The total synthesis of hypodematine

Article abstract of DOI:10.1080/10286020.2013.805749

Hypodematine, isolated from Hypodematium sinense Iwatsuki as an alkaloid with a new skeleton, was synthesized via nine reaction steps, in which the synthesis of 2-aryl-1-benzazocines via Beckmann rearrangement of 5H-benzocyclohepten-5-one oxime mesylate i

Full text of DOI:10.1080/10286020.2013.805749

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The total synthesis of hypodematine
Zhi-Yun Kang a , Qing-Jian Zhang a , Ruo-Yun Chen a , Pei-Cheng
Zhang a & De-Quan Yu a
a State Key Laboratory of Bioactive Substance and Function of
Natural Medicines, Institute of Materia Medica, Peking Union
Medical College and Chinese Academy of Medical Sciences ,
Beijing , 100050 , China
Published online: 25 Jun 2013.
To cite this article: Zhi-Yun Kang , Qing-Jian Zhang , Ruo-Yun Chen , Pei-Cheng Zhang & De-Quan
Yu (2013) The total synthesis of hypodematine, Journal of Asian Natural Products Research, 15:8,
840-848, DOI: 10.1080/10286020.2013.805749
To link to this article: http://dx.doi.org/10.1080/10286020.2013.805749
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Journal of Asian Natural Products Research, 2013
Vol. 15, No. 8, 840–848, http://dx.doi.org/10.1080/10286020.2013.805749
The total synthesis of hypodematine
Zhi-Yun Kang, Qing-Jian Zhang, Ruo-Yun Chen, Pei-Cheng Zhang and De-Quan Yu*
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of
Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences,
Beijing 100050, China
(Received 4 March 2013; final version received 13 May 2013)
Hypodematine, isolated from Hypodematium sinense Iwatsuki as an alkaloid with a
new skeleton, was synthesized via nine reaction steps, in which the synthesis of 2-aryl-
1-benzazocines via Beckmann rearrangement of 5H-benzocyclohepten-5-one oxime
mesylate in dry toluene is discussed.
Keywords: hypodematium; total synthesis; Beckmann rearrangement; Grignard
reagents
1. Introduction
The hydroxy group in the structure
of hypodematine (1) makes it difficult to
prepare this compound. In our early study,
compound 12 was synthesized and used as
the start material to prepare the hypode-
matine by removing the methyl, but the
result showed that hypodematine (1) could
not be prepared with this method, because
the methyl was removed in the acid
condition, and the structure of azocine
was also destroyed in this condition. Each
of the first five steps reacted intensely, and
in this condition, only the methyl could be
used as the protection group of hydroxy,
whereas the compounds with azocine ring
were very unstable, so choosing an
appropriate hydroxy protect group in
different stages is the key factor for
preparing hypodematine (1). The reaction
of methyl removing must be finished
before the azocine is formed. Compounds
6 and 8 are likely to be the right
compounds to remove the methyl. Our
results showed that compound 6 is not fit to
remove the methyl because of the for-
mation of various byproducts. Compound
8 heated in dry dichloromethane (DCM)
with BBr3 gave the sole product 9A in
Hypodematine [1,2] (1 Figure 1) was
isolated from the whole plant of a fern,
Hypodematium sinense Iwatsuki in 1991.
H. sinense was used as a folk medicine to
treat Meniere’s syndrome, and the effec-
tive rate was 95.1%. Pharmacological
experiments showed that it has an
antifertility action, and the rate of inducing
abortion in pregnant rabbits was 86.6%
[1]. Hypodematine is a novel alkaloid of
benzazocine with a phenyl substituent in
C-2-position. There are only a limited
number of natural products that incorpor-
ate the azocine ring. Although the
synthetic route of the skeleton of hypode-
matine has been reported [3], it is difficult
to synthesize the hypodematine because
the azocines are very unstable. Here, we
describe the synthesis of hypodematine
and its analog with azocine ring (Figure 1).
2. Results and discussion
The synthetic route to hypodematine and
its analogs is shown in Scheme 1. Here, we
describe the synthesis and structural
elucidation of these compounds.
*Corresponding author. Email: dqyu@imm.ac.cn
q 2013 Taylor & Francis

Journal of Asian Natural Products Research
841
Grignard reagents were used. Both
rearrangement and unrearrangement pro-
ducts were found in our research. As
shown in Scheme 1, compounds 1 and 12–
18 were prepared easily in dry toluene
promoted by Grignard reagents under
nitrogen. In our ongoing research toward
Beckmann rearrangement promoted
directly by Grignard reagents, another
two kinds of oxime mesylates 19 and
20 (Figure 2) were prepared and used
in Beckmann rearrangement. The similar
methodwas used to prepare the intermediate
(E)-5-methoxy-7H-cyclohepta[a]naphtha-
len-7-one oxime mesylate (19) and (E)-4H-
cyclohepta[b] thiophen-4-one oxime mesy-
late (20) that are described in Schemes 2 and
3. Both aryl and aliphatic Grignard reagents
were used in Beckmann rearrangement
of mesylate 19. We found that the reaction
did not give the rearrangement compound as
expected when the aliphatic Grignard
reagents were used (Scheme 4). Whatever
the kind of Grignard reagents reacted with
HO
N
N
1
Azocine
Figure 1. Structures of hypodematine 1 and
azocine.
almost quantitative yield. We protected the
hydroxy of compound 9A with acetyl to
give compound 9B. The acetyl protective
group can be removed by dibutyltin oxide,
a near-neutral reagent, in methanol [4].
