- INDOLE-YNONE MEDIATED BENZOANNULATION PROCESS FOR THE PREPARATION OF CARBAZOLES- CARBAZOMYCIN A, CALOTHRIXIN B AND STAUROSPORINONE
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The present invention relates to carbazoles of general formula (I), and process for the preparation thereof: wherein 'R1' is H, C1-C6 alkyl, benzyl, or allyl; R2 is H, C1-C6 alkyl, cyclopropyl, phenyl, aryl, heteroaryl, or NO2; R3 is H, C1-C6 alkyl, cyclopropyl, phenyl aryl, heteroaryl, 4-methoxy phenyl, 4-ethyl phenyl, 2-methyl phenyl, or 2-Fluoro phenyl; R4 is H, benzoyl, -CO2Et, -CHO, Br, or -OMe; R5 is OH, OMOM, OMe, CN, or OTf; R6 is H, or O-alkyl; and R3-R4 is -CHNCH2CH2-. This invention also relates to the process for the preparation of carbazomycin A of Formula (1), calothrixin B of Formula (2) and staurosporinone of Formula (3) involving carbazoles of general formula (I) as an intermediate.
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Page/Page column 30-31
(2020/10/20)
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- A General Carbazole Synthesis via Stitching of Indole-Ynones with Nitromethanes: Application to Total Synthesis of Carbazomycin A, Calothrixin B, and Staurosporinone
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A new, one-pot domino benzannulation reaction between indole-3-ynones and various nitromethane derivatives has been explored for a general entry to diversely functionalized carbazole frameworks (28 examples). The scope of this new benzannulation has been
- Singh, Shweta,Samineni, Ramesh,Pabbaraja, Srihari,Mehta, Goverdhan
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p. 3372 - 3376
(2019/05/10)
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- Br?nsted Acid Catalyzed One-Pot Benzannulation of 2-Alkenylindoles under Aerial Oxidation: A Route to Carbazoles and Indolo[2,3- a]carbazole Alkaloids
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A one-pot, protecting-group-free benzannulation of 2-alkenylindoles with readily available 1,3-dicarbonyls is demonstrated to construct structurally diverse carbazoles. The use of a cheap Br?nsted acid catalyst and air as the sole oxidant exemplifies the economic viability of this protocol. The execution of four different reactions successively to generate the medicinally important indolocarbazole core is also achieved. This one-pot protecting-group-free method paved the way for the total synthesis of three medicinally important alkaloids, namely staurosporinone, arcyriaflavin A, and 7-hydroxy-K252c.
- Saha, Shuvendu,Banerjee, Ankush,Maji, Modhu Sudan
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p. 6920 - 6924
(2018/11/21)
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- The total synthesis of K-252c (staurosporinone) via a sequential C-H functionalisation strategy
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A synthesis of the bioactive indolocarbazole alkaloid K-252c (staurosporinone) via a sequential C-H functionalisation strategy is reported. The route exploits direct functionalisation reactions around a simple arene core and comprises of two highly-select
- Fox,Gilligan,Pitts,Bennett,Gaunt
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p. 2706 - 2710
(2016/04/05)
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- Synthetic studies on indolocarbazoles: A facile synthesis of staurosporinone analogues
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Synthesis of indolocarbazoles was achieved through thermal electrocyclization followed by triethyl phosphite-mediated nitrene insertion reactions. Total synthesis of staurosporinone analogues was achieved from commercially available 2-methylindole. The CD
- Raju, Potharaju,Gobi Rajeshwaran, Ganesan,Mohanakrishnan, Arasambattu K.
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p. 7131 - 7145
(2015/11/18)
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- Rapid room-temperature 11C-methylation of arylamines with [ 11C]methyl iodide promoted by solid inorganic-bases in DMF
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[11C]Methyl iodide is the most widely used reagent for labeling radiotracers with carbon-11 (t1/2 = 20.4 min) for molecular imaging with positron emission tomography. However, some substrates for labeling, especially primary arylamin
- Cai, Lisheng,Xu, Rong,Guo, Xuelei,Pike, Victor W.
