5.3 Experimental Procedures and Analytical Data
5.3.3 Concise Synthesis of Lamellarin Alkaloids by C−H/N−H Activation
4-Iodo-2-methoxyphenol (172): Guaiacol (12.4 g, 100 mmol) was dissolved in MeOH (200 mL), then NaI (22.5 g, 149.5 mmol) and NaOH (6.25 g, 150 mmol) were added. Aqueous NaClO solution (15%, 200 mL, 145 mmol) was added dropwise over 40 min at –4 ºC. The mixture was stirred for additional 30 min at this temperature. The mixture was acidified with a HCl solution (4 M) to pH = 7, then Na2S2O3 (10%, 60 mL) was added. MeOH was removed under reduced pressure and the aqueous phase was extracted with EtOAc (3×150 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (2×100 mL) and brine (100 mL), dried over Na2SO4 and concentrated. The residue was filtrated through a short pad of silica gel and further purified by vacuum distillation to give the product 172 (21.0 g, 84%) as an orange oil.
1H NMR (300 MHz, CDCl3) δ = 7.16 (dd, J = 8.3, 1.9 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 5.54 (s, 1H), 3.86 (s, 3H). 13C NMR (125 MHz, CDCl3) δ = 147.3 (Cq), 145.6 (Cq), 130.4 (CH), 119.7 (CH), 116.4 (CH), 80.9 (Cq), 56.2 (CH3). IR (neat): 3489, 2941, 2838, 1601, 1491, 1440, 1218, 1020 cm-1. MS (EI) m/z (relative intensity) 250 (100) [M+], 234 (50), 206 (30), 179 (5), 126 (10), 108 (10). HR-MS (ESI) m/z calcd for C7H7IO2 [M+] 249.9491, found 249.9495.
The analytical data are in accordance with those previously reported in the literature.[147]
4-Iodo-1-isopropoxy-2-methoxybenzene (173): To a suspension of 172 (12.5 g, 50 mmol) and K2CO3
(13.8 g, 100 mmol) in DMSO (200 mL) was added i-PrBr (9.20 g, 75 mmol) at ambient temperature and the
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mixture was heated at 55 ºC for 16 h. At ambient temperature, the mixture was diluted with EtOAc (500 mL) and washed with H2O (4×100 mL) and brine (100 mL). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (n-hexane/EtOAc, 20/1) to give the product 173 (13.7 g, 94%) as a colorless oil.
The analytical data are in accordance with those previously reported in the literature.[122f]
1,2-Bis(4-isopropoxy-3-methoxyphenyl)ethyne (59c): Aryl iodide 173 (8.70 g, 30 mmol), Pd(PPh3)4 (1.04 g, 6 mol %), CuI (285 mg, 10 mol %) were placed into a 250 mL Schlenk flask under a N2 atmosphere. Benzene (80 mL) and DBU (27 mL, 180 mmol) were added via cannula. Degassed H2O (121 mg, 45 mol %) and ethynyltrimethylsilane (2.10 mL, 15 mmol) were added by syringe sequentially. The mixture was kept in dark by aluminum foil and stirred at 60 ºC for 48 h. At ambient temperature, the mixture was diluted with CH2Cl2
(400 mL) and washed with HCl (3 M, 3×75 mL), sat. aq. NH4Cl/NH3 (1/1, 3×75 mL) and brine (75 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane/EtOAc 4/1 to CH2Cl2) to afford the product 59c (3.99 g, 75%) as a white solid.
The analytical data are in accordance with those previously reported in the literature.[148]
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Synthesis of 2-[4-isopropoxy-5-methoxy-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2a)
3-Isopropoxy-4-methoxyphenol (175): Under an argon atmosphere, m-CPBA (70%, 11.8 g, 48 mmol) was added portionwise to a solution of 174 (7.77 g, 40 mmol) in CH2Cl2 (120 mL) at 0 oC. After being stirred at 23 oC for 3 h, to the mixture was added saturated aqueous NaHCO3 (80 mL). The mixture was diluted with H2O (50 mL) and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (3×80 mL).
The combined extract was washed with brine (100 mL), dried over Na2SO4, and evaporated under reduced pressure. The residue was dissolved in MeOH (200 mL) and K2CO3 (13.8 g, 100 mmol) was added portionwise to the solution. After being stirred for 1 h, the mixture was evaporated under reduced pressure.
