A versatile total synthesis of 8-oxyberberine and oxohomoberberines

Article abstract of DOI:10.1002/cjoc.201400612

The total syntheses of 8-oxyberberine and oxohomoberberines were accomplished starting from commercially available 5-bromobenzo[d][1,3]dioxole, piperonal and sesamol in high total yield. The key steps involved a modified Pomeranz-Fritsch reaction and the intramolecular Heck cyclization. This approach is short, convenient and suitable for the preparation of homoberberine analogues.

Full text of DOI:10.1002/cjoc.201400612

FULL PAPER
DOI: 10.1002/cjoc.201400612
A Versatile Total Synthesis of 8-Oxyberberine and
Oxohomoberberines
Yun He, Yang Zheng, Li Hai, and Yong Wu*
Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal
Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China
The total syntheses of 8-oxyberberine and oxohomoberberines were accomplished starting from commercially
available 5-bromobenzo[d][1,3]dioxole, piperonal and sesamol in high total yield. The key steps involved a
modified Pomeranz-Fritsch reaction and the intramolecular Heck cyclization. This approach is short, convenient
and suitable for the preparation of homoberberine analogues.
Keywords synthetic method, total synthesis, oxohomoberberines, modified Pomeranz-Fritsch reaction, in-
tramolecular Heck cyclization
Introduction
enlarging the B-ring of 8-oxyberberine to design the
novel compound 1c and 1d (Figure 1).
[
4c]
8
-Oxyberberine (1a, Figure 1) is a significant natural
However, our group found that previously reported
methods were unsuitable for the synthesis of target
compounds because of low overall yields and needing
compound which was isolated from Acangelisia
gusanlung, Cocculus orbiculatus, Phellodendron
[
1]
amurense and Argemone mexicana Linn. Due to its
biological properties such as antitumor, antiarrhythmic
and anti-inflammatory activities, scientists have con-
centrated on the structural modification of 8-oxyberbe-
[5]
complicated starting materials. Thus, the development
of a convenient and short approach for the oxohomo-
berberines is demanded.
[
2]
rine for decades.
Experimental
Changes in the skeleton of natural alkaloids have
proved beneficial. Cheng et al. modified the
Unless otherwise noted, materials were obtained
from commercial suppliers and used without further
purification. All manipulations involving air-sensitive
materials were performed under argon. TLC was per-
formed using precoated silica gel GF254 (0.2 mm),
while column chromatography was performed using
silica gel (100－200 mesh). The melting point was
measured on a YRT-3 melting point apparatus (Shantou
Keji instrument & Equipment Co. Ltd, Shantou, China).
8
-oxyberberine to get the 8,8-dialkyldihydroberberines
(
8,8-DDBs) and investigated their anti-diabetic activity
[
3]
in 2010. The 8,8-DDBs (I, Figure 1) promoted glu-
cose uptake and AMPK phosphorylation in L6
myoblasts while it also reduced glucose levels in dia-
betic mice.
Mitiglinide (trade name Glufast, II, Figure 1) is an
isoindole compound for the treatment of type 2 diabe-
[4a]
tes. Interestingly, the similar isoindole-skeletons have
been also observed in Gliclazide (III，Figure 1) and
Glisindamide (IV, Figure 1) which were shown to have
1
H NMR spectra were taken on a Varian INOVA400
(
3
Varian, Palo Alto, CA, USA) using CDCl , DMSO-d
6
[
4b]
and D2O as solvent. Chemical shifts are expressed in δ,
an antiatherogenic effect in type 2 diabetes. Thus, it
can be expected that the novel compound 1b (Figure 1)
which was introduced the isoindole moiety to the B-ring
of 8-oxoberberine shared structural homology with the
chemical compounds mentioned earlier and possessed
hypoglycemic ability unique to their parent natural ber-
berine.
with tetramethylsilane (TMS) functioning as the internal
reference, and coupling constants (J) were expressed in
Hz. Mass spectra were recorded on a Bruner AmaZon
SL (Bruker Daltonics, German).
2-(Benzo[d][1,3]dioxol-5-yl)ethanol (5a) A solu-
tion of ethylene oxide (6.6 g, 0.15 mol) in dry THF (100
mL) was added dropwise to the solution of
benzo[d][1,3]dioxol-5-ylmagnesium bromide (13 g,
0.058 mol) in 90 mL of dry THF within 1 h at 0 ℃.
In addition, We also found that the azepane ring in
the sulfonylurea derivatives, Glidazamide (V, Figure 1)
and Glisoxepide (VI, Figure 1) which inspired us into
*
E-mail: tgxx903@163.com
Received September 7, 2014; accepted October 7, 2014; published online November 3, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400612 or from the author.
Chin. J. Chem. 2014, 32, 1121—1127
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1121

He et al.
