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Total Synthesis of Carbazomycins A and B
2018 Volume 66 Issue 2 Pages 178-183
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2018 Volume 66 Issue 2 Pages 178-183
Total syntheses of carbazomycins A and B were demonstrated using a ytterbium-catalyzed Diels–Alder reaction with (silyloxyvinyl)indole as a diene. The densely substituted benzene ring of the target compound was successfully constructed by functionalization of a hydrocarbazolone intermediate and subsequent aromatization using N-bromosuccinimide.
Carbazole is a tricyclic skeleton that is frequently seen as a core structure in biologically active compounds.1–6) Among them, carbazomycins have a simple structure, but attractive biological activities. Especially, carbazomycins A and B, which were isolated from the extract of cultured mycelia of Streptoverticillium ehimensis strain H1051-MY107–9) (Chart 1), show inhibitory activity against 5-lipoxygenase, and have weak antibacterial and antiyeast activities. Carbazomycin B is also active against malaria.10,11) Therefore, carbazomycins have been receiving considerable attention, and there have been several reports on their total synthesis.12–23) In the synthesis of these compounds, the methods used to construct the fully substituted benzene ring in their structure have been the main subject of synthetic strategies, because it is generally difficult to construct a fully substituted benzene ring from benzene derivatives by aromatic substitution and/or cross-coupling strategies due to a shortage of reliable methods for installing a functional group at the desired position.24)
Our group has been focusing on the stereo- and regioselective synthesis of the hydrocarbazole skeleton by the catalytic Diels–Alder reaction using highly acid-sensitive 3-(silyloxyvinyl)indole as a diene25,26) (Chart 2). An asymmetric version of this reaction was promoted by a chiral holmium catalyst, and the optically active hydrocarbazole 6 with three contiguous chiral centers was obtained in a single step. Concise total syntheses of (−)-minovincine27) and natural alkaloid (+)-828) demonstrated the synthetic utility of 6.
During the synthesis of 8, stereoselective hydroxylation of hydrocarbazolone intermediate 9 derived from 6 was the key step. We noticed that the aromatization of 8 would lead a total synthesis of carbazomycins. However, aromatization of 8 itself was unsuccessful because of its instability. Therefore, we explored aromatization methods using the substrates 10 and 12, which were equivalent to compound 8, to obtain the carbazomycin skeleton (Chart 3).
The synthesis began with our Diels–Alder reaction between silyloxyvinylindole 4 and dienophile 5a.25) The racemic reaction of 4 and 5a was promoted by ytterbium triflate,29–31) and the exo-adduct 6a was obtained in 84% yield as a single diastereomer on a 15-g scale32) (Chart 4). From 6a, hydrocarbazolone 9 was synthesized by following the synthetic route to (+)-8 in our previous report,28) via reductive cleavage of the acyl oxazolidinone moiety to a methyl group at C10 and subsequent oxidative conversion of triisopropylsilyl (TIPS) enol ether to enone.
Bromination of 9 with copper bromide33) gave dibrominated product 13 in 92% yield (Chart 5). Treatment with potassium carbonate gave aryl bromide 11. We examined its aromatic substitution with a methoxy group.34) We tried several conditions using copper catalysis for the synthesis of 14, however, only complex mixtures were obtained. Meanwhile, we isolated compound 15, which had a methoxy group at C10, under the conditions described in Chart 5. This type of benzylic oxidation of carbazole derivative has been reported using potassium persulfate in the presence of copper sulfate.35) A mechanistic study of our reaction is underway because compound 15 could be a potential synthetic intermediate for carbazole alkaloids with an oxygen functionality at C10, like compound 3.
Next, we turned our attention to another synthetic route. We performed the methoxylation of hydrocarbazolone via trimethylsilyl (TMS) enol ether.36) After the in situ generation of TMS enol ether 16, we obtained the desired compound 17 in 78% yield along with hydroxy derivative 18 in 20% yield (Chart 6). The relative stereochemistries of 17 and 18 were determined by the key correlations in a nuclear Overhauser effect spectroscopy (NOESY) analysis (Chart 7).
Deprotection of the carbazole nitrogen was realized with potassium carbonate in methanol. However, a subsequent attempt at aromatization gave unexpected hydrocarbazolone 20 with an exocyclic olefin (Chart 8). During this transformation, the stereochemistry of the methoxy group was epimerized. To date, we have had no clear explanation on this epimerization,37) but the structure was unambiguously determined by X-ray crystallographic analysis.38) Compound 20 as well as 19 could not be converted to carbazomycin B under several conditions.
