Engineering of indole-based tethered biheterocyclic alkaloid meridianin into β-carboline-derived tetracyclic polyheterocycles via amino functionalization/6-endo cationic π-cyclization

Article abstract of DOI:10.3762/bjoc.8.220

A mild, efficient and versatile method has been developed for the construction of a functionalized natural product, meridianin, and its post conversion to pyrimido-β-carboline by cationic π-cyclization. The strategy involves the introduction of an amino g

Full text of DOI:10.3762/bjoc.8.220

Engineering of indole-based tethered biheterocyclic
alkaloid meridianin into β-carboline-derived tetra-
cyclic polyheterocycles via amino functionalization/
6-endo cationic π-cyclization
Piyush K. Agarwal, Meena D. Dathi, Mohammad Saifuddin and Bijoy Kundu*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1901–1908.
Division of Medicinal and Process Chemistry, Central Drug Research
Institute, CSIR, Lucknow, 226001, India, Phone: +91 522
2612411-18; Fax: +91 522 2623405
doi:10.3762/bjoc.8.220
Received: 04 September 2012
Accepted: 19 October 2012
Published: 08 November 2012
Email:
Bijoy Kundu* - bijoy_kundu@yahoo.com
Associate Editor: T. J. J. Müller
* Corresponding author
© 2012 Agarwal et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
cyclization; indole; meridianin; natural products; nitrogen heterocycles
Abstract
A mild, efficient and versatile method has been developed for the construction of a functionalized natural product, meridianin, and
its post conversion to pyrimido-β-carboline by cationic π- cyclization. The strategy involves the introduction of an amino group at
the C-5 of the pyrimidine ring and utilizing the nucleophilictiy of the C-2 in the indole ring to facilitate cationic π-cyclization.
Introduction
Indole is an important pharmacophore present in many natural [19,20] and nortopsentins [21-23]), dihydroimidazole (discoder-
and designed polyheterocyclic synthetic products of therapeutic mindole [24]), oxadiazine (alboinon [25]), piperazine (drag-
importance [1-3]. The range of applications for these therapeuti- macidon [26]), maleimide (didemidines [25]), and pyrimidine
cally relevant indole-based polyheterocycles includes protein (meridianins) [27-29]. Among these, meridianins (Figure 1), the
kinase C inhibitors, 5-HT agonists, melatonin agonists, and tethered biheterocycles isolated from the south Atlantic tuni-
glucocorticoid receptor modulators, displaying cytotoxic, cate Aplidium meridianum, represent an interesting synthetic
antiviral, antimicrobial, antiparasitic, anti-inflammatory, anti- target owing to their biological implication involving cytotoxi-
serotonin, Ca2+/calmodulin antagonistic [4] and antitopoiso- city towards murine-tumor cell lines [30,31] and as potent
merase-I activities [5-16].
protein-kinase inhibitor [32].
The presence of a heterocyclic ring at the position 3 of the In continuation of our ongoing studies pertaining to the syn-
indole represents an important class of marine alkaloids, such as thesis of the indole-based natural products, i.e., isocryptolepine,
oxazole (martefragin [17], amazol [18]), imidazole (topsentins δ-carbolines, and α-carbolines; and the indole-based polyhetero-
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Results and Discussion
Our studies commenced with the functionalization of the pyrim-
idine ring in the meridianin followed by the application of
cationic π-cyclization [51-60] to generate an additional pyri-
dine ring as part of β-carboline-derived tetracyclic polyhetero-
cycles. Initial attempts to synthesize amino-functionalized sub-
strate 2a by introducing a nitro or nitroso group at the para pos-
ition (position 5) of the 2-aminopyrimidine linked to the indole
at C-3 position, using various reported protocols, either failed to
produce the desired nitro compound or resulted in an insepa-
rable mixture of compounds (Scheme 1).