FULL PAPER
O
O
O
O
A
B
O
O
O
R
R
N
N
C
O
N
O
O
O
O
O
O
D
1b
I
1
a
R = Me, Et, n-Pr
O
O
O
O
N
H
O
NH
H
O
S
N
N
H
N
O
O
N
N
O
H
O
O
O
HO
III
O
HN
O
II
HN
S
1c
O
IV
O
S
O
O
O
O
O
HN
NH
O
N
O
O
S
N
O
O
N
N
NH
N
H
H
O
O
N
V
O
1d
VI
Figure 1 Important molecules in the discovery of hypoglycemic activity of berberine analogues.
After addition, the reaction mixture was allowed to
warm to room temperature for 2 h. Then 10 mL of
saturated NH Cl was added to quench the reaction. The
4
alcohol 6b (1 g, 3.6 mmol) and the resulting suspension
was stirred for 2 h at room temperature, then extracted
with DCM (30 mL×3). The combined organic phases
resulting mixture was extracted with diethyl ether (100
2 3
were washed with Na CO (2 mol/L, 50 mL), dried with
mL×3). The combined organic layer was washed with
MgSO and concentrated in vacuo to give benzyl bro-
4
2
0 mL of brine, dried over anhydrous sodium sulfate,
mide 7b (1.1 g, 3.3 mmol, 90%) as a white soild which
filtered and concentrated. The residue was purified in
was used without further purification in the next step.
1
vacuum to afford 5a (22.4 g, 0.135 mmol, 90%) as
m.p. 72－74 ℃; H NMR (400 Hz, CDCl
3
) δ: 7.248 (s,
O),
1
colorless oil. H NMR (400 Hz, CDCl
3
) δ: 6.755 (d, J＝
1H, ArH), 6.964 (s, 1H, ArH), 5.993 (s, 2H, OCH
4.557 (s, 2H, ArCH Br).
3 and 4 were prepared following the procedure of
2
7
.6 HZ, 1H, ArH), 6.719 (s, 1H, ArH), 6.673 (d, J＝7.6
2
Hz, 1H, ArH), 5.926 (s, 2H, OCH
2
O), 3.802 (t, J＝6.4
).
b was prepared following the procedure of
[
6]
Hz, 2H, CH
2
), 2.779 (t, J＝6.4 Hz, 2H, CH
2
Yang et al.
3-(3,4-Methlenedioxyphenyl)-1-propanol
The flask was charged with NaBH ( 1.91 g, 51 mmol),
5
(5c)
[
7]
Harrowven et al.
4
(
6-Iodo-1,3-benzodioxol-5-yl)-methanol (6b) To
a cooled (−5 ℃) solution of piperonyl alcohol 5b (0.93
g, 6.11 mmol) in CHCl (13 mL) were added iodine
1.73 g, 6.8 mmol) and silver trifluroacetate (1.5 g, 6.79
acid 4 (3.27 g, 16.8 mmol) and THF (40 mL). After the
flask was cooled to 0 ℃ in an ice bath, a solution of
iodine (4.27 g, 16.8 mol) dissolved in 40 mL of THF
was added slowly and dropwise over 30 min resulting in
vigorous evolution of hydrogen. After addition of the
iodine was complete and gas evolution had ceased, the
flask was heated to reflux for 12 h and then cooled to
room temperature, and methanol was added cautiously
until the mixture became clear then the mixture was
extracted with DCM (30 mL × 3). The combined
3
(
mmol). After stirring for 30 min the reaction was fil-
tered through Celite. The filtrate was washed with satu-
rated Na
trated in vacuo to a yellow solid. Recrystallization from
CHCl gave iodine 6b (1.47 g, 5.29 mmol, 87%) as a
white solid. m.p. 108－110 ℃; H NMR (400 Hz,
CDCl ) δ: 7.232 (s, 1H, ArH), 6.986 (s, 1H, ArH), 5.975
s, 2H, OCH O), 4.588 (s, 2H, ArCH O), 2.031 (br. s,
2 2 3 4
S O (50 mL), dried (MgSO ) and concen-
3
1
3
2 3
organic phases were washed with Na CO (2 mol/L, 50
(
2
2
mL), dried (MgSO ) and concentrated in vacuo to give
4
1
H, OH).
-(Bromomethyl)-6-iodo-1,3-benzodioxole
Concentrated HBr (48%, 4 mL) was slowly added to the
benzylic propanol 5c (2.55 g, 14 mmol, 84%) as a
5
(7b)
yellow oil which was used without further purification
1
in the next step. H NMR (400 Hz, CDCl
3
) δ: 6.719 (d,
1122
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 1121—1127

A Versatile Total Synthesis of 8-Oxyberberine and Oxohomoberberines
J＝7.6 Hz, 1H, ArH), 6.684 (s, 1H, ArH), 6.632 (d, J＝
the crude bromide 7c (1.02 g, 2.8 mmol, 87.5%) as a
7
(
.6 Hz, 1H, ArH), 5.904 (s, 2H, OCH
m, 2H, CH ), 2.629－2.591 (m, 2H, CH
OH), 1.861－1.790 (m, 2H, CH ).