H2O (150 mL) was added to the residue and the aqueous solution was extracted with EtOAc (3×100 mL). The extract was washed with brine (100 mL), dried over Na2SO4, evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/EtOAc 15:1) to yield 175 (6.12 g, 84%) as a colorless solid.
M. p. = 124−125 ºC. 1H NMR (400 MHz, CDCl3) δ = 6.71 (d, J = 8.6 Hz, 1H), 6.45 (d, J = 2.8, 1H), 6.33 (dd, J = 8.6, 2.8 Hz, 1H), 4.42 (hept, J = 6.1 Hz, 1H), 3.76 (s, 3H), 1.30 (d, J = 6.1 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ = 150.2 (Cq), 148.1 (Cq), 144.2 (Cq), 113.5 (CH), 106.5 (CH), 104.1 (CH), 71.3 (CH), 56.8 (CH3), 21.9 (CH3). IR (neat): 3424, 2977, 1606, 1504, 1460, 1287, 1221, 1126 cm-1. MS (EI) m/z (relative intensity) 183 (10) [M+H+], 182 (50) [M+], 140 (70), 125 (100), 111 (10), 97 (30). HR-MS (EI) m/z calcd for C10H14O3
[M+] 182.0943, found 182.0944.
The analytical data are in accordance with those previously reported in the literature.[122i]
118
2-Isopropoxy-1-methoxy-4-(methoxymethoxy)benzene (176): Under argon, a solution of 175 (3.64 g, 20 mmol) in THF (20 mL) was added dropwise to A suspension of NaH (60%, 2.40 g, 60 mmol) in THF (30 mL) at 0 oC. After being stirred for 30 min, chloromethyl methyl ether (2.41 g, 30 mmol) was added and the mixture was stirred for 2 h at 0 °C and additional 1 h at ambient temperature. To the mixture was added saturated aqueous NH4Cl (80 mL) and extracted with EtOAc (3×80 mL). The extract was washed with brine (80 mL), dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (n-hexane/EtOAc 10/1) to give 176 as a colorless oil (3.62 g, 80%).
1H NMR (400 MHz, CDCl3) δ = 6.76 (d, J = 8.8 Hz, 1H), 6.63 (d, J = 2.8 Hz, 1H), 6.57 (dd, J = 8.8, 2.8 Hz,
The analytical data are in accordance with those previously reported in the literature.[122i]
1-Bromo-4-isopropoxy-5-methoxy-2-(methoxymethoxy)benzene (177): A solution of NBS (2.8 g, 15.7 mmol) in DMF (20 mL) was added dropwise to a solution of 176 (3.39 g, 15 mmol) in DMF (15 mL) at 0 °C.
After being stirred for 30 min, to the reaction mixture was added H2O (30 mL) at the same temperature and allowed to warm to ambient temperature. The mixture was diluted with Et2O (250 mL), washed with H2O
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The analytical data are in accordance with those previously reported in the literature.[122i]
2-[4-Isopropoxy-5-methoxy-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2a):
A mixture of 177 (3.05 g, 10 mmol), Et3N (5.6 mL, 40 mmol), Pd(OAc)2 (112 mg, 5 mol %), DPEphos (538 mg, 10 mol %), and 178 (3.84 g, 30 mmol) in 1,4-dioxane (20 mL) was heated at 100 °C for 16 h. At ambient temperature, to the mixture was added saturated NH4Cl (80 mL), and the aqueous solution was extracted with EtOAc (3×60 mL). The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (n-hexane/EtOAc/Et3N 100/10/1) to give 2a (2.92 g, 83%) as a pale yellow oil.
1H NMR (400 MHz, CDCl3) δ = 7.14 (s, 1H), 6.61 (s, 1H), 5.04 (s, 2H), 4.51 (hept, J = 6.1 Hz, 1H), 3.79 (s, 3H), 3.48 (s, 3H), 1.31 (d, J = 6.1 Hz, 6H), 1.27 (s, 12H). 13C NMR (100 MHz, CDCl3) δ = 157.2 (Cq), 150.5 (Cq), 145.3 (Cq), 119.0 (CH), 106.1 (CH), 97.1 (CH2), 83.0 (Cq), 70.9 (CH), 56.3 (CH3), 56.0 (CH3), 24.6 (CH3), 21.7 (CH3). IR (neat): 2976, 2933, 1602, 1507, 1370, 1346, 1202, 1141 cm-1. MS (EI) m/z (relative intensity) 353 (10) [M+H+], 352 (100) [M+], 310 (10), 278 (30), 236 (30), 194 (80). HR-MS (EI) m/z calcd for C18H29BO6 [M+] 352.2057, found 352.2062.
