Total Synthesis of Aspidofractinine Alkaloid Paucidirinine - The

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Total Synthesis of Aspidofractinine Alkaloid Paucidirinine Weiwei Zhang, Shanhao Lin, Chenglong Du, Shangbiao Feng, Zaimin Liu, Jing Zhang, Xingang Xie, Xiaolei Wang, Huilin Li, and Xuegong She* State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China

J. Org. Chem. 2019.84:1111-1116. Downloaded from pubs.acs.org by IOWA STATE UNIV on 01/18/19. For personal use only.

S Supporting Information *

ABSTRACT: The first total synthesis of paucidirinine (1d), a highly congested aspidofractinine alkaloid containing a special contracted five-membered lactam ring, was achieved in 10 steps with 8% overall yield from commercially available materials. Several key maneuvers, including tandem enamination/[4 + 2] cycloaddition reaction and SmI2-promoted radical cyclization, were featured in this potentially scalable strategy.

T

stimulated synthetic efforts by Ban,4a,b Cartier,4c Dufour,4d Wenkert.4e Other approaches to various members of this family of alkaloids have been reported.5−7 Recently, a new member of this family, paucidirinine (1d) bearing a special contracted five-membered lactam ring on this cage-like skeleton,8 was isolated from the stem bark of Kopsia paucif lora. The relative configuration was further confirmed through single-crystal X-ray diffraction analysis. The novel structural features and potent biological activity have defined paucidirinine (1d) as an attractive target alkaloid for total synthesis.2 Herein, we report the first total synthesis of paucidirinine (1d) utilizing highly stereocontrolled Diels−Alder reaction and SmI2-promoted radical cyclization. Our retrosynthetic analysis for the total synthesis of paucidirinine(1d) is shown in Scheme 1. It was envisioned that paucidirinine (1d) could be obtained from lactam 3 through radical cyclization. The alkyl iodide 3 would arise from 4 through p-toluenesulfonic acid catalyzed lactamization and subsequent PMB protection/TBS cleavage/iodination. As for the preparation of 4, it could in turn be obtained from the known amine 6 and aldehyde 7 through a cascade enamination/Diels−Alder cyclization. As depicted in Scheme 2, our synthesis commenced from 1,4-butanediol 8. Installation of a TBS group on one hydroxyl group yielded alcohol 9.7 Oxidation of alcohol 9 with DMP under Dess−Martin conditions afforded aldehyde 10 in 85% yield.9 Then treatment of aldehyde 10 with bromoacetate 11 produced aldehyde 7 successfully in 61% yield.10 The synthesis of key indole precursor 6 is shown in Scheme 3, where tryptamine hydrochloride salt 12 was treated with methyl 3-bromo-2-oxopropanoate 13 under Pictet−Spengler

he aspidofractinine alkaloids (1a−i, Figure 1) are a class of structurally complex alkaloids isolated from the leaves

Figure 1. Structures of the representative aspidofractinine alkaloids.

of Pleiocarpa tubicana and Aspidosperma refractum.1 Related investigations showed that they exhibit significant biological activity and medicinal properties.2 In particular, many members of this family were found to reverse multidrug resistance in vincristine-resistant KB cells.3 The characteristic biological activities and the interesting architectures have © 2018 American Chemical Society

Received: November 27, 2018 Published: December 18, 2018 1111

DOI: 10.1021/acs.joc.8b03023 J. Org. Chem. 2019, 84, 1111−1116

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The Journal of Organic Chemistry

condensation conditions to deliver bromide 14 in 81% yield.11,12 To construct the seven-membered ring, the ringexpansion was successfully achieved under hot pyridine, affording the enamine 15 in 85% yield. Finally, the desired amine 6 was readily accessed via reduction with NaBH3CN in 98% yield. With amine 6 and aldehyde 7 in hand, we set our sights on accessing the elusive synthesis of paucidirinine (1d). Initially, we expected amine 6 to react with aldehyde 7 to directly deliver lactam 16 under a catalytic amount of p-toluenesulfonic acid successively in one pot; unfortunately, this process gave less than 20% yield. To our delight, a Diels−Alder reaction between 6 and a slight excess aldehyde 7 was found to be viable and delivered the cycloadduct 4 (cis/trans = 2:1) (Scheme 4).13 Use of a catalytic amount of p-toluenesulfonic

