Asymmetric total synthesis of (S)-isocorydine

Article abstract of DOI:10.1016/j.tetasy.2015.09.008

The asymmetric total synthesis of (S)-isocorydine, a potential drug for the cure of hepatocellular carcinoma, is described. Asymmetric transfer hydrogenation of 3,4-dihydroisoquinoline using a chiral Ru(II) catalyst was applied to the synthesis of isocory

Full text of DOI:10.1016/j.tetasy.2015.09.008

Tetrahedron: Asymmetry 26 (2015) 1145–1149
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Tetrahedron: Asymmetry
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Asymmetric total synthesis of (S)-isocorydine
a
Mei Zhong a,b, Yunbin Jiang c, Yali Chen d, Qian Yan a,b, Junxi Liu a, , Duolong Di
⇑
a Key Laboratory of Chemistry of Northwestern Plant Resources and Key Laboratory for Natural Medicine of Gansu Province, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou, China
b Graduate University of the Chinese Academy of Sciences, Beijing, China
c Chengdu University of Traditional Chinese Medicine, Chengdu, China
d Gansu Key Laboratory of Preclinical Study for New Drugs, Institute of Pharmacology, School of Basic Medical Science, Lanzhou University, Lanzhou, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric total synthesis of (S)-isocorydine, a potential drug for the cure of hepatocellular
carcinoma, is described. Asymmetric transfer hydrogenation of 3,4-dihydroisoquinoline using a chiral
Ru(II) catalyst was applied to the synthesis of isocorydine as the key step, in which the ee value achieved
is up to 99%. The overall yield is 9.4% after 12 synthetic procedures.
Received 19 June 2015
Accepted 3 September 2015
Available online 3 October 2015
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
H3CO
A
D
B
N
H
Isocorydine (Fig. 1), a tetracyclic aporphine alkaloid, which is
abundant in natural resources, such as Dicranostigma leptopodum
(Maxim.) Fedde, Stephania brachyandra Diets, and Dactylicapnos
scandens (D. Don) Hutch., has wide bioactivities including antiar-
rhythmic, vasodilation, antihypoxic, and so on.1 In 2010, isocory-
dine hydrochloride tablets were approved as a prescription drug
by the China Food and Drug Administration to act as spasmolytic
analgesics to cure the pain caused by spasms of the stomach,
intestines, gallbladder, and pancreas.2 Recent studies have showed
that isocorydine from Papaveraceae sp. had an inhibitory effect on
the growth of hepatocellular carcinoma cell lines through the
induction of G2/M phase cell cycle arrest and apoptosis.3 Further
research indicated that isocorydine could decrease the percentage
of side population cells dramatically in hepatocellular carcinoma
cell lines and sensitized cancer cells to doxorubicin, a conventional
clinical drug for hepatocellular carcinoma. The xenograft model
revealed that isocorydine selectively reduced the size and weight
of the side population-induced tumor masses in vivo. The growth
of side population cells arrested in G2/M in the early stage of iso-
corydine treatment; later it induced apoptosis. Furthermore, the
expression of programed cell death 4, a tumor suppressor gene,
was increased after treatment with isocorydine. These findings
implied that isocorydine is a potential therapeutic drug for target-
ing the side population cancer cells of hepatocellular carcinoma.4
Considering the intermediate anticancer ability of isocorydine
and high dosage needed to achieve an effect on hepatocellular
H3CO
HO
CH3
C
H3CO
Figure 1. Chemical structure of isocorydine.
carcinoma,
a
series of derivatives of isocorydine have been
prepared in order to increase the anticancer activity compared
with isocorydine, among which 8-amino-isocorydine was
a
potential drug for the treatment of liver carcinoma due to its good
inhibitory effect on murine hepatoma H22-induced tumors.5
In general, isocorydine is extracted by chromatographic meth-
ods using silica gel columns from natural plants such as Dicranos-
tigma leptopodum (Maxim.) Fedde, Stephania brachyandra Diets,
and Dactylicapnos scandens (D. Don) Hutch. In particular, isocory-
dine has been abundantly extracted by our team from Dicranos-
tigma leptopodum (Maxim.), which is mainly distributed in the
northwest of China and used as a folk medicine for the treatment
of tonsillitis and hepatitis, and long term inflammation.6 Generally,
isocorydine was obtained from isocorydine-derived plants through
extraction with ethanol or methanol, acidification of the extract,
alkalization, extraction with chloroform, and chromatography on
a silica gel column. The maximum yield of isocorydine extracted
from plants so far is 0.125%.5,6 The disadvantages of this common
method using silica gel column chromatography to obtain isocory-
dine, include the waste of solvent, time, and labor, an excess use of
toxic solvent, which in turn can cause damage to the environment
and also cause harm to human health, the high cost of production,
⇑
Corresponding author. Tel.: +86 931 4968 212; fax: +86 931 8277 088.
