First total synthesis of crispine B by nitro aldol and the Bischler-Napieralski reaction

Article abstract of DOI:10.3987/COM-08-S(F)104

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.

Full text of DOI:10.3987/COM-08-S(F)104

HETEROCYCLES, Vol. 77, No. 2, 2009
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HETEROCYCLES, Vol. 77, No. 2, 2009, pp. 1397 - 1402. © The Japan Institute of Heterocyclic Chemistry
Received, 7th August, 2008, Accepted, 24th September, 2008, Published online, 25th 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*
School of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-Osaka Osaka,
577-8502, Japan
E-mail: muraoka@phar.kindai.ac.jp
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
OH
HO
H
N
H
H
H
N
H
H
N
H
O
O
O
O
O
O
O
O
H
H
H
H
N
γ-lycorane (3)
lycorine (4)
α-lycorane (1)
β-lycorane (2)
Figure 1. Lycoranes and lycorine
† This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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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.
MeO
MeO
MeO
MeO
Cl-
N
N
crispine B (6)
crispine A (5)
Figure 1. Crispine A and B
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.
R2
HO R2
R3
R3
HO R2
H
N
R4
N
N
R1
Cl
R1
R3
O
R4
R4
R4
R1
HO R2
HO R2
O
R3
NO2
O
NO2
NH2
R2
R3
R3
addition
acylation
reduction
R1
R1
R1
Scheme 1. General retrosynthetic pathway for multi-substituted isoquinolines or tetrahydroisoquinoline
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-dimethoxy-

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benzaldehyde (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
OH
OH
O
MeO
MeO
NO2
MeO
MeO
NH2
MeO
MeO
i
ii
iii
H
7
10
11
OH
OH Cl
MeO
MeO
MeO
MeO
MeO
MeO
iv
v
N
HN
O
N
O
Cl
12
13
6
Scheme 2. Reagents and conditions: i MeNO2 (8), MS4A, DMSO, rt, 24 h, 86%; ii H2, Pd-C, EtOH, rt, 2
h; iii Cl(CH2)3COCl (9), TEA, CHCl3, 0 °C, 2 h, 93% (2 steps), iv NaH, DMF, 0 °C, 3 h, 85%; v POCl3,
toluene, reflux, 3.5 h, 81%
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

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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
1
residue afforded 12 as a pale yellow oil (1.409 g, 93%, 2 steps). 11: H 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

HETEROCYCLES, Vol. 77, No. 2, 2009
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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.
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