HETEROCYCLES

Short Paper | Regular issue | Vol. 87, No. 12, 2013, pp. 2633-2640
Received, 16th September, 2013, Accepted, 21st October, 2013, Published online, 31st October, 2013.
DOI: 10.3987/COM-13-12843

■ A New Total Synthesis of (±)-α-Noscapine

Yongjun Mao, Shuai Song, Dongmei Zhao,* and Maosheng Cheng

Key Laboratory of Structure-Based Drugs Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China

Abstract

A new, convergent total synthesis of (±)-α-noscapine was developed on a grams scale through the condensation of 3-trimethylsilyl meconin derivative 9 and the iodized salt cotarnine derivative 20 as the key step. Staring from simple 2,3-dimethoxybenzoic acid, piperonal and 2,2-dimethoxyethanamine, through the traditional chemical processes to give the final product in 11.6% yield over 14 steps.

(–)-α-Noscapine (1, also known as narcotine, nectodon, nospen) (Figure 1) is a benzylisoquinoline alkaloid without significant painkilling properties, which was originally isolated from Papaver somniferum L.1 This agent is primarily used for its antitussive (cough-suppressing) effects,2 which appears to be primarily mediated by its sigma receptor agonist activity.3 It has been also found that (–)-α-noscapine displays other potential clinical utilities for the treatment of cancer,4 stroke,5 anxiety,6 cerebral edema,7 and so on.

Natural (–)-α-noscapine (or erythro-) contains two contiguous chiral carbon centers: C-5’ at tetrahydroisoquinoline ring and C-3 at phthalide framework (Figure 1). In contrast, its diastereoisomers (±)-β-noscapine (6, or threo-noscapine) exhibits less biological activities.
Clinically used narcotine can be provided through extraction from plant resource8 or possible resolution of synthetic (±)-α-noscapine (3). So far, the total synthesis of narcotine or (±)-α-noscapine is still limited.9 The pioneer work was reported by Robinson and Perkin10 who constructed C5’-C3 bond through direct condensation between meconin (8) and cotarnine (18) (Scheme 1), which were produced by degradation of natural narcotine. Shono11 developed zinc-promoted reductive coupling of 3-bromo-meconin to the iminium salt of cotarnine to construct C5’-C3 bond. Alternatively, Kerekes12 and Szántay13 synthesized tetrahydroisoquinoline skeleton through Bischler-Napieralski reaction after formation of C5’-C3 bond. In recent years Xu et al.14 also developed a new blocking group-directed diastereoselective synthetic method based on the Bischler-Napieralski cyclization.

Herein, we report a new approach to synthesis of (±)-α-noscapine (3), which constructs the C5’-C3 bond through the condensation of meconin derivative 9 and cotarnine derivative 20 as the key step (Scheme 1). Meconin (8) was produced from the easier available material 2,3-dimethoxybenzoic acid (7) with good isolated yield.15 Then it was treated with LDA and TMSCl respectively at low temperature to give the 3-trimethylsilyl derivative 9 in high yield,16 which was used directly at the last step for the synthesis of noscapine.
The second fragment 20 was synthesized from piperonal (10) through several steps (Scheme 1). The acetal protected product 11 was treated with n-BuLi and I2 respectively to give the 4-iodo product 12,17 which was substituted by –OMe, deprotected of the acetal to give the key intermediate 14 in 61% yield over five steps.18 2,2-Dimethoxyethanamine (15) and 37% aq. HCHO were used successively in the next reductive amination steps,19 17 was obtained in quantitative yield, which was then conducted the intramolecular cyclization in 20% aq. HCl to give cotarnine 18 in 77% yield over three steps.20 The 4-OH of 18 was eliminated using TFA/NaBH4 condition20a to give the tetrahydroisoquinoline 19 in 98% yield, which was then treated with AcOK and I2 to give the cotarnine iodized salt derivative 20 in 84% isolated yield.21 At the last step, adopting KHF2 to cut the C-Si bond of 9, it was coupled with 20 in DMF to give noscapine.21 The crude products should contain all of the four configurations, that were (±)-α-noscapine (3) and (±)-β-noscapine (6), while the ratio was not detected by us. Resolution of 3 from the crude product was conducted by simple recrystalization from MeOH in 42% overall yield, which was identified by comparison with the natural narcotine sample.
In summary, we have developed a new total synthetic route for (±)-α-noscapine on a grams scale through the condensation of 3-trimethylsilyl-meconin derivative 9 and the iodized salt cotarnine derivative 20 as the key step. Starting from the easy commercial available materials including 2,3-dimethoxybenzoic acid (7), piperonal (10) and 2,2-dimethoxyethanamine (15), through the traditional chemical processes to give the final product 3 in 16.3% yield over 11 steps (from 10). Most of the intermediates were purified by recrystallization.

