Regio- and stereoselective C10β-H functionalization of sinomenine: An access to more potent immunomodulating derivatives

Article abstract of DOI:10.1016/j.tet.2012.01.009

Regio- and stereoselective C_10β-H functionalization of sinomenine, an economically available natural immunomodulating alkaloid, has been studied, developed and successfully applied to the synthesis of new immunosuppressive sinomenine derivatives in a protecting-free fashion. Regioselective oxidation of sinomenine with (diacetoxyiodo)benzene (DIB) in water provided a single stable benzoquinone derivative 4, and subsequent 1,6-conjugated addition of 4 with alcohols, amines, and thiols afforded a new series of C_10β-H functionalized sinomenine derivatives stereoselectively. Some derivatives with a newly introduced 10β- bezenesulfanyl substituent exhibited much higher TNF-α inhibitory potency than their natural parent sinomenine. This work opens a convenient access to novel sinomenine derivatives with medicinal interests.

Full text of DOI:10.1016/j.tet.2012.01.009

Supplementary Material
Regio- and stereoselective C -H functionalization of sinomenine: an
10β
access to more potent immunomodulating derivatives
1
2
3
2
3
Yang-Tong Lou, Li-Yan Ma, Meng Wang, Dongsheng Yin, Ting-Ting Zhou, Ai-Zhong
2
2
2
3
1
2
Chen, Zhao Ma, Chao Bian, Shaozhong Wang, Zhen-Yu Yang,* Bing Sun,* and
1
,3
Zhu-Jun Yao*
1
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032;
2
Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences,
3
Chinese Academy of Sciences, 219 Yueyang Road, Shanghai 200031; State Key Laboratory of
Coordination Chemistry and Nanjing National Laboratory of Microstructures, Institute of
Chemical Biology and Drug Innovation, School of Chemistry and Chemical Engineering,
Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China.
yaoz@sioc.ac.cn or bingsun@sibs.ac.cn
List of content
1
2
3
Experimental details and characterization of new compounds………. ……….
S2-S21
Biological experimental details and results……………………………………
S22-S22
S23-S83
1
13
H NMR, C NMR and 2D NMR copies of new compounds…………………
S1

1
. Experimental details and characterization of new compounds
-1. General
1
All reactions were conducted using oven-dried glassware. All melting points were uncorrected.
Dichloromethane was distilled from CaH , and tetrahydrofuran was distilled from Na prior to use.
2
1
IR spectra were recorded on an FT-IR instrument. H NMR spectra were recorded at 300, 400 or
1
3
5
00 MHz, and C NMR spectra were recorded at 75, 100 or 125 MHz, and assigned in parts per
1
13
million (δ). Reference peaks for chloroform in H NMR and C NMR spectra were set at 7.26
6
1
13
ppm and 77.0 ppm, respectively. For DMSO-d , the reference peaks in H NMR and C NMR
spectra were set at 2.50 ppm and 39.43 ppm, respectively. Petroleum ether and ethyl acetate were
obtained from commercial suppliers and used without further distillations.
1
-2. Oxidation of sinomenine with DIB in MeOH.
N
AcO
e
M O
N
N
1
eq. DIB
MeOH
O
O +
O
O
OH
O
O
OH
O
O
OH
O
1
2
3
To a solution of sinomenine (1, 100 mg, 0.30 mmol, 1 equiv.) in methanol (2.5 mL) was added
iodobenzene diacetate (DIB) (100 mg, 0.31 mmol, 1 equiv.) at rt. The reaction was stirred at rt
until the starting material was consumed. The whole mixture was concentrated under reduced
pressure. The residue was purified by preparative TLC (DCM/MeOH = 15/1) to afford solids 2
o
(
12 mg, 10%) and 3 (58 mg, 53%). 10β-Acetoxysinomenine (2): white solid, m.p. 232-234 C
2
5
1
(
dec.); [α]D -73.5 (c 1.4, CHCl ); H NMR (CDCl , 400 MHz): δ 6.70-6.76 (2H, m), 6.12 (1H,
3
3
brs), 6.03 (1H, s), 5.62 (1H, d, J = 2.0 Hz), 4.34 (1H, d, J = 15.6 Hz), 3.83 (3H, s), 3.50 (3H, s),
.22 (1H, brs), 3.10 (1H, brs), 2.60 (3H, s), 2.53-2.61 (1H, m), 2.45 (1H, d, J = 15.6 Hz), 2.10
3
1
3
(
3H, s), 2.05 (1H, td, J = 11.6, 4.8 Hz), 1.83-1.96 (2H, m); C NMR (CDCl , 75 MHz): δ 193.4,
3
1
4
1
70.2, 150.9, 146.8, 144.3, 129.4, 122.4, 120.6, 116.6, 109.3, 65.0, 60.8, 55.9, 54.5, 49.1, 46.8,
4.8, 42.8, 40.7, 35.8, 21.5; IR (KBr): vmax 3373.8, 2938.9, 2840.3, 2248.7, 1725.8, 1682.0,
-1
634.5, 1488.2, 1463.7, 1283.7, 1234.2, 1145.9, 1058.2, 1006.4, 947.2, 729.7 cm ; HRMS (ESI,
+
m/z) calcd. for C H N O (M+H ): 388.1755, Found: 388.1755. 10β-methoxysinomenine (3):
2
1
26
1
6
o
25
D
1
yellow solid, m.p. 201-203 C (dec.); [α] -38.8 (c 1.4, CHCl ); H NMR (CDCl , 300 MHz): δ
3
3
S2

6
.85 (1H, d, J = 8.4 Hz), 6.72 (1H, d, J = 8.4 Hz), 6.07 (1H, brs), 5.73 (1H, d, J = 2.1 Hz), 4.32
1H, d, J = 15.9 Hz), 4.17 (1H, s), 3.82 (3H, s), 3.55 (3H, s), 3.45 (3H, s), 3.32 (1H, d, J = 3.0
Hz), 3.03 (1H, brs), 2.54 (3H, s), 2.45-2.53 (1H, m), 2.41 (1H, d, J = 15.6 Hz), 1.99 (1H, td, J =
(
1
3
3
1
.6, 11.7 Hz), 1.77-1.93 (2H, m); C NMR (CDCl , 75 MHz): δ 193.6, 150.6, 146.3, 144.2,
3
31.8, 121.9, 120.8, 117.8, 109.1, 72.5, 58.5, 57.6, 56.0, 54.7, 49.3, 46.9, 45.0, 42.6, 40.9, 35.8;
IR (KBr): vmax 3441.6, 2917.4, 2848.2, 2247.1, 1687.1, 1628.8, 1486.4, 1439.7, 1278.0, 1202.5,
-1
1
150.5, 1078.4, 1056.1, 1029.7, 948.8, 827.2, 731.7 cm ; HRMS (ESI, m/z) calcd. for
+
C H N O (M+H ): 360.1806, Found: 360.1809.
20
26
1
5
1
-3. Oxidation of sinomenine with DIB in H O.
2
N
HCl
N
1
.1 eq. DIB
H O
2
O
O
O
OH
O
O
OH
O
1
4
To a solution of sinomenine hydrochloride salt (21 g, 57.4 mmol, 1 equiv) in water (420 mL) was
added DIB (21 g, 65.2 mmol, 1.1 equiv) at rt. The reaction was stirred at the same temperature
for 1 h. Then, the mixture was basified with sat. aq. NaHCO and extracted with CH Cl (100 mL
3
2
2
x 3). The organic layers were combined, washed with water and brine, dried over Na SO , filtered,
2
4
and concentrated. The residue was purified by flash column chromatography on silica gel
o
(
CH Cl /acetone = 1/1) to afford solid 4 (12 g, 67%) as a bright yellow solid. m.p. 187-188 C
2
2
2
5
1
(
dec.); [α]D 563.3 (c 0.80, CHCl ); H NMR (CDCl , 400 MHz): δ 7.04 (1H, d, J = 9.6 Hz),
3 3
6
.56 (1H, d, J = 5.6 Hz), 6.44 (1H, d, J = 9.2 Hz), 5.28 (1H, d, J = 2.0 Hz), 4.06 (1H, d, J = 16.0
Hz), 3.73 (1H, dd, J = 2.8, J = 5.6 Hz), 3.48 (3H, s), 2.96 (1H, brs), 2.58-2.65 (1H, m), 2.42 (3H,
s), 2.37 (1H, d, J = 16.4 Hz), 2.05 (1H, td, J = 3.6, 12.8 Hz), 1.89-1.95 (1H, m), 1.84 (1H, td, J =
1
3
5
1
2
.2, 12.8 Hz); C NMR (CDCl , 100 MHz): δ 192.5, 181.1, 152.4, 147.0, 141.0, 140.3, 139.1,
3
24.8, 116.9, 114.8, 58.0, 54.9, 48.1, 46.5, 45.7, 43.0, 40.2, 35.7; IR (KBr): vmax 2946.3, 2829.9,
-1
254.0, 1684.7, 1627.4, 1466.7, 1363.2, 1199.8, 1150.1, 727.0 cm ; HRMS (ESI, m/z) calcd. for
+
C H N O (M+H ): 314.1387, Found: 314.1399.
18
20
1
4
1
-4. Oxidation of 1-hydroxymethyl sinomenine with DIB in MeOH.
S3

