Synthetic Studies on Plakinidines

Hidetoshi Tokuyama, Takahito Satoh, Touma Adachi, Kentaro Okano, Juri Sakata
2019 Heterocycles  
Synthetic studies on plakinidines are described. As a model study for the construction of the dihydropyridone ring at the final stage of the synthesis, we investigated a Meyer-Schuster rearrangement/aza-Michael cyclization cascade. The B,C,D,E ring system possessing a pyrrolo[2,3,4-kl]acridine structure was constructed via a benzyne-mediated cyclization/functionalization sequence that involved the formation of a β,β-diarylethylamine derivative and a palladium-catalyzed double aryl amination of
more » ... 3-arylindoline intermediate as key processes. N 3 Ts RO OR Br Br NHP 10 11 + MgTMP plakinidines A B C PN PHN N P NH 2 O PN PHN N P NH 2 OH 7 Meyer-Schuster rearrangement PN PHN RO OTf Br double aryl amination 9 cyclization functionalization sequence 6 PN PHN N P 8 D aza-Michael addition PN PHN N P NH O 5 RO P NH 2 HO NH O conditions 1 entry condition 18 yield (%) 12 14 p-TsOH·H 2 O, EtOH, reflux conc. HCl, H 2 O, reflux Bi(OTf) 3 , EtOH/1,2-DCE, 70 °C Sc(OTf) 3 , CH 2 Cl 2 /EtOH, 60 °C AuCl, AgSbF 6 , MeOH/H 2 O, 60 °C SnCl 2 , t-BuOH/H 2 O, reflux PtCl 2 , t-BuOH, 60 °C 2 5 6 4 7 14 34 44 10 0 66 3 NH 2 O 86% MOMO were unsuccessful. 15 These disappointing results could be attributed to the steric hindrance around the reaction site or to the electron-donating properties exerted by the four nitrogen atoms on the B ring. Scheme 3. Benzyne-mediated cyclization/functionalization sequence Scheme 4. Construction of tetracyclic core structure and attempt to introduce propargyl alcohol unit In conclusion, we have established a novel synthetic approach to construct the tetracyclic core of plakinidine. The most salient feature of our synthesis includes the efficient introduction of three nitrogen atoms in the highly fused core skeleton of plakinidine through two cyclization processes, i.e., a benzyne-mediated cyclization/functionalization sequence and a palladium-catalyzed double amination reaction. Further investigation toward the total synthesis of plakinidine alkaloids is currently ongoing in tert-Butyl 7-azido-6-(benzyloxy)-4-bromo-3-(2-(methoxymethoxy)phenyl)indoline- 1-carboxylate (23) A flame-dried 500-mL, two-necked, round-bottomed flask equipped with a magnetic stirring bar, argon gas inlet, and a rubber septum was charged with the carbamate 20 (3.35 g, 5.39 mmol), and THF (20.0 mL). The mixture was cooled in a dry ice-acetone bath, and to the solution was added Mg(TMP)2·2LiCl (0.180 M in THF, 150 mL, 27.0 mmol) at -78 °C dropwise over 5 min. The reaction mixture was allowed to warm to 0 °C and stirred for 1 h. Then, TsN 3 (8.20 mL, 53.6 mmol) was added to the reaction mixture at -78 °C, and the resulting mixture was allowed to warm to 0 °C and stirred for 1 h. The reaction was quenched with sat. aqueous ammonium chloride, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexanes-CH 2 Cl 2 = 1:1 to hexanes-EtOAc = 5:1) to afford azide 23 ( 2.80 g, 4.82 