Both 9A and 9B reacted with hydroxyla-
mine hydrochloride gave the same product
10A in good yields. The esterification of
the oxime 10A and 10B to the correspond-
ing mesylates 11A and 11B, respectively,
was best carried out with methanesulfonyl
chloride and triethylamine in dry DCM.
The target compound 1 and their analogs
were prepared via Beckmann rearrange-
ment of mesylates in dry toluene in which
O
O
O
H3CO
H3CO
a
H3CO
CHO
+
b
OH
OH
OCH3
2
3
4
5
H3CO
RO
H3CO
H3CO
c
e
f
d
Br
Br
O
O
7
O
O
8
9A:R=H
9B:R=Ac
6
RO
RO
RO
RO
g
i
h
+
N
N
N
N
OH
OSO2CH3
R'
R'
1:R=H;R'=H
15:R=H;R'=H
16:R=H;R'=F
17:R=CH3;R'=H
18:R=SO2CH3;R'=H
10A:R=H
10B:R=CH3
11A:R=SO2CH3
11B:R=CH3
12:R=CH3;R'=H
13:R=H;R'=F
14:R=H;R'=OCH3
Scheme 1. Synthesis of hypodematine and its analogs. Reagents and conditions: (a) t-But-OK; (b)
Al/Ni, NaOH; (c) polyphosphoric acid (PPA); (d) AcOH, Br2; (e) LiCl, dimethylformamide (DMF)
reflux; (f) BBr3, CH2Cl2 reflux; (g) NH2-OH-HCl, pyridine, C2H5OH; (h) Et3N CH3SO2Cl; (i) R-Ph-
Mg-Br, toluene, 2208C to 208C.

842
Z.-Y. Kang et al.
studied. This suggests that the activity of
S
the mesylate was the key reason for the
Beckmann rearrangement. The structure of
all compounds was elucidated with 1H
NMR, 13C NMR and MS. The structure of
hypodematine was determined by NMR,
HR-ESI-MS, and X-ray. Unfortunately, the
data of natural products isolated from
Hypodematium sinense Iwatsuki were not
in accord with that of hypodematine and
turned out to be in accord with N-phenyl-a-
naphthalene amine in structure. The hypo-
dematine was synthesized totally.
H3CO
N
N
SO CH
2
O
O SO2CH3
19
20
Figure 2. Another two kinds of oxime
mesylates.
compound 20, no rearrangement product
was found (Scheme 5). In the study of the
rearrangement reaction of three kinds of
oxime mesylate, we found that compounds
11A and 11B were most efficient. When the
compound 19 was studied as the substrate,
rearrangement productscould alsobefound.
But the law of rearrangement was not
in accord with that of compounds 11A
and 11B. The nucleophilic ability order
of Grignard reagents was IsopropylMgBr
. PhCH2MgBr(PhC2H4MgBr). p-CH3-
OPhMgBr. PhMgBr . p-FPhMgBr. The
lowest activity Grignard reagents p-
FPhMgBr reacted with compound 19 to
give the entire rearrangement product 33B.
Compound 25 reacted with 4-fluoroaniline
gave compound 34B in good yield. It was
the lower not the higher active Girgnard
reagents that were easy to produce the
azocines when the compound 19 was
In summary, we have presented a
concise approach of hypodematine. Bio-
logical evaluation of azocines is in
progress.
3. Experimental
3.1 General experimental procedures
Melting points were determined on an
XT5B micro-melting apparatus (Beijing,
China) and are uncorrected. The NMR
spectra were recorded on Varian Mercury-
1
300 spectrometer (300MHz for H NMR
and 75MHz for 13C NMR) and Varian 600
spectrometer (600 MHz for 1H and
150 MHz for 13C) (Varian, Palo Alto, CA,
USA). EI-MS and HR-ESI-MS were
obtained on AutoSpec Ultima-TOF (Micro-
mass, Manchester, UK) and AccuTOF CS
OCH3
OCH3
OCH3
OCH3
O
O
O
O
c
a
b
+
O
O
HO
O
f
HO
22
23
21
OCH3
OCH3
OCH3
OCH3
g
OH
OSO2CH3
N
N
e
d
O
O
Br
Br
19
26
24
25
Scheme 2. Synthesis of compound 19. Reagents and conditions: (a) AlCl3, CH2Cl2; (b) anhydrous
NH2NH2, KOH; (c) PPA; (d) AcOH, Br2; (e) LiCl, DMF, reflux; (f) NH2-OH.HCl, pyridine,
C2H5OH; (g) Et3N, CH3SO2Cl.

