New Synthetic Route to Granulatimide and Its Structural Analogues.

Yoshida, Takuji; Nishiyachi, Masakazu; Nakashima, Nobuyuki; Murase, Masayuki; Kotani, Eiichi

doi:10.1248/cpb.50.872

Cited by 28 publications

(15 citation statements)

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“…Such diversified pharmacological profiles of these complex carbazoles have also spurred great efforts by the synthetic chemists since only a very limited range of synthetic methods have been reported. [23][24][25][26][27][28][29][30][31][32] Naphthalene-1,4-dione-fused carbazoles (naphtho-A C H T U N G T R E N N U N G [2,3-a]carbazole-5,13-diones) represent a unique class of pentacyclic complex carbazoles possessing significant cell growth inhibition against several tumour cell lines. [33,34] However, few syntheses have been reported so far to access this class of electron-deficient com- plex carbazoles which restricted further structure-activity relationship studies on them.…”

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confidence: 99%

One‐Pot Three‐Step Synthesis of Naphtho[2,3‐a]carbazole‐ 5,13‐diones using a Tandem Radical Alkylation–Cyclization– Aromatization Reaction Sequence

Ding

Yao

et al. 2010

Adv Synth Catal

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A three-step, one-pot tandem reaction including radical nucleophilic alkylation/cyclization/ aromatization was developed using 0.3 equivalents of silver(I) acetate (AgOAc) as the catalyst and 2 equivalents of ammonium persulfate [(NH 4 ) 2 S 2 O 8 ] as the oxidant. This strategy is highly efficient for the assembly of pentacyclic complex carbazoles from aryl-fused bromobenzoquinones and indol-3-ylpropanoic acid acids in 52-72% overall yields (three steps). This new approach provides a significant improvement over the previously reported methods and would greatly facilitate analog library construction of pentacyclic complex carbazoles and benefit further biological evaluation of these compounds.

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confidence: 99%

One‐Pot Three‐Step Synthesis of Naphtho[2,3‐a]carbazole‐ 5,13‐diones using a Tandem Radical Alkylation–Cyclization– Aromatization Reaction Sequence

Ding

Yao

et al. 2010

Adv Synth Catal

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“…Direct comparison of 7 with a previously synthesized sample 6) confirmed the identity of the two in all respects [mp, TLC, MS, IR, 1 H-and 13 C-NMR spectra], supporting the HN-17 tautomer structure of 7.…”

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confidence: 52%

“…The chemical shifts were given in ppm (d) values with tetramethylsilane as an internal standard (DMSO-d 6 and CDCl 3 ). Mass spectra were recorded on JEOL JMS-D 300, JMS-HX 110 and Shimadzu QP-5000 spectrometers.…”

Section: Methodsmentioning

confidence: 99%

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Synthesis of Granulatimide Positional Analogues.

