Indole moiety

Formation of a quinonoid carboline-type anhydro-base requires loss of resonance stabilization of the indole moiety. In the carboline anhydro-bases this is counterbalanced by the preservation of a 677 system in the hetero ring. No such balancing factor is present in the case of 3,4-dihydro-j3-carboline derivatives. Formation of the exocyclic anhydro-base in the latter case preserves benzenoid resonance. It is noteworthy that in the two cases where formation of a carboUne-type anhydro-base was reported in dihydro derivatives additional aromatic conjugation is present. 

The inverse electron demand Diels-Alder reaction has also been used to provide expedient access to unnatural 6-carboline alkaloids from 1,2,4-triazines, prepared by microwave-assisted MCR [92]. One-pot reaction of an acyl hydrazide-tethered indole 73, 1,2-diketone and ammonium acetate in acetic acid provided triazines 74 (see Sect. 3.2, Scheme 22), bearing an electron-rich dienophilic indole moiety (Scheme 31). By carrying out the... 

Following on from this, and to further exemplify this pharmacophore model, Huffman [182] described a novel hybrid structure that combined the hydroxydibenzopyran ring of THC and the indole moiety of the AAIs into one molecule. It was found that the hybrid molecule (270) had a similar affinity (19 nM) for the CBi receptor in vitro as (67) (41 nM). The compound was also active in vivo in the mouse tetrad model of cannabimimetic activity and had comparable potency to (67) [182]. 

The classic and most convenient synthesis of the indole moiety is that of Emil Fischer. Recent examples of its use for drug synthesis includes one preparation of the nonsteroidal antiinflammatory agent, indoxole (2). Reaction of ketone 1 with phenylhydrazine in acetic acid leads directly to indoxole (2). Alternately, anisoin (3) can be reacted... 

A fourfold anionic domino process consistingofadominoMichael/aldol/Michael/ aldol process was used by Koo and coworkers for the synthesis of bicyclo[3.3.1]non-anes. They employed 2 equiv. of inexpensive ethyl acetoacetate and 1 equiv. of a simple a, 3-unsaturated aldehyde [290]. Differently substituted dihydroquinolines were assembled in a Michael/aldol/elimination/Friedel-Crafts-type alkylation protocol by the Wessel group [291]. An impressive approach in this field, namely the construction of the indole moiety 2-557, which represents the middle core of the man-zamines, has been published by Marko and coworkers [292]. Manzamine A (2-555) and B (2-556) are members of this unique family of indole alkaloids which were isolated from sponges of the genus Haliclona and Pelina (Scheme 2.126) [293]. 

The formation of the indole moiety has found immense attention, since it exists in many bioactive compounds such as the indole alkaloids [302]. Whilst the Fischer indole synthesis remains the most important procedure, during the past few years several transition metal-catalyzed syntheses have been developed. Recently, a Cu11-catalyzed cyclization of anilines containing an ortho-alkynyl group was published by Hiroya and coworkers [303], which allows a double cyclization in domino fashion to provide annulated indoles. Thus, reaction of 6/4-92 in the presence of... 

A different type of synthesis, which leads to a benzannulated indolo[2,3-3][l,6]naphthyridine 15, is illustrated in Scheme 3 <1999TL3797>, and the use of an azaindolone as starting material may introduce an additional heteroatom into the indole moiety of the product, as in 16 (Equation 2) <1994TL1995>. The dipyrrolo[2,3-3 2, 3 -g][l,8]naphthyridine 18 is produced by reaction of the naphthyridine 17 with ethyl glycinate in the presence of a phase-transfer catalyst (Scheme 4) <2000PS(163)29>. 

Scott was able to leverage the same type of methodology in an impressive display in which /V-methyltryptamine was dimerized directly to afford chimonanthine (7) (Scheme 9.2b) [9c]. Deprotonation of the indole 1H proton with methyl Grignard followed by treatment with FeCl3 accomplished the singleelectron oxidation and dimerization of the indole moiety. The racemic and meso stereoisomeric products were obtained as a mixture in 19 % and 7 % yields, respectively. Takayama later found hypervalent iodine to be a superior oxidant, affording yields of 17 % and 30 %, respectively [9j]. In both cases, however, as in the case of Hendrickson s example, stereocontrol could not be achieved. 

