An efficient, mild and scalable synthesis of bioactive compounds containing the angelicin scaffold

Article abstract of DOI:10.1002/jccs.201200233

An efficient, mild and scalable synthesis of angelicin scaffold based compounds was developed. Particularly, the new synthetic route described here circumvents the need for the previously reported key Fries rearrangement step, which uses impractically har

Full text of DOI:10.1002/jccs.201200233

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
An Efficient, Mild and Scalable Synthesis of Bioactive Compounds Containing the
Angelicin Scaffold
Hui-Yi Shiao,a,* Ching-Chuan Kuo,b Jim-Tong Horng,c Shin-Ru Shih,d Sui-Yuan Chang,e
Chun-Chen Liao,f John T.-A. Hsu,a Prashanth Kumar Amancha,a Yu-Sheng Chaoa and
Hsing-Pang Hsieha,*
aInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 350, Taiwan,
R.O.C.
bNational Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan, R.O.C.
cDepartment of Biochemistry, Department of Medical Biotechnology and Laboratory Science, and Research Center for
Emerging Viral Infections, Chang Gung University, Taoyuan 333, Taiwan, R.O.C.
dDepartment of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan 333, Taiwan, R.O.C.
eDepartment of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of
Medicine, Taipei 106, Taiwan, R.O.C.
fDepartment of Chemistry, Chung Yung Christian University, Chungli 320, Taiwan, R.O.C.
(Received: Apr. 23, 2012; Accepted: Jun. 22, 2012; Published Online: ??; DOI: 10.1002/jccs.201200233)
An efficient, mild and scalable synthesis of angelicin scaffold based compounds was developed. Particu-
larly, the new synthetic route described here circumvents the need for the previously reported key Fries re-
arrangement step, which uses impractically harsh conditions. The new methodology is applied to the syn-
thesis of several, previously reported analogs of angelicin which have potent anti-influenza and anti-can-
cer activities.
Keywords: Furanocoumarin; Angelicin; Fries rearrangement.
INTRODUCTION
Angelicin (1) is a well known natural product with in-
which were resistant to established anti-cancer drugs such
as vincristine (Table 1). Moreover, compound 3 also exhib-
ited excellent activity against several viruses including in-
fluenza, enterovirus and lentivirus (Table 2).
teresting and varied biological activities.1 It is a member of
the furanocoumarin family of natural products,2 of which
there are two types, angular and linear. Angular furano-
coumarins, such as angelicin (1), are generally less photo-
toxic than linear furanocoumarins such as psoralen (2),3
which are well known for their phototoxic effect on many
organisms.4 Recently, we identified a number of com-
pounds with the angelicin core structure, with a wide range
of biological activities at nanomolar concentration.5,6,7 For
example, compound 3 (Figure 1) was found to inhibit the
growth of numerous cancer cell lines in in vitro, some of
In order to exploit and explore the diverse biological
activity of compound 3, a systematic structure-activity re-
lationship (SAR) study was carried out by synthesizing a
series of analogs of 3.5,6 For the purpose of SAR study, we
utilized previously reported three-step synthetic methodol-
ogy to obtain 3 and its analogs from substituted 7-hydroxy-
Table 1. Anti-cancer activities of 35a
IC50
IC50
IC50
Cell Lines
Cell Lines
Cell Lines
(nM)
(nM)
(nM)
HONE1
CPT30
HONE-cis6
KB
2
KB-S15
KB-vin10
TSGH
MCF7
HT29
0.5
2.5
17
4
H9
3.5
8.5
4.5
1.3
CEM
1000
HL60
1000
35000
3500
26700
10800
Hep 3B
Hep G2
Huh 7
Hcc36
KB-CPT100 6.25
7
KB7D
0.8
4
H460
0.5
110
Fig. 1. Furanocoumarin based natural products and
KB-1036
BJAB
bioactive compound 3.
* Corresponding author. Tel.: +886-37-246166 ext. 35725 for HYS, ext 35708 for HPH; Fax: +886-37-586456;
E-mail: hyshiao@nhri.org.tw for HYS; hphsieh@nhri.org.tw for HPH
J. Chin. Chem. Soc. 2012, 59, 000-000
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Article
Shiao et al.
