Synthesis of the namenamicin A–C disaccharide: towards the total synthesis of namenamicin

Abstract

Progress towards the total synthesis of namenamicin (1), the only enediyne antitumor antibiotic of marine origin, is reported. Two methods were investigated for the stereoselective introduction of the highly unusual quaternary C-4 center of the A-ring. Spirocyclic [3,3]-sigmatropic rearrangements of the thiocarbonates 6 and 10 gave products 7 and 11, from processes involving approach of the sulfur atom solely to the α-faces of the substrates. The desired stereochemistry of the quaternary center was ultimately obtained by way of an intramolecular Michael addition of a xanthate anion derived from the α,β-unsaturated methyl ester 18. Further functional group manipulations provided an olefin 25 which underwent dihydroxylation to give a mixture of diastereomeric diols 26, allowing access to both potential diastereomers of the natural product. The A ring intermediate 29 was found to be a viable substrate of glycosidation with a glycosyl fluoride of the C ring aminosugar 30, providing the protected A–C disaccharide subunit of 1.

References

1. (a) Enediyne Antibiotics as Antitumor Agents, ed. D. B. Borders and T. W. Doyle, Marcel Dekker Inc., New York, 1995; (b) A. L. Smith and K. C. Nicolaou, J. Med. Chem., 1996, 39, 2103; (c) K. C. Nicolaou, A. L. Smith and E. W. Yue, Proc. Natl. Acad. Sci. USA, 1993, 90, 5881.
2. L. A. McDonald, T. L. Capson, G. Krishnamurthy, W.-D. Ding, G. A. Ellestad, V. S. Bernan, W. M. Maiese, P. Lassota, C. Discafani, R. A. Kramer and C. M. Ireland, J. Am. Chem. Soc., 1996, 118, 10898.
3. B. S. Davidson, Chem. Rev., 1993, 93, 1771.
4. M. D. Lee, in Enediyne Antibiotics as Antitumor Agents, ed. D. B. Borders and T. W. Doyle, Marcel Dekker Inc., New York, 1995, p. 49.
5. K. S. Lam and S. Forenza, in Enediyne Antibiotics as Antitumor Agents, ed. D. B. Borders and T. W. Doyle, Marcel Dekker Inc., New York, 1995, p. 161.
6. K. C. Nicolaou, C. W. Hummel, M. Nakada, K. Shibayama, E. N. Pitsinos, H. Saimoto, Y. Mizuno, K.-U. Baldenius and A. L. Smith, J. Am. Chem. Soc., 1993, 115, 7625.
7. (a) B. Fraser-Reid and D. L. Walker, Can. J. Chem., 1980, 58, 2694; (b) B. Fraser-Reid, R. Tsang, D. B. Tulshian and K. M. Sun, J. Org. Chem., 1981, 46, 3764; (c) D. B. Tulshian, R. Tsang and B. Fraser-Reid, J. Org. Chem., 1984, 49, 2347; (d) B. Fraser-Reid, D. B. Tulshian, R. Tsang and D. Lowe, Tetrahedron Lett., 1984, 25, 4579.
8. (a) R. D. Groneberg, A. Miyazaki, N. A. Stylianides, T. J. Schulze, W. Stahl, T. Schreiner, T. Suzuki, Y. Iwabuchi, A. L. Smith and K. C. Nicolaou, J. Am. Chem. Soc., 1993, 115, 7593; (b) S. G. Smith, J. Am. Chem. Soc., 1961, 83, 4285; (c) M. S. Chambers, E. J. Thomas and D. J. Williams, J. Chem. Soc., Chem. Commun., 1987, 1228.
9. P. Garner and S. Ramakanth, J. Org. Chem., 1987, 52, 2631.
10. M. J. Robins, J. S. Wilson and F. Hansske, J. Am. Chem. Soc., 1983, 105, 4059.
11. T. Sheradsky, in The Chemistry of the Thiol Group. Part 2, ed. S. Patai, John Wiley & Sons, New York, 1974, p. 686.
12. L. M. Lerner, Carbohydr. Res., 1993, 241, 291.
13. (a) B. H. Lipshutz and J. J. Pegram, Tetrahedron Lett., 1980, 21, 3343; (b) B. H. Lipshutz and T. A. Miller, Tetrahedron Lett., 1989, 30, 7149.
14. S. David and A. ThieVry, J. Chem. Soc., Perkin Trans. 1, 1979, 1568.
15. P. A. Grieco, Y. Yokoyama and E. Williams, J. Org. Chem., 1978, 43, 1283.
16. (a) F. A. Davis, O. D. Stringer and J. M. Billmers, Tetrahedron Lett., 1983, 24, 1213; (b) F. A. Davis, S. Chattopadhyay, J. C. Towson, S. Lal and T. Reddy, J. Org. Chem., 1988, 53, 2087.
17. K. B. Sharpless and M. W. Young, J. Org. Chem., 1975, 40, 947.
18. K. Mori and Y. Nakamura, J. Org. Chem., 1969, 34, 4170.
19. A. Hassner, L. R. Krepski and V. Alexanian, Tetrahedron, 1978, 34, 2069.
20. (a) P. J. Walsh, P. T. Ho, S. B. King and K. B. Sharpless, Tetrahedron Lett., 1994, 35, 5129; (b) T. Sammakia, T. B. Hurley, D. M. Sammond, R. S. Smith, S. B. Sobolov and T. R. Oeschger, Tetrahedron Lett., 1996, 37, 4427.
21. (a) G. R. Sullivan, J. A. Dale and H. S. Mosher, J. Org. Chem., 1973, 38, 2143; (b) B. M. Trost, J. L. Belletire, S. Godleski, P. G. McDougal and J. M. Balkovec, J. Org. Chem., 1986, 51, 2370.
22. K. C. Nicolaou and D. Clark, Angew. Chem., Int. Ed. Engl., 1992, 31, 855.
23. (a) T. Mukaiyama, Y. Hashimoto and S. Shoda, Chem. Lett., 1983, 935; (b) K. C. Nicolaou, J. L. Randall and G. T. Furst, J. Am. Chem. Soc., 1985, 107, 5556.