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Concise Total Synthesis of (±)-Aspidospermidine Haichen Ma, † Xingang Xie, † Peng Jing, † Weiwei Zhang, † Xuegong She*, †, ‡ Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x 5
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Abstract: (±)-Aspidospermidine (1) has been synthesized from the commercially available 2,3-dihydro-1H-carbazol4(9H)-one 6 in 10 steps with 20% overall yield. Key step of the strategy is a one-pot carbonyl reduction / iminium formation / intramolecular conjugate addition reaction that may be applied for the synthesis of other Aspidosperma alkaloids.
Aspidosperma alkaloids, which comprise more than 250 members, share a common pentacyclic skeleton imbedded in an indoline substructure and many of which have significant biological activities.1 The unique structure and diverse bioactivities of Aspidosperma alkaloids have attracted much attention of the synthetic community for many years and have remained a focus of extensive research activities until present day.2 Aspidospermidine (1) was isolated from the leaves and skin of Apocynaceae plants and contains a typical skeleton of indole alkaloids. It also exhibits significantly respiratory stimulant and antibiotic activities. The parent structure has been the primary target for most of the efforts toward Aspidosperma alkaloids syntheses and has served as the ideal test case for recent developed synthetic strategies.3-15 The reported strategies, including Stork’s Fischer-indole approach,3 Harley-Mason’s indoloquinolizidine rearrangement approach,4 Büchi and Wenkert’s Diels-Alder approach,5 and Overman’s aza-Cope rearrangement approach,8 have enriched the chemistry of aspidosperma alkaloids. Although many methods for the synthesis of this type of alkaloids have been reported, the efficient synthetic of Aspidosperma alkaloids is still desirable. To meet this demand, our group has developed a synthesis strategy of Aspidosperma alkaloids by a one-pot carbonyl reduction / iminium formation / intramolecular conjugate addition reaction to construct the required tetracyclic skeleton of (±)Koposihainanine.16 In 2013, Shao’s group used this method to finish the asymmetric synthesis of Aspidospermidine.15 We hope this concise strategy may be applied to synthesis of this kind of alkaloids (Figure 1). Therefore, aspidospermidine (1) was selected as the target and synthesized in order to test the This journal is © The Royal Society of Chemistry [year]
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feasibility of our developed strategy. Herein, we describe our synthesis of aspidospermidine.
Retrosynthetically, aspidospermidine 1 could be derived from tetracyclic lactam 3 via an alkylation reaction (Scheme 1). As for lactam 3, it could be obtained from ketoamide 5 by the one-pot carbonyl reduction/iminium formation/intramolecular conjugate addition reaction which was developed by our group. The requisite ketoamide 5 could be easily prepared from commercially available carbozole 6 through a three-step sequence. The synthesis began with the commercially available carbozole 6 (Scheme 2). After benzyl protection,17 ketone 7 was obtained in 95% yield then treated with LDA and ethyl iodide to give the αethylated ketone 8. Treatment of α-ethylated ketone 8 with methyl acrylate in the presence of t-BuOK afforded the Michael adduct 9 in 78% yield. Then compound 9 reacted with ethanolamine in refluxed EtOH to provided ketoamide 5. It is worth noting that all atoms of the pentacyclic skeleton of the natural product had been introduced at this stage.
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Scheme 1. Retrosynthetic Plan of (±)-Aspidospermidine 16
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With compound 5 in hand, the previous developed method was performed under the standard conditions: after -20 ° C, LiAlH4 selectively reduced ketone 5 into alcohol 4. Then hydrochloric acid was added to quench the reaction, cis junction of lactam ring simultaneously promoted the dehydration reaction to form the α, β-unsaturated iminium ion intermediate 10. The insitu generated intermediate 10 was trapped intramolecularly by the amide to afford the lactam 3.18-27 The satisfied selectivity observed from this tandem reaction could be explained by the formation of the lactam ring in cis junction. To our delight, the anticipant tandem reaction proceeded smoothly to give the desired lactam 3 in 94% yields.
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In summary, a concise and efficient total synthesis of (±)aspidospermidine has been achieved in 10 steps with a 20% overall yield. Our synthesis started from inexpensive commercially available carbazole derivative 6, and all of the reaction conditions were practical and convenient. The developed synthetic strategy is also suitable for the total synthesis of other natural aspidospermidine analogues.
Experimental Section 40
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Compound 8. To a stirred solution of 7 (5.50 g, 20 mmol) in THF was added LDA (10 mL, 20 mmol) dropwise at -78 ℃. After 45 min, ethyl iodide (3.74 g, 24 mmol) was added to the mixture and the reaction mixture was stirred for 30 min at the same temperature. Then it was warmed to room temperature and stirred overnight. The reaction was quenched by slow addition of a saturated NH4Cl aqueous solution and extracted with CH2Cl2 (60 mL×3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4 filtered, and concentrated under vacuum. The obtained residue was purified by column chromatography (silica gel, hexane/EtOAc 5:1) to give pure product 8 as a white solid (5.82 g 96% yield.) mp 133 °C. IR (KBr) νmax 3058, 3033, 2962, 2932, 2871, 2245, 1643, 1611, 1539, 1461, 1397, 1152, 1077, 910, 732, 700 cm-1. 1H NMR (CDCl3, 400 MHz): δ 1.00 (t, J = 7.6 Hz, 3H), 1.54 (m, 1H), 1.97 (m, 2H), 2.32 (m, 2H), 2.81 (m, 2H), 5.22 (s, 2H), 6.99 (t, J = 6.0 Hz, 2H),7.17 (t, J = 6.0 Hz, 2H), 7.24 (m, 4H), 8.31 (d, J = 8.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 11.7, 21.0, 22.3, 27.6, 46.7, 47.6, 109.5, 112.5, 121.5, 122.4, 122.9, 125.1, 126.0, 127.7, 128.9, 136.0, 137.2, 150.9, 196.0; HRMS (ESIMS) Calcd for C21H21NO [M＋Na]+ 326.1515, found 326.1524
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Scheme 2. Synthesis of the Key Intermediate 3
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After obtaining the tetracyclic lactam 3, the remaining task was to construct the last ring of the target molecular. (Scheme 3) A three-step sequence proceeded. The benzyl group of lactam 3 was removed. 28, 29 Then compound 2 was reduced by LiAlH4 to get the corresponding alcohol 11 which was mesylated to give 12 in 50% overall yield over three steps. Finally, a one-pot intramolecular alkylation/reduction was utilized to complete the synthesis of (±)-aspidospermidine. The spectroscopic data of our synthetic compound 1 matched well with those reported for the natural aspidospermidine.