Therefore, we aromatized 17 with N-bromosuccinimide (NBS) before deprotection to give carbazole 21 (Chart 9). Next, Mbs was removed with Na/anthracene to finally accomplish the total synthesis of carbazomycin B, which was converted to carbazomycin A by following Moody’s method.14)
We accomplished the total synthesis of carbazomycins A and B. The key point in our synthesis is that the hydrocarbazole skeleton was built in a single step by using our lanthanoid catalysis, which gave three-fourths of the substituents of carbazomycins A and B. Subsequent installation of a methoxy group and aromatization achieved the construction of a fully substituted benzene ring in the carbazomycin skeleton. Moreover, the application of this new oxidation method at the benzylic position of carbazole derivatives as well as the introduction of substituents to silyloxyvinylindole and the use of a variety of dienophiles opens the way to the construction of a library of carbazomycin derivatives. The biological activities of the synthetic intermediates will be screened in due course.
NMR spectra were recorded at 400 or 600 MHz for 1H-NMR, and at 100 or 150 MHz for 13C-NMR. Chemical shifts for proton are reported in parts per million downfield from tetramethylsilane, and are referenced to residual protium in the NMR solvent (CDCl3 δ: 7.26 ppm). For 13C-NMR, chemical shifts are reported relative to the NMR solvent (CDCl3 δ: 77.0 ppm) as an internal reference. Infrared spectra were recorded on an attenuated total reflectance (ATR). Mass spectra were recorded using electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI) mode with a time of flight (TOF) analyzer. Reactions were carried out in dry solvents under an argon atmosphere, unless otherwise noted. Solvents and reagents were purified by general methods. Flash column chromatography was performed on silica gel 60 µm particles, unless otherwise noted.
(±)-3-(9-((4-Methoxyphenyl)sulfonyl)-2-methyl-4-((triisopropylsilyl)oxy)-2,3,9,9a-tetrahydro-1H-carbazole-1-carbonyl)oxazolidin-2-one (6a)Yb(OTf)3 (1.74 g, 2.8 mmol, 10 mol%) was placed in a 300 mL flask with a stirring bar and heated at 120°C under reduced pressure (<0.01 mmHg) for 30 min. After being cooled to room temperature, the flask was charged with dry argon, and CH2Cl2 (23 mL) were added. The reaction mixture was cooled to 0°C. A solution of dienophile 5a (4.34 g, 28 mmol) in CH2Cl2 (25+5 mL to rinse) was added. A solution of diene 4 (16.3 g, 34 mmol, 1.2 equiv.) in CH2Cl2 (50+5 mL to rinse) was then added, and the mixture was stirred for 2 h under argon at room temperature. The reaction was quenched by the addition of H2O and filtered through a pad of Celite. The water layer was extracted three times with CH2Cl2, and the combined organic layers was dried over Na2SO4, filtered with a plug of cotton, and concentrated under reduced pressure. The residue was purified by flash column chromatography (CHROMATOREX-NH, 1/4=ethyl acetate/hexane) to give 6a as a colorless foam (15 g, 84%). 1H-NMR (CDCl3, 400 MHz) δ: 1.06 (d, J=7.6 Hz, 9H), 1.07 (d, J=7.6 Hz, 9H), 1.09 (d, J=5.6 Hz, 3H), 1.19 (qq, J=7.6, 7.6 Hz, 3H), 2.11 (ddd, J=2.0, 8.0, 16.8 Hz, 1H), 2.28 (m, 1H), 2.46 (ddd, J=2.0, 5.6, 16.8 Hz, 1H), 3.78 (s, 3H), 4.09 (ddd, J=8.8, 8.8, 8.8 Hz, 1H), 4.30 (ddd, J=8.8, 8.8, 8.8 Hz, 1H), 4.34 (dd, J=8.0, 8.0 Hz, 1H), 4.42 (ddd, J=6.0, 8.8, 8.8 Hz, 1H), 4.49 (ddd, J=8.8, 8.8, 8.8 Hz, 1H), 4.75 (td, J=2.0, 8.0 Hz, 1H), 6.84 (d, J=8.8 Hz, 2H), 6.98 (dd, J=7.2, 8.0 Hz, 1H), 7.10 (dd, J=8.0, 8.0 Hz, 1H), 7.56 (d, J=7.2 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.74 (d, J=8.0 Hz, 1H); 13C-NMR (CDCl3, 100 MHz) δ: 13.5, 17.9, 19.9, 32.5, 37.8, 43.0, 48.6, 55.4, 62.0, 65.4, 111.0, 114.0, 115.9, 123.4, 124.0, 126.9, 127.3, 129.0, 130.1, 144.1, 144.7, 153.7, 163.3, 175.0; high resolution (HR)-MS (ESI) m/z Calcd for C33H44N2Na1O7S1Si1 [M+Na]+ 663.2536. Found 663.2528; IR (neat): ν 2945, 2867, 1775, 1678, 1385, 1355, 1162, 1091, 1016 cm−1.