Table 2. Anti-influenza activities of 35b,6,7
scribed before.10 To get an insight into the reasons for poor
regioselectivity of the Fries reaction step, we carried out
molecular modeling studies of AlCl3-associated coumarin
intermediate 9. The HOMO and HOMO-{1} (Figure 2)
(calculated using Hartree-Fock / 3-21G*) of 9 shows that
the electron densities on both sides of hydroxyl group (6-
and 8-positions) to be approximately equal, suggesting that
useful levels of regioselectivity in the rearrangement step
would be difficult to achieve. Second, the harsh conditions
required for the Fries rearrangement step (strong Lewis ac-
ids and high temperatures), greatly narrowed the scope of
the SAR study by limiting the type of substitutions that can
be explored due to the stability of functional groups at these
harsh conditions. For example, Fries reaction of compound
5 bearing an electron-donating group (R2 = p-OMe-Ph) led
to an intractable mixture of products, none of which could
be identified as the desired rearranged product. This ren-
dered a whole class of angelicin analogs inaccessible for us
and greatly delayed the SAR understanding in this series of
compounds.
Virus
IC50 (nM)
Influenza A/Udorn/72 (H3N2)
Influenza A/TW/83/05 (H3N2)
Influenza A/TW/83/05 (H3N2)
Influenza A/WAN/33 (H1N1)
Influenza B/TW/710/05
Influenza B/TW/70325/05
Influenza B/TW/99/07
Enterovirus 71 (4643)
Coxsackie B virus 3
347
57
57
119
102
67
89
2
5
Human rhinovirus
12
1
HIV
coumarins (4) (Scheme I).8 Acylation of 4 with benzoyl
chloride gave 5, which underwent Fries rearrangement at
170 oC in the presence of highly reactive Lewis acid AlCl3
to give the rearranged regioisomer products 6 and 7. The
desired angelicin analogs 8 were finally obtained by react-
ing 6 with a variety of 2-bromoketones under basic condi-
tions. More than one hundred and fifty analogs with the
angelicin core structure were synthesized using this method,
to investigate the SAR in this series of compounds.5,6
Thirdly, isolation/purification of the regioisomer
products 6 and 7 obtained after the Fries reaction was diffi-
cult, due to the poor solubility of the hydroxyl coumarin
moiety in commonly used organic solvents, such as EtOAc,
CH2Cl2, MeOH, etc. This greatly impeded the development
of these molecules into drugs, as the drug development pro-
cess typically required multi-gram quantities of the target
RESULTS AND DISCUSSION
During the synthesis of these compounds, we identi-
fied significant shortcomings in this synthetic approach.
First, the regioselectivity of the key Fries rearrangement
step was poor:9 Two possible rearrangement regioisomer
products 6 and 7 were both obtained in a ratio ranging from
2:1 to 1:2. This led to unacceptably low yields of com-
pound 6 (~30%). Our effort to improve both the selectivity
and the yield for this rearrangement step using various re-
action conditions failed, even after taking into consider-
ations the thermodynamics of the Fries rearrangement de-
Fig. 2. Molecular orbital models of the intermediate 9.
Scheme I Three-step synthesis of Angelicin analogs 8 from 4
2
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis of Bioactive Angelicin Analogs
compounds for pharmacokinetics, toxicity and in vivo effi-
cacy evaluation in preclinical animal models.
Scheme II Pechmann reaction of 10a and Friedel-
Crafts Acylation of 10b
These problems led us to search for an alternative
synthetic route which would be applicable for a wide range
of substituents and provide for increased yield, easy purifi-
cation, and subsequent scale-up to multi-gram scale. Two
modifications to the original synthetic methodology were
deemed essential for this purpose: (1) an alternative key
step instead of Fries rearrangement and (2) a synthetic
route that do not include the hydroxyl-coumarin intermedi-
ate compound to overcome the poor solubility of the prod-
ucts.
To circumvent the difficulties in the previous syn-
thetic strategy, we planned to construct the coumarin ring at
the last step instead of starting from coumarin ring struc-
ture. Initially we used the Pechmann coumarin ring forma-
tion reaction to construct 3 from 10a6a (Scheme II). How-
ever, several attempts using different acid catalysis condi-
tions such as H2SO4, pTSA, I2, TFA, POCl3 and AgOTf,
failed to give the desired furanocoumarin product (See the
Supporting Information). Next, we tried to install an acetyl
group at 5-position of 10b6a using Friedel-Crafts acylation,
with a plan to use compound 11 as a potential precursor to
synthesize the desired coumarin through tandem Wittig/
intramolecular cyclization (see below). However, the prod-
uct obtained from Friedel-Crafts acylation of 10b is the
regioisomer 12 instead of the desired compound 11. The
structure of 12 was confirmed by the NOESY experiment
and single-crystal X-ray diffraction analysis.
TBAF in refluxing tetrahydrofuran to unmask the second-
ary alcohol, which was oxidized without further purifica-
tion to the corresponding ketone using pyridinium dichro-
mate (PDC). Deprotection of the MOM group in refluxing
methanol with catalytic amount of hydrochloric acid and
then cyclizing the resulting crude compound with 2-bro-
moacetophenone under basic conditions gave the benzo-
furan 11 in an overall yield of 62% over four steps. Using
this approach, both intermediates 17 and 11 were success-
fully synthesized on a 15 gram scale.