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Scheme 3.Synthesis of (±)-Aspidospermidine from lactam 3 30
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Compound 9. To a solution of ketone 8 (1.56 g, 5 mmol), in anhydrous THF (100 mL)/t-BuOH (10 mL) at 0℃ was added tBuOK (1.12 g, 10 mmol,) under Ar and the resulting mixture was stirred at 0℃ for 10min. Methyl acrylate (3.6 mL, 40 mmol) was added to the reaction and the resulting mixture was stirred at -20 ℃ for 30 min and at room temperature for 12 h. The reaction mixture was quenched by addition of a saturated NH4Cl at 0℃. The resultant residue was taken up in water (50 mL) and the aqueous mixture was extracted with CH2Cl2 (40 mL×3). The combined organic extracts were washed with brine (40 mL), dried over Na2SO4 filtered and the solvent was removed under vacuum. The residue was purified by column chromatography (silica gel, hexane/EtOAc 5:1) to give pure product 9 (1.52 g, 78% yield) as a yellow solid. IR (KBr) νmax 3060, 3031, 2947, 2881, 2250, 1735, 1641, 1542, 1460, 1437, 1360, 1300, 1199, 1176, 1070, 912, 841, 732, 700, 648 cm-1. 1H NMR (CDCl3, 400 MHz): δ 0.91 (t, J = 7.6 Hz, 3H), 1.68 (m, 2H), 1.87 (m, 1H), 2.08 (m, 3H), 2.37 (m, 2H), 2.91 (m, 2H), 3.63 (s, 3H), 5.30 (s, 2H), 7.03 (d, J = 7.6Hz, 2H), 7.26 (m, 6H), 8.30 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 8.4, 19.1, 27.2, 29.2, 31.4, 46.9, 47.2, 51.5, 109.6, 112.0, 121.7, 122.6, 123.1, 125.4, 126.0, 127.9, 129.0, 136.0, 137.4, 149.8, 174.1, 197.1; HRMS (ESIMS) Calcd for C25H27NO3 [M＋Na]+ 412.1883, found 412.1885. Compound 5. A solution of 9 (1.52 g 3.81mmol) in CH3CN CH3CN was added ethanolamine (2.31g 38mmol) and the resulting solution was stirred and reflux for 10h. A trace of This journal is © The Royal Society of Chemistry [year]
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sodium ethoxide was added to the system. The reaction mixture was extracted with CH2Cl2 (60 mL×3). The combined organic extracts were washed with brine (50 mL) and dried over Na2SO4 and the solvent was removed under vacuum. The mixture residue was purified by column chromatography (silica gel, hexane/EtOAc 2:1) to give the pure product 5(1.38 g 90% yield) as white solid. mp 155 ℃. IR (KBr) νmax 3317, 3060, 2932, 2878, 1725, 1637, 1540, 1459, 1439, 1359, 1196, 1137, 1069, 935, 838, 735, 700, 659, 617 cm-1. 1H NMR (CDCl3, 400 MHz): δ 0.87 (t, J = 7.6 Hz, 3H), 1.43(s, 1H), 1.62 (m, 2H), 1.87 (m, 1H), 2.07 (m, 3H), 2.22 (m, 2H), 2.87 (m, 2H), 3.37 (t, J = 5.0 Hz, 2H), 3.68 (t, J = 4.8 Hz, 2H), 5.24 (s, 2H), 6.84 (s, 1H), 7.01 (d, J = 6.4 Hz, 2H), 7.25 (m, 6H), 8.23 (d, J = 7.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 8.4, 19.0, 27.6, 30.0, 31.0, 31.6, 42.4, 46.8, 47.5, 61.9, 109.7, 111.8, 121.4, 122.6, 123.1, 125.2, 126.0, 127.8, 129.0, 135.7, 137.4, 150.6, 174.5, 198.2; HRMS (ESIMS) Calcd for C26H30N2O3 [M ＋ Na]+ 441.2149, found 441.2153. Compound 3. To a stirred solution of 5(0.44 g 1.04 mmol) in THF was added LAH (0.12 g 3.13 mmol) portion wise at -20℃. Then assembling a drying tube at the flask and stirring for 30 min. The reaction was quenched by water and then adjusted by 2N HCl to attain the target of H (2~3). The aqueous layer was separated and extracted with CH2Cl2 (30 mL×2). The combined organic extracts were washed with brine (30 mL×2) and dried over Na2SO4. The residue was purified by column chromatography (silica gel, EtOAc) to give pure product 3 as white solid(0.40 mg 94% yield) mp 200°C; IR (KBr) νmax 3327, 3055, 2938, 2878, 1705, 1631, 1612, 1463, 1427, 1357, 1302, 1266, 1190, 1051, 1029, 736, 698 cm-1; 1H NMR (CDCl3, 400 MHz): δ 0.85 (t, J = 7.6 Hz, 3H), 1.28(m, 2H), 1.65 (m, 2H), 1.92 (m, 1H), 2.07 (m, 1H), 2.50 (m, 2H), 2.60 (m,1H), 2.73 (m, 1H), 3.31 (m, 1H), 3.55 (m, 1H), 3.63 (m, 1H), 3.74 (m, 1H), 3.96 (s, 1H), 5.28 (s, 2H), 6.92 (d, J = 7.6 Hz, 2H), 7.15 (m, 2H), 7.24 (m, 4H), 7.52 (m, 2H); 13C NMR (CDCl3, 100 MHz): δ 8.0, 19.3, 26.2, 28.1, 29.5, 29.6, 36.9, 46.4, 47.9, 58.9, 63.7, 106.7, 109.6, 117.6, 120.1, 121.6, 125.7, 127.5, 127.9, 128.8, 137.1, 137.3, 174.4; HRMS (ESIMS) Calcd for C26H30N2O2 [M ＋ H]+ 403.2380, found 403.2384. Compound 2. Freshed cut Na (229 mg, 9.96 mmol) was added to liquid ammonia (20 mL) in a 100 ml two-necked flask cooled to – 78℃. After 5 min, a