120 Synthetic Route to Lamellarins D and H:
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Methyl 4,5-bis(4-isopropoxy-3-methoxyphenyl)-1H-pyrrole-2-carboxylate (128a): Methyl 2-acetamidoacrylate (127) (787 mg, 5.50 mmol), 1,2-bis(4-isopropoxy-3-methoxy-phenyl)ethyne (59c) (1.77 g, 5.00 mmol), [RuCl2(p-cymene)]2 (153 mg, 5.0 mol %), AgSbF6 (343 mg, 20 mol %) and Cu(OAc)2·H2O (2.00 g, 10.0 mmol) was placed into a 100 mL sealed tube under a N2 atmosphere. A solvent mixture of MeOH/DCE (20 mL/10 mL) was added via cannula. The reaction mixture was stirred at 110 °C for 24 h. At ambient temperature, the reaction mixture was dry-loaded onto silica gel and purified by column
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[M+], 453 (60), 411 (40), 369 (100), 337 (60). HR-MS (EI) m/z calcd for C28H33NO7 [M+] 495.2257, found 495.2265.
Methyl 3-bromo-4,5-bis(4-isopropoxy-3-methoxyphenyl)-1H-pyrrole-2-carboxylate (144a): to a solution of 128a (1.40g, 3.09 mmol) in DMF (40 mL) was added a solution of NBS (555 mg, 3.12 mmol) in DMF (5 mL) dropwise within 10 min at 0 °C under a N2 atmosphere. The reaction mixture was stirred at 0 °C for 1 h.
Then, the mixture was diluted with EtOAc (200 mL) and washed with H2O (3×60 mL) and brine (60 mL). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by column chromatography over silica gel (n-hexane/EtOAc 5/1) to give 144a (1.61g, 98%) as a colorless solid.
M. p. = 71−72 ºC. 1H NMR (300 MHz, CDCl3) δ = 9.37 (s, 1H), 6.91–6.75 (m, 5H), 6.69 (d, J = 2.0 Hz, 1H), 4.59–4.45 (m, 2H), 3.90 (s, 3H), 3.73 (s, 3H), 3.54 (s, 3H), 1.37 (d, J = 6.1 Hz, 6H), 1.34 (d, J = 6.1 Hz, 6H).
13C NMR (100 MHz, CDCl3) δ = 160.9 (Cq), 149.8 (Cq), 149.7 (Cq), 147.1 (Cq), 146.4 (Cq), 133.6 (Cq), 126.3 (Cq), 124.2 (Cq), 123.6 (Cq), 123.1 (CH), 119.5 (CH), 118.9 (Cq), 115.2 (CH), 115.0 (CH), 114.6 (CH), 111.5 (CH), 106.0 (Cq), 71.1 (CH), 71.1 (CH), 55.7 (CH3), 55.4 (CH3), 51.5 (CH3), 21.9 (CH3), 21.8 (CH3). IR (neat): 3284, 2975, 1671, 1518, 1467, 1383, 1233, 1106, 1032 cm-1. MS (EI) m/z (relative intensity) 533 (40) [M+], 489 (20), 449 (70), 417 (100), 369 (10), 308 (50). HR-MS (EI) m/z calcd for C26H30 100 mL sealed tube under a N2 atmosphere. A solvent mixture of DME/H2O (30 mL/2.4 mL) was added via cannula. The reaction mixture was kept in the dark and stirred at 110 °C for 24 h. After cooling down to ambient temperature, the mixture was evaporated, the residue was diluted with H2O (30 mL) and extracted with CH2Cl2 (4×30 mL). The extracts was washed with brine (2×30 mL), dried over Na2SO4, and evaporated.