Hence, we used a de novo approach to install the
acetyl group at 5-position of the benzofuran ring of com-
pound 11. For this, we began with the 2,4-dihydroxy aceto-
phenone (13) and selectively protected the 4-hydroxy
group with MOMCl. O-Methylation of the other hydroxyl
group was achieved using K2CO3 and MeI to give bis-pro-
tected acetophenone 14 (Scheme III). Conversion of the
keto function present in 14 to a secondary alcohol was ef-
fected by NaBH4/methanol reduction system. The resulting
alcohol functional group was protected with TBSCl to give
an intermediate 15. The resulting fully protected intermedi-
ate 15 could be prepared on a 50 gram scale in good overall
yield of 77% over four steps, with only one final flash chro-
matographic purification step.
Benzofuran 11 was demethylated using BBr3 in
CH2Cl2 to afford 18a, which was used without purification.
The key Wittig reaction followed by an intra-molecular
cyclization of 18a with the stabilized phosphonium ylide
(PPh3=CHCO2Et) constructed the coumarin ring and gave
the angelicin analog 3 with an overall yield of 70% from
compound 11.12 This two-step synthesis could be scaled up
to five gram scale. Thus, the desired compound 3 was ob-
tained in 26% overall yield from commercially available 13
with only four purification stages.
Electron-donating groups such as hydroxyl and meth-
oxyl groups play important roles in SAR exploration. Un-
fortunately, neither 19b (OMe-bearing) nor 19a (OH-bear-
ing; a precursor of 19b) are accessible via the synthetic
Methoxymethyl (MOM) and methoxy group directed
ortho-lithiation of key intermediate 15 followed by acyla-
tion with benzoyl chloride gave 16a in 78% yield.11 The
TBS protection in 16a was removed by treatment with
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Article
Shiao et al.
Scheme III Synthesis of Angelicin analogs
methodology which uses Fries rearrangement as the key
step, due to the fact that the OMe group in 19b cannot sur-
vive under these strong acidic conditions during this harsh
reaction. Therefore, in order to broaden the SAR study of
angelicin analogs and also to demonstrate the scope of the
new synthetic approach, compounds 19a and 19b were also
synthesized using the new method.
the coumarin ring of 3 at the last step instead of starting
from coumarin ring structure. Through the new methodol-
ogy, previously inaccessible OCH3 and OH bearing analogs
of 3 were synthesized, which helped in understanding the
SAR for anti-cancer as well as anti-influenza activity in
this series. More importantly, in the new synthetic method,
all the intermediates and the final products could be easily
synthesized at the gram scale without facing purification
problems enabling detailed in vitro and in vivo biological
evaluation for the compounds, which are underway.
Compound 15 acted as a precursor for the synthesis
of 19a and 19b. Benzoyl chloride was replaced with 4-
methoxyl benzoyl chloride for the ortho-lithiation directed
acylation of compound 15, to give the corresponding inter-
mediate 16b. Using similar reaction conditions to those de-
scribed for the synthesis of 3, compounds 19a and 19b
were finally synthesized in overall yields of 19% and 14%
from 15, respectively.
EXPERIMENTAL SECTION
1-(2-Benzoyl-4-methoxy-3-phenyl-1-benzofuran-7-yl)-
ethanone (12)
To a solution of 10b (300 mg, 0.91 mmol) in dry DCM (25
mL) was added acetyl chloride (155 mg, 1.10 mmol) and AlCl3
powder (545 mg, 4.09 mmol) and stirred at reflux temperature for
12 h. After cooling to rt, H2O was added slowly to quench the re-
action. The mixture was partitioned between H2O and DCM. The
combined organic layers were washed with brine and dried over
In conclusion, to circumvent the difficulties faced in
the previous synthetic strategy, such as harsh reaction con-
ditions, low yield and poor solubility of the intermediates
involved, a new synthetic route for angelicin derivative 3
and its analog were developed. The new method constructs
4
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis of Bioactive Angelicin Analogs
MgSO4, and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel, (EtOAc/
Hexane : 1/4) to furnish 247 mg (73%) of product 12, as white sol-
ids. mp 154.0~154.8 oC; IR (neat) n 3058, 2932, 2840, 1674,
1652, 1598, 1558, 1507, 1367, 1262, 1181, 1098 cm-1; 1H NMR
(400 MHz, CDCl3) d 2.79 (s, 3H, -COCH3), 3.79 (s, 3H, -OCH3),
6.76 (d, J = 8.8 Hz, 1H), 7.29~7.49 (m, 8H), 7.85~7.88 (m, 2H),
8.14 (dd, J = 0.4, 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
30.8 (CH3), 55.8 (CH3), 104.4 (CH), 127.3 (CH x2), 128.0 (CH
x3), 128.2 (C), 129.2 (C), 129.66 (CH x2), 129.72 (C), 130.5 (CH
x2), 130.8 (C), 131.5 (CH), 132.7 (CH), 137.0 (C), 146.9 (C),
154.3 (C), 160.2 (C), 184.9 (C=O), 194.2 (C=O); MS (FAB) m/z
(relative intensity, %) 371 ([M+H]+, 100), 293 (20); HRMS
(FAB) Calcd. for C24H18O4 (M+) 370.1205, found 370.1206.