Scheme 1. Retrosynthetic Analysis of the Paucidirinine (1d)

Scheme 4. Synthesis of the Vital Pentacyclic Intermediate

Scheme 2. Synthesis of the Aldehyde 7

Scheme 3. Preparation of the Key Indole Precursor 6 acid in toluene under air proceeded smoothly, and only the cis diastereomer delivered the key intermediate pentacyclic 16.14 In this process, other acids, for instance, trifluoroacetic acid, hydrochloric acid, or acetic acid, were also screened; all gave lower conversion and resulted in the decomposition of 4 and the deprotection of the hydroxyl group. Then a pmethoxybenzyl group was initially introduced to the indole nitrogen atom in 1615 and lactam 17 was directly used in the next step without further purification, affording the desired alcohol 18 in 72% overall yield for two steps. To construct the critical bicyclic [2.2.2]octane core structure using radical cylization (Scheme 5), the alcohol 18 was initially converted into the methyl dithiocarbonate.16 However, both nBu3SnH/AIBN and SmI2 conditions failed to give the desired cyclized product. Then the radical precursor was changed to alkyl iodide 19 through the common Appel reaction.17,18 Gratifyingly, treatment of 19 with SmI2 (THF/HMPA = 10:1) at 25 °C for 1 h smoothly afforded the desired cycloadduct 2 in 67% yield in two steps.19 In the end, removal of the p1112

DOI: 10.1021/acs.joc.8b03023 J. Org. Chem. 2019, 84, 1111−1116

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The Journal of Organic Chemistry

