Juglone synthesis

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). 

This enzyme exhibits no hydroxylase activity and is involved in the final synthesis of many naturally occurring /t-quinoncs. e.g. the naphthaquinone juglone in walnut (1.58) and the benzoquinone arbutin (hydroquinone-(3-D-glucopyranoside 2.46). Arbutin is a plant cryo-protectant that stabilizes membranes (Hincha et al., 1999). This compound has medicinal properties and has, for example, been used to treat urinary tract infections in humans. It is also used to lighten skin color, because it inhibits tyrosinase and hence the formation of melanin. The derivative deoxyarbutin (2.47 note the difference in the sugar molecule) was recently reported to be considerably more effective as a skin-lightening compound (Boissy et al., 2005). 

Guingant and Barreto [53] published the pioneering paper describing the synthesis of ochromycinone (35) by a Diels-Alder reaction. The dienone (46) was prepared from 3-ethoxy-5-methyl-cyclohex-2-enone (45) in two steps (alternatively, a diene with SPh instead of OMe could be used). The Diels-Alder reaction with juglone (47) was catalyzed with boron triacetate to overcome the somewhat poor reactivity of the electron-deficient diene 46. The primary adduct 48 could not be isolated but directly eliminated and oxidized to ochromycinone (35) (Scheme 13). 

A kinetic resolution with respect to the racemic diene 66 could be achieved in the Diels-Alder reaction promoted by a chiral Lewis acid prepared from BHj in the presence of (S)-3,3 -diphenyl-l,r-binaphthalene-2,2 -diol and juglone (47) in the synthesis of (+)-emycin A and (+)-ochromycinone (35) [66] (compare previous investigations by Kelly [67]). 

Chiral borane reagents similar to those described above were independently reported by Yamamoto and co-workers in the same year (Eq. 2) [2]. These reagents promote the reaction of juglone and a variety of dienes in the synthesis of anthracycli-nones. The borane reagent used is trimethyl borate. Different tartrate derivatives have been tried and (i ,f )-(+)-tartaric acid diamide has proved to be the most efficient. The best results are obtained in the reaction of juglone and (triethylsiloxy)buta-... 

Fig. 7. Synthesis of ptumbagin (24) and a-caiyopterone (28) from juglone through retro Diels-Aider reaction...

The iT-face differentiation in favor of adducts (443) was more pronounced with increasing amounts of the Lewis acid and at lower reaction temperatures (c/. entries 3/4 and 8/9). The cooperative effect of chiral auxiliaries at the diene and at the dienophile units is exemplified by the double diastereoface selective addition presented in entry 2. Particularly noteworthy is the outstanding ir-face selectivity, observed in the [4 + 2] cycloaddition of juglone (445). ° Removal of the prosthetic group from adducts (443) was accomplished via hydrogenolysis or allylic displacement, as illustrated by the key step (447) (448) of a synthesis of enantiomerically enriched (+)-ibogamine (Scheme 105). °° ... 

Oelgemoller, M., Healy, N., de Oliveira, L., Jung, C., Mattay, J., Green Photochemistry Solar Chemical Synthesis of Juglone with Medium Concentrated Sunlight, Green Chem. 2006, 8, 831 834. 

Juglone = 5-hydroxy-l,4-naphthalenedione dienophile in tetracycline synthesis, 318 Julia-Lythgoe olefination, 34 Julia s terpenoid synthesis, 69-70 Juvenile hormone synth. steps, 20, 30, 135, 155... 

In nature, the oxidative dimerization of phenols is controlled by enzymes, as is demonstrated by the axial chirality of the 6,8 -coupled juglone derivative isodiospyrin. In synthesis, however, phenol oxidation only proceeds in high yields when the enzymatic reaction control is replaced by substituent control, that is, if all but one of the positions with high spin density in the radical (ortho-and para positions) are blocked. 

DoM-Suzuki-Miyaura cross-coupling, 144+145 146, and terminated by a DreM-lactonization step, 146 147 (Scheme 14.30) [144aj. Starting from commercially available juglone, defucogilvocarcin V 148 is conquered in nine steps and 16% overall yield, and defucogilvocarcin M 149 as well as defucogilvocarcin E 150 in nine steps and 15% overall yield. The total synthesis of amottin I 151 is achieved in a less satisfactory 11 steps sequence and 2% overall yield. This... 

The DA reaction of methacrolein with 1,3-dienol derivatives was catalyzed by BINOL derived titanium complexes, giving the endo adduct with high enantiose-lectivity [155]. The reaction was performed in the absence of MS, since MS can act as an achiral catalyst in this reaction and compromise the product enantiomeric excess. Similarly, the DA reaction of juglone with butadienyl acetate catalyzed by BINOL-Ti complex proceeds in only 9% ee in the presence of MS, whereas the reaction proceeds in 76-96% ee in the absence of MS to provide the endo adducts useful for the synthesis of anthracyclines and tetracycline [155,156). The drawback of the above method is the instability of the addition products, owing to their high tendency to aromatize. Corey improved this DA reaction with quinone monoacetal as a supplant of juglone or benzoquinone [157] (Scheme 14.64). 

Suzuki and coworkers developed an approach to the juglone portion of angucycline natural products fliat features a cycloaddition between benzyne and silyloxyfiirans [170]. The synthesis of galtamycinone (531), for example, relies on... 

Diels-Alder reaction with nitroalkenes as dienophiles. The B(OAc)3-promoted Diels-Alder reaction of juglone (76) with substituted styrenes (77) in the presence of DDQ produced cycloadducts (78). This methodology provides a route to the total synthesis of tetrangulol (79) and anhydrolandomycinone (80) (Scheme 24) ... 

TOXIN. A poisonous substance that occurs naturally in animals, bacteria, or plants. Examples include botulinum toxin, ricin, and tbe tri-chothecene mycotoxins. Some toxins can be produced artificially through chemical synthesis. The military relevance of toxins was recognized during World War I, when the U. S. Army Chemical Warfare Service (CWS) conducted research and production of selected toxins at the Catholic University of America. Weapons having toxins as their primary payload are controlled as both chemical weapons (CW) (under the Chemical Weapons Convention [CWC]) and biological weapons (BW) (under the Biological and Toxin Weapons Convention [BTWC]). Toxins have also seen use as assassination weapons. See also JUGLONE SAXITOXIN. 

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