EXPERIMENTAL
All commercially available materials and solvents were used as received without any further purification. 1H NMR spectra were recorded on a Bruker ARX-300 spectrometer using TMS as an internal standard. Mass spectra were obtained from a Finnigan MAT-95/711 spectrometer. Melting points were measured on a Buchi B-540 melting point apparatus, which are uncorrected.

6,7-Dimethoxyisobenzofuran-1(3H)-one (8). A stirred mixture of 7 (91.0 g, 0.5 mol), 37% aq. HCHO solution (81 g, 1.0 mol), 37% aq. HCl (80 g, 0.8 mol) and AcOH (200 g) was heated at 50 ~ 60 ºC for 24 h to give a clear solution, which was then poured into chilled water (1 kg). The resulting solid was collected by suction filtration, washed by water (60 g × 3), and dried at 50 ºC to give the crude 8 (95 g) as a tan solid, which was purified by recrystallization from 90% MeOH/H2O (180 g) to give 8 (71.8 g, 74%) as a white solid. mp 100 ~ 101 ºC (ref.,22 102 ~ 103 ºC). 1H NMR (300 Hz, CDCl3): δ 3.92 (s, 3H), 4.11 (s, 3H), 5.20 (s, 2H), 7.09 (d, 1H, J = 8.2 Hz), 7.25 (d, 1H, J = 8.2 Hz). ESI-MS (m/z): 217.0 (M + Na), 411.0 (2M + Na).

6,7-Dimethoxy-3-(trimethylsilyl)isobenzofuran-1(3H)-one (9). A 2 M LDA/THF solution (165 mL, 0.33 mol) was added slowly to the cooled solution of 8 (58.2 g, 0.3 mol) in dry THF (500 g) over 1 h under nitrogen atmosphere to keep the reaction temperature between –70 ~ –50 ºC. The reaction solution was stirred at the temperature for another 30 min and an orange solution was obtained, which was treated dropwise with TMSCl (60.0 g, 0.55 mol) over 1 h. The resulting faint yellow solution was stirred for another 2 h and the reaction temperature was raised to ~0 ºC. The volatile materials were removed and the residuum was triturated with CH2Cl2 (900 g), washed with water (600 g × 3), dried over anhydrous Na2SO4. The solvent was recovered to give 9 (76.7 g, 96%) as a white solid, which was used directly at the next step. mp 107 ~ 110 ºC (ref.,16 110 ~ 112 ºC). 1H NMR (300 Hz, CDCl3): δ 0.10 (s, 9H), 3.91 (s, 3H), 4.10 (s, 3H), 5.16 (s, 1H), 6.92 (d, 1H, J = 8.2 Hz), 7.22 (d, 1H, J = 8.2 Hz). ESI-MS (m/z): 267.0 (M + H), 288.9 (M + Na), 554.9 (2M + Na).