(ESIMS): calcd for C14H16BrN2O2 [M + H]+ 323.0390, found 323.0382. Mp: 135−137 °C. (E)-Methyl 1,2,3,6-Tetrahydroazepino[4,5-b]indole-5-carboxylate (15). The solution of 14 (2.63 g, 8.16 mmol) in pyridine (10 mL) was refluxed under argon atmosphere for 30 min. After being cooled to rt, the solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (20 mL), washed with water (3 × 10 mL), and then dried over anhydrous Na2SO4. After removal of the solvent under reduced pressure, the crude product was purified by column chromatography on silica gel with petroleum−ethyl acetate (1:1 v/v as the eluent to give pure 15 (1.68 g, 85%) as a yellow foam. 1 H NMR (400 MHz, CDCl3): δ 10.43 (s, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.11−7.02 (m, 2H), 5.25 (s, 1H), 3.79 (s, 3H), 3.54 (dd, J = 8.9, 4.5 Hz, 2H), 3.19−3.10 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 171.9, 136.2, 128.2, 126.6, 122.9, 119.9, 118.8, 112.5, 111.2, 63.3, 53.3, 50.4, 40.4, 21.9. IR (KBr) ν (cm−1) 3387, 3052, 2948, 1666, 1606, 1457, 1434, 1296, 1255, 1138, 741. HRMS (ESIMS): calcd for C14H15N2O2 [M + H]+ 243.1128, found 243.1129. Methyl 1,2,3,4,5,6-Hexahydroazepino[4,5-b]indole-5-carboxylate (6). To a stirred slurry of compound 15 (1.675 g, 6.92 mmol) in glacial acetic acid (20 mL) was added sodium cyanoborohydride (1.21 g, 19.24 mmol) in small portions over the period of 30 min. Concentrated hydrochloric acid was added slowly into the reaction mixture, with cooling, until the gas evolution ceased. The reaction mixture was then concentrated under reduced pressure. The residue was poured onto ice and basified with ammonium hydroxide. The aqueous solution was then extracted with CH2Cl2 (3 × 15 mL). The combined organic phase was dried over anhydrous Na2SO4. After removal of the solvent, the expected product 6 (1.65 g, 98%) was obtained as a yellow foam. 1H NMR (400 MHz, CDCl3): δ 8.32 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.12 (dt, J = 20.9, 7.0 Hz, 2H), 3.84 (dd, J = 4.3, 2.9 Hz, 1H), 3.71 (s, 3H), 3.59 (dd, J = 13.8, 4.6 Hz, 1H), 3.35−3.27 (m, 1H), 3.23 (dd, J = 13.8, 2.7 Hz, 1H), 3.02−2.85 (m, 3H), 2.14 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 172.3, 134.9, 131.8, 128.6, 121.7, 119.3, 118.2, 114.5, 110.6, 52.3, 50.7, 49.7, 48.2, 27.8. IR (KBr): ν (cm−1) 3316, 3055, 2956, 1732, 1613, 1460, 1378, 1188, 740. HRMS (ESIMS): calcd for C14H17N2O2 [M + H]+ 245.1285, found 245.1279. 4-((tert-Butyldimethylsilyl)oxy)butan-1-ol (9). To a solution of 1,4-butanediol (9.27 g, 103 mmol) 8 in THF (515 mL, 0.2 M) at 0 °C was added NaH (4.53 g, 60% dispersion in mineral oil, 113.3 mmol). The reaction mixture was stirred at 0 °C for 30 min, warmed to rt, and stirred for 2 h. TBSCl (17.0 g, 108 mmol) was then added, and the solution was stirred at rt for 14 h. The reaction mixture was poured into water (200 mL) and extracted with Et2O (3 × 150 mL). The combined organic phases were dried over Na2SO4, and the solvent was removed by rotary evaporation. The resulting residue was purified by flash chromatography (5:1 hexanes/EtOAc eluent), producing alcohol 9 (20.20 g, 96%) as a colorless oil. 4-((tert-Butyldimethylsilyl)oxy)butanal (10). The monoprotected diol 9 (1.00 g, 4.90 mmol) was dissolved in CH2Cl2 (50 mL) and treated with Dess−Martin periodinane (2.18 g, 5.15 mmol) at rt. The reaction mixture was stirred for 30 min at this temperature. Then Et2O (50 mL) and aq saturated NaHCO3 solution (25 mL) were added. The organic layer was separated, washed with aq saturated NaHCO3 solution and H2O, and dried with Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (EtOAc/hexanes = 1:5) to give 841.3 mg (4.17 mmol, 85%) of the desired aldehyde 10. 1H NMR (400 MHz, CDCl3): δ 9.77 (s, 1H), 3.63 (t, J = 6.0 Hz, 2H), 2.48 (td, J = 7.1, 1.2 Hz, 2H), 1.85 (dd, J = 13.0, 6.5 Hz, 2H), 0.86 (s, 9H), 0.02 (s, 6H). 13 C{1H} NMR (101 MHz, CDCl3): δ 202.6, 62.0, 40.7, 25.9, 25.4, 18.2, −5.5. IR (KBr) ν (cm−1) 2956, 2927, 2856, 1731, 1101. HRMS (ESIMS): calcd for C10H23O2Si [M + H]+ 203.1462, found 203.1461. Methyl 5-((tert-Butyldimethylsilyl)oxy)-3-formylpentanoate (7). A mixture of an aldehyde 10 (2.26 g, 11.19 mol) and diisobutylmine (2.34 mL, 13.43 mmol) in benzene (30 mL) was refluxed under a water separator for 6 h, and then a solution of the methyl bromoacetate 11 (1.6 mL, 16.79 mmol) in acetonitrile (10 mL)

Scheme 5. Completion of the Total Synthesis of Paucidirinine

methoxybenzyl group afforded the final product paucidirinine (1d) in 76% yield.20 In summary, the first total synthesis of paucidirinine was achieved in a 10-step linear sequence with 8% overall yield from commercially available tryptamine hydrochloride salt. The synthetic route features several key transformations, including a tandem intramolecular [4 + 2] cycloaddition reaction to construct the fused 6/5/6/5 ring system, a subsequent lactamization to assemble the pentacyclic key intermediate, and a challenging late-stage SmI2-promoted radical cyclization reaction to generate the bicyclic [2.2.2] central octane. The asymmetric synthesis of aspidofractinine alkaloids is currently underway in our laboratory.