This led us to attempt the synthesis of substrate 2a using an
alternate strategy in a manner that may lead to the generation of
a nitro pyrimidine ring tethered to the indole at position 3
(Scheme 2). For the generation of pyrimidine rings we used the
modified procedure described previously by us [56]. Initial
Figure 1: Structure of meridianins A–G.
cycles, i.e., indolo-quinolines, pericyclic indolo-benzazepines, attempts to synthesize α-nitroketone 5a by using different
iodo-indoloazepinones, indoloindazole, and azepino-indole [33- protocols failed. To achieve this, the carboxylic group of
43], we were prompted to transform the indole-based alkaloid 1-methyl-1H-indole-3-carboxylic acid (3a) was activated
meridianins into annulated indole-based polyheterocycles as by preparing N-acylbenzotriazole [61]. Next,
novel chemprobes.
1H-benzo[d][1,2,3]triazol-1-yl-(1-methyl-1H-indol-3-
yl)methanone (4a) was converted into its α-nitroketone 5a by
For the synthesis of meridianin-inspired indole-based annulated treating with nitromethane in the presence of potassium tert-
polyheterocycles, we proposed to transform tethered bihetero- butoxide in DMSO [62]. 1-(1-Methyl-1H-indol-3-yl)-2-
cycles into β-carboline-based polyheterocycles, a new proto- nitroethanone (5a) was reacted with N,N-dimethylformamide
type hitherto not reported in the literature. β-Carbolines are dimethyl acetal to form (E)-3-(dimethylamino)-1-(1-methyl-1H-
some of the most widely distributed alkaloids, associated with indol-3-yl)-2-nitroprop-2-en-1-one (6a) [63-66], which was
activities ranging from antineoplastic (tubulin binding) [44-46], then converted to 4-(1-methyl-1H-indol-3-yl)-5-nitropyrimidin-
anticonvulsive, hypnotic and anxiolytic (benzodiazepine 2-amine (7a) in the presence of guanidine hydrochloride.
receptor ligands) [47], antimicrobial as well as topoisomerase-II Finally, the desired substrate 4-(1-methyl-1H-indol-3-yl)pyrim-
inhibition [48] to inhibition of cGMP-dependent processes idin-2,5-diamine (2a) was obtained by reducing 7a with H2/Pd
[49,50].
in methanol. Synthesis of substrate 2b with diversity in the phe-
nyl ring of the indole was carried out in a similar manner as
In this communication, we report engineering of naturally described for 2a. In order to introduce diversity in the pyrimi-
occurring tethered indole-based biheterocyclic alkaloid meridi- dine ring of the designed substrate 2, compound 6a was treated
anins into β-carboline-derived tetracyclic polyheterocycles by with 1,1-dimethylguanidine sulfate salt to get N,N-dimethyl-4-
amino functionalization of the pyrimidine ring followed by (1-methyl-1H-indol-3-yl)-5-nitropyrimidin-2-amine (8). The
6-endo cationic π-cyclization.
nitro group in 8 was finally reduced with H2/Pd in methanol to
Scheme 1: Synthesis of functionalized meridianin with an amino group at position 5.
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Beilstein J. Org. Chem. 2012, 8, 1901–1908.
Scheme 2: Synthesis of a functionalized meridianin with an amino group at position 5.
give N2,N2-dimethyl-4-(1-methyl-1H-indol-3-yl)pyrimidine- undergo 6-endo cyclization in the presence of aldehydes
2,5-diamine (2c) as a new substrate (Scheme 3).
(Scheme 4). Initially we treated the substrate 2a with
4-chlorobenzaldehyde using a variety of traditional
After successfully accomplishing the synthesis of amino-func- Pictet–Spengler protocols involving 1% TFA in DCM at rt, with
tionalized meridianins 2, we next examined their abilities to p-TsOH in toluene under reflux, and AcOH in ethanol under
Scheme 3: Synthesis of substrate for the modified Pictet–Spengler reaction.
Scheme 4: The Pictet–Spengler reaction involving substrate 2a. Reagents and conditions: (i) RCHO, 2% triflic acid in DMF, 120 °C, 16 h.
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Beilstein J. Org. Chem. 2012, 8, 1901–1908.