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The residue was purified by column chromatography over silica gel (n-hexane/EtOAc 2/1) to give 145 (1.18 g, 87%) as a pale yellow solid. tube. MeOH (20 mL) was added via cannula. The reaction mixture was stirred at 110 °C for 16 h. At ambient temperature, 40 mL saturated NaHCO3 solution was carefully added. A large amount of precipitate formed during this process. The solid was collected by filtration and further washed with cold H2O (2×5.0 mL) and n-hexane (2×5.0 mL). The obtained pale brown solid 146a (776 mg, 86%) was analytic pure and didn’t need
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The analytical data are in accordance with those previously reported in the literature.[148]
3-(2,2-Dimethoxyethyl)-7-isopropoxy-1,2-bis(4-isopropoxy-3-methoxyphenyl)-8-methoxychromeno[3,4-b]pyrrol-4(3H)-one (148a): Under N2, 146a (867 mg, 1.44 mmol) and Cs2CO3 (3.05 g, 9.36 mmol) were placed in a 100 mL sealed tube. 2-Bromo-1,1-dimethoxyethane (147) (1.60 g, 9.5 mmol) and DMF (30 mL) were added via cannula. The reaction mixture was stirred at 110 °C for 24 h. At ambient temperature, the mixture was diluted with EtOAc (250 mL) and washed with H2O (3×60 mL) and brine (60 mL). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by column chromatography over silica gel (n-hexane/EtOAc 5/1) to give 148a (804 mg, 81%) as a colorless solid.
M. p. = 162−163 ºC. 1H NMR (300 MHz, CDCl3) δ = 6.92 (s, 1H), 6.91 (s, 1H), 6.92–6.78 (m, 4H), 6.79 (d, J
IR (neat): 2975, 2931, 1703, 1517, 1463, 1257, 1107, 1031, 752 cm-1. MS (ESI) m/z (relative intensity) 712 (100) [M+Na+], 690 (50) [M+H +], 658 (80). HR-MS (ESI) m/z calcd for C39H48NO10 [M+H+] 690.3273, found 690.3267.
3,11-Diisopropoxy-14-(4-isopropoxy-3-methoxyphenyl)-2,12-dimethoxy-6H-chromeno[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one (129c): Under N2, a solution of TfOH in CH2Cl2
(1.0 M, 1.1 mL, 1.10 mmol) was added dropwise to a solution of 148a (508 mg, 0.73 mmol) in CH2Cl2 (25 mL) within 10 minat 0 ºC. After stirring at 0 ºC for 30 min, the mixture was warmed to 23 ºC and stirred for additional 1 h. NaHCO3 (919 mg, 11 mmol) and EtOH (10 mL) were added sequentially. Then, the solvent
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was removed and the residue was dry-loaded no silica gel and purified by column chromatography on silica gel (n-hexane/EtOAc 4/1) to yield 129c (429 mg, 94%) as a colorless solid.
M. p. = 190−191 ºC. 1H NMR (400 MHz, CDCl3) δ = 9.08 (d, J = 7.3 Hz, 1H), 7.12–7.11 (m, 2H), 7.10–7.09
The analytical data are in accordance with those previously reported in the literature.[148]
3,11-Dihydroxy-14-(4-hydroxy-3-methoxyphenyl)-2,12-dimethoxy-6H-chromeno[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one (129b): To a solution of 129c (94 mg, 0.15 mmol) in CH2Cl2 (10 mL) was added BCl3
(1.4 mL, 1.0 M in CH2Cl2, 1.40 mmol) under a N2 atmosphere at –78 ºC. After being stirred for 30 min at this temperature, the reaction mixture was allowed to warm to ambient temperature and stirred for additional 3 h.
To the mixture was added saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (4×20 mL). The extract was washed with brine (20 mL), dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/MeOH 1/0 to 10/1) to yield 129b (72 mg, 96%) as a pale green solid.
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(ESI) m/z calcd for C28H22NO8 [M+H+] 500.1340, found 500.1348; C28H21NO8Na[M+Na+] 522.1159, found 522.1163.
The analytical data are in accordance with those previously reported in the literature.[148]
14-(3,4-Dihydroxyphenyl)-2,3,11,12-tetrahydroxy-6H-chromeno[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one (129a): To a solution of 129c (94 mg, 0.15 mmol) in CH2Cl2 (10 mL) was added BBr3 (2.25 mL, 1.0 M in CH2Cl2, 2.25 mmol) under a N2 atmosphere at –78 ºC. After being stirred for 30 min at this temperature, the reaction mixture was allowed to warm to ambient temperature and stirred for additional 16.5 h. After diluting with MeOH (5 mL), the solvent was removed under vacuum. The residue was dissolved in H2O (20 mL) and extracted with EtOAc (4×20 mL). The extracts was washed with brine (20 mL), dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/MeOH 10/1) to yield 129a (64 mg, 93%) as a pale green solid.
