Tryptamine derivatives

In some cases, e.g. the detection of antioxidants [6], the plate is heated to 105 °C for 5 min after being sprayed and the still hot plate placed immediately in an ammonia-vapor chamber. The blue color of the tryptamine derivatives is also stabilized by spraying afterwards with a 5% methanolic ammonia solution [12]. 

The Bischler-Napieralski reaction involves the cyclization of phenethyl amides 1 in the presence of dehydrating agents such as P2O5 or POCI3 to afford 3,4-dihydroisoquinoline products 2. This reaction is one of the most commonly employed and versatile methods for the synthesis of the isoquinoline ring system, which is found in a large number of alkaloid natural products. The Bischler-Napieralski reaction is also frequently used for the conversion of N-acyl tryptamine derivatives 3 into p-carbolines 4 (eq 2). 

Bischler-Napieralski reactions of N-acyl tryptamine derivatives 16 are believed to proceed via a related mechanism involving the initial formation of intermediate spiroindolenines (17) that rearrange to the observed 2-carboline products (18). The presence of these intermediates has been inferred by the observation of dimerized products that are presumably formed by the intermolecular trapping of the spiroindolenine by unreacted indole present in the reaction mixture." ... 

The reactions of tryptophan and of tryptamine derivatives with formaldehyde require special comment. Whereas tryptamine and its 5- and 7-methoxy and i id-A-methyl and -ethyl derivatives react... 

The salt 55 (R = H) did not cyclize on reduction with metal hydrides, but instead yielded the tryptamine derivative 58 (R = H) as the sole... 

These authors formulated the major steps in the biogenesis of the harmala bases as a condensation of a tryptamine derivative (460) with acetaldehyde to yield a l,2,3,4-tetrahydro-)3-carboline (461), which on oxidation in two stages would give harmaline (462 R = OCH3) and then harmine (463 R = OCH3). 

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. 

Etryptamine (23) is a tryptamine derivative which has been used as an antidepressant. Its synthesis involves the condensation of indole-3-carboxaldehyde (21) with the active methylene group of 1-nitropropane to form the inner nitronium salt of the substituted nitrovinyl indole (22). This then is readily reduced to etryptamine (23)... 

Perhaps the advantage of the medicinal chemistry route lies in the flexibility of introducing different alkyl groups on the primary amine through reductive amination on 2-aminoethyl indole 10 and hence allows access to various N, N-dialkyl tryptamine derivatives for structure-activity relationship (SAR) studies. 

We became particularly interested in strychnine when we noticed that the tetracycle 21 (Scheme 4.6), which might be readily available by an intramolecular Diels-Alder cycloaddition of a tryptamine-derived aminodiene, contains much of the complexity of this popular alkaloid target. In fact, this tetracycle is common to many indole monoterpene alkaloids including members of the Strychnos, Aspidosperma, and... 

In the course of our successful synthesis, we identified several limitations of our new method and associated strategy (1) the harsh conditions of the bicyclization reaction do not tolerate base-sensitive functionality such as vinyl halides (2) post-cyclization manipulations such as iododesilylation reactions are complicated by the sensitive/ reactive functionality of the products (a,p-unsaturated aldehyde, indoline, etc.) and (3) the incorporation of the required functionality into the Zincke aldehyde requires the synthesis of a complex tryptamine derivative, resulting in a lengthy, non-convergent route. In order to develop a concise route to strychnine, we would have to address each of these issues, and a straightforward solution to obviate all of these is described below. 

For a Lewis-acid-mediated cyclization reaction of a tryptamine-derived vinylogous amide that affords the Aspidosperma skeleton, see Huizenga RH, Pandit UK (1991) Tetrahedron 47 4155 1164... 

The isolation of calycanthine (9) in 1888 by Eccles [28] and the subsequent proposition for its origins in the oxidative dimerization of tryptamine by Woodward [29] and Robinson [30] had prompted several key synthetic studies based on a biomimetic approach. Hendrickson was the first to experimentally verify the plausibility of forming the C3-C3 linked dimers through an oxidative radical dimerization strategy (Scheme 9.2a). He demonstrated that the sodium enolate of a tryptamine-derived oxindole could be oxidized with iodine to afford a mixture of three possible stereoisomers. The racemic product was isolated in 13 % yield, while the meso product was isolated in 8 % yield. Global reduction of the oxindole and carbamates afforded the first synthetic samples of chimonanthine (7) [9a],... 

The Ir-catalyzed borylation of the indole nucleus is another important development that promises to find widespread use in complex molecule synthesis. Early reports include the functionalization of C(7) and also of C(2), reported by Malezcka and Smith and by Hartwig, respectively [39, 40]. In a report in 2011, Movassaghi, Miller, and coworkers demonstrated the borylation of tryptamine derivative 61 to afford 62 in 70 % yield [41]. This material was subjected to Suzuki-Miyaura cross coupling with 7-bromoindole (63) to set the stage for studying the oxidative rearrangement of 64, which would eventually provide diketopiperazine indole alkaloids such as asperazine (Scheme 11.11). 

The Bischler-Napieralski approach to /J-carboline synthesis is very similar to the Pictet-Spengler one, except that the tryptamine derivative is first... 

Adkins, E. M., Barker, E. L., and Blakely, R. D. (2001) Interactions of tryptamine derivatives with serotonin transporter species variants implicate transmembrane domain I in substrate recognition. Mol. Pharmacol. 59, 514-523. 

TABLE 3. Structures of tryptamine derivatives which have been studied tor potential hallucinogenic activity... 

One of the best studied tryptamine derivatives is DMT (37). DMT and 5-OMeDMT (59) are probably the active constituents of a variety of South American hallucinogenic snuffs. These and related indolealkylamines have been detected in members of at least five different plant families Agaricaceae, Leg-uminosae, Malpighiaceae, Myristicaceae and Rubiaceae (107,109,110,187). In... 

Psilocin has also been the object of considerable investigation using animals as subjects. Much of the initial work with psilocin, as well as other 4-hydroxy-tryptamine derivatives with alterations in the side chain and/or terminal amine, was performed at Sandoz Laboratories in Switzerland (29,245). Subsequent investigations have shown that psilocin produces hyperthermia in rabbits (113), induces the head-twitch in mice (43), disrupts acquisition of avoidance behavior in rats (240), increases startle response magnitudes in rats (68), increases limb-flick behavior in cats (120), and produces discriminative stimulus effects in rats similar to those of 5-OMeDMT (59) (93). 

Brimblecombe, R. W. (1967) Hyperthermic effects of some tryptamine derivatives in relation to their behavioral activity. Int. J. Neuropharmacoi, 6 423-429. 

Holmstedt, B. (1965) Tryptamine derivatives in Epena, an intoxicating snuff used by some South American Indians. Arch. Ini. Pharmacodyn. Ther., 156 285-305. 

Szara, S. (1957) The comparison of the psychotic effect of tryptamine derivatives with the effects of mescaline and LSD-25 in self experiments. In Psychotropic Drugs, edited by S. Garattini and V. Ghetti, pp. 460-467. Elsevier, Amsterdam. 

Szara, S. (1961) Correlation between metabolism and behavioral action of psychotropic tryptamine derivatives. Biochem. Pharmacol, 8 32. 

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