Table 1: Optimization of the reaction conditions for conversion of substrate 2a to 9a.
Entry Brønsted acid
Solvent
Temp (oC)
Time (h)
Producta
1
1% TFA
DCM
DMF
rt
24
24
24
24
24
16
24
16
16
16
16
0
2
1% triflic acid
p-TsOH
rt
0
3
Toluene
Ethanol
ACN
120
100
80
0
4
AcOH
0
5
2% MSA
0
6
2% MSA
DMF
120
80
0
7
2% triflic acid
2% triflic acid
5% triflic acid
1% triflic acid
0.5% triflic acid
ACN
27
87
80
75
35
8
DMF
120
120
120
120
9
DMF
10
11
DMF
DMF
abased on HPLC.
reflux. The conditions failed to favor cationic π-cyclization yield. An increase or decrease in the concentration of triflic acid
even after prolonged stirring and resulted in imines as the only was found to be detrimental (Table 1, entries 9–11). Similarly,
isolated product (Table 1, entries 1–6). Since the role of switching solvents from DMF to ACN in the presence of 2%
Brønsted acids are considered to be an important factor [67] in triflic acid reduced the yield to 27% (Table 1, entry 7). The
promoting cationic π-cyclization by enhancing the elec- scope and limitation of the strategy with substrate 2a and 2c
trophilicity of the imines, we envisaged that employing stronger was established by synthesizing 11 compounds based on
acids may facilitate 6-endo cyclization. Accordingly, the amine pyrimido-β-carbolines 9a–k (Table 2), using eight aromatic
2a was treated with 4-chlorobenzaldehyde by using strong aldehydes.
Brønsted acids, such as triflic acid and methanesulfonic acid
(MSA), to facilitate π-cyclization, and progress of the reaction In general for all reactions, the protocol involving 2% triflic
was monitored by TLC.
acid in DMF at 120 °C for 16 h was employed, furnishing prod-
ucts 9 in good isolated yields (72–86%). Pleasingly, aldehydes
Although no conversion was observed for 2a in the presence of with either an electron-donating or -withdrawing group had no
MSA (Table 1, entry 5 and entry 6) in CH3CN and DMF at adverse effect and afforded 9 with minimal variation in yields.
80 °C and 120 °C, respectively, the presence of 2% triflic acid However, the substrate 2b on application of the protocol
in DMF (Table 1, entry 8) favored complete conversion of 2a involving 2% triflic acid in DMF at 120 °C produced a dihy-
into 9a in >87% purity based on HPLC. The crude product droproduct instead of the oxidized compound. Continuing the
obtained after workup was purified by silica gel column chro- reaction for a further 24 h failed to produce the oxidized pro-
matography with EtOAc/hexane as an eluent in 84% isolated duct (Scheme 5).
Scheme 5: Synthesis of dihydropyrimido-β-carbolines: (i) R-CHO, 2% triflic acid in DMF, 120 °C, 16 h.
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Beilstein J. Org. Chem. 2012, 8, 1901–1908.
Table 2: Pyrimido-β-carbolines based on 9.
Entry
Substrate R-CHO
Pictet–Spengler products 9, R
Yield (%)a
tR (min)b
1
2a
2a
2a
2a
2a
2c
2c
2c
2c
2c
2c
4-Cl-C6H4-CHO
9a
9b
9c
9d
9e
9f
4-Cl-C6H4
84
82
78
85
80
72
76
79
81
86
78
14.92
14.14
13.25
13.90
14.50
15.89
15.82
13.45
12.95
14.82
14.37
2
4-OEt-C6H4-CHO
4-OMe-C6H4-CHO
4-Br-C6H4-CHO
4-OEt-C6H4
4-OMe-C6H4
4-Br-C6H4
3
4
5
3,4-diCl-C6H-CHO
4-Br-C6H4-CHO
3,4-diCl-C6H3
4-Br-C6H4
6
7
4-NO2-C6H4-CHO
4-OMe-C6H4-CHO
3,4-diOMe-C6H3-CHO
4-Cl-C6H4-CHO
9g
9h
9i
4-NO2-C6H4-CHO
4-OMe-C6H4-CHO
3,4-diOMe-C6H3
4-Cl-C6H4
8
9
10
11
9j
2-Cl-C6H4-CHO
9k
2-Cl-C6H4
aIsolated yield. bRetention time on HPLC (C18 reversed-phase column; 150 mm × 4.8 mm; 5 µm) with a linear gradient of 0–100% CH3CN in water
over 30 min. Flow rate of 1.0 mL/min and UV detection at 220/254 nm.
