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Synthesis of a Carbon Analogue of Scytonemin
2015 Volume 63 Issue 4 Pages 273-277
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2015 Volume 63 Issue 4 Pages 273-277
The synthesis of a carbon analogue of scytonemin was accomplished on the basis of molybdenum-mediated intramolecular double Pauson–Khand type reaction of bis(allenyne), followed by the double aldol condensation of the formed double Pauson–Khand type adduct.
Scytonemin (1) is the cyanobacterial dimeric alkaloid pigment, whose chemical structure has been elucidated by Gerwick and co-workers in 1993,1) over 100 years after its discovery. Scytonemin has an intriguing novel structural feature, which consists of a two 1,1′-linked cyclopent[b]indole-2(1H)-one framework possessing 4-hydroxybenzylidenes at the 3-positions of the fused tricyclic systems. The biosynthetic studies of scytonemin have been recently made by Walsh and Balskus.2,3) In 2011, Mårtensson and colleagues achieved the first total synthesis of scytonemin by taking advantage of the tandem Heck carbocyclization/Suzuki–Miyaura coupling and a bioinspired oxidative dimerization.4) Of particular interest is its interesting biological features. Scytonemin is a UV-absorbing pigment that protects important cellular components in a cyanobacteria against harmful UV radiation.5–8) Besides this important function, scytonemin exhibits a biological activity as a small molecule inhibitor of polo-like kinase 19) and possesses anti-inflammatory and antiproliferative properties.10) During our studies on the syntheses of various kind of alkaloids,11–19) we became very interested in the highly conjugated and characteristic dimeric structure of scytonemin as well as its biological activity. We postulated that the origin of the biological activity of scytonemin (1) might be elucidated by comparison with its carbon analogue, in which two nitrogen atoms are replaced by two carbon atoms. Therefore, our endeavor was directed toward the synthesis of 2, a carbon analogue of scytonemin (1) (Chart 1).
In 2005, Liu and Datta developed the efficient synthesis of 1H-cyclopent[a]inden-2-one (4a) from 1-ethynyl-2-(1,2-propadienyl)benzene (3a) through the Mo(CO)3(MeCN)3-mediated carbonylative [2+2+1] ring-closing reaction at 25°C in a stoichiometric manner20) (Chart 2). They also reported the catalytic version of that transformation in the presence of 5 mol% of [RhCl(CO)2]2 at 90°C to furnish 4a in 62% yield along with the by-production of 2-methylnaphthalene (5), the latter of which should be arisen from the Myers–Saito cycloaromatization21–25) of 3a. We have independently reported that treatment of 3-(2-ethynylphenyl)prop-2-ynyl benzenesulfinate (6) with 2.5 mol% of [RhCl(CO)2]2 at 40°C in an atmosphere of CO effected the successive 2,3-sigmatropic rearrangement and carbonylative [2+2+1] ring-closing reaction of the resulting allenyne species 3b to afford the 8-(phenylsulfonyl)-1H-cyclopent[a]inden-2-one (4b) in a high yield.26) In this case, the formation of 2-methylnaphthalene could not be detected in the reaction mixture.
We now report the short-step synthesis of 2, a carbon analogue of scytonemin (1), by taking advantage of the intramolecular double carbonylative [2+2+1] cycloaddition of the bis(allenyne) derivative 7,27,28) which should provide the central linked two tricyclic framework, namely the dimeric 1H-cyclopent[a]inden-2-one 8, in one operation. The outline of our synthetic plan is depicted in Chart 3. The double Pauson–Khand type reaction (PKTR) of bis(allenyne) 7 would proceed under the conditions shown in Chart 2 as is the case of 3 to afford 8. The successive aldol condensation of 8 with the suitably protected 4-hydroxybenzaldehyde 9 and several manipulations would lead to 2.
