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Synlett 2007(12): 1935-1939  
DOI: 10.1055/s-2007-984520
LETTER
© Georg Thieme Verlag Stuttgart · New York

Palladium-Mediated Synthesis of Calothrixin B

Paul H. Bernardo, Wuri Fitriyanto, Christina L. L. Chai*
Institute of Chemical and Engineering Sciences, 1 Pesek Road, Jurong Island, 627833 Singapore
Fax: +6563166184; e-Mail: Christina_Chai@ices.a-star.edu.sg;
Further Information

Publication History

Received 30 April 2007
Publication Date:
25 June 2007 (online)

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Abstract

An efficient synthesis of the indolo[3,2-j]phenanthridine alkaloid calothrixin B is described. The relative ease and high yields of this synthesis make this an attractive route for the preparation of calothrixin B derivatives for structure-activity relationship studies.

Key words

cyclizations - palladium-catalyzed reactions - fused-ring systems - natural products - quinones

10

3-Bromo- N -(2-iodophenyl)-2,5-dimethoxybenzamide ( 14): 3-Bromo-2,5-dimethoxybenzoic acid (12, 1 g, 3.8 mmol) was dissolved in SOCl2 (25 mL) and refluxed for 30 min under argon. The reaction mixture was cooled to r.t., and the solvent was quickly removed in vacuo. The residue was dissolved in anhyd THF (20 mL) and kept under argon. To this solution were added 2-iodoaniline (0.84 g, 3.8 mmol) and anhyd K2CO3 (1.05 g, 7.6 mmol). The reaction mixture was stirred for a further 16 h. The reaction was quenched with sat. NaHCO3 solution (10 mL) and the organic layer was separated. The aqueous layer was further extracted with EtOAc (2 × 20 mL). The combined organic layer was dried with MgSO4, filtered, and the solvent was removed in vacuo to obtain the crude product. Flash chromatography on silica gel (EtOAc-hexanes, 2:3) gave the title compound as a cream-colored solid (1.61 g, 3.5 mmol, 91% yield); R f 0.83 (EtOAc-hexanes, 2:3); mp 99-101 °C. 1H NMR (300 MHz, CDCl3): δ = 3.82 (s, 3 H, OMe), 3.96 (s, 3 H, OMe), 6.91 (m, 1 H, ArH), 7.30-7.43 (m, 2 H, ArH), 7.66 (s, 1 H, ArH), 7.86 (m, 1 H, ArH), 8.49 (d, J = 8 Hz, 1 H, ArH), 10.11 (s, 1 H, NH). 13C NMR (75 MHz, CDCl3; rotamer 1): δ = 55.8 (OMe), 62.8 (OMe), 99.6, 111.9, 117.8, 121.0, 126.0, 129.5, 130.4, 132.1, 139.9, 140.4, 147.3, 155.3, 168.0 (CO). 13C NMR (75 MHz, CDCl3; rotamer 2): δ = 55.9, 62.7, 89.4, 115.0, 118.2, 122.4, 123.6, 128.0, 129.0, 130.0, 139.2, 139.3, 148.6, 156.3, 162.4. MS (EI): m/z (%) = 463 (100) [M+], 461 (100) [M+], 459 (95) [M - H]+, 458 (90) [M - H]+, 446 (68), 444 (68). Two molecular ion peaks [M+] and two [M - OMe]+ peaks were observed due to 81Br and 79Br isotopes. HRMS (EI): m/z calcd for C15H13 79BrINO3: 460.9124; found: 460.9127. FTIR (KBr): 724 (w), 755 (w), 784 (w), 863 (w), 992 (m), 1042 (m), 1239 (m), 1295 (m), 1420 (m), 1471 (s), 1525 (m), 1599 (m), 1678 (m), 1713 (m), 2853 (m), 2925 (m), 3436 (br) cm-1.
