Tetracyclic-fused indole

Fused indole 232 resulted from the reaction of a donor-acceptor cyclopropane with an indole bearing a Michael acceptor at C2.The products were obtained in good yield with high diastereoselectivity (16 examples, 64-90% yield) (140L3954). Tetracyclic-fused indole 233 was prepared by a [3+3]-cycloaddition of an indol-2-yl carbinol with an azadiene (11 examples, 42-90% yield). This could be followed by an oxidative ring expansion promoted by (bis(trifluoroacetoxy)iodo)benzene to produce a series of indole azepinones (6 examples, 59-71% yield) (14CC11181). Fused indole 234 was synthesized by the first calcium(II)-promoted Nazarov cyclization (87% yield).The substituent a to the ester functionality could vary electron-rich arenes, heteroarenes, and secondary alkyl... 

A hydroamination/N-sulfonyliminium cyclization cascade was carried out enantioselectively with gold and BINOL-phosphoric acid catalysts to generate fused indole 188. The method can also be extended to furnish lactams with up to 93% ee (13OL4330). Polycyclic indoline 189 was prepared via an indium/TFA-catalyzed tandem cycloannulation of P-oxodithioesters with tryptamine in yields up to 92% (130L1974). Dixon and colleagues utilized an enantioselective Michael addition/iminium ion cyclization of trypt-amine-derived ureas in the synthesis of tetracyclic indole 190 (22 examples, up to 78% yield and 96% ee) (130L2946). 

A fused tetracyclic a presursor of indole alkaloids was constructed via a 5-exo-dig/6-endo-trig tandem double radical cyclization [82], When the erytkro isomer 207 was subjected to radical cyclization, the tetracyclic cis fused carbamate 208 was obtained. Interestingly, the corresponding threo isomer failed to cyclize due to the formation of a transoid ate complex of silicon during the cyclization process. 

Fused tetracyclic indole derivatives 1149 were obtained from indoles 1148 in the above conditions (Equation 263) <2004JOC5413>. When indoles bearing a methyl on the nitrogen are used, total diastereoselectivity is observed, which almost disappears with nonmethylated substrates 1148 (R = H). 

A gold(I)-catalyzed tand [3,3]-rearrangement/[2+2]-cycloaddition provided cyclobutane-fused indoUnes <05JA16804>. For example, treatment of indole 163 with a gold/sUvo- catalyst system gave tetracyclic indoline 164. 

The quinolizinium ion (28.3) occurs naturally only rarely, for example as a fused ylide in the alkaloid sempervirine, however there are hundreds of indole alkaloids that contain the same tetracyclic system, but with the quinoUzine at an octahydro level, as exemplified above (reserpine). In addition, many simpler qninolizidine alkaloids, such as lupinine, are known. 

Kutney s approach started with isophorone 84, which was converted into the dibenzoate 85, and thence to the acid 86 on treatment with indolyhnagnesium iodide. Conversion to the acid chloride followed by treatment with indolylmagnesium iodide, induced cyclization to the trans-taseA tetracycle 87. Base-catalyzed epimerization to the cM-fused tetracyclic ketone 88, followed successively by hydride reduction, conversion into the benzoate, treatment with the indole Grignard reagent, and deprotection, gave YCK (73) (Scheme 4). The overall yield was however low (4%), but the method allows access to 6a-c z-YCK via the ketone 87 (57,55). 

Seven-membered ring closures via e do-cyclization are by far more widespread than the analogous gndo-modes for five- or six-membered cycles. There are some examples using substructure G (Figure 6.4) as substrate. Joseph and cowoikers [145] reported the synthesis of fused heterocycles bearing a benzazepinone moiety. Tetracycle 202 was obtained in excellent yield starting from indole derivative 201 in the presence of silver salt (Scheme 6.59). 

An efficient three-component domino strategy for the synthesis of multi-functionahzed tetracyclic indeno[l,2-h]indole derivatives has again been reported by Tu, li, and coworkers [62]. The domino reaction between enaminones 57 and 2,2-dihydroxyindene-l,3-dione 105 in acid anhydride generated the fused pyrazoles 106 (tetracyclic 6-5-S-6 skeleton), which involved a nucleophilic substitu-tion/cychzation/methyl migration/aromatization/esterification. On the other hand,... 

Starting from simple 2-ethynylanilines and o-bromobenzylamines, complex indole-fused tetracyclic compounds were easily and directly synthesized in a single reaction vessel. This was the first example of a copper-catalyzed one-pot reaction including three catalytic cycles and the formation of four bonds. In detail, Mannich-type coupling of an ethynylaniline derivative with formaldehyde and M-substituted o-halobenzylamine, indole formation, and arylation of the indole nitrogen were included (Scheme 4.27). 

More recently, Enders et al. disclosed a facile access to tetracyclic double annulated indole derivatives 175, which basically relies on the chemistry of the acidic 2-substituted indole and its nitrogen nucleophilicity. Indeed, the employed quadruple cascade is initiated by the asymmetric aza-Michael-type A-alkylation of indole-2-methylene malono-nitrile derivative 174 to o,p-unsaturated aldehydes 95 under iminium activation (Scheme 2.57). The next weU-known enamine-iminium-enamine sequence, which practically is realized with an intramolecular Michael addition followed by a further intermolecular Michael and aldol reactions, gives access to the titled tetracyclic indole scaffold 175 with A-fused 5-membered rings annulated to cyclohexanes in both diastereo- and enantioselectivity [83]. 

In 2012, Melchiorre et al. reported a novel stereoselective access to chiral frans-fused tetracyclic indole-based products having four stereogenic centres on the basis of a multicatalytic tandem Diels-Alder-benzoin reaction involving JV-Boc protected 3-(2-methyl-indol-3-yl)acrylaldehyde derivative and fra s-l,2-dibenzoylethylene derivative as substrates." As shown in Scheme 2.32, the process was successively induced by chiral diphenylproli-nol trimethylsilyl ether in the presence of bullgr 2,4,6-trimethylbenzoic acid (TMBA) as co-catalyst for the Diels-Alder reaction (trienamine catalysis), and an AT-heterocyclic carbene for the following cross-benzoin condensation... 

In Chap. 4, the author describes a direct access to indole-fused tetracyclic compounds containing a 1,4-diazepine framework by copper-catalyzed domino three-component coupling, cyclization, and A -arylation, which involve the formation of one carbon-carbon bond and three carbon-nitrogen bonds. 

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