The Sonogashira coupling reaction of 1-bromo-2-iodobenzene (10) with trimethylsilylacetylene produced 1-bromo-2-[2-(trimethylsilyl)ethynyl]-benzene (11) in quantitative yield. Treatment of 11 with butyllithium was followed by iodination to afford 12, which was then used for the second Sonogashira coupling reaction with propargyl alcohol resulting in the formation of the cross-coupling adduct 13 in 84% overall yield from 11. The exposure of 13 to Cu(OAc)2·H2O effected the consecutive removal of the trimethylsilyl (TMS) group and homo-coupling of the terminal alkyne moiety29) to afford the tetrayne 14 in 89% yield. The Mitsunobu reaction of 14 with diisopropyl azodicaroboxylate (DIAD) and N-isopropylidene-N′-2-nitrobenzenesulfonyl hydrazine (IPNBSH) was followed by hydrolysis under trifluoroethanol (TFE)/water conditions30) to produce the bis(allenyne) 7, a substrate of PKTR, in 63% yield (Chart 4).
Our endeavor then focused on the intramolecular double carbonylative [2+2+1] cycloaddition of 7 (Table 1). Treatment of 7 with 10 mol% of [RhCl(CO)2]2, which was effective for the PKTR of allenynes 320,26) (Chart 2), in toluene at 70°C produced the desired product 8 in 22% yield along with the formation of unidentified by-products31) (entry 1). Lowering the reaction temperature for suppression of the undesired reactions was not effective. The reaction at 30°C in CH2Cl2 led to a result similar to entry 1 with a prolonged reaction time (entry 2), while no reaction occurred at 0°C (entry 3). The reaction with 2 equiv of Mo(CO)3(MeCN)3,32) being effective for the PKTR of allenynes 320) (Chart 2), at room temperature afforded 8 in 19% yield (entry 4). A slightly higher yield was recorded when treated at 0°C (entry 5). Dimethyl sulfoxide (DMSO) was found to be an effective additive.33) Indeed, the reaction in the presence of 4 equiv of Mo(CO)3(MeCN)3 and DMSO (8 eq) afforded 8 in 44% yield (entry 6). The reaction in a CO atmosphere increased the yield to 59% (entry 7). The highest yield of 8 (61%) was attained when the reaction was performed in toluene (entry 8).
 | |||||
| Entry | Metal reagent (eq) | CO (atm) | Temp. (°C) | Time (h) | Yield (%)a) |
|---|---|---|---|---|---|
| 1b) | [RhCl(CO2)]2 (0.10) | 1 | 70 | 4 | 22 |
| 2 | [RhCl(CO2)]2 (0.20) | 1 | 30 | 23 | 18 |
| 3 | [RhCl(CO2)]2 (0.10) | 1 | 0 | 19 | nr |
| 4 | Mo(CO)3(MeCN)3 (2.0) | — | rt | 1 | 19 |
| 5 | Mo(CO)3(MeCN)3 (2.0) | — | 0 | 5.5 | 28 |
| 6c) | Mo(CO)3(MeCN)3 (4.0) | — | 0 | 8 | 44 |
| 7c) | Mo(CO)3(MeCN)3 (4.0) | 1 | 0 | 24 | 59 |
| 8b,c) | Mo(CO)3(MeCN)3 (4.0) | 1 | 0 | 24 | 61 |
a) Yield of the isolated product. b) Reaction was performed in toluene. c) Reaction was carried out with 8 eq of DMSO. nr=no reaction.
The next task was the introduction of 4-hydroxybenzylidene moieties to the α-positions of the two carbonyl groups of 8 (Chart 5). Treatment of 8 with 4-benzoyloxybenzaldehyde (9a) in the presence of sodium hydroxide resulted in an intractable mixture. The reaction with 4-acetoxybenzaldehyde (9b) gave a similar result. Gratifyingly, the MOM-protected 4-hydroxybenzaldehyde 9c (MOM: methoxymethyl) was shown to afford the desired condensation product 1534) in 51% yield. Finally, the exposure of 15 to acidic conditions resulted in the removal of the MOM group to provide 2, the carbon analogue of scytonemin (1), in 91% yield.35)
In summary, we have completed the short-step synthesis of a carbon analogue of scytonemin from the commercially available 1-bromo-2-iodobenzene (10). The significant features of this synthesis are (i) the intramolecular double PKTR of bis(allenyne), which enabled us to straightforwardly construct the 3,3′-linked dimeric 1H-cyclopent[a]inden-2-one skeleton, and (ii) the stereoselective introduction of the arylidene moiety by aldol condensation. The biological studies of 2 are now in progress.