3-Bromo- N -(2-iodophenyl)-2,5-dimethoxy- N -methoxy-methylbenzamide ( 16): To a solution of 3-bromo-N-(2-iodophenyl)-2,5-dimethoxybenzamide (14, 0.88 g, 1.9 mmol) in anhyd THF (10 mL) under nitrogen were added MOMCl (0.30 mL, 3.9 mmol) and NaH (0.10 g, 4.1 mmol). The reaction mixture was stirred for 16 h at 30 °C following which the reaction mixture was poured into a sat. NaHCO3 solution (20 mL) to quench the reaction. The organic layer was separated and the aqueous layer was further re-extracted with CH2Cl2 (3 × 15 mL). The combined organic layers were dried with MgSO4, filtered and the solvent was removed in vacuo to yield the crude product. Column chromatography on silica gel (EtOAc-hexanes, 2:3) gave the desired compound as a viscous yellow oil which solidified upon standing (0.93 g, 1.8 mmol, 98% yield). Two distinct sets of methoxy signals (three methoxy signals per set) in a ratio of 4:1 were observed in the 1H NMR spectrum which suggested the presence of rotamers, but the aromatic hydrogen signals overlapped. The 13C NMR spectrum showed distinct sets of signals for each rotamer; the carbon resonances of each rotamer are reported below.
R f 0.72 (EtOAc-hexanes, 2:3); mp 40-42 °C. 1H NMR (300 MHz, CDCl3): δ = 3.62 (s, 3 H, OMe), 3.66, 3.78 (s, 3 H, OMe), 3.80, 3.93 (s, 3 H, OMe), 4.60 (d, J = 10 Hz, 1 H, CH aHb), 5.87 (d, J = 10 Hz, 1 H, CHa H b), 6.88-6.91 (m, 2 H, ArH), 7.00-7.08 (m, 1 H, ArH), 7.20 (m, 1 H, ArH), 7.36-7.39 (m, 1 H, ArH), 7.74 (d, J = 8 Hz, 1 H, ArH). 13C NMR (75 MHz, CDCl3; rotamer 1): δ = 55.6 (OMe), 56.7 (OMe), 62.3 (OMe), 76.6 (CH2), 99.5, 109.5, 117.1, 119.9, 128.8, 129.9, 131.3, 132.7, 139.2, 141.8, 146.1, 155.3, 168.2 (CO). 13C NMR (75 MHz, CDCl3; rotamer 2): δ = 55.6 (OMe), 56.7 (OMe), 62.8 (OMe), 76.6 (CH2), 99.5, 111.7, 112.5, 117.6, 120.8, 129.3, 129.9, 131.6, 132.0, 139.7, 147.1, 155.2, 167.8 (CO). MS (EI): m/z (%) = 507 (15) [M+], 505 (15) [M+], 380 (42) [M - I]+, 378 (42) [M - I]+, 245 (97), 243 (100), 45 (92). Two molecular ion peaks [M+] and two [M - I]+ peaks were observed due to 81Br and 79Br isotopes. HRMS (EI): m/z calcd for C17H17 79BrINO4: 504.9380; found: 504.9380. FTIR (KBr): 648 (w), 681 (w), 725 (w), 747 (w), 856 (w), 911 (w), 994 (m), 1018 (m), 1044 (s), 1082 (s), 1225 (s), 1278 (m), 1306 (m), 1374 (m), 1420 (s), 1473 (s), 1562 (w), 1598 (m), 1669 (s), 2831 (w), 2937 (m), 3436 (br) cm-1. Anal. Calcd for C17H17BrINO4: C, 40.34; H, 3.39; N, 2.77. Found: C, 40.66; H, 3.48; N, 2.48.
8-Bromo-7,10-dimethoxy-5-methoxymethyl-phenanthridin-6-one ( 18): To a solution of the tertiary benzamide 16 (0.18 g, 0.35 mmol) in degassed anhyd DMF (15 mL) were added PPh3 (28 mg, 0.11 mmol), anhyd K2CO3 (97 mg, 0.70 mmol) and Pd(OAc)2 (8 mg, 0.035 mmol). The reaction mixture was stirred at 100 °C under an argon atmosphere for 16 h following which the reaction mixture was cooled to r.t. and filtered through Celite. An aliquot of acetone (10 mL) was filtered through the Celite, and the combined filtrates were removed under reduced pressure to yield the crude product. Purification via column chromatography on silica gel (EtOAc-hexanes, 1:1) gave the desired compound as a brown solid (0.12 g, 0.32 mmol, 92% yield); R f 0.74 (EtOAc-hexanes, 1:1); mp 102-104 °C. 1H NMR (400 MHz, CDCl3): δ = 3.51 (s, 3 H, OMe), 3.95 (s, 3 H, OMe), 4.03 (s, 3 H, OMe), 5.77 (s, 2 H, CH2), 7.25-7.29 (m, 2 H, ArH), 