5.6- Dihydroxyindole, synthesis

Despite the merit of pioneering the biomimetic approach to 5,6-dihydroxyindole synthesis, some of these papers contained incorrect structural conclusions that were highlighted in revisions by subsequent workers. Thus, for example, Heacock and co-workers (63JA1825) provided unambiguous proof that in iodo- and bromo-aminochromes the halogen occupies the 7- and not the 2-position, as previously believed. Independent total syntheses of 5,6-dimethoxy-7-iodoindole and of... 

A. Pezzella, D. Vogna and G. Prota, Synthesis of optically active tetrameric intermediates by oxidation of the melanogenic procursor 5,6-dihydroxyindole-2-carboxilic acid under bio-mimetic conditions. Tetrahedron Assymetry 14 (2003) 1133-1140. 

Reductive cyclization of nitrostyrene precursors has also proven to be a useful route to 5,6-dihydroxyindole and its derivatives, as illustrated by the efficient preparation of the system 32 (Scheme 18) <1999S793>. A general synthetic approach to indoles involves a palladium-catalyzed reductive cyclization of 2-nitrostyrenes <1997JOC5838>. This procedure was used in the synthesis of several natural products, e.g., 4-(methoxymethyl)-2-methylindole 33 (Scheme 19), a constituent of a tricholoma species <1999JOC9731, CHEC-III(3.03.2)282>. 

Ty initiates melanin synthesis by the hydroxylation of L-tyrosine to 3,4-dihydroxyphenylalanine (Dopa) and the oxidation of dopa to dopaquinone. In the presence of L-cysteine, dopaquinone rapidly combines with the thiol group to form cysteinyldopas, which undergo nonen-zymatic conversion and polymerization to pheomelanin via benzothiazine intermediates. In the absence of thiol groups, dopaquinone very rapidly undergoes conversion to dopachrome, which is transformed to 5,6-dihydroxyindole-2-carboxylic acid (DHICA) by dopachrome tautomerase. Alternatively, dopachrome is converted nonenzymatically to 5,6-dihydroxyindole (DHI). Oxidation of DHICA and DHI to the corresponding quinones and subsequent polymerization leads to eumelanins. It is still questionable if Ty is involved in this step. 

Melanin is an insoluble, high-molecular-weight polymer of 5,6-dihydroxyindole, which is synthesized from tyrosine (Figure 17-23). It is produced by pigment cells (melanocytes) in cytoplasmic organelles (melanosomes). In the epidermis, melanocytes are associated with keratinocytes, which contain melanosomes supplied by melanocytes via dendritic processes. Color variation in human skin reflects the amount of melanin synthesized in melanosomes. Melanin synthesis is apparently under hormonal and neural regulation. 

Early multistep approaches to 5,6-dihydroxyindole 1 and related derivatives were based on the reductive cyclization of 2,/i-dinitro-4,5-dihydroxystyrenes. The first synthesis was developed in 1948 by Burton and Duffield (48NAT725) and involved the condensation of piperonal with nitromethane followed by nitration in acetic acid to give 2,/i-dinitro-4,5-methylenedioxystyrene which on reduction afforded 5,6-methylenedioxyindole 10 (R = H) (Scheme 2). 

In the 1980s, a series of papers re-awakened interest in the synthesis of 5,6-dihydroxyindoles. In the first of these papers (82JMC263) indole 1 and its 4- and 7-methyl derivatives 16 and 17 were synthesized and evaluated for their ability to inactivate eatechol-O-methyl transferase. The synthetic scheme employed for the methylated derivatives was based on the dinitrostyrene approach starting from an appropriate aeetophenone derivative (Scheme 7). The acetophenones were converted... 

Another study (84JHC1183) was prompted by the value of ester derivatives as storable but ready sources of 5,6-dihydroxyindole 1 for biological studies (67NAT190) (67JPS1019), and focused on the synthesis of the cyclic carbonate derivative 19 (Scheme 8). This procedure starts from 3,4-methylenedioxycinnamic acid and utilizes thermal decomposition of an azide intermediate, produced from a... 

Both tryptophan and tyrosine fiamished melanin. Similar results were also obtained by Allegri et al. (3), who studied melanin synthesis from tryptophan and tyrosine spectrophotometrically. From tyrosine, p-hydro-xyphenylpyruvic acid (15), 4,4-dihydroxybiphenyl (16), 5,6-dihydroxy-indole (17), and 3,5,6-trihydroxyindole (18) were obtained in addition to melanin and from tryptophan, 5,6-dihydroxyindole (17), indole (19), anthranilic acid (20), 3-hydroxyanthranilic acid (21), indolylpyruvic acid (22), 3-hydroxypyrrol-4,5-dicarboxylic acid (23), and isatin (24). 

Some 40 years earlier, Harley-Mason and Cromartie synthesized 5-hydroxyindole in excellent yield via the oxidation of 2,5-dihydroxyphenylalanme with potassium ferricyanide (Scheme 6, equation 1) [9]. This simple oxidation when applied to 2,3-dihydroxypheny-lalanine gave 7-hydroxyindole in 20% yield [9] and 3,4-dihydroxyphenylalanine gave 5,6-dihydroxyindole in 30% yield (but not repeatable) [10], This simple oxidation procedure with ferricyanide was used to synthesize bufotenine and serotonin [11], In chemistry related to the Kita indole synthesis, Clive and Stoffman presented a synthesis of 4-halo-5-hydroxyindoles from the corresponding coumarins... 

Indeed, the biosynthesis of the biopolymer melanin involves the oxidative cyclization of dihydroxyphenylala-nine (DOPA) to phenylalanine-3,4-quinone (dopaquinone), which eventnally forms 5,6-dihydroxyindole (DHI). Polymerization of DHI affords melanin [1], Lim and Patil have exploited this biochemical transformation using commercial mushroom tyrosinase in a synthesis of 5,6-dihydroxyindoles protected as the diacetates (2) (Scheme 1) [2], The parent indole (R = R =H) is obtained in less than 10% yield. Carpender has reported a similar oxidative cyclization using manganese dioxide to give 2 (R =Me) in 80% overall yield from epinine (1, R =Me, R =H) [3]. Other oxidants (H, Hp /FeSO, O, NaOCl, NaClOj/ VjOj) gave little or no product. Choi, Nam, and colleagues have effected an electrochemical oxidation of dopamine (1, R = R =H) to 5,6-dihydroxyindole that polymerizes to form films of polydopamine suitable for neural attachment and function [4]. 

Applications of the Gassman oxindole synthesis in total synthesis are uncommon. Savall and McWhorter prepared a 6,7-dihydroxyindole derivative, part of the potent antihelmintic compound paraherquamide A, by using a chlorosulfonium ion (15) obtained from ethyl methylthioacetate and sulfuryl chloride.The intermediate oxindole 23 was obtained in 80% crude yield. The starting aniline was obtained in good yield from 2,3-dimethoxybenzoic acid via a modified Curtius rearrangement. Removal of the thiomethyl functionality with Raney nickel gave the final product in 62% yield. 

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