solution of t-BuOH (0.5 mL) in THF (5 mL) was added to the blue ammonia solution, followed by a solution of amide 3 (200 mg, 0.50 mmol) in THF (5 mL). The reaction mixture was stirred at –78℃ for 30 min at which the blue color had disappeared. The reaction mixture then was quenched with saturated NH4Cl and ammonia was allowed to evaporate by replacing the cooling bath with a water bath. The mixture solution was extracted by CH2Cl2 (20 mL×3). The residue was dissolved in CH2Cl2 (4 mL) flash column chromatography (EtOAc) of the crude residue yielded 155 mg (85.2%) of amine 2 as dark brown mucus. IR (KBr) νmax 3262, 3057, 2940, 2876, 1610, 1462, 1419, 1330, 1304, 1263, 1121, 1048, 940, 739, 703, 656, 619 cm-1; 1H NMR (CDCl3, 400 MHz): δ 0.87 (t, J = 7.2 Hz, 3H), 1.29(m, 2H), 1.66 (m, 2H), 1.93 (m, 1H), 2.06 (m, 1H), 2.51 (m, 2H), 2.73 (m, 2H), 3.27 (m, 1H), 3.53 (m, 1H), 3.65 (m,
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1H), 3.71 (m, 1H), 4.12 (m, 1H), 4.50 (s, 1H), 7.14 (dd, J = 7.2 Hz, J = 7.6 Hz, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 8.69 (s, 1H), 13C NMR (CDCl3, 100 MHz): δ 8.0, 20.0, 26.3, 28.0, 29.5, 29.7, 37.0, 48.1, 59.1, 63.6, 106.7, 101.0, 117.4, 120.0, 121.6, 128.0, 136.1, 136.2, 174.6; HRMS (ESIMS) Calcd for C19H24N2O2 [M + H]+ 313.1911, found 313.1916.
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Compound 11. To a solution of 2(0.56 g 1.19 mmol) in THF was added LAH (0.14 g 3.56 mmol) dropwise. After 10 min the mixture was warmed to 80℃, then to stir further and reflux for about 4h. The reaction was quenched by saturated NH4Cl. The mixture was diluted with CH2Cl2 (20 mL×3) and washed with brine (30 mL×2). The residue was dissolved in CH2Cl2 (4 mL) flash column chromatography CH2Cl2: MeOH (30:1) of the product yielded 234 mg (66%) of amine 11 as a colorless solid. mp 74℃; IR (KBr) νmax3397, 3217, 3185, 3109, 3058, 2937, 2877, 2794, 1620, 1585, 1461, 1377, 1331, 1308, 1265, 1233, 1169, 1141, 1120, 1041, 739 cm-1; 1H NMR (CDCl3, 400 MHz): δ 0.71 (t, J = 7.6 Hz, 3H), 0.90 (m, 1H), 1.14 (m, 1H), 1.34 (m, 2H), 1.58 (m, 1H), 1.74 (m, 1H), 1.83 (m, 1H), 2.22 (m, 2H), 2.60 (m, 3H), 3.25 (m, 5H), 3.49 (m, 1H), 7.05 (m, 2H), 7.13 (m, 1H), 7.42 (m, 1H), 8.32 (s, 1H); 13C NMR (CDCl3, 100 MHz): δ 7.7, 20.1, 21.9, 24.2, 29.4, 34.6, 37.0, 52.3, 54.0, 57.8, 62.9, 110.0, 110.5, 117.5, 119.1, 120.6, 129.7, 135.5, 136.0; HRMS (ESIMS) Calcd for C19H26N2O [M + H]+ 299.2118, found 299.2117
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Compound 12. To a solution of the alcohol 11 (100 mg, 0.34 mmol) in anhydrous CH2Cl2 (10 mL) at 0℃ were sequentially added triethylamine (9 µl, 0.67 mmol), Methanesulfonyl chloride (31 µl, 0.4 mmol). The mixture was stirred at 0℃ for 30 min and water (3 mL) was added to quench the reaction. The layers were separated and the aqueous layer was extracted with CH2Cl2 (10 mL ×3). The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was concentrated to dryness in vacuo to give a yellow powder. (121 mg 95% yield).
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(±)-Aspidospermidine 1 TM. To a solution of 12(158 mg 0.45 mmol) in CH2Cl2 (6 mL) was added dropwise t-BuOK causing the formation of white precipitate. The reaction stirred for about 16h at room temperature. Then LAH (28.5 mg 0.75 mmol) was added in the mixture solution at 0℃ and stirred for 30 min and saturated NH4Cl was added to quench the reaction the layers were separated and the aqueous layer was extracted with CH2Cl2 (10 mL × 3). The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was concentrated to dryness in vacuo to give the TM. (87 mg 62% yield). IR (KBr) νmax 3635, 3362, 3048, 3027, 2934, 2882, 2861, 2780, 2722, 2678 ，1606, 1481, 1463, 1376, 1331, 1318, 1259, 1179, 1134, 1024, 907, 866, 736, 642 cm-1; 1H NMR (CDCl3, 400 MHz): δ 0.63 (t, J = 7.6 Hz, 3H), 0.87(m, 1H), 1.02 (m, 2H), 1.41 (m, 4H), 1.57 (m, 2H), 1.74 (m, 1H), 1.94 (m, 2H), 2.26 (m, 3H), 3.10 (m, 2H), 3.50 (m, 1H), 3.49 (m, 1H), 6.63 (d, J = 7.6 Hz, 1H), 6.72 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H); 13 C NMR (CDCl3, 100 MHz): δ 6.8, 21.8, 23.0, 28.1, 29.9, 34.5, 35.6, 38.8, 53.0, 53.4, 53.9, 65.6, 71.2, 110.3, 118.9, 122.8, 127.0, 135.7, 149.4; HRMS (ESIMS) Calcd for C19H26N2O [M ＋H]+ 283.2169, found 283.2164.