M. p. ˃300 ºC. 1H NMR (400 MHz, DMSO-d6) δ = 9.98 (sbr, 1H), 9.76 (sbr, 1H), 9.41 (sbr, 1H), 9.19 (sbr, 2H), 8.99 (d, J = 7.4 Hz, 1H), 8.90 (sbr, 1H), 7.14 (d, J = 7.4 Hz, 1H), 7.13 (s, 1H), 6.99 (d, J = 7.9 Hz, 1H), 6.95 (s, 1H), 6.80 (s, 1H), 6.79 (d, J = 2.1 Hz, 1H), 6.71 (dd, J = 7.9, 2.1 Hz, 1H), 6.57 (s, 1H). 13C NMR (125 MHz, DMSO-d6) δ = 154.2 (Cq), 147.4 (Cq), 146.6 (Cq), 146.3 (Cq), 146.0 (Cq), 145.3 (Cq), 145.1 (Cq), 141.8 (Cq), 133.7 (Cq), 128.6 (Cq), 125.3 (Cq), 123.6 (Cq), 121.3 (CH), 121.0 (CH), 117.9 (Cq), 117.4 (CH), 116.8 (CH), 112.3 (CH), 111.2 (CH), 111.2 (Cq), 109.5 (CH), 109.4 (CH), 108.7 (Cq), 106.2 (Cq), 103.2 (CH). IR (neat):
3363, 1670, 1428, 1274, 1153, 1030, 863, 753 cm-1. MS (EI) m/z (relative intensity) 480 (100) [M+Na+], 458 (80) [M+H+], 441 (30), 425 (10), 413 (5). HR-MS (EI) m/z calcd for C25H16NO8 [M+H+] 458.0870, found 458.0883; C25H15NO8Na[M+Na+] 480.0690, found 480.0703.
The analytical data are in accordance with those previously reported in the literature.[122f]
127 Synthesis of Lamellarin Analogue 129d
1,2-Bis(4-isopropoxy-3-methoxyphenyl)chromeno[3,4-b]pyrrol-4(3H)-one (146b): Under N2, 144a (1.06 g, 2.0 mmol), 2b (414 mg, 3.0 mmol), Pd2(dba)3 (91.6 mg, 5.0 mol %), dppf (111 mg, 10 mol %) and Na2CO3
(1.40 g, 13.2 mmol) were placed into a 100 mL sealed tube. A solvent mixture of DME/H2O (30 mL/2.4 mL) was added via cannula. The reaction mixture was kept in the dark and stirred at 110 °C for 36 h. After cooling down to ambient temperature, the mixture was evaporated, and the residue was diluted with H2O (30 mL) and extracted with CH2Cl2 (4×30 mL). The combined organic phase was washed with brine (2×30 mL), dried over Na2SO4, and evaporated. The residue was purified by column chromatography over silica gel (n-hexane/EtOAc 3/1) to give 146b as a colorless solid (935 mg, 91%).
M. p. = 245−247 ºC. 1H NMR (300 MHz, CDCl3) δ = 10.93 (s, 1H), 7.43–7.27 (m, 3H), 7.12 (d, J = 2.2 Hz, 1H), 7.10–6.96 (m, 3H), 7.00–6.90 (m, 2H), 6.81 (d, J = 8.5 Hz, 1H), 4.70–4.60 (m, 1H), 4.58–4.46 (m, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 1.44 (d, J = 6.0 Hz, 6H), 1.37 (d, J = 6.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ = 155.9 (Cq), 151.4 (Cq), 150.8 (Cq), 149.9 (Cq), 147.6 (Cq), 146.9 (Cq), 139.5 (Cq), 128.4 (Cq), 127.6 (Cq), 127.5 (CH), 124.0 (CH), 123.6 (CH), 123.4 (Cq), 123.3 (CH), 120.2 (CH), 118.5 (Cq), 118.1 (Cq), 117.3 (CH), 116.0 (CH), 115.9 (Cq), 114.7 (CH), 114.5 (CH), 111.4 (CH), 71.4 (CH), 71.1 (CH), 56.1 (CH3), 55.7 (CH3), 22.1 (CH3), 22.1 (CH3). IR (neat): 3240, 2976, 1697, 1466, 1416, 1230, 1106, 772 cm-1. MS (EI) m/z (relative
128
intensity) 514 (20) [M+H+], 513 (40) [M+], 471 (10), 429 (100), 369 (10), 337 (10), 325 (10). HR-MS (EI) m/z calcd for C31H31NO6 [M+] 513.2151, found 513.2140.