Two new 3,6-difunctionalized isovoacangines were found in T. sessilifolia (174). The major compound (116, C22H26N205, amorphous, [a]D -55°) had in its mass spectrum fragments from the aliphatic portion similar to those of 115, whereas fragments from the indole moiety were shifted 30 amu. LiAlH4 reduction... 

Chlorination of yohimbine (74) at the (3 position of the indole moiety with tert-butyl hypochlorite and treatment of the resulting chloride (539) with base in... 

Two years after the discovery of the first asymmetric Br0nsted acid-catalyzed Friedel-Crafts alkylation, the You group extended this transformation to the use of indoles as heteroaromatic nucleophiles (Scheme 11). iV-Sulfonylated aldimines 28 are activated with the help of catalytic amounts of BINOL phosphate (5)-3k (10 mol%, R = 1-naphthyl) for the reaction with unprotected indoles 29 to provide 3-indolyl amines 30 in good yields (56-94%) together with excellent enantioselec-tivities (58 to >99% ee) [21], Antilla and coworkers demonstrated that A-benzoyl-protected aldimines can be employed as electrophiles for the addition of iV-benzylated indoles with similar efficiencies [22]. Both protocols tolerate several aryl imines and a variety of substituents at the indole moiety. In addition, one example of the use of an aliphatic imine (56%, 58% ee) was presented. 

The UV spectrum (2max 211, 225, 255, 305, 375, and 447 nm) of malasseziazole A (390) showed the presence of an indolo[3,2-b]carbazole framework. The H-NMR spectrum of malasseziazole A (390) showed signals for two, 2,3-disubstituted, IH-indole moieties interconnected by a C4H2O3 unit containing a -C( = 0)COOH group. This was supported by COSY experiments. Further structural support... 

Using a modification of Sakamoto s indole benzannulation protocol (see Scheme 5.59), Beccalli et al. reported the synthesis of the 3-methoxycarbazole alkaloids hyellazole (245) and 6-chlorohyellazole (246) (540) (Scheme 5.61). Unlike Sakamoto s methodology, this method requires a good leaving group at the 2-position of the indole moiety of the 3-(l,3-butadienyl)indoles 692 to facilitate the aromatization of the intermediate dihydrocarbazole by eliminating the dehydrogenation step. 

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. 

Padwa and co-workers (60,106,107) have been highly active in using carbonyl ylides for the synthesis of a number of bioactive alkaloids (Scheme 4.51). In an approach to the aspidosperma alkaloids, a push-pull carbonyl ylide was used to generate a bicyclic ylide containing a tethered indole moiety. This strategy ultimately allowed for the synthesis of the dehydrovindorosin skeleton (108). Starting from a quaternary substimted piperidone (200), elaboration of the 3-carboxylic acid provided p-ketoester amide 201. Addition of the indole tethered side chain provided a very rapid and efficient method to generate the cycloaddition precursor 203. 

The double bond of the 1,2,5,6-tetrahydropyridine may be part of an indole moiety, as in 2,3,4,9-tetrahydro-l-(chiral-substituted iminomethyl)-l//-pyrido[3,4,-/>]indole 3. Asymmetric alkylation of the A-protected derivative using the same procedure with iodomethane leads to the 1-methyl derivative in good yield and excellent enantioselectivity45. 

The relative abundance of indole-based therapeutic agents is attributable only in part to the fact that this nucleus forms part of a pharmacophore for selected CNS agents. The indole moiety, however, likely simply serves as a rigid bicyclic support in the majority of the agents discussed below. 

The chemical synthesis of the Amanita toxins has presented several problems, in particular those related to the formation of the sulfur bridge. The latter has been explored with model compounds.[2 31 It has been found that the synthesis of the (sulfanyl)indole moiety can be achieved by reacting an indole compound with an alkanesulfenyl chloride. A model tryptathionine compound has been prepared by reacting A-acyl-L-cysteine and /V-acyl-L-tryptophan in the presence of A-chlorosuccinimide in glacial acetic acid at room temperature.[4] The sulfanylation reaction has been subsequently exploited for the selective chemical modification of tryptophan residues in proteins using 2-nitrophenylsulfenyl chlorideJ5 ... 

In the XH NMR spectra of compounds of the dregamine type C(16) stereochemistry the COOCH3 protons absorb 0-58 ppm to low frequency of those in the 16-epi-isomers (257) owing to the influence of the indole moiety. The shielding of the COOCH3 nucleus in dregamine may be a related phenomenon. 

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