Nucleophilic Substitution Reaction of 1-Hydroxytryptophan and 1-Hydroxytryptamine Derivatives (Regioselective Syntheses of 5-Substituted Derivatives of Tryptophane and Tryptamine)

Regioselective nucleophilic substitution at the 5-position of indole nucleus was observed in the reaction of 1-hydroxytryptophan and 1-hydroxytryptamine derivatives with acids, suggesting the mechanism of serotonin formation in the central nervous system.It is generally believed2 that in the central nervous system L-tryptophan (1, Scheme 1) is initially converted to L-5-hydroxytryptophan (2) by the enzyme L-tryptophan hydroxylase, and then decarboxylated to give 5-hydroxytryptamine (serotonin, 3) by the action of 5-hydroxytryptophan decarboxylase.However, the transformation mechanism of 1 to 2 can not be explained in terms of chemistry.With our "1-hydroxyindole hypothesesu3 in mind, we could illustrate the mechanism as follows.Initially, 1 would be oxidized by an oxidase (or with metal and dioxygen, hydrogen peroxide, etc), to the corresponding 1-hydroxyindole (4).directly or via 2.3-dihydroindole.Then. 4 would generate 2 by the elimination of 1-hydroxy group, followed by the nucleophilic attack at the 5 position with water.If the n ucleophile was hydrogen peroxide (or superoxide), 4 would generate indolequinoneimine (5). 5 might be produced by the direct oxidation of 2. Subsequent nucleophilic attack of water on 5 generates neurotoxic 4.5-(6).