Tetrahydro-/?-carbolines, formation

An important application of the Mannich reaction is the synthesis of 3-dialkylaminoindoles. Intramolecular versions of this reaction are also possible, as illustrated by the formation of the tetrahydro-carboline 131. 

The key steps in this synthesis are the direct formation of the substituted indole ester (11) by the acid-catalysed reaction of ethyl pyruvate with methylphenylhyd-razine, the closure of the tetrahydro- -carboline ring by reaction of (11) with... 

In an attempt to simulate in vitro a proposed (2) biogeiietie pathway for physostigmiiie, formaldehyde was reacted with several 3-indolyl-acetamides (VI), under a variety of acidic conditions, the amides rather than the tryptamines being used in the hojje of preventing the formation of 1,2,3,4-tetrahydro- -carbolines. How ever, extensive polymerization occurred during tiiese reactions and none of tiie required products (VII)... 

In Chap. 3, the author describes two direct routes to 1,2,3,4-tetrahydro-/ -carboline derivatives by a copper-catalyzed one-pot three-component coupling-indole formation-nucleophilic cyclization at the 3-position of indole. 

Table 3 Preparation of 4-oxo-tetrahydro- -carboline by domino three-component coupling-indole formation and successive MsOH-induced cyclization...

The binolphosphoric acid (257) catalysed Pictet-Spengler reaction of an iV-(5-oxy-2,4-pentadienyl)tryptamine derivative (254) with methyl 5-oxo-2-(phenylseleno)pentanoate (255) led to the formation of tetrahydro-) -carboline (256) in a 92 8 enantiomeric ratio (Scheme 66). ... 

This reaction is also a key method for the formation of tetrahydro-P-carbolines 5 from indole bases 4 and aldehydes, ketones, or 1,2-di carbonyl compounds 2. These reactions are similarly acid-catalyzed or thermally-induced and have been utilized in the synthesis of numerous indole alkaloids. 

For the kinetically controlled formation of 1,3-disubstituted tetrahydro-P-carbolines, placing both substituents in equatorial positions to reduce 1,3-diaxial interactions resulted in the cw-selectivity usually observed in these reactions." Condensation reactions carried out at or below room temperature in the presence of an acid catalyst gave the kinetic product distribution with the cw-diastereomer being the major product observed, as illustrated by the condensation of L-tryptophan methyl ester 41 with benzaldehyde. At higher reaction temperatures, the condensation reaction was reversible and a thermodynamic product distribution was observed. Cis and trans diastereomers were often obtained in nearly equal amounts suggesting that they have similar energies."... 

The intense blue color which is obtained when tryptophan, in the presence of an aldehyde, is treated with concentrated sulfuric acid containing an oxidizing agent (Adamkiewicz-Hopkins-Cole reaction) was beheved to involve formation of a tetrahydro-j8-carboline intermediate, since most l,2,3,4-tetrahydro-j8-carbohne derivatives yield a similar color with concentrated sulfuric acid containing an oxidizing agent. The two colors have now been shown to have different absorption spectra. The nature of the carboline-blue color is still obscure. 

Tetrahydro-y-carbolines may be prepared by an internal Mannich-type reaction between 2-j8-aminoethyhndoles and formaldehyde. Kebrle et al. prepared 27 by the reaction of 2-lithio-l-methyl-indole with A-benzyl-A-ethylaminoacetone followed by debenzyl-ation treatment of 27 with formaldehyde led to the formation of the tetrahydro-y-carboline 28. Similarly, when the quaternary salts (30) of the Mannich bases (29) are heated at 100°, 1,2,3,4-tetrahydro-y-carbohnium salts (31) are formed. 

Support for this suggestion comes from many quarters. Reduction of the jS-carboline anhydro-bases with sodium and alcohol or with tin and hydrochloric acid gives the 1,2,3,4-tetrahydro derivatives, as does catalytic reduction over platinum oxide in an alkaline medium. On the other hand, catalytic reduction with platinum oxide in acetic acid results in the formation of the 5,6,7,8-tetrahydro-j3-carbolinium derivatives (see Section III,A,2,a). It should be noted, however, that reduction of pyrido[l,2-6]indazole, in which the dipolar structure 211 is the main contributor to the resonance hybrid, could not be effected with hydrogen in the presence of Adams catalyst. 

This dimeric formulation also accounts for the thermal disproportionation of the compound into a mixture of 2-methyl-l,2,3,4-tetrahydro-jS-carbohne and 2-methyl-jS-carboline anhydro-base. Normal pseudobase formation (453 R = CHs ) takes place in the case of 9-methyl-3,4-dihydro-j3-carbohne methiodide (452 R = CHg). Neither the dimeric anhydro-base nor the -methyl pseudo-base undergo a base-catalyzed disproportionation reaction to give the 1,2,3,4-tetrahydro-and the l-oxo-l,2,3,4-tetrahydro-jS-carboline in a manner analogous... 

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. 

Carboline derivatives in various oxidation states have been isolated from a number of natural sources as artifacts. )3-Carboline has been obtained from charred insects, j8-carboline and l-methyl-)3-carboline have been found in cigarette smoke,and the formation of tetrahydro-j8-carboline derivatives has been shown to be responsible for the destruction of tryptophan in acid hydrolyzates of proteins. The golden-yeUow fluorescence observed when enterochromaffin cells are flxed in formaldehyde has been related to their content of... 

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. 

The formation of tetrahydro-jS-carbolines (l,2,3,4-tetrahydro-9//-pyrido[3,4-h]indoles) is well known (510R151), and many examples have been described. We have therefore chosen this plethora some recent transformations of Trp that allow some general conclusions about the stereochemistry of this transformation. 

In 2004, Taylor and Jacobsen suggested a procedure for the enantioselective acetyl-Pictet-Spengler reaction, that is the cyclization of electron-rich aryl or heteroaryl groups onto N-acyliminium ion enabling access to substituted tetrahydro-P-carbolines and tetrahydroisoquinolines that are core structure elements in natural and synthetic organic compounds [202, 203]. Screening various thiourea catalyst candidates such as 47 in the formation of model product Np-acetyl-... 

A partial synthesis of burnamicine (131) from geissoschizine methyl ether (130) takes advantage of the c/D ring cleavage of tetrahydro-/3-carbolines by means of ethyl chloroformate (Scheme 13),79 which simultaneously introduces a function into position 3, thereby facilitating the formation of the 3-oxo-substituent. An exactly analogous route was used for the synthesis of 19,20-dihydroburnamicine (133) from hirsutine (132). 

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