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Boletín de la Sociedad Chilena de Química

Print version ISSN 0366-1644

Bol. Soc. Chil. Quím. vol.46 n.1 Concepción Mar. 2001 



1Instituto de Química, Universidad Católica de Valparaíso, Casilla 4059, Valparaíso, Chile.
2Departamento de Química Farmacéutica, Facultad de Farmacia,
Universidad de Salamanca E-37007, Salamanca, Spain.
3Pharma Mar S.A., Calera 3, Tres Cantos, E-28760, Madrid, Spain.
(Received: December 29, 1999 - Accepted: October 6, 2000)


Several new 2,3-functionally dialkyl-1,4-benzohydroquinone diacetates have been prepared by oxidative cleavage of epoxide compounds III, obtained from the Diels-Alder condensation product between the monoterpene myrcene and 1,4-benzoquinone. The nature of the isolated products is depending of the functionality of the side chain .

KEY WORDS: Quinones, myrcene, terpenylhydroquinones, oxidative cleavage, epoxides.


Se han preparado una serie de nuevos compuestos del tipo diacetatos de 1,4-benzohidroquinona-2,3-dialquilsustituídos, por oxidación degradativa de epóxidos III, obtenidos del producto de condensación Diels-Alder entre el monoterpeno mirceno y la 1,4-benzoquinona. La naturaleza de los productos aislados depende de los grupos funcionales presentes en las cadenas alquílicas.

PALABRAS CLAVES: Quinonas, mirceno, terpenilhidroquinonas, degradación oxidativa, epóxidos.


Avarol and avarone are sesquiterpene-1,4-benzohydroquinone/quinone marine natural products isolated from the sponge Dysidea avara, which are bioactive against several types of tumoral cells1. Their IC50 values are ranged around the mM or higher levels and a number of analogs compounds have been prepared to evaluate the cytotoxic-antineoplastic activity2. Among these, several families of terpenylquinones/hydroquinones have been synthesized from the Diels Alder adduct I and II obtained via condensation between myrcene and 1,4-benzoquinones or 1,4-naphtoquinone, respectively3,4.

The side chain R and the cyclohexene double bond of I and II were functionalized by epoxidation , oxidative degradation, hydrolisis, reduction, oxidation, esterification, etc., and the cytotoxic-antineoplastic activity against cultured cells of P-388 murine leukemia, A-549 human lung carcinoma, HT-29 human colon carcinoma and Mel-28 human malignan melanoma was evaluated for each new derivative. The IC50 values found ranged between 0.3-20.0 mM for naftoquinone derivatives I and between 8.0-34.0 mM for antraquinone derivatives II. In general, naphtoquinone/hydroquinone derivatives are more potent than those of antraquinones and aromatization of the cyclohexene moiety improves the cytotoxic-antineoplastic activity. The high bioactivity against P-388 was observed in compounds 1-3 ( IC50 = 0.3-0.4 mM).

In a recent study 5, new series of 1,4-naphtohydroquinone diacetate derivatives were prepared and tested against previously mentioned cultured cells. From these studies it was observed that a higher saturation degree of the terpenic part, including the side chain and the ring, is important for the activity and it was also confirmed that aromatization of the ring fused to hydroquinone diacetate moiety improves the cytotoxic potency. Compounds 4-6 showed the high bioactivity against P-388 (IC50= 0.3 mM).

Until now, bioactivity studies have been focused only in the naphtoquinone/hydroquinone and antraquinone derivatives of the monoterpene myrcene but diacetate derivatives have not been still studies. Bioactivity in other 1,4-benzohydroquinones series like paniceines, avarol/avarone and others6-8, have been previously reported and if naphtoquinone/hydroquinone derivatives from I are more potent than those antraquinones from II it is possible to expect an improvement in the cytotoxicity of these 1,4-benzohydroquinone derivatives of myrcene. One synthetic approach to these kind of compound is the oxidative degradation cleavage of epoxides of the structure III. It is known that epoxides are useful intermediates to modify the structure of either simple or complex molecules9,10. For instance, they can be oxidative cleaved to carbonyl compounds with lead tetraacetate, sodium periodate/formic acid or directly with periodic acid. The oxidative degradation with the last two reagents can be formulated as proceeding through the diol and cyclic periodate ester formation, followed by 1,2 elimination. If this reaction is applied to epoxides III, diacetate ketoaldehydes of general structure IV would be the expected product and they can serve as precursor to analog derivatives ( Ec. 1).

