Tryptamine synthesis

The stereochemistry at positions 3,15, and 20 is preserved in alloyo-himbone (LXIV) and its reduction product, alloyohimbane (3a, 15a,20a-yohimbane, LXV), of which several syntheses have been reported (Volume VII, p. 58) (30). In a recent synthesis, tryptamine (XXVI) was condensed with 4-methoxyhomophthalic anhydride (LXVI) to the amide LXVII. This in the five stages shown was converted to LXVIII and the latter, through another series of reactions, converted to LXX consisting of two epimers which were separable. Tosylation of the hydroxyl and ultimate reduction with lithium aluminum hydride generated alloyohimbane (LXV) (31). 

A variation on the tryptamine synthesis is to use diethyl (3-chloropropyl)-malonate as the substrate for a one-pot Japp-Klingemann/Fischer procedure. The chloropropyl group alkylates the ct-nitrogen, forming the tryptamine side-chain. The precise stage at which the alkylation occurs is unclear[4]. 

The appearance of the 2-(indol-3yl)ethylamine (tryptamine) unit in both tryptophan-derived natural products and in synthetic materials having potential pharmacological activity has generated a great deal of interest in the synthesis of such compounds. Several procedures which involve either direct 3-alkylation or tandem 3-functionalization/modification have been developed. Similarly, methodology applicable to preparation of tryptophan analogues has been widely explored. 

Marazano and co-workers have also applied the reactions of tryptamine with various Zincke salts, including 115 (Scheme 8.4.39), in the synthesis of pyridinium salts such as 116. This type of product is useful for further conversion to dihydropyridine or 2-pyridone derivatives. For example, in a different study, Zincke-derived chiral pyridinium salts could be oxidized site-selectively with potassium ferricyanide under basic conditions as a means of chiral 2-pyridone synthesis (117 —> 118, Scheme 8.4.40). 

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). 

Ganellin and Ridley subsequently showed that this reaction was of wide applicability and could be applied to the synthesis of tryptamine (23) itself and a number of indole derivatives with 3-(S-mono- or 3- -dialkylaminoalkyl side chains where the side chain contained two or more carbon atoms.A number of compounds of this general type including 79, 80, 81, 82, 83, 84, 85, and 86 have been prepared by these authors. Trace quantities of the corresponding l-(/8-dialkylaminoethyl)indole derivatives were formed atthe same time as other isomers. However, only the A-substituted product. 

The decarboxylated products are obtained directly, however, if condensation of tryptamine with the a-oxo acid is carried out in aqueous solution at elevated temperature. This direct synthesis of a l-substituted-l,2,3,4-tetrahydro-j8-carboline has been carried out with... 

Emphasis in recent applications of the method has been placed on the synthesis of tetra- and penta-cyclic structures containing a di-hydro-j8-carboline system or its equivalent. Thus the tetracyclic system 100 was obtained from the amide (99) of tryptamine and hip-puric acid. ... 

The acid-catalyzed conversion of the l,2,3,4-tetrahydro-j8-carboline derivative 337 (R = CHg) into the strychnine-type ring system 338 has been attributed to an equilibrium involving the protonated Schiff s base 339 of tryptamine (i.e., the intermediate in the Pictet-Spengler type synthesis of tetrahydro-j8-carbolines, cf. Section III, A, 1, a), and the a- (337) and the j8-condensation products (340). 

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)... 

Woodward s strychnine synthesis commences with a Fischer indole synthesis using phenylhydrazine (24) and acetoveratrone (25) as starting materials (see Scheme 2). In the presence of polyphosphor-ic acid, intermediates 24 and 25 combine to afford 2-veratrylindole (23) through the reaction processes illustrated in Scheme 2. With its a position suitably masked, 2-veratrylindole (23) reacts smoothly at the ft position with the Schiff base derived from the action of dimethylamine on formaldehyde to give intermediate 22 in 92% yield. TV-Methylation of the dimethylamino substituent in 22 with methyl iodide, followed by exposure of the resultant quaternary ammonium iodide to sodium cyanide in DMF, provides nitrile 26 in an overall yield of 97%. Condensation of 2-veratryl-tryptamine (20), the product of a lithium aluminum hydride reduction of nitrile 26, with ethyl glyoxylate (21) furnishes Schiff base 19 in a yield of 92%. 