Melting points were measured with Yanagimoto (Tokyo, Japan) micro melting point apparatus, and were uncorrected. Infrared spectra were measured with a Shimadzu FTIR-8700 spectrometer (Kyoto, Japan) for samples in CHCl3. 1H-NMR spectra were measured with JNM-ECS400 or JNM-ECA600 spectrometers for samples in CDCl3. Tetramethylsilane (0.00 ppm) for compounds with a phenyl group or CHCl3 (7.26 ppm) were used as an internal reference. 13C-NMR spectra were measured with JNM-ECS400 or JNM-ECA600 spectrometers for samples in CDCl3. CDCl3 (77.00 ppm) was used as an internal reference. High-resolution mass spectra (HR-MS) and MS were measured with JMS-SX102A (FAB) or JMS-T100TD (Direct Analysis in Real Time: DART) mass spectrometers. UV visible absorption spectra were measured with UV-3150 (Shimadzu). Commercially available anhydrous tetrahydrofuran (THF), CH2Cl2, and toluene were employed for reactions. DMSO was distilled from CaSO4. [RhCl(CO)2]2 was purchased from Kanto Chemical Co. (Tokyo, Japan). Other reagents were commercially available and used without further purification. All reactions were carried out under a nitrogen atmosphere. Silica gel (silica gel 60, 230–400 mesh) was used for chromatography. Organic extracts were dried over anhydrous Na2SO4.
1-Bromo-2-[2-(trimethylsilyl)ethynyl]-benzene (11)To a solution of 1-bromo-2-iodobenzene (10, 1.0 mL, 8.0 mmol) in THF (50 mL) were added PdCl2(PPh3)2 (112 mg, 0.16 mmol), CuI (15 mg, 0.080 mmol), trimethylsilylacetylene (1.4 mL, 8.8 mmol) and iPr2NH (7.8 mL, 56 mmol) at room temperature. After being stirred for 5 h, the mixture was quenched by addition of saturated aqueous NH4Cl and extracted with hexane. The extract was washed with water and brine, dried and concentrated to dryness. The residue was chromatographed with hexane to give 11 (2.28 g, quantitative yield) as a pale yellow oil: 1H-NMR (400 MHz, CDCl3) δ: 7.61 (d, 1H, J=8.1 Hz), 7.53 (dd, 1H, J=7.8, 1.4 Hz), 7.28 (dd, 1H, J=7.8, 7.8 Hz), 7.19 (dd, 1H, J=8.1, 7.8 Hz), 0.32 (s, 9H). NMR data is identical to literature data.36)
3-[2-(2-(Trimethylsilyl)ethynyl)phenyl]-2-propyn-1-ol (13)To a solution of 11 (2.03 g, 8.0 mmol) in THF (42 mL) was added butyllithium (1.61 M in hexane, 7.0 mL, 11 mmol) at −78°C. After being stirred for 30 min, I2 (3.0 g, 12 mmol) was added to the reaction mixture at –78°C. The mixture was stirred for 2 h at room temperature, quenched by addition of saturated aqueous Na2S2O3 and extracted with hexane. The extract was washed with water and brine, dried and concentrated to dryness. To a solution of the residue in THF (50 mL) were added PdCl2(PPh3)2 (109 mg, 0.16 mmol), CuI (15 mg, 0.078 mmol), propargyl alcohol (0.70 mL, 12 mmol) and iPr2NH (7.7 mL, 55 mmol) at room temperature. After being stirred for 25 h, the mixture was quenched by addition of saturated aqueous NH4Cl, and extracted with AcOEt. The extract was washed with water and brine, dried and concentrated to dryness. The residue was chromatographed with hexane–AcOEt (5 : 1) to give 13 (1.53 g, 84% yield from 11) as a yellow oil: 1H-NMR (400 MHz, CDCl3) δ: 7.48–7.41 (m, 2H), 7.27–7.24 (m, 2H), 4.54 (br s, 2H), 0.27 (s, 9H). NMR data is identical to literature data.37)
