Pathway oxindole

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. 

The same group recently disclosed a related free radical process, namely an efficient one-pot sequence comprising a homolytic aromatic substitution followed by an ionic Homer-Wadsworth-Emmons olefination, for the production of a small library of a,/3-unsaturated oxindoles (Scheme 6.164) [311]. Suitable TEMPO-derived alkoxy-amine precursors were exposed to microwave irradiation in N,N-dimethylformam-ide for 2 min to generate an oxindole intermediate via a radical reaction pathway (intramolecular homolytic aromatic substitution). After the addition of potassium tert-butoxide base (1.2 equivalents) and a suitable aromatic aldehyde (10-20 equivalents), the mixture was further exposed to microwave irradiation at 180 °C for 6 min to provide the a,jS-unsaturated oxindoles in moderate to high overall yields. A number of related oxindoles were also prepared via the same one-pot radical/ionic pathway (Scheme 6.164). 

The probable pathway of the reaction is shown in Fig. 14 and it seems to be an addition of the indole to the carbonyl group of isatin, followed by the condensation of a second indole moiety on the same carbon, resulting in the formation of 3,3-di (3-indolyl)oxindole. 

The utility of the neutral pathway is highlighted in the synthesis of chiral 3,3-disubstituted oxindoles from the corresponding acyclic Z iodide substrates, which can be realized with enantioselectivities as high as 97% ee under neutral conditions (Scheme 8G.18, Table 8G.1)... 

The analogous Z aryl triflate 19.1 reacts under the cationic manifold to give, ultimately, oxindole (/ )-17.3a in 72% yield and 43-48% ee (Scheme 8G.19) [38]. An important synthetic advance is the observation that Heck cyclization of this substrate could be diverted to the more selective neutral pathway by addition of halide salts. For example, Heck cyclization of triflate 19.1 in the presence of 1 equiv. of n-Bu4NI gave (/ )-17.3a in 62% yield and 90% ee, which is similar to the enantioselectivity obtained for cyclization of the corresponding iodide 18.1c under neutral conditions (see entry 6, Table 8G, 1). Conversely, cyclization of iodide 18.1c in the... 

Their most detailed investigations focused on the Heck cyclization of iodide 18.1c to form oxindole 17.3a (Scheme 8G.18) [38a,b]. A chiral-amplification study [47] established that the catalytically active species is a monomeric Pd-BINAP complex, a conclusion also corroborated by NMR studies by Amatore and co-workers [42d,43], In addition, two possibilities for the enantioselective step of the neutral pathway were easily eliminated [38a], Oxidative addition was precluded as the enantioselective step, because iodides cyclize with very different enantioselectivities in the presence of Ag(I) salts. A scenario where migratory insertion is reversible and [l-hydridc elimination is the enantioselective step was also ruled out, because this is not consistent with the dependence of enantioselectivity on the geometry of the double bond of the cyclization precursor. 

In the diaryl amine series 191 (Scheme 47), additional, synthetically valuable, anionic pathways provide routes to anthranilates 190, oxindoles 192, and dibenzazepinones 194. Although not explored in terms of its scope [75c], the lateral metalation-cydization, 191 -> 192, is extensively precedented [69] but harbors intriguing potential for subsequent DreM chemistry. The rearrangement 191 —> 190 is an N —> ortho C anionic Fries equivalent of the aryl O-carbamate migration (Scheme 3E) [75c] and after N-methylation, 190 may be transformed into 1,2,3-trisubstituted systems 193 [76]. In another appealing manifestation of CIPE, the efficient conversion of 191 into dibenzazepinone 194 has been applied in an effective synthesis of the antiepileptic drug oxcarbazepine (Trileptal ) 195 [77] and may also be... 

Scheme 47. Anionic pathways to oxindoles, anthranilates, and dibenzazepinones.

Another pathway of peroxynitrite-mediated modification of aromatic amino acid residues is hydroxylation. Products of peroxynitrite reaction with phenylalanine include p-, m-, and o-tyrosine. Peroxynitrite also forms dityrosine from tyrosine (V2). Major products of oxidative modifications of tryptophan by peroxynitrite include hydropyrroloindole, oxindole, and IV-formylkynurenine (K4). 

Chromatography) (equation 82). These complexes are used as enantioselective nucleophilic catalysts for reactions such as the rearrangements of O-acylated azlactones, oxindoles, and benzofuranones, and the kinetic resolution of secondary alcohols via acylation. X-ray crystal structures have been obtained for iV-acylated derivatives of (366), allowing for characterization of a likely intermediate along the catalytic pathway. 

