Design and synthesis of novel anti-hyperalgesic agents based on 6-prenylnaringenin as the T-type calcium channel blockers

Article abstract of DOI:10.1016/j.bmc.2018.07.023

Since 6-prenylnaringenin (6-PNG) was recently identified as a novel T-type calcium channel blocker with the IC₅₀ value around 1 μM, a series of flavanone derivatives were designed, synthesized and subsequently evaluated for T-channel-blocking a

Full text of DOI:10.1016/j.bmc.2018.07.023

Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design and synthesis of novel anti-hyperalgesic agents based on 6-
prenylnaringenin as the T-type calcium channel blockers
Huy Du Nguyena, Takuya Okadaa, Shun Kitamurab, Sakura Yamaokac, Yamato Horaguchic,
Yoshihito Kasanamic, Fumiko Sekiguchic, Maho Tsubotac, Shigeru Yoshidad,
⁎
Hiroyuki Nishikawac, Atsufumi Kawabatac,⁎, Naoki Toyookaa,e,
a
Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan
Faculty of Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
Faculty of Pharmacy, Kindai University, Higashi-Osaka 577-8502, Japan
Faculty of Science and Engineering, Kindai University, Higashi-Osaka 577-8502, Japan
b
c
d
e
Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan
A R T I C L E I N F O
A B S T R A C T
Keywords:
Since 6-prenylnaringenin (6-PNG) was recently identified as a novel T-type calcium channel blocker with the
IC50 value around 1 µM, a series of flavanone derivatives were designed, synthesized and subsequently evaluated
for T-channel-blocking activity in HEK293 cells transfected with Cav3.2 T-type channels using a patch-clamp
technique. As a result, several new flavanones blocked Cav3.2-dependent T-currents more potently than 6-PNG.
In the synthesized compounds, 6-(3-ethylpent-2-enyl)-5,7-dihydroxy-2-(2-hydroxyphenyl)chroman-4-one 8j, 6-
(3-ethylpent-2-enyl)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one 11b, 6-(2-cyclopentylideneethyl)-5,7-
dihydroxy-2-(4-hydroxyphenyl)chroman-4-one 11d, and 6-(2-Cyclopentylethyl)-5,7-dihydroxy-2-(4-hydro-
xyphenyl)chroman-4-one 12c were more potent blocker than 6-PNG with the IC50 value of 0.39, 0.26, 0.46, and
0.50 µM, respectively. Among the above four derivatives, the compound 8j provided the best result in the in vivo
experiments; i.e. systemic administration of 8j at the minimum dose completely restored neuropathic pain in-
duced by partial sciatic nerve ligation in mice.
6-Prenylnaringenin
T-type calcium channel blocker
Flavanone derivative
Neuropathic pain
Mechanical allodynia
1. Introduction
(IC50 = 1 µM)7 and a series of 3,4-dihydroquinazoline analogues were
shown to block T-channels more potently than mibefradil.8–11 It is also
Low voltage-activated or transient (T)-type calcium channels (T-
channels) consist of three subtypes: Cav3.1, Cav3.2 and Cav3.3 chan-
nels, which have unique electrophysiological and pharmacological
profiles distinct from high voltage-activated calcium channels.1,2 These
channels are abundantly expressed in the brain and the primary affer-
ents, and implicated in regulation of neuronal excitation and neuro-
transmitter release.3 Currently, T-channel-blocking compounds are
considered useful as antiepileptics, anti-hyperalgesics and possibly an-
tipsychotics. For example, T-channel blocker ethosuximide
(IC50 = 600 µM) is clinically used as an antiepileptic drug,4 and the
analgesic or anti-hyperalgesic property of several T-channel blockers
including ethosuximide have been demonstrated by preclinical stu-
dies.5,6 A growing number of studies thus suggest the necessity of the
discovery of more effective T-channel blockers. McCalmont et al. for-
mulated T-channel blockers with the potency comparable to mibefradil
to be noted that T-channel blockers might be useful not only for pain
therapies, but also to treat certain types of cancer.12,13 However, the
potential adverse effects of T-channel blockers such as sedation and
cardiovascular dysfunction have to be taken into consideration; a well-
known case for this matter is the drug interactions of mibefradil,
leading to irregular heart rhythm.14
In 2016, we reported that the prenylflavanones (PFVNs) including
sophoraflavanone G, 6-prenylnaringenin (6-PNG) and 8-pre-
nylnaringenin (8-PNG) blocked T-channels with the IC50 values around
1 µM, while these PFVNs had little inhibitory effect on L-type calcium
channels.15 This evidence supports the previous reports showing the
medical usefulness of PFVNs, which possess extensive biological ac-
tivities, such as anti-oxidant, anti-cancer, immunomodulatory and es-
trogenic activity.16,17 In addition, these PFVNs were structurally far
different from known T-channel blockers, except valproic acid and
⁎
Corresponding authors at: Faculty of Pharmacy, Kindai University, Higashi-Osaka 577-8502, Japan (A. Kawabata); Graduate School of Innovative Life Science,
University of Toyama, Toyama 930-8555, Japan (N. Toyooka).
E-mail address: toyooka@eng.u-toyama.ac.jp (N. Toyooka).
https://doi.org/10.1016/j.bmc.2018.07.023
Received 18 June 2018; Received in revised form 11 July 2018; Accepted 12 July 2018
0968-0896/©2018ElsevierLtd.Allrightsreserved.
Pleasecitethisarticleas:Nguyen,H.D.,Bioorganic&MedicinalChemistry(2018),https://doi.org/10.1016/j.bmc.2018.07.023

H. Du Nguyen et al.
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Finally, deprotection of acetyl group on 10a–d provided 11a–d, and
hydrogenation of the resulting olefins 11a, 11b and 11d furnished the
saturated derivatives 12a–c (Scheme 2).
arundic acid. Several recent studies18,19 attempted to discover the se-
lective and potent inhibitors of T-channels for pain therapies, whereas
they are not necessarily successful because of serious side effects.13
Therefore, it is a new and unique approach to develop novel T-channel-
blocking PFVNs useful as analgesic or anti-hyperalgesic drugs with
minimum side effects.
2.2. In vitro biological evaluations
The effects of synthesized compounds on Ba2+ currents (T-currents)
in human Cav3.2-HEK293 cells were evaluated using a whole cell patch
clamp technique, and summarized in Table 1. On the deoxy-derivatives
on the 7-position, allyl-derivatives 4d–f showed good blockade than
prenyl-derivatives 7e–g. In the case of 7-hydroxy derivatives, effects of
the blockade of allyl- (5g and 5n–o) and prenyl-derivatives (8h and
8p–q) were almost the same. However, derivatives with higher po-
larity, which have several hydroxyl groups on the phenyl ring on the
flavanone, prenyl-derivatives (8i and 8k–o) showed more potent
blocking activity than allyl-derivatives 5h–m. Overall, the prenyl-de-
rivatives were superior to the allyl-derivatives. In the case of the deri-
vatives having larger substituent on the 6-position (8d and 8j), deri-
vative 8j was much better blocker than the corresponding prenyl-
derivative 8i and allyl-derivative 5h. On the comparison of 8j and its
deoxy-derivative 8d, derivative 8j revealed much better effect than 8d.
According to these results, we anticipated that the structural element
for potent blockers was slightly large substituent on the 6-position and
presence of hydroxyl group on the 7-position. In addition, the deriva-
tives having slightly large substituent on the 6-position 11b, 11d and its
saturated derivatives 12a, 12c also showed good blocking effects.
