Indole, polycyclic

Iwasawa and co-workers developed a facile method for the construction of polycyclic indole derivatives 190a and 190b by the tungsten(0)-catalyzed reaction of A-(2-(l-alkynyl)phenyl)imine 188 with the electron-rich alkenes 189a and 189b (Scheme 32).42b Photoirradiation of a mixture of imine 188 and ketene silyl acetal 189a with 10mol% of... 

Moreover, polycyclic indole alkaloid-type molecules 225 with a ketopiperazine were prepared by Wang et al. using Ugi-Pictet-Spengler process [68]. Ketocar-boxylic acids 227 were used as bifunctional substrates in Ugi reaction to yield lactams of varying ring sizes (Scheme 41). A diastereomer of hexacyclic indole derivative was crystallized and yielded X-ray diffraction suitable crystal to assign the stereochemistry. 

Scheme 41 Synthesis of polycyclic indole alkaloid-type compounds 225. The X-ray structure of compound 225D is shown in blue sticks (CCDC-749252)...

Wang W, Herdtweck E, Domling A (2010) Polycyclic indole aUcalold-type compounds by MCR. Chem Commun 46(5) 770-772... 

Blechert et al. have proposed a new effective approach to the synthesis of different indole alkaloids using cation domino reactions (95S592, 97AGE1474). The total yield of uleine (7a), produced on the basis of this concept, is 32%, which is quite unique in the synthesis of polycyclic indole alkaloids. Note that this is the total yield, starting from cyclohexenone 46 the yield of the key step of the synthesis - the cyclization of carbazole 47 into 7a is 95% (Scheme 12). 

The reaction of vinylindoles containing the vinyl function incorporated in a carbocyclic ring provide access to novel polycyclic indole derivatives. The reaction of 46 with DMAD under forced conditions gave a mixture of Diels-Alder (47), Michael (48), and ene (49) adducts (91LA357). 

Although not described as such, this reactivity of silver as a Lewis acid in C-C bond formation via enamines was already known and actually described in the synthesis of complex indole alkaloids. A A-sulfonyldienamine embedded within a polycyclic indole ring system added to the trimethylsilylated propargyl arm of this system, leading in high yield to a new six-membered ring (Scheme 10.71).110... 

In contrast to the polycyclic indole, isoquinoline, or terpene alkaloids, the di- and polyamine alkaloids seem to be of much simpler construction. This first impression is misleading. Special structural features render this group of alkaloids even more difficult to handle than the above-mentioned ones. It should be noted that the structures of several polyamine alkaloids have had to be revised. Because of this, two main factors should be mentioned. (1) The alkaloids sometimes occur as mixtures that are very difficult to separate, and (2) the results from spectral or chemical analyses are equivocal (cf. references on structural elucidation in Section V). This group of alkaloids was the subject of several review papers (26-28) and especially covering the subject of synthesis (29-32). Some general aspects of the difficulties associated with the isolation and structure elucidation of the polyamine alkaloids are discussed. 

Polycyclic indoles. The treatment of the 3-benzoylindoles 1 and 3 with palladium acetate (0.5 equiv.) in acetic acid leads to 2 and 4, respectively, by intramolecular oxidative ring closure. ... 

Synthesis of polycyclic indole alkaloids using compounds of metals 84YZ701. 

Shortly after this, palladium-catalyzed intramolecular cyclizations on indole were also reported. Work by Grigg [23], Kozikowski [24] and Merour [25] showed that under analogous Pd(0) conditions, at high temperature, a variety of polycyclic indoles could be made (Scheme 11). 

The Pictet-Spengler reaction has been combined with Ugi multi-component chemistry to construct a number of polycyclic indoles. Isonitrile derivatives prepared from tryptamine (or methyl tryptophanate), a carboxylic acid and formaldehyde condense with aminoacetaldehyde diethyl acetal. A few examples employed substituted aldehydes [352]. 

Biechy A, Zard SZ (2009) A flexible, convergent approach to polycyclic indole structures formal synthesis of ( )-mersicarpine. Org Lett 11 2800-2803... 