E-mail address: liujx@licp.cas.cn (J. Liu).
http://dx.doi.org/10.1016/j.tetasy.2015.09.008
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

1146
M. Zhong et al. / Tetrahedron: Asymmetry 26 (2015) 1145–1149
low efficiency, and so on. Moreover, with the restriction of isocory-
dine from natural sources, it is necessary to develop a simple and
efficient synthetic method for isocorydine to solve the resource
problem and provide technical support for studying the synthesis
of isocorydine derivatives in future work. Although several total
syntheses7 of isocorydine have been reported, the asymmetric syn-
thesis of isocorydine has not yet been studied. Herein, an asym-
metric synthetic route of isocorydine was developed and the
overall yield was 9.4% after 12 steps with an ee value up to 99%.
The purification of the intermediate products in this route was
simplified using recrystallization or removing further purification
altogether. Hence the need for flash column chromatography was
minimized, which would impede future production of isocorydine
on a large scale. Meanwhile, the need for toxic solvents and labor
was also reduced and thus this route would be an environmentally
friendly method.
cyclic imines and has also been demonstrated to enantioselectively
hydrogenate dihydroisoquinolines14,18 with excellent selectivities
(93–95% ee). The single enantiomer 1,2,3,4-tetrohydroisoquinloine
11 was obtained with high ee under N2 in DMF, in the presence of
catalyst 15 and formic acid/triethylamine (v/v = 5/2). Purification
of the free amine 11 was successfully carried out by treatment of
the acid hydrochloride during the work-up procedure and product
11 was precipitated as its hydrochloride salt. Another key step was
the construction of the C ring with Pd(OAc)2, K2CO3 and PPh3 under
N2 in N,N-dimethylacetamide. The mechanism of the intramolecu-
lar coupling reaction involved in the oxidative addition, involved
C–H activation and reductive elimination.19
3. Conclusion
A feasible synthetic route for the asymmetric total synthesis of
(S)-isocorydine has been developed. The enantiomeric excess of
the asymmetric hydrogenation of 3,4-dihydroisoquinolie reached
99% with the use of Noyori’s catalyst. The overall yield is 9.4% after
12 steps. This study uses regular reactions and reagents and pro-
vides the synthesis of isocorydine and sufficient material for future
studies on structure–activity relationships.
2. Results and discussion
Due to the restriction of isocorydine from a natural resource
and the good anticancer activities of isocorydine3,4 and isocorydine
derivatives against hepatocellular carcinoma,5 there is a need to
develop a synthetic method to obtain isocorydine. Based on the
various synthetic methods of aporphine alkaloids and a retrosyn-
thetic analysis of isocorydine, we realized that the key points of
the synthetic route to isocorydine were the construction of the
tetracyclic structure and the stereogenic center. The B ring was
firstly constructed via a Bischler–Napieralski reaction by which
the dihydroisoquinoline fragment in isocorydine could be built.
The C ring could be constructed by an intramolecular coupling
reaction using a transition metal and finally the tetracyclic struc-
ture of isocorydine was successfully established. The stereogenic
center of isocorydine was created using suitably designed chiral
Ru(II) complexes developed by Noyori et al.8 The synthetic route
to isocorydine is designed and described in Scheme 1.
4. Experimental
4.1. General
3-Hydroxy-4-methoxybenzaldehyde,
3,4-dimethoxypheny
lethylamine, chiral catalyst RuCl[(R,R)-TsDPEN](p-cymene)] 15,
and palladium acetate Pd(OAc)2 were purchased from J&K Scien-
tific Ltd. The Pd/C (10%) catalyst was purchased from Sinopharm
Chemical Reagent Co., Ltd (Shanghai, China). Column chromatogra-
phy was performed on silica gel (200–300 mesh, Qingdao Hailang
Silica Gel Desiccant Co., Ltd, Qingdao, China). TLC was carried out
on silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd, Qingdao,
China), and spots were visualized under UV light. The solvents
were purified by standard procedures and other reagents were
purchased from commercial vendors and were used without fur-
ther purification. NMR spectra were recorded on a Varian INOVA-
400 MHz-FTNMR spectrometer with TMS as the internal standard.
HRMS (ESI) was recorded on a Bruker Apex II. The enantiomeric
excess was determined by Waters 515 system equipped with a
ChiralPAK IB column and a UV detector.