After successfully establishing the strategy on 2a-c, we then designed a substrate 18 (Scheme 6) for the Pictet–Spengler
decided to replace the indole nucleus by another activated reaction using a similar approach as was used for the synthesis
nucleus such as trimethoxy- and dimethoxybenzene and of substrates 2.
Scheme 6: Synthesis of substrates 18a–c for the modified Pictet–Spengler reaction.
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Beilstein J. Org. Chem. 2012, 8, 1901–1908.
Scheme 7: General strategy for the Pictet–Spengler reaction involving substrates 18. Reagents and conditions: (i) R-CHO, 2% triflic acid in DMF, 120
°C, 16 h.
The synthesis of substrates 18 is depicted in Scheme 6. Initially, matography furnishing pyrimido[5,4-c]isoquinolines 20a–l
the carboxylic group of benzoic acids 13a,b was activated by (Table 3) in 79–92% isolated yields.
preparing N-acylbenzotriazoles 14, which were then converted
into their α-nitroketones 15 by treatment with nitromethane in Conclusion
the presence of potassium tert-butoxide in DMSO. Reaction of In conclusion, we have developed a mild and efficient protocol
15 with N,N-dimethylformamide dimethyl acetal provided 16, for the synthesis of pyrimido[5,4-c]isoquinolones and pyrimido-
which was cyclized in the presence of guanidine hydrochloride β-carbolines using a modified Pictet–Spengler strategy. Our
and N,N-dimethylguanidine sulfate to give the nitro products method offers a unique opportunity to introduce rigidity in these
17a,b and 17c. Finally, the desired substrates 18 were obtained flexible molecules, as well as diversity, which enables the
by reducing 17 with H2/Pd in methanol. Next, substrates 18 design of a library based on the natural product. Our
were exposed to the cationic π-cyclization with a variety of methodology further demonstrated a broad substrate
aldehydes using the protocol involving 2% triflic acid in DMF scope and reactivity, and thus it can be applied for the
at 120 °C (Scheme 7). The crude endo-cyclized product synthesis of a variety of novel polycyclic skeletons based on
obtained after workup was purified by silica-gel column chro- natural products.
Table 3: Pyrimido[5,4-c]isoquinolines based on 20.
Entry
Substrate
R3-CHO
Pictet–Spengler products 20, R3
Yield (%)a
tR (min)b
1
18a
18a
18a
18b
18b
18b
18b
18c
18c
18c
18c
18c
4-F-C6H4-CHO
20a
20b
20c
20d
20e
20f
4-F-C6H4-CHO
85
87
83
89
92
91
87
81
84
83
79
87
20.12
21.95
25.25
21.42
20.65
21.98
22.85
20.46
21.56
21.45
20.12
19.89
2
4-Br-C6H4-CHO
4-Cl-C6H4-CHO
4-OMe-C6H4-CHO
4-Cl-C6H4-CHO
4-F-C6H4-CHO
4-Br-C6H4-CHO
4-Cl-C6H4-CHO
4-OMe-C6H4-CHO
4-Cl-C6H4-CHO
4-F-C6H4-CHO
3
4
5
6
7
4-Br-C6H4-CHO
4-NO2-C6H4-CHO
3,4-diOMe-C6H3-CHO
3,4-diCl-C6H3-CHO
4-Br-C6H4-CHO
4-OMe-C6H4-CHO
20g
20h
20i
4-Br-C6H4-CHO
4-NO2-C6H4-CHO
3,4-diOMe-C6H3-CHO
3,4-diCl-C6H3-CHO
4-Br-C6H4-CHO
4-OMe-C6H4-CHO
8
9
10
11
12
20j
20k
20l
aIsolated yield.
bRetention time on HPLC (C18 reversed-phase column; 150 mm × 4.8 mm; 5 µm) with a linear gradient of 0–100% CH3CN in water over 30 min. Flow
rate of 1.0 mL/min and UV detection at 220/254 nm.