4-Methoxybenzo[d][1,3]dioxole-5-carbaldehyde (14). A mixture of piperonal (150.1 g, 1.0 mol), CH(OMe)3 (138.0 g, 1.3 mol) and anhydrous MeOH (400 g) was stirred and heated at 50 ~ 60 ºC for 1 h. The volatile materials were removed to give 5-(dimethoxy-methyl)benzo[d][1,3]dioxole (11) as a faint yellow oil.
A 2.5 M n-BuLi/THF solution (440 mL, 1.1 mol) was added slowly to the cooled solution of 11 (196 g, 1.0 mol) in dry THF (800 g) over 1 h under nitrogen atmosphere to keep the reaction temperature between –10 ~ –5 ºC. The reaction solution was stirred at the temperature for another 30 min and a red solution was obtained. I2 (280.0 g, 1.1 mol) was added portionwise into the reaction mixture over 1 h to keep the reaction temperature below 0 ºC. The resulting dark red solution was stirred for another 30 min at 0 ºC. The volatile materials were removed and the residuum was dissolved in CH2Cl2 (2 kg), washed with 10% aq. Na2SO3 (1.5 kg × 2), water (1.5 kg × 2), dried over anhydrous Na2SO4. The solvent was recovered to give 5-(dimethoxymethyl)-4-iodobenzo[d][1,3]dioxole 12 (287 g, 89%) as a tan solid.
A mixture of 12 (287 g, 0.89 mol), NaOMe (96.0 g, 1.78 mol) and CuI (17.1 g, 0.09 mol) in dry DMF (1 kg) was stirred and heated at 60 ~ 70 ºC for 12 h to give a dark brown solution. The reaction solution was cooled to rt and filtered through a celite pad. The filtrate was concentrated under reduced pressure and around 600 g DMF was recovered. The residuum was dissolved in CH2Cl2 (1.5 kg) and washed with water (1 kg × 3). The CH2Cl2 solution was stirred rapidly with 10% aq. HCl solution (600 g) at rt for 4 h. The organic layer was separated, washed with water (1 kg × 2), 5% aq. NaHCO3 (1 kg × 2) respectively, dried over anhydrous Na2SO4. The solvent was recovered to give crude 14 (146 g) as a yellow-brown solid, which was purified by recrystallization from 85% MeOH/H2O (290 g) one time to give the pure 14 (110 g, 69%) as a grey needle. mp 101 ~ 103 ºC (ref.,23 101 ~ 102 ºC). 1H NMR (300 Hz, CDCl3): δ 4.13 (s, 3H), 6.04 (s, 2H), 6.59 (d, 1H, J = 8.1 Hz), 7.47 (d, 1H, J = 8.1 Hz), 10.22 (s, 1H). ESI-MS (m/z): 203.0 (M + Na), 383.0 (2M + Na).

4-Methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-8-ol (18). A mixture of compound 14 (90.0 g, 0.5 mol) and 15 (55.2 g, 0.53 mol) in anhydrous MeOH (500 g) was stirred at rt for 1 h before it was cooled to 0 ~ 10 ºC. NaBH4 (11.5 g, 0.3 mol) was added portionwise into the reaction mixture over 1 h to keep the reaction temperature below 20 ºC. The reaction solution was stirred for another 30 min at rt. The volatile materials were removed and the residuum was dissolved in CH2Cl2 (1 kg), washed with water (1 kg × 3). The solvent was recovered to give 2,2-dimethoxy-N-((4-methoxy- benzo[d][1,3]dioxol-5-yl)methyl)ethanamine 16 (135 g) as a faint yellow oil.
A mixture of compound 16 (135 g, 0.5 mol) and 37% aq. HCHO solution (61 g, 0.75 mol) in MeOH (600 g) was stirred at rt for 1 h before it was cooled to 0 ~ 10 ºC. NaBH4 (15.0 g, 0.4 mol) was added portionwise into the reaction mixture over 1 h to keep the reaction temperature below 20 ºC. The reaction solution was stirred for another 1 h at rt. The volatile materials were removed and the residuum was dissolved in CH2Cl2 (1 kg), washed with water (1 kg × 3). The solvent was recovered to give 2,2-dimethoxy-N-((4-methoxybenzo[d][1,3]dioxol-5-yl)methyl)-N-methylethanamine 17 (142 g) as a faint yellow oil.
Compound 17 (142 g, 0.5 mol) was mixed with 20% aq. HCl (600 g) and stirred at rt for 24 h. 50% aq. NaOH solution was then added slowly into the reaction mixture to adjust the solution pH 10 ~ 11, and keep the solution temperature below 40 ºC. The resulting brown-yellow solid was collected by suction filtration, washed by water (100 g × 3), and dried at 50 ºC to give the crude 18 (114 g) as a tan solid, which was purified by recrystallization from 90% EtOH/H2O (230 g) to give pure 18 (91.2 g, 77%) as a white solid. mp 151 ~ 153 ºC (ref.,20 153 ~ 154 ºC). 1H NMR (300 Hz, CDCl3): δ 2.45 (s, 3H), 2.87-3.11 (m, 3H), 3.71 (m, 1H), 3.99 (s, 3H), 4.46 (m, 1H), 5.89 (s, 2H), 6.59 (s, 1H). ESI-MS (m/z): 238.0 (M + H), 497.0 (2M + Na).