-(2-Bromoethoxy)benzo[d][1,3]dioxole (5d) The
2
O), 3.648－3.616
yellow oil, which was carried on to the next step
without any further purification. H NMR (400 Hz,
1
2
2
), 2.506 (s, 1H,
2
CDCl
(s, 2H, OCH
2.755 (m, 2 H, CH
3
) δ: 7.200 (s, 1H, ArH), 6.707 (s, 1H, ArH), 5.928
O), 3.428－3.395 (m, 2H, CH ), 2.793－
), 2.115－2.045 (m, 2H, CH ).
5
2
2
mixture of sesamol 2d (2 g, 14.5 mmol), sodium
hydroxide (695 mg, 17 mmol), TBAB (467 mg, 1.4
mmol) and alcohol (20 mL) was cooled to 30 ℃ after
it was heated and refluxed for 1 h. 1,2-Dibromoethane
2
2
5-(2-Bromoethyl)-6-iodobenzo[d][1,3]dioxole (7a)
7a was prepared as the above step (yield 91%) as a yel-
1
low solid. m.p. 82－84 ℃; H NMR (400 Hz, CDCl
3
) δ:
(
3.76 mL, 43.4 mmol) was added, heated and refluxed
7.234 (s, 1H, ArH), 6.776 (s, 1H, ArH), 5.968 (s, 2H,
OCH O), 3.499 (t, J＝7.6 Hz, 2H, CH ), 3.186 (t, J＝
7.6 Hz, 2H, CH ).
7,8-Dimethoxyisoquinolin-1(2H)-one (10)
2,3-dimethoxybenzoic acid (8) (2 g, 11 mmol) was
added SOCl (20 mL), and the mixture was stirred at 80
℃ for 1 h, then the remaining SOCl was removed. To
for 24 h, and it was condensed, extracted with ethyl
acetate. The organic phase was washed with water, dried
over Na
due, which was purified by silica gel column chroma-
tography using AcOEt/PE (1∶10) as a white solid (1.9
2
2
2
2
4
SO , and concentrated in vacuo to give a resi-
To
2
1
g, 7.8 mmol, 53%). m.p. 74－76 ℃; H NMR (400 Hz,
2
CDCl
ArH), 6.342 (d, J＝7.2 Hz, 1H, ArH), 5.921 (s, 2H,
OCH O), 4.211 (t, J＝4.4 Hz, 2H, CH ), 3.598 (t, J＝
.4 Hz, 2H, CH ).
-(6-Iodobenzo[d][1,3]dioxol-5-yl)propan-1-ol (6c)
A solution of I (6.66 g, 26 mmol) in dry CHCl (15 mL)
was added over a suspension of CF COOAg (6.28 g, 28
mmol) and propanol 5c (3.94 g, 22 mmol) in dry CHCl
20 mL). After the reaction mixture was stirred at room
3
) δ: 6.702 (d, J＝7.2 Hz, 1H, ArH), 6.519 (s, 1H,
the residue in dry DCM (20 mL) at 0 ℃ was added
DIPEA (3 mL, 16.9 mmol). The reaction was stirred for
4 min at 0 ℃ before adding 2,2-dimethoxyethanamine
(0.9 g, 8 mmol). The reaction was allowed to warm to
room temperature and stirred for 20 h. The reaction was
washed with 1 equiv. HCl (50 mL), water (50 mL),
saturated NaHCO (50 mL), dried over MgSO , filtered
3 4
and concentrated to give the N-(2,2-dimethoxyethyl)
benzamide (9) as a yellow oil. To 9 (2.49 g, 9.25 mmol)
2
2
4
2
3
2
3
3
3
(
temperature for 2 h, the resulting AgI precipitate was
filtered, and the filtrate was washed with saturated
2 4
was added 80% H SO (25 mL) at 0 ℃. The reaction
was allowed to warm to room temperature and stirred
for 22 h. It was then poured over ice and then quenched
Na
vacuo to a yellow solid. Recrystallisation from Et
gave iodine 6c (5.35 g, 17 mmol, 80%) as a white solid.
2 2 3 4
S O (50 mL), dried (MgSO ) and concentrated in
2
O
with saturated NaHCO
extracted with DCM (30 mL × 3). The combined
organic phases were dried over MgSO and concen-
3
. The aqueous solution was
1
m.p. 28－30 ℃; H NMR (400 Hz, CDCl
3
) δ: 7.210 (s,
H, ArH), 6.709 (s, 1H, ArH), 5.931 (s, 2H, OCH O),
.701－3.668 (m, 2H, CH ), 2.742－2.703 (m, 2H,
), 1.923 (br s, 1H, OH), 1.855－1.769 (m, 2H,
).
