Tryptamine and Its Derivatives

Like gramine, tryptamine is more familiar as an intermediate in preparative indole chemistry than as an alkaloid. It was first synthesized 

Dipterine, the iVb-methyl derivative of tryptamine, occurs in two Asiatic members of the family Chenopodiaceae, Girgensohnia diplera Bge. (71, 72) and Arthrophytum leptocladum Popov (73), and also in the bark of Piptadenia peregrina Benth. (73a). Arthrophytum leptocladum also contains a closely related base, leptocladine (74), identified as Nb-methyltetrahydroharman by synthesis from dipterine and acetaldehyde (73). 

A-dimethyltryptamine was isolated (77). A7,Ar-Dim ethyltry ptamine also occurs in the leaves of Lespedeza bicolor vax. japonica (Leguminosae) (78), and in the roots of Mimosa hostilis Benth. (40, 79). The latter plant is also the source of an extract used by the local (Brazilian) Indians in their mysticoreligious ceremonies for its hallucinogenic properties. These rituals have been described by Gongalves de Lima, who recorded the extraction of nigeiine from Mimosa hostilis, but did not identify it as N,N-dimethyltryptamine (79). 

On account of the activity of these plant extracts and the isolation from them of iV,iV-dimethyltryptamine, the physiological activity of this base in humans is of interest. When injected intramuscularly, it causes hallucinations and illusions, which are characterized by their rapid appearance and brief duration (80). Apparently, dimethyltrypt-amine is rapidly metabolized and excreted mainly as indoleacetic acid, although the urine is enriched with 5-hydroxyindoleacetic acid whether this is the result of oxidation at the 5-position or stimulation of the metabolism of serotonin in the brain is not yet known (80). 

The seeds of Piptadenia peregrina and P. macrocarpa also contain AjA-dimethyltryptamine oxide (75). Since A,A-dimethyltryptamine is readily oxidized on exposure to air, the oxide of this base may be an artifact. 

---

Indole chemistry has already been discussed in Chapter 4. This is one of the major groups of naturally occurring bioactive alkaloids, and can be classified into three main categories tryptamine and its derivatives, ergoline and its derivatives, and (3-carboline and its derivatives. 

The spectra of N-alkylated tryptamines (9)23 show a consistent difference in chemical shift for N(a) and N(b) substitution, the N(a) peak appearing at lower field. There is no evidence in the spectra of tryptamine and its derivatives for the existence of a cyclic tautomer (10). 

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... 

Dimerization is also prevented by the presence of a formal positive charge on a j8-substituent, thus tryptamine cannot be dimerized. The formation of the trimer can be rationalized by analogy with the reactions of gramine and its derivatives. Thus, Thesing and Mayer found that methylphenylskatylamine (49) reacts with... 

Acylation of the tryptamine-based /3-enamino esters 458 with acryloyl chloride and its derivatives results in acylation of the enamine nitrogen and formation of the pyridiniminium ion intermediate 459. Electrophilic attack at C-3 of the indole and rearrangement of the spiro intermediate gives the indoloquinolizines 460 (Scheme 102) <2003TL6527>. 

Incubation of tryptamine derivatives with 5-methyl-tetrahydrofolic acid and an enzyme preparation from brain gives tryptolines. Dopamine and its derivatives form related tetrahydroisoquinolines such as the product that arises from reaction with acetaldehyde (see Eq. 30-5). This product has been found in elevated amounts in alcoholics (who synthesize excess acetaldehyde), in phenylketonurics, and in L-dopa-treated patients with Parkinson disease.1136... 

Tryptamine and its Al-methyl and A/Al-dimethyl derivatives (Figure 6.70) are widely distributed in plants, as are simple hydroxylated derivatives such as 5-hydroxytryptamine (serotonin). These are formed (Figure 6.70) by a series of decarboxylation, methylation, and hydroxylation reactions, though the sequences of these reactions are found to vary according to final product and/or... 

Tryptamine and its simple derivatives (117) are of interest mainly as hallucinogens, although the Australian grass PAaZaris tuberosa, the cause of Phalaris staggers in sheep, contains iV,A -dimethyltryptamine and its... 

Among the indole Mannich bases, the alkaloid gramine (3-dimethylaminomethylindole) and its derivatives have foimd the most extensive applications. They are valuable intermediate products in the synthesis of different important eompounds - heteroauxine, tryptophane, and the series of tryptamines. 

