HETEROCYCLES

Note | Special issue | Vol. 77, No. 2, 2009, pp. 1397-1402
Received, 7th August, 2008, Accepted, 24th September, 2008, Published online, 24th September, 2008.
DOI: 10.3987/COM-08-S(F)104

■ First Total Synthesis of Crispine B by Nitro Aldol and the Bischler-Napieralski Reaction

Tomohisa Yasuhara, Naoko Zaima, Satoko Hashimoto, Masako Yamazaki, and Osamu Muraoka*

Faculty of Pharmaceutical Sciences, Kinki University, 3-4-1, Kowakae, Higashi-Osaka 577-8502, Japan

Abstract

A pyrrolo[2,1-a]isoquinoline alkaloid, crispine B, was firstly synthesized in 55% overall yield from 3,4-dimethoxyaldehyde via five steps by employing nitro-aldol reaction and the Bischler-Napieralski reaction.

INTRODUCTION
We have been involved in the total synthesis of biologically active multi-substituted tetrahydroisoquinoline alkaloids by utilizing the high nucleophilicity of carbanions generated at the α-nitric position,1 such as nitro-aldol reaction or conjugate addition of the anions to α,β-unsaturated esters. In our previous studies, α- (1) , β- (2) and γ-lycoranes (3), which are deoxygenated skeletons of amaryllidaceae tetrahydroisoquinoline alkaloid lycorine (4), were successfully synthesized2,3 by the strategy mentioned above, chemoselective conjugate addition of aryllithium to a nitroalkene and subsequent stereoselective intramolecular nitro-Michael cyclization being employed.4

Recently, another pyrroloisoquinoline type of alkaloids, such as crispine A (5) and B (6), have been isolated as bioactive constituents from a Chinese fork medicine Carduus crispus L. which has been used for the treatment of cold, stomachache and rheumatism.5 Significant cytotoxic activities6,7 of these compounds on some human-cancer cell line have also been reported. Of these two bioactive alkaloids, enantioselective total syntheses of 5 were accomplished by several groups,7-16 but compound 6 has still been left unsynthesized so far.

As a part of our continuing study on the synthesis of multi-substituted tetrahydroisoquinoline alkaloids, we describe herein the facile first total synthesis of crispine B (6) by applying our general strategy, as is shown in Scheme 1, for the synthesis of such kind of alkaloids. In the present study, the target compound 6 was synthesized in 55% overall yield in five steps by using 3,4-dimethoxybenzaldehyde (7, R1 = (-OMe)2, R2 = H), nitromethane (8, R3 = H) and 4-chlorobutyric acid (9, R4 = -CH2CH2CH2Cl) as substrates.

RESULTS AND DISCUSSION
As for the Henry reaction of the first step, we employed the simple and practical method recently developed by Oriyama and co-workers.17 Thus, in the presence of MS4A, treatment of 3,4-dimethoxy­benzaldehyde (7) with nitromethane (8) in DMSO for 24 h at room temperature afforded 1-(3,4-dimethoxy­phenyl)-2-nitroethanol (10) in 86% yield (Scheme 2). Palladium catalyzed reduction of the nitro group of 10 with hydrogen gave 2-amino-1-(3,4-di­methoxyphenyl)ethanol (11), which was then treated, without purification, with 4-chlorobutyloyl chloride (9) in the presence of triethylamine at 0 °C to give the desired N-acylated product, 4-chloro-N-[2-(3,4-dimethoxy­phenyl)-2-hydroxy­ethyl]­butyramide 12 in 93% yield from 10. Intramolecular cyclization reaction of 12 with sodium hydride in DMF for 3 h at 0 °C afforded 1-[2-(3,4-dimethoxy­phenyl)-2-hydroxy­ethyl]­pyrrolidin-2-one (13) in 85% yield. The Bischler-Napieralski reaction9,18-20 of 13 and dehydration reaction with phosphoryl chloride in toluene under reflux for 3.5 h gave crispine B (6) in 81% yield. Spectroscopic data and the melting point of the synthetic crispine B (6) were in good accordance with those reported.6

Thus, facile total synthesis of crispine B (6) was accomplished in 55% overall yield from 3,4-dimethoxyaldehyde via five steps. Synthesis of other multi-substituted tetrahydroisoquinoline alkaloids by employing the general strategy shown in Scheme 1 is in progress.