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The authors declare no competing financial interest. We wish to thank the generous financial support by the NSFC (21125207, 21372103), the MOST (2010CB833200) and the SRFDP (20130211110018).
Notes and references
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(25) Y, Ergun.; S, Patir.; G, Okay.; Heterocycl. Chem. 2002, 39, 315 – 317; (26) R. V, Ohri.; A. T, Radosevich.; K. J, Hrovat.; C, Musich.; D, Huang.; T. R, Holman.; F. D, Toste. Org. Lett. 2005, 7, 2501 – 2504; (27) G, Cravotto.; G. B, Giovenzana.; A, Maspero.; T, Pilati.; A, Penoni.; G, Palmisano.; Tetrahedron Lett. 2006, 47, 6439 – 6443. (28) A. J, Birch. J. Chem. Soc. 1944, 430-436; (29) L. E, Overman.; Y, Shin. Org. Lett. 2007, 9, 339-341.
† State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, People’s Republic of China. *E-mail: 10
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Collaborative lnnovation Center of Chemical Science and Engineering Tianjin(P.R. China)
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Electronic Supplementary Information (ESI) available: Detailed experimental procedures, characterizations and copies of 1H- and 13 C-NMR spectra of new compounds. See DOI: 10.1039/b000000x/ (1) a) J. E, Saxton. in Chemistry of Heterocyclic Compounds, Wiley, New York, 2008, pp. 331 – 437; b) J. E, Saxton,; in the Alkaloids: Chemistry and Biology, Vol. 50 (Ed.: G. A. Cordell), Academic Press, New York, 1998; c) M, Toyota.; M, Ihara. Nat.Prod. Rep.1998, 15, 327 – 340; d) J. E, Saxton.; the Indoles: the monoterpe noidindole alkaloids, Vol. 25, Wiley-Interscience, 1983. (2) “Synthesis of the Aspidosperma Alkaloids”: J. E, Saxton. in the Alkaloids, Vol. 50 (Ed.: G. A.Cordell), Academic Press, San Dieg o. 1998, pp. 343 – 376. (3) For pioneering syntheses: G, Stork.; J. E, Dolfini. J. Am. Chem. Soc. 1963, 85, 2872-2873. (4) J, Harley-Mason.; M, Kaplan. J. Chem. Soc., Chem. Commun. 1967, 915-916. (5) G, Büchi.; K. E, Matsumoto. J. Am. Chem. Soc. 1971, 93, 3299-3301. (6) P, Le Me´nez.; N, Kunesch.; S, Liu.; E, Wenkert. J. Org. Chem. 1991, 56, 2915-2918. (7) T, Gallagher.; P, Magnus.; J, Huffman. J. Am. Chem. Soc. 1982, 104, 1140-1141. (8) L. E, Overman.; M, Sworin.; R. M, Burk. J. Org. Chem. 1983, 48, 2685-2690. (9) B, Patro.; J. A, Murphy. Org. Lett. 2000, 2, 3599-3601. (10) M. A, Toczko.; C. H, Heathcock. J. Org. Chem. 2000, 65, 2642. (11) O, Callaghan.; C, Lampard.; A. R, Kennedy.; J. A, Murphy. J. Chem. Soc., Perkin Trans. 1 1999, 995-1001. (12) A, Urrutia.; J. G, Rodriguez. Tetrahedron 1999, 55, 11095. (13) J. F, Quinn.; M. E, Bos.; W. D, Wulff. Org. Lett. 1999, 1, 161-164. (14) S. A, Kozmin.; V. H, Rawal. J. Am. Chem. Soc. 1998, 120, 1352313524 (15) Z, Li.; S, Zhang.; S, Wu.; X, Shen.; L, Zou.; F, Wang.; X, Li.; F, Peng.; H, Zhang.; Z, Shao. Angew. Chem., Int. Ed. 2013, 52, 41174121. (16) P, Jing.; Z, Yang.; C,Zhao.; H, Zheng.; B, Fang.; X, Xie.; X, She.; Chem. Eur. J. 2012, 18, 6729. (17) D, Sissouma.; L, Maingot.; S, Collet.; J. Org. Chem. 2006, 71, 8384 –8389. (18) For a reports on iminium ion intermediates, see: L. G, Humber.; E, Ferdinandi.; C. A, Demerson.; S, Ahmed.; U, Shah.; D, Mobilio.; J, Sabatucci.; B, De Lange.; Labbadia, F.; J. Med. Chem. 1988, 31, 1712 –1719; (19). J, Bergman,.; S, Bergman.; J. O, Lindstroem,. Tetrahedron Lett. 1989, 30, 5337 –5340;
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(20) L, Castedo.; J. C, Estevez.; R. J, Estevez.; J. A, Seijas.; M. P, Vazquez Tato.; M. C, Villaverde. An. Quim. 1990, 86, 805 – 807; (21) D, Desma le.; J. d, Angelo. Tetrahedron Lett. 1990, 31, 883 – 886; (22) D, Desma le.; J. d, Angelo.; J. Org.Chem.1994, 59, 2292 – 2303; (23) B, Jiang.; J. M, Smallheer.; C, Amaral-Ly.; M. A, Wuonola.; J. Org. Chem. 1994, 59, 6823 –6827; (24) Y, Ergun.; S, Patir.; G. J, Okay.; Heterocycl. Chem. 2002, 39, 315 – 317;
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Abstract: (±)-Aspidospermidine (1) has been synthesized from the commercially available 2,3-dihydro-1H-carbazol-4(9H)-one 6 in 10 steps with 20% overall yield. Key step of the strategy is a one-pot carbonyl reduction / iminium formation / intramolecular conjugate addition reaction that may be applied for synthesis of other kind of Aspidosperma alkaloids.