3-Hydroxy-4-methoxybenzaldehyde 1 was chosen as the start-
ing material, through aromatic electrophilic substitution of hydro-
gen by bromine to obtain compound
2 in 65% yield after
recrystallization from ethanol.9 The phenolic hydroxyl was pro-
tected by a benzyl group to give compound 3 in 86% yield, which
could be readily removed in the final step.10 The reduction of the
formyl group by NaBH4 at room temperature11 provided the
benzylic alcohol 4 in 90% yield. The substitution of hydroxyl by
chloride12 gave benzylic chloride 5 in 99% yield. Substitution of
the chloride by cyano12 afforded phenylacetonitrile 6 in 84% yield,
which extended the carbon chain. Hydrolysis of the cyano group
with sodium hydroxide provided the key intermediate trisubsti-
tuted phenylacetic acid 7 in 83% yield after recrystallization from
ethyl acetate.13 Acid 7 and 3,4-dimethoxyphenethylamine 8 were
heated at 175 °C for 3 h to obtain amide 9 in 89% yield after recrys-
tallization in ethyl acetate.14 The subsequent Bischler–Napieralski
reaction of amide 9 with POCl3 in CH3CN gave the B ring via
cyclodehydration to give 3,4-dihydroisoquinline 10 in 95% yield,
which is unstable at room temperature and thus should be used
directly in the next step without further purification.15 Imine 10
underwent asymmetric hydrogenation using the Noyori chiral
catalyst RuCl[(R,R)-TsDPEN](p-cymene)] 15 to provide tetrahy-
droisoquinoline 11 in 80% yield and with 99% ee, followed by
N-methylation16 to obtain phenylalkyltetrahydroisoquinoline 12
in 93% yield. Intramolecular coupling of phenylalkyltetrahydroiso-
quinoline 12 using Pd(OAc)2 to construct ring C provided com-
pound 13 in 50% yield,17 after which hydrolysis of the protecting
benzyl group furnished the target product isocorydine 14.
4.1.1. 2-Bromo-3-hydroxy-4-methoxybenzaldehyde 2
To a mixture of 1 (10.0 g, 0.066 mol), NaOAc (10.8 g, 0.132 mol),
Fe powder (0.34 g, 0.006 mol) was added acetic acid (60 mL), and
then the mixture was stirred for 30 min at room temperature.
Next, Br2 (3.5 mL, 0.07 mol) in 15 mL of acetic acid was slowly
added to the above mixture at room temperature. The mixture
was stirred for another 3 h at the same temperature. Ice-water
(125 mL) was then added into the mixture and stirred for another
1 h and filtered. The solid was dried and then recrystallized from
EtOH to give 2 as a gray solid (9.9 g, 65%). 1H NMR (400 MHz,
Acetone-d6): d 10.23(s, 1H, –CHO), 7.49 (d, J = 8.0 Hz, 1H), 7.14
(d, J = 8.0 Hz, 1H), 4.00 (s, 3H, –OCH3); 13C NMR (100 MHz,
Acetone-d6): d 192.1, 154.7, 146.0, 129.0, 123.5, 114.5, 111.7,
57.8. HRMS (ESI): m/z calcd for [M+Na]+ C8H7BrNaO3 252.9471,
obsd 252.9454.