AcO
H CO
OH
3
N
N
N
HO
HO
+
1
.1 eq. DIB
MeOH
O
O
O
O
OH
O
O
OH
O
O
OH
O
5
6
7
To a solution of 1-hydroxylmethyl sinomenine (5, 100 mg, 0.28 mmol, 1 equiv.) in methanol (2.5
mL) was added iodobenzene diacetate (DIB) (100 mg, 0.31 mmol, 1.1 equiv) at rt. The reaction
was stirred at the same temperature until the starting material was consumed. The mixture was
then basified with sat. aq. NaHCO and extracted with CH Cl (10 mL x 4). The combined
3
2
2
organic layers were combined, washed with water and brine, dried over Na SO , filtered, and
2
4
concentrated. The residue was purified by preparative TLC (DCM/MeOH = 10/1) to afford solids
6
(18 mg, 22%) and 7 (59 mg, 54%). 1-Hydroxylmethyl 10β-acetoxysinomenine (6): light
o
26
D
1
yellow solid, m.p. 176-178 C (dec.); [α] -54.3 (c 0.2, CHCl ); H NMR (CDCl , 500 MHz): δ
3
3
6
.96 (1H, s), 6.23 (1H, brs), 6.15 (1H, s), 5.54 (1H, d, J = 1.5 Hz), 4.50 (1H, d, J = 13.0), 4.42
(
1H, d, J = 12.5 Hz), 4.38 (1H, d, J = 15.5 Hz), 3.85 (3H, s), 3.49 (3H, s), 3.31 (1H, brs), 3.18
1H, brs), 2.66 (3H, s), 2.58-2.63 (1H, m), 2.46 (1H, d, J = 16.0 Hz), 2.09 (3H, s), 2.01-2.08 (1H,
(
13
m), 1.91-1.96 (2H, m); C NMR (CDCl , 125 MHz): δ 193.3, 169.7, 150.9, 147.2, 143.8, 131.6,
3
1
25.0, 122.5, 116.0, 109.9, 63.2, 62.0, 60.6, 56.0, 54.5, 48.8, 47.1, 43.8, 42.5, 40.6, 35.1, 21.3; IR
(KBr): vmax 3419.3, 2937.2, 2842.3, 1730.0, 1688.5, 1631.2, 1464.3, 1438.5, 1371.0, 1288.7,
-
1
+
1
4
1
4
230.0, 1150.2, 1107.5, 1076.1, 1014.7 cm ; HRMS (ESI, m/z) calcd. for C H N O (M+H ):
22 28 1 7
18.1860, Found: 418.1871. 1-Hydroxylmethyl 10β-methoxysinomenine (7): yellow solid, m.p.
o
26
1
67-169 C; [α]D -62.3 (c 0.2, CHCl ); H NMR (CDCl , 500 MHz): δ 6.85 (1H, s), 5.66 (1H, s),
3
3
.55 (1H, d, J = 12.0 Hz), 4.56 (3H, s), 4.37 (1H, d, J = 12.0 Hz), 4.35 (1H, d, J = 15.5 Hz), 3.81
(3H, s), 3.56 (3H, s), 3.50 (1H, brs), 3.42 (3H, s), 3.21 (1H, brs), 2.59-2.63 (1H, m), 2.61 (3H, s),
1
3
2
1
4
1
.44 (1H, d, J = 16.0 Hz), 2.02-2.08 (1H, m), 1.89-1.98 (2H, m); C NMR (CDCl , 125 MHz): δ
3
93.3, 150.8, 146.8, 143.9, 132.6, 128.6, 122.1, 116.6, 111.5, 71.1, 63.7, 57.4, 55.9, 55.7, 54.7,
8.8, 47.0, 43.6, 42.1, 40.8, 34.6; IR (KBr): vmax 3381.2, 2938.1, 1685.9, 1630.0, 1600.9, 1465.8,
-1
289.6, 1202.4, 1107.1, 1073.7, 1035.7, 947.8 cm ; HRMS (ESI, m/z) calcd. for C H N O
2
1
28
1
6
+
(
M+H ): 390.1911, Found: 390.1912.
S4

1
-5. Oxidation of 10β-methoxysinomenine with DIB in MeOH.
MeO
N
O
OCH3
N
N
1
eq. DIB
MeOH
H CO
3
O
O
+
O
O
OH
O
O
OH
O
H CO
OH
O
3
3
8
9
To a solution of 10β-methoxysinomenine (3, 100 mg, 0.28 mmol, 1 equiv.) in methanol (2.5 mL)
was added iodobenzene diacetate (DIB) (90 mg, 0.28 mmol, 1 equiv.) at rt. The reaction was
stirred at the same temperature until the reaction was completed. The mixture was then basified
with sat. aq. NaHCO and extracted with CH Cl (10 mL x 3). The combined organic layers were
3
2
2
combined, washed with water and brine, dried over Na SO , filtered, and concentrated. The
2
4
residue was purified by preparative TLC (EtOAc/MeOH = 10/1) to afford solids 8 (11 mg, 12%)
o
25
D
and 9 (41 mg, 41%). Data for 8: yellow solid, m.p. 219-221 C (dec.); [α]
-190.5 (c 0.7,
1
CHCl ); H NMR (CDCl , 400 MHz): δ 7.65 (1H, d, J = 8.4 Hz), 6.80 (1H, d, J = 8.4 Hz), 6.11
3
3
(1H, brs), 5.35 (1H, d, J = 2.0 Hz), 4.35 (1H, d, J = 16.0 Hz), 3.91 (3H, s), 3.43 (3H, s), 3.37 (1H,
d, J = 3.6 Hz), 3.19-3.24 (1H, m), 2.64-2.73 (1H, m), 2.47 (1H, d, J = 16.0 Hz), 2.39 (3H, s),
1
3
1
.94-2.12 (3H, m); C NMR (CDCl , 75 MHz): δ 193.2, 192.7, 152.9, 151.9, 144.1, 129.7, 126.2,
3
119.5, 113.4, 108.8, 67.0, 56.1, 54.9, 49.3, 47.2, 46.4, 43.1, 41.4, 35.2; IR (KBr): 3421.2, 2937.8,
2
842.4, 2248.6, 1691.2, 1627.3, 1590.9, 1482.8, 1457.9, 1351.0, 1310.5, 1275.5, 1201.8, 1174.7,
-1
+
1
152.1, 1099.3, 1050.8, 733.6 cm ; HRMS (ESI, m/z) calcd. for C H N O (M+H ): 344.1493,
19 22 1 5
o
25
D
Found: 344.1496. Data for 9: light yellow solid, m.p. 181-183 C (dec.); [α]
-28.8 (c 1.5,
1
CHCl ); H NMR (CDCl , 300 MHz): δ 7.15 (1H, d, J = 8.7 Hz), 6.73 (1H, d, J = 8.7 Hz), 5.86
3
3
(
1H, d, J = 1.8 Hz), 4.29 (1H, d, J = 15.3 Hz), 3.84 (3H, s), 3.49 (3H, s), 3.40 (3H, s), 3.24-3.32
2H, m), 2.95 (3H, s), 2.72 (3H, s), 2.54 (1H, td, J = 3.3, 12.6 Hz), 2.36-2.47 (2H, m), 1.89 (1H,
(
1
3
td, J = 4.8, 12.6 Hz), 1.53-1.63 (1H, m); C NMR (CDCl , 75 MHz): δ 194.1, 148.9, 147.0,
3
1
4
1
44.0, 128.7, 122.4, 119.6, 119.4, 107.8, 97.5, 61.3, 55.9, 54.5, 49.4, 48.9, 48.3, 45.4, 43.4, 42.5,
1.8, 32.8; IR (KBr): vmax 3436.1, 2918.4, 2848.9, 1686.0, 1625.9, 1482.2, 1439.0, 1310.9,
-1
273.6, 1203.5, 1151.1, 1115.7, 1075.8, 732.5 cm ; HRMS (ESI, m/z) calcd. for C H N O
2
1
28
1
6
+
(
M+H ): 390.1911, Found: 390.1919.
1
-6. General procedure for the syntheses of compounds 10a-10d.
S5

RO
N
N
DCM
°-rt
O
O
+ ROH
0
HO
OH
a-10d
O
O
OH
O
4
10
A mixture of 4 (2.0 g, 6.38 mmol) in the corresponding alcohol (20 mL) was stirred at rt until the
reaction was completed. The solvent was removed under reduced pressure. The residue was
purified by column chromatography on silica gel to afford sinomenine derivatives 10a-10d.
o
25
D
1
0a: light yellow solid, 64% yield (DCM/MeOH = 10/1). m.p. 159-160 C (dec.); [α] -56.8 (c
1
0
.26, CHCl -CH OH = 10:1); H NMR (DMSO-d , 400 MHz): δ 9.38 (1H, s), 8.05 (1H, s), 6.63
3
3
6
(2H, s), 5.76 (1H, d, J = 2.0 Hz), 4.14 (1H, d, J = 15.2 Hz), 4.06 (1H,s), 3.45 (3H, s), 3.30 (3H, s),
3
1
1
3
1
3
.21-3.25 (1H, m), 2.90 (1H, brs), 2.40 (3H, s), 2.36 (1H, d, J = 15.6 Hz), 1.75-1.85 (1H, m),
1
3
.67-1.73 (2H, m); C NMR (DMSO-d , 100 MHz): δ 192.4, 149.4, 143.6, 144.1, 130.4, 122.7,
6
20.5, 119.0, 113.1, 72.1, 57.2, 56.9, 53.8, 48.6, 46.3, 44.1, 42.1, 40.2, 35.1; IR (KBr): vmax
284.2, 2941.2, 2811.4, 1674.4, 1629.6, 1479.1, 1363.6, 1288.5, 1200.2, 1150.5, 1087.3, 1073.9,
-1
+
007.0, 919.5, 828.6 cm ; HRMS (ESI, m/z) calcd. for C H N O (M+H ): 346.1649, Found:
1
9
24
1
5
46.1665.
o
26
1
0
6
0b: light yellow solid, 44% yield (DCM/MeOH = 20/1). m.p. 191-193 C (dec.); [α] -28.3 (c
D
1
.40, CHCl -CH OH = 10:1); H NMR (DMSO-d , 300 MHz): δ 9.41 (1H, brs), 8.09 (1H, s),
3
3
6
.64 (1H, d, J = 8.1 Hz), 6.60 (1H, d, J = 8.4 Hz), 5.82 (1H, d, J = 1.8 Hz), 4.16 (1H, s), 4.14 (1H,
d, J = 15.3 Hz), 3.68-3.81 (1H, m), 3.53-3.66 (1H, m), 3.32 (3H, s), 3.17-3.22 (1H, m), 2.90 (1H,
brs), 2.39 (3H, s), 2.31-2.38 (2H, m), 1.80 (1H, td, J = 5.1, 10.2 Hz), 1.64-1.75 (2H, m), 1.17 (3H,
1
3
t, J = 6.9 Hz); C NMR (DMSO-d , 75 MHz): δ 192.4, 149.1, 144.2, 143.5, 130.60, 122.7, 120.5,
6
119.2, 113.2, 70.1, 64.1, 57.8, 53.7, 48.5, 46.3, 44.0, 42.1, 40.2, 35.1, 15.6; IR (KBr): vmax 3414.2,
3
288.8, 2968.7, 2935.2, 2901.7, 1697.7, 1681.6, 1627.3, 1483.2, 1349.3, 1291.3, 1198.6, 1152.1,
-1
+
1
090.8, 1071.2, 921.7 cm ; HRMS (ESI, m/z) calcd. for C H N Na O (M+Na ): 382.1625,
20 25 1 1 5
Found: 382.1640.
o
26
1
0c: light yellow solid, 65% yield (DCM/MeOH = 20/1). m.p. 188-190 C (dec.); [α] -29.7 (c
D
S6

