Blocking group-directed diastereoselective total synthesis of (±)-α-noscapine

Article abstract of DOI:10.1016/j.tet.2011.05.060

A new approach for the diastereoselective synthesis of (±)-α- noscapine, a phthalide tetrahydroisoquinoline alkaloid exhibiting several biological activities, is described. The strategy features a blocking group-directed Bischler-Napieralski reaction followed by diastereoselective reduction (α/β>23:1). One of the key intermediates, phthalide-3-carboxylic acid, could be efficiently prepared from simple benzoic acid derivative and glyoxylic acid in one-pot.

Full text of DOI:10.1016/j.tet.2011.05.060

Tetrahedron 67 (2011) 5162e5167
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Blocking group-directed diastereoselective total synthesis of (ꢀ)-
a-noscapine
Jizhi Ni , Heping Xiao , Lipeng Weng , Xiaofeng Wei a , Youjun Xu a
a
,
b
a
,
b
a
,
b
,
b
,b,
*
a
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
b
Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A
new approach for the diastereoselective synthesis of (ꢀ)-
a-noscapine, a phthalide tetrahy-
Received 21 February 2011
Received in revised form 5 May 2011
Accepted 13 May 2011
droisoquinoline alkaloid exhibiting several biological activities, is described. The strategy features
a blocking group-directed BischlereNapieralski reaction followed by diastereoselective reduction
(
a
/
b
>23:1). One of the key intermediates, phthalide-3-carboxylic acid, could be efficiently prepared from
Available online 19 May 2011
simple benzoic acid derivative and glyoxylic acid in one-pot.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Noscapine
Phthalide-3-carboxylic acid
Blocking group
Total synthesis
Diastereoselective synthesis
1
. Introduction
noscapine and/or other regioisomers. Therefore, efficient diaster-
eoselective total synthesis of (ꢀ)- -noscapine without production
of any undesired regioisomers is still very important.
a
Opium alkaloid (ꢁ)-
a-noscapine (narcotine), which was origi-
1
nally isolated from Papaver somniferum L., is a classical non-
addictive antitussive agent without significant toxicity. It has
2
1
'
9'
8'
been found that (ꢁ)-
a-noscapine also displays other potential
O
7'
O
O
3
clinical utilities for the treatment of cancer, stroke, anxiety, cere-
2'
6
'
5' N
N
H
bral edema, and so on. Natural noscapine (
contains two contiguous chiral carbon centers: C-5 at tetrahy-
droisoquinoline ring and C-3 at phthalide framework. In contrast,
a
- or erythro-form)
O
Me
Me
3'
4'
MeO
H
H
H
O
0
4
MeO
O 3
5
its diastereoisomers (
b
-noscapine, threo-form) are synthetic com-
pounds exhibiting less biological activities.
Clinically used (ꢁ)- -noscapine can be provided through ex-
traction from plant resource or possible resolution of synthetic
ꢀ)- -noscapine (1). So far, the total synthesis of (ꢀ)- -noscapine is
still limited. The pioneer work was reported by Robinson and Per-
1
4
O
O
7
6
OMe
OMe
MeO
MeO
a
5
α-noscapine (ery thro-form)
β-noscapine (threo-form)
(
a
a
6
0
kin who constructed C5 eC3 bond through direct condensation
2. Results and discussion
between cortanine and meconine, which were produced by deg-
7
radation of natural (ꢁ)-
a
-noscapine. Shono et al. developed
Herein, we report
a
new approach employing Bisch-
zinc-promoted reductive coupling of 3-bromo-meconine to the
lereNapieralski cyclization as a key step for the total synthesis of
(ꢀ)- -noscapine (Scheme 1). We envisioned that by installing
a removable blocking group (such as Br) onto C-9 position, the
0
iminium salt of cotarnine to construct C5 eC3 bond. Alternatively,
a
Kerekes and Bogn aꢀ r.8 and Sz aꢀ ntay et al. synthesized tetrahy-
9
0
10
0
0
droisoquinoline skeleton through BischlereNapieralski reaction
after formation of C5 eC3 bond. However, the main problem for
these procedures was formation of nearly equivalent (ꢀ)-
formation of undesired regioisomers (C5 eC9 connection) would
be exclusively avoided during BischlereNapieralski cyclization. The
produced imine could be diastereoselectively reduced into tetra-
hydroisoquinoline. The intermediate 2 could be obtained from
meconine-3-carboxylic acid (3a) and arylethylamine 4. We would
also describe here a facile synthesis of 3a from commercially
available carboxylic acid 5a and glyoxylic acid (6).
0
b-
*
Corresponding author. Tel./fax: þ86 24 23986411; e-mail address: xuyoujun@
syphu.edu.cn (Y. Xu).
0
040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.060

J. Ni et al. / Tetrahedron 67 (2011) 5162e5167
5163
(entries 5 and 6) or Lewis acids (entries 7e9) afforded poor
to moderate yield. In addition, neither use of other solvent (e.g.,
entry 11) nor elevation of reaction temperature (entry 12) could
improve the reaction yield furthermore.
