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The reaction of dihydrolipoic acid (DHLA) with 5-hydroxy-1,4-naphthoquinone (juglone) gives rise to the novel naphtho[1,4]dithiepine derivatives through ring expansion of an unstable spirocyclic 1,3-dithiane intermediate, which was isolated and completely characterized. Reported herein is also the characterization of novel reaction products of DHLA with other naphthoquinones and the extension of the study to the spirocyclic adduct formed by reaction with a representative 2-substituted naphthoquinone.

NaClO2/NaI in the presence of HCl is a mild, cheap, and non-toxic reagent for the iodination of phenols, including estradiol and naphthol, aromatic amines, and heterocyclic substrates, e.g., indoles, 8-hydroxyquinoline, imidazole, in fair to excellent yields by a very simple isolation protocol. The scope of the procedure is exemplified by the first iodination of 5-nitroindole to 3-iodo-5-nitroindole in 75% yield.

Oxidation of 5 x 10(-3) M noradrenaline in aqueous phosphate buffer, pH 7.4, with K3Fe(CN)(6), NaIO4 or Fe2+/EDTA/H2O2 followed by extraction with ethyl acetate and acetylation with Ac2O/Pyr led to a main reaction product which was isolated and identified as 4-[bis-(1H-5,6-diacetoxyindol-2-yl)methyl]-1,2-diacetoxybenzene, an unprecedented [bis-(indol-2-yl)methyl] -benzene derivative unsubstituted on the 3-position of the indole rings. This product was also obtained in 40% yield by reaction of 5,6-dihydroxyindole with 3,4-dihydroxybenzaldehyde. Other components of the oxidation mixture were 1-acetyl-3,5,6-triacetoxyindole, derived from noradrenolutin, and 5,6-diacetoxyindole, originating from cyclisation/dehydration of the o-quinone of noradrenaline, along with some 3,4-diacetoxybenzaldehyde. Inspection of the aqueous phase revealed the presence of 3,4-dihydroxymandelic acid and 3,4-dihydroxybenzaldehyde, derived from oxidative breakdown of the 2-amino-1-hydroxyethyl chain via a p-quinomethane intermediate. These results disclose new aspects of the oxidative chemistry of noradrenaline beyond the aminochrome stage and provide a route to novel [bis-(indol-2-yl)methyl]-benzene derivatives of potential pharmacological interest. (c) 2005 Elsevier Ltd. All rights reserved.

Oxidative degradation of natural and synthetic eumelanins with alkaline H2O2 afforded a complex mixture of low molecular weight products which comprised, besides 1 and 2, three novel pyrrole acids. These were isolated and identified as 2-carboxyhydroxymethylpyrrole-3,5-dicarboxylic acid (3), 2-carboxymethylpyrrole-3,5-dicarboxylic acid (4) and 2-hydroxymethylpyrrole-3,5-dicarboxylic acid (5). Investigation of the oxidative degradation of the eumelanin precursors 5,6-dihydroxyindole and 5,6-dihydroxyindole-2-carboxylic acid, as well as of the oligomers 6-10 showed that pyrrole acids 3-5 originate by peroxidative disruption of both carboxylated and non-carboxylated indole units, and that pyrrole 4 arises mainly from indole units not substituted at the 7-position. None of the new pyrroles was converted to 1 by treatment with alkaline H2O2. suggesting that they are formed by different degradation routes. These results can be accommodated into an improved mechanistic scheme for rationalising the origin of pyrrole acids by H2O2 degradation of eumelanins.

Previous studies on the oxidative polymerisation of 5,6-dihydroxyindole-2-carboxylic acid, a key intermediate in the biosynthesis of eumelanins, had delineated a reaction pathway involving mainly repeated coupling of the indole units through the 4- and 7- positions. Using an improved HPLC methodology for the direct analysis of oligomer intermediates, we have now obtained evidence for a more complex mode of polymerisation, involving formation, besides the 4,4′ and 4,7′ coupled dimers 5 and 6, of three new dimers, which have been isolated and identified as the 3,4′-, 3,7′- and 7,7′-biindolyls 7–9. The observed implication of the 3-position is unprecedented in the oxidative polymerisation of 5,6-dihydroxyindoles and yields important clues for future studies aimed at elucidating the chemical constitution of natural and synthetic eumelanins.

Enzymatic and chemical oxidation of 4-S-cysteaminylphenol (1) and 4-S-cysteaminylcatechol (2) leads to the formation of the hitherto unknown dihydrobenzothiazine-6,7-quinone 4 via intramolecular cyclisation of the o-quinone 6. Oxidation of 4-S-cysteinylcatechol (3) gives the corresponding dihydrobenzothiazinequinone 9, which undergoes rearrangement with partial decarboxylation to give 6,7-dihydroxybenzothiazine derivatives, isolated as 8 and 5 after reduction and acetylation of the mixture. Oxidation of 2 and 3 with periodate or iodate gives mainly the iodinated quinones 7 and 13, respectively.