PFVNs usually exhibit the bio-activities better than their flavanone
skeletons. This phenomenon may be explained as follows: PFVNs are
usually more lipophilic than their flavanone skeletons, which results in
a higher affinity to biological membranes and a better interaction with
target proteins.20 Moreover, each T-channel contains an interactive
pore for the selective passage of Ca2+ ions and a voltage sensor for
controlling pore gating, so the T-channel blocking actions of PFVNs
probably relate to their hydroxyl groups. These initial assumptions re-
vealed that the relationship between the chemical structure of PFVNs
and their channel-blocking actions may be rather complicated. There-
fore, a series of the screening PFVNs should be synthesized and sub-
sequently evaluated for their blocking effects on the Cav3.2 channels
transfected into HEK293 cells to search out a lead compound. These
screening PFVNs were designed as follows: the allyl-substituent at the
6-position of PFVNs was varied according to the length of carbon chain
and the degree of saturation, and the hydroxyl groups of PFVNs were
altered in the quantity and position or replaced with less polar func-
tional groups, such as chloro, methoxyl or ethoxyl group, as shown in
Fig. 1. This is a new requirement for the synthesis of designed deriva-
tives, so several reaction sequences of previous studies will be applied
or cleverly combined in order to suggest appropriate synthetic routes
for the designed derivatives.
2.3. In vivo biological evaluations
According to these results, we selected 8 compounds (8c, 8i, 8j, 8k,
11b, 11d, and 12a, 12c) and conducted further evaluations for their
IC50 values, and the results were summarized in Table 2. In the syn-
thesized compounds, 12c, 11d, 8j, and 11b were more potent as T-
channel blockers than 6-PNG, the IC50 value of which was 0.50 µM,
0.46 µM, 0.39 µM, and 0.26 µM, respectively. In the in vivo evaluations,
as shown in Figs. 2–6, the compound 8j, among the above four deri-
vatives, most potently suppressed the mechanical allodynia induced by
partial sciatic nerve ligation (PSNL) in mice, an animal model of neu-
ropathic pain. It was particularly of interest that 8j produced remark-
able and significant anti-allodynic effect at a small dose, 10 mg/kg, at
which 6-PNG had no effect, and that 8j at 20 mg/kg achieved almost
complete inhibition of the PSNL-induced neuropathy, as depicted in
Figs. 2 and 3.
2. Results and discussions
2.1. Synthesis
According to our initial results, 6-PNG was able to inhibit the Cav3.2
channel transfected into HEK-293 cells, while the naringenin was in-
active, so the prenyl group at the 6-position may play an important role
in the blocking actions of 6-PNG. To explore the importance of sub-
stituent on the 6-position or the phenyl ring of flavanone nuclei (Fig. 1),
we started the flexible synthesis of these derivatives including the 7-
deoxy ones as shown in Scheme 1. The compounds 1a21 and 1b22 were
converted to the corresponding chalcones 2a–o,23 which were trans-
formed into the flavanones 3a–o.24 The Claisen rearrangement of 3a-o
provided the 6-allyl derivatives 4a–o.25 The 6-allyl derivatives of 4c
and 4g–n were converted to the corresponding acetate 6c and 6g–n via
the corresponding phenol 5c and 5g–o. The cross-metathesis reaction of
4a–b, 5c, 4d–f and 5g–o with appropriate olefin using Grubbs catalyst
2nd generation afforded the corresponding olefins 7a–q. Finally, de-
protection of acetyl group on 7c–d and 7h–q furnished 8c–d and 8h–q.
For more simple synthesis of the derivatives having the 4′-hydro-
xyphenyl ring on the flavanone, we selected the commercially available
naringenin as the starting material. The synthesis began with the known
di-acetate 9, prepared from naringenin in 3 steps,25 which was con-
verted to the corresponding olefins 10a–d by the cross-metathesis re-
action with appropriate olefin using Grubbs catalyst 2nd generation.
3. Conclusion
In summary, a series of 6-PNG derivatives were synthesized. The
synthetic modifications were mainly explored on the prenyl group at the
6-position of 6-PNG. Among the synthesized derivatives, four compounds
having
a
modified prenyl group (8j, IC50 = 0.39 μM, 11b,
IC50 = 0.26 μM, and 11d, IC50 = 0.46 μM,) or saturated side chain (12c,
IC50 = 0.50 μM) showed more potent blockade activity against human
Cav3.2-HEK293 cells than 6-PNG (IC50 = ∼1 μM). In addition, selected
all four compounds suppressed the mechanical allodynia induced by
Fig. 1. The designation of screening derivatives.
2

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Scheme 1. Reagents and conditions: a: AllylBr, K2CO3, acetone, 50 °C for 2g–o; b: Ba(OH)2, EtOH, H2O, 40 °C; c: NaOAc, EtOH, H2O, reflux; d: Eu(fod)3, ClCH2CH2Cl,
100 °C, sealed tube; e: conc. HCl, MeOH, rt; f: Ac2O, pyridine, rt; g: (Me)2C = CH2 or (Et)2C = CH2, Grubbs catalyst, 2nd Generation, benzene, 100 °C, sealed tube; h:
K2CO3, MeOH, rt.
Scheme 2. Reagents and conditions: a: (Me)2C = CH2 or (Et)2C = CH2 or (n-Pr)2C = CH2, Grubbs catalyst, 2nd Generation, benzene, 100 °C, sealed tube; b: K2CO3,
MeOH, rt; c: H2, Pd/C, EtOAc, rt.
partial sciatic nerve ligation (PSNL) in mice, an animal model of neu-
ropathic pain (Figs. 2–6). Especially, the 6-ethylpent-2-enyl instead of
prenyl and 2-hydroxyphenyl instead of 4-hydroxyphenyl derivative, 8j,
showed remarkable and significant anti-allodynic effect at 10 mg/kg,
which was a subeffective dose of 6-PNG, and achieved almost complete
inhibition of the PSNL-induced neuropathy at 20 mg/kg.
3

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Table 1
T-current suppression by the synthesized derivatives in human Cav3.2-HEK293 cells.
Compound
T-current at 3 μM
(% control)
Compound
T-current at 3 μM
(% control)
Compound
T-current at 3 μM
(% control)
6-PNG
4a
4b
5c
4d
4e
4f
5g
5h
5i
12.78
90.13
72.69
31.96
58.96
65.19
35.93
70.13
62.99
76.85
83.85
–
1.74
5m
5n
5o
7a
7b
8c
8d
7e
7f
74.83
50.76
51.93
100.17
102.99
3.77
16.11
81.93
57.84
78.45
72.64
2.04
14.73
9.35
7.57
15.09
13.58
2.71
7.59
17.55
8.63
15.83
9.52
1.15
0.17
8k
8l
8m
8n
8o
2.09
0.54
12.61
13.62
10.84
8.22
4.40
11.66
8.89
7.71
12.79
8.95
67.12
10.26
14.67
80.90
47.63
59.71
22.23
36.75
1.44
4.71
4.73
8.16
7.62
5.94
7.76
3.21
0.28
0.50
3.09
2.31
8p
8q
11b
11c
11d
12a
12b
12c
7g
8h
8i
5j
5k
5l
16.87
1.69
10.09
5.42
86.67
13.57
8j
0.33
T-currents were determined at 1 μM.
QP 500 mass spectrometer (Shimadzu Corp., Kyoto, Japan), JEOL D-
200, or JEOL AX505 mass spectrometer (JEOL Ltd., Tokyo, Japan) in
the electron impact mode at the ionization potential of 70 eV.
Table 2
IC50 values of the selected 8 compounds T-current inhibition.
Compound
IC50 (μM)
Compound
IC50 (μM)
6-PNG
8c
8i
8j
8k
1.00
1.25
0.64
0.39
1.02
11b
11d
12a
12c
0.26
0.46
0.48
0.50
4.1.2. General procedure of allylation for 2g–o and Claisen-Schmidt
condensation for 2a–o
To a stirred solution of 1b (860 mg, 4.05 mmol) in acetone (12 mL)
were added K2CO3 (300 mg, 2.43 mmol) and AllylBr (0.38 mL,
4.46 mmol), and the reaction mixture was stirred for 24 h at 50 °C. After
cooling, K2CO3 was removed through a Celite pad and washed with
acetone (3 mL × 3). The organic layer and washings were combined
and evaporated to give a yellow oil, which was used directly in the next
step.