tert-Butyl{1-[2-methoxy-4-(methoxymethoxy)phenyl]-
ethoxy}dimethylsilane (15)
-CHCH3), 3.47 (s, 3H, -OCH3), 3.77 (s, 3H, -OCH3), 5.11 (q, J =
6.0 Hz, 1H, -CH-OTBS), 5.14 (s, 2H, -OCH2O-), 6.50 (d, J = 2.2
Hz, 1H), 6.61 (dd, J = 2.2, 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H);
13C NMR (100 MHz, CDCl3) d -5.0 (CH3), -4.9 (CH3), 18.2 (C),
25.7 (CH3), 25.9 (CH3 x3), 55.2 (CH3), 56.0 (CH3), 64.8 (CH),
94.7 (CH2), 99.4 (CH), 107.1 (CH), 126.5 (CH), 129.1 (C), 156.0
(C), 157.0 (C); MS (FAB) m/z (relative intensity, %) 326 (M+, 5),
311 (14), 269 (100).
[3-(1-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-2-methoxy-
6-(methoxymethoxy)phenyl](phenyl)methanone (16a)
To a solution of 15 (326 mg, 1.0 mmol) in dry THF (10 mL)
was added nBuLi (0.8 mL, 2.0 M solution in hexane) dropwise at
0 oC. After the addition was completed, the mixture was stirred at
same temperature for 10 min, and the benzoyl chloride (0.15 mL,
1.28 mmol) solution added dropwise. The reaction was warmed to
rt and stirred for 2 h. The reaction was quenched by addition of
water, extracted with EtOAc, dried over MgSO4, filtered and con-
centrated. The residue was purified by column chromatography
on silica gel, (EtOAc/Hexane : 1/15) to furnish 335 mg (78%) of
16a, as a colorless oil. The reaction could be carried out at a scale
of 7 gram of SM with 66% yield. IR (neat) n 2955, 2930, 2856,
1678, 1597, 1478, 1450, 1402, 1365, 1313, 1258, 1193, 1155,
1114, 1057, 1003 cm-1; 1H NMR (400 MHz, CDCl3) d -0.01 (s,
3H, -SiCH3), 0.06 (s, 3H, -SiCH3), 0.9 (s, 9H, -SiC(CH3)3), 1.40
(d, J = 6.0 Hz, 3H, -CHCH3), 3.25 (s, 3H, -OCH3), 3.65 (s, 3H,
-OCH3), 5.01 5.04 (ABq, J = 6.8 Hz, 2H, -OCH2O-), 5.12 (q, J =
6.0 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 7.41~7.46 (m, 2H), 7.53~
7.57 (m, 2H), 7.83~7.85 (m, 2H); 13C NMR (100 MHz, CDCl3) d
-4.9 (CH3), -4.8 (CH3), 18.2 (C), 25.9 (CH3 x3), 26.6 (CH3), 56.1
(CH), 62.8 (C), 64.8 (CH), 94.5 (CH2), 100.4 (CH), 123.3 (C),
128.46 (CH x2), 128.54 (CH), 129.4 (CH x2), 133.4 (CH), 133.8
(C), 137.7 (C), 153.7 (C), 153.8 (C), 195.4 (C=O); MS (FAB) m/z
(relative intensity, %) 430 (M+, 5), 413 (14), 373 (100), 299 (30);
HRMS (ESI) Calcd. for C24H34NaO5Si ([M+Na]+) 453.2073,
found 453.2062.
To a solution of 13 (4.0 g, 26.29 mmol) in DCM (100 mL)
was added DIPEA (6.8 mL, 38.93 mmol) and MOMCl (2.4 mL,
29.81 mmol). The mixture was stirred at rt for 12 h and the solvent
removed under reduced pressure. The residue was diluted with
100 mL acetone and refluxed with MeI (7.5 g, 52.60 mmol) and
K2CO3 (5.4 g, 39.36 mmol) for 24 h. Additional MeI (4.26 g, 30.1
mmol) was added to the reaction and stirred at same temperature
for another 12 h. Acetone was removed under reduced pressure.