Biosynthesis of oxindole alkaloids in Mitragyna species was studied by Shellard and Houghton, who fed ajmalicine (80) and 3-isoajmalicine to young plants of Sri Lankan M. parvifolia. Both precursors were incorporated into mitraphylline (149) and isomitraphylline (148) produced by M. parvifolia (97). This and a similar series of biosynthetic experiments led to the modification of a previously postulated hypothesis for the biosynthesis of oxindole alkaloids. This modified biosynthethic pathway to oxindole alkaloids in Mitragyna species is presented in Scheme 11. 

Scheme 11. Biosynthetic pathways to oxindole alkaloids in Mitragyna species.

Another pathway has been shown to occur in tomato, where lAA-aspartate is also oxidized to oxIAA-aspartate but is then A-glycosylated to form the glucopyranosyl-P-1 -A-oxindole-3-acetyl-A-aspartate and glucopyranosyl-p-1 -4-glucopyranosyl- 3-1 -N-... 

This cleavage of the oxindole alkaloids, e.g. (100), or the 2,3-seco-derivatives of type (101) to bicyclic piperidine derivatives is of considerable interest, and has provided new pathways for the partial synthesis of other alkaloids. Alternative ways of achieving the cleavage involve the application of the Hobson reaction to pteropodine (100), followed by hydrogenolysis of the intermediate (106) (Scheme 14) a similar sequence of reactions on 2,3-seco-2,3-dihydroakuammigine (101)... 

It has been observed that labeled strictosidine [3] geis-soschizine [4] (80,85,86) stemmadenine [7] (86,87) and tabersonine [7b,9] (86-88) were all incorporated into both catharanthine [8] and vindoline [10] in Catharanthus roseus plants, indicating that these are the main precursors in the biosynthetic pathway to the Aspidosperma-lboga alkaloids. Other intermediates such as geissoschizine oxindole [5], preakuammicine [6] have been detected 28-40 hours after germination of c. roseus seeds (85,87,89) provided strong evidence for the formation of catharanthine [8] and vindoline [10] as presented in schemes I and ll. 

Extracts of U. rhynchophylla have been shown to be anticonvulsive, antioxidant, neuroprotective, and cytotoxic [34, 38-40]. Some of these activities are attributed to the tetracyclic oxindole alkaloids rhynchophylline and isorhynchophylline. They have been shown to inhibit NMDA receptors [41], These receptors are transducers of postsynaptic signals in the central nervous system of mammals. Inhibitors of NMDA receptors could be used to treat disorders caused by excessive activation of this pathway, like cerebral ischemia, Parkinson s, and Huntington s diseases [42]. 

There has been a summary of computational and experimental studies of the use of palladium complexes with A -heterocyclic carbenes (NHCs) in the asymmetric coupling of -hybridized carbon-hydrogen bonds with aryl halides. It has been shown that the electronic and catalytic properties of NHCs fused to porphyrins may be modified by varying the inner metal in the porphyrin. A DPT study of the use of palladium-NHC complexes in the asymmetric intramolecular a-arylation of 2-bromoaryl amides to give 3,3-disubstituted oxindoles (101) has been reported. The likely pathway involves insertion of the palladium into the arene-bromine bond to form a palladacycle which deprotonates to give an (9-enolate. Conversion into the C-enolate followed by reductive elimination gives the product. The intramolecular reaction of 0 a cyclopropane carbon-hydrogen bond in a 2-bromoanilide derivative has been used to form cyclopropyloxindoles, (102), in a palladium-catalysed, silver-mediated reaction. 

In 2010, Jaegli et al. reported a novel palladium-catalyzed intramolecular domino spirocyclization process for the preparation of biologically relevant spiropyrroUdine-3,3 -oxindoles 86 [32] (Scheme 6.19). Oxidative addition of the aryl halide to Pd(0) aminopalladation via the coordinated intermediate 84 leads to palladacycle 85 reductive elimination of complex 85 generates the final product. Both Heck reaction and aminopalladation processes were viable pathways from amide 83, and the route that occurs is dependent on the ligand chosen. The use of tBuMePhos as the ligand is required for the successful formation of spirooxindoles. 

A f-BuONa-mediated synthesis of 3,3-disubstituted aza-oxindoles via a Truce-Smiles rearrangement-cyclization pathway has been reported (Scheme 181). ... 

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