4. Experimental
4.1. Chemistry
To a stirred solution of acetophenone 1 (1.19 mmol) in EtOH
(15 mL) and H2O (3 mL) were added appropriate benzaldehyde
(3.57 mmol) and Ba(OH)2·8H2O (4.28 mmol), and the reaction mixture
was stirred for 20 h at 40 °C. After cooling, EtOH was evaporated and
the aqueous mixture was extracted with CH2Cl2 (3 mL × 5). The or-
ganic extracts were combined, dried and evaporated to give an orange
oil, which was chromatographed on SiO2 (10 g, EtOAc/n-hexane = 1/
10) to give 2a–o.
4.1.1. General information
Chemicals were purchased from Sigma-Aldrich, Merck, Nakalai
Tesque, Wako Pure Chemicals, Tokyo Chemical Industry (TCI), and
Kanto Chemicals, and used without further purification. Column chro-
matography was done on Cica silica gel 60N (spherical, neutral; particle
size, 63–210 nm, Kanto Chemical Co., Inc., Tokyo, Japan), while thin-
layer chromatography (TLC) was performed on Merck silica gel 60F254
plates (Merck KGaA, Darmstadt, Germany). Melting points were taken
on a Yanaco micromelting point apparatus and are uncorrected. The
nuclear magnetic resonance (NMR) spectra were acquired in the spe-
cified solvent, in a JEOL JNM-A400 (400 and 100 MHz for 1H and 13C,
respectively) or JEOL JNM-ECX500 (500 and 125 MHz for 1H and 13C,
respectively). The chemical shifts (δ) are reported in ppm downfield
from TMS and coupling constants (J) are expressed in Hertz. IR spectra
were measured with a JASCO FT/IR-460 Plus spectrophotometer
(JASCO Corp.). The low-resolution mass spectra (MS) and high-re-
solution mass spectra (HRMS) were obtained with a Shimadzu GCMS-
4.1.2.1. 1-(2-Allyloxy-6-hydroxyphenyl)-3-phenylpropenone (2a). Yield:
87%; 1H NMR (400 MHz CDCl3) δ: 4.65 (2H, dt, J = 5.6, 1.2 Hz),
5.33 (1H, dd, J = 10.4, 1.2 Hz), 5.48 (1H, dd, J = 17.2, 1.2 Hz), 6.12
(1H, ddt, J = 17.2, 10.4, 5.6 Hz), 6.43 (1H, d, J = 8.6 Hz), 6.63 (1H, d,
J = 8.6 Hz), 7.35 (1H, t, J = 8.6 Hz), 7.39–7.42 (3H, m), 7.58–7.62
(2H, m), 7.81 (1H, d, J = 15.6 Hz), 7.95 (1H, d, J = 15.6 Hz), 13.10
(1H, s); 13C NMR (100 MHz CDCl3) δ: 69.76, 102.57, 111.05, 112.21,
118.72, 127.71, 128.53, 128.84, 130.28, 132.30, 135.20, 135.85,
142.80, 159.90, 164.76, 194.50; IR (KBr): 1632, 1609, 1583, 1560,
Fig. 2. 6-Prenylnaringenin (6-PNG) at 10–30 mg/kg
or vehicle (V; 0.5% carboxymethyl cellulose) was
administered i.p. to mice 7 days after partial sciatic
nerve ligation (PSNL). Nociceptive threshold in the
ipsilateral hindpaw was assessed by the von Frey
test. Data show the mean with S.E.M. for 5–11 mice.
**P < 0.01 vs. vehicle in sham. †P < 0.05,
††P < 0.01 vs. vehicle in PSNL.
0.8
0.7
Vehicle in sham
in PSNL
Vehicle
0.6
0.5
0.4
0.3
0.2
0.1
6-PNG 10 mg/kg
6-PNG 20 mg/kg
6-PNG 30 mg/kg
**
90
**
75
**
**
**
**
60
**
45
0
Before
0
15
30
PSNL
Time (min) after i.p. 6-PNG injection
4

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Fig. 3. 8j at 10 or 20 mg/kg or vehicle (V; 0.5%
carboxymethyl cellulose) was administered i.p. to
mice 7 days after partial sciatic nerve ligation
(PSNL). Nociceptive threshold in the ipsilateral
hindpaw was assessed by the von Frey test. Data
show the mean with S.E.M. for 5–6 mice.
**P < 0.01 vs. vehicle in sham. †P < 0.05,
††P < 0.01 vs. vehicle in PSNL.
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Vehicle in sham
in PSNL
Vehicle
8j 10 mg/kg
8j 20 mg/kg
**
45
**
90
**
0
**
75
**
15
**
30
**
60
0
Before
PSNL
Time (min) after i.p. 8j injection
1468, 1448, 1421, 1360, 1231, 1204, 1078, 984, 939, 874, 796,
735 cm−1; mp: 76–78 °C; MS (EI): m/z 280 (M+); HRMS (EI) Calcd
for C18H16O3 280.1099 (M+); Found 280.1112.
m/z 340 (M+); HRMS (EI) Calcd for C20H20O5 340.1311 (M+); Found
340.1311.
4.1.2.4. 1-(2-Allyloxy-6-hydroxyphenyl)-3-(4-methoxyphenyl)-propenone
(2d). Yield: 69%; 1H NMR (400 MHz CDCl3) δ: 3.85 (3H, s), 4.64 (2H,
dt, J = 5.0, 1.2 Hz), 5.33 (1H, dd, J = 10.4, 1.2 Hz), 5.48 (1H, dd,
J = 17.2, 1.2 Hz), 6.12 (1H, ddt, J = 17.2, 10.4, 5.0 Hz), 6.42 (1H, d,
J = 8.0 Hz), 6.62 (1H, d, J = 8.0 Hz), 6.92 (2H, dt, J = 8.6, 2.4 Hz),
7.33 (1H, t, J = 8.0 Hz), 7.56 (2H, dt, J = 8.6, 2.4 Hz), 7.82 (2H, d,
J = 5.4 Hz), 13.17 (1H, s); 13C NMR (100 MHz CDCl3) δ: 55.38, 69.71,
102.57, 111.04, 112.30, 114.32, 118.56, 125.36, 127.97, 130.32,
132.38, 135.54, 142.95, 159.82, 161.52, 164.70, 194.35; IR (KBr):
1632, 1607, 1578, 1560, 1512, 1473, 1466, 1458, 1447, 1421, 1362,
1261, 1232, 1171, 1074, 1028, 831 cm−1; mp: 68–70 °C; MS (EI): m/z
310 (M+); HRMS (EI) Calcd for C19H18O4 310.1205 (M+); Found
310.1195.
4.1.2.2. 1-(2-Allyloxy-6-hydroxyphenyl)-3-p-tolylpropenone (2b). Yield:
81%; 1H NMR (400 MHz CDCl3) δ: 2.39 (3H, s), 4.65 (2H, d,
J = 5.6 Hz), 5.34 (1H, dd, J = 10.4, 1.2 Hz), 5.48 (1H, dd, J = 17.2,
1.2 Hz), 6.12 (1H, ddt, J = 17.2, 10.4, 5.6 Hz), 6.42 (1H, d, J = 8.4 Hz),
6.62 (1H, d, J = 8.4 Hz), 7.21 (2H, d, J = 8.0 Hz), 7.34 (1H, t,
J = 8.4 Hz), 7.51 (2H, d, J = 8.0 Hz), 7.81 (1H, d, J = 15.4 Hz), 7.95
(1H, d, J = 15.4 Hz), 13.10 (1H, s); 13C NMR (100 MHz CDCl3) δ:
21.48, 69.70, 102.52, 110.98, 112.20, 118.62, 126.65, 128.55, 129.57,
132.30, 132.43, 135.68, 140.80, 142.99, 159.84, 164.71, 194.48; IR
(KBr): 1634, 1607, 1583, 1560, 1510, 1474, 1466, 1446, 1423, 1360,
1329, 1240, 1230, 1205, 1180, 1171, 1076, 1033, 983, 932, 876, 815,
746 cm−1; mp: 75–77 °C; MS (EI): m/z 294 (M+); HRMS (EI) Calcd for
C
19H18O3 294.1256 (M+); Found 294.1250.
