Pathway indole

It could be argued that the cyclization does not proceed by C-H activation, but by formation of an electrophilic T -complex 3.25, which is then attacked by the electron-rich indole (pathway 1). If this were the ease, a distereoisomeric t -complex 3.26, with palladium trans to the indole would be involved, whereas, by the C-H activation mechanism (pathway 2), the palladium and the indole in the intermediate 3.30 would have the cis relationship, resulting from alkene insertion. As the C-Pd bond is converted to a C-H bond, the same final product is obtained. The C-H activation mechanism of pathway 2 was demonstrated by using NaBD4 to introduce deuterium, in place of hydrogen (Scheme 3.12). The product 3.31 was found to have D cis to the indole. 

While catalytic reduction of the indole ring is feasible, it is slow because of the aromatic character of the C2-C3 double bond. The relative basicity of the indole ring, however, opens an acid-catalysed pathway through 3if-indoleninm intermediates. 

The reactions of enamines with positively activated olefins have been extended to arylations with />-quinones (350,362-369) and quinone sulfoni-mides (365-368,370). Thus a new pathway for the facile formation of benzofurans and indoles became available. 

In the arylations of enamines with very reactive aryl halides (352,370) such as 2,4-dinitrochlorobenzene, the closely related mechanistic pathway of addition of the enamine to the aromatic system, followed by elimination of halide ion, can be assumed. The use of n-nitroarylhalides furnishes compounds which can be converted to indolic products by reductive cycliza-tion. Less reactive aryl halides, such as p-nitrochlorobenzene, lead only to N-arylation or oxidation products of the enamines under more vigorous conditions. 

A number of reaction pathways have been proposed for the Fischer indolization reaction. The mechanism proposed by Robinson and Robinson in 1918, which was extended by Allen and Wilson in 1943 and interpreted in light of modem electronic theory by Carlin and Fischer in 1948 is now generally accepted. The mechanism consists of three stages (I) hydrazone-ene-hydrazine equilibrium (II) formation of the new C-C bond via a [3,3]-sigmatropic rearrangement (III) generation of the indole nucleus by loss of... 

At least two pathways have been proposed for the Nenitzescu reaction. The mechanism outlined below is generally accepted." Illustrated here is the indolization of the 1,4-benzoquinone (4) with ethyl 3-aminocrotonate (5). The mechanism consists of four stages (I) Michael addition of the carbon terminal of the enamine 5 to quinone 4 (II) Oxidation of the resulting hydroquinone 10 to the quinone 11 either by the starting quinone 4 or the quinonimmonium intermediate 13, which is generated at a later stage (HI) Cyclization of the quinone adduct 11, if in the cw-configuration, to the carbinolamine 12 or quinonimmonium intermediate 13 (IV) Reduction of the intermediates 12 or 13 to the 5-hydroxyindole 6 by the initial hydroquinone adduct 7 (or 8, 9,10). 

Two reaction mechanisms, such as SN1 and SN2 mechanisms, seem to be possible for explaining formations of 158a-c (Scheme 25). The former requires a resonance-stabilized indolyl cation 165 as an intermediate, while the latter indicates the presence of a transition state like 167. The introduction of a methoxy group into the 5 position of 165 should stabilize the corresponding cation 166, in which nucleophilic substitution on indole nitrogen would become a predominant pathway. 

However, thermolysis of the phosphonium salts (X=+PPh3) leads directly to the indolic products without need of acid catalyst or PPh3, and thus may not proceed via a normal Wittig pathway. Alternatively, Hughes has effected a solid-phase version of this reaction employing a polymer-hound phosphonium salt and potassium tert-butoxide as base <96TL7595>. In this case, the phosphine oxide by-product remains bound to the polymer resin. 

FIGURE 10.3 Pathways for degradation of L-tryptophan by (a) tryptophanase, (b) deamination and oxidation, and (c) side-chain oxidation and decarboxylation to indole. 

Nevertheless, the further mechanistic steps leading to indole dimerization is not defined and a computational investigation could suggest feasible reaction pathways, providing important anticipation about IR and UV absorption spectra, which could be very useful for the assignment of the intermediates involved. It has been experimentally proposed that the semiquinone 1-SQ may decay via disproportionation to... 

The in vivo transformation of [6-14C]strictosidine (19) to gelsemine in Gelsemium sempervirens was claimed with an incorporation of 0.47% (33). This provides another experimental support to the proposal that strictosidine appears to be the original precursor in the biosynthesis of monoterpenoid indole alkaloids, although the detailed pathway of this biosynthetic process still remains obscure. 

In regard to the experimental evidence available, a substantial number of reports on the chemical constituents of the plant are available, but much less work has been done with the pharmacological properties. Kasture et al., however, made the important observation that a triterpene isolated from R. cordifolia induces anxiety in rodents, an effect accompanied with an increase in serotonin contents in the brain (30). An interesting development from that observation would be to explore further the molecular-pharmacological pathway and the effect of this agent on the serotoninergic system because terpenes, compared with indole alkaloids, are seldom reported for serotoninergic activities. 

The microbial pathways observed for the degradation of indole differ significantly between microorganisms. Four pathways have been reported for indole degradation. In the first pathway, the degradation of indole by Desulfobacterium indolicum was reported [339,340] to occur via isatin and anthranilate (Fig. 25). 

The anthranilate intermediate is believed to be metabolized to denitrogenated products. The list of proposed metabolites is also included in Fig. 25. A consortium of anaerobic and denitrifying bacteria was found to degrade indole via oxindole [341], but further details were not given to ensure if pathway 1 was followed. 

Methyl-substituted indole has been the subject of an investigation and the degradation metabolites were identified [346], An indole-degrading methanogenic consortium induced a two-step reaction on 3-methylindole, through a hydroxylation pathway that... 

Figure 26. Indole degradation pathway with A. niger.

Some of the enzymes involved in the known pathways for the degradation of quinoline have been isolated and purified. However, not all enzymes have been identified, or characterized. In this section, we will consider the enzymes associated with the degradation of quinoline (and related compounds), carbazole and indole. To examine the enzymatic work, the reader is referred to the previous section, in which the metabolic pathways were detailed. 

An enzymatic pathway for indole degradation was found in A. niger, inducible by the substrate within a 5-h period during growth. Among the enzymes found, anthranilate hydroxylase, N-formylanthranilate deformylase, 2,3-dihydroxybenzoate decarboxylase, and catechol dioxygenase were isolated, and their activities were demonstrated in a cell-free system [342],... 

Alcaligenes sp. Strain IN3 [326] Susanne Fetzner Selective to indole. Degrade through the anthranilic acid pathway... 

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