Palladium-Mediated Synthesis of Calothrixin B

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

References and Notes

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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 _aH_b), 5.87 (d, J = 10 Hz, 1 H, CH_a 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 Initiator^TM 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).