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Beilstein J. Org. Chem. 2012, 8, 1901–1908.
14.Saifuddin, M.; Agarwal, P. K.; Sharma, S. K.; Madadapu, A. K.;
Gupta, S.; Harit, V. K.; Kundu, B. Eur. J. Org. Chem. 2010, 5108–5117.
doi:10.1002/ejoc.201000596
Supporting Information
Supporting Information File 1
15.Quintanar-Audelo, M.; Fernández-Carvajal, A.; Van Den Nest, W.;
Carreño, C.; Ferrer-Montiel, A.; Albericio, F. J. Med. Chem. 2007, 50,
6133–6143. doi:10.1021/jm070612v
Experimental section, 1H and 13C NMR spectra of the
compounds 2a–c, 4a–7a, 4b–7b, 8, 9a–k, 12a–d, 14a–18a,
14b–16b, 17–18c, 17b–18b, 20a–l.
16.Ferlin, M. G.; Chiarelotto, G.; Gasparotto, V.; Via, L. D.; Pezzi, V.;
Barzon, L.; Palù, G.; Castagliuolo, I. J. Med. Chem. 2005, 48,
3417–3427. doi:10.1021/jm049387x
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-220-S1.pdf]
17.Vervoort, H. C.; Richards-Gross, S. E.; Fenical, W.; Lee, A. Y.;
Clardy, J. J. Org. Chem. 1997, 62, 1486–1490. doi:10.1021/jo961789s
18.Takahashi, S.; Matsunaga, T.; Hasegawa, C.; Saito, H.; Fujita, D.;
Kiuchi, F.; Tsuda, Y. Chem. Pharm. Bull. 1998, 46, 1527–1529.
doi:10.1248/cpb.46.1527
Acknowledgements
P. K. A. and M. S. are thankful to CSIR, New Delhi for
providing fellowship. The author would like to thank SAIF,
CDRI, India for providing NMR data. CDRI Communication
No. 8330.
19.Kawasaki, Y.; Yamashita, M.; Ohta, S.
J. Chem. Soc., Chem. Commun. 1994, 2085–2086.
doi:10.1039/C39940002085
20.Kawasaki, Y.; Yamashita, M.; Ohta, S. Chem. Pharm. Bull. 1996, 44,
1831–1839. doi:10.1248/cpb.44.1831
21.Bartik, K.; Braekman, J.-C.; Daloze, D.; Stoller, C.; Huysecom, J.;
Vandevyver, G.; Ottinger, R. Can. J. Chem. 1987, 65, 2118–2121.
doi:10.1139/v87-352
References
1. Faulkner, D. J. Nat. Prod. Rep. 2001, 18, R1–R49.
doi:10.1039/b006897g
22.Tsuji, S.; Rinehart, K. L.; Gunasekera, S. P.; Kashman, Y.;
Cross, S. S.; Lui, M. S.; Pomponi, S. A.; Diaz, M. C. J. Org. Chem.
1988, 53, 5446–5453. doi:10.1021/jo00258a009
2. Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875–2911.
doi:10.1021/cr0505270
3. Takayama, H.; Tsutsumi, S.-i.; Kitajima, M.; Santiarworn, D.;
Liawruangrath, B.; Aimi, N. Chem. Pharm. Bull. 2003, 51, 232–233.
doi:10.1248/cpb.51.232
23.Kawasaki, I.; Katsuma, H.; Nakayama, Y.; Yamashita, M.; Otha, S.
