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DOI: 10.1039/CS9972600387 (Review Article) Reference Section for: Chem. Soc. Rev., 1997, 26, 387-399

Approaches to the synthesis of ingenol

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Sanghee Kim and Jeffrey D. Winkler

Abstract

Ingenol is a highly oxygenated tetracyclic diterpene which mimics the function of diacylglycerol, the endogenous activator of protein kinase C. One of the most imposing challenges in the synthesis of ingenol is the establishment of the highly strained ‘inside–outside’ or trans-intrabridgehead stereochemical relationship of the carbocyclic ring system of the ingenanes. The approaches that have been examined in several laboratories towards the synthesis of the ingenanes are summarized. Our own work, using the intramolecular dioxenone photocycloaddition to establish this unique stereochemical feature, is described.

References

  1. H. Opferkuch and E. Hecker, Tetrahedron Lett., 1974, 15, 261 Search PubMed.
  2. R. R. Upadhyay and G. Mohaddes, Curr. Sci., 1987, 56(20), 1058 Search PubMed.
  3. For recent reviews, see P. J. Blackshear, J. Biol. Chem., 1993, 268, 1501 Search PubMed; L. V. Decker and P. J. Parker, Trends in Biochem. Sci., 1994, 19, 73 Search PubMed.
  4. R. Schmidt and A. Aitken, in Naturally Occuring Phorbol Esters, ed. F. Evans, CRC Press, Inc., Boca Raton, 1986, pp. 245; Search PubMed; E. Hecker, in Carcinogenesis: A Comprehensive Survey, Mechanisms of Tumor Promotion and Cocarcinogenesis, vol. 2; ed. T. J. Slaga, A. Sivak and R. K. Boutwell, Raven, New York, 1987, p. 11. Search PubMed.
  5. J. D. Winkler, B.-C. Hong and S. Kim, Synlett, 1995, 533 Search PubMed and references cited therein.
  6. Recently X-ray crystal structure of PKC–phorbol ester complex have been advanced to explain the pharmacophore of the PKC activators, see Chem. Eng. News, 1995, Oct. 23, p. 21; and references cited therein. Search PubMed.
  7. B. Shearer, B. Sullivan, J. Carter, R. Mathew, P. Waid, J. Connor, R. Patch and R. Buch, J. Med. Chem., 1991, 34, 2931 Search PubMed and for a review of PKC regulation; P. C. Gordge and W. J. Ryves, Cellular Signalling, 1994, 6, 871 Search PubMed.
  8. P. Wender and F. McDonald, J. Am. Chem. Soc., 1990, 112, 4956 Search PubMed.
  9. For recent review of the synthesis of tumour-promoting diterpenes, see: J. H. Rigby, in Studies in Natural Products Chemistry, ed. A.-u. Rahman; Elsevier Science Publishers, Amsterdam, 1993, 12, p. 233. Search PubMed.
  10. For a recent review of inside-outside chemistry, see: R. W. Alder and S. P. East, Chem. Rev., 1996, 96, 2097 Search PubMed.
  11. R. Funk, T. A. Olmstead and M. Parvez, J. Am. Chem. Soc., 1988, 110, 3298 Search PubMed.
  12. J. H. Rigby, S. D. Rege, V. P. Sandanayaka and M. Kirova, J. Org. Chem., 1996, 61, 842 Search PubMed.
  13. J. H. Rigby and S. V. Cuisiat, J. Org. Chem., 1993, 58, 6286 Search PubMed.
  14. R. Funk and G. Bolton, J. Am. Chem. Soc., 1986, 108, 4655 Search PubMed.
  15. M. Harmata, S. Elahmad and C. L. Barnes, Tetrahedron Lett., 1995, 36, 1397 Search PubMed.
  16. G. Mehta and V. Pathak, J. Chem. Soc., Chem. Commun., 1987, 876 Search PubMed.
  17. L. Paquette, R. Ross and J. Springer, J. Am. Chem. Soc., 1988, 110, 6192 Search PubMed and references cited therein.
  18. R. Funk, T. A. Olmstead, M. Parvez and J. B. Stallman, J. Org. Chem., 1993, 58, 5873 Search PubMed.
  19. J. H. Rigby, V. S. Claire, S. V. Cuisiat and M. J. Heeg, J. Org. Chem., 1996, 61, 7992 Search PubMed.
  20. J. D. Winkler, B.-C. Hong, A. Bahador, M. G. Kazanietz and P. M. Blumberg, J. Org. Chem., 1995, 60, 1381 Search PubMed and references cited therein..
  21. J. D. Winkler, K. Henegar and P. Williard, J. Am. Chem. Soc., 1987, 109, 2850 Search PubMed.
  22. For a review describing this general strategy, see J. D. Winkler, C. M. Bowen and F. Liotta, Chem. Rev., 1995, 95, 2003 Search PubMed.
  23. For other reviews of [2 + 2] photocycloaddition, see: M. T. Crimmins, Chem. Rev., 1988, 88, 1453 Search PubMed; D. I. Schuster, G. Lem and N. A. Kaprinidis, Chem. Rev., 1993, 93, 3 Search PubMed.
  24. P. de Mayo, Pure Appl. Chem., 1964, 9, 597 Search PubMed.
  25. S. W. Baldwin and J. M. Wilkinson, J. Am. Chem. Soc., 1980, 102, 3634 Search PubMed.
  26. J. D. Winkler, J. P. Hey, F. J. Hannon and P. G. Williard, Heterocycles, 1987, 25, 55 Search PubMed.
  27. J. D. Winkler, B.-C. Hong, J. P. Hey and P. G. Williard, J. Am. Chem. Soc., 1991, 113, 8839 Search PubMed.
  28. J. D. Winkler, K. E. Henegar, B.-C. Hong and P. G. Williard, J. Am. Chem. Soc., 1994, 116, 4183 Search PubMed.
  29. J. D. Winkler, unpublished results..
  30. J. D. Winkler, S. Kim and B.-C. Hong, 212th American Chemical Society National Meeting, 1996, Aug., ORGN, No. 161. Search PubMed.
  31. For the first synthesis of a biologically active analogue of ingenol, see J. D. Winkler, B.-C. Hong, A. Bahador, M. G. Kazanietz and P. M. Blumberg, Bioorg. Med. Chem. Lett., 1993, 3, 577 Search PubMed and ref. 20.
  32. B. B. Lohray, Synthesis, 1992, 1035 Search PubMed.
  33. (a) S. K. Kang, D. H. Lee, Y. S. Kim and S. C. Kang, Synth. Commun., 1992, 22, 1109 Search PubMed; (b) Y. L. Bennani and K. B. Sharpless, Tetrahedron Lett., 1993, 34, 2083 Search PubMed.
  34. M. Tada, T. Kokubo and T. Sato, Bull. Chem. Soc. Jpn., 1970, 43, 2162 Search PubMed.
  35. J. D. Winkler and B. Shao, Tetrahedron Lett., 1993, 34, 3355 Search PubMed.