EXPERIMENTAL
Column chromatography was effected over Fuji Silysia Chemical silica gel BW-200. NMR spectra (400 MHz 1H, 100 MHz 13C) were measured in CDCl3 on a JEOL AL-400 spectrometer using tetramethylsilane as an internal standard unless otherwise noted. Chemical shifts (δ) and coupling constants (J) are given in ppm and Hz, respectively. IR spectra were measured on a Shimadzu IR-455 spectrometer, and wavenumbers of maximum absorption peaks are presented in cm-1. MS spectra were measured on a JEOL tandem MStaion JMS-700 spectrometer. All melting points were taken on a hot stage apparatus and are uncorrected. Combined organic extracts were dried over anhydrous sodium sulfate prior to evaporation.

1-(3,4-Dimethoxyphenyl)-2-nitroethanol (10). To a solution of 3,4-dimethoxybenzaldehyde (7, 4.99 g, 30 mmol) in DMSO (180 mL) were added powdered MS4A (6.0 g) and nitromethane (8.06 mL, 150 mmol) under argon atmosphere. After stirring at rt for 24 h, the reaction mixture was quenched with phosphate buffer (pH 7, 50 mL), and extracted with EtOAc (100 mL x 3). Combined organic layers were washed successively with water (20 mL x 3) and brine (20 mL), and dried. Concentration and column chromatography (hexane : EtOAc = 4 : 1) of the residue afforded 10 as a pale yellow solid (5.81 g, 86%); mp 91–92 °C (lit.,21 92–93.5 °C (from benzene–petroleum ether)). 1H NMR δ: 3.89 (3H, s), 3.89 (3H, s), 4.50 (1H, dd, J = 3.2, 13.2), 4.62 (1H, dd, J = 10.0, 13.2), 4.10 (1H, ddd, J = 3.2, 6.4, 9.6), 6.86–6.94 (3H, m). 13C NMR δ: 55.8, 55.8, 70.8, 81.2, 108.8, 111.2, 118.2 (C x 2), 130.7, 149.2. IR (CHCl3): 3422, 2939, 2839, 1558, 1458, 1420, 1377, 1238, 1142, 1076, 1026. FAB-MS m/z: 228 [M+H]+.

4-Chloro-N-[2-(3,4-dimethoxyphenyl)-2-hydroxyethyl]butyramide (12). To a solution of 10 (1.14 g, 5.02 mmol) in MeOH (10 mL), palladium on carbon (500 mg) was added, and the reaction mixture was stirred at rt for 2 h under hydrogen atmosphere. Then the mixture was filtrated, and concentration of the filtrate afforded crude 11 as a colorless oil. The resulting oil was then dissolved in CHCl3 (10 mL), and to the solution triethylamine (1.0 mL, 6.9 mmol) and 4-chlorobutyric chloride (0.60 mL, 5.5 mmol) were added under ice-cooling. After stirring for 2 h at 0 °C, the reaction mixture was washed successively with 10% hydrochloric acid (10 mL x 2), saturated NaHCO3 aq (10 mL x 2) and brine (10 mL). The organic layer was dried and concentrated. Column chromatography (hexane : EtOAc = 4 : 1) of the residue afforded 12 as a pale yellow oil (1.409 g, 93%, 2 steps). 11: 1H NMR δ: 2.90–3.12 (2H, m), 3.76 (3H, s), 3.78 (3H, s), 4.81 (1H, brs), 5.29 (3H, brs), 6.70 (1H, d, J = 8.4), 6.79 (1H, d, J = 8.4), 6.89 (1H, s). 13C NMR δ: 47.7, 55.7, 55.7, 71.8, 109.1, 110.9, 117.9, 133.9, 148.4, 148.8. 12: 1H NMR δ: 2.08 (2H, tt, J = 6.2, 7.0), 2.36 (2H, t, J = 7.0), 3.33 (1H, ddd, J = 5.2, 8.0, 14.0), 3.56 (2H, t, J = 6.2), 3.64 (1H, ddd, J = 3.2, 6.8, 14.0), 3.88 (3H, s), 3.89 (3H, s), 4.76 (1H, dd, J = 3.2, 8.0), 6.22 (1H, brs), 6.82 (1H, d, J = 8.0), 6.87 (1H, d, J = 8.0), 6.91 (1H, s). 13C NMR δ: 28.0, 33.0, 44.3, 47.3, 55.8, 55.9, 73.1, 108.9, 111.0, 117.9, 134.3, 148.5, 149.0, 172.9. IR (CHCl3): 3345, 2940, 1647, 1597, 1516, 1466, 1261, 1219. FAB-MS m/z: 302 [M+H]+. HR-FAB-MS m/z: Calcd for C14H21ClNO4: 302.1159. Found 302.1165.