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EXPERIMENTAL SECTION

General Information. All reactions sensitive to air or moisture were carried out under argon atmosphere in dry and freshly distilled solvents under anhydrous conditions, unless otherwise noted. Column chromatography was performed on silica gel (200−300 mesh). 1H and 13C NMR spectra were obtained using 600, 400, and 100 MHz NMR spectrometers, respectively. Chemical shifts (δ) are given in ppm with reference to solvent signals [1H NMR: CDCl3 (7.26); 13C NMR: CDCl3 (77.0)]. The high-resolution mass spectra (HRMS) were recorded on an FT-ICR mass spectrometer using electrospray ionization (ESI). Melting points were measured on a melting point apparatus and are uncorrected. Experimental Procedures. Methyl 1-(Bromomethyl)-2,3,4,9tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate (14). A mixture of tryptamine hydrochloride salt 12 (9.80 g, 50 mmol), methyl bromopyruvate 13 (7.2 mL, 60 mmol), and decolorizing charcoal (0.5 g) in anhydrous MeOH (120 mL) was heated at reflux for 18 h under argon atmosphere. The resulting mixture was cooled to rt, filtered, and concentrated under reduced pressure to ∼20 mL and then diluted with water (150 mL). Concentrated ammonium hydroxide was added slowly until the aqueous phase became strongly basic. The resulting mixture was filtered, and the filtrate was rinsed with 5 mL of ether. Recrystallization from acetone/water afforded 6.94 g of yellow crystalline product 14. On concentration under reduced pressure, a further 6.10 g of product 14 was obtained as above for a combined yield of 81%. 1H NMR (400 MHz, CDCl3): δ 8.33 (s, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 4.22 (d, J = 10.8 Hz, 1H), 3.85 (s, 3H), 3.79 (d, J = 10.8 Hz, 1H), 3.25 (t, J = 5.6 Hz, 2H), 3.05 (br, s, 1H), 2.80 (td, J = 5.5, 2.8 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 171.9, 136.2, 128.2, 126.6, 122.9, 119.9, 118.8, 112.5, 111.2, 63.3, 53.3, 50.4, 40.4, 21.9. IR (KBr) ν (cm−1) 3392, 3251, 3055, 2953, 1741, 1604, 1453, 1436, 1297, 1256, 1138, 742. HRMS 1113

DOI: 10.1021/acs.joc.8b03023 J. Org. Chem. 2019, 84, 1111−1116

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The Journal of Organic Chemistry