4-Methoxy-6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinoline (19). NaHB4 (15.1 g, 0.4 mol) was added portionwise into a stirred solution of compound 18 (71.2 g, 0.3 mol) and TFA (137 g, 1.2 mol) in CH2Cl2 (600 g) over 1 h to keep the reaction temperature below 25 ºC and the reaction mixture was stirred at rt for another 24 h. Then it was cooled to 0 ~ 10 ºC and 20% aq. NaOH solution was added slowly into the reaction mixture to adjust the solution pH 10~11, and keep the solution temperature below 40 ºC. The organic layer was separated, washed by water (600 g × 4), dried over anhydrous Na2SO4. The solvent was recovered to give 19 (64.7 g, 98%) as a faint-yellow solid. mp 43 ~ 46 ºC (ref.,20a 44 ~ 45 ºC). 1H NMR (300 Hz, CDCl3): δ 2.45 (s, 3H), 2.59 (t, 2H, J = 5.9 Hz), 2.79 (t, 2H, J = 5.9 Hz), 3.44 (s, 2H), 3.97 (s, 3H), 5.84 (s, 2H), 6.30 (s, 1H). ESI-MS (m/z): 220.0 (M + H).

4-Methoxy-6-methyl-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-6-ium iodide (20). A mixture of compound 19 (60 g, 0.27 mol), anhydrous AcOK (29.4 g, 0.3 mol) and I2 (77.4 g, 0.3 mol) in anhydrous EtOH (500 g) was heated to reflux for 3 h before it was cooled to 0 ~ 10 ºC. The resulting faint-yellow solid was collected by suction filtration, washed by cooled EtOH (60 g × 3), and dried at 50 ºC to give the crude 20 (89 g), which was purified by recrystallization from anhydrous EtOH (380 g) to give pure 20 (79.5 g, 84%) as a faint-yellow solid. mp 178 ~ 181 ºC (ref.,23 183 ~ 184 ºC). 1H NMR (300 Hz, DMSO-d6): δ 3.06 (t, 2H, J = 8.1 Hz), 3.67 (s, 3H), 3.85 (t, 2H, J = 8.1 Hz), 4.11 (s, 3H), 6.20 (s, 2H), 6.83 (s, 1H), 8.99 (s, 1H).

(±)-α-Noscapine (3). A mixture of 9 (53.3 g, 0.2 mol), 20 (69.4 g, 0.2 mol) and anhydrous KHF2 (19.5 g, 0.25 mol) in dry DMF (700 g) was stirred at rt for 24 h under nitrogen atmosphere to give a orange solution. The reaction solution was filtered through a celite pad. The filtrate was concentrated under reduced pressure and around 500 g DMF was recovered. The residuum was triturated with water (600 g), stirred at rt for 1 h, the resulting brown-yellow solid was collected by suction filtration, washed by water (60 g × 3), and dried at 50 ºC to give the noscapine diastereoisomers (77 g, 92%), which was purified by recrystallization from anhydrous MeOH (390 g) to give 3 (34.7 g, 42%) as a white solid. mp 228 ~ 230 ºC (ref.,24 232 ºC). 1H NMR (300 Hz, CDCl3): δ 1.95 (br s, 1H), 2.37 (br s, 2H), 2.56 (s, 3H), 2.58 (br s, 1H), 3.86 (s, 3H), 4.02 (br s, 3H), 4.09 (s, 3H), 4.41 (br s, 1H), 5.59 (br s, 1H), 5.93 (s, 2H), 6.11 (br s, 1H), 6.31 (s, 1H), 6.96 (m, 1H). ESI-MS (m/z): 414.1 (M + H), 436.0 (M + Na), 452.0 (M + K), 849.1 (2M + Na).

ACKNOWLEDGEMENT
Supported by Program for Innovative Research Team of the Ministry of Education and Program for Liaoning Innovative Research Team in University.