1-[2-(3,4-Dimethoxyphenyl)-2-hydroxyethyl]pyrrolidin-2-one (13). To a suspension of sodium hydride (160 mg, 4.0 mmol) in dry DMF (40 mL), a solution of 12 (1.0 g, 3.3 mmol) in dry DMF (10 mL) was added dropwise at 0 °C. After stirring for 2 h at 0 °C, the reaction was quenched with saturated ammonium chloride aq (20 mL), and the resulting mixture was extracted with EtOAc (20 mL x 3). Combined organic extracts were washed successively with water (20 mL x 3) and brine (20 mL), and dried. Concentration and column chromatography (hexane : EtOAc = 2 : 1) of the residue afforded 13 as a colorless solid (995 mg, 85%). For analytical purpose a small portion was recrystallized from hexane–EtOAc to give colorless crystals; mp 90–92 °C (lit.,22 90-91 °C). 1H NMR: δ: 1.99 (2H, m), 2.42 (2H, t, J = 7.4 Hz), 3.26 (1H, ddd, J = 6.8, 7.6, 9.6 Hz), 3.36 (1H, ddd, J = 6.8, 7.2, 9.6 Hz), 3.50 (1H, dd, J = 4.0, 14.4 Hz) , 3.56 (1H, dd, J = 7.2, 14.0 Hz), 3.88 (3H, s), 3.90 (3H, s), 4.00 (1H, brs), 4.92 (1H, brs), 6.84 (1H, d, J = 8.0 Hz), 6.89 (1H, d, J = 8.0 Hz), 6.96 (1H, s). 13C NMR δ: 18.4, 30.8, 49.5, 51.9, 55.9 (C x 2), 72.9, 108.9, 110.9, 118.0, 134.7, 148.5, 149.1, 177.1. IR (CHCl3): 3333, 1666, 1516, 1466, 1261, 1219. FAB-MS m/z: 266 [M+H]+.

Crispine B (6). To a refluxing solution of 13 (143 mg, 0.54 mmol) in dry-toluene (3 mL), phosphoryl chloride (1.2 mL, 1.29 mmol) was added, and the resulting mixture was stirred under reflux for 3.5 h. Concentration and column chromatography afforded 6 as a colorless solid (116 mg, 81%). Analytical sample of 6 was obtained as colorless crystals by recrystallization from CHCl3–hexane; mp 212–214 °C (lit.,6 213–215 °C). 1H NMR (MeOH-d4): δ: 2.63 (2H, tt, J = 7.6, 8.0 Hz), 3.89 (2H, t, J = 8.0 Hz), 4.08 (3H, s), 4.10 (3H, s), 4.91 (2H, t, J = 7.6 Hz), 7.57 (1H, s), 7.65 (1H, s), 8.07 (1H, d, J = 6.8 Hz), 8.36 (1H, d, J = 6.8 Hz). 13C NMR δ: 22.0, 32.5, 57.2, 57.4, 60.2, 106.5, 107.4, 122.4, 123.8, 130.9, 137.0, 154.7, 159.1, 159.7. IR (Nujol): 2943, 2855, 1458, 1377. FAB-MS m/z: 230 [M-Cl-]+.

ACKNOWLEDGEMENTS
This work was supported by “High-Tech Research Center” Project for Private Universities: matching fund subsidy from MEXT (Ministry of Education, Culture, Sports, Science and Technology), 2007-2011.


† This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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