TABLE OF CONTENTS

I.	Introduction	1
II.	Origin, Toxicity, and Uses	2
III.	Historical Background	4
IV.	Synthesis	7
V.	Further Work	13
VI.	Conclusion	18
VII.	References	19
VIII.	Appendix	21

I. Introduction

Cantharidin (I) is the active ingredient of cantharides, a toxic preparation isolated from thedried bodies of blister beetles (Lytta vesicatoria or Cantharisvesicatoria), which, besides its notoriety as the reputed aphrodisiac in "Spanish fly," hasfound commercial applications as a potent vesicant (blister-causing agent), counterirritant, and inthe removal of benign epithelial growths such as common warts.

I

Since its initial isolation in crystalline form by the French pharmacist Robiquet in 1810,¹ cantharidin has been subject to extensive structural and syntheticinvestigations, owing to its relatively simple structure and extraordinary physiological properties. The seemingly-obvious synthesis of this molecule via a concerted [4+2] Diels-Alder cycloadditionreaction between furan and dimethylmaleic anhydride, followed by hydrogenation, wasinvestigated as early as the 1920s,^2,3but such a direct synthetic approach failed. Although some early attempts at the stereospecificsyntheses of 1 had been successful,^4-6 the length andcomplexity of these efforts stand in sharp contrast to the uncomplicated structure of I. It is onlyrecently that a short and efficient total synthesis of I was achieved by a Diels-Alder reaction,carried out under high pressure between furan and a dihydrothrophene anhydride, a cyclic sulfidederivative of dimethylmaleic anhydride.⁷

This report will examine the historical background of cantharidin and its recent synthesis. Thebiological origin (including biosynthesis), toxicity, and practical uses of the compound will bebriefly mentioned. Then, the historical background of the compound, particularly the earlyinvestigations that led to the determination of the correct structure and the earlyattempts--successful or otherwise--at its synthesis, will be described. Finally, the most recentsynthesis of cantharidin will be described in detail, including the problems associated with it, itspreparative scale, the advantages it has over previous syntheses, and the current efforts beingmade for its improvement. A new synthesis of the compound will also be suggested.

II. Origin, Toxcity, and Uses

Cantharidin (1) is naturally found in various species of blister beetles (familyMeloidae), the most familiar of which is the "spanish fly" Lyttavesicatoria (or Cantharis vesicatoria). Used as a defensive substance inthese beetles, cantharidin is biosynthesized in the adult male beetles during mating and iscompletely transferred into the females (which do not produce cantharidin on their own) throughthe sex organs.¹⁴ It was also found that the male beetlescontinue to produce cantharidin after mating, an evidence which suggests that the biosynthesis ofcantharidin in the male beetles is stimulated during copulation and occurs in the accessory glandsof the male sexual organs.¹⁴ Labelling studies usingradioactive isotopes of carbon (¹⁴C) and hydrogen (³H), andnonradioactive oxygen (¹⁸O), with mass spectrometry have indicated that thebiosynthesis proceeds by an unprecedented degradation of farnesol (II),¹⁵

Commercially, cantharidin is available as CANTHARONE^®, a cantharidin(0.7%) collodion used for the removal of benign epithelial growths such as warts and molluseumcontagiosum.¹⁹ The apparently original characteristics ofcantharidin-induced inflammation (absence of involvement from immunological processes) mayalso make it useful for the testing of anti-inflammatory and anti-allergic drugs.²⁰ The reputation of cantharidin as an aphrodisiac upon ingestion is widely accepted due to theresulting irritation of the urethra (male genital duct), which may result in priapism (persistenterection of the penis).¹⁸ However, as already mentionedabove, its ingestion is dangerous, sometimes lethal.²¹

VII. References

(1)	Robique. M. Ann. Chim. 1810, 76, 302-307.
(2)	von Bruchhausen, F.; Bersch, II. W. Arch. Pharm. Ber. Disch. Phurm. Ges. 1928, 266, 697-702.
(3)	Diels. O.; Alder, K. Ber. 1929, 62, 554-562.
(4)	Ziegler, L.; Schenck, G.; Krockow, E. W.; Siebert, A.; Wenz, A.; Weber, H. Justus Liebigs Ann. Chem. 1942. 551, 1-79.
(5)	Stork, G.; van Tamelen, E. E.; Friedman, L. I.; Burgstahler, A. W. J. Am. Chem. Soc. 1953, 75, 384-392.
(6)	Schenck, G.; Wirtz, R. Naturwissenshaften 1953, 40, 531.
(7)	Dauben, W. G.; Kessel, C. R.; Takemura, K. H. J. Am. Chem. Soc. 1980, 102, 6893-6894.
(8)	Dauben, W. G.; Krabbenhoft, II. O. J. Am. Chem. Soc. 1976, 98, 1992-1993.
(9)	Gladysz, J. A. CHEMTECH 1979, 372-377.
(10)	Jurezak, J.; Kozluk, T.; Filipek, S.; Eugster, C. H. Helv. Chim. Acta 1982, 65, 1021-1024.
(11)	McCormick, J. P.; Shimmyozu, T. J. Org. Chem. 1982, 47, 4011- 4012.
(12)	Matsumoto, K.; Hashimoto, S.; Ikemi, Y.; Otani, S.; Uchida, T. Heterocycles, 1986, 24, 1835-1839.
(13)	Grieco, P. A.; Nunes, J. J.; Gaul, M. D. J. Am. Chem. Soc. 1990, 112, 4595-4596.
(14)	Sierra, J. R.; Woggon, W. D.; Schmid, H. Experientia 1976, 32, 142-144.
(15)	McCormick, J. P.; Carrel, J. E.; Doom, J. P. J. Am. Chem. Soc. 1986, 108, 8071-8074.
(16)	Peter, M. G.; Woggon, W. -D.; Schmid, H. Helv Chim. Acta 1977, 60, 2756-2762.
(17)	Graziano, M. J.; Casida, J. E.; Waterhouse, A. L. Biochem. Biophys. Res. Comm. 1987, 149, 79-85.
(18)	Waddell, T. G.; Jones, H.; Keith, A. L. J. Chem. Educ. 1980, 57, 341-342.
(19)	Physicians' Desk Reference to Pharmaceutical Specialties and Biologicals; Medical Economics, Inc.: New Jersey, 1970; p 1727.