Carbonyl ylides, most often in the form of isomunchnones (formed by decomposition of diketo diazo compounds in the presence of rhodium (II) acetate, and subsequent cyclization of the intermediate rhodium carbenoid species) are by far the most studied 1,3-dipolar cycloaddition partners for indole derivatives. These cycloadditions have been employed in elegant examples of complex ring construction en route to a number of polycyclic indole-containing natural products. Preliminary work by Pirrung [54, 55] (Scheme 23) on simple intermolecular cycloadditions was followed shortly by the utilization of intramolecular examples by Padwa, Boger and others. 

In a biomimetic approach toward the synthesis of communesin B (29), Stoltz and coworkers [22] described the IDA reaction of a polycyclic indole derivative 26 and a quinone methide imine formed in situ utilizing conditions previously reported by Corey (Scheme 9) [23]. 

Perez-Castells and coworkers devised a tandem enyne methathesis Diels-Alder reaction strategy for the assembly of polycyclic indole structures [109]. The enyne metathesis reaction using Grubbs s catalyst (311) with the 2-alkynylaniline 310 in the absence of a dienophile proceeded to form the mono- and bis-indole derivatives 313 and 314 (Scheme 66). Testing the hypothesis that a Diels-Alder cycloaddition with an activated diene might be faster than the undesired cross-metathesis reaction which led to the formation of 314, a one-pot reaction with maleic anhydride (312) as the dienophile was conducted. Disappointingly, the above reaction resulted in a... 

Blechert S, Knier R et al (1995) Domino reactions - new concepts in the synthesis of indole alkaloids and other polycyclic indole derivatives. Synthesis 592-604... 

Haplophytine (183), (Fig. 8), a polycyclic indole alkaloid, was first isolated by Snyder and coworkers in 1952, and identified as the principle bioactive component of the wild Mexican flower Haplophyton cimicidum A.D.C. (Apocynaceae) [72-77]. Haplophytine is of comparable toxicity to several widely used insecticides, and it was found to be toxic to a wide range of insects including European com borers, Mexican bean beetle larvae, Colorado potato beetle larvae and adults, grasshoppers, egg-plant lace bugs, and codling moths [75]. 

The core skeleton of geissoschizine, an important biosynthetic precursor to numerous polycyclic indole scaffolds, was the target of a nickel-catalyzed alkylative coupling strategy. Cyclization precursor 13 was prepared by ozonolysis and double reductive amination of cyclopentene 12 (Scheme 8.13) [35]. Nickeldeprotection/oxidation sequence followed, and chromatography led to complete inversion of the C3 stereocenter. A Fisher indole synthesis followed to afford ( )-deformyl-isogeissoschizine, the core skeleton of geissoschizine. 

Polycyclic indole alkaloid augustilobine B has a tetrahydrooxepin moiety as one of the structural fragments <87Mi902-02>. 

This method has been applied to the preparation of polycyclic Indoles and azaindoles as well. 

Oxidative Cyclization and Ring Contraction. An intramolecular cychzation/carboalkoxylation reaction takes place when 2-(penten-l-yl)-indole is treated with Pd2(dba)3 and a stoichiometric amount of copper (II) chloride in methanol under CO (1 atm). The polycyclic indole derivative was obtained in 68% yield, along with the minor C(3)-chlorinated by-product. A het-erobimetaUic Pd/Cu complex was proposed as the active catalyst in this transformation (eq 47). ... 

Chiral polycyclic indoles are ubiquitous and important ring systems found in many bioactive alkaloids and pharmaceuticals. Various methods have been developed for the efficient construction of the polycyclic indole derivatives. Recently, an unprecedented approach to a wide range of diverse, enantioenriched 2,3-dihydro-lH-pyrrolo[l,2-a]indoles 75 was demonstrated by Chen, Xiao, and co-workers. In the presence of 5 mol% Cu(OTf)2 and 5 mol% commercially available bisoxazoline 76 in toluene at 0 °C, the AFC alkylation/N-hemiacetalization cascade reaction of substituted indoles with P,y-unsaturated a-keto esters 74 occurred smoothly to afford products 75 in high yields with excellent diastereo- and enantioselectivity (Table 6.9). 