In this paper we wish to report the results of of degradative oxidation achieved on epoxides of general structure III with periodic acid to obtain the new hydroquinone diacetate derivatives IV and related derivatives. All new compounds have been properly characterized by usual spectroscopic techniques.


IR spectra were recorded on a Perkin Elmer FT IR 1600 spectrophotometer as a film over sodium chloride discs. NMR spectra were obtained at 200 MHz for 1H and 50 MHz for 13C, in CDCl3 with TMS as internal reference, on a Bruker AC-200 spectrophotometer; chemical shift values are expressed in ppm, followed by multiplicity and coupling constants J in Hz. All the compounds were purified by column chromatography (CC) with silicagel 60, 230-400 mesh ASTM and they were isolated as solids or viscous oils.

Chemistry procedures

The following reactions were performed according to previously reported procedures3-5: Epoxidation with m-chloroperbenzoic acid (MCPBA) in dichlorometane and in the presence of NaHCO3; reduction of aldehydes or epoxides with LAH in dry ether; acid hydrolysis of epoxides with HCl/H2O/t-BuOH ; acetylation with acetic anhydride/pyridine; aldehyde oxidation with NaClO2/NaH2PO4/H2O/t-BuOH/2-methyl-2-butene catalyst; methylation with CH2N2/ether; selective catalytic hydrogenation in ethyl acetate with Pd/CaCO3catalyst ; fully catalytic hydrogenation in ethyl acetate with Pd/C catalyst.

Epoxides were degraded treating 0.6 mmol of the compound in 10 mL THF with a solution of 1.2 mmol of H5IO6 in 6 mL of H2O, at room temperature. The progress of the reaction was monitored by TLC and after completation, the reaction mixture was diluted with 50 mL of ether. The organic layer was washed with aqueous 5% Na2S2O3 (3x30 mL), water until neutral pH of the aqueous layer and dried over anhydrous Na2SO4. After evaporation of the solvents, the reaction product was purified by CC, using hexane/ ethyl acetate in variable proportions as eluent.


Using these reactions, the following new compounds were prepared:

Compound 13. Obtained by degradative H5IO6 oxidation of the epoxide 11. (72%); oil; IR cm-1 3084 (aromatic CH), 2954 -2869 (aliphatic CH), 2725 (aldehyde CH), 1765 (C=O ester), 1721 (C=O aldehyde); 1H NMR (Table 1); 13C NMR (Table 2).

Anal. Calcd. for C20H26O6: C, 66.30; H, 7.18. Found: C, 66.23; H, 7.10.

Compound 14. Obtained by degradative H5IO6 oxidation of the epoxide 12. (66%); oil; IR cm-1 3060 (aromatic CH), 2960-2870 (aliphatic CH), 2731 (aldehyde CH), 1765 (C=O ester), 1720 (C=O aldehyde); 1H NMR (Table 1); 13C NMR (Table 2).

Anal. Calcd. for C19H22O8: C, 60.32; H, 5.87. Found: C, 60.26; H, 5.90.

Compound 15. Obtained by LAH reduction of 13, followed by pyridine/acetic anhydride acetilation. (53 %); mp 98-99 ºC; IR cm-1 3061 (aromatic CH), 2952-2863 (aliphatic CH), 1769 (C=O ester), 1739 (C=O ester); 1H NMR (Table 1); 13C NMR (Table 2).

Anal. Calcd. for C24H34O8: C, 64.00; H, 7.56. Found: C, 63.85; H, 7.50.