3-(2,2-Dimethoxyethyl)-1,2-bis(4-isopropoxy-3-methoxyphenyl)chromeno[3,4-b]pyrrol-4(3H)-one (148b): Under N2, 146b (514 mg, 1.0 mmol) and Cs2CO3 (2.11 g, 6.50 mmol) were placed into a 100 mL sealed tube. 2-Bromo-1,1-dimethoxyethane (147) (1.11 g, 6.60 mmol) and solvent DMF (15 mL) were added via cannula. The reaction mixture was stirred at 110 °C for 36 h. At ambient temperature, the mixture was diluted with EtOAc (200 mL) and washed with H2O (3×50 mL) and brine (50 mL). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by column chromatography over silica gel (n-hexane/EtOAc 6/1) to give 148b as a colorless solid (493 mg, 82%).
M. p. = 169−170 ºC. 1H NMR (600 MHz, CDCl3) δ = 7.48 (dd, J = 8.0, 1.6 Hz, 1H), 7.36 (dd, J = 8.3, 1.2 Hz,
129
and EtOH (8.0 mL) were added sequentially. Then, the solvent was removed and the residue was dry-loaded on to silica gel and purified by column chromatography on silica gel (n-hexane/EtOAc 4/1) to yield 129d (318 mg, 91%) as a colorless solid.
M. p. = 177−178 ºC. 1H NMR (400 MHz, CDCl3) δ = 9.11 (d, J = 7.3 Hz, 1H), 7.35–7.28 (m, 1H), 7.31–7.23 (m, 2H), 7.13–7.03 (m, 4H), 7.02 (s, 1H), 7.02–6.93 (m, 1H), 6.93 (d, J = 7.4 Hz, 1H), 4.69–4.59 (m, 2H), 3.81 (s, 3H), 3.40 (s, 3H), 1.46 (d, J = 6.1 Hz, 3H), 1.41–1.37 (m, 9H). 13C NMR (100 MHz, CDCl3) δ = 154.9 (Cq), 151.6 (Cq), 151.2 (Cq), 150.1 (Cq), 148.3 (Cq), 147.2 (Cq), 134.3 (Cq), 128.4 (Cq), 128.3 (Cq), 128.1 (CH), 124.5 (Cq), 124.0 (CH), 123.6 (CH), 123.5 (CH), 122.8 (CH), 118.9 (Cq), 117.9 (Cq), 117.1 (CH), 116.4 (CH), 114.7 (CH), 112.6 (CH), 112.0 (Cq), 110.3 (CH), 108.2 (Cq), 105.5 (CH), 71.3 (CH), 71.1 (CH), 56.0 (CH3), 54.9 (CH3), 22.2 (CH3), 21.8 (CH3), 21.8 (CH3), 21.6 (CH3). IR (neat): 2976, 2933, 1701, 1473, 1398, 1259, 1218, 1175, 745 cm-1. MS (ESI) m/z (relative intensity) 560 (20) [M+Na+], 538 (100) [M+H+], 478 (20), 443 (10), 381 (20). HR-MS (ESI) m/z calcd for C33H32NO6 [M+H+] 538.2224, found 538.2234.
Synthesis of Lamellarin Analogue 129e
Methyl 2-acetamidoacrylate (127) (472 mg, 3.30 mmol), 1,2-diphenylethyne (59c) (534 mg, 3.00 mmol), [RuCl2(p-cymene)]2 (46 mg, 2.5 mol %), AgSbF6 (103 mg, 10 mol %) and Cu(OAc)2·H2O (1.20 g, 6.0 mmol) were placed into a 100 mL sealed tube under a N2 atmosphere. A solvent mixture of MeOH/DCE (12 mL/6.0 mL) was added via cannula. The reaction mixture was stirred at 110 °C for 24 h. At ambient temperature, the reaction mixture was dry-loaded onto silica gel and purified by column chromatography (n-hexane/EtOAc
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20/1) to afford the desired product 128b (740 mg, 89%) as a colorless solid and 128b´ (57 mg, 6%) as a pale yellow oil.