7.49 (s, 1 H, ArH), 7.52-7.58 (m, 1 H, ArH), 9.13 (d, J = 8 Hz, 1 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 56.4 (OMe), 56.7 (OMe), 61.7 (OMe), 74.2 (CH2), 115.1, 118.1, 118.4, 119.9, 121.3, 122.5, 125.4, 128.7, 129.3, 136.7, 152.0, 153.4, 159.5 (CO). MS (EI): m/z (%) = 379 (90) [M+], 377 (86) [M+], 347 (50), 345 (48), 336 (52), 334 (68), 319 (100), 317 (88), 304 (73). HRMS (EI): m/z calcd for C17H16 79BrNO4: 377.0263; found: 377.0265. HRMS (EI): m/z calcd for C17H16 81BrNO4: 379.0242; found: 379.0252. FTIR (KBr): 758 (w), 1052 (s), 1076 (s), 1224 (m), 1276 (w), 1297 (w), 1363 (w), 1458 (s), 1655 (s), 2824 (w), 2932 (w), 2962 (w), 3435 (br) cm-1. Anal. Calcd for C17H16BrNO4: C, 53.99; H, 4.26; N, 3.70. Found: C, 53.84; H, 4.56; N, 3.68.
8-(Nitrophenyl-2-yl)-7,10-dimethoxy-5-methoxymethyl-phenanthridin-6-one ( 27): To a rigorously degassed solution of the 8-bromophenanthridinone 18 (0.1 g, 0.26 mmol) in DMF (10 mL) were added K2CO3 (73 mg, 0.53 mmol), PPh3 (21 mg, 0.082 mmol, 30 mol%), and Pd(OAc)2 (6 mg, 0.026 mmol, 10 mol%). To the reaction mixture was added nitrophenyl-2-boronic acid (26, 2 equiv). The reaction mixture was stirred at 150 °C for 16 h under argon. The reaction mixture was cooled to r.t. and sat. NaHCO3 (10 mL) was added. The solvent was then removed under reduced pressure, and the residue was partitioned between CHCl3 (20 mL) and sat. NaHCO3 (20 mL). The aqueous layer was further extracted with CHCl3 (2 × 20 mL) and the combined organic layer was dried with MgSO4, filtered, and the solvent was removed in vacuo to obtain the crude product. Purification by column chromatography on silica gel gave the desired product as a yellow solid (0.106 g, 0.25 mmol, 96% yield); R f 0.34 (EtOAc-hexanes, 1:2); mp 146-148 °C. 1H NMR (400 MHz, CDCl3): δ = 3.51 (s, 3 H, OMe), 3.56 (s, 3 H, OMe), 4.02 (s, 3 H, OMe), 5.78 (br s, 2 H, NCH2), 7.18 (s, 1 H, ArH), 7.26 (app. t, J = 7 Hz, 1 H, ArH), 7.50 (app. t, J = 7 Hz, 1 H, ArH), 7.52 (m, 3 H, ArH), 7.69 (app. t, J = 7 Hz, 1 H, ArH), 8.05 (d, J = 7 Hz, 1 H, ArH), 9.20 (d, J = 8 Hz, 1 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 56.4 (OMe), 56.7 (OCMe), 61.6 (OMe), 74.1 (CH2), 115.1, 116.5, 118.5, 120.3, 122.5, 124.3, 126.1, 128.7, 128.8, 129.3, 132.3, 132.4, 132.5, 132.7, 136.9, 149.2, 151.9, 153.2, 160.2 (CO). MS (EI): m/z (%) = 420 (40) [M+], 405 (25) [M - OMe]+, 393 (30), 381 (45), 343 (56), 331 (52), 293 (100), 281 (77), 269 (43), 243 (85), 231 (97), 219 (80). HRMS (EI): m/z calcd for C23H20N2O6: 420.1321; found: 420.1363. Anal. Calcd for C23H20N2O6: C, 65.71; H, 4.79; N, 6.66. Found: C, 65.30; H, 4.97; N, 6.25.
Intramolecular Cyclization of the Nitrophenylphen-anthridinone 27 via Microwave-Assisted Cadogan Reaction: A solution of 8-(nitrophenyl-2-yl)-7,10-dimeth-oxy-5-methoxymethylphenanthridin-6-one (27, 0.10 g, 0.24 mmol) in triethylphosphite (1 mL) was heated at 174 °C for 1 h in a sealed vessel using the Biotage InitiatorTM EXP microwave reactor. The reaction mixture was cooled to r.t. and the solvent was removed in vacuo. The residue was partitioned between CHCl3 (10 mL) and sat. NaHCO3 (10 mL). The organic layer was dried with MgSO4, filtered, and the solvent was removed. Purification via column chromatography on silica gel (EtOAc-hexanes, 1:1) gave the desired product 25 as a yellow solid (82 mg, 0.21 mmol, 89% yield); R f 0.21 (EtOAc-hexanes, 1:3). 