1
0
.50, CHCl -CH OH = 10:1); H NMR (DMSO-d , 300 MHz): δ 9.40 (1H, brs), 8.10 (1H, brs),
3 3 6
6
.64 (1H, d, J = 8.4 Hz), 6.60 (1H, d, J = 8.1 Hz), 5.79 (1H, d, J = 1.8 Hz), 4.15 (1H, s), 4.14 (1H,
d, J = 15.3 Hz), 3.62-3.72 (1H, m), 3.46-3.57 (1H, m), 3.31 (3H, s), 3.17-3.23 (1H, m), 2.90 (1H,
brs), 2.39 (3H, s), 2.31-2.38 (2H, m), 1.80 (1H, td, J = 5.1, 10.2 Hz), 1.64-1.75 (2H, m),
1
3
1
1
3
1
3
.49-1.63 (2H, m), 0.93 (3H, t, J = 7.2 Hz); C NMR (DMSO-d , 75 MHz): δ 192.4, 149.3,
6
44.1, 143.5, 130.8, 122.7, 120.4, 119.0, 113.2, 70.9, 70.4, 57.8, 53.7, 48.6, 46.3, 44.1, 42.1, 40.2,
5.1, 23.0, 10.8; IR (KBr): 3269.1, 2956.7, 2931.3, 2909.5, 1682.0, 1625.3, 1490.0, 1348.7,
-1
+
306.0, 1286.3, 1197.6, 1071.5, 807.6 cm ; HRMS (ESI, m/z) calcd. for C H N O (M+H ):
2
1
28
1
5
74.1962, Found: 374.1958.
o
25
1
0
6
0d: light yellow solid, 57% yield (DCM/MeOH = 20/1). m.p. 182-184 C (dec.); [α] -26.3 (c
D
1
.50, CHCl -CH OH = 10:1); H NMR (DMSO-d , 400 MHz): δ 9.38 (1H, brs), 8.07 (1H, brs),
3
3
6
.64 (1H, d, J = 8.4 Hz), 6.60 (1H, d, J = 8.4 Hz), 5.78 (1H, d, J = 2.0 Hz), 4.15 (1H, s), 4.14 (1H,
d, J = 15.2 Hz), 3.67-3.75 (1H, m), 3.50-3.58 (1H, m), 3.32 (3H, s), 3.14-3.22 (1H, m), 2.90 (1H,
brs), 2.39 (3H, s), 2.31-2.38 (2H, m), 1.81 (1H, td, J = 4.8, 10.8 Hz), 1.64-1.75 (2H, m),
1
3
1
1
4
1
.46-1.60 (2H, m), 1.32-1.43 (2H, m), 0.91 (3H, t, J = 7.2 Hz); C NMR (DMSO-d , 75 MHz): δ
6
92.3, 149.3, 144.1, 143.5, 130.8, 122.7, 120.4, 119.0, 113.2, 70.5, 68.7, 57.8, 53.6, 48.5, 46.3,
4.0, 42.1, 40.2, 35.0, 31.8, 18.9, 13.6; IR (KBr): vmax 3443.0, 2953.3, 2912.2, 2858.5, 2508.6,
-1
690.8, 1633.3, 1582.1, 1483.4, 1289.9, 1229.7, 1147.6, 1073.3, 1005.7, 795.5 cm ; HRMS (ESI,
+
m/z) calcd. for C H N O (M+H ): 388.2119, Found: 388.2135.
2
2
30
1
5
1
-7. General procedure for the syntheses of compounds 10e-10g.
RS
N
N
DCM
°C~rt
O
O
+ RSH
0
HO
OH
e~10
g
O
O
OH
O
4
10
To a solution of 4 (0.5 g, 1.60 mmol) in DCM (10 mL) was added the thiophenol (1.76 mmol, 1.1
o
equiv) in DCM (5 mL) at 0 C. The reaction was stirred at rt until completion of the reaction.
Petroleum ether was added to the reaction mixture. The resulting solid was filtered, washed with
petroleum ether and dried to afford sinomenine derivatives 10e-10g.
S7

o
25
1
0e: light yellow solid, 81% yield. m.p. 210-212 C (dec.); [α]D -3.4 (c 0.20, CHCl -CH OH =
3 3
1
1
0:1); H NMR (DMSO-d , 400 MHz): δ 9.49 (1H, s), 8.19 (1H, s), 7.68 (1H, d, J = 7.2 Hz), 7.43
6
(
2H, t, J = 7.2 Hz), 7.36 (1H, t, J = 7.2 Hz), 7.01 (1H, d, J = 8.4 Hz), 6.67 (1H, d, J = 8.0 Hz),
.26 (1H, d, J = 2.0 Hz), 4.55 (1H, s), 4.18 (1H, d, J = 15.2 Hz), 3.53 (3H, s), 3.15 (1H, d, J = 2.8
Hz), 3.00 (1H, brs), 2.39 (1H, d, J = 15.2 Hz), 2.26-2.34 (1H, m), 1.96 (3H, s), 1.82 (1H, td, J =
6
1
3
4
1
4
1
.8, 10.8 Hz), 1.67-1.76 (2H, m); C NMR (DMSO-d , 75 MHz): δ 192.5, 149.4, 144.0, 144.0,
6
35.6, 132.3, 129.2, 128.2, 127.6, 123.8, 120.3, 117.8, 113.3, 59.8, 53.9, 48.4, 46.0, 44.7, 43.4,
1.7, 35.5; IR (KBr): vmax 3449.4, 2932.2, 2497.0, 1692.9, 1630.6, 1580.5, 1481.4, 1381.9,
-1
286.7, 1202.0, 1145.5, 1001.2, 812.9, 750.2 cm ; HRMS (ESI, m/z) calcd. for C H N O S
4 1
2
4
26
1
+
(
M+H ): 424.1577, Found: 424.1577.
o
26
1
0f: light yellow solid, 79% yield. m.p. 224-225 C (dec.); [α] 7.0 (c 0.50, CHCl -CH OH =
D 3 3
1
1
0:1); H NMR (DMSO-d , 400 MHz): δ 9.47 (1H, s), 8.18 (1H, s), 7.57 (2H, d, J = 8.0 Hz), 7.25
6
(
2H, d, J = 7.6 Hz), 7.02 (1H, d, J = 8.4 Hz), 6.67 (1H, d, J = 8.0 Hz), 6.27 (1H, d, J = 2.0 Hz),
.47 (1H, s), 4.18 (1H, d, J = 15.2 Hz), 3.53 (3H, s), 3.11-3.18 (1H, m), 2.99 (1H, brs), 2.39 (1H,
d, J = 15.2 Hz), 2.33 (3H, s), 2.24-2.32 (1H, m), 1.93 (3H, s), 1.80 (1H, td, J = 4.4, 10.8 Hz),
4
1
3
1
1
.62-1.76 (2H, m); C NMR (DMSO-d , 75 MHz): δ 192.4, 149.4, 143.9, 137.3, 132.7, 132.0,
6
29.8, 128.3, 123.7, 120.3, 117.8, 113.3, 59.7, 53.9, 48.4, 45.9, 44.7, 43.6, 41.7, 35.5, 20.6; IR
(KBr): vmax 3325.9, 2940.9, 2831.0, 1666.8, 1619.8, 1491.3, 1291.3, 1202.0, 1151.8, 1092.9,
-1
+
8
08.1, 497.4 cm ; HRMS (ESI, m/z) calcd. for C H N O S (M+H ): 438.1734, Found:
25 28 1 4 1
4
38.1742.
1
0g: The analytical sample of 10g was purified by silica gel column chromatography
o
25
D
(
DCM/MeOH = 20/1). Light yellow solid, 67% yield. m.p. 232-233 C (dec.); [α] 5.84 (c 0.30,
1
CHCl -CH OH = 10:1); H NMR (DMSO-d , 400 MHz): δ 9.47 (1H, s), 8.18 (1H, s), 7.58 (2H, d,
3
3
6
J = 8.0 Hz), 7.44 (2H, d, J = 8.4 Hz), 7.00 (1H, d, J = 8.4 Hz), 6.67 (1H, d, J = 8.4 Hz), 6.26 (1H,
d, J = 1.6 Hz), 4.51 (1H, s), 4.18 (1H, d, J = 15.2 Hz), 3.53 (3H, s), 3.14 (1H, brs), 2.99 (1H, brs),
2
1
1
4
1
.39 (1H, d, J = 15.2 Hz), 2.25-2.35 (1H, m), 1.96 (3H, s), 1.82 (1H, td, J = 4.8, 10.8 Hz),
1
3
.66-1.76 (2H, m), 1.29 (9H, s); C NMR (CDCl /CD OD = 10/1, 75 MHz): δ 195.0, 151.2,
3
3
50.2, 143.9, 143.4, 132.4, 132.2, 128.9, 126.2, 122.7, 121.0, 117.8, 113.6, 60.6, 54.6, 48.9, 46.5,
5.5, 43.9, 41.8, 40.3, 35.9, 34.5, 31.1; IR (KBr): vmax 3439.7, 2935.5, 2866.3, 2359.0, 1693.1,
-1
631.3, 1482.2, 1286.6, 1202.5, 1146.2, 813.6 cm ; HRMS (ESI, m/z) calcd. for C H N O S
2
8
34
1
4
1
S8

+
(
M+H ): 480.2203, Found: 480.2208.
1
-8. General procedure for the syntheses of compounds 10h-10i.
RHN
N
N
DCM
°C~rt
O
O
+ RNH2
0
HO
OH
10h~10i
O
O
OH
O
4
To a solution of 4 (0.5 g, 1.6 mmol) in DCM (10 mL) was added the aniline (1.76 mmol, 1.1
o
equiv) at 0 C. The reaction was stirred at room temperature and monitored by TLC. Ethyl ether
was added to the reaction mixture. The resulting solid was filtered and purified by silica gel
column chromatography to afford sinomenine derivatives 10h-10i.
o
26
D
1
0h: white solid, 65% yield (DCM/MeOH = 20/1). m.p. 195-197 C (dec.); [α] 25.1 (c 0.60,
1
CHCl -CH OH = 10:1); H NMR (CDCl /CD OD = 10/1, 400 MHz): δ 7.17 (2H, t, J = 7.6 Hz),
3
3
3
3
6
.61-6.75 (3H, m), 6.58 (2H, d, J = 7.6 Hz), 5.79 (1H, s), 4.58 (1H, s), 4.34 (1H, d, J = 15.2 Hz),
.47 (3H, s), 3.36 (1H, brs), 2.99 (1H, brs), 2.66 (3H, s), 2.43-2.53 (1H, m), 2.38 (1H, d, J = 15.6
3
1
3
Hz), 2.07-2.22 (1H, m), 1.69-1.94 (3H, m); C NMR (CDCl /CD OD = 10/1, 75 MHz): δ 194.9,
3
3
1
4
1
4
50.0, 146.2, 143.8, 130.8, 129.6, 122.1, 120.4, 117.3, 117.2, 113.9, 111.7, 58.6, 54.6, 48.8, 47.7,
6.7, 44.5, 42.4, 40.5, 35.2; IR (KBr): vmax 3421.2, 3254.5, 2910.6, 2855.4, 1680.9, 1600.9,
-1
+
500.3, 1307.0, 1289.0, 1200.7, 749.2 cm ; HRMS (ESI, m/z) calcd. for C H N O (M+H ):
24
27
2
4
07.1965, Found: 407.1965.
o
25
D
1
0i: yellow solid, 57% yield (DCM/MeOH = 20/1). m.p. 165-168 C (dec.); [α] 14.0 (c 0.10,
1
CHCl -CH OH = 10:1); H NMR (DMSO-d , 500 MHz): δ 9.45 (1H, brs), 8.21 (1H, brs), 7.12
3
3
6
(
1H, t, J = 7.5 Hz), 7.04 (1H, d, J = 7.0 Hz), 6.83 (1H, d, J = 8.0 Hz), 6.67 (1H, d, J = 8.0 Hz),
.55-6.62 (2H, m), 5.90 (1H, s), 4.52 (1H, d, J = 5.5 Hz), 4.22 (1H, d, J = 15.0 Hz), 3.68 (1H, d, J
6.0 Hz), 3.43 (3H, s), 3.17 (1H, brs), 3.04 (1H, brs), 2.61 (3H, s), 2.40-2.47 (2H, m), 2.06-2.13
6
=
1
3
(
1H, m), 2.04 (3H, s), 1.63-1.84 (2H, m); C NMR (DMSO-d , 125 MHz): δ 192.5, 150.1, 145.1,
6
1
4
44.1, 143.9, 131.5, 130.1, 127.1, 123.2, 120.8, 119.1, 117.3, 116.1, 113.9, 108.4, 59.6, 54.1, 48.7,
8.5, 46.0, 43.3, 42.6, 40.2, 34.3, 17.4; IR (KBr): vmax 3503.2, 3461.0, 3011.8, 2928.6, 2848.8,
S9