-(6-Iodobenzo[d][1,3]dioxol-5-yl)ethanol
a was prepared as the above step (yield 89%) as a yel-
4
1
3
2
trated in vacuo to give 7,8-dimethoxyisoquinolin-1(2H)-
one 10 (1.63 g, 8 mmol, 86%) as a yellow solid which
2
1
CH
CH
2
was used without purification. m.p. 150－152 ℃; H
2
3
NMR (400 Hz, CDCl ) δ: 11.183 (br s, 1H, NH), 7.358
(d, J＝8.4 Hz, 1H, ArH), 7.288 (d, J＝8.4 Hz, 1H, ArH),
7.058 (d, J＝7.2 Hz, 1H, CH＝CH), 6.442 (d, J＝7.2
2
(6a)
6
1
low oil. H NMR (400 Hz, CDCl
3
) δ: 7.212 (s, 1H, ArH),
.818 (s, 1H, ArH), 5.929 (s, 2H, OCH O), 4.876 (br. s,
H, OH), 3.653 (t, J＝7.2 Hz, 2H, CH ), 2.867 (t, J＝
.2 Hz, 2H, CH ).
-(2-Bromoethoxy)-6-iodobenzo[d][1,3]dioxole
7d) 7d was prepared as the above step (yield＝83%)
Hz, 1H, CH＝CH), 3.999 (s, 3H, OCH
3 3
OCH ); C NMR (400 Hz, CDCl ) δ: 155.6, 152.7,
3
), 3.954 (s, 3H,
13
6
1
7
2
2
149.1, 128.6, 127.7, 124.8, 119.8, 117.7, 105.5, 60.9,
56.1; LC-MS m/z: 206.1 [M＋H].
2
5
2-(2-(6-Iodobenzo[d][1,3]dioxol-5-yl)ethyl)-7,8-
dimethoxyisoquinolin-1(2H)-one (11a) To 7,8-di-
methoxyisoquinolin-1(2H)-one 10 (0.26 g, 1.28 mmol)
and dry DMF ( 10 mL) was added 60% sodium hydride
in mineral oil (0.06 g, 1.54 mmol). The resulting
suspension was allowed to stir at 0 ℃ for 1 h. Com-
pound 7a (0.5 g, 1.4 mmol) in dry DMF (5 mL) was
added and the reaction was allowed to watm to room
temperature. This suspension was allowed to stir for an
additional 15 h. It was then poured into 50 mL water
and extracted with DCM (30 mL×3). The combined
(
1
as a brown solid. m.p. 91－93 ℃; H NMR (400 Hz,
CDCl ) δ: 7.166 (s, 1H, ArH), 6.533 (s, 1H, ArH), 5.959
s, 2H, OCH O), 4.236 (t, J＝6.8 Hz, 2H, CH ), 3.648 (t,
J＝6.8 Hz, 2H, CH ).
-(3-Bromopropyl)-6-iodobenzo[d][1,3]dioxole
7c) A solution of the iodine 6c (1 g, 3.2 mmol) in dry
CH Cl (10 mL) at 0 ℃ was treated with CBr (1.14 g,
.4 mmol) followed by the portionwise addition of
3
(
2
2
2
5
(
2
2
4
3
triphenylphosphine (0.9 g, 3.4 mmol). The reaction was
allowed to warm to room temperature and monitored by
TLC. After no starting material was detected, the
solvent was removed under reduced pressure. The
resulting solid was resuspended in a 1∶1 mixture of
organic phases were dried (MgSO
vacuo to give 2-(2-(6-iodobenzo[d][1,3]dioxol-5-yl)-
ethyl)-7,8-dimethoxyisoquinolin-1(2H)-one (11a)
(0.527 g, 1.1 mmol, 78.5%) as a yellow solid. m.p. 159
4
) and concentrated in
1
Et
2
O/pentane and filtered through a pad of silica. The
－161 ℃; H NMR (400 Hz, CDCl
3
) δ: 7.317 (d, J＝
solvent was removed under rotary evaporator to provide
8.8 Hz, 1H, ArH), 7.264 (s, 1H, ArH), 7.220 (d, J＝8.8
Chin. J. Chem. 2014, 32, 1121—1127
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1123

He et al.
FULL PAPER
Hz, 1H, ArH), 6.819 (d, J＝7.2 Hz, 1H, CH＝CH),
13
3.931 (s, 3H, OCH ); C NMR (100 Hz, CDCl ) δ:
3 3
6
5
4
.800 (s, 1H, ArH), 6.301 (d, J＝7.2 Hz, 1H, CH＝CH),
.940 (s, 2H, OCH O), 4.084 (t, J＝7.2 Hz, 2H, CH ),
.006 (s, 3H, OCH ), 3.947 (s, 3H, OCH ), 3.136 (t,
); C NMR (100 Hz, CDCl ) δ:
60.066, 151.572, 149.468, 148.556, 147.221, 134.195,
32.732, 129.953, 124.305, 122.778, 118.650, 118.386,
16.041, 105.371, 101.537, 87.779, 61.568, 56.746,
9.609, 39.373; LC-MS m/z: 480.0 [M＋H].