Yohimbine (104), also from the bark of C.johimbe K Schum. and from the roots of R. serpentina (1. ) Benth. has a folk history (unsubstantiated) of use as an aphrodisiac. Its use has been confirmed experimentally as a local anesthetic, with occasional employment for rehef ia angiaa pectoris and arteriosclerosis, but is frequently contraindicated by its undesired renal effects. Yohimbine and some of its derivatives have been reported as hahuciaogenic (70). In addition, its pattern of pharmacological activities ia a variety of animal models is so broad that its general use is avoided. All ten carbon atoms of secologanin (102) as well as the entire skeleton of tryptamine (98, R = H) are clearly seen as iatact portions of this alkaloid. 

The second line of circumstantial evidence quoted in support of this hypothesis is the ready formation of l,2,3,4-tetrahydro-/3-carboline derivatives under pseudo-physiological conditions of temperature, pH, and concentration. Tryptamine and aldehydes, trypt-amine and a-keto acids, and tryptophan and aldehydes condense at room temperature in a Pictet-Spengler type intramolecular Mannich reaction in the pH range 5.2-8.0 (cf. Section III, A, 1, a). It was argued that experiments of this type serve as models for biochemical reactions and may be used in evidence. 

Nearly all the derivatives of 2,5-DMA exhibited radioligand binding charae-teristies at 5-HT2 serotonin reeeptors that were consistent with those of serotonin and other tryptamine agonists. It has been demonstrated... 

To the solution of the N,N-dibenzyltryptamine derivative in EtOH were added HC02NH4 (15 mol/mol tryptamine) and Pd black (2 mol Pd/mol tryptamine) and the mixture was refluxed under N2 for 12 hours. It was brought to room temperature and another batch of HC02NH4 and Pd black was added with stirring. This was followed by the addition of formic acid, and the reaction mixture was refluxed for another 12 hours.350... 

Since tryptophan (and its decarboxylation product, tryptamine) serve as precursors in many synthetic and biosynthetic routes to /J-carbolincs, it is not surprising that C-1 of the /J-carbolinc ring is the most common site of substitution (as it is the only ring atom of the /J-carbolinc ring system not derived from tryptophan). Indeed, this is the only site of substitution for many /J-carboline natural products. Two examples of naturally occurring /J-carbolines substituted only at C-1 which possess antitumor activity are manzamine A and manzamine C (Fig. 2). Owing to its greater simplicity and nearly equal antitumor activity, most initial synthetic efforts were directed toward manzamine C [11,12]. 

Important indole derivatives (see Scheme 2) include (i) indigo, a vat dye known and widely used since antiquity, and originally obtained from indican, a (3-glucoside of indoxyl which occurs in some plants. Indigo is now prepared synthetically. Tyrian purple, a natural dye used since classical times, is 6,6 -dibromoindigo (ii) the numerous indole alkaloids, with complex derivatives such as yohimbine and strychnine (iii) tryptophan, an essential amino acid found in most proteins. Its metabolites include skatole and tryptamine and (iv) 3-indoleacetic acid, which is important as a plant growth hormone. 

An efficient synthesis of ( )-quebrachamine is based on the construction of a suitable precursor via ring cleavage of an a-diketone monothioketal (810) (80JCS(P1)457). This monothioketal, available from 4-ethoxycarbonylcyclohexanone ethylene ketal, was fragmented to the dithianyl half ester (811) with sodium hydride in the presence of water. Reaction of (811) with tryptamine and DCC provided an amide which was converted to the stereoisomeric lactams (812) on hydrolysis of the dithiane function. Reduction of either the a- or /3-ethyl isomer with lithium aluminum hydride followed by conversion of the derived amino alcohol to its mesylate produced the amorphous quaternary salt (813). On reduction with sodium in liquid ammonia, the isomeric salts provided ( )-quebrachamine (814 Scheme 190). 

The procedure has also been applied for the hydroxylation of aromatic amines. Aniline and its /V-alkyl-substimted derivatives show similar behavior under similar conditions to afford the meta-substi tuted aminophenols as the major hydroxylated product.627 Product formation was interpreted by the attack of protonated hydrogen peroxide on the anilinium ion protected by /V-protonation from oxidation or degradation. Indoles, indolines, and tetrahydroquinoline have also been successfully hydroxylated with H202 in HF-SbF5 with the hydroxyl group meta to the nitrogen function.559,628 Hydroxylation of tryptophane and tryptamine derivatives affords pretonine and serotonine derivatives in 42% and 38% yields, respectively.629... 

---