-1
1
685.8, 1615.9, 1603.6, 1584.5, 1503.9, 1446.5, 1308.5, 1283.9, 1197.6, 758.9 cm ; HRMS (ESI,
+
m/z) calcd. for C H N O (M+H ): 421.2122, Found: 421.2120.
2
5
29
2
4
1
-9. Synthesis of compound 10j.
To a solution of 4 (0.5 g, 1.6 mmol) in DMF (10 mL) was added imidazole (0.163 g, 2.39 mmol,
.5 equiv). The reaction mixture was stirred at room temperature until the reaction was completed.
1
The mixture was concentrated under reduced pressure. The residue was purified by column
chromatography (DCM/MeOH = 10/1) to afford 10j (0.18 g, 29%) as a yellow solid. m.p.
o
26
1
2
11-213 C (dec.); [α]D 82.8 (c 0.40, CHCl -CH OH = 10:1); H NMR (DMSO-d , 400 MHz):
3 3 6
δ 9.73 (1H, brs), 8.41 (1H, brs), 7.12 (1H, s), 7.01 (1H, s), 6.93 (1H, s), 6.73 (1H, d, J = 8.4 Hz),
.51 (1H, d, J = 8.0 Hz), 5.32 (1H, s), 4.66 (1H, d, J = 2.4 Hz), 4.25 (1H, d, J = 15.2 Hz), 3.14
3H, s), 2.97 (1H, brs), 2.54 (1H, s), 2.42-2.48 (1H, m), 2.43 (1H, d, J = 15.2 Hz), 1.83-1.96 (1H,
6
(
1
3
m), 1.69-1.82 (2H, m); C NMR (DMSO-d , 75 MHz): δ 192.3, 149.7, 145.0, 144.4, 137.0,
6
1
27.9, 125.0, 124.2, 120.7, 119.5, 115.5, 113.6, 62.6, 53.2, 50.1, 48.3, 46.3, 43.8, 42.3, 35.4; IR
(KBr): vmax 3410.7, 2937.8, 2917.8, 2850.4, 2536.1, 1697.0, 1628.4, 1586.1, 1485.1, 1390.8,
-1
1
295.2, 1223.1, 1150.9, 1068.4, 917.5, 742.5, 497.0 cm ; HRMS (ESI, m/z) calcd. for
+
C H N Na O (M+Na ): 404.1581, Found: 404.1586.
21
23
3
1
4
1
-10. Synthesis of compound 10k.
A solution of compound 4 (0.5 g, 1.6 mmol) in 1 M HCl (10 mL) was stirred at room temperature
until the reaction was completed. The mixture was basified with sat. aq. NaHCO , and
3
concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (DCM/MeOH = 10/1) to afford 10k (0.14 g, 53%) as a yellow solid. m.p.
o
26
1
1
71-173 C (dec.); [α]D -44.9 (c 0.10, CHCl -CH OH = 10:1); H NMR (DMSO-d , 400 MHz):
3 3 6
δ 9.33 (1H, brs), 8.04 (1H, brs), 6.69 (1H, d, J = 8.4 Hz), 6.64 (1H, d, J = 8.0 Hz), 5.89 (1H, d, J
2.0 Hz), 4.93 (1H, brs), 4.53 (1H, s), 4.15 (1H, d, J = 15.2 Hz), 3.34 (3H, s), 3.09 (1H, brs),
=
1
3
2
7
4
1
.90 (1H, brs), 2.27-2.46 (5H, m), 1.77-1.90 (1H, m), 1.61-1.75 (2H, m); C NMR (DMSO-d ,
6
5 MHz): δ 192.5, 149.2, 143.9, 143.5, 132.8, 122.4, 120.0, 119.2, 113.3, 62.5, 61.7, 53.8, 48.6,
6.3, 43.8, 42.4, 40.3, 35.0; IR (KBr): vmax 3383.0, 2960.5, 2897.1, 1674.2, 1621.2, 1492.5,
-1
285.5, 1201.6, 1155.2, 1103.7, 1025.1, 831.2 cm ; HRMS (ESI, m/z) calcd. for C H N O
5
1
8
22
1
+
(
M+H ): 332.1493, Found: 332.1490.
S10

1
-11. Synthesis of compound 10l.
To a solution of 4 (0.507 g, 1.6 mmol, 1 equiv) in pyridine (10 mL) was added acetic anhydride
5 mL, 2 mmol, 1.25 equiv) at rt. The mixture was stirred at the same temperature until the
(
reaction was completed. The mixture was concentrated under reduced pressure. The residue was
basified with sat. aq. NaHCO , and extracted with DCM three times. The combined DCM
3
extracts were washed with water and brine, dried over Na SO , filtered, and concentrated to
2
4
o
26
D
1
afford 10i (0.57 g, 79%) as a white solid. m.p. 198-199 C; [α] -82.0 (c 0.50, CHCl ); H NMR
3
(
DMSO-d , 400 MHz): δ 7.22 (1H, d, J = 8.8 Hz), 7.18 (1H, d, J = 8.4 Hz), 5.89 (1H, d, J = 2.0
6
Hz), 3.50 (1H, d, J = 15.6 Hz), 3.39 (3H, s), 3.26 (1H, d, J = 1.8 Hz), 3.06 (1H, brs), 2.73 (1H,
1
1
1
2
1
5.6), 2.46 (3H, s), 2.39-2.45 (1H, m), 2.36 (3H, s), 2.22 (3H, s), 2.09 (3H, s), 1.76-1.88 (2H, m),
13
.38 (1H, d, J = 9.6 Hz); C NMR (DMSO-d , 75 MHz): δ 190.7, 169.6, 167.7, 149.8, 142.6,
6
40.7, 135.1, 130.9, 127.4, 122.2, 117.6, 64.0, 58.6, 54.0, 49.0, 45.6, 43.4, 42.2, 40.4, 35.9, 21.0,
+
0.5, 20.4; MS (ESI, m/z): 458.7 (M+H ). IR (KBr): v 3411.8, 2938.0, 2845.7, 1777.1, 1727.3,
max
-1
691.0, 1632.9, 1375.0, 1234.9, 1200.7, 1146.6, 1014.8 cm ; HRMS (ESI, m/z) calcd. for
+
C H N O (M+H ): 458.1804, Found: 458.1804.
24
28
1
8
1
-12. Synthesis of compound 10m.
To a solution of 4 (1 g, 3.2 mmol, 1 equiv.) in DMSO (10 mL) was added acetone (2.5 mL, 1.91
mmol, 10.6 equiv), L-proline (0.1 g, 0.87 mmol, 0.27 equiv) at rt. The reaction mixture was
stirred at room temperature overnight. Water (20 mL) was added and the whole mixture was
extracted with DCM three times. The combined DCM extracts were washed with water and brine,
dried over Na SO , filtered, and concentrated. Purification by silica gel column chromatography
2
4
o
(
eluent: DCM/MeOH 10/1) afforded 10m (0.17 g, 14%) as a yellow solid. m.p. 219-221 C;
2
6
1
[
α]D -64.9 (c 0.30, CHCl -CH OH = 10:1); H NMR (DMSO-d , 400 MHz): δ 9.21 (1H, brs),
3 3 6
8
.02 (1H, brs), 6.57 (1H, d, J = 8.4 Hz), 6.40 (1H, d, J = 8.4 Hz), 5.84 (1H, d, J = 2.0 Hz), 4.19
(1H, d, J = 15.2 Hz), 3.44 (3H, s), 3.41 (1H, dd, J = 8.4, 3.6 Hz), 2.88-3.02 (3H, m), 2.82 (1H, dd,
J = 13.5, 3.6 Hz), 2.36 (1H, d, J = 15.2 Hz), 2.33-2.36 (1H, m), 2.32 (3H, s), 2.17 (3H, s),
1
3
1
1
2
1
3
.83-1.93 (1H, m), 1.67-1.75 (2H, m); C NMR (DMSO-d , 125 MHz): δ 207.5, 192.6, 150.2,
6
43.9, 142.6, 133.2, 122.9, 117.5, 116.9, 113.5, 60.1, 54.1, 51.7, 48.6, 46.2, 45.2, 42.3, 35.8, 30.0,
7.9; IR (KBr): vmax 3486.4, 3017.7, 2931.8, 2859.7, 1688.6, 1626.8, 1488.0, 1450.5, 1365.7,
-1
+
286.2, 1203.7, 1147.4, 1086.0, 807.9 cm ; HRMS (ESI, m/z) calcd. for C H NO (M+H ):
21
26
5
72.1806, Found: 372.1820.
S11

1
-13. General procedure for the syntheses of compounds 11a-11p
RS
N
N
DCM
°-rt
O
O
+ RSH
0
HO
OH
a-11
p
O
O
OH
O
4
11
.
To a solution of 4 (1 g, 3.19 mmol) in DCM (30 mL) was added the thiophenol or thiols (3.51
o
mmol, 1.1 equiv) in DCM (15 mL) at 0 C. After addition, the reaction was stirred at r.t. until
completion of the reaction. Then the reaction mixture was purified by three methods: 1. the
mixture was directly filtered and the resulting residue was washed with DCM; 2. the mixture was
concentrated and the resulting residue was refluxed in the mixture solvents of acetone (20 mL)
petroleum ether (40 mL), filtered, washed with ethyl ether; 3. the mixture was concentrated and
purified by column chromatography (DCM/MeOH 50/1 to 30/1) to afford sinomenine derivatives
11a-11p.
o
27
D
1
1
1a: white solid, 87% yield. m.p.228-229 C (dec.); [α]
-43.4 (c 0.50, DMSO); H NMR
(
DMSO-d , 400 MHz): δ 9.34 (1H, s), 8.07 (1H, s), 6.87 (1H, d, J = 8.0 Hz), 6.61 (1H, d, J = 8.0
6
Hz), 6.23 (1H, s), 4.16 (1H, d, J = 15.2 Hz), 4.00 (1H, s), 3.41 (3H, s), 3.35-3.41 (1H, m), 3.01
1
3
(
1H, s), 2.65-2.85 (2H, m), 2.21-2.44 (5H, m), 1.77-1.94 (1H, m), 1.61-1.77 (2H, m); C NMR
(
DMSO-d , 100 MHz): δ 192.5, 149.5, 143.8, 143.5, 130.0, 123.5, 120.6, 117.8, 113.2, 61.4, 53.9,
6
4
1
8.5, 46.0, 44.9, 42.0, 39.7, 38.3, 35.5, 26.4, 14.7; IR (KBr): vmax 3415.6, 2948.4, 2852.2, 1695.5,
-1
624.8, 1586.1, 1479.9, 1396.7, 1292.7, 1176.0, 1005.9, 909.6, 498.4 cm ; HRMS (MALDI, m/z)
+
calcd. for C H NO S (M+H ): 376.1577, Found: 376.1582.
2
0
26
4
o
27
D
1
1
1b: white solid, 82% yield. m.p. 207-208 C (dec.); [α]
-35.1 (c 0.50, DMSO); H NMR
(
DMSO-d , 400 MHz): δ 9.35 (1H, s), 8.08 (1H, s), 6.86 (1H, d, J = 8.4 Hz), 6.61 (1H, d, J = 8.4
6
Hz), 6.24 (1H, d, J = 2.0 Hz), 4.16 (1H, d, J = 15.2 Hz), 3.97 (1H, s), 3.41 (3H, s), 3.35-3.40 (1H,
m), 3.01 (1H, s), 2.71-2.82 (1H, m), 2.59-2.71 (1H, m), 2.38 (1H, d, J = 15.2 Hz), 2.31-2.34 (1H,
1
3
m), 2.31 (3H, s), 1.82 (1H, dt, J = 4.0, 11.2 Hz), 1.58-1.76 (4H, m), 1.02 (3H, t, J = 7.2 Hz); C
NMR (DMSO-d , 100 MHz): δ 192.5, 149.4, 143.7, 143.5, 130.0, 123.5, 120.5, 117.8, 113.2,
6
S12

