Synthesis of rac-hippospongic acid A and revision of the structure

Abstract

rac-Hippospongic acid A of the reported structure 1 and the revised structure 2 were synthesized. The synthetic strategy of these compounds consists of homologation of (2E,6E,10E )-geranylgeraniol and (2E,6E )-farnesol, respectively, Wadsworth–Emmons reaction, and cyclization to form the tetrahydropyran ring bearing an α-methylene group on the carboxylic moiety. Spectral comparisons of the synthetic compounds 1, 2 and the natural product suggested that hippospongic acid A bears the structure of 2.

References

1. W. H. Gerwick, P. J. Proteau, D. G. Nagle, E. Hamel, A. Blokhin and D. L. Slate, J. Org. Chem., 1994, 59, 1243; A. V. Blokhin, H.-D. Yoo, R. S. Geralds, D. G. Nagle, W. H. Gerwick and E. Hamel, Mol. Pharmacol., 1995, 48, 523.
2. M. Tsuda, H. Shigemori, M. Ishibashi, T. Sasaki and J. Kobayashi, J. Org. Chem., 1992, 57, 3503.
3. S. Ohta, M. Uno, M. Yoshimura, Y. Hiraga and S. Ikegami, Tetrahedron Lett., 1996, 37, 2265.
4. T. Nemoto, M. Ojika and Y. Sakagami, Tetrahedron Lett., 1997, 38, 5667.
5. S. Ohta, M. Uno, M. Tokumasu, Y. Hiraga and S. Ikegami, Tetrahedron Lett., 1996, 37, 7765.
6. Kodama has also suggested that the structure of the natural product is that of 2 H. Hioki, H. Ooi, Y. Mimura, S. Yoshio and M. Kodama, Synlett, 1998, 729; H. Hioki, M. Hamano, Y. Mimura, M. Kodama, S. Ohta, M. Yanai and S. Ikegami, Tetrahedron Lett., 1998, 39, 7745.
7. R. Takagi, A. Sasaoka, S. Kojima and K. Ohkata, Chem. Commun., 1997, 1887; R. Takagi, A. Sasaoka, H. Nishitani, S. Kojima, Y. Hiraga and K. Ohkata, J. Chem. Soc., Perkin Trans. 1, 1998, 925.
8. R. Takagi, A. Sasaoka, S. Kojima and K. Ohkata, Heterocycles, 1997, 45, 2313.
9. W. S. Johnson, L. Werthemann, W. R. Bartlett, T. J. Brocksom, T. Li, D. J. Faulkner and M. R. Petersen, J. Am. Chem. Soc., 1970, 92, 741.