Journal of Asian Natural Products Research
843
O
O
O
O
O
O
b
S
S
a
S
S
c
OH
OH
+
27
28
S
S
S
S
g
f
e
d
N
N
Br
O
O
OSO2CH3
O
Br
30
OH
29
31
32
20
Scheme 3. Synthesis of compound 20. Reagents and conditions: (a) AlCl3, CH2Cl2; (b) anhydrous
NH2NH2, KOH; (c) PPA; (d) phenyltrimethylammonium tribromide (PTAT)/tetrahydrofuran
(THF); (e) LiCl, DMF, reflux; (f) NH2-OH.HCl, pyridine, C2H5OH; (g) Et3N, CH3SO2Cl.
(JEOL, Tokyo, Japan) mass spectrometer,
respectively.
sulfate, and concentrated in vacuo. The
residue was purified by flash column
chromatography on silica gel (elution
with ethyl acetate/petroleum ether 1:9).
Compound 12 was obtained as a yellow
solid in 90% yield. Compounds 1 and 13–
18 were synthesized by the same pro-
cedure. Compounds 1, 13, and 14 are
yellow solid in 48.6%, 33%, and 87%
yield, respectively. Compounds 15 and 16
are orange-red solid in 17% and 23%
yield, respectively. Compounds 17 and 18
are orange solid in a little amount.
3.2 General procedures for compounds
1 and 12–18
PhMgBr (0.5 ml of a 3 M ethereal solution,
1.5 mmol) was added to a solution of
benzotropone oxime mesylate 4 (279 mg,
1 mmol) in dry toluene (5 ml) at 2208C.
The resulting solution was stirred at
2208C for 30 min and at 08C for 1 h. The
reaction was carried out under an argon
atmosphere all the time. Ether enriched
with water was used to quench the
reaction, and the aqueous layer was
separated and extracted with ether. The
combined organic layers were washed
with brine, dried over anhydrous sodium
3.2.1 Compound 1
1H NMR (300 MHz, CD3COCD3) d
(ppm): 8.08 (s, 1H), 7.91 (d, J ¼ 6.6 Hz,
2H), 7.45 (m, 1H), 7.43 (m, 2H), 6.78 (br s,
OCH3
OCH3
OCH3
R-Mg-Br
+
R
OSO2CH3
N
N
N
R
dry toluene
34A:R=Ph
33A:R=Ph
33B:R=p-FPh
19
34B:R=p-FPh
34C:R=p-CH3O-Ph
34D:R=PhCH2
34E:R=PhC2H4
34F:R=isopropyl
Scheme 4. The rearrangement reaction of compound 19.

844
Z.-Y. Kang et al.
S
S
R-Mg-Br
dry toluene
N
R
N
OSO2CH3
35A:R=Ph
35B:R=PhCH2
20
35C:R=n-butyl
Scheme 5. The rearrangement reaction of compound 20.
2H), 6.50 (m, 1H), 6.48 (d, J ¼ 2.1 Hz,
1H), 6.30 (ddd, J ¼ 0.9, 3.6, 11.7 Hz, 1H),
6.14 (dd, J ¼ 3.6, 11.7 Hz, 1H); 13C NMR
(75 MHz, CD3COCD3) d (ppm): 167.2,
154.5, 144.7, 139.2, 135.6, 133.4, 132.1,
131.3 (2C), 129.1 (2C), 129.0, 128.5 (2C),
124.2, 116.1, 115.8. HR-ESI-MS: m/z
[M þ H]þ (calcd for C17H13NOF,
266.0981).
3.2.4 Compound 14
1H NMR (600 MHz, CD3COCD3) d
(ppm): 8.07 (s, 1H), 7.86 (d, J ¼ 9.3 Hz,
2H), 6.96 (d, J ¼ 9.3 Hz, 2H), 6.77 (dt,
J ¼ 14.4, 5.5 Hz, 2H), 6.48 (m, 2H), 6.45
(s, 1H), 6.28(dd, J ¼ 11.4, 3.3 Hz, 1H), 6.13
248.1061
C17H14NO, 248.1075).
[M þ H]þ
(calcd
for
(dd, J ¼ 11.4, 3.3 Hz, 1H), 3.85 (s, 3H). 13
C
NMR (150MHz, CD3COCD3) d (ppm):
166.4, 162.6, 154.2, 144.9, 135.2, 133.4,
132.0, 131.8, 131.4, 130.0 (2C), 129.1,
124.2, 116.0, 115.7, 114.3(2C), 55.7.HR-
ESI-MS: m/z 278.1179 [M þ H]þ (calcd for
C18H16NO2, 278.1181).
