Cantharidin synthesis

Cannabinol, A -3,4-trans-tetrahydro-biological activity, 3, 877 Cannabinol, (—)-A -3,4- ran5-tetrahydro-as pharmaceutical, 1, 151 Cannabinolic acid synthesis, 3, 721 Cannabinolic acid, tetrahydro-photochemistry, 3, 721 Cannabis, citrylidene-, 3, 675 Cantharidin synthesis, 1, 440 Capillarin occurrence, 3, 677 ozonolysis, 3, 681... 

Singlet oxygen adds to cyclic 1,3-dienes to afford 1,4-endoperoxides 609). This type of reaction has first been applied successfully to the synthesis of ascaridole from a-terpinene 610) (6.4) and of the vesicatory compound cantharidine 6U) (6.5) some 25 years ago. 

Diels-Alder route to cantharidin. Use of high pressure to facilitate. Diels-Alder reactions has led to a simple synthesis of cantharidin.1 The obvious dienophile component, dimethylmaleic anhydride, is unreactive to furane even under high pressure, but 2,5-dihydrothiophene-3,4-dicarboxylic anhydride (l)2 reacts with furane at 25° under 15 kbar of pressure to give the exo-adduct (2) and the endo-isomer as a 85 15 mixture. The major adduct is converted into cantharidin (3) by reduction and desulfurization over Raney nickel in 63% overall yield. 

Cantharidin (24) [31] represents the simplest known inhibitor of the ser-ine/threonine protein phosphatases 1 and 2A, and can be isolated from dried beetles (Cantharis vesycatoria). The simplest synthesis of 24 from furan and dimethylmaleic anhydride met with failure, even at pressures as high as 6.0 GPa either at rt or at temperatures of up to 350 °C, presumably due to the thermodynamic instability of the adduct at normal pressure, e.g., when pressure is released [32], However, if this reaction could be carried out in the presence of Pd/C and H2,24 might be obtained in one step. Nevertheless, high-pressure cycloaddition turned out to be very useful for the synthesis of cantharidin and its derivatives [31-33]. For instance, ( )-palasonin was synthesized from furan and citraconic anhydride (21) at 0.8 GPa for 138 h, followed by hydrogenation over Pd/C. Neither high temperatures nor... 

The direct synthesis of cantharidin by a Diels-Alder reaction of furan with dimethyl maleic anhydride 6 is not possible. However, cycloaddition can be carried out with 2,5-dihydrothiophene-3,4-dicarboxylic acid anhydride 8 as dienophile. The cycloadduct 9 exolendo mixture 85 15) is subsequently hydrogenated and the tetrahydrothiophene ring in 10 is cleaved by a reductive desulfurization [17] ... 

Synthesis and biological activities of cantharidin (2,6-dimethyl-4,10-dioxatricyclo-[5.2.1.0 ]decane-3,5-dione) and its derivatives 06CJO579. 

Cantharidin is a powerfiil vesicant that can be isolated from dried beetles Cantharis vesicatoria, or Spanish fly ). Outlined here is the stereospecific synthesis of cantharidin reported by Gilbert Stork (Columbia University). Supply the missing reagents (a)-(n). 

However, synthesis of the cantharidin based on the Diels—Alder reaction between the two reactants also involves an equilibrium that is very unfavorable to the product. The instability of the exo adduct in this case is due to the repulsion between the methyl groups and also to the repulsion between the hydrogens located at C-5 and C-6. 

Synthesis of cantharidin has indeed been achieved by performing Diels—Alder reaction under high pressure. Subsequent hydrogenation/ desulfurization of the exo adduct is carried out by using Raney nickel. 

PROBLEM 12.62 Propose a synthesis of the powerful vesicant (blister inducer) cantharidin, the active ingredient in the putative aphrodisiac Spanish fly. You may assume that organic starting materials containing no more than six carbon atoms are available, along with any inorganic materials you may need. Hint The thermodynamically more stable exo Diels-Alder adducts of furan are generally isolable. 

But here they obviously had lost sight of the fact that, in trying to use the Diels/Alder reaction for their synthesis of cantharidin, it was them who had penetrated into the hunting-ground of the Kiel chemists. The latter promptly responded [3] ... 

The case history of cantharidin conforms to a long standing expectation, namely that flexibility in preparative chemistry improves the chances of target-directed synthesis. Before Dauben or Grieco could successfully apply their exceptional reaction conditions for a short synthesis of cantharidin, G. Stork et al. [11] and G.O. Schenck, K. Ziegler [12] had accomplished this goal each of them in a multi-step synthesis with a Diels/Alder reaction placed in a strategically crucial position. 

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