The analytical data are in accordance with those previously reported in the literature.[100, 124f]
Methyl 1-acetyl-4,5-diphenyl-1H-pyrrole-2-carboxylate (128b´):
The analytical data are in accordance with those previously reported in the literature.[100]
Methyl 3-bromo-4,5-diphenyl-1H-pyrrole-2-carboxylate (144b): To a solution of 128b (693 mg, 2.50 mmol) in DMF (30 mL), the solution of NBS (449 mg, 2.52 mmol) in DMF (5 mL) was added dropwise within 10 min at 0 °C under a N2 atmosphere. The reaction mixture was stirred at 0 °C for 1 h. Then, the mixture was diluted with EtOAc (200 mL) and washed with H2O (3×60 mL) and brine (60 mL). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by column chromatography over silica gel (n-hexane/EtOAc 20/1) to give 144b (881 mg, 99%) as a colorless solid.
M. p. = 190−191 ºC. 1H NMR (400 MHz, CDCl3) δ = 9.53 (s, 1H), 7.37–7.30 (m, 3H), 7.30–7.20 (m, 7H), 3.89 (s, 3H). 13C NMR (100 MHz, CDCl3) δ = 160.9 (Cq), 133.5 (Cq), 133.3 (Cq), 130.8 (Cq), 130.7 (CH),
131
128.7 (CH), 128.3 (CH), 128.2 (CH), 127.5 (CH), 127.3 (CH), 125.1 (Cq), 119.8 (Cq), 106.0 (Cq), 51.8 (CH3).
IR (neat): 3303, 1672, 1461, 1438, 1399, 1288, 1206, 774, 693, 537 cm-1. MS (EI) m/z (relative intensity) 355 (80) [M+], 325 (60), 295 (10), 269 (10), 244 (10), 216 (100). HR-MS (EI) m/z calcd for C18H14 DME/H2O (30 mL/2.4 mL) was added via cannula. The reaction mixture was kept in the dark and stirred at 110 °C for 36 h. After cooling to ambient temperature, the mixture was evaporated, and the residue was diluted with H2O (30 mL) and extracted with CH2Cl2 (4×30 mL). The extract was washed with brine (2×30 mL), dried over Na2SO4, and evaporated. The residue was purified by column chromatography over silica gel (n-hexane/EtOAc 3/1) to give 146c as a colorless solid (526 mg, 78%).
M. p. = 273−274 ºC. 1H NMR (400 MHz, CDCl3) δ = 10.27 (s, 1H), 7.51–7.38 (m, 6H), 7.37–7.25 (m, 7H), 2-Bromo-1,1-dimethoxyethane (147) (1.11 g, 6.6 mmol) and DMF (15 mL) were added via cannula. The reaction mixture was stirred at 110 °C for 36 h. At ambient temperature, the mixture was diluted with EtOAc (200 mL) and washed with H2O (3×50 mL) and brine (50 mL). The organic phase was dried over Na2SO4 and concentrated.
The residue was purified by column chromatography over silica gel (n-hexane/EtOAc 6/1) to give 148c (264 mg, 62%) as a colorless solid.
132 solvent mixture of CF3COOH/(CF3CO)2O (3.0 mL/1.0 mL) was added via cannula. The mixture was stirred at 75 °C for 48 h. At ambient temperature, the excess anhydride and acid were removed by evaporation. NEt3
(0.50 mL) was added and this mixture was dry-loaded onto silica gel and purified by column chromatography over silica gel (n-hexane/EtOAc 20/1) to give 129e (24 mg, 64%) as a colorless solid.
M. p. ˃ 300 ºC. 1H NMR (300 MHz, CDCl3) δ = 9.36 (d, J = 7.4 Hz, 1H), 7.72–7.69 (m, 1H), 7.67–7.62 (m,
The analytical data are in accordance with those previously reported in the literature.[122b, 122g]
133