pressure. The residue was purified by flash column chromatography to afford alcohol 18 (264.0 mg, 72%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.27 (dd, J = 8.6, 5.9 Hz, 2H), 7.06−6.97 (m, 3H), 6.89 (d, J = 8.1 Hz, 1H), 6.78 (t, J = 5.7 Hz, 2H), 5.22−5.03 (m, 2H), 4.22−4.06 (m, 1H), 3.90 (s, 1H), 3.76 (d, J = 6.9 Hz, 3H), 3.55 (s, 3H), 3.45 (t, J = 6.7 Hz, 2H), 3.30−3.17 (m, 1H), 2.79−2.64 (m, 2H), 2.22 (d, J = 15.9 Hz, 1H), 1.97 (d, J = 16.3 Hz, 1H), 1.92−1.83 (m, 2H), 1.27 (dd, J = 7.3, 5.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 176.6, 167.3, 158.7, 146.8, 136.2, 128.7, 128.3, 128.2, 121.6, 121.2, 113.7, 109.3, 94.5, 74.3, 59.1, 55.9, 55.2, 51.3, 49.1, 44.5, 43.6, 43.4, 42.9, 36.7, 31.6. IR (KBr) ν (cm−1) 3403, 3053, 2955, 1682, 1646, 1592, 1463, 1378, 1265, 740. HRMS (ESIMS): calcd for C28H31N2O5 [M + H]+ 475.2227, found 475.2227. Methyl (2aR,2a1S,9bR)-2a-(2-Iodoethyl)-5-(4-methoxybenzyl)-1oxo-1,2,2a,2a1,3,5,10,11-octahydropyrrolizino[1,7-cd]carbazole-4carboxylate (19). A round-bottom flask was charged with 18 (0.038 mmol, 18.0 mg) and CH2Cl2 (15 mL). The solution was cooled to 0 °C and PPh3 (0.057 mmol, 15.0 mg) and imidazole (0.084 mmol, 6.0 mg) were added, followed by the portionwise addition of iodine (0.076 mmol, 20.0 mg). The solution was allowed to warm to room temperature and stirred at this temperature for 1 h. The reaction mixture was quenched with 10% (aq) Na2S2O3 (5 mL), the organic layer was isolated, and the resulting aqueous layer was further extracted two more times with CH2Cl2 (15 mL). The combined organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 19 (19.0 mg, 86%) as a yellow oil, which was immediately used in the following step. Methyl (2aR,2a1S,4R,4aR,9bR)-5-(4-Methoxybenzyl)-1-oxo1,2,3,4,10,11-hexahydro-2a1H,5H-2a,4a-ethanopyrrolizino[1,7-cd]carbazole-4-carboxylate (2). A solution of 19 (44.0 mg, 0.075 mmol) in degassed THF (6 mL) under argon was treated with HMPA (1.2 mL) followed by SmI2 (6 mL, 0.1 M in THF, 0.6 mmol). The reaction mixture was allowed to stir under Ar for 30 min before the reaction was quenched with the addition of 10 mL of saturated aqueous NaHCO3 and extracted with EtOAc (6 mL × 3). The combined organic phase was washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 2 (27.0 mg, 78%) as a white solid. 