4.1.2. 3-Benzyloxy-2-bromo-4-methoxybenzaldehyde 3
Compound 2 (9.9 g, 0.043 mol) was dissolved in anhydrous
DMF (108 mL). Benzyl bromide (8.55 g, 0.50 mol) was then added
slowly, followed by K2CO3 (14.3 g, 0.11 mol). The yellow mixture
was stirred violently at room temperature for 2.5 h. The mixture
The key enantioselective reduction step using a Noyori transfer
hydrogenation is a powerful method for the hydrogenation of

M. Zhong et al. / Tetrahedron: Asymmetry 26 (2015) 1145–1149
1147
Br
Br
Br
HO
CHO
HO
CHO
BnO
CH2OH
BnO
CHO
b
c
a
H3CO
H3CO
H3CO
H3CO
1
2
4
3
Br
Br
Br
BnO
CH2COOH
BnO
CH2CN
BnO
CH2Cl
d
e
f
H3CO
H3CO
H3CO
5
6
7
Br
BnO
CH2COOH
H3CO
Br
H
N
N
H3CO
H3CO
OBn
H3CO
H3CO
h
g
7
O
H3CO
OCH3
NH2
Br
9
H3CO
H3CO
OBn
10
8
H3CO
H3CO
H3CO
NH
H
N
H
H3CO
H3CO
N
H
H3CO
H3CO
CH3
H3CO
BnO
CH3
j
k
l
i
Br
Br
H3CO
OBn
11
OBn
12
13
H3CO
A
C
B
TsO2S
N
H
H3CO
HO
CH3
N
Ru
N
Cl
D
H2
H3CO
15, Noyori's catalyst RuCl[(R,R)-TsDPEN](p-cymene)]
ICD, 14
Scheme 1. Synthesis of (S)-isocorydine. Reagents and conditions: (a) Br2, NaOAc, AcOH, rt, 65%; (b) BnBr, K2CO3, DMF, rt, 86%; (c) NaBH4, CH3OH, rt, 90%; (d) SOCl2, DMF,
CH2Cl2, 0 °C, 99%; (e) KCN, DMF, H2O, 100 °C, 84%; (f) NaOH, 1,4-dioxane, CH3OH, H2O, 100 °C, 83%; (g) 170 °C, N2, 89%; (h) POCl3, CH3CN, N2; (i) Ru(II) catalyst (15, CAS:
192139-92-7), HCOOH/NEt3 = 5:2, DMF, N2, 8 h, rt, 80%; (j) HCHO, NaBH4, CH3OH, 93%; (k) Pd(OAc)2, K2CO3, PPh3, N,N-dimethylacetamide, 175 °C, 50%; (l) Pd/C, H2, MeOH,
86%.
was parted into an ether–water mixture (1:1, 200 mL of each) and
stirred. The organic and aqueous layers were separated, and the
aqueous layer was extracted with ether (2 Â 50 mL). The combined
organic layer was washed with water (2 Â 100 mL) and saturated
NaCl (100 mL), dried over anhydrous Na2SO4, and concentrated
to give 3 as a white solid (11.8 g, 86%). 1H NMR (400 MHz,
DMSO-d6): d 10.11 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.54–7.34
(m, 5H), 7.27 (d, J = 8.4 Hz, 1H), 5.01 (s, 2H, –CH2–), 3.97 (s, 3H);
13C NMR (100 MHz, DMSO-d6): d 190.8, 159.0, 144.9, 137.1,
128.8, 128.7, 128.6, 127.4, 127.2, 122.2, 112.6, 74.5 (–CH2), 57.1
HRMS (ESI): m/z calcd for [M+Na]+ C15H13BrNaO3 342.9940, obsd
342.9939.
to give 4 as a white solid (6.0 g, 90%). 1H NMR (400 MHz, DMSO-
d6): 7.53–7.34 (m, 5H), 7.24 (d, J = 8.0 Hz, 1H), 7.11
(d, J = 8.0 Hz, 1H), 4.95 (s, 2H), 4.46 (s, 2H, –CH2–), 3.85 (s, 3H);
13C NMR (100 MHz, DMSO-d6): d 152.6, 144.6, 137.5, 134.2,
128.7, 128.6, 128.4, 123.7, 117.2, 112.3, 74.3, 63.0 (–CH2–), 56.6.