-((6-Iodobenzo[d][1,3]dioxol-5-yl)methyl)-7,8-
160.241, 152.278, 151.532, 149.467, 148.861, 142.623,
133.066, 132.011, 122.039, 120.665, 118.812, 117.590,
105.033, 101.731, 95.749, 73.069, 68.181, 61.550,
56.794, 49.156; LC-MS m/z: 496.02 [M＋H].
8-Oxyberberine (1a) A mixture of 2-(2-(6-iodo-
benzo[d][1,3]dioxol-5-yl)ethyl)-7,8-dimethoxyisoquino-
lin-1(2H)-one (11a) (0.3 g, 0.625 mmol), palladium(II)
2
2
3
3
1
3
J＝7.2 Hz, 2H, CH
1
1
1
4
2
3
acetate (0.03 g, 0.125 mmol), PCy (0.073 g, 0.25
3
2
mmol), Ag CO (0.086 g, 0.312 mmol) and potassium
2
3
dimethoxyisoquinolin-1(2H)-one (11b) To 7,8-di-
methoxyisoquinolin-1(2H)-one (10) (0.12 g, 0.59 mmol)
and dry DMF ( 10 mL) was added 60% sodium hydride
in mineral oil (0.03 g, 0.76 mmol). The resulting
suspension was allowed to stir at 0 ℃ for 1h. Benzyl
bromide 7b (0.24 g, 0.7 mmol) in dry DMF (5 mL) was
added and the reaction was allowed to watm to room
temperature. This suspension was allowed to stir for an
additional 15 h. It was then poured into 50 mL water
and extracted with DCM (30 mL×3). The combined
carbonate (0.173 g, 1.25 mmol) in 5 mL of anhydrous
acetonitrile was purged with nitrogen and refluxed at
1
20 ℃ for 8 h. At this time the reaction was complete
(as monitored by TLC). After cooled down, the resulting
solid was collected by filtration, washed with 2 mL of
acetonitrile, and concentrated in vacuo to get a brown
solid which was purified by column chromatography on
silica gel eluting with PE/acetone gradient (50∶1－1∶
1
2
8
5) as a yellow solid 1a (0.165 g, 0.47 mmol, 75%). m.p.
1
38－240 ℃; H NMR (400 Hz, CDCl ) δ: 7.32 (d, J＝
3
4
organic phases were dried (MgSO ) and concentrated in
vacuo to give 2-((6-iodobenzo[d][1,3]dioxol-5-yl)meth-
yl)-7,8-dimethoxyisoquinolin-1(2H)-one (11b) (0.293 g,
.4 Hz, 1H, ArH), 7.286 (s, 1H, ArH), 7.268 (s, 1H,
ArH), 7.213 (s, 1H, ArH), 6.71 (d, J＝8.4 Hz, 1H, ArH),
6
4
6
1
1
1
5
.007 (s, 2H, OCH O), 4.290 (t, J＝6.4 Hz, 2H, CH ),
2
2
0
.63 mmol, 90%) as a yellow solid. m.p. 144－146 ℃;
.014 (s, 3H, OCH
.4 Hz, 2H, CH
3
), 3.949 (s, 3H, OCH
); C NMR (100 Hz, CDCl ) δ:
3
3
), 2.889 (t, J＝
1
H NMR (400 Hz, CDCl
3
) δ: 7.327 (d, J＝8.4 Hz, 1H,
13
2
ArH), 7.250 (s, 1H, ArH), 7.236 (d, J＝8.4 Hz, 1H,
ArH), 6.899 (d, J＝7.6 Hz, 1H, CH＝CH), 6.653 (s, 1H,
ArH), 6.370 (d, J＝7.6 Hz, 1H, CH＝CH), 5.919 (s, 2H,
60.248, 153.788, 151.613, 149.508, 148.113, 141.819,
32.919, 131.127, 130.886, 130.346, 122.027, 119.179,
07.991, 105.663, 98.198, 73.665, 66.944, 62.343,
6.238, 48.333; LC-MS m/z: 352.1 [M＋H]. Anal. calcd
OCH
2
O), 5.135 (s, 2H, CH
2
), 3.974 (s, 3H, OCH
3
),
13
3
1
1
1
5
.943 (s, 3H, OCH
3
); C NMR (100 Hz, CDCl ) δ:
3
for C H NO : C 68.37, H 4.88, N 3.99; found C 68.21,
2
0
17
5
60.109, 151.836, 149.651, 148.829, 147.889, 132.556,
32.476, 129.085, 122.086, 120.804, 118.676, 118.486,
08.808, 106.026, 101.688, 86.366, 61.594, 56.704,
5.502; LC-MS m/z: 466.04 [M＋H].
H 4.94, N 4.02.