3.2.2 Compound 12
1H NMR (300 MHz, CD3COCD3) d
(ppm): 7.92 (dd, J ¼ 7.5, 1.2 Hz, 2H),
7.40–7.50 (m, 3H), 6.88 (m, 2H), 6.56 (d,
J ¼ 6.3 Hz, 2H), 6.49 (d, J ¼ 11.4 Hz,
1H), 6.29 (dd, J ¼ 11.4, 3.0 Hz, 1H), 6.16
(dd, J ¼ 11.4, 3.0 Hz, 1H), 3.75 (s, 3H);
13C NMR (75 MHz, CD3COCD3) d (ppm):
167.4, 156.9, 145.6, 139.0, 135.6, 133.3,
132.2, 131.3, 131.2, 129.2 (2C), 128.4
(2C), 124.1, 115.0, 114.1, 55.6. EI-MS:
m/z: 262.2 [M þ H]þ.
3.2.5 Compound 15
1H NMR (300 MHz, CD3COCD3) d
(ppm): 9.75(s, 1H), 8.18 (d, J ¼ 8.7 Hz,
1H), 7.32 (t, J ¼ 7.8 Hz, 2H), 7.14 (dd,
J ¼ 2.7, 9.0 Hz, 1H), 6.90 (m, 1H), 6.88 (m,
2H), 6.80 (d, J ¼ 7.8 Hz, 2H), 6.40 (m, 3H).
13C NMR(75MHz, CD3COCD3) d (ppm):
163.3, 159.8, 152.2, 138.1, 137.2(2C),
132.6, 132.0, 129.9 (2C), 129.1, 127.5,
123.8, 120.6(2C), 119.0, 117.2. HR-ESI-
MS: m/z 248.1077 [M þ H]þ (calcd for
C17H14NO,248.1075).
3.2.3 Compound 13
1H NMR (600 MHz, CD3COCD3) d
(ppm): 8.16 (s, 1H), 7.96 (dd, J ¼ 5.4,
9.0 Hz, 2H), 7.19 (t, J ¼ 9.0 Hz, 2H), 6.79
(dd, J ¼ 2.4, 8.4 Hz, 1H), 6.76 (d,
J ¼ 8.4 Hz, 1H),6.47 (m, 1H), 6.31 (dd,
J ¼ 12, 3.6 Hz, 1H), 6.14 (dd, J ¼ 12,
3.6 Hz, 1H). 13C NMR (150 MHz,
CD3COCD3) d (ppm): 166.0, 164.3,
154.5, 144.4, 135.9, 135.6 (3C), 133.4,
132.1, 130.9, 130.8 (2C), 129.0, 124.2,
116.1, 115.9. HR-ESI-MS: m/z 266.0967
3.2.6 Compound 16
Orange solid, 1H NMR (600 MHz,
CD3COCD3) d (ppm): 8.94 (s, 1H), 8.16
(d, J ¼ 9.0 Hz, 1H), 7.10 (dd, J ¼ 4.8,
9.0 Hz, 2H), 7.08 (m, 1H), 6.99 (dd,

Journal of Asian Natural Products Research
845
J ¼ 2.4, 10.8 Hz, 1H), 6.96 (d, J ¼ 3.0 Hz,
1H), 6.83 (dd, J ¼ 4.8, 9.0 Hz, 2H), 6.47
(ddd, J ¼ 2.4, 7.2, 10.2 Hz, 1H), 6.43 (ddd,
J ¼ 2.4, 7.2, 10.8 Hz, 1H), 6.37 (dd,
J ¼ 2.4, 10.2 Hz, 1H). 13C NMR
(150 MHz, CD3COCD3) d (ppm): 164.0,
160.8, 159.8, 159.3, 148.4, 138.1, 132.5,
132.1, 131.4, 128.9, 127.6, 122.2, 122.1,
119.1, 117.2, 116.5, 116.4. HR-ESI-MS:
m/z 266.0987 [M þ H]þ(calcd for
C17H13NOF, 266.0981).
washed with brine and dried over anhy-
drous sodium sulfate and then concen-
trated in vacuo. The residue was washed
with methanol. Compound 19 was
obtained as a yellow powder in 87%
yield. Compounds 11A, 11B, and 20 were
synthesized by the same procedure.
3.3.1 Compound 19
1H NMR (300 MHz, DMSO) d (ppm): 8.50
(d, J ¼ 7.8 Hz, 1H), 8.29 (dd, J ¼ 7.8,
1.8 Hz, 1H), 8.08 (d, J ¼ 12.0 Hz, 1H),
7.73 (m, 2H), 7.25 (s, 1H), 6.84 (m, 2H),
3.2.7 Compound 17
6.74 (m, 1H), 4.09(s, 3H), 3.44 (s, 3H). 13
C
1H NMR (300 MHz, CD3COCD3) d
(ppm): 8.24 (d, J ¼ 9.0 Hz, 1H), 7.33 (t,
J ¼ 7.8 Hz, 2H), 7.16 (dd, J ¼ 2.7, 9.0 Hz,
1H), 7.05 (m, 3H), 6.80(d, J ¼ 7.8 Hz,
NMR (75 MHz, DMSO) d (ppm): 162.1,
156.6, 132.4, 131.7, 130.4, 129.8, 128.3,
127.3, 126.3, 125.7, 125.6, 125.0, 122.0,
120.6, 103.3, 55.9, 36.7; ESI-MS: m/z 330
[M þ H]þ.