The crude products were partitioned between H2O and DCM and
the collected organic layers concentrated to give the crude inter-
mediates 14. To a solution of above crudes in MeOH (80 mL) was
added NaBH4 (1058 mg. 27.97 mmol) at 0 oC in three portions.
After the final portion of NaBH4 was added, the mixture was
stirred for 30 min and then allowed to warm to rt for another 30
min. The reaction was quenched by addition of 1 N HCl and wa-
ter, extracted with Et2O, dried over MgSO4, filtered and concen-
trated. The residue was diluted with dry DMF. TBSCl (4.7 g, 31.4
mmol), Et3N (7.8 mL, 52.4 mmol) and imidazole (2664 mg, 39.3
mmol) were then added to the solution and stirred at 60 oC for 24
h. The majority of DMF was removed under reduced pressure; the
crude products were partitioned between H2O and Et2O. The com-
bined organic layers were washed by brine and dried over
MgSO4, and concentrated under reduced pressure. The residues
was purified by column chromatography on silica gel, (EtOAc/
Hexane : 1/15) to furnish 6.6 g (77%, over 4 steps) of product 15,
as colorless oil. The reaction could be carried out at a scale of 30
gram of SM with an overall yield of 70% for four steps. IR (neat)
n 2955, 2929, 2895, 2856, 1611, 1590, 1504, 1464, 1417, 1389,
1363, 1278, 1255, 1214, 1189, 1131, 1084, 1019, 960, 928, 835
cm-1; 1H NMR (400 MHz, CDCl3) d -0.05 (s, 3H, -SiCH3), 0.02
(s, 3H, -SiCH3), 0.87 (s, 9H, -SiC(CH3)3), 1.30 (d, J = 6.0 Hz, 3H,
1-(2-Benzoyl-4-methoxy-3-phenyl-1-benzofuran-5-yl)-
ethanone (11)
A solution of 16a (230 mg, 0.53 mmol) in dry THF (15 mL)
was refluxed with TBAF (1.6 mL, 1.0 M in THF) for 12 h. The so-
lution was cooled to room temperature and solvent was removed
under reduced pressure. To the residue was added H2O and ex-
tracted with EtOAc, dried over MgSO4, filtered and concentrated.
The residue was diluted with dry DCM, and PDC (300 mg, 0.8
mml) and Celite (800 mg) were then added to the solution. The
mixture was stirred at reflux temperature for 3 h. The reaction was
filtered and DCM was removed under reduced pressure. The resi-
due was diluted with MeOH (20 mL) and conc. HCl (one drop)
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Shiao et al.
was added, and refluxed for 4 h. The reaction was diluted with
water, extracted with EtOAc, dried over MgSO4, filtered and con-
centrated. To a solution of the residue in ACN (20 mL) was added
K2CO3 (178 mg, 1.28 mmol) and 2-bromo acetophenone and re-
acted at reflux temperature for 12 h. The reaction was diluted with
water, extracted with EtOAc, dried over MgSO4, filtered and con-
centrated. The residue was purified by column chromatography
on silica gel, (EtOAc/Hexane : 1/4) to furnish 105 mg (62%) of
11, as yellow solid. The reaction could be carried out at a scale of
5 gram of SM with a yield of 60%. mp 123.3~125.1 oC; IR (neat)
n 3057, 2997, 2924 , 2829, 1674, 1651, 1598, 1582, 1557, 1278,
[3-(1-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-2-methoxy-
6-(methoxymethoxy)phenyl](4-methoxyphenyl)meth-
anone (16b)
Similar procedure as for the synthesis of 16a was applied to
synthesize 16b with an overall yield of 65%. IR (neat) n 2955,
2930, 2900, 2856, 1666, 1598, 1509, 1473, 1420, 1363, 1312,
1
1257, 1155, 1092, 1056, 1004, 835 cm-1; H NMR (400 MHz,
CDCl3) d -0.037 (s, 3H, -SiCH3), 0.038 (s, 3H, -SiCH3), 0.88 (s,
9H, -SiC(CH3)3), 1.37 (d, J = 6.0 Hz, 3H, -CHCH3), 3.26 (s, 3H,
-OCH3), 3.63 (s, 3H, -OCH3), 3.83 (s, 3H, -OCH3), 5.00 5.03
(Abq, J = 6.8 Hz, 2H, -OCH2O-), 5.10 (q, J = 6.0 Hz, 1H,
-CHOTBS), 6.87~6.90 (m, 2H), 6.94 (d, J = 8.8 Hz, 1H), 7.53 (d,
J = 8.8 Hz, 1H), 7.77~7.81 (m, 2H); 13C NMR (100 MHz, CDCl3)
d -4.9 (CH3), -4.8 (CH3), 18.2 (C), 15.8 (CH3 x3), 26.6 (CH3),
55.4 (CH3), 56.1 (CH3), 62.7 (CH3), 64.8 (CH), 94.5 (CH2), 110.5
(CH), 113.7 (CH x2), 123.5 (C), 128.2 (CH), 130.9 (C), 131.8
(CH x2), 133.7 (C), 153.57 (C), 153.63 (C), 163.8 (C), 193.8
(C=O); MS (FAB) m/z (relative intensity, %) 461 ([M+H]+, 17),
429 (50), 403 (100), 353 (26), 329 (26); HRMS (FAB) Calcd. for
C25H36O6Si 460.2281, found 460.2292.