1H NMR (600 MHz, CDCl3): δ 7.21 (d, J = 8.7 Hz, 2H), 7.09 (dd, J = 7.2, 1.0 Hz, 1H), 6.96 (td, J = 7.7, 1.3 Hz, 1H), 6.90−6.84 (m, 2H), 6.74 (td, J = 7.4, 0.9 Hz, 1H), 6.11 (d, J = 7.8 Hz, 1H), 4.60 (d, J = 15.3 Hz, 1H), 4.09 (dd, J = 11.7, 8.1 Hz, 1H), 3.85 (t, J = 7.6 Hz, 2H), 3.80 (s, 3H), 3.30−3.23 (m, 4H), 3.19−3.10 (m, 1H), 3.06 (t, J = 9.7 Hz, 1H), 2.54 (d, J = 14.7 Hz, 1H), 2.34−2.24 (m, 1H), 2.06 (d, J = 14.6 Hz, 1H), 1.86−1.78 (m, 1H), 1.71 (ddd, J = 21.6, 11.4, 6.3 Hz, 3H), 1.64−1.57 (m, 2H). 13 C{1H} NMR (151 MHz, CDCl3): δ 178.3 (s), 173.2 (s), 158.3 (s), 151.0 (s), 136.5 (s), 130.8 (s), 127.9 (s), 127.4 (s), 120.6 (s), 119.1 (s), 113.7 (s), 110.1 (s), 72.5 (s), 71.7 (s), 55.3 (s), 54.9 (s), 52.2 (s), 49.2 (s), 44.6 (d, J = 20.2 Hz), 41.8 (s), 41.4 (s), 36.3 (s), 30.8 (s), 28.1 (s), 27.7 (s). IR (KBr): ν (cm−1) 3051, 2956, 1731, 1700, 1609, 1512, 1463, 1352, 1246, 1171, 1037, 740. HRMS (ESIMS): calcd for C28H31N2O4 [M + H]+ 459.2278, found 459.2279. Mp: 240−242 °C. Paucidirinine (1d). Thiophenol (0.12 mL, 1.09 mmol, 10.0 equiv) was added to a solution of 2 (50.0 mg, 0.1092 mmol, 1 equiv) in trifluoroacetic acid (5.00 mL) at 25 °C. The reaction mixture was heated to 60 °C. After 8 h, the solution was concentrated in vacuo, and the resulting residue was purified by flash column chromatography on silica gel to give paucidirinine (28.0 mg, 76%, 1:1 hexanes/ EtOAc eluent) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.07 (dt, J = 4.7, 3.5 Hz, 2H), 6.77 (t, J = 7.4 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 4.01 (dd, J = 11.8, 8.3 Hz, 1H), 3.91 (s, 1H), 3.82 (s, 1H), 3.72 (s, 3H), 3.20 (td, J = 11.6, 6.3 Hz, 1H), 2.94 (t, J = 9.7 Hz, 1H), 2.79−2.67 (m, 1H), 2.51 (d, J = 14.7 Hz, 1H), 2.19 (ddd, J = 13.2, 9.8, 3.0 Hz, 1H), 2.12−2.06 (m, 1H), 2.05−2.00 (m, 2H), 1.83 (dt, J = 17.8, 8.9 Hz, 1H), 1.68 (t, J = 10.9 Hz, 1H), 1.61 (dd, J = 14.3, 9.8 Hz, 1H), 1.43 (dd, J = 13.3, 6.2 Hz, 1H), 1.39−1.31 (m, 1H). 13 C{1H} NMR (101 MHz, CDCl3): δ 178.6, 173.2, 149.6, 136.4, 128.2, 121.7, 120.1, 111.6, 71.5, 66.9, 55.8, 52.3, 44.9, 44.7, 43.1, 42.3,