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scheme or table
p. 1303 - 1310
(2012/04/04)
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- Friedel-Crafts alkylation on indolocarbazoles catalyzed by two dimethylallyltryptophan synthases from Aspergillus
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Prenylated indolocarbazoles have been reported neither from natural sources, nor by chemical synthetic approaches. In this Letter, we report a regiospecific prenylation of indolocarbazoles at the para-position of the indole N-atom by two recombinant enzymes from the dimethylallyltryptophan synthase (DMATS) superfamily, that is, 5-DMATS from Aspergillus clavatus and FgaPT2 from Aspergillus fumigatus.
- Yu, Xia,Yang, Aigang,Lin, Wenhan,Li, Shu-Ming
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p. 6861 - 6864
(2013/01/15)
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- Synthetic studies on indolocarbazoles: Total synthesis of staurosporine aglycon
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A synthesis of staurosporine aglycon and its analogs was achieved in a 28-36% overall yield starting from 2-methylindole. The prominent key steps for the synthesis of the indolocarbazole alkaloids involved electrocyclization and nitrene insertion reactions.
- Rajeshwaran, Ganesan Gobi,Mohanakrishnan, Arasambattu K
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supporting information; experimental part
p. 1418 - 1421
(2011/05/04)
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- Synthetic staurosporines via a ring closing metathesis strategy as potent JAK3 inhibitors and modulators of allergic responses
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The synthesis and biological evaluation of JAK3 based staurosporine compounds is described. The compounds are constructed completely de novo, and a ring closing metathesis strategy is used to assemble the sugar mimetic portion. These analogs show potent J
- Wilson, Lawrence J.,Malaviya, Ravi,Yang, Cangming,Argentieri, Rochelle,Wang, Bingbing,Chen, Xin,Murray, William V.,Cavender, Druie
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supporting information; experimental part
p. 3333 - 3338
(2010/07/03)
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- Synthesis of N-protected staurosporinones
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We report a method for the synthesis of N-protected staurosporinones, which are useful for the synthesis of indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids and related compounds. An interaction of gramine methiodide (2) with 3-(N-benzyl)indolylacetonitrile
- Wada, Yasuhiro,Nagasaki, Hideo,Tokuda, Masao,Orito, Kazuhiko
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p. 2008 - 2014
(2007/10/03)
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- Nonenzymatic oxidative steps accompanying action of the cytochrome P450 enzymes StaP and RebP in the biosynthesis of staurosporine and rebeccamycin
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In the biosynthesis of the indolocarbazole natural products staurosporine and rebeccamycin, a complex set of oxidative transformations results in dimerization and oxidative cross-linking of a pair of l-tryptophan monomers. Most intriguing among the oxidative enzymes involved in this pathway is StaP (or its homologue, RebP), which appears to catalyze the four- to eight-electron oxidation of chromopyrrolic acid to give a set of three aglycones, differing in oxidation state in the pyrrole-derived ring. In this work, we sought to clarify the catalytic role of StaP in this process and gain insight into the apparent lack of specificity in its product profile. Through the preparation of a putative intermediate, we show that all steps downstream of aryl-aryl coupling can occur nonenzymatically in solution, pinpointing the function of StaP as a two-electron aryl-aryl coupling catalyst that acts on chromopyrrolic acid. StaP thus joins a small but growing family of aryl-aryl coupling enzymes that use P450-based chemistry to facilitate this oxidative transformation. Furthermore, using ring-deuterated substrate, we show that this aryl-aryl coupling process is not a rate-limiting step in the overall formation of the aglycones. This work expands on our previous studies on the biosynthetic enzymes involved in the staurosporine and rebeccamycin pathways and acts to illuminate the specific roles of StaP and Rebp in the context of these biosyntheses. Copyright
- Howard-Jones, Annaleise R.,Walsh, Christopher T.
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p. 11016 - 11017
(2008/03/14)
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- Simplified staurosporine analogs as potent JAK3 inhibitors
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Simplification of bottom ring and regioselective functionalization of the indolocarbazole unit of staurosporine (2) are described. The modification led to a new series of simplified staurosporine analogs, which exhibited significant inhibitory activity ag
- Yang, Shyh-Ming,Malaviya, Ravi,Wilson, Lawrence J.,Argentieri, Rochelle,Chen, Xin,Yang, Cangming,Wang, Bingbing,Cavender, Druie,Murray, William V.