Heterocycles 1998, 48, 1887–1901. doi:10.3987/COM-98-8225
24.Sun, H. H.; Sakemi, S. J. Org. Chem. 1991, 56, 4307–4308.
doi:10.1021/jo00013a045
4. Lanteri, M. L.; Pagnussat, G. C.; Lamattina, L. J. Exp. Bot. 2006, 57,
1341–1351. doi:10.1093/jxb/erj109
25.Bergmann, T.; Schories, D.; Steffan, B. Tetrahedron 1997, 53,
2055–2060. doi:10.1016/S0040-4020(96)01168-4
26.Kohmoto, S.; Kashman, Y.; McConnell, O. J.; Rinehart, K. L., Jr.;
Wright, A.; Koehn, F. J. Org. Chem. 1988, 53, 3116–3118.
doi:10.1021/jo00248a040
5. Xie, G.; Zimmermann, J.; Meyer, T.; Lown, J. W.
Bioorg. Med. Chem. Lett. 1995, 5, 497–500.
doi:10.1016/0960-894X(95)00060-7
6. Chambers, M. S.; Street, L. J.; Goodacre, S.; Hobbs, S. C.; Hunt, P. H.;
Jelley, R. A.; Matassa, V. G.; Reeve, A. J.; Sternfeld, F.; Beer, M. S.;
Stanton, J. A.; Rathbone, D.; Watt, A. P.; MacLeod, A. M.
J. Med. Chem. 1999, 42, 691–705. doi:10.1021/jm980569z
7. Faust, R.; Garratt, P. J.; Jones, R.; Yeh, L.-K. J. Med. Chem. 2000, 43,
1050–1061. doi:10.1021/jm980684+
27.Franco, L. H.; Joffe, E. B. K.; Puricelly, L.; Tatian, M.; Seldes, A. M.;
Palermo, J. A. J. Nat. Prod. 1998, 61, 1130–1132.
doi:10.1021/np970493u
28.Seldes, A. M.; Brasco, M. F. R.; Hernández Franco, L.; Palermo, J. A.
Nat. Prod. Res. 2007, 21, 555–563. doi:10.1080/14786410601133517
29.Sperry, J. Tetrahedron Lett. 2011, 52, 4537–4538.
doi:10.1016/j.tetlet.2011.06.073
8. Roach, S. L.; Higuchi, R. I.; Adams, M. E.; Liu, Y.; Karanewsky, D. S.;
Marschke, K. B.; Mais, D. E.; Miner, J. N.; Zhi, L.
Bioorg. Med. Chem. Lett. 2008, 18, 3504–3508.
30.Jiang, B.; Yang, C.-G.; Xiong, W.-N.; Wang, J. Bioorg. Med. Chem.
2001, 9, 1149–1154. doi:10.1016/S0968-0896(00)00337-0
31.Rossignol, E.; Debiton, E.; Fabbro, D.; Moreau, P.; Prudhomme, M.;
Anizon, F. Anti-Cancer Drugs 2008, 19, 789–792.
doi:10.1016/j.bmcl.2008.05.029
9. Chaturvedula, V. S. P.; Sprague, S.; Schilling, J. K.; Kingston, D. G. I.
J. Nat. Prod. 2003, 66, 528–531. doi:10.1021/np020548e
10.Zhao, Z.; Wolkenberg, S. E.; Lu, M.; Munshi, V.; Moyer, G.; Feng, M.;
Carella, A. V.; Ecto, L. T.; Gabryelski, L. J.; Lai, M.-T.; Prasad, S. G.;
Yan, Y.; McGaughey, G. B.; Miller, M. D.; Lindsley, C. W.;
Hartman, G. D.; Vacca, J. P.; Williams, T. M. Bioorg. Med. Chem. Lett.