HRMS (ESI): m/z calcd for [M+Na]+ C15H15BrNaO3 345.0097, obsd
345.0099.
d
4.1.4. 3-Benzyloxy-2-bromo-4-methoxybenzyl chloride 5
To the solution of 4 (6.0 g, 0.019 mol) dissolved in freshly dis-
tilled CH2Cl2 (60 mL), a catalytic amount of DMF (31 lL) was
added. With continuous stirring, SOCl2 (2.3 mL, 32 mmol) was
added to the reaction mixture. After 1 h of stirring at 0 °C, the sol-
vent and excess SOCl2 were removed on a rotary evaporator to give
5 as a white solid (6.3 g, 99%). The product was used in the next
step without further purification. 1H NMR (400 MHz, CDCl3): d
7.53–7.32 (m, 5H), 7.19 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H),
5.01 (s, 2H), 4.68 (s, 2H, –CH2–), 3.84 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 153.9, 145.6, 137.0, 129.6, 128.3, 128.3, 128.0, 126.1,
4.1.3. 3-Benzyloxy-2-bromo-4-methoxypenzyl alcohol 4
To a solution of 3 (6.6 g, 0.021 mol) in methanol (50 mL) was
added NaBH4 (0.5 g, 0.013 mol). After stirring for 2 h at room tem-
perature, the mixture was evaporated and the residue was dis-
solved in CHCl3 (40 mL). The organic layer was washed with
water (2 Â 30 mL), dried over anhydrous Na2SO4, and concentrated

1148
M. Zhong et al. / Tetrahedron: Asymmetry 26 (2015) 1145–1149
120.4, 111.2, 74.6, 56.1, 46.6 (–CH2Cl). HRMS (ESI): m/z calcd for
concentrated to yield yellow oil which was dissolved in CH2Cl2
(20 mL) which was adjusted to pH 7–8 with saturated NaHCO3.
The aqueous layer was extracted with CH2Cl2 (3 Â 60 mL). The
combined CH2Cl2 layer was washed with NaCl solution
(2 Â 20 mL), dried over anhydrous Na2SO4, filtered, and then con-
centrated to give 10 as a yellow solid (2.05 g, 95%) which is unsta-
ble at room temperature.10 1H NMR (400 MHz, CDCl3): d 7.57–7.33
(m, 5H), 7.02 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H), 6.80 (d, J = 8.0 Hz, 1H),
6.97 (s, 1H), 5.01 (s, 2H), 4.18 (s, 2H), 3.89 (s, 3H), 3.82 (s, 3H), 3.77
(s, 3H), 3.74 (t, J = 8.0 Hz, 2H), 2.70 (t, J = 8.0 Hz, 2H); 13C NMR
(100 MHz , CDCl3): d 165.5, 152.3, 150.8, 147.4, 145.4, 137.2,
131.6, 130.4, 128.4, 128.3, 128.0, 124.9, 121.3, 120.6, 111.6,
110.2, 109.2, 74.5, 56.2, 56.0, 55.9, 47.1, 42.0, 25.7. HRMS (ESI):
m/z calcd for [M+H]+ C26H27BrNO4 496.1118, obsd 496.1109.
[M+Na]+ C15H14BrClNaO2 362.9758, obsd 362.9776.
4.1.5. 3-Benzyloxy-2-bromo-4-methoxybenzyl cyanide 6
Compound 5 (6.3 g, 19 mmol) was dissolved in DMF (28 mL).
Next, KCN (5.4 g, 83 mmol) and water (8 mL) were added and the
mixture was heated at 100 °C for 2.5 h. The reaction mixture was
cooled to temperature, diluted with water (22 mL) and extracted
with CH2Cl2 (3 Â 20 mL). The exacts were washed with water
(2 Â 30 mL), dried over anhydrous Na2SO4, and concentrated to
give 6 as a red oil (5.4 g, 84%). The product was used in the next
step without further purification. 1H NMR (400 MHz, DMSO-d6):
d 7.53–7.35 (m, 5 H), 7.31 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz,
1H), 4.98 (s, 2H), 4.00 (s, 2 H, –CH2–), 3.86 (s, 3H); 13C NMR
(100 MHz, DMSO-d6): d 153.5, 145.5, 137.3, 128.7, 128.7, 128.5,
125.9, 123.7, 119.5 (–CN), 118.6, 112.8, 74.4, 56.6, 24.1 (–CH2–).
HRMS (ESI): m/z calcd for [M+Na]+ C16H14BrNNaO2 354.0100, obsd
354.0106.
4.1.9. (S)-1-(3-Benzyloxy-2-bromo-4-methoxy)benzyl-6,7-dime-
thoxy-1,2,3,4-tetrahydroisoquinoline 11
Freshly prepared imine 10 (2.05 g, 4 mmol) was dissolved in
anhydrous DMF, and the solution was degassed for 10 min with
N2. Next, RuCl[(R,R)-TsDPEN](p-cymene)] 15 (CAS: 192139-92-7)
(26 mg, 1 mol %) was added followed by HCOOH/NEt3 (v/v = 5:2,
2.4 mL), and the reaction mixture was stirred at room temperature
for 8 h under N2. The reaction was quenched with saturated
NaHCO3 and extracted with ethyl acetate (50 mL Â 3). The com-
bined organic layer was washed with saturated NaCl, dried over
anhydrous Na2SO4, and concentrated to yield green oil which
was relatively pure, but was rather unstable at room temperature.