The Pictet-Spengler reaction has mainly been investigated as a potential source of polycyclic heterocycles for combinatorial apphcations or in natural product synthesis [149]. Tryptophan or differently substituted tryptamines are the preferred substrates in a cyclocondensation that involves also aldehydes or activated ketones in the presence of an acid catalyst. Several versions of microwave-assisted Pictet-Spengler reactions have been reported in the hter-ature. Microwave irradiation allowed the use of mild Lewis acid catalysts such as Sc(OTf)3 in the reaction of tryptophan methyl esters 234 with different substituted aldehydes (aliphatic or aromatic) [150]. Under these conditions the reaction was carried out in a one-pot process without initial formation of the imine (Scheme 86). 

A number of genetic diseases that result in defects of tryptophan metabolism are associated with the development of pellagra despite an apparently adequate intake of both tryptophan and niacin. Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan, resulting in large losses due to intestinal malabsorption and failure of the renal resorption mechanism. In carcinoid syndrome there is metastasis of a primary liver tumor of enterochromaffin cells which synthesize 5-hydroxy-tryptamine. Overproduction of 5-hydroxytryptamine may account for as much as 60% of the body s tryptophan metabolism, causing pellagra because of the diversion away from NAD synthesis. 

Figure 13.7 Synthesis and structure of the trace amines phenylethylamine, /)-tyramine and tryptamine. These are all formed by decarboxylation rather than hydroxylation of the precursors of the established monoamine neurotransmitters, dopamine and 5-HT. (1) Decarboxylation by aromatic L-amino acid decarboxylase (2) phenylaline hydroxylase (3) tyrosine hydroxylase (4) tryptophan hydroxylase...

Scheme 4.16 Trost (+)-ibogamine synthesis plan (1 978). (a) Heat (90%) (b) tryptamine (c) 1/4NaBH4, (93%, 2 steps) (cl) Pd(PPh3)4 (cat.), (45%) (e) PdCl2(CH3CN)2 (cat.), AgBp4, then NaBH4 (45%).

The key Fisher indole synthesis using diethyl 4-chlorobutanal (8) suffered from poor yield to make the primary tryptamine 10, which then calls for reductive amination to complete the synthesis. 

Scheme 4.2 Fisher indole synthesis of N,N-dimethyl tryptamines.

Scheme 6 Indoles from o-haloanilines synthesis of tryptamines and tryptophols via re-gioselective hydroformylation of functionalized anilines...

In a recently published report by MacMillan s group [121] on the enantioselective synthesis of pyrroloindoline and furanoindoline natural products such as (-)-flustramine B 2-219 [122], enantiopure amines 2-215 were used as organocatalysts to promote a domino Michael addition/cyclization sequence (Scheme 2.51). As substrates, the substituted tryptamine 2-214 and a, 3-unsaturated aldehydes were used. Reaction of 2-214 and acrolein in the presence of 2-215 probably leads to the intermediate 2-216, which cyclizes to give the pyrroloindole moiety 2-217 with subsequent hydrolysis of the enamine moiety and reconstitution of the imidazolid-inone catalyst. After reduction of the aldehyde functionality in 2-217 with NaBH4 the flustramine precursor 2-218 was isolated in very good 90 % ee and 78 % yield. 

The formation of an iminium ion as 2-530 is also proposed by Heaney and coworkers in the synthesis of a tetrahydro- 3-carboline 2-531 (Scheme 2.120) [282]. Herein, heating a solution of tryptamine (2-526) and the acetal 2-527 in the presence of 10 mol% of Sc(OTf)3 gives in the first step the N, O-acetal 2-528, which then leads to the lactam 2-529 and further to the iminium ion 2-530 by elimination of methanol. The last step is a well-known Pictet-Spengler type cyclization to give the final product 2-531 in 91% yield. 

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. 

These epipolythiodiketopiperazine alkaloids, together with the calycanthaceous alkaloids (Fig. 9.1b), form a superfamily of natural products termed the dimeric hexahydropyrroloindole alkaloids [6-8]. The main dichotomy within this superfamily arises from the biogenetic elaboration of tryptamine versus tryptophan building blocks. The tryptamine-based calycanthaceous alkaloids, boasting members such as chimonanthine (7), calycanthine (9), and folicanthine (8), are largely plant derived and have a long and rich history in the context of natural product synthesis [7, 9]. 

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). 

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