In the chemistry of 1-hydroxyindoles

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... 

Somei, M., Recent Advances in the Chemistry of 1-Hydroxyindoles, 1-Hydroxytryptophans, and 1-Hydroxytryptamines, 82, 101. 

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. 

An early report of annulation of an iminophosphorane (formed in situ) to a malonylidene function describes the synthesis of a thienopyrrole in high yield [3084a]. A different procedure gives the isomeric [3,4-c] product [3492a]. A styryl phenyl ketone is converted into a 1-hydroxyindole by warming with potassium cyanide [2163] the chemistry of 1-hydroxyindoles has been reviewed [3906]. 

Presently, the chemistry of 1-hydroxyindoles, -tryptamines, and -tryptophans seems to have become a gold mine in which we can find new facts and reactions everywhere. In this review, we would like to report briefly on the progress we have made since om previous reviews (up to the end of August, 2005) avoiding any overlap with their contents [5-7]. 

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. 

The third chapter A Frontier in Indole Chemistry 1-Hydroxyindoles, 1-Hydroxytryptamines, and 1-Hydroxy tryptophans by Masanori Somei presents a very comprehensive review on chemistry of 1 -hydroxy-indoles, -tryptamines, and -tryptophans as a frontier in indole chemistry. In fact, these new members of indole derivatives were not much known about 30 years ago in the long histry of indole alkaloids and related chemistry. Nowadays, these new families of indole compounds have been demonstrated to play their important role in life and nature by the pioneering works of Somei and his coworkers. The interesting biological and pharmaceutical activities have been found in these derivatives. 

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). 

Applications of our results in 1-hydroxyindole chemistry and our tungstate method to the syntheses of novel heterocyclic compounds and biologically active natural products are summarized in this section. 

An important variation of the Jones-Schmid indole synthesis is the base-mediated cyclization onto esters, which affords 3-hydroxyindoles (indoxyl tautomers) under mild conditions. Three case studies are shown in Scheme 2 (equations 1-3) [18-20]. This chemistry, like that in Table 1 (Entries 4-11), represents a powerful route to C-3 functionalized indoles. Kraus and coworkers use the steri-cally hindered phosphazine base, P -t-Bu, to prepare the 5,6-dihydroindolo[2,l-a]isoquinoline ring system (equation 4) [21]. Several derivatives display immunosuppressive activity. 

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... 

Abstract Many new members of the 1-hydroxyindole, -tryptamine, and -tryptophan families are prepared. They demonstrate totally different reactivities from those of the corresponding indoles upon electrophilic substitution reactions. They also undergo nucleophilic substitution reactions that are unprecedented in indole chemistry. Doors to various kinds of new reactions and novel products open depending on the substrate... 

It is said Necessity is the mother of invention . We believe that Imagination is also the mother of invention . About 30 years ago when we conceived the 1-hydroxyindole hypothesis [1-7], it was an imaginary story because it involved two impossible problems set against common sense in indole chemistry at that time [8]. The first problem was the lack of both synthetic and natural products having 1-hydroxyindole skeletons. In addition, no one knew how to synthesize the imknown 1-hydroxytryptamines and -tryptophans. The second was the prediction that they would imdergo unprecedented nucleophihc substitution reactions. 

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