2H), 6.38–6.45 (m, 3H), 3.88 (s, 3H). 13
C
NMR (75 MHz, CD3COCD3) d (ppm):
163.1, 160.6, 150.7, 136.9, 136.8, 132.3,
131.9, 130.8, 129.5 (2C), 128.9, 127.2,
123.6, 120.2 (2C), 117.9, 115.0, 55.3. HR-
ESI-MS: m/z 262.1242 [M þ H]þ (calcd
for C17H16NO,262.1232).
3.3.2 Compound 11A
1H NMR (300 MHz, CDCl3) d (ppm): 7.94
(d, J ¼ 6.6 Hz, 1H), 7.55 (m, 2H), 7.05 (d,
J ¼ 11.7Hz, 1H), 6.89 (d, J ¼ 11.7Hz,
1H), 6.60 (dd, J ¼ 11.4, 7.2 Hz, 1H), 6.46
(dd, J ¼ 11.4, 7.2 Hz, 1H), 3.51(s, 3H), 3.44
(s, 3H). 13C NMR (75 MHz, CDCl3) d
(ppm): 161.0, 151.6, 138.4, 135.1, 132.6,
131.6,128.5,124.7,124.5,122.1,37.7, 36.8;
ESI-MS: m/z 344.02 [M þ H]þ, 248.04 [M-
CH3SO3]þ, 709.02 [2M þ Na]þ.
3.2.8 Compound 18
1H NMR (500 MHz, CDCl3) d (ppm): 8.28
(d, J ¼ 8.5 Hz, 1H), 7.46 (dd, J ¼ 8.5,
2.0 Hz, 1H), 7.37 (d, J ¼ 2.0 Hz, 1H), 7.34
(d, J ¼ 8.0 Hz, 2H), 7.11(t, J ¼ 8.0 Hz,
1H), 6.96 (d, J ¼ 11.5 Hz, 1H),6.89 (dd,
J ¼ 8.0, 1.0 Hz, 2H),6.48 (m,1H), 6.41 (d,
J ¼ 4.0 Hz, 2H), 3.18 (s, 3H). 13C NMR
(125 MHz, CDCl3) d (ppm): 162.9, 150.0,
149.9, 137.4, 137.1, 134.9, 132.0, 129.5,
129.2 (2C), 128.9, 128.1, 124.0, 123.4,
123.3, 120.0 (2C), 37.6.
3.3.3 Compound 11B
1H NMR (300 MHz, CDCl3) d (ppm): 7.92
(d, J ¼ 9.0 Hz, 1H), 7.10 (dd, J ¼ 9.0,
2.1 Hz, 1H), 6.95 (m, 3H), 6.58 (dd,
J ¼ 11.7, 6.9 Hz, 1H), 6.47 (dd, J ¼ 11.7,
4.5 Hz, 1H), 3.89 (s, 3H), 3.21 (s, 3H).
3.3 General procedures for compounds
11A, 11B, 19, and 20
3.3.4 Compound 20
To a solution of 26 (125 mg, 0.01 mol) in
100 ml dry DCM, Et3N of 6 ml was added.
The reaction was cooled to 08C, and 0.8 ml
methylsufonyl chloride was added and
stirred for 10 min. The reaction was diluted
with DCM, and the organic phase was
m.p. 136–1378C. 1H NMR (300 MHz,
CD3COCD3) d (ppm): 7.90 (d, J ¼ 5.7 Hz,
1H), 7.74 (d, J ¼ 5.7 Hz, 1H), 7.30 (d,
J ¼ 11.4 Hz, 1H), 7.16 (d, J ¼ 12.6 Hz,
1H), 6.91 (dd, J ¼ 12.6, 8.1 Hz, 1H), 6.56
(dd, J ¼ 11.8, 8.1 Hz, 1H). 13C NMR

846
Z.-Y. Kang et al.
(75 MHz, CD3COCD3) d (ppm): 158.3,
135.5, 132.2, 130.0, 128.5, 125.3, 121.2,
36.5.
124.5, 122.7, 116.1, 115.7, 113.1, 101.3,
55.9. HR-MS-ESI: m/z 330.1290 [M þ H]þ
(calcd for C22H17FNO, 330.1294).
