Juglon

The importance of both electronic and steric effects is clear in cycloadditions as in cross-oxidations. One example is a heterocycHc modification leading to the thermodynamically less stable natural form of juglone derivatives such as ventiloquinones JT [124917-64-2] (84) and I [124917-65-3] (85) (83). The yields are 97% (84) from 6-chloro-2,3-dimethoxy-l,4-ben2oquinone [30839-34-0] and 100% (85) upon hydrolysis. 

Derivatives of the natural product juglone [77189-69-6] eg (109), have been obtained ia 90% yield ia a single reaction involving halogenation and oxidation by A/-bromosucciniinide (115). 

Juglone [481-39-0] (Cl Natural Brown 7 Cl 75500) was isolated from the husks of walnuts in 1856 (50). Juglone belongs to the Juglandaceae family of which there are a number of species Jug/ans cinerea (butter nuts), J. regia (Persian walnuts), and J. nigra (black walnuts). Persian walnuts were known to the ancient Romans who brought them over from Asia Minor to Europe. As early as 1664, the American colonists knew how to extract the brown dye from the nuts of the black walnut and butternut trees, both native to eastern North America (51). 

In 1885, from a detailed study of juglone (52) it was proposed that its stmcture was 5-hydroxy-l,4-naphthoquinone (9). This stmcture was confirmed by oxidizing 1,5-dihydroxynaphthalene with potassium dichromate in sulfuric acid (53). Juglone occurs in walnuts as a glycoside of its reduced form, 1,4,5-trihydroxynaphthalene (54). Later it was deterrnined that the sugar is in the 4-position (10) (55). 

Juglone is most readily synthesized by Bemthsen s method. However, this method is too drastic and results in low yields (56). Somewhat better yields are obtained by using Fremy s salt (potassium nitroso disulfonate) as the oxidant (57). By using thallium trinitrate to oxidize 1,5-dihydroxynaphthalene, yields as high as 70% of juglone have been reported (58). 

In the past, juglone had been used to dye wool and cotton a yellowish brown. Although it no longer has any commercial value as a dye, it is a fungicide and as such finds use in the treatment of skin diseases. Its toxic properties have been made use of in catching fish. Juglone has been used to detect very small amounts of nickel salts since it gives a deep violet color with such salts. 

The toxic influence exerted by Juglans nigra (black walnut) on other plants has been attributed to 5-hydroxy-1,4-naphthoquinone (juglone) (11,31). Hydrojuglone is present in the root bark, leaves, and fruit husks. This compound is not considered toxic, but it is oxidized to the toxic juglone upon exposure to air (51). Rainfall... 

The aqueous [4+2] cycloaddition reaction of 1,4-naphthoquinones 115 with methoxy cyclohexadiene performed in the presence of bovine serum albumin (BSA) is one of the first examples of protein-promoted Diels Alder reactions [79]. Some results are reported in Table 4.18. The globular protein does not affect the regioisomer ratio of adducts. The highest enantiomeric excess was obtained in the cycloaddition of juglone 115 (R = H) with 1-methoxy-1,3-cyclohexadiene 116. 

Perlinger JA, W Angst, RP Schwarzenbach (1996) Kinetics of the reduction of hexachloroethane by juglone in solutions containing hydrogen sulfide. Environ Sci Technol 30 3408-3417. 

Davis (19) in 1940 extracted and purified the toxic substance frcm the hulls and roots of walnut (JugIans) and found it to be identical to juglone (5-hydroxy-l,4-naphthoquinone). This compound proved to be a powerful toxin when injected into the stems of tomato, potato and alfalfa plants. The allelopathic action in the case of juglone (walnut tree and its vicinity) is well established. 

Effects of Allelochemlcals on ATPases. Several flavonoid compounds inhibit ATPase activity that is associated with mineral absorption. Phloretin and quercetin (100 pM) inhibited the plasma membrane ATPase Isolated from oat roots (33). The naphthoquinone juglone was inhibitory also. However, neither ferulic acid nor salicylic acid inhibited the ATPase. Additional research has shown that even at 10 mM salicylic acid inhibits ATPase activity only 10-15% (49). This lack of activity by salicylic acid was substantiated with the plasma membrane ATPase Isolated from Neurospora crassa (50) however, the flavonols fisetln, morin, myricetin, quercetin, and rutin were inhibitory to the Neurospora ATPase. Flavonoids inhibited the transport ATPases of several animal systems also (51-53). Thus, it appears that flavonoids but not phenolic acids might affect mineral transport by inhibiting ATPase enzymes. 

Our retrosynthesis of (—)-kinamycin F (6) is shown in Scheme 3.20 [45]. It was envisioned that (—)-kinamycin F (6) could be prepared from the protected diazofluorene 114 by conversion of the ketone function of 114 to a trans-], 2-diol, followed by deprotection of the acetonide and methoxymethyl ether protecting groups. The diazofluorene 114 was envisioned to arise from diazo transfer to the hydroxyfulvene 115. The cyclopentadiene substructure of 115 was deconstructed by a two-step annulation sequence, to provide the bromoquinone 116 and the p-trimethylsilylmethyl unsaturated ketone 117. The latter two intermediates were prepared from juglone (118) and the silyl ether 119, respectively. 

The synthesis of the naphthoquinone 116 is shown in Scheme 3.24. Bromination of juglone (118) afforded the dibromojuglone derivative 134. Protection of the phenol group as its methoxymethyl ether formed the product 135 (50 % yield over two steps). Finally, the C-3 bromide substituent was regioselectively substituted with methoxide by heating 135 in methanol in the presence of sodium carbonate (96 %). The methoxy group was installed to impart electronic bias to the naphthoquinone in the TASF(Et) coupling (vide infra). 

Colaric M, Veberic R, Solar A, Hudina M and Stampar F. 2005. Phenolic acids, syringaldehyde, and juglone in fruits of different cultivars of Juglans regia L. J Agric Food Chem 53(16) 6390-6396. 

---