1
1105, 1069 cm-1; H NMR (400 MHz, CDCl3) d 2.66 (s, 3H,
-COCH3), 3.17 (s, 3H, -OCH3), 7.29~7.33 (m, 5H), 7.42~7.48 (m,
4H), 7.79~7.81 (m, 2H), 7.90 (d, J = 8.8 Hz, 1H); 13C NMR (100
MHz, CDCl3) d 31.1 (CH3), 63.1 (CH3), 108.9 (CH), 121.4 (C),
127.8 (CH x2), 128.1 (CH x2), 128.2 (C), 128.4 (CH), 128.8 (C),
129.7 (CH x2), 130.0 (CH), 130.4 (CH x2), 130.6 (C), 132.9
(CH), 136.8 (C), 147.9 (C), 156.9 (C), 157.9 (C), 185.4 (C=O),
198.9 (C=O); MS (EI) m/z (relative intensity, %) 370 (M+, 28),
292 (38), 105 (73), 77 (100); HRMS (EI) Calcd. for C24H18O4
(M+) 370.1205, found 370.1208.
1-[2-Benzoyl-4-methoxy-3-(4-methoxyphenyl)-1-benzo-
furan-5-yl]ethanone (17)
8-Benzoyl-4-methyl-9-phenyl-2H-furo[2,3-h]chromen-
2-one (3)
Similar procedure as for the synthesis of 11 was applied to
synthesize 17 with an overall yield of 67%. mp 121.2~122.4 oC;
IR (neat) n 3064, 2997, 2934, 2829, 1670, 1653, 1598, 1581,
1448, 1357, 1279, 1175, 1068 cm-1; 1H NMR (400 MHz, CDCl3)
d 2.67 (s, 3H, -COCH3), 3.22 (s, 3H, -OCH3), 3.80 (s, 3H,
-OCH3), 6.83~6.86 (m, 2H), 7.31~7.35 (m, 2H), 7.40~7.49 (m,
4H), 7.79~7.81 (m, 2H), 7.89 (d, J = 8.8 Hz, 1H); 13C NMR (100
MHz, CDCl3) d 31.1 (CH3), 55.2 (CH3), 63.1 (CH3), 108.9 (CH),
113.2 (CH x2), 121.4 (C), 122.6 (C), 128.08 (C), 128.11 (CH x2),
128.7 (C), 129.7 (CH x2), 130.0 (CH), 131.8 (CH x2), 132.8
(CH), 136.9 (C), 147.7 (C), 156.9 (C) 158.0 (C), 159.7 (C), 158.5
(C), 198.9 (C=O); MS (EI) m/z (relative intensity, %) 400 (M+,
100), 385 (28), 369 (10), 105 (46), 77 (28); HRMS (EI) Calcd. for
C25H20O5 (M+) 400.1311, found 400.1312.