mmol, 89%) as a pale yellow oil. R f = 0.27 (hexanes-EtOAc = 5:1); IR (neat, cm -1 ): 2120, 1712, 1336, 1154, 1001, 754; 1 H NMR (400 MHz, CDCl 3 ): δ 7.52-7.15 (m, 6H), 7.10 (d, 1H, J = 8.4 Hz), 6.86-6.82 (m, 2H), 6.67 (d, 1H, J = 7.2 Hz), 5.26 (d, 1H, J = 6.4 Hz), 5.21 (d, 1H, J = 6.4 Hz), 5.12 (s, 2H), 4.54 (dd, 1H, J = 8.0, 2.0 Hz), 4.21 (dd, 1H, J = 11.2, 8.0 Hz), 4.08 (dd, 1H, J = 11.2, 2.0 Hz), 3.44 (s, 3H), 1.39 (s, 9H); 13 C NMR (100 MHz, CDCl3): δ 154.HRMS (EI) m/z: calcd. for C 28 H 29 79 BrN 4 O 5 [M + ] 580.1321, found 580.1306. tert-Butyl 7-amino-6-(benzyloxy)-4-bromo-3-(2-(methoxymethoxy)phenyl)indoline- 1-carboxylate A 50-mL, two-necked, round-bottomed flask equipped with a magnetic stirring bar, argon gas inlet, and a rubber septum was charged with azide 23 (2.30 g, 3.96 mmol), and THF (10.0 mL). To the mixture was added tri-n-butylphosphine (1.48 mL, 5.94 mmol) dropwise at 0 ºC. Nitrogen gas started to evolve within 5 min. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. To the iminophosphorane generated in situ was added H 2 O (5.00 mL), and the reaction mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with EtOAc and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexanes-EtOAc = 6:1) to afford the aniline (1.49 g, 2.68 mmol, 68%) as a white powder. HRMS (ESI) m/z: calcd. for C 28 H 32 79 Br 2 N 2 O 5 [M+H + ] 555.1489, found 555.1463. tert-Butyl 6-(benzyloxy)-4-bromo-3-(2-hydroxyphenyl)-7-((methoxycarbonyl)amino)indoline-1-carboxylate (25) A 30-mL, two-necked, round-bottomed flask equipped with a magnetic stirring bar, argon gas inlet, and a rubber septum was charged with the aniline (1.49 g, 2.68 mmol), and CH 2 Cl 2 (13.0 mL). The mixture was cooled in ice-water bath, and to the solution was added pyridine (325 µL, 4.02 mmol) and methyl chloroformate (249 µL, 3.22 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 10 minutes. The reaction was quenched with 1 M aqueous HCl and aqueous layer was extracted with CH 2 Cl 2 . The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a crude carbamate, which was used to the next reaction without further purification. A 100-mL, round-bottomed flask equipped with a magnetic stirring bar, argon gas inlet, and a rubber septum was charged with the crude carbamate, i-PrOH (65.0 mL), and THF ( 65.0 mL). To the mixture was added conc. HCl (16.8 mL, 201 mmol) at room temperature and the reaction mixture was stirred at room temperature for 40 h. The reaction mixture was diluted with EtOAc and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexanes-EtOAc = 4:1 to 2:1) to afford the phenol 25 (499 mg, 877 µmol, 33% over 2 steps from aniline) as a pink powder. R f = 0.16 (hexanes-EtOAc = 3:1); IR (neat, cm -1 ): 1699, 1684, 1507, 1457; 1 H NMR (400 MHz, CDCl 3 ): δ 7.74 (brs, 1H), 7.44-7.33 (m, 5H), 7.10 (ddd, 1H, J = 8.0, 8.0, 1.2 Hz), 6.90 (s, 1H), 6.80 (dd, 1H, J = 8.0, 6.8 Hz), 6.76 (d, 1H, J = 8.0 Hz), 6.71 (d, 1H, J = 6.8 Hz), 5.10 (s, 2H), 4.97 (brs, 1H), 4.54 (dd, 1H, J = 8.8, 2.HRMS (ESI) m/z: calcd. for