Cyclopent indole

FIGURE 7.21 Enriched 13C-NMR spectrum of cyclopent[ ]indole reductive activation... 

The structures, biological activities, and syntheses of marine natural products containing indole and dihydroindole nuclei have been reviewed <91H(32)l39l>. Among them, several cyclopent[ ]indoles... 

A number of antitumor agents have been made available through Fischer indole syntheses (Scheme 32). Cyclopent[ ] indol-3-ones were used to prepare novel antitumor aziridinyl... 

The rationale for the cyclopent[Z>]indole design discussed above was that the quinone methide would build up in solution and intercalate/alkylate DNA. Enriched 13C-NMR studies indicate that the quinone methide builds up in solution and persists for hours, even under aerobic conditions (Fig. 7.21). In contrast, the quinone methide species formed by known antitumor agents (mitomycin C) are short lived and highly reactive. The spectrum shown in Fig. 7.21 also shows the N to O acyl transfer product that we isolated and identified. However, we could not determine if the quinone methide structure actually has the acetyl group on the N or O centers. 

SCHEME 7.20 Cyclopent[6]indole analogues. Quinone methide structure shown with internal hydrogen bonding. 

In vivo studies were carried on the aziridinated cyclopent[Z ]indole quinone out before it was discovered that the aziridinyl ring did not participate in DNA alkylation. The results in Fig. 7.22 for the B16 melanoma syngraft model reveal that there was substantial reduction of tumor mass at 3 mg/kg. However, toxicity (animal deaths) became apparent at 5 mg/kg. On the other hand, human lung cancer xenografts in SCID (severe combined immunodeficient) mice were reduced to 50% mass with 3x1 mg/kg doses without any animal deaths. 

Xing, C. Skibo, E. B. Dorr, R. T. Aziridinyl quinone antitumor agents based on indoles and cyclopent[6]indoles structure-activity relationships for cytotoxicity and antitumor activity. J. Med. Chem. 2001, 44, 3545-3562. 

Generation of 3-indolylacyl radicals from the selenoesters 149, using either /j-Bu3SnH or tris(trimethylsilyl)silane (TTMSS) followed by reaction with various alkenes, offers a route to 3-acylindoles 150. On the other hand, the use of n-Bu Sn2 under irradiation gave cyclopent[6]indole derivatives such as 151 via a cascade involving initial addition of the acyl radical to the alkene, and a subsequent oxidative cyclization at the indole C-2 <02JOC6268>. 

By reaction of secondary V-arylketoenamines in the aminocyclopentenone series and quinones, the cyclopent[Z ]indole skeleton and dibenzo[6,d]cyclopent[/]azepines are accessible. The reaction involves an oxidative cyclization of the Michael adduct by attack of either the nucleophilic nitrogen atom or of the aromatic o-position of the aniline moiety on the quinone317 (equation 235). 

B. N-Benzyl Cyclopent[g]indole-based Medicaments Title sPLA2 Inhibitors... 

Hydroximino-l-(4-methyl-phenyl)-E14b, 313 (aus En-on) fram-l-tN-Methyl-anilinojA-oxo-E16d, 794 (Anilinierung) Cyclopenten n.s-5-Anilino-3-hydroxy- Vl/la, 1, 461 Cyclopent[b indol 8b-Hydroxy-l,2,3,3a,4,8b-hexahydro- E6b/1, 577 (2-Br —anilin + R-CO-CI/... 

A total synthesis of the herbindoles, strucmrally related cyclopent[g]indole natural products, utilized a t3qre la condensation reaction <05OL1215>. Treatment of quinone imine 94 with cyclopentadiene produced cycloadduct 95 which cycUzed to indole 96 in the presence of hydrochloric acid. The latter was elaborated into ( )-c -tiikentrin B 97. 

CycIopema 4,5]pynx>Io(2,1 -<)-l triazole 3-lhione, 1256 Cyclopenia(6]quinoline, 1058 Cyclopem[d imidazole, 741 Cyclopem[6]indole, 1250 Cyclopent[cdlindol-2-one, 1183 Cyclopent rd]isoindole, 1183... 

The structures of asperparalines A (123), B (124), and C (125) were determined to be spiro compounds made up of an A -methyl succinimide and a cyclopent[f]indolizine having an A methyl amide bridge. Another structural characteristic of asperparalines is a bicyclo[2,2,2]diazaoctane core, and various compounds, such as those of the paraherquamide family mentioned in the following section, contain the same core in their structures. However, all these compounds have an indole moiety in their structures so, it is of great interest that asperparalines have no indole part in their structures. 

A similar reaction affords a simple route to cyclopent[b]indoles. Indole-3-carbinol (68) reacts with j8-methylstyrene in the presence of titanium tetrachloride to give compound (70) <93TL8527>. The presumed four-membered spiroindolenine (69) in this sequence receives support from the observation that the conversion of the D-tryptophan derived compound (71) to its mesylate leads to the formation of racemic cyclopent[b]indole (73) via the achiral intermediate (72) (Scheme 17) <93TL439>. 

For indoles, such as cyclopent[b]indole (216a), tetrahydrocarbazole (216b) and cyclohepta[b]indole (216c), which already possess a ring annulated in the 2,3-position, the above reactions lead to the formation of propellanes 218a-d in modest yields (Scheme 59). 

Azaquinones have also been used as partners in IDA cycloadditions with indoles. In an interesting example, the reaction of commercially available 2,3-dihydro-17/-cyclopent[b]indole (21) with an electrogenerated o-azaquinone 22 produced the indolobenzoxazine product 23 in low yield (Scheme 7) [20],... 

Abstract The occurrence, structure, physiological activities as well as the synthesis of alkaloids having a carbazole skeleton is briefly reviewed. Emphasis is made on the synthesis, in particular on approaches towards girinimbine and the carbazomycines. Some new synthetic approaches based on indoles and 2-vinylindoles, and the use of carbazoles in the synthesis of the cyclopent[b]indole alkaloid yuehchukene will also be discussed. 

In another project aimed at the synthesis of cyclopent [h>]-indole alkaloids such as yuehchukene (29)which exhibits anti implantatory effects, it was found that carbazole derivatives like 27 could be readily prepared (Scheme 13). After dehydrogenation to 28, a dienone rearrangement gave the desired carbazole 26b. 

Scheme 10 Michael addition of indole on cyclopent-2-enone.

Table 7 Comparison of gluconic acid aqueous solutions ("GAAS") with other solvents for the Michael addition of indole on cyclopent-2-enone. ...

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