6
2
4
1.3, 53.8, 48.4, 46.0, 44.9, 42.0, 39.7, 38.6, 35.5, 34.4, 22.3, 13.3; IR (KBr): vmax 3442.6, 2943.0,
852.6, 1689.1, 1627.2, 1583.8, 1450.8, 1381.4, 1289.4, 1203.3, 1149.1, 1092.8, 910.0, 816.2,
-1
+
97.6 cm ; HRMS (MALDI, m/z) calcd. for C H NO S (M+H ): 390.1734, Found: 390.1733.
2
1
28
4
o
27
D
1
1
1c: white solid, 85% yield. m.p. 193-194 C (dec.); [α]
-32.9 (c 0.60, DMSO); H NMR
(
DMSO-d , 400 MHz): δ 9.35 (1H, s), 8.08 (1H, s), 6.86 (1H, d, J = 8.4 Hz), 6.14 (1H, d, J = 8.4
6
Hz), 6.23 (1H, d, J = 2.0 Hz), 4.16 (1H, d, J = 15.2 Hz), 3.98 (1H, s), 3.41 (3H, s), 3.35-3.40 (1H,
m), 3.01 (1H, s), 2.64-2.81 (2H, m), 2.37 (1H, d, J = 15.2 Hz), 2.31-2.36 (1H, m), 2.32 (3H, s),
1
.82 (1H, dt, J = 4.4, 11.2 Hz), 1.70-1.77 (2H, m), 1.57-1.70 (2H, m), 1.36-1.52 (2H, m), 0.93
1
3
(
3H, t, J = 7.2 Hz); C NMR (DMSO-d , 100 MHz): δ 192.5, 149.4, 143.8, 143.5, 130.0, 123.5,
6
1
20.5, 117.8, 113.3, 61.3, 53.8, 48.5, 46.0, 44.9, 42.0, 39.7, 38.6, 35.5, 32.0, 31.1, 21.4, 13.5; IR
(KBr): vmax 3443.9, 2951.9, 2854.4, 1686.9, 1631.1, 1584.3, 1481.0, 1380.4, 1288.1, 1148.7,
-1
+
1
095.6, 816.0 cm ; HRMS (MALDI, m/z) calcd. for C H NO S (M+H ): 404.1890, Found:
2
2
30
4
4
04.1900.
o
27
D
1
1
1d: brown solid, 60% yield. m.p. 101-103 C (dec.); [α]
-12.8 (c 0.60, DMSO); H NMR
(
DMSO-d , 400 MHz): δ 9.34 (1H, s), 8.07 (1H, s), 6.85 (1H, d, J = 8.4 Hz), 6.61 (1H, d, J = 8.4
6
Hz), 6.23 (1H, d, J = 4.0 Hz), 4.16 (1H, d, J = 15.2 Hz), 3.98 (1H, s), 3.41 (3H, s), 3.34-3.39 (1H,
m), 3.01 (1H, s), 2.62-2.81 (2H, m), 2.37 (1H, d, J = 15.2 Hz), 2.31-2.36 (1H, m), 2.31 (3H, s),
1
.83 (1H, dt, J = 4.4, 10.8 Hz), 1.57-1.77 (4H, m), 1.37-1.51 (2H, m), 1.17-1.34 (16H, m), 0.85
1
3
(
3H, t, J = 6.8 Hz); C NMR (DMSO-d , 100 MHz): δ 192.4, 149.4, 143.7, 143.5, 129.9, 123.4,
6
1
2
1
20.5, 117.7, 113.2, 61.3, 53.8, 48.4, 46.0, 44.9, 41.9, 39.7, 38.6, 35.5, 32.4, 31.2, 29.0, 29.0, 28.9,
8.9, 28.8, 28.6, 28.5, 28.2, 22.0, 13.8; IR (KBr): vmax 3377.0, 2923.6, 2852.1, 1686.1, 1625.9,
-
1
479.9, 1378.2, 1340.5, 1287.2, 1203.6, 1175.3, 1147.9, 910.0, 814.8 cm ; HRMS (MALDI, m/z)
+
calcd. for C H NO S (M+H ): 516.3142, Found: 516.3157.
3
0
46
4
o
27
D
1
1
1e: brown solid, 59% yield. m.p. 160-161 C (dec.); [α]
-14.1 (c 0.50, DMSO); H NMR
(
DMSO-d , 400 MHz): δ 9.35 (1H, s), 8.08 (1H, s), 6.85 (1H, d, J = 8.4 Hz), 6.61 (1H, d, J = 8.4
6
Hz), 6.22 (1H, d, J = 2.0 Hz), 4.16 (1H, d, J = 15.6 Hz), 3.97 (1H, s), 3.41 (3H, s), 3.34-3.39 (1H,
m), 3.00 (1H, s), 2.62-2.81 (2H, m), 2.37 (1H, d, J = 15.2 Hz), 2.31-2.35 (1H, m), 2.31 (3H, s),
1
.82 (1H, dt, J = 4.0, 11.2 Hz), 1.56-1.77 (4H, m), 1.36-1.51 (2H, m), 1.16-1.35 (28H, m), 0.85
1
3
(
3H, t, J = 7.2 Hz); C NMR (DMSO-d , 100 MHz): δ 192.3, 149.5, 143.8, 143.5, 129.8, 123.4,
6
S13

1
2
20.4, 117.5, 113.2, 61.4, 53.7, 48.5, 46.0, 44.9, 41.9, 38.6, 35.5, 32.4, 31.3 29.1, 28.7, 28.6, 28.3,
2.0, 13.7; IR (KBr): vmax 3353.8, 2922.4, 2851.6, 1689.4, 1625.8, 1466.8, 1378.3, 1287.3,
-1
+
1
148.2, 910.6, 815.3 cm ; MS (MALDI, m/z): 600.5 (M+H) , Anal. Calcd. for C H NO S
3
6
57
4
requires C: 72.08; H: 9.58; N: 2.33, found C: 72.06; H: 9.35; N: 2.44.
o
27
D
1
1
1f: white solid, 80% yield. m.p. 226-227 C (dec.); [α]
-77.0 (c 0.50, DMSO); H NMR
(
DMSO-d , 400 MHz): δ 9.37 (1H, s), 8.10 (3H, s), 7.49 (2H, d, J = 7.6 Hz), 7.33-7.42 (2H, m),
6
7
4
2
.23-7.31 (1H, m), 6.64 (1H, d, J = 8.4 Hz), 6.57 (1H, d, J = 8.4 Hz), 6.25 (1H, d, J = 2.0 Hz),
.15 (1H, d, J = 15.2 Hz), 4.00 (2H, s), 3.87 (1H, s), 3.44 (3H, s), 3.37-3.42 (1H, m), 3.00 (1H, s),
1
3
.37 (1H, d, J = 15.6 Hz), 2.24-2.32 (1H, m), 2.16 (3H, s), 1.61-1.77 (3H, m); C NMR
(
DMSO-d , 100 MHz): δ 192.5, 149.5, 143.7, 143.5, 138.5, 129.9, 129.0, 128.4, 126.9, 123.4,
6
1
3
7
20.4, 117.7, 113.3, 61.0, 53.9, 48.4, 46.0, 44.9, 42.1, 40.1, 38.3, 36.8, 35.4; IR (KBr): vmax
434.6, 2943.2, 1692.4, 1627.4, 1581.3, 1481.1, 1449.8, 1379.6, 1287.8, 1208.7, 1151.2, 815.5,
-1
+
03.5 cm ; HRMS (MALDI, m/z) calcd. for C H NO S (M+H ): 438.1734, Found: 438.1735.
2
5
28
4
o
27
D
1
1
1g: white solid, 79% yield. m.p. 164-166 C (dec.); [α]
-94.7 (c 0.60, DMSO); H NMR
(
DMSO-d , 400 MHz): δ 9.30 (1H, s), 8.05 (1H, s), 6.79 (1H, d, J = 8.4 Hz), 6.62 (1H, d, J = 8.4
6
Hz), 6.22 (1H, d, J = 1.6 Hz), 4.15 (1H, d, J = 15.2 Hz), 4.01 (1H, s), 3.49 (1H, d, J = 3.2 Hz),
.45 (1H, s), 3.00 (1H, s), 2.43 (3H, s), 2.36 (1H, d, J = 15.6 Hz), 2.30-2.38 (1H, m), 1.92 (1H, dt,
3
13
J = 4.0, 10.8 Hz), 1.63-1.78 (2H, m), 1.43 (9H, s); C NMR (DMSO-d , 100 MHz): δ 192.5,
6
1
3
1
49.7, 143.5, 143.1, 131.6, 123.2, 121.0, 117.2, 113.4, 64.3, 53.9, 48.3, 45.9, 44.5, 44.3, 42.9,
9.5, 36.9, 34.9, 31.1; IR (KBr): vmax 3528.4, 3493.7, 2971.5, 1685.8, 1625.4, 1483.6, 1378.3,
-1
337.1, 1307.0, 1281.6, 1201.2, 1153.4, 1098.8, 909.8, 815.0 cm ; HRMS (MALDI, m/z) calcd.
+
for C H NO S (M+H ): 404.1890, Found: 404.1904.
2
2
30
4
o
27
D
1
1
1h: white solid, 90%. m.p. 230-231 C (dec.); [α]
-10.6 (c 0.40, DMSO); H NMR
(
DMSO-d , 400 MHz): δ 9.48 (1H, s), 8.18 (1H, s), 7.70 (2H, d, J = 8.4 Hz), 7.48 (2H, d, J = 8.4
6
Hz), 7.00 (1H, d, J = 8.0 Hz), 6.67 (1H, d, J = 8.4 Hz), 6.24 (1H, d, J = 2.0 Hz), 4.56 (1H, s),
4
.18 (1H, d, J = 15.2 Hz), 3.52 (3H, s), 3.14 (1H, d, J = 2.1 Hz), 3.00 (1H, s), 2.40 (1H, d, J =
13
1
5.6 Hz), 2.26-2.35 (1H, m), 2.00 (3H, s), 1.83 (1H, dt, J = 5.6, 11.2 Hz), 1.65-1.76 (2H, m); C
NMR (DMSO-d , 100 MHz): δ 192.4, 149.5, 144.1, 144.0, 134.6, 133.8, 132.3, 129.1, 127.9,
6
1
23.8, 120.4, 117.7, 113.3, 59.9, 53.9, 48.4, 45.9, 44.7, 43.6, 41.8, 39.7, 35.4; IR (KBr): vmax
S14