4.1.2.5. 1-(2-Allyloxy-6-hydroxyphenyl)-3-(4-ethoxyphenyl)-propenone (2e).
Yield: 51%; 1H NMR (400 MHz CDCl3) δ: 1.44 (3H, t, J = 7.0 Hz), 4.08 (2H,
q, J = 7.0 Hz), 4.64 (2H, d, J = 5.6 Hz), 5.33 (1H, d, J = 10.4 Hz), 5.48
(1H, d, J = 17.2 Hz), 6.12 (1H, ddt, J = 17.2, 10.4, 5.6 Hz), 6.41 (1H, d,
J = 8.0 Hz), 6.62 (1H, d, J = 8.0 Hz), 6.90 (2H, d, J = 8.4 Hz), 7.33 (1H, t,
J = 8.0 Hz), 7.55 (2H, d, J = 8.4 Hz), 7.82 (2H, d, J = 4.8 Hz), 13.17 (1H,
s); 13C NMR (100 MHz CDCl3) δ: 14.72, 63.61, 69.71, 102.58, 111.03,
112.31, 114.79, 118.54, 125.22, 127.78, 130.34, 132.39, 135.51, 143.06,
159.81, 160.96, 164.69, 194.36; IR (KBr): 1622, 1607, 1578, 1545, 1512,
1474, 1458, 1423, 1362, 1258, 1236, 1198, 1177, 1076, 1032 cm−1; mp:
76–78 °C; MS (EI): m/z 324 (M+); HRMS (EI) Calcd for C20H20O4 324.1362
(M+); Found 324.1358.
4.1.2.3. 1-(2-Allyloxy-6-hydroxyphenyl)-3-(2-methoxymethoxy-phenyl)propenone
(2c). Yield: 56%; 1H NMR (400 MHz CDCl3) δ: 3.51 (3H, s), 4.66 (2H, dt,
J = 6.8, 2.0 Hz), 5.28 (2H, s), 5.32 (1H, dd, J = 11.2, 2.0 Hz), 5.46 (1H, dd,
J = 17.2, 2.0 Hz), 6.12 (1H, ddt, J = 17.2, 11.2, 6.8 Hz), 6.42 (1H, d,
J = 8.0 Hz), 6.62 (1H, d, J = 8.0 Hz), 7.02 (1H, t, J = 8.0 Hz), 7.18 (1H, d,
J = 8.0 Hz), 7.34 (2H, t, J = 8.0 Hz), 7.65 (1H, dd, J = 8.0, 2.0 Hz), 7.94 (1H,
d, J = 15.6 Hz), 8.26 (1H, d, J = 15.6 Hz), 13.10 (1H, s); 13C NMR (100 MHz
CDCl3) δ: 56.26, 69.71, 94.56, 102.61, 110.97, 111.96, 114.88, 118.51,
121.78, 124.85, 127.73, 127.81, 131.61, 132.36, 135.65, 137.59, 156.38,
159.85, 164.66, 194.70; IR (neat): 1629, 1598, 1577, 1570, 1558, 1485, 1472,
1457, 1448, 1355, 1235, 1200, 1153, 1078, 1028, 990, 754 cm−1; MS (EI):
Fig. 4. 11b at 10–30 mg/kg or vehicle (V; 0.5%
carboxymethyl cellulose) was administered i.p. to
mice 7 days after partial sciatic nerve ligation
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Vehicle in sham
in PSNL
Vehicle
(PSNL). Nociceptive threshold in the ipsilateral
hindpaw was assessed by the von Frey test. Data
show the mean with S.E.M. for 5–6 mice.
**P < 0.01 vs. vehicle in sham. †P < 0.05,
††P < 0.01 vs. vehicle in PSNL.
11b 10 mg/kg
11b 20 mg/kg
11b 30 mg/kg
**
75
**
90
**
**
0
**
30
**
45
**
60
0
Before
15
PSNL
Time (min) after i.p. 11b injection
5

H. Du Nguyen et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
Fig. 5. 11d at 10 or 20 mg/kg or vehicle (V; 0.5%
carboxymethyl cellulose) was administered i.p. to
mice 7 days after partial sciatic nerve ligation
(PSNL). Nociceptive threshold in the ipsilateral
hindpaw was assessed by the von Frey test. Data
show the mean with S.E.M. for 5–7 mice.
**P < 0.01 vs. vehicle in sham. †P < 0.05,
††P < 0.01 vs. vehicle in PSNL.
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Vehicle in sham
in PSNL
Vehicle
11d 10 mg/kg
11d 20 mg/kg
**
15
**
30
**
**
45
**
60
** **
75 90
0
Before
0
PSNL
Time (min) after i.p. 11d injection
4.1.2.6. 1-(2-Allyloxy-6-hydroxyphenyl)-3-(4-chlorophenyl)-propenone
(2f). Yield: 61%; 1H NMR (400 MHz CDCl3) δ: 4.64 (2H, d, J = 5.2 Hz),
5.34 (1H, d, J = 11.0, 1.2 Hz), 5.48 (1H, dd, J = 17.2, 1.2 Hz), 6.12
(1H, ddt, J = 17.2, 11.0, 5.2 Hz), 6.43 (1H, d, J = 8.6 Hz), 6.63 (1H, d,
J = 8.6 Hz), 7.36 (1H, t, J = 8.6 Hz), 7.37 (2H, d, J = 8.6 Hz), 7.53
(2H, d, J = 8.6 Hz), 7.73 (1H, d, J = 16.0 Hz), 7.90 (1H, d,
J = 16.0 Hz), 13.00 (1H, s); 13C NMR (100 MHz CDCl3) δ: 69.74,
102.53, 111.09, 112.11, 118.78, 128.24, 129.12, 129.60, 132.28,
133.71, 136.01, 136.11, 141.14, 159.86, 164.78, 194.24; IR (KBr):
1634, 1607, 1583, 1560, 1491, 1474, 1457, 1445, 1360, 1239, 1231,
1205, 1088, 1076, 1030, 986, 822, 748 cm−1; mp: 68–70 °C; MS (EI):
m/z 314 (M+); HRMS (EI) Calcd for C18H15ClO3 314.0710 (M+); Found
310.0713.
J = 5.2 Hz), 5.20 (2H, s), 5.27 (2H, s), 5.34 (1H, d, J = 10.8 Hz),
5.47 (1H, d, J = 17.2 Hz), 6.07 (1H, d, J = 2.4 Hz), 6.11 (1H, ddt,
J = 17.2, 10.8, 5.2 Hz), 6.27 (1H, d, J = 2.4 Hz), 7.01 (1H, t,
J = 7.6 Hz), 7.18 (1H, d, J = 7.6 Hz), 7.33 (1H, td, J = 7.6, 1.6 Hz),
7.64 (1H, dd, J = 7.6, 1.6 Hz), 7.96 (1H, d, J = 15.6 Hz), 8.23 (1H, d,
J = 15.6 Hz), 14.03 (1H, s); 13C NMR (100 MHz CDCl3) δ: 56.21, 56.37,
69.72, 92.65, 93.97, 94.52, 96.65, 107.22, 114.83, 118.83, 121.74,
125.02, 127.58, 127.69, 131.37, 132.14, 137.02, 156.22, 161.41,
163.41, 167.51, 193.09; IR (KBr): 1622, 1576, 1558, 1343, 1235,
1217, 1204, 1161, 1153, 1104, 1076, 1040, 991, 950, 835 cm−1; mp:
94–96 °C; MS (EI): m/z 400 (M+); HRMS (EI) Calcd for C22H24O7
400.1522 (M+); Found 400.1529.