(±)-3,3-Dibromo-9-((4-methoxyphenyl)sulfonyl)-1,2-dimethyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (13)To a solution of 9 (38 mg, 0.1 mmol) in AcOEt (0.3 mL) was added CuBr2 (132.5 mg, 0.6 mmol) at room temperature. Then the resulting mixture was heated to reflux and stirred for 1 d under argon. After being cooled to room temperature, H2O was added to the reaction mixture. The organic layer was washed with water, dried over Na2SO4, filtered with a plug of cotton, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 1/4=ethyl acetate/hexane) to give 13 as a colorless foam (49.7 mg, 92%). 1H-NMR (CDCl3, 400 MHz) δ: 1.75 (d, J=6.8 Hz, 3H), 1.77 (d, J=6.4 Hz, 3H), 2.38–2.41 (m, 1H), 3.47–3.51 (m, 1H), 3.74 (s, 3H), 6.72 (d, J=8.8 Hz, 2H), 7.32–7.34 (m, 2H), 7.56 (d, J=8.8 Hz, 2H), 8.00–8.02 (m, 1H), 8.11–8.13 (m, 1H); 13C-NMR (CDCl3, 150 MHz) δ: 18.1, 22.7, 38.6, 52.5, 55.6, 75.9, 113.5, 114.3, 115.4, 122.0, 125.7, 126.1, 126.5, 128.2, 129.1, 137.9, 154.7, 164.1, 181.8; HR-MS (APCI) m/z Calcd for C21H19Br2N1O4S1 [M+H]+ 539.9480. Found 539.9465; IR (neat): ν 2970, 1688, 1591, 1396, 1266, 1180, 1087 cm−1.
3-Bromo-9-((4-methoxyphenyl)sulfonyl)-1,2-dimethyl-9H-carbazol-4-ol (11)To a solution of 13 (29 mg, 0.05 mmol) in N,N-dimethylformamide (DMF) (0.3 mL) was added K2CO3 (15 mg, 0.10 mmol, 2.0 equiv.) at room temperature. The mixture was stirred at room temperature for 8 h. The resulting mixture was diluted with CH2Cl2 and the organic phase was washed with water, dried over Na2SO4, filtered with a plug of cotton, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 1/5=ethyl acetate/hexane) to give 11 as a yellow solid (19.2 mg, 78%). 1H-NMR (CDCl3, 400 MHz) δ: 2.54 (s, 3H), 3.70 (s, 3H), 3.67 (s, 3H), 5.94 (s, 1H), 6.49 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 7.25 (t, J=7.6 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 8.09 (d, J=7.6 Hz, 1H); 13C-NMR (CDCl3, 150 MHz) δ: 19.8, 20.8, 55.4, 111.6, 113.1, 117.0, 119.4, 122.6, 123.4, 125.9, 126.3, 126.4, 129.1, 129.3, 136.3, 141.4, 141.5, 145.1, 163.2; HR-MS (APCI) m/z Calcd for C21H17Br1N1O4S1 [M–H]− 458.0062. Found 458.0060; IR (neat): ν 2925, 1738, 1593, 1364, 1259, 1166 cm−1.