Yoshida

Nishiyachi

Nakashima

et al. 2003

CHEMICAL & PHARMACEUTICAL BULLETIN

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Granulatimide (1) and isogranulatimide (2), isolated from the Brazilian ascidian Didemnum granulatum, [1][2][3] are without precedent among natural alkaloids having indole/ maleimide/imidazole-containing aromatic heterocyclic skeletons, and they show strong activity as G2 checkpoint inhibitors.4) Total syntheses of 1, 2, and their structural analogues, isogranulatimide A (3), isogranulatimide B (4), and isogranulatimide C (6) have already been reported by Piers and colleagues. 1,5) In a previous paper, we presented a new synthetic route to granulatimide (1), 10-methylgranulatimide (7), 17-methylgranulatimide (8) and 10,17-dimethylgranulatimide (9).6) The latter analogues are congeners of the structural isomers 10, 11 and 12 in the imidazole moiety (Fig. 1).Previous syntheses of granulatimide and its analogues employed the Stille coupling reaction of stannylindole with 4-iodoimidazole in the presence of PdCl 2 (PPh 3 ) 2 , affording the 2,4Ј-indole-imidazole coupling product as a key intermediate. Subsequent reaction of indolyl Grignard reagents with 3,4-dibromomaleimide gave the condensation product, which was converted to granulatimide analogues by photocyclization (route A). Here we wish to report the preparation of new analogues of 1, 10-methylgranulatimide (10), 15-methylgranulatimide (11), and 10,15-dimethylgranulatimide (12), as well as 10-methylisogranulatimide B (5), by the use of 5-iodoimidazole instead of 4-iodoimidazole in the same synthetic strategy (route B) (Chart 1). Results and DiscussionTo obtain the new granulatimide analogues 10, 11, 12 and the 2,5Ј-indole-imidazole coupling product for further structural manipulation, we needed to replace the 4-iodoimidazole moiety with a 5-iodoimidazole derivative. Thus, introduction of imidazole into compound 14 (or 27) was carried out using 1-methoxy-2-tributylstannylindole (13) (Chart 2).The 5-iodo-1-methyl-2-phenylthioimidazole (14) and 5-iodo-1-methoxymethyl-2-phenylthioimidazole (27) were synthesized from 1-methylimidazole (or imidazole) according to reported methods.7) The stannyl derivative 13 was itself prepared from 1-methoxyindole 8,9) by regioselective lithiation with n-BuLi 10-12) and subsequent reaction with chlorotributylstannane.13) The Stille coupling reaction 14,15) of 13 with the imidazole 14 in the presence of PdCl 2 (PPh 3 ) 2 in toluene afforded the 2,5Ј-indole-imidazole coupling product 15 in 65% yield.On the other hand, the reaction of 13 with the imidazole 27 under similar reaction conditions, but in benzene instead of toluene, afforded 28 in 64% yield. Subsequent deprotection of the 1-methoxy group in 15 and 28 was readily achieved with Mg-MeOH to give, in 92 and 76% yields, 5-(1H-indol-2-yl)-1-methyl-2-phenylthio-1H-imidazole (16) and 5-(1H-indol-2-yl)-1-methoxymethyl-2-phenylthio-1H-imidazole (29), key intermediates for synthesizing new analogues. To confirm the coupling reaction, compounds 15 and 29 were subjected to a heteronuclear multiple bond connectivity The Stille coupling reaction of the stannylindole 13 with the 5-iodoimi...

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“…The first one by Piers et al proceeded via their putative biosynthetic precursor didemnimide A and was based on the condensation of the substituted imidazole 1 with indole-3-acetamide (route A) [21]. The other one proposed by Yoshida et al relied on a key Stille coupling reaction between stannylindole 2 and 4-iodoimidazole in the presence of PdCl 2 (PPh) 3 [22] (route B).…”

Section: Marine-related Metabolites and Positional Analoguesmentioning

confidence: 99%

Marine Pyrrolocarbazoles and Analogues: Synthesis and Kinase Inhibition

2009

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Granulatimide and isogranulatimide are alkaloids obtained from marine sources which have been shown to inhibit cell-cycle G2-checkpoint, targeting more particularly checkpoint 1 kinase (Chk1). At a structural level, they possess a characteristic pyrrolocarbazole framework also shared by the well-known rebeccamycin and staurosporine microbial metabolites which have been described to inhibit topoisomerase I and diverse kinases, respectively. This review reports precisely on the synthesis and kinase inhibitory activities of pyrrolocarbazole-based analogues of granulatimide.

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New Synthetic Route to Granulatimide and Its Structural Analogues.

Cited by 28 publications

References 14 publications

One‐Pot Three‐Step Synthesis of Naphtho[2,3‐a]carbazole‐ 5,13‐diones using a Tandem Radical Alkylation–Cyclization– Aromatization Reaction Sequence

One‐Pot Three‐Step Synthesis of Naphtho[2,3‐a]carbazole‐ 5,13‐diones using a Tandem Radical Alkylation–Cyclization– Aromatization Reaction Sequence

Synthesis of Granulatimide Positional Analogues.

Marine Pyrrolocarbazoles and Analogues: Synthesis and Kinase Inhibition

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