3.4 General procedures for compounds
33A, 33B, 34A, 34B, 34C, 34D, 34E, and
34F
3.4.3 Compound 34A
1H NMR (300 MHz, CD3COCD3) d
(ppm): 8.50 (d, J ¼ 8.4 Hz, 1H), 8.35
(dd, J ¼ 7.2, 1.2 Hz, 1H), 8.03 (d,
J ¼ 7.8 Hz, 1H), 7.76 (s, 1H), 7.71 (dt,
J ¼ 7.2, 1.8 Hz, 1H), 7.65 (dt, J ¼ 7.2,
1.2 Hz, 1H), 7.37 (dt, J ¼ 7.8, 1.2 Hz, 2H),
7.09 (dt, J ¼ 0.6, 1.8 Hz, 1H), 6.90 (dd,
J ¼ 7.8, 1.2 Hz, 2H), 6.70 (ddd, J ¼ 1.2,
6.0, 7.8 Hz, 1H), 6.59 (dd, J ¼ 10.8, 6.0 Hz,
1H), 6.36 (d, J ¼ 10.8Hz, 1H), 4.15 (s, 3H).
13C NMR (75 MHz, CD3COCD3) d (ppm):
165.3, 157.8, 151.9, 140.6, 133.5, 132.0,
130.9, 130.1 (2C), 129.0, 128.7, 127.5,
127.3, 126.1 (2C), 125.8, 124.5, 123.1,
120.9 (2C), 105.2, 56.3. HR-ESI-MS: m/z
312.1387 [M þ H]þ (calcd for C22H18NO,
312.1388).
Compounds 33A, 33B, 34A, 34B, 34C,
34D, 34E, and 34F were synthesized by
the same procedure as compound 12.
Compounds 33A, 33B, 34A, 34B, and 34C
were isolated by HPLC in lower yield less
than 10%. Compounds 34D, 34E, and 34F
were prepared in quantitative yields.
3.4.1 Compound 33A
1H NMR (300 MHz, CD3COCD3) d
(ppm): 8.17 (dd, J ¼ 8.4, 1.2 Hz, 1H),
7.99 (dd, J ¼ 1.2, 0.6 Hz, 2H), 7.76 (d,
J ¼ 6.0 Hz, 1H), 7.52 (m, 1H), 7.49 (m,
3H), 7.41 (dt, J ¼ 8.4, 0.6 Hz, 1H), 6.90 (d,
J ¼ 11.4 Hz, 1H), 6.60 (s, 1H), 6.57 (d,
J ¼ 11.4 Hz, 1H), 6.40 (dd, J ¼ 11.4,
3.6 Hz, 1H), 6.36 (dd, J ¼ 11.4, 3.6 Hz,
1H), 4.02 (s, 3H). 13C NMR (75 MHz,
CD3COCD3) d (ppm): 167.4, 156.4, 151.4,
138.9, 136.8, 134.3, 132.6, 131.6, 131.2,
129.3 (3C), 128.8 (2C), 127.8, 124.8,
124.7, 123.9, 122.9, 113.2, 101.6, 56.1.
HR-MS-ESI: m/z 312.1388 [M þ H]þ
(calcd for C22H18NO, 312.1388).
3.4.4 Compound 34B
1H NMR (600 MHz, CD3COCD3) d
(ppm): 6.38 (d, J ¼ 11.7 Hz, 1H), 6.62
(dd, J ¼ 11.7, 6.6 Hz, 1H), 6.70 (ddd,
J ¼ 6.6, 3.6, 1.2, Hz, 1H), 8.02 (d,
J ¼ 11.4 Hz, 1H), 8.35 (dd, J ¼ 9.3,
1.5 Hz, 1H), 7.70 (m, 1H), 7.64 (m, 1H),
8.47 (d, J ¼ 5.7 Hz, 1H), 7.73 (s, 1H), 6.94
(m, 2H), 7.14 (t, J ¼ 8.0, 7.0 Hz, 2H), 4.14 (s,
3H). 13C NMR (150 MHz, CD3COCD3) d
(ppm): 165.2, 161.3 (F-C), 158.2 (F-C),
157.1, 156.2, 147.2, 139.7, 132.7, 131.4,
130.2, 128.0, 127.9, 126.8, 126.6, 126.5,
125.4, 125.0, 122.4, 121.9, 121.8, 116.0,
115.7, 104.4, 55.5. HR-MS-ESI: m/z
330.1290 [M þ H]þ (calcd for C22H17FNO,
330.1303).