3-Bromo-1-(methoxymethyl)-9-((4-methoxyphenyl)sulfonyl)-2-methyl-9H-carbazol-4-ol (15)To a solution of 11 (17 mg, 0.036 mmol) in MeOH (0.4 mL) in sealed tube was added AcOEt/toluene (1/1, 0.2 mL), CuBr (10 mg, 0.07 mmol, 2 equiv.), NaOMe (25 mg, 0.36 mmol, 10 equiv.) at room temperature. Then the resulting mixture was heated to 80°C and stirred for 3 d under argon. After being cooled to room temperature, H2O was added to the reaction mixture. The organic layer was washed with water, dried over Na2SO4, filtered with a plug of cotton, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 1/3=ethyl acetate/hexane) to give 15 as a colorless solid (4.5 mg, 27%). 1H-NMR (CDCl3, 400 MHz) δ: 2.65 (s, 3H), 3.31 (s, 3H), 3.67 (s, 3H), 5.09 (s, 2H), 6.47 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 7.23 (t, J=7.6, 1H), 7.36 (t, J=7.6, 1H), 7.84 (d, J=7.6 Hz, 1H), 8.08 (d, J=7.6 Hz, 1H); 13C-NMR (CDCl3, 150 MHz) δ: 21.1, 55.4, 57.8, 70.3, 112.7, 113.1, 116.5, 119.4, 122.7, 123.5, 125.9, 126.0, 126.5, 128.6, 129.4, 138.5, 141.2, 141.3, 146.5, 163.4; HR-MS (ESI) m/z Calcd for C21H20Br1N1Na1O5S1 [M+Na]+ 512.0143. Found 512.0137; IR (neat): ν 2924, 1726, 1366, 1167, 1087 cm−1.
(±)-3-Methoxy-9-((4-methoxyphenyl)sulfonyl)-1,2-dimethyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (17), and (±)-3-hydroxy-9-((4-methoxyphenyl)sulfonyl)-1,2-dimethyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (18)Trimethylsilyl trifluoromethanesulfonate (TMSOTf) (0.75 mL, 4.2 mmol, 2 equiv.) was added dropwise to a solution of 9 (800 mg, 2.1 mmol) and N,N-diisopropylethylamine (DIEA) (1.4 mL, 8.4 mmol, 4 equiv.) in CH2Cl2 (11 mL) at 0°C under argon. The mixture was warmed up to room temperature and stirred for 6 h. Then the mixture was concentrated under reduced pressure. Volatile materials were further removed under reduced pressure (ca. 5 mmHg) for 6 h. Then, the residue was dissolved in MeOH and added PhI(O2CCF3)2 (1.4 g, 3.2 mmol, 1.5 equiv.) at −50°C. The resulting mixture was stirred for 1 d at the same temperature. The mixture was diluted with CH2Cl2 and the organic layer was washed with water, dried over Na2SO4, filtered with a plug of cotton, and concentrated under reduced pressure. The residue was purified by flash column chromatography (CHROMATOREX-NH, 1/2=ethyl acetate/hexane) to give 17 as a colorless form (676.5 mg, 78%) and 18 as a colorless foam (167.6 mg, 20%). For 17, 1H-NMR (CDCl3, 600 MHz) δ: 0.91 (d, J=7.2 Hz, 3H), 1.71 (d, J=6.6 Hz, 3H), 2.46–2.79 (m, 1H), 3.65 (s, 3H), 3.73–3.77 (m, 1H), 3.79 (s, 3H), 4.29 (d, J=4.8 Hz, 1H), 6.86 (d, J=9.0 Hz, 2H), 7.33–7.37 (m, 2H), 7.71 (d, J=9.0 Hz, 2H), 8.12–8.14 (m, 1H), 8.18–8.20 (m, 1H); 13C-NMR (CDCl3, 150 MHz) δ: 13.7, 20.8, 37.3, 41.5, 55.8, 59.1, 81.3, 114.5, 114.6, 116.3, 121.8, 125.2, 125.5, 125.8, 128.7, 129.5, 136.8, 153.3, 164.2, 193.1; HR-MS (ESI) m/z Calcd for C22H23N1Na1O5S1 [M+Na]+ 436.1195. Found 436.1199; IR (neat): ν 2970, 2932, 1680, 1592, 1370, 1267, 1167, 1088 cm−1. For 18, 1H-NMR (CDCl3, 600 MHz) δ: 0.84 (d, J=6.6 Hz, 3H), 1.71 (d, J=6.6 Hz, 3H), 2.65–2.69 (m, 1H), 3.66 (br s, 1H), 3.78–3.81 (m, 1H), 3.80 (s, 3H), 4.76 (d, J=4.8 Hz, 1H), 6.87 (d, J=8.4 Hz, 2H), 7.33–7.39 (m, 2H), 7.72 (d, J=8.4 Hz, 2H), 8.13–8.17 (m, 2H); 13C-NMR (CDCl3, 150 MHz) δ: 13.1, 20.5, 37.1, 43.0, 55.8, 72.3, 114.7, 121.5, 125.3, 125.4, 125.6, 128.8, 129.6, 136.9, 155.0, 164.3, 194.6; HR-MS (ESI) m/z Calcd for C21H21N1Na1O5S1 [M+Na]+ 422.1034. Found 422.1038; IR (neat): ν 3055, 2983, 1672, 1595, 1384, 1264, 1169, 731 cm−1.