2008, 18, 554–559. doi:10.1016/j.bmcl.2007.11.085
11.Scribner, A.; Moore, J. A., III; Ouvry, G.; Fisher, M.; Wyvratt, M.;
Leavitt, P.; Liberator, P.; Gurnett, A.; Brown, C.; Mathew, J.;
Thompson, D.; Schmatz, D.; Biftu, T. Bioorg. Med. Chem. Lett. 2009,
19, 1517–1521. doi:10.1016/j.bmcl.2009.01.001
doi:10.1097/CAD.0b013e32830ce4d8
32.Gompel, M.; Leost, M.; Joffe, E. B. K.; Puricelli, L.; Franco, L. H.;
Palermo, J.; Meijer, L. Bioorg. Med. Chem. Lett. 2004, 14, 1703–1707.
doi:10.1016/j.bmcl.2004.01.050
33.Saifuddin, M.; Agarwal, P. K.; Sharma, S. K.; Mandadapu, A. K.;
Gupta, S.; Harit, V. K.; Kundu, B. Eur. J. Org. Chem. 2010, 5108–5117.
doi:10.1002/ejoc.201000596
34.Sharma, S. K.; Gupta, S.; Saifuddin, M.; Mandadapu, A. K.;
Agarwal, P. K.; Gauniyal, H. M.; Kundu, B. Tetrahedron Lett. 2011, 52,
65–68. doi:10.1016/j.tetlet.2010.10.147
12.Doebel, K. J.; Wasley, J. W. F. J. Med. Chem. 1972, 15, 1081–1082.
doi:10.1021/jm00280a027
35.Sharma, S. K.; Mandadapu, A. K.; Saifuddin, M.; Gupta, S.;
Agarwal, P. K.; Mandwal, A. K.; Gauniyal, H. M.; Kundu, B.
Tetrahedron Lett. 2010, 51, 6022–6024.
13.Remy, D. C.; Rittle, K. E.; Hunt, C. A.; Anderson, P. S.;
Engelhardt, E. L.; Clineschmidt, B. V.; Scriabine, A. J. Med. Chem.
1977, 20, 1681–1684. doi:10.1021/jm00222a031
doi:10.1016/j.tetlet.2010.09.054
1907

Beilstein J. Org. Chem. 2012, 8, 1901–1908.
36.Agarwal, P. K.; Sawant, D.; Sharma, S.; Kundu, B. Eur. J. Org. Chem.
2009, 292–303. doi:10.1002/ejoc.200800929
64.Fresneda, P. M.; Molina, P.; Delgado, S.; Bleda, J. A. Tetrahedron Lett.
2000, 41, 4777–4780. doi:10.1016/S0040-4039(00)00728-0
65.Karpov, A. S.; Merkul, E.; Rominger, F.; Müller, T. J. J.
Angew. Chem., Int. Ed. 2005, 44, 6951–6956.
37.Sharma, S. K.; Sharma, S.; Agarwal, P. K.; Kundu, B.
Eur. J. Org. Chem. 2009, 1309–1312. doi:10.1002/ejoc.200801201
38.Saha, B.; Sharma, S.; Sawant, D.; Kundu, B. Tetrahedron Lett. 2007,
48, 1379–1383. doi:10.1016/j.tetlet.2006.12.112
doi:10.1002/anie.200501703
66.Rossignol, E.; Youssef, A.; Moreau, P.; Prudhomme, M.; Anizon, F.
Tetrahedron 2007, 63, 10169–10176. doi:10.1016/j.tet.2007.07.095
67.Cox, E. D.; Cook, J. Chem. Rev. 1995, 95, 1797–1842.
doi:10.1021/cr00038a004
39.Sharma, S.; Kundu, B. Tetrahedron Lett. 2008, 49, 7062–7065.
doi:10.1016/j.tetlet.2008.09.154
40.Gupta, S.; Kumar, B.; Kundu, B. J. Org. Chem. 2011, 76,
10154–10162. doi:10.1021/jo201994v
41.Gupta, S.; Sharma, S. K.; Mandadapu, A. K.; Gauniyal, H. M.;
Kundu, B. Tetrahedron Lett. 2011, 52, 4288–4291.
doi:10.1016/j.tetlet.2011.06.021
License and Terms
42.Sharma, S. K.; Mandadapu, A. K.; Kumar, B.; Kundu, B. J. Org. Chem.
