4- Hydroxyindoles

E. Syntheses of 1-Hydroxyindoles Cairying an Electi on-Withdrawing Group. 107... 

VI. Studies towaid Biologically Active 1-Hydroxyindole Derivatives. 146... 

Based on the strong desire to verify these hypotheses, we have concentrated on developing general synthetic methods suitable for 1-hydroxyindoles. In 1989,... 

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. 

However, even this second method, including the one modified later by Acheson and co-workers [84JCR(M) 1301], was ineffective in realizing our imaginary compounds (la-c, 2, 3, etc.). Their birth and the start of studies on the verification of the 1-Hydroxyindole Hypotheses had to wait until 1989 when Somei s method, the third method, was discovered. 

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... 

In spite of these successful results, we continue to search for a proper reagent that can transform indole derivatives directly to the corresponding 1-hydroxyindoles. 

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.

Other newly synthesized 1-hydroxyindoles appear in the following sections. 

Once an electron-withdrawing group is introduced onto the indole nucleus, no matter which position it is, 1-hydroxyindoles become stable (91YGK205, 99H1157). For the preparation of such stable 1-hydroxyindoles, various reagents and conditions can be employed and many approaches have been reported, as summarized in previous reviews (79MI1, 90AHC105). 

The values of the 1-hydroxy moiety of (5)-(- -)-iVb-acetyl- 1-hydroxytrypto-phan methyl ester (32), methyl l-hydroxyindole-3-butylate (33), iVb-methoxy-carbonyl-l-hydroxytryptamine (34), 1-hydroxymelatonm (19), l-hydroxy-6-nitroindole (35), and l-hydroxy-5-nitroindole (36) are determined to be 9.8, 8.4, 8.2, 8.1, 6.9, and 6.8, respectively (Fig. 2) (2000H1881). Thus, 1-hydroxyindoles are weak acids, stronger than phenol and weaker than succinimide. Therefore,... 

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. 

Methylation of 1-hydroxyindoles can be achieved readily by the reaction with diazomethane, Mel, orMc2S04 in the presence of an appropriate base, as described in previous reviews (79MI1, 90AHC105, 91YGK205, 99H1157). Alkylation and acylation also work well with alkyl halides, acyl halides, acid anhydrides, and acids in the presence of acid activators such as DCC and so on. 

In 1991, we proposed in our 1-Hydroxyindole Hypotheses (91YGK205) that some types of 1-hydroxyindoles (117) would undergo a rearrangement reaetion to provide 2-oxindole 118 and/or 3-oxindole 119 as illustrated in Seheme 18. As suitable substrates for realizing the predietions, we have sueeeeded in finding l,2,3,4-tetrahydro-9-hydroxy-/3-earboline eompounds 11 and 16a. 

Its structural determination had to wait for 25 years until 1998 (98H2481), when we reached the stage where we could apply suitable characteristic reactions found in 1-hydroxyindole chemistry to the synthesis of the authentic 6-ethoxy-2-phenylindole (148). 

---