(±)-3-Methoxy-1,2-dimethyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (19)To a solution of 17 (41.3 mg, 0.1 mmol) in MeOH (0.2 mL) was added K2CO3 (55 mg, 0.4 mmol, 4 equiv.) at room temperature. The mixture was stirred for 4 h at 50°C. The resulting mixture was cooled to room temperature and diluted with CH2Cl2. The organic layer was washed with water, dried over Na2SO4, filtered with a plug of cotton, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 2/1=ethyl acetate/hexane) to give 19 as a white solid (20.7 mg, 85%). 1H-NMR (CDCl3, 600 MHz) δ: 1.27 (d, J=6.0 Hz, 3H), 1.51 (d, J=6.6 Hz, 3H), 2.15–2.17 (m, 1H), 2.90–2.93 (m, 1H), 3.63 (d, J=10.2 Hz, 1H), 3.68 (s, 3H), 7.24–7.27 (m, 2H), 7.34 (d, J=7.8 Hz, 1H), 8.22 (d, J=6.6 Hz, 1H), 8.35 (br s, 1H); 13C-NMR (CDCl3, 150 MHz) δ : 16.0, 17.0, 35.6, 43.6, 59.6, 86.6, 110.8, 111.9, 121.8, 122.7, 123.6, 125.0, 136.2, 152.5, 192.5; HR-MS (ESI) m/z caled for C15H17N1Na1O2 [M+Na]+ 266.1157. Found 266.1163; IR (neat): ν 3217, 2970, 1737, 1634, 1471, 1373, 1229, 1217 cm−1.
(±)-3-Methoxy-2-methyl-1-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one (20)To a solution of 19 (8 mg, 0.03 mmol) in CH2Cl2 (0.2 mL) was added 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (30 mg, 0.13 mmol, 4 equiv.) at room temperature and the mixture was stirred for 1 d. The resulting mixture was taken up in CH2Cl2, and the organic phase was washed with water, dried over Na2SO4, filtered with a plug of cotton, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 2/1=ethyl acetate/hexane) to give 20 as a colorless solid (5 mg, 62%). 1H-NMR (CDCl3, 600 MHz) δ: 1.31 (d, J=7.2 Hz, 3H), 3.16–3.19 (m, 1H), 3.55 (s, 3H), 3.62 (d, J=6.0 Hz, 1H), 5.47 (d, J=1.2 Hz, 1H), 5.63 (s, 1H), 7.26–7.30 (m, 2H), 7.38 (d, J=7.2 Hz, 1H), 8.22 (d, J=7.2 Hz, 1H), 8.62 (br s, 1H); 13C-NMR (CDCl3, 150 MHz) δ: 16.9, 43.0, 58.8, 86.6, 111.1, 111.5, 111.8, 122.2, 122.9, 124.8, 125.1, 136.7, 137.8, 144.1, 191.6; HR-MS (ESI) m/z Calcd for C15H16N1Na1O2 [M+Na]+ 264.1001. Found 264.1002; IR (neat): ν 2970, 1738, 1726, 1367, 1228, 1217, 1029 cm−1.