was introduced while heating was maintained for a further 20 h. Hydrolysis of the product was effected by adding aq acetic acid (HOAc/H2O = 1:3, 12 mL) to the boiling solution. After 2 h, the reaction mixture was cooled, diluted with water, and separated into layers. The upper phase was washed free of acetic acid and dried with Na2SO4, and the solvent was removed by rotary evaporation. The resulting residue was purified by flash chromatography (5:1 hexanes/ EtOAc eluent), producing 7 (1.87 g, 61%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 9.71 (s, 1H), 3.69 (s, 1H), 3.67 (s, 1H), 3.67 (s, 3H), 3.01−2.88 (m, 1H), 2.75 (dd, J = 16.6, 7.7 Hz, 1H), 2.44 (dd, J = 16.6, 5.7 Hz, 1H), 2.02−1.90 (m, 1H), 1.84 (dt, J = 8.1, 6.1 Hz, 1H), 0.87 (d, J = 13.0 Hz, 9H), 0.02 (d, J = 1.7 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 202.6, 172.4, 60.0, 51.8, 45.2, 32.3, 31.5, 25.8, 18.2, −5.6. IR (KBr) ν (cm−1) 2955, 2930, 2857, 1774, 1738, 1257, 1163. HRMS (ESIMS): calcd for C13H27O4Si [M + H]+ 275.1673, found 275.1672. Methyl (3aS,4S,11bR)-4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-4(2-methoxy-2-oxoethyl)-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate (4). A solution of 6 (1.14 g, 4.67 mmol) and 7 (1.54 g, 5.61 mmol) in dry benzene (25 mL) was heated at reflux for 20 h, and the solvent was then evaporated under reduced pressure. The residue was dissolved in water (25 mL), the aqueous phase was extracted with dichloromethane (3 × 20 mL), and the extract was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (dichloromethane/methanol, 20:1) to give 4 (1.55 g, 66%), which was immediately used in the following step. Methyl (2aS,2a1S,9bR)-2a-(2-((tert-Butyldimethylsilyl)oxy)ethyl)1-oxo-1,2,2a,2a1,3,5,10,11-octahydropyrrolizino[1,7-cd]carbazole4-carboxylate (16). To a stirred solution of 4 (1.55 g, 3.08 mmol) in toluene (20 mL) was added catalytic p-toluenesulfonic acid (58.6 mg, 0.31 mmol) at room temperature. The mixture was stirred at reflux for 12 h and then concentrated under vacuum. Aqueous NH3 (10 mL) was added to the resulting residue, the mixture was diluted with dichloromethane (20 mL), and the aqueous phase was extracted with dichloromethane (3 × 20 mL), dried over anhydrous Na2SO4, concentrated, and purified by column chromatography on silica gel (dichloromethane/methanol = 20:1) to give 16 (1.09 g, 50%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 9.03 (s, 1H), 7.21 (dd, J = 15.7, 7.7 Hz, 2H), 6.92 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 4.15 (dd, J = 11.8, 6.3 Hz, 1H), 3.95 (s, 1H), 3.76 (s, 3H), 3.63−3.45 (m, 2H), 3.18 (td, J = 11.7, 6.2 Hz, 1H), 2.74 (dd, J = 29.8, 15.7 Hz, 2H), 2.25 (d, J = 16.2 Hz, 1H), 1.98−1.80 (m, 3H), 1.57−1.37 (m, 2H), 0.83 (s, 9H), −0.03 (d, J = 8.4 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 176.7 (s), 168.2 (s), 163.2 (s), 143.1 (s), 135.7 (s), 128.6 (s), 121.6 (s), 121.3 (s), 109.7 (s), 91.03 (s), 72.7 (s), 59.6 (s), 54.8 (s), 51.1 (s), 45.0 (s), 43.9 (s), 42.5 (d, J = 16.8 Hz), 37.5 (s), 27.4 (s), 25.8 (s), 18.2 (s), −5.6 (d, J = 3.3 Hz). IR (KBr): ν (cm−1) 3328, 3058, 2956, 1706, 1610, 1463, 1378, 739. HRMS (ESIMS): calcd for C26H37N2O4Si [M + H]+ 469.2517, found 469.2515. Methyl (2aS,2a1S,9bR)-2a-(2-((tert-Butyldimethylsilyl)oxy)ethyl)5-(4-methoxybenzyl)-1-oxo-1,2,2a,2a1,3,5,10,11octahydropyrrolizino[1,7-cd]carbazole-4-carboxylate (17). To a solution of 16 (362.0 mg, 0.78 mmol) in N,N-dimethylformamide (6 mL) at room temperature were added NaH (40.0 mg, 60% dispersion in mineral oil, 0.61 mmol) and p-methoxybenzyl chloride (0.25 mL, 1.55 mmol) successively. After being stirred at room temperature overnight, the reaction was quenched with aqueous NH4OH (5 mL) and extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with saturated brine until removal of N,N-dimethylformamide, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Residue 17, without furthermore purification, was immediately used in the following step. Methyl (2aS,2a1S,9bR)-2a-(2-Hydroxyethyl)-5-(4-methoxybenzyl)-1-oxo-1,2,2a,2a1,3,5,10,11-octahydropyrrolizino[1,7-cd]carbazole-4-carboxylate (18). To crude 17 in THF (20 mL) was added TBAF (1.02 g, 3.9 mmol), and the mixture was stirred at rt for 8 h. The reaction was quenched with H2O (20 mL) and extracted with EtOAc (15 mL × 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced 1114

DOI: 10.1021/acs.joc.8b03023 J. Org. Chem. 2019, 84, 1111−1116

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The Journal of Organic Chemistry 36.6, 35.9, 30.6, 28.2. IR (KBr): ν (cm−1) 3351, 3049, 2954, 1728, 1694, 1608, 1462, 1377, 1214, 746. HRMS (ESIMS): calcd for C20H23N2O3 [M + H]+ 339.1703, found 339.1708. Mp: 186−188 °C.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b03023. 1

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H and 13C NMR spectra of all compounds (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail:[email protected]. Fax: +86-931-8912582. ORCID

Xuegong She: 0000-0002-3002-2433 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Science Foundation of China (21732001, 21871118, and 21572088) and IRT_15R28.

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REFERENCES

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