We then applied the above optimal reaction conditions for other
benzoic acid derivative substrates. The results are shown in Table 2.
Electron-donating groups seemed to be important for the reaction.
Phthalide-3-carboxylic acids 3bef were easily obtained in up to 81%
yield.
Table 2
a
Concise synthesis of some phthalide-3-carboxylic acids (3)
R1
R1
O
6
(2 equiv)
R2
R3
CO H
R2
R3
2
conc. H SO (2 equiv)
2
4
O
in HOAc (or TFA)
0 °C, 5 h
5
CO H
R4
5
R4
3
2
OMe
O
Scheme 1. Retrosynthetic analysis of (ꢀ)-
a-noscapine.
O
O
MeO
MeO
MeO
O
O
O
MeO
3
-Substituted-phthalides are very important molecules as
CO
3a, 74%
2
H
CO
3b, 81%
2
H
2
CO H
3c, 75%
valuable pharmacological compounds and versatile building blocks
11
for medicinal chemistry. Among them, phthalide-3-carboxylic
acid derivatives, such as 3a are supposed to be potentially useful
intermediates for the synthesis of many phthalide tetrahy-
O
O
Br
O
MeO
MeO
MeO
O
O
12
O
O
O
droisoquinoline alkaloids.
The preparation of phthalide-3-
carboxylic acids have been well documented over the past
CO
2
H
OMe
2
CO H
decades,13 however, those procedures inevitably involved many
OMe
d, 55%
2
CO H
OMe
3f, 48%
3
3e, 76%
unsatisfactory aspects, such as the use of strong organic base (LDA)
or very toxic reagent (KCN or Pb(OAc) ), air/moisture-sensitive
4
conditions, multi-steps’ sequence, low reaction yield, and so on.
We gratifyingly found that meconine-3-carboxylic acid (3a)
could be easily prepared from simple 2,3-dimethoxybenzoic acid
a
The reactions were carried out with 0.1 mol of 5 and 0.2 mol of 6 with H
0 mL HOAc (3aee) or in 50 mL TFA (3f) at 50 C for 5 h. The isolated yield was
2
SO
4
in
ꢂ
5
shown for each product.
The synthesis of another intermediate 4 (Scheme 2) commenced
with the transformation of commerciallyavailable gallic acid (7) into
the bromo-substituted aryl carboxylate 8, which was quantita-
(
5a) and glyoxylic acid (6) in the presence of concentrated sulfuric
ꢂ
14
acid with acetic acid as solvent at 50 C in one-pot (Table 1, entry
ꢂ
2
vs 1). Two equivalents of sulfuric acid were found to be optimal
tively reduced into the benzyl alcohol 9 by DIBALH at 0 C. Sub-
for high yield (entry 3 vs 2 and 4). The reaction could also proceed
similarly in trifluoroacetic acid as solvent (entry 10). Further opti-
mization studies revealed that the use of other Brønsted acids
sequent cyanation took place to afford the nitrile 10 in 85% yield over
two steps. Next, reduction of the nitrile into primary amine was
15
3 2
achieved with BH $Me S in refluxed THF. Further treatment of
Table 1
Optimization of the reaction between 5a and 6
O
CO
2
H
(
2 equiv)
H
CO H
2
6
O
MeO
CO
2
H
MeO
acid, HOAc, 50°C
OMe
5a
OMe
3a
O
Entrya
Acid (equiv)
None
Time (h)
Yield (%)
b
1
2
3
4
5
6
7
8
9
20
5
5
5
5
0
46
80
64
61
8
67
25
18
77
14
77
2
H SO
2
H SO
2
H SO
4
4
4
(1.0)
(2.0)
(3.0)
TfOH (2.0)
TsOH (2.0)
5
BF
TiCl
ZnCl
3
$Et
2
O (2.0)
20
20
20
5
5
5
4
(2.0)
(2.0)
2
1
1
1
0c
2
H SO
2
H SO
2
H SO
4
4
4
(2.0)
(2.0)
(2.0)
d
1
2
Scheme 2. Synthesis of intermediate 4.
e
a
Reactions were carried out with 0.1 mol of 5a and 0.2 mol of 6 in 50 mL HOAc at
C.
the amine with hydrochloric ethyl acetate afforded stable hydro-
chloric 4. Thus, blocking group Br was successfully installed and was
ꢂ
5
0
b
c
Determined by HPLC analysis.
Reaction was run in 50 mL TFA.
Reaction was run in 50 mL THF.
ready for the completion of our total synthesis of (ꢀ)-
a-noscapine.
d
e
With the meconine-3-carboxylic acid 3a and hydrochloric 4 in
ꢂ
0
Reaction was run at 60 C.
hand, we easily conducted the amide formation (C5 eC3 bond

5164
J. Ni et al. / Tetrahedron 67 (2011) 5162e5167
formation) from the acyl chloride of 3a and free amine 4 in 89%
yield (Scheme 3). The next step was typical BischlereNapieralski
Table 3
Investigation of the diastereoselective reduction
Br
O
Br
3
reaction in the presence of POCl . As we had expected, cyclization
smoothly occurred to afford labile imine, which was then directly
reduced to generate tetrahydroisoquinoline. After extensive tuning
of this reduction, it was found that low reaction temperature was
crucial for the high diastereoselectivity and relatively high yields by
O
O
NH
O
NH
H
1
) POCl3
H
O
H
H
O
MeO
+
MeO
2
2) conditions
using NaBH
4
or NaBH
3
CN (Table 3, entries 1e6,100 mg scale). In the
ꢂ
case of L-Selectride, the reduction did not occur at ꢁ78 C (entry 7).