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p. 326 - 331
(2007/10/03)
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- Novel cycloalkene indole carbazole alkaloids via the ring closing metathesis reaction
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Methodology for the synthesis of a series of carbocyclic indole carbazole natural product analogs is presented. The chemistry involves construction of the core indole, followed by attachment of double bond tethered side chains of three and four carbon len
- Wilson, Lawrence J.,Yang, Cangming,Murray, William V.
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p. 7399 - 7403
(2008/03/13)
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- Staurosporine and rebeccamycin aglycones are assembled by the oxidative action of StaP, StaC, and RebC on chromopyrrolic acid
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In the biosynthesis of the antitumor indolocarbazoles rebeccamycin and staurosporine by streptomycetes, assembly of the aglycones involves a complex set of oxidative condensations. Overall formation of aglycones K252c and arcyriaflavin A from their biosynthetic precursor chromopyrrolic acid involves four- and eight-electron oxidations, respectively. This process is catalyzed by the remarkable enzyme StaP, with StaC and RebC acting to direct the level of oxidation in the newly formed five-membered ring. An aryl-aryl coupling reaction is integral to this transformation as well as oxidative decarboxylation of the dicarboxypyrrole moiety of chromopyrrolic acid. Herein we describe the heterologous expression of staP, staC, and rebC in Escherichia coli and the activity of the corresponding enzymes in constructing the two distinct six-ring scaffolds. StaP is a cytochrome P450 enzyme, requiring dioxygen, ferredoxin, flavodoxin NADP+-reductase, and NAD(P)H for activity. StaP on its own converts chromopyrrolic acid into three aglycone products, K252c, arcyriaflavin A, and 7-hydroxy-K252c; in the presence of StaC, K252c is the predominant product, while the presence of RebC directs formation of arcyriaflavin A. 18O-Labeling studies indicate that the oxygen(s) of the pyrrolinone and maleimide functionalities of the aglycones formed are all derived from dioxygen. This work allowed for the in vitro reconstitution of the full biosynthetic pathway from L-tryptophan to the staurosporine and rebeccamycin aglycones, K252c and 1,11-dichloroarcyriaflavin A.
- Howard-Jones, Annaleise R.,Walsh, Christopher T.
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p. 12289 - 12298
(2007/10/03)
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- A short synthesis of staurosporinone (K-252c)
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A new, simple, high-yield synthesis of the indolo[2,3-a]carbazole alkaloid staurosporinone is described.
- Gaudêncio, Susana P.,Santos, Maria M. M.,Lobo, Ana M.,Prabhakar, Sundaresan
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p. 2577 - 2578
(2007/10/03)
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- A facile synthesis of indolo[2,3-a]pyrrolo[3,4-c]carbazoles via oxidative photocyclization of bisindolylmaleimides
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A simple and inexpensive oxidative photocyclization of the bisindolylmaleimides in the presence of a catalytic amount of iodine leading to indolo[2,3-a]pyrrolo[3,4-c]carbazoles in 84-90% yields is described.
- Reddy, G. Mahesh,Chen, Shyh-Yeon,Uang, Biing-Jiun
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p. 497 - 500
(2007/10/03)
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- Synthesis of pyrrolidin-2-ones and of staurosporine aglycon (K-252c) by intermolecular Michael reaction
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Indolo[2,3-a]pyrrolo[3,4-c]carbazoles were isolated from nature, e.g., from low plants, especially fungi, as structurally rare natural substances. Responsible for naming and also the most important representative of this type is staurosporine (1), isolated from Streptomyces staurosporeus, and its aglycon (2), also known as staurosporinone or K-252c. 3,4-Disubstituted pyrrolidin-2-ones, a group of compounds with many interesting biological properties are related to staurosporinone. The most important property is the inhibition of protein kinase C (PKC), so that this antiproliferative agent can interfere with the cell cycle. The synthetic strategy, developed by us, allows the synthesis of pyrrolidin-2-ones by an intermolecular Michael addition, starting from nitroethene derivatives and substituted acetate Michael donors. With this method also enantioselective syntheses can be carried out using chiral auxiliaries. After reduction of the nitro group and subsequent lactamization, the lactam partial structure, which is essential for the biological activity, is obtained. Besides indole substituents, which were used for the synthesis of staurosporinone, substituted indole-, phenyl- , and pyridyl- as well as enantiomerically pure (S)-proline derivatives were used. Here, considerably high diastereoselectivity and enantioselectivity ((S)-pyrrolidine) could be detected. Just like the total synthesis of staurosporinone within three steps, the easiest and shortest approach reported up to now, with good to moderate yields, this sequence allows highly diastereoselective syntheses, which open the easy access to a new family of compounds.