C 28 H 29 79 BrN 2 NaO 6 [M+Na + ] 591.1101, found 591.1074. tert-Butyl 6-(benzyloxy)-4-bromo-7-((methoxycarbonyl)amino)-3-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)indoline-1-carboxylate (26) A 20-mL, two-necked, round-bottomed flask equipped with a magnetic stirring bar, argon gas inlet, and a rubber septum was charged with the phenol 25 (499 mg, 877 µmol), and CH 2 Cl 2 (9.00 mL). The mixture was cooled in ice-water bath, and to the solution was added Et 3 N (184 µL, 1.32 mmol) and Tf 2 O (148 µL, 880 µmol). The solution was then stirred at same temperature for 5 min. The reaction was quenched with sat. aqueous ammonium chloride and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexanes-EtOAc = 6:1) to afford the triflate 26 (551 mg, 785 µmol, 90%) as a white foam. R f = 0.35 (hexanes-EtOAc = 3:1); HRMS (ESI) m/z: calcd. for C 29 H 28 79 BrF 3 N 2 NaO 8 S [M+Na + ] 723.0594, found 723.0568. Di-tert-butyl 4-(benzyloxy)-3-((methoxycarbonyl)amino)-1,10b-dihydropyrrolo-[2,3,4-kl]acridine-2,6-dicarboxylate (27) A 20-mL, two-necked, round-bottomed flask equipped with a magnetic stirring bar, argon gas inlet, and a rubber septum was charged with Pd 2 (dba) 3 ·CHCl 3 (163 mg, 157 µmol), Xantphos (182 mg, 314 µmol), and xylene (2.60 mL). Triflate 26 (551 mg, 785 µmol), BocNH 2 (139 mg, 1.18 mmol), and K 3 PO 4 (500 mg, 2.36 mmol) were added to the reaction mixture. The reaction mixture was stirred and heated at 100 ºC for 5 h. The reaction was quenched with sat. aqueous ammonium chloride and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexanes-EtOAc = 3:1) to afford the dihydroacridine 27 (320 mg, 545 µmol, 69%) as a red foam. R f = 0.28 (hexanes-EtOAc = 3:1); IR (neat, cm -1 ): 1714, 1349, 1153, 732; 1 H NMR (400 MHz, CDCl 3 ): δ 7.84-7.60 (m, 3H), 7.50-7.22 (m, 4H), 7.17 (dd, 1H, J = 8.0, 6.4 Hz), 7.07 (s, 1H), 7.03 (d, 1H, J = 8.0 Hz), 5.11 (s, 2H), 4.87 (dd, 1H, J = 9.6, 9.6 Hz), 4.44 (dd, 1H, J = 9.6, 9.6 Hz), 4.03 (dd, 1H, J = 9.6, 9.6 Hz), 3.66 (s, 3H), 1.58 (s, 9H), 1.53 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): δ 170.7, 154.3, 153.7, 153.0, 152.mixture of two rotamer); HRMS (ESI) m/z: calcd. for C 33 H 38 N 3 O 7 [M+H + ] 588.2704, found 588.2682. Di-tert-butyl 4-hydroxy-3-((methoxycarbonyl)amino)-1,10b-dihydropyrrolo[2,3,4-kl]acridine-2,6-dicarboxylate (28) A 50-mL, two-necked, round-bottomed flask equipped with a magnetic stirring bar, argon gas inlet, and a rubber septum was charged with benzyl ether 27 (311 mg, 530 mmol), 10% palladium on activated carbon (56.4 mg, 53.0 µmol), EtOAc (2.50 mL), and EtOH (2.50 mL). The mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 10 h. The reaction mixture was filtered through a pad of Celite ® , and the filter cake was washed thoroughly with EtOAc. Then, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexanes-EtOAc = 7:1) to afford the phenol 28 ( 216 mg, 434 µmol, 82%) as a pale yellow oil. R f = 0.39 (hexanes-EtOAc = 3:1); IR (neat, cm -1 ): 3155, 1714, 1351, 1155, 733; 1 H NMR (400 MHz, CDCl 