1H NMR (400 MHz, CDCl3): δ = 3.55 (s, 3 H, OMe), 3.90 (s, 3 H, OMe), 4.20 (s, 3 H, OMe), 5.82 (br s, 2 H, NCH2), 7.28-7.36 (m, 2 H, ArH), 7.48 (m, 3 H, ArH), 7.59 (d, J = 8 Hz, 1 H, ArH), 8.42 (d, J = 8 Hz, 1 H, ArH), 8.67 (br s, 1 H, NH), 9.17 (d, J = 8 Hz, 1 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 56.6 (OMe), 60.2 (OMe), 61.6 (OMe), 73.8 (CH2), 110.7, 111.3, 115.3, 118.8, 118.9, 121.0, 122.8, 122.8, 123.7, 125.0, 126.9, 127.4, 129.0, 136.6, 137.8, 138.3, 139.9, 155.7, 161.1 (CO). MS (ESI): m/z (%) = 412 (38) [M + Na]+, 390 (100) [M + H]+. HRMS (ESI): m/z [M+ H]+ calcd for C23H20N2O4: 389.1496; found: 389.1499.
LiAlH 4 -Mediated Reduction of the Pentacyclic Lactam 25 to 7,10-dimethoxyindolo[3,2- j ]phenanthridine ( 8): To a solution of the lactam 25 (10 mg, 0.026 mmol) in anhyd Et2O (1 mL) at 0 °C were added freshly crushed pellets of LiAlH4 (3 mg, 0.08 mmol). The reaction mixture was warmed to r.t. and stirred for a further 1 h. The reaction was stopped by the careful addition of distilled H2O (1 mL). The reaction was then acidified to pH 1 using 6 N HCl. The mixture was stirred for a further 1 h. The reaction mixture was then made basic by the slow addition of 1 M NaOH until a clear biphasic solution was obtained. The organic layer was separated, and the aqueous layer was further extracted with EtOAc (10 mL). The combined organic layer was dried with MgSO4 and filtered. The solvent was removed in vacuo to obtain the crude product; R f 0.86 (EtOAc-hexanes, 1:1). 1H NMR (400 MHz, CDCl3): δ = 4.07 (s, 3 H, OMe), 4.16 (s, 3 H, OMe), 7.01 (app. t, J = 7 Hz, 1 H, ArH), 7.48 (m, 2 H, ArH), 7.70 (app. t, J = 7 Hz, 1 H, ArH), 7.92 (d, J = 8 Hz, 1 H, ArH), 8.02 (d, J = 8 Hz, 1 H, ArH), 8.09 (d, J = 8 Hz, 1 H, ArH), 8.95 (d, J = 8 Hz, 1 H, ArH), 9.57 (br s, 1 H, ArH), 11.07 (br s, 1 H, NH).
Conversion of 8 into Calothrixin B ( 2): To a solution of the crude dimethyl ether 8 in anhyd CH2Cl2 (1 mL) at 0 °C was added 1 M BBr3 (0.1 mL). The reaction mixture was warmed to r.t. and stirred for 1 h. The reaction was stopped by the addition of anhyd MeOH (1 mL) and stirred in the presence of air for 1 h. The solvent was carefully removed in vacuo, and the residue was partitioned between sat. NaHCO3 (10 mL) and EtOAc (10 mL). The organic layer was dried with MgSO4 and filtered, and the solvent was removed under reduced pressure. Purification by column chromatography on silica gel yielded calothrixin B as a red solid (7.5 mg, 0.025 mmol, 97% yield over 2 steps from 25); R f 0.47 (EtOAc-hexanes, 1:2); mp >>300 °C (Lit. [1] >>300 °C). 1H NMR (400 MHz, DMSO-d): δ = 7.40 (app. t, J = 7 Hz, 1 H, ArH), 7.47 (app. t, J = 7 Hz, 1 H, ArH), 7.62 (d, J = 8 Hz, 1 H, ArH), 7.89 (app. t, J = 8 Hz, 1 H, ArH), 7.96 (app. t, J = 8 Hz, 1 H, ArH), 8.17 (d, J = 8 Hz, 1 H, ArH), 8.18 (d, J = 8 Hz, 1 H, ArH), 9.58 (d, J = 9 Hz, 1 H, ArH), 9.62 (s, 1 H, ArH).