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Concise Total Synthesis of (±)-Aspidospermidine Haichen Ma, † Xingang Xie, † Peng Jing, † Weiwei Zhang, † Xuegong She*, †, ‡ Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x 5
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Abstract: (±)-Aspidospermidine (1) has been synthesized from the commercially available 2,3-dihydro-1H-carbazol4(9H)-one 6 in 10 steps with 20% overall yield. Key step of the strategy is a one-pot carbonyl reduction / iminium formation / intramolecular conjugate addition reaction that may be applied for the synthesis of other Aspidosperma alkaloids.
Aspidosperma alkaloids, which comprise more than 250 members, share a common pentacyclic skeleton imbedded in an indoline substructure and many of which have significant biological activities.1 The unique structure and diverse bioactivities of Aspidosperma alkaloids have attracted much attention of the synthetic community for many years and have remained a focus of extensive research activities until present day.2 Aspidospermidine (1) was isolated from the leaves and skin of Apocynaceae plants and contains a typical skeleton of indole alkaloids. It also exhibits significantly respiratory stimulant and antibiotic activities. The parent structure has been the primary target for most of the efforts toward Aspidosperma alkaloids syntheses and has served as the ideal test case for recent developed synthetic strategies.3-15 The reported strategies, including Stork’s Fischer-indole approach,3 Harley-Mason’s indoloquinolizidine rearrangement approach,4 Büchi and Wenkert’s Diels-Alder approach,5 and Overman’s aza-Cope rearrangement approach,8 have enriched the chemistry of aspidosperma alkaloids. Although many methods for the synthesis of this type of alkaloids have been reported, the efficient synthetic of Aspidosperma alkaloids is still desirable. To meet this demand, our group has developed a synthesis strategy of Aspidosperma alkaloids by a one-pot carbonyl reduction / iminium formation / intramolecular conjugate addition reaction to construct the required tetracyclic skeleton of (±)Koposihainanine.16 In 2013, Shao’s group used this method to finish the asymmetric synthesis of Aspidospermidine.15 We hope this concise strategy may be applied to synthesis of this kind of alkaloids (Figure 1). Therefore, aspidospermidine (1) was selected as the target and synthesized in order to test the This journal is © The Royal Society of Chemistry [year]
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feasibility of our developed strategy. Herein, we describe our synthesis of aspidospermidine.
Retrosynthetically, aspidospermidine 1 could be derived from tetracyclic lactam 3 via an alkylation reaction (Scheme 1). As for lactam 3, it could be obtained from ketoamide 5 by the one-pot carbonyl reduction/iminium formation/intramolecular conjugate addition reaction which was developed by our group. The requisite ketoamide 5 could be easily prepared from commercially available carbozole 6 through a three-step sequence. The synthesis began with the commercially available carbozole 6 (Scheme 2). After benzyl protection,17 ketone 7 was obtained in 95% yield then treated with LDA and ethyl iodide to give the αethylated ketone 8. Treatment of α-ethylated ketone 8 with methyl acrylate in the presence of t-BuOK afforded the Michael adduct 9 in 78% yield. Then compound 9 reacted with ethanolamine in refluxed EtOH to provided ketoamide 5. It is worth noting that all atoms of the pentacyclic skeleton of the natural product had been introduced at this stage.
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Scheme 1. Retrosynthetic Plan of (±)-Aspidospermidine 16
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With compound 5 in hand, the previous developed method was performed under the standard conditions: after -20 ° C, LiAlH4 selectively reduced ketone 5 into alcohol 4. Then hydrochloric acid was added to quench the reaction, cis junction of lactam ring simultaneously promoted the dehydration reaction to form the α, β-unsaturated iminium ion intermediate 10. The insitu generated intermediate 10 was trapped intramolecularly by the amide to afford the lactam 3.18-27 The satisfied selectivity observed from this tandem reaction could be explained by the formation of the lactam ring in cis junction. To our delight, the anticipant tandem reaction proceeded smoothly to give the desired lactam 3 in 94% yields.
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In summary, a concise and efficient total synthesis of (±)aspidospermidine has been achieved in 10 steps with a 20% overall yield. Our synthesis started from inexpensive commercially available carbazole derivative 6, and all of the reaction conditions were practical and convenient. The developed synthetic strategy is also suitable for the total synthesis of other natural aspidospermidine analogues.
Experimental Section 40
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Compound 8. To a stirred solution of 7 (5.50 g, 20 mmol) in THF was added LDA (10 mL, 20 mmol) dropwise at -78 ℃. After 45 min, ethyl iodide (3.74 g, 24 mmol) was added to the mixture and the reaction mixture was stirred for 30 min at the same temperature. Then it was warmed to room temperature and stirred overnight. The reaction was quenched by slow addition of a saturated NH4Cl aqueous solution and extracted with CH2Cl2 (60 mL×3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4 filtered, and concentrated under vacuum. The obtained residue was purified by column chromatography (silica gel, hexane/EtOAc 5:1) to give pure product 8 as a white solid (5.82 g 96% yield.) mp 133 °C. IR (KBr) νmax 3058, 3033, 2962, 2932, 2871, 2245, 1643, 1611, 1539, 1461, 1397, 1152, 1077, 910, 732, 700 cm-1. 1H NMR (CDCl3, 400 MHz): δ 1.00 (t, J = 7.6 Hz, 3H), 1.54 (m, 1H), 1.97 (m, 2H), 2.32 (m, 2H), 2.81 (m, 2H), 5.22 (s, 2H), 6.99 (t, J = 6.0 Hz, 2H),7.17 (t, J = 6.0 Hz, 2H), 7.24 (m, 4H), 8.31 (d, J = 8.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 11.7, 21.0, 22.3, 27.6, 46.7, 47.6, 109.5, 112.5, 121.5, 122.4, 122.9, 125.1, 126.0, 127.7, 128.9, 136.0, 137.2, 150.9, 196.0; HRMS (ESIMS) Calcd for C21H21NO [M＋Na]+ 326.1515, found 326.1524
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Scheme 2. Synthesis of the Key Intermediate 3
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After obtaining the tetracyclic lactam 3, the remaining task was to construct the last ring of the target molecular. (Scheme 3) A three-step sequence proceeded. The benzyl group of lactam 3 was removed. 28, 29 Then compound 2 was reduced by LiAlH4 to get the corresponding alcohol 11 which was mesylated to give 12 in 50% overall yield over three steps. Finally, a one-pot intramolecular alkylation/reduction was utilized to complete the synthesis of (±)-aspidospermidine. The spectroscopic data of our synthetic compound 1 matched well with those reported for the natural aspidospermidine.