4.1.2.9. 1-(2-Allyloxy-6-hydroxy-4-methoxymethoxyphenyl)-3-(3-methox
4.1.2.7. 1-(2-Allyloxy-6-hydroxy-4-methoxymethoxyphenyl)-3-phenylpro
penone (2g). Yield: 68% in 2 steps; 1H NMR (400 MHz CDCl3) δ: 3.49
(3H, s), 4.62 (2H, dd, J = 5.2, 1.2 Hz), 5.20 (2H, s), 5.36 (1H, dd,
J = 10.8, 1.2 Hz), 5.48 (1H, dd, J = 15.6, 1.2 Hz), 6.08 (1H, d,
J = 2.0 Hz), 6.12 (1H, ddt, J = 15.6, 10.8, 5.2 Hz), 6.28 (1H, d,
J = 2.0 Hz), 7.35–7.43 (3H, m), 7.54–7.62 (2H, m), 7.78 (1H, d,
J = 15.2 Hz), 7.97 (1H, d, J = 15.2 Hz), 13.10 (1H, s); 13C NMR
(100 MHz CDCl3) δ: 56.42, 69.77, 92.67, 94.01, 96.70, 107.16,
119.04, 127.62, 128.41, 128.78, 130.05, 132.09, 135.38, 142.28,
161.47, 163.57, 167.60, 192.88; IR (KBr): 1632, 1623, 1580, 1564,
1423, 1340, 1223, 1211, 1150, 1105, 1080, 1022, 976, 939, 824,
746 cm−1; mp: 74–76 °C; MS (EI): m/z 340 (M+); HRMS (EI) Calcd for
ymethoxyphenyl)propenone (2i). Yield: 90% in 2
steps; 1H NMR
(400 MHz CDCl3) δ: 3.43 (3H, s), 3.45 (3H, s), 4.56 (2H, d,
J = 5.6 Hz), 5.15 (2H, s), 5.16 (2H, s), 5.30 (1H, d, J = 10.4 Hz),
5.42 (1H, d, J = 17.2 Hz), 6.02 (1H, d, J = 2.4 Hz), 6.10 (1H, ddt,
J = 17.2, 10.4, 5.6 Hz), 6.22 (1H, d, J = 2.4 Hz), 7.07 (1H, d,
J = 8.0 Hz), 7.23 (3H, m), 7.66 (1H, d, J = 15.6 Hz), 7.89 (1H, d,
J = 15.6 Hz), 13.92 (1H, s); 13C NMR (100 MHz CDCl3) δ: 55.98, 56.39,
69.80, 92.61, 93.98, 94.32, 96.65, 107.10, 115.53, 118.06, 119.09,
122.36, 127.91, 129.75, 132.06, 136.82, 142.02, 157.54, 161.45,
163.57, 167.61, 192.77; IR (neat): 1653, 1634, 1623, 1617, 1577,
1569, 1558, 1505, 1343, 1218, 1151, 1082, 1025 cm−1; MS (EI): m/z
400 (M+); HRMS (EI) Calcd for C22H24O7 400.1522 (M+); Found
400.1529.
C
20H20O5 340.1311 (M+); Found 340.1327.
4.1.2.8. 1-(2-Allyloxy-6-hydroxy-4-methoxymethoxyphenyl)-3-(2-methox
ymethoxyphenyl)propenone (2h). Yield: 85% in
steps; 1H NMR
(400 MHz CDCl3) δ: 3.49 (3H, s), 3.51 (3H, s), 4.62 (2H, d,
4.1.2.10. 1-(2-Allyloxy-6-hydroxy-4-methoxymethoxyphenyl)-3-(2,3-bism
ethoxymethoxyphenyl)propenone (2j). Yield: 99% in 2 steps; 1H NMR
(400 MHz CDCl3) δ: 3.49 (3H, s), 3.51 (3H, s), 3.65 (3H, s), 4.61 (2H, d,
2
Fig. 6. 12c at 10 or 20 mg/kg or vehicle (V; 0.5%
carboxymethyl cellulose) was administered i.p. to
mice 7 days after partial sciatic nerve ligation
(PSNL). Nociceptive threshold in the ipsilateral
hindpaw was assessed by the von Frey test. Data
show the mean with S.E.M. for 5 mice. **P < 0.01
vs. vehicle in sham. †P < 0.05 vs. vehicle in PSNL.
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Vehicle in sham
in PSNL
Vehicle
12c 10 mg/kg
12c 20 mg/kg
**
0
**
60
**
30
**
45
**
75
**
15
**
90
0
Before
PSNL
Time (min) after i.p. 12c injection
6

H. Du Nguyen et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
J = 5.2 Hz), 5.18 (2H, s), 5.19 (2H, s), 5.22 (2H, s), 5.34 (1H, dd,
J = 10.4, 1.2 Hz), 5.47 (1H, dd, J = 17.2, 1.2 Hz), 6.07 (1H, d,
J = 2.4 Hz), 6.12 (1H, ddt, J = 17.2, 10.4, 5.2 Hz), 6.27 (1H, d,
J = 2.4 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.18 (1H, dd, J = 8.0, 1.2 Hz),
7.32 (1H, dd, J = 8.0, 1.2 Hz), 7.93 (1H, d, J = 15.6 Hz), 8.23 (1H, d,
J = 15.6 Hz), 14.04 (1H, s); 13C NMR (100 MHz CDCl3) δ: 56.21, 56.35,
57.86, 69.73, 92.59, 93.94, 95.05, 96.60, 99.35, 107.11, 117.84,
118.97, 120.18, 124.29, 128.47, 130.54, 132.09, 137.13, 146.24,
150.26, 161.41, 163.45, 167.56, 192.81; IR (neat): 1653, 1624, 1617,
1577, 1570, 1565, 1559, 1480, 1461, 1262, 1223, 1210, 1155, 1083,
1030, 952 cm−1; MS (EI): m/z 460 (M+); HRMS (EI) Calcd for
C24H28O9 460.1733 (M+); Found 460.1735.
114.25, 118.90, 125.24, 128.13, 130.16, 132.16, 142.41, 161.32,
161.38, 163.34, 167.53, 192.81; IR (KBr): 1624, 1589, 1564, 1560,
1512, 1421, 1346, 1288, 1256, 1225, 1177, 1151, 1103, 1080, 1022,
980, 949, 833, 825 cm−1; mp: 57–59 °C; MS (EI): m/z 370 (M+); HRMS
(EI) Calcd for C21H22O6 370.1416 (M+); Found 370.1410.
4.1.2.15. 1-(2-Allyloxy-6-hydroxy-4-methoxymethoxyphenyl)-3-(4-chloro
phenyl)propenone (2o). Yield: 77% in 2 steps; 1H NMR (400 MHz
CDCl3) δ: 3.48 (3H, s), 4.59 (2H, d, J = 5.2 Hz), 5.19 (2H, s), 5.36
(1H, d, J = 10.0 Hz), 5.48 (1H, d, J = 17.4 Hz), 6.06 (1H, d,
J = 2.4 Hz), 6.12 (1H, ddt, J = 17.4, 10.0, 5.2 Hz), 6.26 (1H, d,
J = 2.4 Hz), 7.35 (2H, d, J = 8.4 Hz), 7.49 (2H, d, J = 8.4 Hz), 7.69
(1H, d, J = 16.0 Hz), 7.97 (1H, d, J = 16.0 Hz), 13.92 (1H, s); 13C NMR
(100 MHz CDCl3) δ: 56.43, 69.75, 92.66, 94.01, 96.72, 107.07, 119.11,
128.17, 129.04, 129.48, 132.06, 133.90, 135.83, 140.63, 161.43,
163.59, 167.63, 192.57; IR (KBr): 1630, 1584, 1564, 1491, 1425,
1340, 1227, 1209, 1163, 1103, 1080, 1040, 1026, 978, 943, 926, 837,
822, 795 cm−1; mp: 89–91 °C; MS (EI): m/z 374 (M+); HRMS (EI) Calcd
for C20H19ClO5 374.0921 (M+); Found 374.0935.