3.4.2 Compound 33B
1H NMR (300 MHz, CD3COCD3) d
(ppm): 8.17 (d, J ¼ 7.5 Hz, 1H), 8.04
(dd, J ¼ 5.4, 2.1 Hz, 2H), 7.75 (d,
J ¼ 8.4 Hz, 1H), 7.50 (dt, J ¼ 8.4,
1.5 Hz, 1H), 7.41 (dt, J ¼ 7.5, 1.5, Hz,
1H), 7.24 (dd, J ¼ 5.4, 2.1 Hz, 2H), 6.90
(d, J ¼ 7.8 Hz, 1H), 6.60 (s, 1H), 6.56 (d,
J ¼ 11.1 Hz, 1H), 6.39 (dd, J ¼ 15.0,
3.6 Hz, 1H), 6.35 (dd, J ¼ 7.8, 3.6 Hz,
1H), 4.02 (s, 3H). 13C NMR (75 MHz,
CD3COCD3) d (ppm): 166.9, 156.2, 151.0,
137.0, 135.5, 135.3, 135.1, 134.1, 132.5,
130.7, 131.6, 130.1, 130.0, 127.6, 124.6,
3.4.5 Compound 34C
1H NMR (300 MHz, CD3COCD3) d
(ppm): 8.46 (d, J ¼ 8.4 Hz, 1H), 8.34
(dd, J ¼ 8.4, 1.5 Hz, 1H), 8.00 (d,
J ¼ 12.0 Hz, 1H), 7.73 (s, 1H), 7.68 (dd,

Journal of Asian Natural Products Research
J ¼ 8.4, 1.5 Hz, 1H), 7.66 (dd, J ¼ 8.4, 3.4.8 Compound 34F
847
1H NMR (300 MHz, CD3COCD3) d
(ppm): 8.37 (d, J ¼ 8.4 Hz, 1H), 8.30
(dd, J ¼ 7.2, 1.5 Hz, 1H), 7.88 (d,
J ¼ 12.6 Hz, 1H), 7.65 (dt, J ¼ 8.4,
1.5 Hz, 1H), 7.57 (dt, J ¼ 7.2, 1.2 Hz,
1H), 7.27 (s, 1H), 6.60 (m, 3H), 4.11 (m,
1H), 4.06 (s, 3H), 1.17 (d, J ¼ 3.3 Hz, 6H).
13C NMR (75 MHz, CD3COCD3) d (ppm):
162.3, 157.2, 141.2, 132.9 (2C), 130.2,
130.1, 128.2, 126.8 (2C), 126.6, 125.4,
124.1, 122.9, 105.3, 56.0, 50.1, 23.8 (2C).
HR-MS-ESI: m/z 278.1539 [M þ H]þ
(calcd for C19H20NO, 278.1545).
1.5 Hz, 1H), 6.95 (dd, J ¼ 6.3, 3.0 Hz,
2H), 6.90 (dd, J ¼ 6.3, 3.0 Hz, 2H), 6.68
(dd, J ¼ 12.0, 6.6 Hz, 1H), 6.59 (dd,
J ¼ 12.0, 6.6 Hz, 1H), 6.41 (d,
J ¼ 12.0 Hz, 1H), 4.18 (s, 3H), 3.83 (s,
3H). 13C NMR (75 MHz, CD3COCD3) d
(ppm): 164.8, 157.5, 157.4, 144.2, 140.6,
133.2, 131.4, 130.6, 129.2, 128.4, 127.2,
127.1, 127.0, 125.7, 125.6, 122.9, 122.4
(2C), 115.0 (2C), 105.0, 56.0, 55.6. HR-
MS-ESI: m/z 342.1501 [M þ H]þ (calcd
for C23H20NO2, 342.1494).
3.4.6 Compound 34D
1H NMR (300 MHz, CD3COCD3) d
(ppm): 8.42 (d, J ¼ 11.7 Hz, 1H), 8.32
(d, J ¼ 8.1 Hz, 1H), 7.95 (d, J ¼ 12.9 Hz,
1H), 7.67 (dt, J ¼ 8.1, 1.2 Hz, 1H), 7.60
(dt, J ¼ 11.7, 0.9 Hz, 1H), 7.46 (t,
J ¼ 7.5 Hz, 2H), 7.33 (t, J ¼ 6.9 Hz, 2H),
7.44 (s, 1H), 7.22 (t, J ¼ 7.5 Hz, 1H), 6.66
(m, 3H), 4.81 (s, 2H), 3.90 (s, 3H). 13C
NMR (75 MHz, CD3COCD3) d (ppm):
164.9, 156.4, 140.8, 140.3, 132.0, 129.7,
129.5, 128.1 (2C), 127.3, 127.5 (2C),
126.2 (2C), 125.9, 125.8, 125.7, 124.5,
123.5, 122.0, 104.2, 55.1, 53.8. HR-MS-
ESI: m/z 326.1550 [M þ H]þ (calcd for
C23H20NO, 326.1545).
3.5 General procedures for compounds
35A, 35B, and 35C
To a solution of 20 (50 mg, 0.19 mmol) in
10 ml dry toluene, PhMgBr (0.1 ml of 2.8
M ethereal solution) at 2208C was added.
The resulting solution was stirred at
2208C for 30 min. The reaction was
carried out under an argon atmosphere all
the time. Brine was used to quench the
reaction, and the aqueous layer was
separated and extracted with ether. The
combined organic layers were washed
with brine, dried over anhydrous sodium
sulfate, and concentrated in vacuo. The
residue was purified by flash column
chromatography on silica gel (elution
with petroleum ether). Compound 35A
was obtained as a red solid in quantitative
yield. Compounds 35B and 35C were
synthesized by the same procedure.