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Scheme 3.Synthesis of (±)-Aspidospermidine from lactam 3 30
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Compound 9. To a solution of ketone 8 (1.56 g, 5 mmol), in anhydrous THF (100 mL)/t-BuOH (10 mL) at 0℃ was added tBuOK (1.12 g, 10 mmol,) under Ar and the resulting mixture was stirred at 0℃ for 10min. Methyl acrylate (3.6 mL, 40 mmol) was added to the reaction and the resulting mixture was stirred at -20 ℃ for 30 min and at room temperature for 12 h. The reaction mixture was quenched by addition of a saturated NH4Cl at 0℃. The resultant residue was taken up in water (50 mL) and the aqueous mixture was extracted with CH2Cl2 (40 mL×3). The combined organic extracts were washed with brine (40 mL), dried over Na2SO4 filtered and the solvent was removed under vacuum. The residue was purified by column chromatography (silica gel, hexane/EtOAc 5:1) to give pure product 9 (1.52 g, 78% yield) as a yellow solid. IR (KBr) νmax 3060, 3031, 2947, 2881, 2250, 1735, 1641, 1542, 1460, 1437, 1360, 1300, 1199, 1176, 1070, 912, 841, 732, 700, 648 cm-1. 1H NMR (CDCl3, 400 MHz): δ 0.91 (t, J = 7.6 Hz, 3H), 1.68 (m, 2H), 1.87 (m, 1H), 2.08 (m, 3H), 2.37 (m, 2H), 2.91 (m, 2H), 3.63 (s, 3H), 5.30 (s, 2H), 7.03 (d, J = 7.6Hz, 2H), 7.26 (m, 6H), 8.30 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 8.4, 19.1, 27.2, 29.2, 31.4, 46.9, 47.2, 51.5, 109.6, 112.0, 121.7, 122.6, 123.1, 125.4, 126.0, 127.9, 129.0, 136.0, 137.4, 149.8, 174.1, 197.1; HRMS (ESIMS) Calcd for C25H27NO3 [M＋Na]+ 412.1883, found 412.1885. Compound 5. A solution of 9 (1.52 g 3.81mmol) in CH3CN CH3CN was added ethanolamine (2.31g 38mmol) and the resulting solution was stirred and reflux for 10h. A trace of This journal is © The Royal Society of Chemistry [year]
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sodium ethoxide was added to the system. The reaction mixture was extracted with CH2Cl2 (60 mL×3). The combined organic extracts were washed with brine (50 mL) and dried over Na2SO4 and the solvent was removed under vacuum. The mixture residue was purified by column chromatography (silica gel, hexane/EtOAc 2:1) to give the pure product 5(1.38 g 90% yield) as white solid. mp 155 ℃. IR (KBr) νmax 3317, 3060, 2932, 2878, 1725, 1637, 1540, 1459, 1439, 1359, 1196, 1137, 1069, 935, 838, 735, 700, 659, 617 cm-1. 1H NMR (CDCl3, 400 MHz): δ 0.87 (t, J = 7.6 Hz, 3H), 1.43(s, 1H), 1.62 (m, 2H), 1.87 (m, 1H), 2.07 (m, 3H), 2.22 (m, 2H), 2.87 (m, 2H), 3.37 (t, J = 5.0 Hz, 2H), 3.68 (t, J = 4.8 Hz, 2H), 5.24 (s, 2H), 6.84 (s, 1H), 7.01 (d, J = 6.4 Hz, 2H), 7.25 (m, 6H), 8.23 (d, J = 7.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 8.4, 19.0, 27.6, 30.0, 31.0, 31.6, 42.4, 46.8, 47.5, 61.9, 109.7, 111.8, 121.4, 122.6, 123.1, 125.2, 126.0, 127.8, 129.0, 135.7, 137.4, 150.6, 174.5, 198.2; HRMS (ESIMS) Calcd for C26H30N2O3 [M ＋ Na]+ 441.2149, found 441.2153. Compound 3. To a stirred solution of 5(0.44 g 1.04 mmol) in THF was added LAH (0.12 g 3.13 mmol) portion wise at -20℃. Then assembling a drying tube at the flask and stirring for 30 min. The reaction was quenched by water and then adjusted by 2N HCl to attain the target of H (2~3). The aqueous layer was separated and extracted with CH2Cl2 (30 mL×2). The combined organic extracts were washed with brine (30 mL×2) and dried over Na2SO4. The residue was purified by column chromatography (silica gel, EtOAc) to give pure product 3 as white solid(0.40 mg 94% yield) mp 200°C; IR (KBr) νmax 3327, 3055, 2938, 2878, 1705, 1631, 1612, 1463, 1427, 1357, 1302, 1266, 1190, 1051, 1029, 736, 698 cm-1; 1H NMR (CDCl3, 400 MHz): δ 0.85 (t, J = 7.6 Hz, 3H), 1.28(m, 2H), 1.65 (m, 2H), 1.92 (m, 1H), 2.07 (m, 1H), 2.50 (m, 2H), 2.60 (m,1H), 2.73 (m, 1H), 3.31 (m, 1H), 3.55 (m, 1H), 3.63 (m, 1H), 3.74 (m, 1H), 3.96 (s, 1H), 5.28 (s, 2H), 6.92 (d, J = 7.6 Hz, 2H), 7.15 (m, 2H), 7.24 (m, 4H), 7.52 (m, 2H); 13C NMR (CDCl3, 100 MHz): δ 8.0, 19.3, 26.2, 28.1, 29.5, 29.6, 36.9, 46.4, 47.9, 58.9, 63.7, 106.7, 109.6, 117.6, 120.1, 121.6, 125.7, 127.5, 127.9, 128.8, 137.1, 137.3, 174.4; HRMS (ESIMS) Calcd for C26H30N2O2 [M ＋ H]+ 403.2380, found 403.2384. Compound 2. Freshed cut Na (229 mg, 9.96 mmol) was added to liquid ammonia (20 mL) in a 100 ml two-necked flask cooled to – 78℃. After 5 min, a