-1
3
350.8, 2940.3, 1665.9, 1620.6, 1490.8, 1474.9, 1290.9, 1203.1, 1152.0, 1093.0, 815.3 cm ;
+
HRMS (MALDI, m/z) calcd. for C H NO SCl (M+H ): 458.1187, Found: 458.1195.
2
4
25
4
o
27
D
1
1
1i: white solid, 96% yield. m.p. 224-225 C (dec.); [α]
-20.5 (c 0.50, DMSO); H NMR
(
DMSO-d , 400 MHz): δ 9.53 (1H, s), 8.22 (1H, s), 7.55-7.73 (4H, m), 6.99 (1H, d, J = 8.4 Hz),
6
6
(
.67 (1H, d, J = 8.4 Hz), 6.22 (1H, d, J = 2.0 Hz), 4.57 (1H, s), 4.18 (1H, d, J = 15.2 Hz), 3.51
3H, s), 3.14 (1H, d, J = 2.8 Hz), 3.00 (1H, s), 2.40 (1H, d, J = 15.6 Hz), 2.27-2.35 (1H, m), 2.01
1
3
(
3H, s), 1.77-1.88 (1H, m), 1.65-1.77 (2H, m); C NMR (DMSO-d , 100 MHz): δ 192.5, 149.5,
6
1
4
1
44.2, 144.0, 135.2, 134.0, 132.1, 127.8, 123.8, 120.7, 120.4, 117.7, 113.3, 59.9, 54.0, 48.4, 45.9,
4.7, 43.5, 41.8, 39.8, 35.4; IR (KBr): vmax 3311.5, 2936.4, 1665.3, 1621.8, 1490.8, 1472.3,
-1
587.2, 1490.8, 1472.3, 1380.1, 1290.5, 1177.4, 1150.7, 1089.9, 1005.2, 813.5, 611.9 cm ;
+
HRMS (MALDI, m/z) calcd. for C H NO SBr (M+H ): 502.0682, Found: 502.0697.
2
4
25
4
o
27
D
1
1
1j: light yellow solid, 87% yield. m.p. 220-221 C (dec.); [α]
-11.1 (c 0.60, DMSO); H
NMR (DMSO-d , 400 MHz): δ 9.48 (1H, s), 8.19 (1H, s), 7.72-7.79 (2H, m), 7.28 (2H, t, J = 8.8
6
Hz), 7.04 (1H, d, J = 8.0 Hz), 6.67 (1H, d, J = 8.4 Hz), 6.27 (1H, d, J = 2.0 Hz), 4.46 (1H, s),
4
.18 (1H, d, J = 15.2 Hz), 3.52 (3H, s), 3.14 ( 1H, d, J = 3.2 Hz), 3.00 (1H, s), 2.39 (1H, d, J =
1
3
1
5.2 Hz), 2.25-2.35 (1H, m), 1.91 (3H, s), 1.80 (1H, dt, J = 4.4, 10.8 Hz), 1.65-1.75 (2H, m); C
NMR (DMSO-d , 100 MHz): δ 192.4, 161.8 (d, J = 244.1 Hz), 149.5, 144.1, 144.0, 135.3 (d, J =
6
8
5
1
.4 Hz), 131.0 (d, J = 3.0 Hz), 128.0, 123.8, 120.4, 117.8, 116.2 (d, J = 21.7 Hz), 113.3, 59.6,
3.9, 48.4, 45.9, 44.8, 44.1, 41.6, 39.8, 35.5; IR (KBr): vmax 3350.0, 2948.4, 2836.5, 1666.2,
-1
615.2, 1589.9, 1489.4, 1291.7, 1200.2, 1176.0, 1092.6, 904.8, 814.0 cm ; HRMS (ESI, m/z)
+
calcd. for C H NO SF (M+H ): 442.1483, Found: 442.1496.
2
4
25
4
o
26
D
1
1
1k: white solid, 79% yield. m.p. 245-246 C (dec.); [α]
-14.2 (c 0.60, DMSO); H NMR
(
DMSO-d , 400 MHz): δ 9.72 (1H, s), 9.43 (1H, s), 8.14 (1H, s), 7.52 (2H, d, J = 8.0 Hz), 7.04
6
(1H, d, J = 8.0 Hz), 6.82 (2H,d, J = 8.0 Hz), 6.66 (1H, d, J = 8.4 Hz), 6.31 (1H, s), 4.26 (1H, s),
4
.17 (1H, d, J = 15.2 Hz), 3.51 (3H, s), 3.16 (1H, s), 2.98 (1H, s), 2.38 (1H, d, J = 15.2 Hz), 2.28
13
(
1H, d, J = 9.6 Hz), 1.84 (3H, s), 1.61-1.80 (3H, m); C NMR (DMSO-d , 100 MHz): δ 192.5,
6
157.7, 149.5, 144.0, 143.9, 135.7, 128.6, 123.9, 123.8, 120.4, 118.1, 116.2, 113.3, 59.5, 54.0, 48.6,
46.1, 45.0, 44.5, 41.6, 39.9, 35.7; IR (KBr): vmax 3481.9, 3305.0, 2902.3, 1672.3, 1630.6, 1582.0,
1493.7, 1478.4, 1379.5, 1315.8, 1285.7, 1264.7, 1225.2, 1202.9, 1170.3, 1149.3, 910.1, 832.0
S15

-1
+
cm ; HRMS (ESI, m/z) calcd. for C H NO S (M+H ): 440.1526, Found: 440.1535.
2
4
26
5
o
27
D
1
1
1l: white solid, 77% yield. m.p. 240-241 C (dec.); [α]
-19.9 (c 0.60, DMSO); H NMR
(
DMSO-d , 400 MHz): δ 9.53 (1H, s), 8.24 (1H, s), 7.82 (2H, d, J = 8.4 Hz), 7.75 (2H, d, J = 8.0
6
Hz), 6.96 (1H, d, J = 8.4 Hz), 6.68 (1H, d, J = 8.0 Hz), 6.19 (1H, d, J = 2.0 Hz), 4.79 (1H, s),
4
.19 (1H, d, J = 15.2 Hz), 3.53 (3H, s), 3.18 (1H, d, J = 2.8 Hz), 3.03 (1H, s), 2.41 (1H, d, J =
1
9
1
5.2 Hz), 2.31-2.39 (1H, m), 2.16 (3H, s), 1.84-1.97 (1H, m), 1.68-1.78 (2H, m); F NMR
3437.6, 2954.3, 1692.0, 1682.3, 1629.7, 1484.1,
(CDCl , 400 MHz): δ-59.69; IR (KBr): v
3
max
-1
1
323.9, 1286.4, 1202.8, 1173.2, 1116.4, 1091.5, 1061.8, 812.2 cm ; MS (ESI, m/z): 492.0
+
(
M+H) , Anal. Calcd. for C H F NO S requires C: 61.09; H: 4.92; N: 2.85, found C: 60.97; H:
25
24
3
4
4
.98; N: 2.68.
o
27
1
1
1m: white solid, 95% yield. m.p.204-205 C (dec.); [α]D 0.4 (c 0.50, DMSO); H NMR
(
DMSO-d , 400 MHz): δ 9.53 (1H, s), 8.22 (1H, s), 7.93 (1H, dd, J = 1.2, 8.0 Hz), 7.75 (1H, dd, J
6
=
1.2, 8.0 Hz), 7.47 (1H, dt, J = 1.2, 7.6 Hz), 7.29 (1H, dt, J = 1.2, 8.0 Hz), 7.08 (1H, d, J = 8.4
Hz), 6.69 (1H, d, J = 8.4 Hz), 6.42 (1H, d, J = 2.0 Hz), 4.66 (1H, s), 4.19 (1H, d, J = 15.2 Hz),
3
1
.54 (3H, s), 3.06 (1H, d, J = 2.8 Hz), 3.03 (1H, s), 2.41 (1H, d, J = 15.6 Hz), 2.28-2.36 (1H, m),
13
.96 (3H, s), 1.85 (1H, dt, J = 4.2, 10.0 Hz), 1.67-1.78 (2H, m); C NMR (DMSO-d , 100 MHz):
6
δ 192.4, 149.5, 144.3, 144.1, 135.9, 134.1, 133.2, 129.3, 128.4, 127.4, 126.6, 124.1, 120.3, 117.8,
113.4, 59.7, 54.1, 48.5, 45.9, 44.5, 42.8, 41.7, 39.8, 35.3; IR (KBr): vmax 3467.2, 2948.6, 1677.2,
-1
1
617.6, 1486.7, 1447.7, 1378.9, 1281.5, 1199.7, 1146.9, 1099.5, 819.1, 761.5 cm ; HRMS (ESI,
+
m/z) calcd. for C H NO SBr (M+H ): 502.0682, Found: 502.0695.
2
4
25
4
o
27
1
1
1n: light yellow solid, 78% yield. m.p. 205-207 C (dec.); [α] 14.7 (c 0.50, DMSO); H NMR
D
(
DMSO-d , 400 MHz): δ 9.50 (1H, s), 8.20 (1H, s), 7.90 (1H, t, J = 1.6 Hz), 7.65 (1H, d, J = 8.0
6
Hz), 7.53 (1H, d, J = 8.0 Hz), 7.37 (1H, t, J = 8.0 Hz), 7.00 (1H, d, J = 8.4 Hz), 6.67 (1H, d, J =
.4 Hz), 6.23 (1H, d, J = 2.0 Hz), 4.66 (1H, s), 4.18 (1H, d, J = 15.2 Hz), 3.52 (3H, s), 3.15 (1H,
d, J = 2.8 Hz), 3.01 (1H, s), 2.40 (1H, d, J = 15.2 Hz), 2.28-2.36 (1H, m), 2.06 (3H, s), 1.79-1.91
8
13
(
1H, m), 1.66-1.78 (2H, m); C NMR (DMSO-d , 100 MHz): δ 192.4, 149.5, 144.1, 144.0, 138.4,
6
1
4
1
33.4, 131.0, 130.4, 130.1, 127.6, 123.8, 122.1, 120.5, 117.7, 113.3, 59.9, 53.9, 48.4, 45.9, 44.6,
3.3, 41.7, 39.7, 35.3; IR (KBr): vmax 3457.1, 2932.2, 1694.1, 1626.4, 1556.6, 1484.5, 1449.8,
-1
379.7, 1286.9, 1203.5, 1175.0, 1146.3, 1085.5, 1001.8, 911.9, 787.3, 514.0 cm ; HRMS (ESI,
S16