Therefore, the crude greenish product was converted into its HCl
salt by treatment with concentrated HCl–MeOH–diether
(v/v/v = 1:100:100) ether solution at À20 °C to obtain a light
greenish solid 11ÁHCl (1.81 g, 80%, >99% ee of the free base).
4.1.6. 3-Benzyloxy-2-bromo-4-methoxyphenylacetic acid 7
Compound 6 (5.4 g, 16 mmol) in methanol (57.6 mL) and
1,4-dioxane (19.2 mL) was refluxed with NaOH (13.6 g, 0.34 mol)
in water (6.4 mL) for 25 h at 100 °C. Evaporation left an oily resi-
due, which was dissolved in water (25 mL). The aqueous solution
was acidified with concentrated HCl to pH = 2 in an ice bath, and
then the solution was extracted with ethyl acetate (3 Â 40 mL).
The organic layer was dried over anhydrous Na2SO4, and concen-
trated to give a yellow solid, which was then recrystallized from
ethyl acetate to give 7 as a white solid (4.6 g, 83%). 1H NMR
(400 MHz, DMSO-d6): d 12.39 (s, 1H, –COOH), 7.53–7.34 (m, 5H),
7.15 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 4.94 (s, 2H), 3.85
(s, 3H), 3.68 (s, 2H). 13C NMR (100 MHz, DMSO-d6): d 172.2
(–COOH), 152.7, 144.9, 137.6, 128.7, 128.6, 128.4, 128.3, 127.4,
120.7, 112.3, 74.3, 56.6, 41.3. HRMS (ESI): m/z calcd for [M+Na]+
C16H15BrNaO4 373.0046, obsd 373.0058.
[a]
24 = +63.0 (c 1.12, CH2Cl2). HPLC (Chiralpak IB, UV 230, iso-
D
propanol/hexane 1:4, 1.0 mL/min), tr [(S)-stereomer] 29.816 min
and tr [(R)-stereomer] 35.483 min. 1H NMR (400 MHz, CDCl3): d
7.58–7.32 (m, 5H), 6.99 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H),
6.73 (s, 1H), 6.59 (s, 1H), 5.05 (s, 2H), 4.24 (dd, J = 3.6, 9.6 Hz, 1H,
–CH–), 3.85 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H), 3.35–3.21 (m, 2H),
2.98–2.92 (m, 2H), 2.75 (t, J = 4.0 Hz, 2H), 2.34 (br, 1H, –NH–);
13C NMR (100 MHz, CDCl3): d 152.5, 147.6, 147.1, 145.5, 137.2,
131.6, 130.6, 128.4, 128.3, 128.0, 127.1, 126.7, 120.9,
111.8, 111.3, 109.8, 74.6, 56.2, 56.0, 55.9, 54.8, 42.8, 40.0, 29.4.
HRMS (ESI): m/z calcd for [M+H]+ C26H29BrNO4 498.1274, obsd
498.1275.
4.1.7. 2-(3-Benzyloxy-2-bromo-4-methoxyphenyl)-N-(3,4-dime-
thoxyphenethyl)acetamide 9
A mixture of compound 7 (1.4 g, 4 mmol) and compound 8
(0.7 g, 4 mmol) contained in a 250 mL four-neck-flask was evacu-
ated and refilled with nitrogen and then placed in an oil bath at
170 °C while passing a slow continuous stream of nitrogen over
the solid. The mixture was heated for another 3 h at which point
compound 7 had completely melted. The reaction mixture was
cooled to room temperature, and the residue was dissolved in
CH2Cl2 (18 mL). The solution was washed with saturated aqueous
NaHCO3 (2 Â 5 mL), aqueous HCl (10%, 2 Â 4 mL), and brine
(8 mL). The organic layer was dried over anhydrous Na2SO4, fil-
tered and concentrated by rotary evaporation to provide a brown
solid, which was recrystallized from hot ethyl acetate to provide
9 as a white solid (1.82 g, 89%). 1H NMR (400 MHz, DMSO-d6): d
7.93 (t, J = 4.0 Hz, –CONH–, 1H), 7.54–7.34 (m, 5H), 7.03 (s, 2H),
6.86 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H), 6.72 (d, J = 8.0 Hz, 1H), 4.93
(s, 2H), 3.84 (s, 3H), 3.72 (s, 3H), 3.71 (s, 3H), 3.52 (s, 2H), 3.31
(dd, J = 6.0, 12.4 Hz, 2H), 2.67 (t, J = 4.0 Hz, 2H); 13C NMR
(100 MHz, DMSO-d6): d 169.4 (–CONH–), 152.5, 149.1, 147.7,
144.9, 137.6, 132.4, 129.2, 128.7, 128.6, 128.4, 127.0, 120.9,
120.6, 113.1, 112.4, 112.2, 74.2, 56.6, 56.0, 55.9, 42.6, 40.9, 35.2.
