Hydroxytryptamines

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... 

Table I lists some (but not all) new members of the 1-hydroxytryptamine family and related 1-hydroxyindoles (9) produced via the tungstate method from 1999 through 2000.

Michael addition reaction of 1-hydroxytryptamines to Q ,/3-unsaturated carbonyl compounds is worthy of note (99H2815). Addition of Ab-acetyl- 1-hydroxy-tryptamine (39) to methyl acrylate and methyl crotonate in the presence of... 

The reaction of Ab-acetyl-1 -hydroxytryptamine (39) with mesyl chloride (MsCl) in THF in the presence of EtsN provides 1-acetyl-1,2,3,8-tetrahydropyrrolo[2,3-(j] indole (49a, 35%) (70JA343), Ab-acetyl-6-mesyloxytryptamine (50a, 4%), Ab-acetyl-2,3-dihydro-2-oxotryptamine (51a, 5%), l-acetyl-3a-(4-chlorobutoxy)-l,2,3,3a,8,8a-hexahydropyrrolo[2,3-(j]indole (52a, 7%), and Ab-acetyltryptamine (53a, 2%) as shown in Scheme 6 (2000H483). In the same reaction with MsCl, l-hydroxy-Ab-methoxycarbonyltryptamine (34) produces 50b (7%), 51b (34%), and 52b (9%), while the formation of 49b is not observed at all. In the case of Ab-trifluoroacetyl-l-hydroxytryptamine (48), 49c (45%), 50c (8%), 51c (4%), and 52c (6%) are produced. These data suggest that the yield of 49 increases, whereas the yield of 51 decreases in the order of electron-withdrawing ability of Ab substituents (COOMe < COMe < COCF3). Stability of 49 seems to govern the quantity of 51, which is probably formed by hydrolysis of 49. 

The reaction of p-toluenesulfonyl chloride (TsCl) with 1-hydroxytryptamines was expected to follow the same reaction pathways as that of MsCl described in Section IV.B. 1. In fact, it is different from the expectation (2000H2487). Thus, 39 reacts with TsCl in THF to provide 49a (42%), 51a (6%), 53a (3%), 60 (0.5%), and... 

Attempts to extend the reaetion to the syntheses of 5-ehloro and 5-bromo derivatives have led us to diseover that treating 1-hydroxytryptamines simply with aqueous hydrogen halides at room temperature is suffieient to meet our end (99H2815). 

Leptosins D-F (258a-c, Scheme 39) [94JCS(P1)1859] were isolated by Takahashi and co-workers from the culture of a strain of Leptosphaeria sp. as cytotoxic substances against the P388 lymphocytic leukemia cell line comparable to that of mitomycin C. Utilizing the nucleophilic substitution reaction of 1-hydroxytryptamines, a simple methodology for the synthesis of core structures of leptosins has been developed (2000H1255). 

Serotonin, A-methylserotonin, bufotenine, and 5-methoxy-A-methyltryptamine become readily available in a simple way by applying nucleophilic substitution reactions in 1-hydroxytryptamine chemistry (99H1157, 2001CPB87). 

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. 

The chemistry of 1-hydroxyindoles, especially 1-hydroxytryptamines and -tryptophans, is still in its cradle at present, yet its future development is promising. It seems to be a treasure trove whose excavation will yield many new reactions and findings. 

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,... 

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