solution of t-BuOH (0.5 mL) in THF (5 mL) was added to the blue ammonia solution, followed by a solution of amide 3 (200 mg, 0.50 mmol) in THF (5 mL). The reaction mixture was stirred at –78℃ for 30 min at which the blue color had disappeared. The reaction mixture then was quenched with saturated NH4Cl and ammonia was allowed to evaporate by replacing the cooling bath with a water bath. The mixture solution was extracted by CH2Cl2 (20 mL×3). The residue was dissolved in CH2Cl2 (4 mL) flash column chromatography (EtOAc) of the crude residue yielded 155 mg (85.2%) of amine 2 as dark brown mucus. IR (KBr) νmax 3262, 3057, 2940, 2876, 1610, 1462, 1419, 1330, 1304, 1263, 1121, 1048, 940, 739, 703, 656, 619 cm-1; 1H NMR (CDCl3, 400 MHz): δ 0.87 (t, J = 7.2 Hz, 3H), 1.29(m, 2H), 1.66 (m, 2H), 1.93 (m, 1H), 2.06 (m, 1H), 2.51 (m, 2H), 2.73 (m, 2H), 3.27 (m, 1H), 3.53 (m, 1H), 3.65 (m,
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1H), 3.71 (m, 1H), 4.12 (m, 1H), 4.50 (s, 1H), 7.14 (dd, J = 7.2 Hz, J = 7.6 Hz, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 8.69 (s, 1H), 13C NMR (CDCl3, 100 MHz): δ 8.0, 20.0, 26.3, 28.0, 29.5, 29.7, 37.0, 48.1, 59.1, 63.6, 106.7, 101.0, 117.4, 120.0, 121.6, 128.0, 136.1, 136.2, 174.6; HRMS (ESIMS) Calcd for C19H24N2O2 [M + H]+ 313.1911, found 313.1916.
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Compound 11. To a solution of 2(0.56 g 1.19 mmol) in THF was added LAH (0.14 g 3.56 mmol) dropwise. After 10 min the mixture was warmed to 80℃, then to stir further and reflux for about 4h. The reaction was quenched by saturated NH4Cl. The mixture was diluted with CH2Cl2 (20 mL×3) and washed with brine (30 mL×2). The residue was dissolved in CH2Cl2 (4 mL) flash column chromatography CH2Cl2: MeOH (30:1) of the product yielded 234 mg (66%) of amine 11 as a colorless solid. mp 74℃; IR (KBr) νmax3397, 3217, 3185, 3109, 3058, 2937, 2877, 2794, 1620, 1585, 1461, 1377, 1331, 1308, 1265, 1233, 1169, 1141, 1120, 1041, 739 cm-1; 1H NMR (CDCl3, 400 MHz): δ 0.71 (t, J = 7.6 Hz, 3H), 0.90 (m, 1H), 1.14 (m, 1H), 1.34 (m, 2H), 1.58 (m, 1H), 1.74 (m, 1H), 1.83 (m, 1H), 2.22 (m, 2H), 2.60 (m, 3H), 3.25 (m, 5H), 3.49 (m, 1H), 7.05 (m, 2H), 7.13 (m, 1H), 7.42 (m, 1H), 8.32 (s, 1H); 13C NMR (CDCl3, 100 MHz): δ 7.7, 20.1, 21.9, 24.2, 29.4, 34.6, 37.0, 52.3, 54.0, 57.8, 62.9, 110.0, 110.5, 117.5, 119.1, 120.6, 129.7, 135.5, 136.0; HRMS (ESIMS) Calcd for C19H26N2O [M + H]+ 299.2118, found 299.2117
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Compound 12. To a solution of the alcohol 11 (100 mg, 0.34 mmol) in anhydrous CH2Cl2 (10 mL) at 0℃ were sequentially added triethylamine (9 µl, 0.67 mmol), Methanesulfonyl chloride (31 µl, 0.4 mmol). The mixture was stirred at 0℃ for 30 min and water (3 mL) was added to quench the reaction. The layers were separated and the aqueous layer was extracted with CH2Cl2 (10 mL ×3). The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was concentrated to dryness in vacuo to give a yellow powder. (121 mg 95% yield).
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(±)-Aspidospermidine 1 TM. To a solution of 12(158 mg 0.45 mmol) in CH2Cl2 (6 mL) was added dropwise t-BuOK causing the formation of white precipitate. The reaction stirred for about 16h at room temperature. Then LAH (28.5 mg 0.75 mmol) was added in the mixture solution at 0℃ and stirred for 30 min and saturated NH4Cl was added to quench the reaction the layers were separated and the aqueous layer was extracted with CH2Cl2 (10 mL × 3). The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was concentrated to dryness in vacuo to give the TM. (87 mg 62% yield). IR (KBr) νmax 3635, 3362, 3048, 3027, 2934, 2882, 2861, 2780, 2722, 2678 ，1606, 1481, 1463, 1376, 1331, 1318, 1259, 1179, 1134, 1024, 907, 866, 736, 642 cm-1; 1H NMR (CDCl3, 400 MHz): δ 0.63 (t, J = 7.6 Hz, 3H), 0.87(m, 1H), 1.02 (m, 2H), 1.41 (m, 4H), 1.57 (m, 2H), 1.74 (m, 1H), 1.94 (m, 2H), 2.26 (m, 3H), 3.10 (m, 2H), 3.50 (m, 1H), 3.49 (m, 1H), 6.63 (d, J = 7.6 Hz, 1H), 6.72 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H); 13 C NMR (CDCl3, 100 MHz): δ 6.8, 21.8, 23.0, 28.1, 29.9, 34.5, 35.6, 38.8, 53.0, 53.4, 53.9, 65.6, 71.2, 110.3, 118.9, 122.8, 127.0, 135.7, 149.4; HRMS (ESIMS) Calcd for C19H26N2O [M ＋H]+ 283.2169, found 283.2164.