3 ): δ 9.96 (brs, 1H), 8.28 (brs, 1H), 7.74 (dd, 1H, J = 8.4, 1.2 Hz), 7.31-7.24 (m, 1H), 7.16 (ddd, 1H, J = 7.6, 7.2, 1.2 Hz), 7.09 (s, 1H), 7.01 (d, 1H, J = 7.6 Hz), 4.90 (dd, 1H, J = 10.0, 9.2 Hz), 4.40 (dd, 1H, J = 10.0, 8.8 Hz), 3.97 (dd, 1H, J = 9.2, 8.8 Hz), 3.79 (s, 3H), 1.60 (s, 9H), 1.57 (s, 9H); 13 C NMR (100 MHz, HRMS (ESI) m/z: calcd. for C 26 H 31 N 3 NaO 7 [M+Na + ] 520.2054, found 520.2043. Di-tert-butyl 4-hydroxy-3-((methoxycarbonyl)amino)-5-nitro-1,10b-dihydropyrrolo-[2,3,4-kl]acridine-2,6-dicarboxylate (29) A 20-mL, two-necked, round-bottomed flask equipped with a magnetic stirring bar, argon gas inlet, and a rubber septum was charged with Tf 2 O (73.0 µL, 434 µmol), n-Bu 4 NNO 3 (132 mg, 434 µmol), and CH 2 Cl 2 (2.00 mL). The mixture was cooled in dry ice-acetone bath, and to the reaction mixture was added phenol 28 (216 mg, 434 µmol) in CH 2 Cl 2 (2.50 mL). The reaction mixture was stirred for 10 min at same temperature for 10 min. The reaction was quenched with sat. aqueous NaHCO 3 and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexanes-EtOAc = 3:1) to afford the nitrophenol 29 (59.0 mg, 109 µmol, 25%) as a red oil. R f = 0.1 (hexanes-EtOAc = 3:1); IR (neat, cm -1 ): 2979, 1723, 1540, 1349, 1152, 732; 1 H NMR (400 MHz, CDCl 3 ): δ 10.9 (s, 1H), 8.27 (brs, 1H), 7.87 (d, 1H, J = 7.2 Hz), 7.36 (dd, 1H, J = 8.4, 7.2 Hz), 7.33-7.20 (m, 1H), 7.08 (d, 1H, J = 8.0 Hz), 4.87 (dd, 1H, J = 10.8, 9.6 Hz), 4.46 (dd, 1H, J = 10.0, 9.6 Hz), 4.11 (dd, 1H, J = 10.8, 10.0 Hz), 3.74 (s, 3H), 1.60 (s, 9H), 1.45 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): δ 154.8, 152.7, 151.3, 151.HRMS (ESI) m/z: calcd. for C 26 H 30 N 4 NaO 9 [M+Na + ] 565.1905, found 565.1901. Di-tert-butyl 5-amino-4-hydroxy-3-((methoxycarbonyl)amino)-1,10b-dihydropyrrolo-[2,3,4-kl]acridine-2,6-dicarboxylate A 10-mL, Schlenk tube equipped with a magnetic stirring bar, argon gas inlet, and a rubber septum was charged with nitrophenol 29 (55.7 mg, 103 µmol), 10% palladium on activated carbon (11.0 mg, 10.3 µmol), EtOAc (500 µL), and EtOH (500 µL). The mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 2 h. The reaction mixture was filtered through a pad of Celite ® , and the filter cake was washed thoroughly with EtOAc. Then, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexanes-EtOAc = 3:1) to afford aminophenol (43.6 mg, 85.1 µmol, 83%) as a pale yellow solid. R f = 0.31 (hexanes-EtOAc = 3:1); HRMS (ESI) m/z: calcd. for C 26 H 33 N 4 O 7 [M+H + ] 513.2344, found 513.2377. Di-tert-butyl 5-amino-3-((methoxycarbonyl)amino)-4-(((trifluoromethyl)sulfonyl)oxy)- 1,10b-dihydropyrrolo[2,3,4-kl]acridine-2,6-dicarboxylate (30) A 30-mL, two-necked, round-bottomed flask equipped with a magnetic stirring bar, argon gas inlet, and a rubber septum was charged with aminophenol (43.0 mg, 83.9 µmol), and CH 2 Cl 2 (800 µL). The mixture was cooled in a dry ice-acetone bath, to the solution was added Et 3 N (14.0 µL, 100 µmol) and Tf 2 O (14.0
doi:10.3987/com-18-s(f)26 fatcat:sv4z6xjsxnhqvaspibjwaubcge