3-Methoxy-9-((4-methoxyphenyl)sulfonyl)-1,2-dimethyl-9H-carbazol-4-ol (21)To a solution of 17 (165 mg, 0.4 mmol) in tetrahydrofuran (THF) (4 mL) was added NBS (267 mg, 1.5 mmol, 4 equiv.) at room temperature. The mixture was stirred for 12 h. The resulting mixture was dissolved in CH2Cl2, and the organic layer was washed with water, dried over Na2SO4, filtered with a plug of cotton, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 1/2=ethyl acetate/hexane) to give 21 as a yellow solid (135 mg, 82%). 1H-NMR (CDCl3, 600 MHz) δ: 2.37 (s, 3H), 2.62 (s, 3H), 3.67 (s, 3H), 3.81 (s, 3H), 5.85 (s, 1H), 6.47 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 7.24 (t, J=7.2 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 8.07 (d, J=7.2 Hz, 1H); 13C-NMR (CDCl3, 150 MHz) δ: 13.4, 18.5, 55.3, 61.3, 112.9, 116.8, 119.6, 122.3, 122.7, 125.7, 125.8, 126.3, 129.3, 129.8, 123.0, 137.9, 141.5, 141.5, 143.5, 163.1; HR-MS (ESI) m/z Calcd for C22H21N1Na1O5S1 [M+Na]+ 434.1038. Found 434.1035; IR (neat): ν 2970, 2858, 1366, 1170, 1065, 908 cm−1.
3-Methoxy-1,2-dimethyl-9H-carbazol-4-ol (2, Carbazomycin B)To a solution of anthracene (90 mg, 0.5 mmol, 5 equiv.) in THF (2 mL) was added Na (excess) at room temperature, and the mixture was stirred for 0.5 h. To this mixture, was added 21 (41.3 mg, 0.1 mmol) in THF (0.2 mL), and the whole mixture was stirred for 1 h. The supernatant was diluted with CH2Cl2, and to this mixture was added water. The organic layer was washed with water, dried over Na2SO4, filtered with a plug of cotton, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 1/2=ethyl acetate/hexane) to give carbazomycin B (2) as a yellow solid (15.9 mg, 66%). 1H-NMR (CDCl3, 600 MHz) δ: 2.38 (s, 3H), 2.40 (s, 3H), 3.83 (s, 3H), 6.02 (s, 1H), 7.22 (t, J=7.2 Hz, 1H), 7.36 (t, J=7.2 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.78 (br s, 1H), 8.24 (d, J=7.8 Hz, 1H); 13C-NMR (CDCl3, 150 MHz) δ: 12.8, 13.2, 61.5, 109.3, 109.3, 110.0, 119.5, 122.6, 123.2, 124.8, 127.0, 136.7, 138.4, 139.2, 140.0; HR-MS (ESI) m/z Calcd for C15H16N1O2 [M+H]+ 242.1183. Found 242.1181; IR (neat): ν 3426, 1454, 1411, 750 cm−1.
3,4-Dimethoxy-1,2-dimethyl-9H-carbazole (1, Carbazomycin A)To a solution of 2 (6 mg, 0.025 mmol) in acetone (2 mL) was added K2CO3 (50 mg, 0.36 mmol, 14 equiv.) and methyl iodide (MeI) (0.3 mL) at room temperature. The mixture was heated under reflux for 5 h. The resulting mixture was diluted with CH2Cl2 and the organic layer was washed with water, dried over Na2SO4, filtered with a plug of cotton, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 1/10=ethyl acetate/hexane) to give carbazomycin A (1) as a pale yellow solid (6 mg, 93%). 1H-NMR (CDCl3, 600 MHz) δ: 2.38 (s, 3H), 2.40 (s, 3H), 3.83 (s, 3H), 6.02 (s, 1H), 7.22 (t, J=7.2 Hz, 1H), 7.36 (t, J=7.2 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.78 (br s, 1H), 8.24 (d, J=7.8 Hz, 1H); 13C-NMR (CDCl3, 150 MHz) δ: 12.7, 13.7, 60.6, 61.2, 110.3, 113.6, 114.5, 119.6, 122.6, 123.0, 125.1, 128.9, 136.5, 139.5, 144.6, 146.1; HR-MS (ESI) m/z Calcd for C16H18N1O2 [M+H]+ 256.1338. Found 256.1337; IR (neat): ν 3428, 2926, 1454, 1292, 1013 cm−1.
This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI [Grant Numbers 25460006, 16K08154 (SH), 14J03297 (TM), and 25293001, 17H03969 (AN)], the Takeda Science Foundation (SH), and the Tokyo Biochemical Research Foundation (SH).
The authors declare no conflict of interest.
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