2,2′-(Buta-1,3-diyne-1,4-diyl)bis[(3-hydroxypropynyl)benzene] (14)To a solution of 13 (2.20 g, 9.6 mmol) in MeOH (30 mL) and pyridine (30 mL) was added Cu(OAc)2·H2O (3.9 g, 19 mmol) at room temperature. After stirring for 9 h at 60°C, the reaction was quenched by addition of 10% aqueous HCl, and extracted with Et2O. The extract was washed with water and brine, dried, and concentrated to dryness. The residue was chromatographed with hexane–AcOEt (2 : 1) to afford 14 (1.32 g, 89% yield) as a pale brown solid: mp 105–106°C; IR 3601, 3420, 2399, 1522, 1475, 1448, 1383, 1022, 951, 930 cm−1; 1H-NMR (600 MHz, CDCl3) δ: 7.51 (d, 2H, J=6.9 Hz), 7.42 (d, 2H, J=7.2 Hz), 7.31–7.26 (m, 4H), 4.58 (d, 4H, J=5.8 Hz), 2.97 (t, 2H, J=5.8 Hz); 13C-NMR (151 MHz, CDCl3) δ: 132.7, 131.8, 128.9, 128.1, 126.3, 124.3, 92.3, 83.7, 81.2, 77.5, 51.5; DART MS m/z 311 (M++1, 29.0); DART HR-MS Calcd for C22H15O2 311.1072, Found 311.1077.
2,2′-(Buta-1,3-diyne-1,4-diyl)bis[(1,2-propadienyl)benzene] (7)To a solution of 14 (151 mg, 0.49 mmol) in THF (4.9 mL) were successively added PPh3 (498 mg, 1.9 mmol), IPNBSH (490 mg, 1.9 mmol), and DIAD (0.40 mL, 1.9 mmol) at 0°C. After stirring for 5 h at room temperature, TFE–H2O (1 : 1, 5.0 mL) was added to the reaction mixture. After stirring for 1 h at room temperature, the reaction was quenched by addition of water, and the mixture was extracted with AcOEt. The extract was washed with water and brine, dried, and concentrated to dryness. The residue was chromatographed with hexane to afford 7 (57 mg, 51% yield) as a pale yellow solid: mp 68°C (decomposed); IR 1940, 1481, 1447, 854, 667 cm−1; 1H-NMR (600 MHz, CDCl3) δ: 7.51–7.47 (m, 4H), 7.31 (br s, 2H), 7.16 (br s, 2H), 6.74 (br s, 1H), 5.21–5.20 (m, 5H); 13C-NMR (151 MHz, CDCl3) δ: 210.7, 137.1, 133.3, 129.3, 126.64, 126.61, 119.4, 92.0, 80.7, 79.1, 78.3; DART MS m/z 279 (M++1, 42.9); DART HR-MS Calcd for C22H15 279.1174, Found 279.1188.
[3,3′-Bi(cyclopent[a]inden)]-2,2′(1H,1′H)-dione (8)To a solution of 7 (29 mg, 0.10 mmol) in toluene (1.0 mL) were added Mo(CO)3(MeCN)3 (126 mg, 0.42 mmol) and DMSO (59 µL, 0.83 mmol). The reaction mixture was stirred at 0°C for 24 h under CO (1 atm). The reaction mixture was chromatographed with hexane–CH2Cl2–AcOEt (8 : 1 : 1) to afford 8 (21 mg, 61% yield) as a red solid: mp over 300°C; IR 1713, 1607, 1443, 1327, 1306, 1277, 1207, 1177, 1150 cm−1; 1H-NMR (600 MHz, CDCl3) δ: 7.28 (dd, 2H, J=7.6, 7.6 Hz), 7.19 (d, 2H, J=7.2 Hz), 7.11 (d, 2H, J=7.2 Hz), 6.98 (dd, 2H, J=7.6, 7.2 Hz), 6.56 (s, 2H), 3.43 (s, 4H); 13C-NMR (151 MHz, CDCl3) δ: 203.2, 168.6, 148.2, 140.6, 132.2, 130.0, 129.1, 127.1, 125.6, 124.2, 121.8, 35.5; DART MS m/z 335 (M++1, 100); DART HR-MS Calcd for C24H15O2 335.1072, Found 335.1065.