To a solution of 11 (50 mg, 0.13 mmol) in dry DCM was
added BBr3 (0.7 mL, 1.0 M in DCM) dropwise at 0 oC. After the
addition was completed, the reaction was warmed to rt and stirred
for 5 h. The reaction was quenched by addition of water, and ex-
tracted with DCM. The organic layers were collected, dried over
MgSO4, filtered and concentrated. The residue was diluted with
dry toluene and refluxed with ethyl(triphenylphosphoranyliden)-
acetate (70 mg, 0.20 mmol) for 24 h. The solvent was then re-
moved, and the residue purified by column chromatography on
silica gel, (EtOAc/Hexane : 1/4) to furnish 36 mg (70%) of 3, as
pale yellow solid. The reaction could be carried out at a scale of 5
o
gram of SM with same yield. mp 206.4~208.1 C; IR (neat) n
3063, 3029, 1731, 1651, 1601, 1553, 1493, 1472, 1446, 1356,
1260, 1241, 1174, 1080 cm-1; 1H NMR (400 MHz, CDCl3) d 2.48
(s, 3H, -CH3), 6.23 (s, 1H), 7.25~7.30 (m, 5H), 7.40~7.46 (m,
3H), 7.55 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.74~7.76
(m, 2H); 13C NMR (100 MHz, CDCl3) d 19.5 (CH3), 108.9 (CH),
113.5 (CH), 115.3 (C), 116.2 (C), 124.2 (CH), 127.7 (CH x2),
128.0 (CH x2), 128.6 (C), 128.7 (CH), 129.55 (C), 129.60 (CH
x2), 130.6 (CH x2), 132.8 (CH), 136.5 (C), 148.0 (C), 149.9 (C),
152.8 (C), 156.4 (C), 159.4 (C), 185.4 (C=O); MS (EI) m/z (rela-
tive intensity, %) 380 (M+, 33), 351 (6), 86 (100), 77 (9), 51 (22);
HRMS (EI) Calcd. for C25H16O4 (M+) 380.1049, found
380.1048.
8-Benzoyl-9-(4-hydroxyphenyl)-4-methyl-2H-furo[2,3-
h]chromen-2-one (19a)
Similar procedure as for the synthesis of 3 was applied to
synthesize 19a with an overall yield of 57%. mp 247.3~248.8 oC;
IR (neat) n 3350 (br), 2957, 2925, 2853, 1731, 1708, 1647, 1601,
1552, 1509, 1472, 1447, 1357, 1269, 1172, 1081 cm-1; 1H NMR
(300 MHz, d6-DMSO) d 2.49 (s, 3H, -CH3), 6.36 (s, 1H), 6.51 (d,
J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.35~7.40 (m, 2H),
7.51~7.56 (m, 1H), 7.69~7.72 (m, 2H), 7.76 (d, J = 9.3 Hz, 1H),
7.93 (d, J = 9.3 Hz, 1H); 13C NMR (75 MHz, d6-DMSO) d 19.0
(CH3), 108.9 (CH), 112.7 (CH), 114.4 (CH x2), 115.1 (C), 115.5
6
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© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2012, 59, 000-000

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis of Bioactive Angelicin Analogs
212, 927. (c) Altamirano-Dimas, M.; Hudson, J. B.; Towers,
G. H. N. Photochem. Photobio. 1986, 44, 187.
(C), 119.8 (C), 125.3 (CH), 128.1 (C), 128.2 (CH x2), 129.3 (CH
x2), 132.1 (CH x2), 132.9 (CH), 136.6 (C), 147.1 (C), 149.4 (C),
154.0 (C), 155.9 (C), 157.6 (C), 158.9 (C), 185.1 (C=O); MS (EI)
m/z (relative intensity, %) 396 (M+, 16), 105 (5), 79 (25), 78 (100),
63 (82); HRMS (EI) Calcd. for C25H16O5 (M+) 396.0998, found
396.0998.
2. (a) Marumoto, S.; Oda, Y.; Miyazawa, M. Environ. Mol.
Mutagen. 2011, 52, 646. (b) El-Ansary, S. L.; Mikhail, A. N.;
Taliawi, G. M. El; Farag, N. A. H. Bull. Fac. Pharm. (Cairo
Univ.) 1998, 36, 73.
3. (a) Isoldi, M. C.; Scarparo, A. C.; Schumacher, R. I.;
Castrucci, A. M. Pigm. Cell Res. 1999, 12, 367. (b) Gawron,
A.; Kruk, I. Pol. J. Pharmacol. Pharm. 1992, 44, 51. (c)
Veronese, F. M.; Schiavon, O.; Bevilacqua, R.; Bordin, F.;
Rodighiero, G. Photochem. Photobio. 1981, 34, 351.
4. Bethea, D.; Fullmer, B.; Syed, S.; Seltzer, G.; Tiano, J.;
Rischko, C.; Gillespie, L.; Brown, D.; Gasparro, F. P. J.
Dermatol. Sci. 1999, 19, 78.