Table 6.16 Enantioselective synthesis of polycyclic indole derivatives 190 via the in situ formation and migration of spiroindolenine intermediates reported by You.

Recently, the Stanley group reported an asymmetric intramolecular hydroacylation reaction allowing a rapid access to polycyclic indole derivatives. When (5)-MeO-BIPHEP L2 was employed as a chiral ligand, the cyclization product 24, the core structure of natural product yuremamine, could be obtained with moderate to high yields and excellent enantioselec-tivity (Scheme 8.11). 

Despite the vagaries of the mechanism, the Bischler indole synthesis is extremely useful, and several variations are known. Buu-Hoi and colleagues anployed a modified version of this indole synthesis to the preparation of 2-arylindoles [12] and polycyclic indoles [13] (Scheme 2, equation 2). Their modification was to heat the w-ary lamino ketone at 230-250 °C in inert silicone oil. Some indoles... 

Funk and Huntley converted divinylpyrrolidine 10 to diene 11, and thence to an indole precursor 12 of )-cis-trikentrin B. A similar sequence was used to synthesize ( )-ci5 -trikentrin B. Dihydropyrrole 10 was assembled in five steps from A-Boc-2-pyrrolidinone. Fiirstner and coworkers synthesized several pyrrolo[2,3-c]carbazole alkaloids, the dictyodendrins B, C, and E, that featured a photochemical 6it-elecirocyclization and in situ dehydrogenation (equation 2) [21], Danheiser and colleagues effected an intramolecular benzyne generation and cycloaddition onto an alkynylpyrrole to afford a polycyclic indole (equation 3) [22],... 

Scheme 19.11 Smiles rearrangements in Zhang s polycyclic indole synthesis.

Larock heteroannulation reaction was further extended and an intramolecular Larock indole synthesis of 2-chloroanilines bearing tethered acetylenes 106 was developed for the elaboration of a variety of polycyclic indole skeletons 107, for example, in 108-112. This intramolecular indolization method unveiled an unusual >sy -anidopalladation pathway of a tethered alkyne. The major side product is the dechlorinated starting material as a result of a reductive process. 

In 1992, Smith and his group described the total synthesis of indole diterpenes (+)-paspalicine and (+)-paspalinine based on the use of Sommelet-Hauser reaction for the formation of the polycyclic indole... 

Nonetheless, this stoichiometric methodology was successfully applied by others for the syntheses of a variety of complex indole derivatives. For instance, Katritzky utilized this chemistry to obtain benzotriazolyl-substituted indoles, valuable intermediates in the synthesis of fused and polycyclic indole-derived structures [244,245]. Shvartsberg used Castro s protocol for the assembly of benz[g]indolediones [246], whereas the synthesis of pharmacologically important 1-aminoindole derivatives was reported by Prikhod ko [247, 248]. 

Iwasawa has reported the gold(III)-catalyzed reaction of N-(o-ethynylphenyl)imi-nes with electron-rich alkenes to form polycyclic indole derivatives [26]. As an example, reaction of N-[l-(l-pentynyl)phenyl]imine 28 and tert-butyl vinyl ether with a catalytic amount of AuBrs in toluene at room temperature led to isolation of the polycyclic indole 29 in 80% yield as a mixture of diastereomers (Scheme 11.3). Conversion of 28 to 29 presumably occurs via initial intramolecular hydroamination to form the gold carbene containing azomethine ylide 30 that undergoes intermo-lecular [3 + 2] cydoaddition with tert-butyl vinyl ether to form the carbene complex 31. 1,2-Migration of the 7t-propyl group to the metal-bound carbon atom coupled with deauration then forms 29. This transformation is also catalyzed efficiently by PtCl2 [26]. 

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