4.1.2.11. 1-(2-Allyloxy-6-hydroxy-4-methoxymethoxyphenyl)-3-(2,6-bism
ethoxymethoxyphenyl)propenone (2k). Yield: 78% in 2 steps; 1H NMR
(400 MHz CDCl3) δ: 3.48 (6H, s), 3.49 (3H, s), 4.65 (2H, d, J = 4.8 Hz),
5.20 (1H, dd, J = 10.4, 1.2 Hz), 5.25 (6H, s), 5.39 (1H, dd, J = 17.2,
1.2 Hz), 6.02 (1H, ddt, J = 17.2, 10.4, 4.8 Hz), 6.06 (1H, d, J = 2.4 Hz),
6.27 (1H, d, J = 2.4 Hz), 6.85 (2H, d, J = 8.0 Hz), 7.23 (1H, t,
J = 8.0 Hz), 8.26 (2H, d, J = 10.4 Hz), 14.02 (1H, s); 13C NMR
(100 MHz CDCl3) δ: 56.27, 56.38, 69.68, 92.95, 94.01, 94.64, 96.66,
107.68, 108.12, 115.0, 117.61, 131.03, 132.41, 133.54, 157.74,
161.45, 163.16, 167.25, 194.48; IR (neat): 1623, 1595, 1577, 1573,
1558, 1472, 1334, 1202, 1152, 1100, 1083, 1037, 921 cm−1; MS (EI):
m/z 460 (M+); HRMS (EI) Calcd for C24H28O9 460.1733 (M+); Found
460.1739.
4.1.3. General procedure for the synthesis of C-5-O-allyl ether flavanone
intermediates 3a–o
To a stirred solution of 2a–o (0.87 mmol) in EtOH (10 mL) and H2O
(1 mL) was added NaOAc·3H2O (5.25 mmol), and the reaction mixture
was reflexed for 24 h at 100 °C. After cooling, EtOH was evaporated,
and then the aqueous mixture was extracted with CH2Cl2 (3 mL × 3).
The organic extracts were combined, dried and evaporated to give an
orange oil, which was chromatographed on SiO2 (10 g, EtOAc/n-
hexane = 1/10) to give the corresponding product 3a–o.
4.1.2.12. 1-(2-Allyloxy-6-hydroxy-4-methoxymethoxyphenyl)-3-(3,4-bism
ethoxymethoxyphenyl)propenone (2l). Yield: 83% in 2 steps; 1H NMR
(400 MHz CDCl3) δ: 3.47 (3H, s), 3.51 (3H, s), 3.52 (3H, s), 4.60 (2H, d,
J = 5.6 Hz), 5.18 (2H, s), 5.25 (2H, s), 5.26 (2H, s), 5.33 (1H, dd,
J = 10.4, 1.2 Hz), 5.46 (1H, dd, J = 17.2, 1.2 Hz), 6.05 (1H, d,
J = 2.4 Hz), 6.15 (1H, ddt, J = 17.2, 10.4, 5.6 Hz), 6.25 (1H, d,
J = 2.4 Hz), 7.15 (1H, d, J = 8.4 Hz), 7.20 (1H, d, J = 8.4 Hz), 7.42
(1H, d, J = 1.6 Hz), 7.72 (1H, d, J = 16.4 Hz), 7.85 (1H, d,
J = 16.4 Hz), 14.05 (1H, s); 13C NMR (100 MHz CDCl3) δ: 56.22,
56.29, 56.37, 69.80, 92.57, 93.98, 95.03, 95.36, 96.65, 107.11,
115.61, 115.97, 118.93, 124.02, 126.04, 129.84, 132.13, 142.31,
147.27, 149.06, 161.38, 163.39, 167.58, 192.66; IR (KBr): 1652,
1628, 1598, 1577, 1558, 1507, 1419, 1345, 1257, 1221, 1199, 1155,
1131, 1104, 1092, 1079, 1026, 1009, 997, 978 cm−1; mp: 63–64 °C; MS
(EI): m/z 460 (M+); HRMS (EI) Calcd for C24H28O9 460.1733 (M+);
Found 460.1718.
4.1.3.1. 5-Allyloxy-2-phenylchroman-4-one (3a). Yield: 61%; 1H NMR
(400 MHz CDCl3) δ: 2.85 (1H, dd, J = 16.6, 2.9 Hz), 3.08 (1H, dd,
J = 16.6, 13.2 Hz), 4.65 (2H, d, J = 4.8 Hz), 5.34 (1H, dd, J = 10.4,
1.2 Hz), 5.44 (1H, dd, J = 13.2, 2.9 Hz), 5.66 (1H, dd, J = 17.6,
1.2 Hz), 6.10 (1H, ddt, J = 17.6, 10.4, 4.8 Hz), 6.54 (1H, d,
J = 8.8 Hz), 6.66 (1H, d, J = 8.8 Hz), 7.03–7.05 (6H, m); 13C NMR
(100 MHz CDCl3) δ: 45.95, 69.31, 78.86, 105.24, 110.14, 111.51,
117.47, 126.00, 128.55, 128.68, 132.24, 135.78, 138.64, 159.52,
163.02, 190.25; IR (KBr): 1680, 1603, 1570, 1474, 1456, 1450, 1379,
1333, 1263, 1231, 1124, 1072, 926, 783, 760, 733, 700 cm−1; mp:
77–79 °C; MS (EI): m/z 280 (M+); HRMS (EI) Calcd for C18H16O3
280.1099 (M+); Found 280.1110.
4.1.3.2. 5-Allyloxy-2-p-tolylchroman-4-one (3b). Yield: 55%; 1H NMR
(400 MHz CDCl3) δ: 2.38 (3H, s), 2.83 (1H, dd, J = 16.4, 3.2 Hz), 3.08
(1H, dd, J = 16.4, 13.0 Hz), 4.65 (2H, dt, J = 4.0, 1.6 Hz), 5.34 (1H,
dd, J = 10.4, 1.6 Hz), 5.40 (1H, dd, J = 13.0, 3.2 Hz), 5.66 (1H, dd,
J = 17.0, 1.6 Hz), 6.10 (1H, ddt, J = 17.0, 10.4, 4.0 Hz), 6.53 (1H, d,
J = 7.2 Hz), 6.65 (1H, d, J = 7.2 Hz), 7.23 (2H, d, J = 8.0 Hz), 7.24
(1H, t, J = 7.2 Hz), 7.38 (2H, d, J = 8.0 Hz); 13C NMR (100 MHz CDCl3)
δ: 21.15, 45.89, 69.36, 78.86, 105.21, 110.23, 111.55, 117.51, 126.09,
129.37, 132.31, 135.69, 135.77, 138.52, 159.56, 163.17, 190.54; IR
(KBr): 1686, 1597, 1574, 1472, 1454, 1325, 1256, 1225, 1119, 1065,
1042, 932, 893, 826, 791 cm−1; mp: 85–87 °C; MS (EI): m/z 294 (M+);
HRMS (EI) Calcd for C19H18O3 294.1256 (M+); Found 294.1266.
4.1.2.13. 1-(2-Allyloxy-6-hydroxy-4-methoxymethoxyphenyl)-3-(3,5-bism
ethoxymethoxyphenyl)propenone (2m). Yield: 87% in 2 steps; 1H NMR
(400 MHz CDCl3) δ: 3.49 (9H, s), 4.61 (2H, d, J = 5.2 Hz), 5.18 (4H, s),
5.20 (2H, s), 5.35 (1H, dd, J = 10.8, 1.2 Hz), 5.48 (1H, dd, J = 17.2,
1.2 Hz), 6.07 (1H, d, J = 2.4 Hz), 6.17 (1H, ddt, J = 17.2, 10.8, 5.2 Hz),
6.27 (1H, d, J = 2.4 Hz), 6.76 (1H, t, J = 2.4 Hz), 6.95 (2H, d,
J = 2.4 Hz), 7.67 (1H, d, J = 15.2 Hz), 7.91 (1H, d, J = 15.2 Hz),
14.03 (1H, s); 13C NMR (100 MHz CDCl3) δ: 56.19, 56.54, 69.99,
92.73, 94.13, 94.54, 96.78, 106.83, 107.23, 109.71, 119.27, 128.31,
132.21, 137.57, 142.15, 158.59, 161.60, 163.74, 167.77, 192.86; IR
(KBr): 1617, 1590, 1581, 1559, 1279, 1212, 1148, 1085, 1030, 948,
924 cm−1; mp: 67–69 °C; MS (EI): m/z 460 (M+); HRMS (EI) Calcd for
C
24H28O9 460.1733 (M+); Found 460.1739.