3.4.7 Compound 34E
1H NMR (300 MHz, CD3COCD3) d
(ppm): 8.40 (d, J ¼ 12.3 Hz, 1H), 8.30
(d, J ¼ 8.1 Hz, 1H), 7.89 (d, J ¼ 12.3 Hz,
1H), 7.66 (dt, J ¼ 8.1, 1.5 Hz, 1H), 7.57 (t,
J ¼ 12.3 Hz, 1H), 7.36 (d, J ¼ 7.2 Hz, 2H),
7.29 (t, J ¼ 6.6 Hz, 3H), 7.18 (m, 1H), 6.58
(m, 2H), 6.48 (m, 1H), 4.07 (s, 3H), 3.82 (t,
J ¼ 6.9 Hz, 2H), 3.06 (t, J ¼ 6.9 Hz, 2H).
13C NMR (75 MHz, CD3COCD3) d (ppm):
165.3, 127.1, 130.0, 126.7, 130.2, 124.3,
132.9, 125.4, 128.3, 126.8, 122.9, 124.3,
157.2, 105.4, 141.2, 141.7, 129.9 (2C),
128.9(2C), 126.7, 38.0, 52.8, 56.0. HR-
MS-ESI: m/z 340.1691 [M þ H]þ (calcd
for C24H22NO, 340.1701).
3.5.1 Compound 35A
1H NMR (300 MHz, CD3COCD3) d
(ppm): 7.92 (d, J ¼ 5.4 Hz, 1H), 7.78 (d,
J ¼ 5.4 Hz, 1H), 7.74 (t, J ¼ 5.1 Hz, 2H),
7.18 (d, J ¼ 11.1 Hz, 1H), 7.04 (t,
J ¼ 7.5 Hz, 1H), 6.79 (d, J ¼ 5.1 Hz,
2H), 6.58 (m, 2H), 6.04–6.44 (m, 1H).
13C NMR (75 MHz, CD3COCD3) d (ppm):
158.5, 152.1, 144.0, 143.2, 132.9, 131.2,
130.6, 130.2 (2C), 129.6, 128.4, 125.5,
123.5, 120.4 (2C).

848
Z.-Y. Kang et al.
3.5.2 Compound 35B
1H), 6.74 (d, J ¼ 12.6 Hz, 1H), 6.56 (dd,
1H NMR (300 MHz, CD3COCD3) d
(ppm): 8.14 (d, J ¼ 5.4 Hz, 1H), 7.80 (d,
J ¼ 5.4 Hz, 1H), 7.49 (d, J ¼ 7.2 Hz, 2H),
7.30 (q, J ¼ 7.2, 2.7 Hz, 3H), 7.22 (t,
J ¼ 7.2 Hz, 1H), 7.00 (d, J ¼ 12.3 Hz,
1H), 6.86 (dd, J ¼ 12.6, 8.1 Hz, 1H), 6.55
(dd, J ¼ 10.8, 7.5 Hz, 1H), 4.73 (s, 2H).
13C NMR (75 MHz, CD3COCD3) d (ppm):
159.3, 143.4, 142.7, 141.1, 133.9, 131.1,
131.0, 130.2 (2C), 128.8 (2C), 128.3,
127.0, 126.0, 125.3, 52.8; ESI-MS: m/z
252.1179 [M þ H]þ.
J ¼ 12.6, 7.8 Hz, 1H), 6.32 (dd, J ¼ 12.6,
7.8 Hz, 1H), 3.38 (t, J ¼ 6.6 Hz, 2H), 1.71
(m, 2H), 1.63 (m, 2H), 0.96 (t, J ¼ 7.2 Hz,
3H). 13C NMR (75 MHz, CD3COCD3) d
(ppm): 158.4, 145.0, 140.4, 131.2 (2C),
129.5, 128.9, 126.6, 124.8, 50.3, 34.2,
21.4, 14.3; ESI-MS: m/z 218.1420
[M þ H]þ.
References
[1] Y.M. Chen, Y.H. Lu, and D.Q. Yu, Acta
Pharm. Sin. 26, 123 (1991).
[2] Y.M. Chen, Y.H. Lu, and Y.J. Chen,
J. Chin. Pharm. Sci. 2, 1 (1992).
3.5.3 Compound 35C
[3] Z.B. Ma, S.J. Dai, and D.Q. Yu, Tetra-
hedron Lett. 47, 4721 (2006).
[4] D.Z. Li, Y.B. Tang, and D.Q. Yu, J. Asian
Nat. Prod. Res. 11, 613 (2009).
1H NMR (300 MHz, CD3COCD3) d
(ppm): 7.70 (d, J ¼ 5.1 Hz, 1H), 7.60 (d,
J ¼ 5.1 Hz, 1H), 7.02 (d, J ¼ 12.6 Hz,