- Mahboobi, Siavosh,Eibler, Ernst,Koller, Markus,Kumar KC, Sunil,Popp, Alfred,Schollmeyer, Dieter
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p. 4697 - 4704
(2007/10/03)
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- Complete regioselectivity in staurosporine chromophore formation
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For the preparation of regioselectively N-substituted indolocarbazole alkaloids two strategies have been employed: 1. the exploitation of different electronic situations at the nitrogen atoms, and 2. the utilization of an orthogonal protecting group strategy that allows regioselective glycoside formation.
- Eils, Stefan,Winterfeldt, Ekkehard
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p. 275 - 281
(2007/10/03)
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- A new synthesis of staurosporinone
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A new six steps synthesis of staurosporinone 4, starting from 3-cyano- 3-(1H-indol-3-yl)-2-oxo-propionic and ethyl ester 5, is reported.
- Beccalli, Egle M.,Gelmi, Maria Luisa,Marchesini, Alessandro
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p. 6909 - 6918
(2007/10/03)
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- Design and implementation of an efficient synthetic approach to furanosylated indolocarbazoles: Total synthesis of (+)- and (-)-K252a
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The first total synthesis of the natural product (+)-K252a (2) has been achieved in 12 steps from commercially available materials, with a longest linear sequence of seven steps and an overall yield of 21%. The synthetic strategy employs novel rhodium carbenoid chemistry in the construction of both the indolocarbazole aglycon (4) and the carbohydrate moiety (9).
- Wood, John L.,Stoltz, Brian M.,Dietrich, Hans-Jürgen,Pflum, Derek A.,Petsch, Dejah T.
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p. 9641 - 9651
(2007/10/03)
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- A facile synthesis of staurosporine aglycone
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A highly efficient method is described for the synthesis of staurosporine aglycone 3 from the readily available dibromomaleic acid in six steps.
- Xie, Guojian,Lown, J. William
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p. 5555 - 5558
(2007/10/02)
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- Oxidative cyclisations with palladium acetate. A short synthesis of staurosporine aglycone
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A palladium acetate mediated oxidative cyclisation has been used as the key step for the syntheses staurosporine aglycone and related analogues.
- Harris,Hill,Keech,Malsher
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p. 8361 - 8364
(2007/10/02)
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- Synthesis of the Staurosporine Aglycon
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A short synthesis of the staurosporine aglycon (6) is reported, the indolocarbazole skeleton being constructed by an intramolecular Diels-Alder reaction followed by a nitrene-mediated ring closure.The synthesis starts by acylation of ethyl indole-2-acetat
- Moody, Christopher J.,Rahimtoola, Kulsum F.,Porter, Barry,Ross, Barry C.
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p. 2105 - 2114
(2007/10/02)
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- Synthesis of the Indolocarbazole Natural Products Staurosporinone and Arcyriaflavin B
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Flexible synthetic routes involving double nitrene insertions are described leading to the indolocarbazole systems present in a growing group of natural products.The methods are exemplified by the total synthesis of two members of this group stauro
- Hughes, Ian,Nolan, William P.,Raphael, Ralph A.
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p. 2475 - 2480
(2007/10/02)
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- REACTIONS WITH INDOLE DERIVATIVES, XLVIII. A Simple Synthesis of Staurosporine Aglycon
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The staurosporine aglycon is prepared from tryptamine and β-indole acetic acid in two consecutive cyclization reactions.
- Sarstedt, Burkhard,Winterfeldt, Ekkehard
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p. 469 - 476
(2007/10/02)
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