4.1.3.3. 5-Allyloxy-2-(2-methoxymethoxyphenyl)chroman-4-one
(3c).
Yield: 45%; 1H NMR (400 MHz CDCl3) δ: 2.91 (2H, d, J = 7.6 Hz),
3.34 (3H, s), 4.63 (2H, d, J = 4.0 Hz), 5.18 (2H, s), 5.32 (1H, d,
J = 10.8 Hz), 5.66 (1H, d, J = 17.2 Hz), 5.80 (1H, t, J = 7.6 Hz), 6.07
(1H, ddt, J = 17.2, 10.8, 4.0 Hz), 6.51 (1H, d, J = 8.4 Hz), 6.65 (1H, d,
J = 8.4 Hz), 7.07 (1H, t, J = 7.6 Hz), 7.12 (1H, d, J = 7.6 Hz), 7.28
(1H, t, J = 7.6 Hz), 7.35 (1H, t, J = 8.4 Hz), 7.60 (1H, d, J = 7.6 Hz);
13C NMR (100 MHz CDCl3) δ: 45.31, 56.20, 69.36, 74.12, 94.24,
105.18, 110.26, 111.89, 113.79, 117.48, 121.97, 126.35, 128.00,
129.31, 132.32, 135.70, 153.45, 159.68, 163.62, 191.04; IR (neat):
4.1.2.14. 1-(2-Allyloxy-6-hydroxy-4-methoxymethoxyphenyl)-3-(4-metho
xyphenyl)propenone (2n). Yield: 41% in 2 steps; 1H NMR (400 MHz
CDCl3) δ: 3.48 (3H, s), 3.85 (3H, s), 4.61 (2H, d, J = 5.2 Hz), 5.19 (2H,
s), 5.36 (1H, dd, J = 10.4, 1.2 Hz), 5.50 (1H, dd, J = 17.2, 1.2 Hz), 6.07
(1H, d, J = 2.4 Hz), 6.12 (1H, ddt, J = 17.2, 10.4, 5.2 Hz), 6.27 (1H, d,
J = 2.4 Hz), 6.91 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 8.4 Hz), 7.77
(1H, d, J = 15.2 Hz), 7.87 (1H, d, J = 15.2 Hz), 14.08 (1H, s); 13C NMR
(100 MHz CDCl3) δ: 55.34, 56.40, 69.71, 92.63, 94.00, 96.70, 107.18,
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1694, 1684, 1602, 1575, 1558, 1507, 1490, 1472, 1457, 1259, 1153,
45.00, 56.18, 56.36, 69.30, 74.26, 94.01, 94.18, 94.97, 96.23, 106.83,
113.07, 117.55, 121.91, 126.27, 128.00, 129.22, 132.09, 153.38,
161.13, 163.19, 165.05, 189.74; IR (KBr): 1683, 1669, 1608, 1576,
1559, 1490, 1458, 1437, 1355, 1257, 1251, 1233, 1215, 1153, 1126,
1111, 1053, 1046, 1035, 998, 993, 950, 925, 917, 826, 754 cm−1; mp:
80–82 °C; MS (EI): m/z 400 (M+); HRMS (EI) Calcd for C22H24O7
400.1522 (M+); Found 400.1529.
1078, 992 cm−1; MS (EI): m/z 340 (M+); HRMS (EI) Calcd for
C
20H20O5 340.1311 (M+); Found 340.1315.
4.1.3.4. 5-Allyloxy-2-(4-methoxyphenyl)chroman-4-one
(3d). Yield:
32%; 1H NMR (400 MHz CDCl3) δ: 2.82 (1H, dd, J = 16.4, 2.8 Hz),
3.08 (1H, dd, J = 16.4, 13.0 Hz), 3.83 (3H, s), 4.65 (2H, dt, J = 4.8,
1.6 Hz), 5.34 (1H, dd, J = 9.2, 1.6 Hz), 5.38 (1H, dd, J = 13.2, 2.8 Hz),
5.66 (1H, dd, J = 16.8, 1.6 Hz), 6.09 (1H, ddt, J = 16.8, 9.2, 4.8 Hz),
6.52 (1H, d, J = 8.4 Hz), 6.63 (1H, d, J = 8.4 Hz), 6.95 (2H, d,
J = 8.4 Hz), 7.36 (1H, t, J = 8.4 Hz), 7.39 (2H, d, J = 8.4 Hz); 13C
NMR (100 MHz CDCl3) δ: 45.89, 55.33, 69.36, 78.72, 105.26, 110.26,
111.59, 114.12, 117.57, 127.67, 130.75, 132.35, 135.80, 159.62,
159.88, 163.22, 190.65; IR (KBr): 1684, 1603, 1576, 1558, 1516,
1472, 1456, 1256, 1231, 1175, 1123, 1082, 1073, 1030, 833,
775 cm−1; mp: 74–76 °C; MS (EI): m/z 310 (M+); HRMS (EI) Calcd
for C19H18O4 310.1205 (M+); Found 310.1199.
4.1.3.9. 5-Allyloxy-7-methoxymethoxy-2-(3-methoxymethoxy-phenyl)chro
man-4-one (3i). Yield: 56%; 1H NMR (400 MHz CDCl3) δ: 2.79 (1H, dd,
J = 17.2, 2.4 Hz), 3.00 (1H, dd, J = 17.2, 12.8 Hz), 3.48 (3H, s), 3.49
(3H, s), 4.61 (2H, d, J = 4.8 Hz), 5.17 (2H, d, J = 1.2 Hz), 5.20 (2H, d,
J = 1.2 Hz), 5.34 (1H, dd, J = 10.4, 1.6 Hz), 5.37 (1H, dd, J = 12.8,
2.4 Hz), 5.66 (1H, dd, J = 17.2, 1.6 Hz), 6.07 (1H, ddt, J = 17.2, 10.4,
4.8 Hz), 6.19 (1H, d, J = 2.4 Hz), 6.34 (1H, d, J = 2.4 Hz), 7.04 (1H,
dd, J = 8.0, 2.0 Hz), 7.08 (1H, d, J = 8.0 Hz), 7.13 (1H, t, J = 2.0 Hz),
7.33 (1H, t, J = 8.0 Hz); 13C NMR (100 MHz CDCl3) δ: 45.65, 55.96,
56.33, 69.32, 78.84, 93.99, 94.31, 95.09, 96.21, 106.70, 114.01,
116.11, 117.60, 119.34, 129.77, 132.06, 140.30, 157.46, 161.01,
163.25, 164.46, 188.90; IR (neat): 1683, 1680, 1608, 1573, 1436,
1259, 1211, 1150, 1124, 1107, 1083, 1055, 1031, 994 cm−1; MS (EI):
m/z 400 (M+); HRMS (EI) Calcd for C22H24O7 400.1522 (M+); Found
400.1529.
