1.2.3.4- Tetrahydro-//-carboline derivatives

The major product in Ziegler s 1969 synthesis120" of 16,17-dehydroque-brachamine was subsequently suggested1206 to be the tetrahydro-/ -carboline derivative (205) (stereochemistry not assigned). The structure and sterochemistry of (205) have now been established121 by examination of its n.m.r. spectrum (not... 

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. 

Scheme 1 Two direct routes to l,2,3,4-tetrahydro-/ -carboline derivatives...

Wang et al. have developed an efficient SPINOL-phosphoric acid (160) catalysed asymmetric Pictet-Spengler reaction of a-naphthylmethyl ttyptamines (158) with a wide range of aliphatic and aromatic aldehydes, affording a series of highly enantioenriched tetrahydro-) -carboline derivatives (159) (Scheme 57)7 ... 

Anhydro-bases derived from quaternary )S-carbolinium salts are reduced to p /r-A-substituted-l,2,3,4-tetrahydro-j8-carboline derivatives on hydrogenation over Adams catalyst in methanol solution made alkaline to ensure the presence of anhydro-base. ... 

A large number of compounds containing an extended 3,4-dihydro-/5-carbolinium system (82) have been converted similarly into the corresponding tetrahydro-j8-carboline derivatives (83a and 83b). In many cases the reaction is stereospecific and one or the other of the epimers 83a and 83b has been isolated as the sole or major product. Sodium and ethanoH tin and hydrochloric acid zinc and... 

Hi) Dehydrogenation. j3-Carboline derivatives may be obtained from tetrahydro-)3-carbohnes by zinc dust distillation or high temperatmre dehydrogenation with selenium or palladium black. Many of the complex indole alkaloids may be degraded, with bond cleavage, to yield simple )3-carbolines under these conditions and this approach has become a standard method in structural elucidations. Examples are numerous but outside the scope of this review. 

It is interesting to note that whereas 7-methoxy-l-methyl-l,2,3,4-tetrahydro-jS-carboline condenses with diazobenzenesulfonic acid to give an azo compound (presumably the 6-arylazo derivative) and 7-methoxy-l-methyl-3,4-dihydro-j8-carbohne gives a bisazo compound, none of the fully aromatic j8-carboline derivatives studied by Perkin and Robinson underwent azo-coupling. 

Only in one case was the structure of the adduct rigorously established, but it would appear most likely that these adducts are 1-cyano- or 1 -hydroxylamino-1,2,3,4-tetrahydro-j8-carboline derivatives (308). 

Acetylation of a 3,4-dihydro-j8-carboline derivative has been reported. O. Fischer described an A-acetylharmaline which was formulated as 310 since on controlled permanganate oxidation it yielded a neutral product (311), which on hydrolysis gave 7-methoxy-l-oxo-l,2,3,4-tetrahydro-j8-carboline (313) the constitution of 313... 

Tertiary p2/ -V-alkyl-l,2,3,4-tetrahydro-j8- and -y-carboline derivatives can be quaternized at the same site to give 2,2-dialkyl-l,2,3,4-tetrahydro-j8- and -y-carbolinium... 

Acylation of l,2,3,4-tetrahydro-j8-carboline derivatives takes place preferentially at the pyr-N. Thus l,2,3,4-tetrahydro-j8-carboline yields a 2-formyl and a 2-acetyl derivative, which give 2-methyl- ... 

A number of intramolecular rearrangements of 1,2,3,4-tetrahydro-j8-carboline derivatives have been reported. Some of these lead into other naturally occurring heterocyclic ring systems and are therefore of particular interest. 

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). 

The same general intermediate (342 X = OOH) may be invoked in the reaction of tetrahydro-)S-carboline derivatives with perbenzoic acid 285 ozone.From the reaction [342 (X = OOH)- 353- ... 

The Hofmann and Emde degradation of tetrahydro-j8-carboline derivatives has been reported in a number of instances, but only in one... 

Ring cleavage of l-oxo-l,2,3,4-tetrahydro-jS-carboline derivatives (374) may be accomplished by base-catalyzed hydrolysis to yield tryptamine-2-carboxylic acids (375). In the case of the 1,9-dimethyl derivative decarboxylation accompanied acid-catalyzed ring-opening, and the corresponding tryptamine (376) was obtained directly. 

Mannich reaction, and this method has recently been extended and repeatedly applied (see Section IV, B, 2). It involves treating a 1-m-hydroxybenzyl-1,2,3,4-tetrahydro-jS-carboline derivative (389) with formaldehyde at pH 4.4. When the aqueous solution of the hydrochloride of the hydroxymethyl derivative so formed is made basic with sodium carbonate, the pentacyclic base (390) precipitates. 

The benzindolopyrrocoline system (413) was obtained by oxidative cyclization of the l-benzyl-l,2,3,4-tetrahydro-j8-carboline derivative (337 R = H or CHg) using either ferricyanide or silver oxide, a reaction analogous to that described by Robinson and by Schopf... 

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. 

Partial dehydrogenation of a tetrahydro-j3-carboline derivative has been postulated to account for the origin of 7-hydroxy-l-... 

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... 

In summary, based on the results of relatively limited studies, the dihydro beta-carboline, harmaline (80), is more active than either its fully unsaturated derivative harmine (79) or its reduced derivative tetrahydroharmine (81). The positional isomer of harmine, 6-methoxyharmalan (85), is slightly more potent than harmaline. Reduction to the tetrahydro derivative 86 reduces potency. Although thorough dose-effect studies have not yet been performed, none of the beta-carboline derivatives has been found to be significantly more potent than DMT (37). 

A neat, biomimetic synthesis of brevicolline (21a) employs as essential starting material the (lS,3S)-tetrahydro-j3-carboline derivative (22), which is the major... 

N. Ide, M. Ichikawa, K. Ryu, K. Ogasawara, J. Yoshida, S. Yoshida, T. Sasaoka, S.-I. Sumi, and H. Sumiyoshi, Antioxidants in processed garlic. II. Tetrahydro-b-carboline derivatives identified in aged garlic extract, in G, 2002, 449 150. 

The enaminones 87, derived from tryptamine, undergo Pictet-Spengler cyclization to the tetrahydro-/ -carbolines 88 with BTIB (Scheme 26) (98TL2865). Admixture of 87 (R = Me, R = OEt) with DAIB or HTIB did not result in cyclization of the substrate. 

Cook s stereospecific synthesis19" of trans-1,3 -disubstituted tetrahydro-/ -carbolines by condensation of iVb-benzyltryptophan methyl ester with aldehydes, coupled with a simple 13C n.m.r. method for differentiating cis- and trans-tetrahydro-/ -carbolines,196 should afford a promising starting point for the synthesis of complex alkaloids. Angenot and his collaborators have also discussed the 13C n.m.r. spectra of a number of / -carboline and 3,4-dihydro-/Tcarboline derivatives.19"... 

Brown et al. (28) obtained (—)-deoxytubulosine (17) by a similar condensation of tryptamine (108) with (—)-protoemetine (11) derived from secolo-ganin (98) and alternatively, from the (-l-)-piperidone 33 through the corresponding aldehyde and the (+)-tetrahydro-/ -carboline 117. 

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