References

1. P. J. Robiquet, Ann. Chim. Phys., 1817, 5, 275.
2. (a) D. W. Empey, L. A. Laitinen, G. A. Young, C. E. Bye, and D. T. Hughes, Eur. J. Clin. Pharmacol., 1979, 16, 393; CrossRef (b) B. Dahlstrom, T. Mellstrand, C. G. Lofdahl, and M. Johansson, Eur. J. Clin. Pharmacol., 1982, 22, 535; CrossRef (c) M. O. Karlsson, B. Dahlstrom, S. A. Eckernas, M. Johansson, and A. Tufvesson Alm, Eur. J. Clin. Pharmacol., 1990, 39, 275. CrossRef
3. J. Kamei, Pulm. Pharmacol., 1996, 9, 349. CrossRef
4. (a) K. Ye, N. Keshava, J. Shanks, J. A. Kapp, R. R. Tekmal, J. Petros, and H. C. Joshi, Proc. Natl. Acad. Sci., USA, 1998, 95, 1601; CrossRef (b) J. W. Landen, V. Hau, M. Wang, T. Davis, B. Ciliax, B. H. Wainer, E. G. Van Meir, J. D. Glass, H. C. Joshi, and D. R. Archer, Clin. Cancer Res., 2004, 10, 5187. CrossRef
5. (a) C. G. Sobey, Br. J. Pharmacol., 2003, 139, 1369; CrossRef (b) M. Mahmoudian, M. Mehrpour, F. Benaissa, and Z. Siadatpour, Eur. J. Clin. Pharmacol., 2003, 59, 579. CrossRef
6. P. Khodarahmi, P. Rostami, A. Rashidi, and I. Khodarahmi, Pharmacol. Rep., 2006, 58, 568.
7. J. M. Stewart, Curr. Pharm. Des., 2003, 9, 2036. CrossRef
8. R. Bognar, G. D. Gaal, P. Kerekes, and S. Szabo, Pharmazie, 1967, 22, 452.
9. (a) E. Hope and R. Robinson, J. Chem. Soc., Trans., 1914, 105, 2085; CrossRef (b) M. A. Marshall, F. L. Pyman, and R. Robinson, J. Chem. Soc., 1934, 1315; CrossRef (c) D. U. Lee, Bull. Korean Chem. Soc., 2002, 23, 1548. CrossRef
10. W. H. Perkin, Jr. and R. Robinson, J. Chem. Soc., Trans., 1911, 99, 775. CrossRef
11. T. Shono, H. Hamaguchi, M. Sasaki, S. Fujita, and K. Nagami, J. Org. Chem., 1983, 48,1621. CrossRef
12. V. P. Kerekes and R. J. Bognar, J. Prakt. Chem., 1971, 313, 923. CrossRef
13. Z. Varga, G. Blasko, G. Dornyei, and C. Szántay, Acta Chim. Hung., 1991, 128, 831.
14. J. Ni, H. Xiao, L. Weng, X. Wei, and Y. Xu, Tetrahedron, 2011, 67, 5162. CrossRef
15. M. Machida, M. Nakamura, K. Oda, H. Takechi, K. Ohno, H. Nakai, Y. Sato, and Y. Kanaoka, Heterocycles, 1987, 26, 2683. CrossRef
16. V. K. Satinder, S. Paramjit, P. K. Nachhattar, C. Usha, S. Kalpana, A. Punam, and D. Venugopal, J. Org. Chem., 1991, 56, 3908. CrossRef
17. (a) G. A. Baramki, H. S. Chang, and J. T. Edward, Can. J. Chem., 1962, 40, 441; CrossRef (b) S. T. Chadwick, R. A. Rennels, J. L. Rutherford, and D. B. Collum, J. Am. Chem. Soc., 2000, 122, 8640. CrossRef
18. (a) A. I. Meyers and K. Lutomski, J. Org. Chem., 1979, 24, 4464; CrossRef (b) P. R. R. Costa, A. J. M. da Silva, M. L. A. A. Vasconcellos, C. C. Lopes, and R. S. C. Lopes, Synlett, 1996, 783. CrossRef
19. (a) A. I. Meyers, D. A. Dickman, and M. Boes, Tetrahedron, 1987, 43, 5095; CrossRef (b) K. T. Wanner, I. Praschak, and U. Nagel, Arch. Pharm., 1990, 323, 335. CrossRef
20. (a) T. Shirasaka, Y. Takuma, T. Shimpuku, and N. Imaki, J. Org. Chem., 1990, 55, 3767; CrossRef (b) M. Schlosser, G. Simig, and H. Geneste, Tetrahedron, 1998, 54, 9023. CrossRef
21. (a) T. Shono, Y. Usui, and H. Hamaguchi, Tetrahedron Lett., 1980, 21, 1351; CrossRef (b) J. L. Bloomer and M. E. Lankin, Tetrahedron Lett., 1992, 33, 2769; CrossRef (c) R. Marsden and D. B. MacLean, Can. J. Chem., 1984, 62, 306. CrossRef
22. http://www.drugfuture.com/chemdata/meconin.html.
23. (a) F. E. Ziegler and K. W. Fowler, J. Org. Chem., 1976, 41, 1564; CrossRef (b) T. Shirasaka, Y. Takuma, and N. Imaki, Synth. Commun., 1990, 20, 1213. CrossRef
24. http://www.drugfuture.com/chemdata/noscapine.html.