+
m/z) calcd. for C H NO SBr (M+H ): 502.0682, Found: 502.0691.
2
4
25
4
o
27
D
1
1
1o: white solid, 76% yield. m.p. 216-217 C (dec.); [α]
-18.4 (c 0.50, DMSO); H NMR
(
DMSO-d , 400 MHz): δ 9.49 (1H, s), 8.19 (1H, s), 7.70-7.78 (1H, m), 7.31-7.38 (1H, m),
6
7
.22-7.31 (2H, m), 7.02 (1H, d, J = 8.4 Hz), 6.68 (1H, d, J = 8.4 Hz), 6.36 (1H, d, J = 2.0 Hz),
.45 (1H, s), 4.19 (1H, d, J = 15.2 Hz), 3.53 (3H, s), 3.13 (1H, d, J = 3.2 Hz), 3.02 (1H, s), 2.41
4
(1H, d, J = 15.2 Hz), 2.26-2.36 (1H, m), 1.94 (3H, s), 1.84 (1H, dt, J = 4.8, 11.2 Hz), 1.65-1.78
1
3
(
2H, m); C NMR (DMSO-d , 100 MHz): δ 192.4, 149.5, 144.0, 144.0, 139.2, 134.5, 132.7,
6
1
3
30.5, 128.3, 127.5, 126.5, 123.9, 120.2, 117.8, 113.4, 60.1, 53.9, 48.5, 45.9, 44.6, 42.4, 41.7,
9.8, 35.3, 20.3; IR (KBr): vmax 3448.4, 2944.5, 1683.1, 1647.4, 1479.5, 1379.7, 1283.3, 1200.7,
-1
+
1
146.3, 912.9, 812.5, 761.9 cm ; HRMS (MALDI, m/z) calcd. for C H NO S (M+H ):
25 28 4
4
38.1734, Found: 438.1750.
o
27
D
1
1
1p: white solid, 80% yield. m.p. 230-231 C (dec.); [α]
1.7 (c 0.60, DMSO); H NMR
(
DMSO-d , 400 MHz): δ 9.50 (1H, s), 8.21 (1H, s), 7.49 (1H, s), 7.45 (1H, d, J = 7.2 Hz), 7.30
6
(1H, t, J = 7.2 Hz), 7.16 (1H, d, J = 6.8 Hz), 7.01 (1H, d, J = 8.4 Hz), 6.67 (1H, d, J = 8.0 Hz),
6
.26 (1H, s), 4.55 (1H, s), 4.19 (1H, d, J = 15.2 Hz), 3.53 (3H, s), 3.16 (1H, s), 2.99 (1H, s), 2.39
(1H, d, J = 15.6), 2.33 (3H, s), 2.21-2.36 (1H, m), 1.99 (3H, s), 1.78-1.90 (1H, m), 1.60-1.78 (2H,
13
m); C NMR (DMSO-d , 100 MHz): δ 192.4, 149.4, 144.0, 138.6 135.4, 132.4, 129.0, 128.2,
6
1
3
23.7, 120.3, 117.8, 113.3, 59.8, 53.9, 48.4, 45.9, 44.7, 43.2, 41.7, 35.4, 20.7; IR (KBr): vmax
-1
435.5, 2938.8, 1693.4, 1625.5, 1483.7, 1450.5, 1275.0, 1202.9, 1023.8, 787.9, 726.6, 516.8 cm ;
+
HRMS (MALDI m/z) calcd. for C H NO S (M+H ): 438.1734, Found: 438.1741.
2
5
28
4
1
-14. General procedure for the syntheses of compounds 12a-12h
S17

R2
R2
S
Ac O/Py/0°-rt
S
2
N
N
H
H
O
O
HO
OH
O
AcO
OAc
O
11
1
2a-12h
To a solution of 11 (0.91 mmol) in pyridine (4 mL) was added acetic anhydride (1.82 mmol, 2
o
equiv) at 0 C. After addition, the reaction was stirred at r.t. until the completion of reaction. Then
the reaction mixture was concentrated and purified by column chromatography (DCM/CH OH
3
5
0/1) to afford sinomenine derivatives 12a-12h.
o
26
D
1
1
2a: white solid, 90% yield. m.p. 206-207 C; [α]
-42.9 (c 0.40, CHCl ); H NMR (CDCl ,
3 3
4
00 MHz): δ 7.67 (1H, d, J = 8.8 Hz), 7.50 (2H, d, J = 8.0 Hz), 7.16-7.24 (3H, m), 6.28 (1H, d, J
2.0 Hz), 4.41 (1H, s), 3.77 (1H, d, J = 16.0 Hz), 3.64 (3H, s), 3.43 (1H, d, J = 3.2 Hz), 3.08 (1H,
s), 2.51 ( 1H, d, J = 16.0 Hz), 2.38 (3H, s), 2.37 (3H, s), 2.32-2.37 (1H, m), 2.22 (3H, s), 2.04 (3H,
=
13
s), 1.94 (1H, dt, J = 2.8, 12.0 Hz), 1.84 (1H, dt, J = 4.4, 12.4 Hz), 1.56 (1H, d, J = 12.0 Hz); C
NMR (CDCl , 100 MHz): δ 191.7, 168.0, 167.5, 150.9, 142.2, 141.0, 138.5, 136.3, 133.2, 132.0,
3
1
2
30.9, 130.2, 128.0, 121.8, 116.8, 60.7, 54.9, 50.2, 46.0, 45.7, 44.3, 42.1, 40.8, 37.5, 21.2, 21.0,
0.9; IR (KBr): vmax 3418.8, 2929.8, 1774.5, 1689.6, 1622.1, 1472.0, 1372.9, 1262.9, 1203.3,
-1
+
1
177.8, 1144.3, 1088.3, 1013.3, 929.7, 812.0, 500.0 cm ;. MS (MALDI, m/z): 522.1 (M+H) ,
Anal. Calcd. for C H NO S requires C: 66.77; H: 5.99; N: 2.69, found C: 66.86; H: 6.02; N:
2
9
31
6
2
.79.
o
26
D
1
1
2b: white solid, 87% yield. m.p. 176-178 C; [α]
-60.4 (c 0.50, CHCl ); H NMR (CDCl ,
3 3
4
00 MHz): δ 7.62 (1H, d, J = 8.8 Hz), 7.54 (2H, d, J = 8.4 Hz), 7.39 (2H, d, J = 8.4 Hz), 7.20 (1H,
d, J = 8.8 Hz), 6.20 (1H, d, J = 2.0 Hz), 4.44 (1H, s), 3.77 (1H, d, J = 15.6 Hz), 3.63 (3H, s), 3.41
(
1H, d, J = 3.2 Hz), 3.10 ( 1H, s), 2.51 (1H, d, J = 16.0 Hz), 2.37-2.44 (1H, m), 2.38 (3H, s), 2.22
3H, s), 2.10 (3H, s), 1.96 (1H, dt, J = 2.8, 12.4 Hz), 1.86 (1H, dt, J = 4.4, 12.0 Hz), 1.57 (1H, d,
(
1
3
J = 12.0 Hz); C NMR (CDCl , 100 MHz): δ 191.6, 167.9, 167.5, 151.0, 142.3, 141.0, 135.7,
3
1
34.7, 134.1, 133.9, 130.9, 129.6, 127.9, 121.9, 116.3, 60.9, 54.9, 50.1, 45.8, 45.5, 44.4, 42.1,
S18

4
1
0.7, 37.3, 20.9, 20.8; IR (KBr): vmax 3448.4, 2932.9, 1774.5, 1693.0, 1624.7, 1475.0, 1438.9,
-1
370.6, 1263.6, 1202.0, 1171.1, 1145.8, 1093.1, 1011.7. 931.2, 818.3 cm ;. MS (ESI, m/z): 541.9
+
(
M+H) , Anal. Calcd. for C H ClNO S requires C: 62.04; H: 5.21; N: 2.58, found C: 61.75; H:
2
8
28
6
5
.33; N: 2.73.
o
26
D
1
1
2c: white solid, 87% yield. m.p. 122-124 C; [α]
-46.8 (c 0.40, CHCl ); H NMR (CDCl ,
3 3
4
00 MHz): δ 7.61 (1H, d, J = 8.8 Hz), 7.54 (2H, d, J = 8.4 Hz), 7.46 (2H, d, J = 8.4 Hz), 7.20 (1H,
d, J = 8.8 Hz), 6.19 (1H, d, J = 2.0 Hz), 4.45 (1H, s), 3.77 (1H, d, J = 15.6 Hz), 3.63 (3H, s), 3.41
(
1H, d, J = 3.2 Hz), 3.10 (1H, s), 2.51 (1H, d, J = 15.6 Hz), 2.38-2.45 (1H, m), 2.38 (3H, s), 2.22
3H, s), 2.11 (3H, s), 1.96 (1H, dt, J = 2.4, 12.0 Hz), 1.86 (1H, dt, J = 4.4, 12.4 Hz), 1.57 (1H, d,
(
1
3
J = 12.4 Hz); C NMR (CDCl , 100 MHz): δ 191.5, 167.9, 167.5, 151.0, 142.3, 141.0, 135.6,
3
1
4
1
34.7, 134.0, 132.5, 130.9, 127.9, 122.3, 121.9, 116.2, 60.9, 54.8, 50.0, 45.8, 45.4, 44.2, 42.1,
0.7, 37.2, 20.9, 20.8; IR (KBr): vmax 3400.7, 2931.5, 1774.0, 1692.0, 1624.7, 1473.6, 1370.4,
-1
263.6, 1201.5, 1170.3, 1145.0, 1088.6, 1007.2, 930.8, 816.6 cm ; HRMS (MALDI, m/z) calcd.
+
for C H NO SBr (M+H ): 586.0894, Found: 586.0908.
2
8
29
6
o
26
D
1
1
2d: light yellow solid, 85% yield. m.p. 185-187 C; [α]
-53.6 (c 0.50, CHCl ); H NMR
3
(
CDCl , 400 MHz): δ 7.65 (1H, d, J =8.4 Hz), 7.57-7.63 (2H, m), 7.20 (1H, d, J = 8.4 Hz),
3
7.07-7.17 (2H, m), 6.24 (1H, d, J = 2.0 Hz), 4.36 (1H, s), 3.77 (1H, d, J = 16.0 Hz), 3.63 (3H, s),
3.42 (1H, d, J = 3.2 Hz), 3.10 (1H, s), 2.51 (1H, d, J = 16.0 Hz), 2.36-2.43 (1H, m), 2.38 (3H, s),
2.22 (3H, s), 2.02 (3H, s), 1.93 (1H, dt, J = 2.8, 12.4 Hz), 1.85 (1H, dt, J = 4.4, 12.4 Hz), 1.57
1
9
13
(
1H, d, J = 12.4 Hz); F NMR (CDCl , 400 MHz): -110.93; C NMR (CDCl , 100 MHz): δ
3
3
1
1
4
1
8
91.6, 167.9, 167.5, 162.8 (d, J = 248 Hz), 151.0, 142.2, 141.0, 135.8, 135.5 (d, J = 8.2 Hz),
30.9, 130.6 (d, J = 3.4 Hz), 127.9, 121.8, 116.6 (d, J = 21.8 Hz), 116.4, 60.7, 54.9, 50.1, 45.8,
5.5, 44.8, 41.9, 40.7, 37.3, 20.9, 20.8; IR (KBr): vmax 3435.1, 2928.5, 1774.2, 1694.0, 1624.1,
587.8, 1489.2, 1474.4, 1371.7, 1263.7, 1202.7, 1173.2, 1145.2, 1089.1, 1012.8, 931.1, 836.6,
-1
+
16.8 cm ; HRMS (MALDI, m/z) calcd. for C H NO SF (M+H ): 526.1694, Found: 526.1701.
2
8
29
6
o
26
D
1
1
2e: white solid, 97% yield. m.p. 111-113 C; [α]
-44.1 (c 0.50, CHCl ); H NMR (CDCl ,
3 3
4
00 MHz): δ 7.62-7.69 （4H, m）, 7.57 (1H, d, J = 8.8 Hz), 7.20 (1H, d, J = 8.4 Hz), 6.16 (1H, d,
J = 2.0 Hz), 4.62 (1H, s), 3.78 (1H, d, J = 16.0 Hz), 3.64 (3H, s), 3.43 (1H, d, J = 3. Hz), 3.12
(1H, s), 2.53 (1H, d, J = 16.0 Hz), 2.40-2.47 (1H, m), 2.39 (3H, s), 2.23 (3H, s), 2.22 (3H, s), 2.02
S19