Compound 16. Obtained by NaClO2 oxidation of 13, followed by CH2N2 methylation . (64%); mp 107-109 ºC; IR cm-13065 (aromatic CH), 2967-2880 (aliphatic CH), 1767 (C=O ester), 1733 (C=O ester); 1H NMR (Table 1); 13C NMR (Table 2).

Anal. Calcd. for C21H28O7: C,64.29; H, 7.14. Found: C, 64.20; H, 7.16.

Compound 17. Obtained by LAH reduction of 14, followed by pyridine/acetic anhydride acetylation. (59%); mp 82-83 ºC; IR cm-1 3068 (aromatic CH), 2919-2860 (aliphatic CH), 1772 (C=O ester), 1731 (C=O ester); 1H NMR (Table 1); 13C NMR (Table 2).

Anal. Calcd. for C23H30O10: C, 59.23; H, 6.44. Found: C, 59.30; H, 6.49.

Compound 18. Obtained by NaClO2 oxidation of 14, followed by CH2N2 methylation . (71%); mp 114-115 ºC; IR cm-13061 (aromatic CH), 2954-2849 (aliphatic CH), 1772 (C=O ester), 1742 (C=O ester); 1H NMR (Table 1); 13C NMR (Table 2).

Anal. Calcd. for C20H24O9: C, 58.82; H, 5.88. Found: C, 58.75; H, 5.90.


In a previous work5 we have reported that when the degradative oxidation reaction is achieved with the epoxide 7 and 8, the unexpected hydroxy-spiroether 9 (Ec. 2) and the hydroxylactone 10 (Ec. 3) are obtained. Formation of spiro-ether 9 can be explained assuming that the reaction is stopped at the diol stage and periodic acid promotes the cyclization by dehydration. In a similar pathway, 10 is formed due to a transesterification between ester side chain group and one of the hydroxylic group of the intermediate diol.

Following this investigation, the oxidative degradation of the previously prepared epoxides5 11 and 12 was achieved in the same reaction conditions. The results obtained and additional transformations of the respectively isolated products 13 and 14 are shown in the Scheme 1 .

As it can be seen, when the epoxides 11 and 12 are oxidative degraded with H5IO6, the total epoxide ring cleavage is attained and the expected ketoaldehydehydroquinone diacetates 13 and 14 are formed. These results mean that the reaction follows the normal pathway because there is not interaction between acyclic side chain and the diol formed at the first step of the degradation.

In conclusion, the nature of the products obtained by the oxidative degradation of epoxides of the general structure III with periodic acid, is depending on the functionality of the side chain R in each epoxide. If the diol formed in the first step of the degradation cannot interact with the functional group of the side chain (11, 12) , the oxidative degradation is complete and ketoaldehyde derivatives (13, 14) are obtained. If the interaction is possible, the oxidative degradation is stopped at diol formation step and a new cycle is formed, as it was previously reported 5.

Further chemical transformations were achieved in the ketoaldehyde- hydroquinone diacetates 13 and 14. They were transformed to polyacetylated derivatives 15 and 17 by reduction with LAH followed by acetylation with Ac2O/Pyridine and also they were oxidized to the corresponding carboxylic acids with NaClO2, isolated as the methyl esters 16 and 18. Physical and analytical data of all six new 1,4-benzohydroquinonediacetate derivatives prepared from the epoxides 11 and 12 are given in the Experimental section. In Table 1 are listed only the most significant data in the 1H NMR spectra and the 13C NMR information is reported in Table 2. The evaluation of the cytotoxic-antineoplastic bioactivities of these compounds is currently in progress


The authors acknowledge financial support from the Dirección de Investigación de la Universidad Católica de Valparaíso, Chile (Proyecto DGI 125.796-97, 125.713-99) and the Junta de Castilla y León, España (Consejería de Educación y Cultura, SA-26/97 and SA-57/96). This work also has been developed under the auspices of the "Programa Iberoamericano de Ciencia y Tecnología para el Desarrollo. CYTED. Subprograma X".


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