2011, 76, 6798–6805. doi:10.1021/jo201228t
This is an Open Access article under the terms of the
Creative Commons Attribution License
43.Saha, B.; Kumar, R.; Maulik, P. R.; Kundu, B. Tetrahedron Lett. 2006,
47, 2765–2769. doi:10.1016/j.tetlet.2006.02.072
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
44.Takasu, K.; Shimogama, T.; Saiin, C.; Kim, H.-S.; Wataya, Y.; Ihara, M.
Bioorg. Med. Chem. Lett. 2004, 14, 1689–1692.
doi:10.1016/j.bmcl.2004.01.055
45.Boursereau, Y.; Coldham, I. Bioorg. Med. Chem. Lett. 2004, 14,
5841–5844. doi:10.1016/j.bmcl.2004.09.036
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
46.Wu, Y.; Zhao, M.; Wang, C.; Peng, S. Bioorg. Med. Chem. Lett. 2002,
12, 2331–2333. doi:10.1016/S0960-894X(02)00403-1
47.Behforouz, M.; Merriman, R. L. Methods of using lavendamycin
analogs. U.S. Patent 5,646,150, July 8, 1997.
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
48.Batch, A.; Dodd, R. H. J. Org. Chem. 1998, 63, 872–877.
doi:10.1021/jo971485l
doi:10.3762/bjoc.8.220
49.Pommier, Y.; MacDonald, T. L.; Madalengoitia, J. S. U.S. Patent
5,622,960, April 22, 1997.
50.Daugan, C. M.; Labaudiniere, R. F.
Tetrahydroimidazopyridoindolediones and their use as medicaments.
WO/1996/032003, Oct 17, 1996.
51.Kundu, B.; Sawant, D.; Chhabra, R. A. J. Comb. Chem. 2005, 7,
317–321. doi:10.1021/cc049851j
52.Kundu, B.; Sawant, D.; Partani, P.; Kesarwani, A. P. J. Org. Chem.
2005, 70, 4889–4892. doi:10.1021/jo050384h
53.Duggineni, S.; Sawant, D.; Saha, B.; Kundu, B. Tetrahedron 2006, 62,
3228–3241. doi:10.1016/j.tet.2006.01.063
54.Sharma, S.; Saha, B.; Sawant, D.; Kundu, B. J. Comb. Chem. 2007, 9,
783–792. doi:10.1021/cc0700445
55.Saha, B.; Sharma, S.; Sawant, D.; Kundu, B. Tetrahedron 2008, 64,
8676–8684. doi:10.1016/j.tet.2008.07.003
56.Agarwal, P. K.; Sharma, S. K.; Sawant, D.; Kundu, B. Tetrahedron
2009, 65, 1153–1161. doi:10.1016/j.tet.2008.11.067
57.Agarwal, P. K.; Saifuddin, M.; Kundu, B. Tetrahedron 2010, 66,
862–870. doi:10.1016/j.tet.2009.11.115
58.Mandadapu, A. K.; Saifuddin, M.; Agarwal, P. K.; Kundu, B.
Org. Biomol. Chem. 2009, 7, 2796–2803. doi:10.1039/b905696c
59.Kundu, B.; Partani, P.; Duggineni, S.; Sawant, D. J. Comb. Chem.
2005, 7, 909–915. doi:10.1021/cc0500699
60.Sharma, S.; Kundu, B. J. Comb. Chem. 2009, 11, 720–731.
doi:10.1021/cc9000345
61.Katritzky, A. R.; Zhang, Y.; Singh, S. K. Synthesis 2003, 2795–2798.
doi:10.1055/s-2003-42462
62.Katritzky, A. R.; Abdel-Fattah, A. A. A.; Gromova, A. V.; Witek, R.;
Steel, P. J. J. Org. Chem. 2005, 70, 9211–9214.
doi:10.1021/jo051231x
63.Bredereck, H.; Effenberger, F.; Botsch, H.; Rehn, H. Chem. Ber. 1965,
98, 1081–1806. doi:10.1002/cber.19650980412
1908