,9-Dimethoxy-[1,3]dioxolo[4',5':5,6]isoindolo[2,1-
8
b]isoquinolin-7(5H)-one (1b) A mixture of 2-((6-
iodobenzo[d][1,3]dioxol-5-yl)methyl)-7,8-dimethoxyiso-
quinolin-1(2H)-one (11b) (0.1 g, 0.2 mmol), palladi-
2
-(3-(6-Iodobenzo[d][1,3]dioxol-5-yl)propyl)-7,8-
dimethoxyisoquinolin-1(2H)-one (11c) 11c was pre-
um(II) acetate (0.01 g, 0.04 mmol), PCy (0.024 g, 0.08
3
pared as the above step (yield 93%) as a yellow solid.
1
mmol), Ag CO (0.03 g, 0.1 mmol) and potassium
2 3
m.p. 148－150 ℃; H NMR (400 Hz, CDCl
3
) δ: 7.308
carbonate (0.06 g, 0.4 mmol) in 5 mL of anhydrous
acetonitrile was purged with nitrogen and refluxed at
(
d, J＝8.4 Hz, 1H, ArH), 7.236 (s, 1H, ArH), 7.208 (d,
J＝8.4 Hz, 1H, ArH), 6.925 (d, J＝7.6 Hz, 1H, CH＝
CH), 6.749 (s, 1H, ArH), 6.360 (d, J＝7.6 Hz, 1H,
1
20 ℃ for 14 h. At this time the reaction was complete
(as monitored by TLC). After cooled down, the resulting
CH＝CH), 5.942 (s, 2H, OCH
CH ), 3.984 (s, 3H, OCH ), 3.939 (s, 3H, OCH
2.705 (m, 2 H, CH ), 2.065－2.007 (m, 2H, CH
NMR (100 Hz, CDCl ) δ: 159.916, 151.556, 149.426,
2
O), 4.035－3.998 (m, 2H,
solid was collected by filtration, washed with 2 mL of
acetonitrile, and concentrated in vacuo to get a brown
solid which was purified by column chromatography on
silica gel eluting with PE/acetone gradient (100∶1－
2
3
3
), 2.760
2
); C
1
3
－
2
3
1
1
8
48.342, 146.632, 136.874, 134.812, 132.577, 129.749,
21.872, 118.465, 118.333, 109.010, 105.396, 101.379,
7.535, 61.480, 56.673, 48.562, 37.789, 29.614; LC-MS
1
7
7
∶10) as a yellow solid 1b (0.0521 g, 0.154 mmol,
1
7%). m.p. 140－142 ℃; H NMR (400 Hz, CDCl ) δ:
3
.345 (s, 2H, ArH), 7.135 (s, 1H, ArH), 6.990 (s, 1H,
m/z: 494.10 [M＋H].
-(2-((6-Iodobenzo[d][1,3]dioxol-5-yl)oxy)ethyl)-
,8-dimethoxyisoquinolin-1(2H)-one (11d) 11d was
prepared as the above step (yield 79%) as a white solid.
ArH), 6.742 (s, 1H, ArH), 6.077 (s, 2H, OCH O), 5.053
2
2
(
s, 2H, CH ), 4.030 (s, 3 H, OCH ), 3.961 (s, 3H,
7
2
3
13
OCH ); C NMR (100 Hz, CDCl ) δ: 159.894, 151.010,
3
3
1
1
49.688, 140.518, 139.874, 133.923, 131.908, 127.514,
m.p. 188－190 ℃; H NMR (400 Hz, CDCl
3
) δ: 7.323
(
d, J＝3.2 Hz, 1H, ArH), 7.302 (d, J＝3.2 Hz, 1H, ArH),
.230 (d, J＝8.8 Hz, 1H, CH＝CH), 7.122 (s, 1H, ArH),
.444 (s, 1H, ArH), 6.385 (d, J＝8.8 Hz, 1H, CH＝CH),
122.311, 121.878, 118.833, 118.465, 103.750, 101.857,
100.626, 96.240, 61.756, 56.845, 51.891; LC-MS m/z:
338.2 [M ＋ H], 360.2 [M ＋ Na]. Anal. calcd for
7
6
5
4
.909 (s, 2H, OCH
.266 (t, J＝4.8 Hz, 2H, CH
2
O), 4.376 (t, J＝4.8 Hz, 2H, CH
), 3.977 (s, 3H, OCH
2
),
),
C
19
H15NO
5
: C 67.65, H 4.48, N 4.15; found C 67.43, H
4.59, N 4.20.
2
3
1124
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 1121—1127

A Versatile Total Synthesis of 8-Oxyberberine and Oxohomoberberines
1
0,11-Dimethoxy-6,7-dihydro[1,3]dioxolo[4'',5'':
',5']benzo[1',2':3,4]azepino[1,2-b]isoquinolin-9(5H)-
one (1c) 1c was prepared as the above step (yield＝
4
7
7
56.837, 49.106; LC-MS m/z: 368.6 [M＋H]. Anal. calcd
: C 65.39, H 4.66, N 3.81; found C 65.42,
H 4.59, N 3.78.