HRMS (ESI): m/z calcd for [M+Na]+ C26H28BrNNaO5 538.1024, obsd
538.1007.
4.1.10. (S)-1-(3-Benzyloxy-2-bromo-4-methoxy)benzyl-6,7-
dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinloine 12
To a solution of 11 (1.02 g, 2.04 mmol) in MeOH (64 mL) was
added formalin (37%, 4.2 mL). After the mixture was stirred for
30 min at room temperature, it was cooled to 0 °C, after which
NaBH4 (2.32 g, 6.13 mmol) was slowly added and the reaction mix-
ture was warmed to room temperature. Stirring for additional
40 min and evaporation of the solvents produced a colorless solid,
which was dissolved in 1 M NaOH (150 mL) and extracted with
CH2Cl2 (3 Â 100 mL). The combined organic layers were dried over
anhydrous NaSO4, filtered, and the solvents removed to give 12 as a
light yellow solid (0.973 g, 93%). [a]
24 = +70.0 (c 1.03, CH2Cl2). 1H
D
NMR (400 MHz, CDCl3): d 7.58–7.31 (m, 5H), 6.75 (d, J = 8 Hz,
1H), 6.68 (d, J = 8.0 Hz, 1H), 6.57 (s, 1H), 5.94 (s, 1H), 5.03 (dd,
J = 8.0, 16.0 Hz, 2H), 3.89 (t, J = 8.0 Hz, 1H, –CH–), 3.82 (s, 3H),
3.82 (s, 3H), 3.52 (s, 3H), 3.30–3.25 (m, 2H), 2.91–2.83 (m, 2H),
2.63–2.58 (m, 2H), 2.52 (s, 3H, –NCH3); 13C NMR (100 MHz, CDCl3):
d 152.1, 147.3, 146.2, 145.2, 137.2, 132.2, 129.0, 128.4, 128.3,
128.0, 127.5, 125.9, 121.1, 111.4, 111.3, 111.0, 74.6, 62.1, 56.2,
55.8, 55.4, 46.0, 42.5, 40.9, 25.0. HRMS (ESI): m/z calcd for [M]+
C27H30BrNO4 512.1431, obsd 512.1340.
4.1.8. 1-(3-Benzyloxy-2-bromo-4-methoxy)benzyl-6,7-dimeth-
oxy-3,4-dihydroisoquinoline 10
To a solution of amide 9 (2.2 g, 4.3 mmol) in dry CH3CN (95 mL)
was added POCl3 (2.4 mL). The mixture was heated at reflux under
N2 for 2 h, and then it was cooled to room temperature and

M. Zhong et al. / Tetrahedron: Asymmetry 26 (2015) 1145–1149
1149
4.1.11. (S)-11-Benzyloxy-5,6,6a,7-tetrahydro-1,2,10-trimethoxy-
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d 8.63 (s, 1H, –OH), 6.99 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.90 (d,
J = 8.0 Hz, 1H), 4.08–4.04 (m, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.66
(s, 3H), 3.39–3.36 (m, 2H), 3.26–3.17 (m, 2H), 3.08–2.98 (m, 2H),
2.50 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d 152.9, 149.1,
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NMR data corresponded with those in the literature.21
Acknowledgments
This work was supported by ‘West Light Program’, of the
Chinese Academy of Sciences (090NKCA127) and the Science and
Technology Program of Gansu (1304FKCA062).