Hydroxytryptophans

Recent Advances in the Chemistry of 1-HydroxyindoIes, 1-Hydroxytryptophans, and 1-Hydroxytryptamines... 

As a result, we could open the door to a new frontier in indole chemistry. Various 1-hydroxyindoles (4a), l-hydroxytryptophans(la), 1-hydroxytryptamines (lb), and their derivatives have been given birth for the first time. As predicted, 1-hydroxytryptophan and 1-hydroxytryptamine derivatives are found to undergo previously unknown nucleophilic substitution reactions. In addition, we have been uncovering many interesting reactivities characteristic of 1-hydroxyindole structures. From the synthetic point of view, useful building blocks for indole alkaloids, hither to inaccessible by the well-known electrophilic reactions in indole chemistry, have now become readily available. Many biologically interesting compounds have been prepared as well. 

In this review, our recent developments in the chemistry of 1-hydroxyindoles, 1-hydroxytryptophans, and 1-hydroxytryptamines, attained between the beginning of 1999 and the end of May 2001, are summarized together with results obtained... 

Hydroxyindoles carrying a side chain containing a free NH2, OH, or COOH functional group are unstable. Therefore, 1-hydroxytryptophan, -tryptamine, and -indole-3-acetic acid have not been prepared yet. 

Regioselective nucleophilic substitution at the 5 position is proved to occur when 1-hydroxytryptophan and -tryptamine derivatives are treated with 85% HCOOH (99H1157). Truly amazing is the fact that only substrates carrying a C—C—N structure in the side chain at the 3 position can undergo this regioselective substitution. 

In contrast, substrates having other struetural types of side ehain at the 3 position dimerize under aeidie eonditions, and never produee the 5-substituted produets. These faets seem to support the 1-Hydroxyindole Hypotheses, whieh elaim the formation of serotonin from 1-hydroxytryptophan and/or -tryptamine in the aeidie eompartment within eukaryotie eells. 

With 1-hydroxytryptophan derivatives, similar substituent effects are observed (99H2815). In order to realize better yields of 5-substituted tryptophans, car-boxy and amino groups are transformed to ester and/or amide groups, choosing the 1-methoxy moiety as a leaving group. As a result, ( )-Ab-acetyl-5-chlorotryptophan methyl ester (219, 52%) is obtained together with 220 (7%) from ( )-218 by the reaction with aqueous HCl (Scheme 32). ( )-5-Bromo-Ab-methoxycarbonyltryptophan methylamide (222, 50%) becomes readily available... 

Final examples of applications of our results (91CPB1905, 99H1157) in 1-hydroxytryptophan chemistry come from the work of Boger and co-workers (99JA6197) on the synthesis of HUN 7293 (293, Scheme 46) (96MI69) and from Kitahara and co-workers (200 IHl) on the synthesis of apicidin (301) (96TL8077). 

Very little is known about the occurrence of 1-hydroxytryptamine and/or 1-hydroxytryptophan derivatives in living organisms. Many 1-methoxyindole derivatives have been isolated as natural products (87MI629, 88BCJ285, 92H1877, 93MI22) for the simple reason that they are stable under isolating processes. 

No 1 -hydroxytryptamine or -tryptophan alkaloid that lacks a stabilizing group on the indole nucleus has been reported yet. However, isolation of37,38a, 38b, HUN-7293 (293) (96MI69), and apicidin (301) (96TL8077) offers indirect evidence for the existence of 1-hydroxytryptamines and/or 1-hydroxytryptophans in living organisms. We believe their isolation will be reported in the near future. 

Homolytic substitution of heteroaromatic compounds, 16, 123 Hydantoins, chemistry of, 38, 177 Hydrogen cyanide derivatives, synthesis of heterocycles from, 41, 1 Hydrogen exchange base-catalyzed, 16, 1 one-step (labeling) methods, 15, 137 Hydrogenated porphyrin derivatives hydroporphyrins, 43, 73 Hydroxamic acids, cyclic, 10, 199 1 -Hydroxyindoles, 1 -hydroxytryptophans, and 1-hydroxytryptamines,... 

Somei et al. have also shown that nucleophilic additions occur on the indole nucleus of 1-hydroxyindole and 1-hydroxytryptophan residues in the presence of 85% formic acid [3]. For example, indole displaces the hydroxyl group from (DL)-1-hydroxytryptophan methyl ester (106) to provide the l-(indol-3-yl)indole 107 in 51% yield. When other nucleophiles such as phenol, naphthol, and pyrrole are used, a more complicated mixture of products is isolated. 

Somei M (2006) A Frontier in indole chemistry 1-hydroxyindoles, 1-hydroxytryptamines, and 1-hydroxytryptophans. In Topics in heterocyclic chemistry. Springer, Berlin/Heidelberg, pp 77-111... 

III. Physical Properties of 1-Hydroxyindoles, 1-Hydroxytryptophans, and 1-Hydroxy tryptamines... 

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