4
for C20H17NO
6
1
3
2%) as a yellow oil. H NMR (400 Hz, CDCl ) δ:
.329 (d, J＝8.8 Hz, 1H, ArH), 7.240 (s, 1H, ArH),
.004 (s, 1H, ArH), 6.721 (s, 1H, ArH), 6.382 (s, 1H,
Results and Discussion
Our strategy for the synthesis of 8-oxyberberine 1a
is shown in Scheme 1. The corresponding 2-phenyl-
ethanol 5a was readily prepared by Grignard reaction of
benzo[d][1,3]dioxol-5-ylmagnesium bromide with eth-
ylene oxide in dry THF. The iodination reaction of al-
ArH), 6.016 (s, 2H, OCH
2
O), 5.074－5.0273 (m, 1H,
CH), 4.022 (s, 3H, OCH
3
), 3.954 (s, 3H, OCH
.187－3.110 (m, 1H, CH), 2.626－2.520 (m, 2H, CH
3
),
),
3
2
2
.422－2.338 (m, 1H, CH), 1.899－1.835 (m, 1H, CH);
1
3
3
C NMR (100 Hz, CDCl ) δ: 159.979, 151.645,
cohol 5a was performed with I
2
and CF
3
COOAg to give
1
1
1
3
49.519, 148.288, 146.359, 142.309, 134.882, 132.677,
29.805, 121.901, 120.919, 118.568, 109.063, 108.183,
05.466, 101.265, 61.523, 56.754, 48.854, 32.679,
0.596; LC-MS m/z: 366.2 [M＋H]. Anal. calcd for
[
7,8]
compound 6a.
Appel-Lee synthesis of compound 7a
[
9]
was from 6a.
The synthesis of oxohomoberberine 1b and 1c is
shown in Scheme 2. Knoevenagel condensation of
malonic acid and commercially available piperonal 2b
in pyridine/piperidine gave the corresponding acids 3,
followed by palladium-catalyzed hydrogenation to form
acid 4 that was used without purification in the next
C
5
21
H
19NO
5
: C 69.03, H 5.24, N 3.83; found C 69.10, H
.45, N 3.78.
0,11-Dimethoxy-6H-[1,3]dioxolo[4'',5'':4',5']-
benzo[1',2':6,7][1,4]oxazepino[4,5-b]isoquinolin-
(7H)-one (1d) 1d was prepared as the above step
1
9
[
6]
1
step. Piperonal 2b was also reduced to benzylic alco-
hol 5b by using NaBH while the NaBH /I system was
(yield 39%) as a yellow oil. H NMR (400 Hz, CDCl
3
) δ:
7
.301 (s, 1H, ArH), 7.218 (s, 1H, ArH), 7.029 (d, J＝7.2
4
4 2
chosen to deoxidize the acid 4 to yield benzylic propa-
nol 5c. The iodination reaction of alcohol 5b and pro-
Hz, 1H, ArH), 6.661 (d, J＝7.2 Hz, 1H, ArH), 6.454 (s,
1
2
H, ArH), 5.887 (s, 2H, OCH
2
O), 4.304 (t, J＝4.4 Hz,
), 4.252 (t, J＝4.4 Hz, 2H, CH ), 3.975 (s, 3H,
3
); C NMR (100 Hz, CDCl )
panol 5c was performed with I
compound 6b and compound 6c, respectively.
Lee synthesis of 1-(3-bromopropyl)-2-iodobenzene (7c)
2 3
and CF COOAg to give
H, CH
2
2
[7,8]
13
Appel-
OCH
3
), 3.935 (s, 3H, OCH
3
δ: 160.247, 153.798, 151.653, 149.558, 148.213,
[9]
was from 6c. Meanwhile, the benzyl bromide 7b was
prepared from 6b with 48% aqueous HBr, identically in
1
1
41.839, 132.929, 131.147, 122.394, 119.069, 107.891,
05.683, 101.115, 98.098, 73.665, 66.974, 61.593,
Scheme 1 Synthesis of 8-oxyberberine (1a)
I , CF COOAg,
2
3
OH
Br
OH
O
O
O
O
O
O
1
) Mg, THF
NaHCO , CHCl
3
3
2
5 oC, 1.5 h
2) ethylene oxide
I
2a
5a
6a
Br
O
O
CBr , PPh , DCM
0 oC to r.t., 3 h
4
3
I
7a
OMe
OMe
H
COOH
OMe
O
NH
N
O
1) SOCl2, reflux
) 2,2-dimethoxy-
OMe
80% H SO
2
4
OMe
2
o
OMe
0 to 25 C, overnight
ethanamine, DIPEA
0 oC to r.t., overnight
OMe
8
OMe
9
10
O
Pd(OAc) , PCy , Ag CO ,
O
2
3
2
3
K CO , CH CN
N
O
2
3
3
O
NaH, DMF
N
O
O
I
0 oC to r.t., 15 h
120 oC, 8 h
OMe
OMe
OMe
OMe
11a
1a
Chin. J. Chem. 2014, 32, 1121—1127
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1125

He et al.
