehyde 3 is formed by introduction of the thiazole moiety by a Wittig reaction and subsequent functional group transformation. An efficient route to keto acid 5 is described.

Synthesis of the C6C16 polyene fragment of ratjadone, a potent cytotoxic metabolite from Sorangium cellulosum

Abstract The Pd-catalyzed synthesis of the polyene fragment of ratjadone is described. This strategy employs the Stille-coupling for the coupling of the tetrahydropyran subunit and the Suzuki coupling for attaching the unsaturated lactone to the polyene chain.