O
O
OMe
OMe
Eventually, the reaction was scaled up as described in entry 8 (3.0 g
MeO
MeO
threo-form
ꢂ
erythro-form
scale) by NaBH
4
at ꢁ78 C to give the intermediate in 52% isolated
1
6
yield with >23:1 dr. Subsequently, EschweilereClarke reaction
took place to furnish N-methylation compound 12 in 75% yield.
Finally, the tetrahydroisoquinoline underwent atmospheric hy-
drogenation in the presence of Raney Ni-W2 to remove the block-
ing group Br cleanly.17 Further recrystallization afforded pure
Entrya
Reducing agent (3.0 equiv)
Temp ( C)
ꢂ
drb
(a/b)
Yieldc (%)
1
2
3
4
5
6
NaBH
NaBH
NaBH
NaBH
NaBH4
NaBH
4
4
4
3
0
ꢁ25
ꢁ50
ꢁ50
ꢁ78
ꢁ78
ꢁ78
ꢁ78
13:1
16:1
22:1
11:1
23:1
15:1
ND
55
57
61
56
62
58
trace
52
CN
CN
(ꢀ)-a
-noscapine (1) in 82% yield over two steps.
3
d
7
8
L-Selectride
NaBH
4
28:1
a
Reactions were run in methanol for 10 h. Entries 1e7 were carried out on
1
00 mg scale, whereas entry 8 was on 3.0 g scale.
The dr (a/b or erythro/threo) was determined by LCeMS and HPLC analysis of the
b
crude reaction mixture.
c
HPLC yield for entries 1e7, and isolated yield for entry 8.
Reaction was run in THF for 10 h.
d
4
4
. Experimental section
.1. General information
Infrared (IR) spectra were recorded on a Bruker IFS 55 Fourier
transform infrared spectrophotometer. NMR spectra were recorded
on Bruker ARX-300 MHz or 600 MHz spectrometer. Chemical shifts
in CDCl
DMSO-d
3
or DMSO-d
6
were reported in the scale relative to TMS or
1
5
(0 or 2.50 ppm for H NMR), and CDCl or DMSO-d (77.0
3 6
13
or 39.6 ppm for C NMR) as an internal reference, respectively.
HRMS were measured on a Bruker MicrOTOF-Q spectrometer. HPLC
and LCeMS analysis was carried out on the same liquid chro-
matographic systems, containing Agilent HP1100 LC/MS Ion Trap SL
ꢂ
(
positive mode; Phenomen kromasil C18 column; 30 C; methanol/
aqueous ammonium acetate (10 mM)/formic acid¼50/50/0.4 (v/v%)
as mobile phase; 0.5 mL/min. HPLC was detected by UV at 234 nm.
MS was detected by 4000 V capillary voltage; 8 L/min drying gas
ꢂ
flow at 325 C; 30 psi nebulizing gas pressure; helium as
collision gas). Column chromatography was performed with silica
gel (300e400 mesh). Melting points were determined with
FishereJohns melting point apparatus and are uncorrected.
Tetrahydrofuran (THF) was freshly distilled over sodium benzo-
phenone ketyl. Toluene and dichloromethane were distilled from
2
CaH . Reactions were carried out using flame-dried glasswares in
dry solvents under an argon atmosphere unless otherwise stated.
Scheme 3. Completion of the synthesis of 1.
3
. Conclusions
4.2. Experimental procedures
In summary, the first diastereoselective total synthesis of (ꢀ)-
a-
noscapine has been completed. The prominent features of our strat-
egy include: (i) a concise synthesis of key intermediate phthalide-3-
carboxylic acid from benzoic acid derivative and glyoxylic acid in
the presence of concentrated sulfuric acid with HOAc or TFA as sol-
vent; (ii) the installation of Br as a removable blocking group to avoid
the formation of undesired regioisomers in BischlereNapieralski cy-
4.2.1. General procedure for the synthesis of phthalide-3-carboxylic
acid 3 (3aee). A mixture of the aromatic carboxylic acid 5
(0.1 mol), glyoxylic acid monohydrate (6) (0.2 mol), concd H SO
2 4
(10.7 mL, 0.2 mol) and glacial acetic acid (50.0 mL) was stirred at
ꢂ
50 C for 5 h until the completion of the reaction indicated by TLC. It
was cooled to room temperature, then poured into ice water. The
formed precipitate was filtered, washed with cold water, and dried
to give the phthalide-3-carboxylic acid 3.