(1E,1′E)-1,1′-Bis[4-(methoxymethyl)oxybenzylidene]-[3,3′-bi(cyclopent[a]inden)]-2,2′(1H,1′H)-dione (15)To a solution of 8 (54 mg, 0.16 mmol) in MeOH (1.5 mL) and CH2Cl2 (1.5 mL) were added NaOH (27 mg, 0.68 mmol) and 4-(methoxymethyl)oxy-benzaldehyde (9c, 108 mg, 0.65 mmol) at room temperature. The reaction mixture was stirred for 2 h, quenched by addition of ice-cold water, neutralized by aqueous solution of 10% HCl and the mixture was extracted with CH2Cl2. The extract was washed with water and brine, dried, and concentrated to dryness. The residue was chromatographed with hexane–AcOEt–CH2Cl2 (8 : 1 : 1) to afford 15 (53 mg, 51% yield) as a dark brown solid: mp 242–244°C; IR 1701, 1634, 1603, 1508, 1242, 1153, 1080, 997, 835 cm−1; 1H-NMR (600 MHz, CDCl3) δ: 7.74 (d, 4H, J=8.6 Hz), 7.51 (s, 2H), 7.30 (dd, 2H, J=7.6, 7.2 Hz), 7.24 (d, 4H, J=7.2 Hz) 7.17 (d, 4H, J=8.6 Hz), 7.11 (s, 2H), 7.06 (dd, 2H, J=7.6, 7.2 Hz), 5.27 (s, 4H), 3.53 (s, 6H); 13C-NMR (151 MHz, CDCl3) δ: 194.6, 164.8, 158.3, 148.6, 139.6, 132.5, 132.0, 131.7, 130.7, 129.0, 127.5, 127.4, 126.6, 125.1, 124.3, 122.5, 116.3, 94.2, 56.2; DART MS m/z 631 (M++1, 4.66); DART HR-MS Calcd for C42H31O6 631.2121, Found 631.2128.
(1E,1′E)-1,1′-Bis(4-hydroxybenzylidene)-[3,3′-bi(cyclopent[a]inden)]-2,2′(1H,1′H)-dione (2)To a solution of 15 (86 mg, 0.14 mmol) in EtOH (1.5 mL) and CH2Cl2 (1.5 mL) was added p-TsOH·H2O (156 mg, 0.82 mmol) at room temperature. After stirring for 4 h at 60°C, EtOH was evaporated off. The residue was dissolved in acetone, extracted with CH2Cl2, washed with water and brine, dried, and concentrated to dryness. The residue was chromatographed with hexane–AcOEt (4 : 3) to afford 2 (67 mg, 91% yield) as a dark brown solid: mp 261–262°C; IR (KBr) 1684, 1664, 1630, 1601, 1580, 1560, 1510, 1437, 1288, 1159, 1088, 1040 cm−1; 1H-NMR (600 MHz, acetone-d6) δ: 9.15 (br s, 2H), 7.82 (d, 4H, J=8.6 Hz), 7.43 (s, 2H), 7.40–7.35 (m, 6H), 7.30 (d, 2H, J=7.6 Hz), 7.10 (dd, 2H, J=6.9, 6.5 Hz), 7.05 (d, 4H, J=8.6 Hz); 13C-NMR (151 MHz, acetone-d6) δ: 194.8, 165.2, 160.2, 149.7, 140.4, 133.5, 133.3, 133.1, 131.4, 128.22, 128.17, 127.5, 127.4, 125.3, 124.5, 123.6, 116.7; DART MS m/z 543 (M++1, 100); DART HR-MS Calcd for C38H23O4 543.1596, Found 543.1607.
This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, for which we are thankful. We thank Prof. Dr. Akira Odani for UV-visible absorption spectroscopy analysis of 2.
The authors declare no conflict of interest.
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