A new total synthesis of (±)-α-noscapine

Article abstract of DOI:10.3987/COM-13-12843

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.

Full text of DOI:10.3987/COM-13-12843

HETEROCYCLES, Vol. 87, No. 12, 2013
2633
HETEROCYCLES, Vol. 87, No. 12, 2013, pp. 2633 - 2640. © 2013 The Japan Institute of Heterocyclic Chemistry
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 Drug Design and Discovery (Shenyang
Pharmaceutical University), Ministry of Education, Shenyang Pharmaceutical
University, 103 Wenhua Road, Shenyang 110016, PR China. Email:
dongmeiz-67@163.com
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
1
2
somniferum L. This agent is primarily used for its antitussive (cough-suppressing) effects, which
3
appears to be primarily mediated by its sigma receptor agonist activity. It has been also found that
4
5
6
(
–)-α-noscapine displays other potential clinical utilities for the treatment of cancer, stroke, anxiety,
7
cerebral edema, and so on.
1'
9'
8'
O
7'
O
O
O
O
O
O
2'
6
'
5
R
' N
N
H
N
H
N
H
Me
Me
Me
Me
3
'O
4'
S
R
S
H
MeO H
MeO H
MeO H
MeO H
S
R
R
S
4
3
O 2
O
O
O
O
O
O
5
1
O
6
7
MeO
MeO
MeO
MeO
OMe
OMe
OMe
OMe
1
2
4
5
3, ()--noscapine (erythro-)
6, ()--noscapine (threo-)
Figure 1. Stereochemical Structures of Noscapine
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

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HETEROCYCLES, Vol. 87, No. 12, 2013
(±)-β-noscapine (6, or threo-noscapine) exhibits less biological activities.
8
Clinically used narcotine can be provided through extraction from plant resource or possible resolution
9
of synthetic (±)-α-noscapine (3). So far, the total synthesis of narcotine or (±)-α-noscapine is still limited.
1
0
The pioneer work was reported by Robinson and Perkin who constructed C5’-C3 bond through direct
condensation between meconin (8) and cotarnine (18) (Scheme 1), which were produced by degradation
1
1
of natural narcotine. Shono developed zinc-promoted reductive coupling of 3-bromo-meconin to the
1
2
13
iminium salt of cotarnine to construct C5’-C3 bond. Alternatively, Kerekes and Szántay synthesized
tetrahydroisoquinoline skeleton through Bischler-Napieralski reaction after formation of C5’-C3 bond. In
1
4
recent years Xu et al. also developed a new blocking group-directed diastereoselective synthetic method
based on the Bischler-Napieralski cyclization.
Me
Me
Me
Si
a
b
O
O
HO C
OMe
OMe
2
OMe
O
OMe
OMe
O
OMe
7
8
9
O
O
O
O
O
O
O
O
c
d
e
OMe
OMe
OMe
OMe
CHO
OMe OMe
13
OMe
I
10
11
1
2
OMe
H N
MeO OMe
N
2
MeO OMe
O
O
OMe
O
O
O
f
h
i
1
5
CHO
NH
O
Me
g
OMe
OMe
OMe
1
4
16
17
OH
O
O
j
O
O
O
O
k
I
9
3
N
N
N
Me
Me
Me
l
OMe
OMe
OMe
18
19
20
Scheme 1. Reagents and conditions: (a) 37% aq. HCl, 37% aq. HCHO, AcOH, 50 ~ 60 ºC, 24 h, 74%; (b)
i) LDA, THF, −70 ~ −50 ºC, 1 h; ii) TMSCl, −70 ~0 ºC, 2 h, 96%; (c) CH(OMe) , MeOH, 50 ~ 60 ºC, 1 h;
3
(
d) i) n-BuLi, THF, −10 ~ −5 ºC, 1 h; ii) I , −10 ~ −5 ºC, 1 h, 89%; (e) NaOMe, CuI, DMF, 60 ~ 70 ºC,
2
1
2 h; (f) 10% aq. HCl, CH Cl , rt, 4 h, 69%; (g) MeOH, NaBH , 0 ºC ~ rt, 1 h; (h) MeOH, 37% aq.
2 2 4
HCHO, NaBH , 0 ºC ~ rt, 1 h; (i) 20% aq. HCl, rt, 24 h, 77%; (j) TFA, NaBH , 0 ºC ~ rt, 24 h, 98%; (k)
4
4
AcOK, I , EtOH, 80 ºC, 3 h, 84%; (l) KHF , DMF, rt, 24 h, 42%.
2
2