4
clization; and (iii) highly diastereoselective reduction with NaBH at
low temperature afforded desired erythro-type phthalide tetrahy-
droisoquinoline structure. It should also be noted here some in-
termediates (such as 4 and 10e12) were easily purified by
recrystallization without performing column chromatography.
4 . 2 . 1 . 1 . 1 , 3 - D i h y d r o - 4 , 5 - d i m e t h o x y - 3 - o x o - 1 -
isobenzofurancarboxylic acid (3a). Yield: 73%; white solid, mp

J. Ni et al. / Tetrahedron 67 (2011) 5162e5167
5165
ꢂ
1
ꢁ1
1
7
57e159 C; H NMR (300 MHz, DMSO-d
.32 (d, 1H, J¼8.3 Hz), 6.00 (s, 1H), 3.90 (s, 3H), 3.85 (s, 3H);
NMR(75 MHz, CDCl ): 171.6, 166.8, 153.6, 148.6, 135.6, 119.6, 117.5,
6
):
d
7.49 (d, 1H, J¼8.3 Hz),
1595, 1488, 1432, 1326, 936, 757 cm ; HRMS (ESI): calcd for
C H10BrO
10 5
13
[MþH]þ 288.9706, found 288.9713.
C
3
d
1
16.7, 75.5, 62.5, 56.8; IR (KBr) 3308, 1775, 1598, 1497, 1454, 1273,
4
.2.4. 4-Bromo-7-methoxy-1,3-benzodioxole-5-methanol (9). To a so-
ꢁ
1
[MþH]þ
1168, 1042, 1024 cm ; HRMS (ESI): calcd for C11
H
11
O
6
ꢂ
lution of 8 (14.4 g, 50.0 mmol) in THF (100.0 mL) at 0 C was added
dropwise DIBALH (1.0 mol/L in hexane, 150.0 mL, 150.0 mmol). This
mixture was stirred at 0 C for 30 min, then quenched by aq
Rochelle salt (1 mol/L, 200 mL). It was evaporated in vacuo to
2
39.0550, found 239.0554.
ꢂ
4
.2.1.2. 1,3-Dihydro-5-methoxy-3-oxo-1-isobenzofurancarboxylic
ꢂ
1
acid (3b). Yield: 81%; white solid, mp 169e171 C; H NMR
remove the organic solvents, and water (100 mL) and CH
100 mL) was added to the residue. The organic layer was sepa-
rated, and the water layer was extracted with CH Cl
(100 mLꢃ2).
The combined organic layer was washed with brine (150 mLꢃ2),
dried over anhydrous Na SO , filtered through a short silica gel pad
and concentrated in vacuo to give 9 (13.0 g) as a white solid. Yield:
2 2
Cl
(
(
600 MHz, DMSO-d
d, 1H, J¼8.70 Hz), 7.37 (s, 1H), 6.13 (s, 1H), 3.86 (s, 3H);
): 169.5, 168.4, 160.9, 137.4, 125.8, 124.1,
6
):
d
13.88 (br s, 1H), 7.62 (d, 1H, J¼8.70 Hz), 7.40
(
13
C
2
2
NMR(75 MHz, DMSO-d
6
d
123.2, 107.8, 77.3, 56.0; IR (KBr) 3428, 2843, 2636, 1782, 1735, 1622,
2
4
ꢁ
1
[MþH]þ 209.0444,
1493, 1291 cm ; HRMS (ESI): calcd for C10
9 5
H O
found 209.0448.
ꢂ
1
9
9%; mp 139e141 C; H NMR (300 MHz, CDCl
s, 2H), 4.68 (d, 2H, J¼6.24 Hz), 3.91 (s, 3H), 1.88 (t, 1H, J¼6.24 Hz);
13
3
): d 6.71 (s, 1H), 6.06
(
4
. 2 . 1 . 3 . 1 , 3 - D i h y d r o - 5 , 6 - d i m e t h o x y - 3 - o x o - 1 -
3
C NMR (75 MHz, CDCl ): d 147.0, 142.9, 135.0, 133.5, 108.4, 102.0,
isobenzofurancarboxylic acid (3c). Yield: 75%; white solid, mp
2
1
9
3.3, 64.5, 56.7; IR (KBr) 3213, 2904, 1628, 1446, 1342, 1161, 1106,
ꢂ
1
03e205 C; H NMR (600 MHz, DMSO-d
H), 6.04 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H); C NMR(75 MHz,
): 169.7, 168.5, 155.0, 150.9, 139.5, 116.0, 106.1, 104.5,
6
):
d
7.32 (s, 1H), 7.15 (s,
ꢁ1
Na [MþNa]þ
1036, 699 cm ; HRMS (ESI): calcd for C
H BrO
9 9 4
13
2
82.9576, found 282.9571.
DMSO-d
6
d
7
6.9, 56.3, 56.1; IR (KBr) 3239, 3006, 2945, 1778, 1604, 1500, 1457,
4
.2.5. 4-Bromo-7-methoxy-1,3-benzodioxole-5-acetonitrile (10). To
ꢁ1
[MþH]þ 239.0550,
1318 cm ; HRMS (ESI): calcd for C11
11 6
H O
a stirred solution of 9 (13.0 g, 50.0 mmol) and Et
in CH
3
N (7.7 mL, 0.55 mol)
found 239.0553.