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Acknowledgements
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The authors declare no competing financial interest. We wish to thank the generous financial support by the NSFC (21125207, 21372103), the MOST (2010CB833200) and the SRFDP (20130211110018).
Notes and references
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(25) Y, Ergun.; S, Patir.; G, Okay.; Heterocycl. Chem. 2002, 39, 315 – 317; (26) R. V, Ohri.; A. T, Radosevich.; K. J, Hrovat.; C, Musich.; D, Huang.; T. R, Holman.; F. D, Toste. Org. Lett. 2005, 7, 2501 – 2504; (27) G, Cravotto.; G. B, Giovenzana.; A, Maspero.; T, Pilati.; A, Penoni.; G, Palmisano.; Tetrahedron Lett. 2006, 47, 6439 – 6443. (28) A. J, Birch. J. Chem. Soc. 1944, 430-436; (29) L. E, Overman.; Y, Shin. Org. Lett. 2007, 9, 339-341.
† State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, People’s Republic of China. *E-mail: 10
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Collaborative lnnovation Center of Chemical Science and Engineering Tianjin(P.R. China)
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Electronic Supplementary Information (ESI) available: Detailed experimental procedures, characterizations and copies of 1H- and 13 C-NMR spectra of new compounds. See DOI: 10.1039/b000000x/ (1) a) J. E, Saxton. in Chemistry of Heterocyclic Compounds, Wiley, New York, 2008, pp. 331 – 437; b) J. E, Saxton,; in the Alkaloids: Chemistry and Biology, Vol. 50 (Ed.: G. A. Cordell), Academic Press, New York, 1998; c) M, Toyota.; M, Ihara. Nat.Prod. Rep.1998, 15, 327 – 340; d) J. E, Saxton.; the Indoles: the monoterpe noidindole alkaloids, Vol. 25, Wiley-Interscience, 1983. (2) “Synthesis of the Aspidosperma Alkaloids”: J. E, Saxton. in the Alkaloids, Vol. 50 (Ed.: G. A.Cordell), Academic Press, San Dieg o. 1998, pp. 343 – 376. (3) For pioneering syntheses: G, Stork.; J. E, Dolfini. J. Am. Chem. Soc. 1963, 85, 2872-2873. (4) J, Harley-Mason.; M, Kaplan. J. Chem. Soc., Chem. Commun. 1967, 915-916. (5) G, Büchi.; K. E, Matsumoto. J. Am. Chem. Soc. 1971, 93, 3299-3301. (6) P, Le Me´nez.; N, Kunesch.; S, Liu.; E, Wenkert. J. Org. Chem. 1991, 56, 2915-2918. (7) T, Gallagher.; P, Magnus.; J, Huffman. J. Am. Chem. Soc. 1982, 104, 1140-1141. (8) L. E, Overman.; M, Sworin.; R. M, Burk. J. Org. Chem. 1983, 48, 2685-2690. (9) B, Patro.; J. A, Murphy. Org. Lett. 2000, 2, 3599-3601. (10) M. A, Toczko.; C. H, Heathcock. J. Org. Chem. 2000, 65, 2642. (11) O, Callaghan.; C, Lampard.; A. R, Kennedy.; J. A, Murphy. J. Chem. Soc., Perkin Trans. 1 1999, 995-1001. (12) A, Urrutia.; J. G, Rodriguez. Tetrahedron 1999, 55, 11095. (13) J. F, Quinn.; M. E, Bos.; W. D, Wulff. Org. Lett. 1999, 1, 161-164. (14) S. A, Kozmin.; V. H, Rawal. J. Am. Chem. Soc. 1998, 120, 1352313524 (15) Z, Li.; S, Zhang.; S, Wu.; X, Shen.; L, Zou.; F, Wang.; X, Li.; F, Peng.; H, Zhang.; Z, Shao. Angew. Chem., Int. Ed. 2013, 52, 41174121. (16) P, Jing.; Z, Yang.; C,Zhao.; H, Zheng.; B, Fang.; X, Xie.; X, She.; Chem. Eur. J. 2012, 18, 6729. (17) D, Sissouma.; L, Maingot.; S, Collet.; J. Org. Chem. 2006, 71, 8384 –8389. (18) For a reports on iminium ion intermediates, see: L. G, Humber.; E, Ferdinandi.; C. A, Demerson.; S, Ahmed.; U, Shah.; D, Mobilio.; J, Sabatucci.; B, De Lange.; Labbadia, F.; J. Med. Chem. 1988, 31, 1712 –1719; (19). J, Bergman,.; S, Bergman.; J. O, Lindstroem,. Tetrahedron Lett. 1989, 30, 5337 –5340;
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(20) L, Castedo.; J. C, Estevez.; R. J, Estevez.; J. A, Seijas.; M. P, Vazquez Tato.; M. C, Villaverde. An. Quim. 1990, 86, 805 – 807; (21) D, Desma le.; J. d, Angelo. Tetrahedron Lett. 1990, 31, 883 – 886; (22) D, Desma le.; J. d, Angelo.; J. Org.Chem.1994, 59, 2292 – 2303; (23) B, Jiang.; J. M, Smallheer.; C, Amaral-Ly.; M. A, Wuonola.; J. Org. Chem. 1994, 59, 6823 –6827; (24) Y, Ergun.; S, Patir.; G. J, Okay.; Heterocycl. Chem. 2002, 39, 315 – 317;
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Abstract: (±)-Aspidospermidine (1) has been synthesized from the commercially available 2,3-dihydro-1H-carbazol-4(9H)-one 6 in 10 steps with 20% overall yield. Key step of the strategy is a one-pot carbonyl reduction / iminium formation / intramolecular conjugate addition reaction that may be applied for synthesis of other kind of Aspidosperma alkaloids.
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