1
9
(
1H, dt, J = 2.8, 12.4 Hz), 1.87 (1H, dt, J = 4.4, 12.4 Hz), 1.57 (1H, d, J = 12.8 Hz); F NMR
1
3
(
CDCl , 400 MHz): δ -61.40; C NMR (CDCl , 100 MHz): δ 191.5, 167.9, 167.5, 151.1, 142.4,
3
3
1
1
2
1
5
41.1, 140.9, 135.3, 130.9, 129.6 (q, J = 42.7 Hz), 127.9, 126.2 (q, J = 3.6 Hz), 125.2, 122.5,
22.0, 116.0, 61.3, 54.8, 50.0, 45.8, 45.2, 43.5, 42.3, 40.7, 37.1, 20.9, 20.8; IR (KBr): vmax 3521.5,
934.7, 1776.8, 1693.3, 1626.0, 1604.4, 1475.9, 1372.6, 1326.3, 1263.4, 1202.5, 1169.8, 1121.4,
-1
+
061.9, 1013.2, 946.1, 819.9 cm ; HRMS (MALDI, m/z) calcd. for C H NO SF (M+H ):
29
29
6
3
76.1662, Found: 576.1681.
2f: light yellow solid, 90% yield. m.p. 196-198 C (dec.); [α] -11.8 (c 0.50, CHCl ); H NMR
o
26
D
1
1
3
(
CDCl , 400 MHz): δ 7.78 (1H, d, J = 8.8 Hz), 7.67-7.76 (2H, m), 7.39 (1H, dt, J = 1.2, 7.6 Hz),
3
7.18-7.25 (2H, m), 6.45 (1H, d, J = 2.0 Hz), 4.62 (1H, s), 3.78 (1H, d, J = 16.0 Hz), 3.66 (3H, s),
3.32 (1H, d, J = 12.8 Hz), 3.10 (1H, s), 2.52 (1H, d, J = 16.0 Hz), 2.35-2.43 (1H, m), 2.38 (3H, s),
2.22 (3H, s), 2.01 (3H, s), 1.93-2.00 (1H, m), 1.86 (1H, dt, J = 4.4, 12.4 Hz), 1.53-1.58 (1H, m);
IR (KBr): vmax 3435.3, 2932.1, 1774.6, 1693.6, 1618.6, 1473.0, 1442.5, 1420.9, 1369.9, 1263.4,
-1
+
1
200.6, 1174.8, 1143.9, 1017.1, 928.8, 877.9, 751.5 cm ; MS (MALDI, m/z): 586.3 (M+H) ,
Anal. Calcd. for C H BrNO S requires C: 57.34; H: 4.81; N: 2.39, found C: 57.09; H: 4.79; N:
2
8
28
6
2
.25.
o
26
D
1
1
2g: white solid, 92% yield. m.p. 188-190 C; [α]
-38.9 (c 0.50, CHCl ); H NMR (CDCl ,
3 3
4
00 MHz): δ 7.66 (1H, d, J = 9.2 Hz), 7.59-7.64 (1H, m), 7.23-7.33 (3H, m), 7.20 (1H, d, J = 8.4
Hz), 6.36 (1H, d, J = 2.0 Hz), 4.41 (1H, s), 3.78 (1H, d, J = 16.0 Hz), 3.65 (3H, s), 3.38 (1H, d, J
3.2 Hz), 3.10 (1H, s), 2.56 (3H, s), 2.52 (1H, d, J = 16.0 Hz), 2.33-2.42 (1H, m), 2.38 (3H, s),
.22 (3H, s), 2.01 (3H, s), 1.96 (1H, dt, J = 2.8, 12.4 Hz), 1.85 (1H, dt, J = 4.4, 12.4 Hz), 1.57
=
2
1
3
(
1H, d, J = 12.4 Hz); C NMR (CDCl , 100 MHz): δ 191.6, 167.9, 167.5, 150.9, 142.1, 141.0,
3
1
4
1
40.2, 136.1, 134.3, 133.5, 131.0, 130.9, 128.3, 127.7, 126.7, 121.8, 116.7, 60.6, 54.8, 50.2, 45.8,
5.5, 42.8, 41.9, 40.7, 37.3, 20.9, 20.9, 20.8; IR (KBr): vmax 3444.8, 2919.7, 1774.3, 1693.2,
-1
621.3, 1470.8, 1373.3, 1262.6, 1201.8, 1144.1, 1013.3, 930.7 cm ; MS (ESI, m/z): 522.0
+
(
M+H) , Anal. Calcd. for C H NO S requires C: 66.77; H: 5.99; N: 2.69, found C: 66.78; H:
29
31
6
6
.05; N: 2.81.
o
26
D
1
1
2h: yellow solid, 83% yield. m.p. 166-168 C (dec.); [α]
-28.8 (c 0.50, CHCl ); H NMR
3
(
CDCl , 400 MHz): δ 7.66 (1H, d, J = 8.4 Hz), 7.40 (2H, d, J = 8.0 Hz), 7.26-7.32 (1H, m), 7.20
3
S20

(
1H, d, J = 8.8 Hz), 7.16 (1H, d, J = 7.6 Hz), 6.27 (1H, d, J = 2.0 Hz), 4.48 (1H, s), 3.77 (1H, d, J
16.0 Hz), 3.65 (3H, s), 3.44 (1H, d, J = 2.8 Hz), 3.10 (1H, s), 2.51 (1H, d, J = 15.6 Hz),
.38-2.45 (1H, m), 2.39 (3H, s), 2.38 (3H, s), 2.22 (3H, s), 2.08 (3H, s), 1.97 (1H, dt, J = 2.8,
=
2
1
1
3
2.4 Hz), 1.86 (1H, dt, J = 4.4, 12.4 Hz), 1.57 (1H, d, J = 12.4 Hz); C NMR (CDCl , 100 MHz):
3
δ 191.6, 167.9, 167.5, 150.9, 142.1, 140.9, 139.3, 136.0, 135.2, 133.1, 130.8, 129.5, 129.2, 128.9,
28.0, 121.8, 116.6, 60.7, 54.9, 50.1, 45.9, 45.5, 43.9, 41.9, 40.7, 37.3, 21.3, 20.9, 20.8; IR (KBr):
vmax 3428.0, 2930.0, 1771.0, 1695.6, 1629.2, 1476.0, 1370.5, 1262.9, 1203.2, 1174.5, 1144.4,
1
-1
+
1
012.8, 879.0 cm ; HRMS (MALDI, m/z) calcd. for C H NO S (M+H ): 522.1945, Found:
29 32 6
5
22.1850.
S21

2
2
. Biological experimental details and results
.1 Cell culture
The mouse macrophage cell line J774 was used to evaluate the pro-inflammatory cytokine
TNF-α under the lipopolysaccharide (LPS)-stimulation. Cells were grown in Dulbecco’s
Modified Eagle’s Medium (DMEM) containing 10% fetal bovine serum (FBS), 100 U/mL
o
penicillin, and 100 U/mL streptomycin at 37 C in a humidified atmosphere of 6% CO .
2
2
.2 Procedure
Sinomenine and its derivatives were dissolved in dimethyl sulfoxide (DMSO) and added at
concentration of 0.1%. The same amount of 1% DMSO was added to the control cultures.
5
Immunoassay of TNF-α cells were plated in 48-well plates at 10 cells/well and incubated for 12
h. Then 1µg/ml LPS in the presence or absence of 10 μM of compounds in DMEM culture
medium with 10% FBS was added to each and well treated for 6 h. The culture supernatants were
collected and used for assaying the inhibitory activity on TNF-α production by ELISA kit
(R&D).
a
2
.3 Results of TNF-α inhibitory and stimulating effects. (Figure 3 and 4 in the manuscript)
b
b
b
Compounds
LPS+
LPS-
SB202190
IR (TNF-α, %)
Compounds
10g
IR (TNF-α, %) Compounds IR (TNF-α, %)
0
100
92
-27
3.6
-5.7
4.0
-14
-13
-31
-1.7
-5.2
-9.9
55
11j
11k
11l
27
6.0
58
30
56
36
49
41
46
54
39
56
39
27
41
10h
10i
10j
10k
10l
10m
11a
11b
11c
11d
11e
1
(SIN)
6.8
-47
-46
-67
-60
-9.9
-18
-25
-25
-28
-27
25
11m
11n
11o
11p
12a
12b
12c
12d
12e
12f
2
3
6
7
8
9
1
1
0a
0b
-14
7.9
-15
34
1
0c
0d
0e
0f
11f
11g
11h
11i
1
1
1
12g
12h
61
38
a
Compounds were assayed in 10 µM concentration, and 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-
b
1
H-imidazole (SB202190) was used as the positive control. IR: inhibitory rate.
S22

1
13
3
. H NMR, C NMR and 2D NMR copies of new compounds
AcO
A
c
O
N
N
O
O
O
O
O
O
H
H
O
O
3
3
( )
2 (400M, CDCl )
00
,
C C
2 4 M D l
AcO
N
O
O
OH
O
2
(75M, CDCl )
3
S23

AcO
N
O
O
OH
O
2
(400M, CDCl )
3
S24

AcO
N
O
O
OH
O
2
(400M, CDCl )
3
S25

AcO
N
O
O
OH
O
2
(400M, CDCl )
3
S26

AcO
N
O
O
OH
O
2
(400M, CDCl )
3
S27

AcO
N
O
O
OH
O
2
(400M, CDCl )
3
S28

MeO
N
O
O
OH
O
3
3
(300M, CDCl )
MeO
N
O
O
OH
O
3
(75M, CDCl )
3
S29

MeO
N
O
O
OH
O
3
(400M, CDCl )
3
S30