2
Cl
2
(200 mL), SOCl
2
(5.5 mL, 75.0 mmol) was added dropwise
ꢂ
ꢂ
at 0 C. The mixture was gradually warmed to 30 C and then kept at
this temperature for 4 h. It was cooled, and then poured into ice
water (150 mL). The organic layer was separated and the aqueous
layer was extracted with CH
extracts were successively washed with brine (100 mLꢃ2) and sat-
urated aq NaHCO (100 mL), dried over anhydrous Na SO , filtered
4
. 2 . 1 . 4 . 1 , 3 - D i h y d r o - 5 , 7 - d i m e t h o x y - 3 - o x o - 1 -
isobenzofurancarboxylic acid (3d). Yield: 55%; white solid, mp
ꢂ
1
1
1
1
2
84e187 C; H NMR (300 MHz, DMSO-d
H), 3.86 (s, 6H); 13C NMR(75 MHz, DMSO-d
55.1, 127.2. 126.1, 105.6, 99.3, 77.0, 56.3, 56.2; IR (KBr) 3463, 2940,
6
):
d
6.94 (s, 2H), 5.88 (s,
2
Cl
2
(100 mLꢃ2). The combined organic
6
): d 169.7, 168.1, 163.0,
3
2
4
ꢁ
1
842, 2527, 1962, 1735, 1625, 1498, 1329, 1031 cm ; HRMS (ESI):
through a short silica gel pad and concentrated in vacuo. The
obtained crude was dissolved in DMF (100 mL), and NaCN (2.7 g,
calcd for C11
H
11
O
6
[MþH]þ 239.0550, found 239.0555.
5
5.0 mmol) was added. The mixture was stirred at room tempera-
4
. 2 .1. 5 . 1, 3 - D i h y d r o - 5 , 6 , 7 - t r i m e t h o x y - 3 - o x o - 1 -
ture overnight and poured into water (250 mL). The precipitate was
filtered, washed with water (20 mLꢃ2) and dried. The crude was
recrystallized from EtOH to give 10 (11.5 g) as a white solid. Yield:
isobenzofurancarboxylic acid (3e). Yield: 76%; white solid, mp
ꢂ
1
1
(
(
1
1
39e142 C; H NMR (600 MHz, DMSO-d
s, 1H), 6.00 (s, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.82 (s, 3H); C NMR
75 MHz, CDCl ): 171.1, 169.4, 156.8, 148.0, 147.2, 129.2, 120.4,
03.1, 75.7, 61.2, 60.9, 56.6; IR (KBr) 3430, 3017, 2954, 1872, 1725,
615, 1482, 1615, 1482, 1352, 1109 cm ; HRMS (ESI): calcd for
H
6
): d 13.90 (br s, 1H), 7.22
13
ꢂ
1
8
5%; mp 171e173 C; H NMR (CDCl
3
, 300 MHz)
d
6.65 (s,1H), 6.02 (s,
3
d
13
2H), 3.86 (s, 3H), 3.69 (s, 2H); C NMR (CDCl
3
, 150 MHz) 146.6,
d
142.0, 134.6, 122.1, 116.1, 108.2, 101.2, 93.4, 56.0, 22.8; IR (KBr) 2978,
ꢁ
1
ꢁ1
909, 2248,1637,1490,1445,1327,1175, 815, 699 cm ; HRMS (ESI):
2
þ
C
12
13
O
7
[MþH] 239.0656, found 239.0659.
Na [MþNa]þ 291.9581, found 291.9580.