8-Benzoyl-9-(4-methoxyphenyl)-4-methyl-2H-furo[2,3-
h]chromen-2-one (19b)
To a solution of 19a (40 mg, 0.1 mmol) in acetone (10 mL)
was added K2CO3 (28 mg, 0.2 mmol) and MeI (28 mg, 0.2 mmol)
and the mixture was refluxed for 12 h. The reaction was concen-
trated and the residue was purified by column chromatography on
silica gel, (EtOAc/Hexane : 1/1) to furnish 31 mg (75%) of 19a, as
white solid. mp 114.3~115.9 oC; IR (neat) n 3058, 2927, 2834,
1730, 1652, 1602 cm-1; 1H NMR (400 MHz, CDCl3) d 2.48 (d, J =
1.2 Hz, 3H, -CH3), 3.78 (s, 3H, -OCH3), 6.24 (q, J = 1.2 Hz, 1H),
6.80~6.84 (m, 2H), 7.26~7.30 (m, 2H), 7.34~7.46 (m, 3H), 7.54
(d, J = 8.8 Hz, 1H), 7.69~7.75 (m, 3H); 13C NMR (100 MHz,
CDCl3) d 19.6 (CH3), 55.2 (CH3), 109.0 (CH), 113.3 (CH x2),
113.5 (CH), 115.3 (C), 116.4 (C), 121.6 (C), 124.1 (CH), 128.1
(CH x2), 128.7 (C), 129.7 (CH x2), 132.1 (CH x2), 132.8 (CH),
136.7 (C), 148.0 (C), 150.1 (C), 152.9 (C), 156.5 (C), 159.6 (C),
160.0 (C), 185.6 (C=O); MS (EI) m/z (relative intensity, %) 410
(M+, 62), 152 (11), 105 (78), 77 (100), 57 (43), 55 (36); HRMS
(EI) Calcd. for C26H18O5 (M+) 410.1154, found 410.1153.
5. (a) Hsieh, H.-P.; Chang, J.-Y.; Kuo, C.-C.; Chao, Y.-S. PCT
WO 2009152210, 2009. (b) Hsieh, H.-P.; Hsu, J. T.-A.; Yeh,
J.-Y.; Horng, J.-T.; Shih, S.-R.; Chang, S.-Y.; Chao, Y.-S. US
Patent 20090312406, 2009.
6. (a) Yeh, J.-Y.; Coumar, M. S.; Horng, J.-T.; Shiao, H.-Y.;
Kuo, F.-M.; Lee, H.-L.; Chen, I.-C.; Chang, C.-W.; Tang,
W.-F.; Tseng, S.-N.; Chen, C.-J.; Shih, S.-R.; Hsu, J. T.-A.;
Liao, C.-C.; Chao, Y.-S.; Hsieh, H.-P. J. Med. Chem. 2010,
53, 1519. (b) Shih, S.-R.; Horng, J.-T.; Poon, L. L.-M.; Chen,
T.-C.; Yeh, J.-Y.; Hsieh, H.-P.; Tseng, S.-N.; Chiang, C.; Li,
W.-L.; Chao, Y.-S. J. Antimicrob. Chemother. 2010, 65, 63.
7. Lin, P.-Y.; Ke, Y.-Y.; Su, C.-T.; Shiao, H.-Y.; Hsieh, H.-P.;
Chao, Y.-K.; Lee, C.-N.; Kao, C.-L.; Chao, Y.-S.; Chan,
S.-Y. J. Virol. 2011, 85, 9114.
8. Geetanjali, Y.; Rajitha, B.; Rao, M. K.; Indian J. Chem., Sect.
B: Org. Chem. Incl. Med. Chem. 1983, 22B, 164.
ACKNOWLEDGMENTS
9. (a) Paul, S.; Gupta, M. Synthesis 2004, 1789. (b) Commarieu,
A.; Hoelderich, W.; Laffitte, J. A.; Dupont, M.-P. J. Mol.
Catal. A: Chem. 2002, 137, 182. (c) Traven, V. F. Molecules
2004, 9, 50.
The authors acknowledge the financial support by
National Health Research Institutes, National Tsing Hua
University and National Science Council, Taiwan (Grant
No. NSC-99-2113-M-400-002-MY3 for HYS, NSC-98-
2119-M-400-001-MY3 for HPH).
10. Traven, V. F.; Podhaluzina, N. Y.; Vasilyev, A. V.; Manaev,
A. V. ARKIVOC 2000, (vi), 931.
Supporting Information
Scans of 1H and 13C NMR spectra of all compounds
11. Pocci, M.; Bertini, V.; Lucchesini, F.; De Munno, A.; Picci,
N.; Iemma, F.; Alfei, S. Tetrahedron Lett. 2001, 42, 1351.
12. Michellys, P.; Boehm, M. F.; Chen, J.-H.; Grese, T. A.;
Karanewsky, D. S.; Leibowitz, M. D.; Liu, S.; Mais, D. A.;
Mapes, C. M.; Reifel-Miller, A.; Ogilvie, K. M.; Rungta, D.;
Thompson, A. W.; Tyhonas, J. S.; Yumibe, N.; Ardecky, R. J.
Bioorg. Med. Chem. Lett. 2003, 13, 4071.
are available.
REFERENCES
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J. Chin. Chem. Soc. 2012, 59, 000-000
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