HETEROCYCLES, Vol. 87, No. 12, 2013
2635
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
1
5
isolated yield. Then it was treated with LDA and TMSCl respectively at low temperature to give the
1
6
3
-trimethylsilyl derivative 9 in high yield, 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
17
acetal protected product 11 was treated with n-BuLi and I respectively to give the 4-iodo product 12,
2
which was substituted by –OMe, deprotected of the acetal to give the key intermediate 14 in 61% yield
1
8
over five steps. 2,2-Dimethoxyethanamine (15) and 37% aq. HCHO were used successively in the next
1
9
reductive amination steps, 17 was obtained in quantitative yield, which was then conducted the
2
0
intramolecular cyclization in 20% aq. HCl to give cotarnine 18 in 77% yield over three steps. The 4-OH
2
0a
of 18 was eliminated using TFA/NaBH condition to give the tetrahydroisoquinoline 19 in 98% yield,
4
which was then treated with AcOK and I to give the cotarnine iodized salt derivative 20 in 84% isolated
2
2
1
yield. At the last step, adopting KHF to cut the C-Si bond of 9, it was coupled with 20 in DMF to give
2
2
1
noscapine. 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.
1
H 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

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HETEROCYCLES, Vol. 87, No. 12, 2013
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/H O (180 g) to give 8 (71.8 g, 74%)
2
2
2
1
as a white solid. mp 100 ~ 101 ºC (ref., 102 ~ 103 ºC). H NMR (300 Hz, CDCl ): δ 3.92 (s, 3H), 4.11
3
(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),
4
11.0 (2M + Na).
6
,7-Dimethoxy-3-(trimethylsilyl)isobenzofuran-1(3H)-one (9). A 2 M LDA/THF solution (165 mL,
.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
0
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 CH Cl (900 g), washed with water (600 g × 3), dried over anhydrous
2
2
Na SO . The solvent was recovered to give 9 (76.7 g, 96%) as a white solid, which was used directly at
2
4
1
6
1
the next step. mp 107 ~ 110 ºC (ref., 110 ~ 112 ºC). H NMR (300 Hz, CDCl ): δ 0.10 (s, 9H), 3.91 (s,
3
3
H), 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) (138.0 g, 1.3 mol) and anhydrous MeOH (400 g) was stirred and heated at 50 ~ 60 ºC for 1 h.
3
The volatile materials were removed to give 5-(dimethoxymethyl)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. I (280.0 g, 1.1 mol) was added portionwise into the reaction mixture over 1 h to keep the
2
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 CH Cl (2 kg), washed with 10%
2
2
aq. Na SO (1.5 kg × 2), water (1.5 kg × 2), dried over anhydrous Na SO . The solvent was recovered to
2
3
2
4
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

HETEROCYCLES, Vol. 87, No. 12, 2013
2637
around 600 g DMF was recovered. The residuum was dissolved in CH Cl (1.5 kg) and washed with
2
2
water (1 kg × 3). The CH Cl solution was stirred rapidly with 10% aq. HCl solution (600 g) at rt for 4 h.
2
2
The organic layer was separated, washed with water (1 kg × 2), 5% aq. NaHCO (1 kg × 2) respectively,
3
dried over anhydrous Na SO . The solvent was recovered to give crude 14 (146 g) as a yellow-brown
2
4
solid, which was purified by recrystallization from 85% MeOH/H O (290 g) one time to give the pure 14
2
2
3
1
(
110 g, 69%) as a grey needle. mp 101 ~ 103 ºC (ref., 101 ~ 102 ºC). H NMR (300 Hz, CDCl ): δ 4.13
3
(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):
2
03.0 (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
h before it was cooled to 0 ~ 10 ºC. NaBH (11.5 g, 0.3 mol) was added portionwise into the reaction
1
4
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 CH Cl (1
2
2
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. NaBH (15.0 g, 0.4 mol) was added
4
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 CH Cl (1 kg), washed with water (1 kg × 3). The solvent was recovered to give
2
2
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/H O (230 g) to give pure 18 (91.2 g, 77%) as a
2
2
0
1
white solid. mp 151 ~ 153 ºC (ref., 153 ~ 154 ºC). H NMR (300 Hz, CDCl ): δ 2.45 (s, 3H), 2.87-3.11
3
(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). NaHB (15.1 g, 0.4 mol)
4
was added portionwise into a stirred solution of compound 18 (71.2 g, 0.3 mol) and TFA (137 g, 1.2 mol)

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HETEROCYCLES, Vol. 87, No. 12, 2013
in CH Cl (600 g) over 1 h to keep the reaction temperature below 25 ºC and the reaction mixture was
2
2
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
4
0 ºC. The organic layer was separated, washed by water (600 g × 4), dried over anhydrous Na SO . The
2 4
2
0a
solvent was recovered to give 19 (64.7 g, 98%) as a faint-yellow solid. mp 43 ~ 46 ºC (ref., 44 ~ 45 ºC).
1
H NMR (300 Hz, CDCl ): 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
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 I (77.4 g, 0.3 mol) in anhydrous
2
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
2
3
1
(
79.5 g, 84%) as a faint-yellow solid. mp 178 ~ 181 ºC (ref., 183 ~ 184 ºC). H NMR (300 Hz,
DMSO-d ): 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
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 KHF (19.5 g,
2
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
2
4
1
(
ref., 232 ºC). H NMR (300 Hz, CDCl ): δ 1.95 (br s, 1H), 2.37 (br s, 2H), 2.56 (s, 3H), 2.58 (br s, 1H),
3
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.

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