8 3
calcd for C10H BrNO
4
.2.2. 8-Bromo-4-methoxy-5,7-dihydro-7-oxo-1,3-benzodioxole-5-
4.2.6. 4-Bromo-7-methoxy-1,3-benzodioxole-5-ethanamine hydro-
carboxylic acid (3f). A mixture of 2-bromo-5-methoxy-3,4-
methylenedioxybenzoic acid (2.8 g, 10.0 mmol), glyoxylic acid
chloride (hydrochloric 4). To a solution of 10 (6.7 g, 25.0 mmol)inTHF
(30.0 mL), boraneemethyl sulfide complex in THF (1.0 mol/L,
50.0 mL, 50.0 mmol) was added slowly at 50 C. After the reaction
monohydrate (1.84 g, 20.0 mmol), concd
H
2
SO
4
(1.1 mL,
ꢂ
ꢂ
2
0.0 mmol), and trifluoroacetic acid (5.0 mL) was stirred at 50
C
for 5 h until the completion of the reaction indicated by TLC. It
was cooled to room temperature, poured into ice water (50 mL),
mixture was refluxed for 10 h, it was quenched with methanol
ꢂ
(5.0 mL) at 0 C and concentrated in vacuo. The residue was boiled
and extracted with CH
layer was washed with brine (50 mLꢃ2), dried over anhydrous
Na SO , filtered through a short silica gel pad and concentrated in
vacuo to give the title compound 3f (1.6 g). Yield: 48%; white
2
Cl
2
(20 mLꢃ3). The combined organic
with aq HCl (1.0 mol/L, 100 mL) for 1 h, and then cooled. After it was
extracted off with ether (30 mLꢃ2), the remaining aqueous layer was
adjusted pH 12 with aq NaOH (2.0 mol/L), and extracted with ethyl
acetate (100 mLꢃ3). The organic layer was washed with brine
(150 mLꢃ2), dried over anhydrous Na SO . The organic was rotately
2
4
ꢂ
1
solid, mp 180e182 C; H NMR (300 MHz, DMSO-d
1
6
):
H), 6.30 (s, 1H), 5.87 (s, 1H), 3.97 (s, 3H); C NMR (75 MHz,
DMSO-d ): 167.7, 166.8, 150.2, 142.3, 136.6, 134.7, 116.3, 104.1,
d
6.34 (s,
2
4
13
distilled to around 30 mL, and treated with 1.0 mol/L hydrochloric
ꢂ
d
ethyl acetate (30 mL) at 0 C. The formed white solid was filtered and
6
dried to give hydrochloric 4 (6.4 g). Yield: 83%; white solid, mp
9
0.3, 75.4, 59.9; IR (KBr) 3430, 2922, 2317, 1780, 1626, 1497, 1439,
ꢂ
1
ꢁ
1
[MþH]þ
1331, 1122, 1056 cm ; HRMS (ESI), calcd for C11
8
H BrO
7
231e233 C; H NMR (300 MHz, DMSO-d
1
6
):
d
7.91 (br s, 2H), 6.70 (s,
13
H), 6.08 (s, 2H), 3.83 (s, 3H), 2.90e2.96 (m, 4H); C NMR (75 MHz,
DMSO-d ): 146.8,142.6,134.3,129.9,110.3,101.9, 94.3, 56.6, 32.2; IR
3
30.9448, found 330.9447.
6
d
(
KBr) 3400, 3051, 2897, 2014, 1628, 1496, 1434, 1165, 1104, 933,
4
.2.3. Methyl 4-bromo-7-methoxy-1,3-benzodioxole-5-carboxylate
ꢁ1
[MþH]þ 274.0073,
(8). Prepared from commercially available gallic acid in four
822 cm ; HRMS (ESI): calcd for C10
found 274.0079.
H13BrNO
3
14
ꢂ
1
steps. Yield: 57% (for four steps); white solid, mp 104e106 C; H
NMR (300 MHz, CDCl ): 7.25 (s, 1H), 6.13 (s, 2H), 3.93 (s, 3H), 3.91
s, 3H); 13C NMR (75 MHz, CDCl
): 165.5, 147.9, 142.2, 138.3, 124.2,
12.3, 102.4, 94.5, 56.7, 52.3; IR (KBr) 2949, 2838, 1855, 1724, 1625,
3
d
(
1
3
d
4.2.7. N-[2-(4-bromo-7-methoxy-1,3-benzodioxol-5-yl)ethyl]-1,3-
dihydro-4,5-dimethoxy-3-oxo-1-isobenzofurancarboxamide (2). A

5166
J. Ni et al. / Tetrahedron 67 (2011) 5162e5167
mixture of 3a (2.4 g, 10 mmol) and SOCl
h, and vacuum evaporated to remove the excess SOCl
residue was dissolved in CH Cl (20 mL) and a solution of com-
Cl (20 mL) was added slowly at
2
(10.0 mL) was refluxed for
942 cmꢁ1; HRMS (ESI): calcd for C22
found 492.0655.
H
23BrNO
7
[MþH]þ 492.0652,
2
2
. Then the
2
2
pound 4 (5.48 g, 20.0 mmol) in CH
2
2
4.2.10. (ꢀ)-
Et N (0.14 mL, 1.0 mol), Raney Ni-W2 (0.2 g) and ethanol (20 mL)
was refluxed for 30 h under atmospheric hydrogen. After filtration
and removal of the solvent, the residue was treated with CH Cl
(20 mL). The organic layer was washed with brine (10 mLꢃ2), dried
over anhydrous Na SO and concentrated to give the crude, which
was recrystallized from ethanol to afford -noscapine (1) as a pure
product (0.17 g). Yield: 82%; white solid. The data of (ꢀ)- -nosca-
a-Noscapine (1). A mixture of 12 (0.25 g, 0.5 mmol),
ꢂ
0
C. After the addition, it was further stirred for 1 h, and the
3
hydrochloric 4 (2.3 g) was recovered by filtration. The filtrate was
SO , fil-
washed with brine (30 mLꢃ2), dried over anhydrous Na
2
4
2
2
tered through a short silica gel pad and concentrated in vacuo to
give the title compound 2 (4.4 g). Yield: 89%; white solid, mp
2
4
ꢂ
1
1
74e176 C; H NMR (300 MHz, CDCl
3
,):
d
7.51e7.49 (m, 1H),
a
7
4
2
1
9
.27e7.25 (m, 1H), 6.58 (s, 1H), 6.33 (s, 1H), 6.02 (s, 2H), 5.63 (s, 1H),
a
9
,18
ꢂ
9
.10 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 3.50 (q, 2H, J¼13.2, 6.6 Hz),
pine (erythro-1) is in accordance with lit.
mp 231e234 C (lit.