FULL PAPER
Scheme 2 Synthesis of oxohomoberberines 1b and 1c
malonic acid,
pyridine/piperidine,
COOH reflux, 2 h
CHO
O
O
O
NaBH , EtOH
O
O
4
OH
o
25 C, 30 min
O
3
2b
5b
I , CF COOAg,
2
3
1
0% Pd/C,
NaHCO , CHCl ,
MeOH,
r.t., overnight
3
3
o
25 C, 1.5 h
O
O
OH
O
O
COOH
OH
I
O
O
NaBH /I , dry THF
4
2
o
0
to 66 C, 12 h
5c
6b
4
I , CF COOAg,
2
3
NaHCO , CHCl ,
3
3
o
4
8% HBr, 25 C, 2 h
o
25 C, 1.5 h
O
Br
O
O
O
Br
I
OH
CBr , PPh , DCM
0 oC to r.t., 3 h
4
3
O
I
O
I
7c
7b
6c
H
N
O
NaH, DMF
NaH, DMF
OMe
OMe
0 oC to r.t.
o
0 C to r.t.
10
O
OMe
OMe
O
O
OMe
OMe
N
O
O
O
N
I
1
1c
I
11b
Pd(OAc) , PCy ,
2
3
Ag CO , K CO ,
2
3
2
3
o
CH CN, 120 C
3
Pd(OAc) , PCy ,
2 3
Ag CO , K CO ,
2
3
2
3
o
O
O
CH CN, 120 C
3
N
O
O
O
O
N
OMe
OMe
OMe
1c
OMe
1b
[
8]
all aspects with the Harrowven’s report.
The isoquinolinone 10 was treated with NaH and bromo
compound 7a, 7b, 7c or 7d (respectively) to afford the
key intermediates－N-substituted isoquinoline-1(2H)-
The synthesis of oxohomoberberine 1d is shown in
Scheme 3. Compound 5d was prepared by the reaction
of sesamol 2d with ethylene dibromide in EtOH. Then,
compound 7d was prepared from 5d by Appel-Lee syn-
thesis.
Treatment of benzoic acid 8 with SOCl
,2-dimethoxyethanamine resulted in N-(2,2-dimeth-
[
11]
one 11a, 11b, 11c and 11d.
Next, we turned our attention to the cyclization of
11a, 11b, 11c and 11d. Among the existing method of
cyclization, the closest competing methodology to the
[
9]
2
and
[12]
2
intramolecular Heck reaction is radical cyclization.
oxyethyl)benzamide (9) without purification followed
by cyclization to form the isoquinolinone core 10 as a
modified Pomeranz-Fritsch reaction in Scheme 1.
Although both methods typically give efficient exo ring
closure, radical cyclization (usually mediated by
n-Bu SnH) is often characterized by reduction leading
3
[
10]
1126
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 1121—1127

A Versatile Total Synthesis of 8-Oxyberberine and Oxohomoberberines
Scheme 3 Synthesis of oxohomoberberine 1d
I , CF COOAg,
H
2
3
BrCH CH Br
TBAB, NaOH,
EtOH, reflux, 24 h
2
2
N
O
NaHCO , CHCl ,
O
I
3
3
O
O
OH
O
O
O
O
O
Br
o
Br
25 C
OMe
OMe
7d
2d
5d
10
Pd(OAc) , PCy ,
2
3
O
O
O
Ag CO , K CO ,
2
3
2
3
o
O
N
O
NaH, DMF
0 oC to r.t., 15 h
CH CN, 120 C, 24 h
3
O
N
O
I
O
OMe
OMe
OMe
OMe
1d
11d
to a reductive cyclization. Heck reaction is generally not
reductive because beta-hydride elimination is the usual
outcome. In addition, another drawback of radical cy-
clization is the use of stoichiometric quantities of
Science Foundation of China (No. 81373259).
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3
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Conclusions
In summary, we have successfully presented a syn-
thetic route for the synthesis of 8-oxyberberine 1a with
high total yield of 43% from 5-bromobenzo[d][1,3]-
dioxole (2a) in 7 steps. Meanwhile, we firstly described
the synthesis of the oxohomoberberines 1b, 1c and 1d in
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4
6.2% (7 steps), 22.9% (9 steps), and 14% (6 steps)
overall yields, respectively. Considering oxyberberine
possesses excellent hypoglycemic activity, our work
might provide an efficient synthetic route for its phar-
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Acknowledgement
This work was supported by the National Natural
(Pan, B.; Qin, X.)
Chin. J. Chem. 2014, 32, 1121—1127
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1127