6.95 (d, 1H, J¼8.2 Hz),
1
3
ꢂ
1
.86 (t, 2H, J¼6.9 Hz); C NMR (75 MHz, CDCl
48.2, 147.0, 142.8, 137.5, 134.3, 131.1, 119.9, 118.3, 116.0, 109.6, 101.8,
5.2, 62.3, 56.8, 39.2, 34.6; IR (KBr) 3352, 2939, 1762, 1677, 1498,
3
):
d
166.9, 153.2,
234e236 C); H NMR (300 MHz, CDCl ):d
3
6.30 (s,1H), 6.07 (d,1H, J¼8.2 Hz), 5.93 (s, 2H), 5.57 (d,1H, J¼4.1 Hz),
4.39 (d, 1H, J¼4.1 Hz), 4.09 (s, 3H), 4.04 (s, 3H), 3.86 (s, 3H),
ꢁ1
1435, 1274, 1166, 1025, 935 cm
;
HRMS (ESI): calcd for
2.64e2.57 (m, 1H), 2.54 (s, 3H), 2.41e2.29 (m, 2H), 1.95e1.85 (m,
þ
13
C
21
H
21BrNO
8
[MþH] 494.0440, found 494.0445.
1H); C NMR (75 MHz, CDCl
3
):
d
168.1, 152.1, 148.3, 147.6, 141.1,
140.4, 134.0, 132.1, 120.2, 118.1, 117.6, 117.1, 102.3, 100.7, 81.8, 62.3,
4
[
.2.8. (ꢀ)-
a
-3-(9-Bromo-5,6,7,8-tetrahydro-4-methoxy-1,3-dioxolo
4,5-g]isoquinolin-5-yl)-6,7-dimethoxy-1(3H)-isobenzofuranone hy-
drochloride (11). A mixture of the amide 2 (2.96 g, 6.0 mmol) and
POCl (22.9 mL, 0.25 mol) was refluxed for 2.0 h. It was concen-
trated, and then vacuum evaporated twice with dry toluene
. The residue in
60.8, 59.4, 56.7, 50.0, 46.3, 28.1; IR (KBr) 3430, 2941, 2317, 1756,
ꢁ1
1623, 1496, 1273, 1086, 1035, 1008 cm ; HRMS (ESI), calcd for
C
22
H24NO
7
[MþH]þ 414.1547, found 414.1545.
3
Acknowledgements
(
25 mLꢃ2) for complete removal of the excess POCl
3
methanol (60 mL) was portionwisely added NaBH
4
(0.68 g,
This work was financially supported by National Natural Science
Foundation of China (No. 30672520). Generous support was also
provided by the Ministry of Education of China for the Key Labo-
ratory of Structure-Based Drug Design & Discovery.
ꢂ
1
8.0 mmol) at ꢁ78 C. It was further stirred at the temperature for
1
0.0 h, and quenched with 1.0 mol/L hydrochloric methanol
12.0 mL). After rotary removal of methanol, the residue was dis-
solved in water (50 mL). The aqueous solution was neutralized with
0% aqueous ammonia and extracted with CH Cl
(30 mLꢃ3). The
combined organic layer was washed with brine (30 mLꢃ3), and
dried over anhydrous Na SO . Following the removal of CH Cl , it
(
1
2
2
Supplementary data
Copies of H and 13C NMR spectra are provided. Supplementary
data associated with this article can be found in the online version
at doi:10.1016/j.tet.2011.05.060.
1
2
4
2
2
was dissolved in ethyl acetate (10.0 mL) and then treated with
ꢂ
1.0 mol/L hydrochloric ethyl acetate (8.0 mL, 8.0 mmol) at 0 C. The
obtained crude was recrystallized from ethanol to give pure
ꢂ
1
erythro-11 as a white solid (1.60 g). Yield: 52%; mp 221e223 C; H
NMR (300 MHz, DMSO-d ):
References and notes
6
d
7.36 (d, 1H, J¼8.3 Hz), 6.56 (d, 1H,
1
. Robiquet, P. J. Ann. Chim. Phys. 1817, 5, 275e278.
J¼8.3 Hz), 6.13 (s, 1H), 6.11 (s, 1H), 5.81 (s, 1H, J¼3.3 Hz), 4.76 (s, 1H,
J¼3.3 Hz), 3.88 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 2.90e2.85 (m, 1H),
2. (a) Empey, D. W.; Laitinen, L. A.; Young, G. A.; Bye, C. E.; Hughes, D. T. Eur. J. Clin.
Pharmacol. 1979, 16, 393e397; (b) Dahlstr o€ m, B.; Mellstrand, T.; L o€ fdahl, C.-G.;
13
2
.47e2.43 (m, 1H), 2.35e2.28 (m, 1H); C NMR(75 MHz, DMSO-
Johansson, M. Eur. J. Clin. Pharmacol. 1982, 22, 535e539; (c) Karlsson, M. O.;
Dahlstr
o€ m, B.; Eckern €a s, S.-A.; Johansson, M.; Tufvesson Alm, A. Eur. J. Clin.
ꢁ
6
d ): d 166.2, 152.6, 147.7, 147.0, 139.0, 138.8, 134.0, 127.0, 120.4, 118.6,
Pharmacol. 1990, 39, 275e279.
1
3
17.4,112.9,102.0, 95.1, 77.8, 61.7, 59.0, 56.8, 52.0, 37.4, 24.8; IR (KBr)
3
. (a) Zhou, J.; Gupta, K.; Yao, J.; Ye, K.; Panda, D.; Giannakakou, P.; Joshi, H. C. J.
Biol. Chem. 2002, 277, 39777e39785; (b) Ke, Y.; Ye, K.; Grossniklaus, H. E.;
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ꢁ1
430, 3144, 2995, 2904, 1763, 1613, 1493, 1449, 1265, 1032 cm
;
HRMS (ESI)：calcd for C21
78.0500.
H
21BrNO
7
[MþH]þ 478.0496, found
217e225; (c) Landen, J. W.; Lang, R.; McMahon, S. J.; Rusan, N. M.; Yvon, A.-M.;
4
Adams, A. W.; Sorcinelli, M. D.; Campbell, R.; Bonaccorsi, P.; Ansel, J. C.; Archer,
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4
.2.9. (ꢀ)-
a-3-(9-Bromo-5,6,7,8-tetrahydro-4-methoxy-6-methyl-
1,3-dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxy-1(3H)-iso-
10, 5187e5201; (e) Mahmoudian, M.; Mehrpour, M.; Benaissa, F.; Siadatpour, Z.
benzofuranone (12). After the mixture of compound 11 (0.51 g,
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1
.0 mmol) in 37% formaldehyde (2.0 mL, 26.6 mmol) and 88% for-
ꢂ
4. For the total synthesis of
b-noscapine, see: (a) Hope, E.; Robinson, R. J. Chem.
mic acid (5.0 mL) was stirred at 100 C for 2 h, it was concentrated
Soc., Trans. 1914, 105, 2085e2104; (b) Marshall, M. A.; Pyman, F. L.; Robinson, R.
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1548e1552 See also Ref. 7 and 8.
. Bogn ꢀa r, R.; Ga ꢀa l, G. D.; Kerekes, P.; Szab oꢀ , S. Pharmazie 1967, 22, 452e454.
. Perkin, W. H., Jr.; Robinson, R. J. Chem. Soc., Trans. 1911, 99, 775e792.
in vacuo. The residue was treated with aq HCl (1.0 mol/L, 12.0 mL)
ꢂ
and activated charcoal (0.1 g) at 70 C for 1 h. Following the fil-
5
6
tration, the aqueous layer was adjusted pH 10 with 10% aqueous
ꢂ
ammonia at 0 C, and extracted with CH
2
Cl
2
(10 mLꢃ3). The com-
7. Shono, T.; Hamaguchi, H.; Sasaki, M.; Fujita, S.; Nagami, K. J. Org. Chem. 1983, 48,
bined organic layer was washed with brine (10 mLꢃ3), dried over
anhydrous Na SO and concentrated to give the crude, which was
further recrystallized from ethanol to afford the title compound 12
1621e1628.
8
9
. Kerekes, V. P.; Bogn ꢀa r, R. J. Prakt. Chem. 1971, 313, 923e928.
2
4
. Varga, Z.; Blask oꢀ , G.; D o€ rnyei, G.; Sz aꢀ ntay, C. Acta Chim. Hung. 1991, 128,
831e837.
ꢂ
1
(
0.37 g). Yield: 75%; white solid, mp 152e152 C; H NMR
300 MHz, CDCl ):
7.03 (d, 1H, J¼8.2 Hz), 6.31 (d, 2H, J¼8.2 Hz),
.03 (s, 2H), 5.50 (d, 1H, J¼4.5 Hz), 4.34 (d, 1H, J¼4.5 Hz), 4.10 (s,
H), 3.99 (s, 3H), 3.89 (s, 3H), 2.76e2.64 (m, 2H), 2.52 (s, 3H),
.48e2.43 (m, 1H), 2.01e1.92 (m, 1H); C NMR (75 MHz, CDCl
168.0, 152.3, 147.8, 146.5, 141.2, 140.0, 134.2, 130.3, 119.6, 119.0,
18.3, 117.5, 101.0, 95.5, 81.3, 62.3, 60.9, 59.4, 56.8, 48.4, 45.2, 25.9;
IR (KBr) 3437, 2942, 2849, 2798, 1755, 1610, 1499, 1441, 1265, 1032,
10. For the preparation of halogenated noscapine derivatives from natural nosca-
(
3
d
pine, see: (a) Aneja, R.; Vangapandu, S. N.; Joshi, H. C. Bioorg. Med. Chem. 2006,
14, 8352e8358; (b) Verma, A. K.; Bansal, S.; Singh, J.; Tiwari, R. K.; Sankar, V. K.;
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3
2
d
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3
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