4.1.3.5. 5-Allyloxy-2-(4-ethoxyphenyl)chroman-4-one (3e). Yield: 45%;
1H NMR (400 MHz CDCl3) δ: 1.42 (3H, t, J = 7.0 Hz), 2.81 (1H, dd,
J = 16.4, 3.0 Hz), 3.08 (1H, dd, J = 16.4, 13.4 Hz), 4.05 (2H, q,
J = 7.0 Hz), 4.64 (2H, d, J = 4.0 Hz), 5.34 (1H, dd, J = 10.4, 1.4 Hz),
5.37 (1H, dd, J = 13.4, 3.0 Hz), 5.66 (1H, dd, J = 17.0, 1.4 Hz), 6.09
(1H, ddt, J = 17.0, 10.4, 4.0 Hz), 6.52 (1H, d, J = 8.2 Hz), 6.63 (1H, d,
J = 8.2 Hz), 6.93 (2H, d, J = 8.4 Hz), 7.36 (1H, t, J = 8.2 Hz), 7.38
(2H, d, J = 8.4 Hz); 13C NMR (100 MHz CDCl3) δ: 14.74, 45.81, 63.48,
69.38, 78.72, 105.21, 110.24, 111.57, 114.61, 117.51, 127.62, 130.54,
132.33, 135.75, 159.22, 159.58, 163.21, 190.62; IR (KBr): 1678, 1605,
1583, 1574, 1516, 1472, 1454, 1423, 1340, 1263, 1245, 1232, 1196,
1086, 1051, 824 cm−1; mp: 85–87 °C; MS (EI): m/z 324 (M+); HRMS
(EI) Calcd for C20H20O4 324.1362 (M+); Found 324.1367.
4.1.3.10. 5-Allyloxy-2-(3,4-bismethoxymethoxyphenyl)-7-methoxymethox
ychroman-4-one (3j). Yield: 40%; 1H NMR (400 MHz CDCl3) δ: 2.86
(1H, d, J = 3.2 Hz), 2.90 (1H, d, J = 12.8 Hz), 3.46 (3H, s), 3.47 (3H,
s), 3.48 (3H, s), 4.60 (2H, d, J = 5.2 Hz), 5.12 (2H, s), 5.15 (2H, s), 5.18
(2H, s), 5.33 (1H, dd, J = 10.4, 1.6 Hz), 5.66 (1H, dd, J = 17.2, 1.6 Hz),
5.83 (1H, dd, J = 12.8, 3.2 Hz), 6.07 (1H, ddt, J = 17.2, 10.4, 5.2 Hz),
6.18 (1H, d, J = 2.4 Hz), 6.30 (1H, d, J = 2.4 Hz), 7.11 (1H, t,
J = 8.0 Hz), 7.14 (1H, d, J = 8.0 Hz), 7.27 (1H, t, J = 8.0 Hz); 13C
NMR (100 MHz CDCl3) δ: 45.10, 56.23, 56.37, 57.60, 69.38, 74.23,
94.03, 94.98, 95.07, 96.22, 99.26, 106.74, 116.38, 117.64, 119.73,
124.75, 132.14, 133.39, 143.91, 149.46, 161.09, 163.16, 164.84,
189.44; IR (neat): 1684, 1680, 1608, 1570, 1562, 1476, 1437, 1260,
1152, 1126, 1108, 1085, 1070, 1038, 1020, 959, 928 cm−1; MS (EI):
m/z 460 (M+); HRMS (EI) Calcd for C24H28O9 460.1733 (M+); Found
460.1743.
4.1.3.6. 5-Allyloxy-2-(4-chlorophenyl)chroman-4-one (3f). Yield: 58%;
1H NMR (400 MHz CDCl3) δ: 2.84 (1H, dd, J = 16.4, 2.8 Hz), 3.02
(1H, dd, J = 16.4, 13.0 Hz), 4.65 (2H, d, J = 4.0 Hz), 5.34 (1H, dd,
J = 10.6, 1.6 Hz), 5.42 (1H, dd, J = 13.0, 2.8 Hz), 5.65 (1H, dd,
J = 17.0, 1.6 Hz), 6.08 (1H, ddt, J = 17.0, 10.6, 4.0 Hz), 6.54 (1H, d,
J = 8.0 Hz), 6.65 (1H, d, J = 8.0 Hz), 7.26–7.44 (5H, m); 13C NMR
(100 MHz CDCl3) δ: 45.77, 69.26, 78.01, 105.36, 110.01, 111.39,
117.46, 127.34, 128.79, 132.15, 134.24, 135.82, 137.17, 159.46,
162.70, 189.69; IR (KBr): 1732, 1676, 1601, 1574, 1491, 1472, 1458,
1329, 1279, 1259, 1252, 1225, 1121, 1078, 1015, 839, 787 cm−1; mp:
71–73 °C; MS (EI): m/z 314 (M+); HRMS (EI) Calcd for C18H15ClO3
314.0710 (M+); Found 314.0715.
4.1.3.11. 5-Allyloxy-2-(2,6-bismethoxymethoxyphenyl)-7-methoxymethox
ychroman-4-one (3k). Yield: 27%; 1H NMR (400 MHz CDCl3) δ: 2.54
(1H, dd, J = 17.2, 3.2 Hz), 3.44 (6H, s), 3.45 (3H, s), 3.82 (1H, dd,
J = 17.2, 14.0 Hz), 4.62 (2H, d, J = 6.4 Hz), 5.14 (2H, d, J = 3.2 Hz),
5.17 (4H, s), 5.33 (1H, dd, J = 10.4, 1.2 Hz), 5.68 (1H, dd, J = 17.2,
1.2 Hz), 6.08 (1H, ddt, J = 17.2, 10.4, 6.4 Hz), 6.09 (1H, dd, J = 14.0,
3.2 Hz), 6.17 (1H, d, J = 2.4 Hz), 6.23 (1H, d, J = 2.4 Hz), 6.82 (2H, d,
J = 8.4 Hz), 7.23 (1H, t, J = 8.4 Hz); 13C NMR (100 MHz CDCl3) δ:
42.12, 56.25, 56.34, 69.32, 71.66, 93.99, 94.55, 96.01, 106.80, 108.56,
115.63, 117.54, 130.41, 132.22, 156.56, 161.23, 162.96, 165.66,
190.86; IR (KBr): 1683, 1669, 1616, 1601, 1576, 1472, 1265, 1246,
1153, 1107, 1098, 1087, 1047, 1035, 919 cm−1; mp: 79–81 °C; MS (EI):
m/z 460 (M+); HRMS (EI) Calcd for C24H28O9 460.1733 (M+); Found
460.1718.
4.1.3.7. 5-Allyloxy-7-methoxymethoxy-2-phenylchroman-4-one (3g). Yield:
54%; 1H NMR (400 MHz CDCl3) δ: 2.80 (1H, dd, J = 16.4, 3.0 Hz), 3.02
(1H, dd, J = 16.4, 13.2 Hz), 3.48 (3H, s), 4.65 (2H, dd, J = 6.0, 1.2 Hz),
5.18 (2H, s), 5.35 (1H, dd, J = 11.2, 1.2 Hz), 5.41 (1H, dd, J = 13.2,
3.0 Hz), 5.67 (1H, dd, J = 17.2, 1.2 Hz), 6.08 (1H, ddt, J = 17.2, 11.2,
6.0 Hz), 6.20 (1H, d, J = 2.0 Hz), 6.34 (1H, d, J = 2.0 Hz), 7.30–7.48 (5H,
m); 13C NMR (100 MHz CDCl3) δ: 45.73, 56.42, 69.40, 79.14, 94.07,
95.14, 96.25, 106.79, 117.69, 126.06, 128.60, 128.73, 132.12, 138.77,
161.11, 163.33, 164.60, 189.07; IR (KBr): 1674, 1611, 1572, 1456, 1435,
1261, 1248, 1221, 1209, 1148, 1124, 1105, 1084, 1055, 1034, 989 cm−1
;
mp: 100–102 °C; MS (EI): m/z 340 (M+); HRMS (EI) Calcd for C20H20O5
4.1.3.12. 5-Allyloxy-2-(3,4-bismethoxymethoxyphenyl)-7-methoxymethox
ychroman-4-one (3l). Yield: 43%; 1H NMR (400 MHz CDCl3) δ: 2.77
(1H, dd, J = 17.2, 3.2 Hz), 3.07 (1H, dd, J = 17.2, 13.6 Hz), 3.33 (2H,
d, J = 6.0 Hz), 3.43 (3H, s), 3.50 (3H, s), 3.51 (3H, s), 4.94 (1H, dd,
J = 10.4, 2.0 Hz), 4.99 (1H, dd, J = 17.2, 2.0 Hz), 5.18 (2H, d,
J = 3.2 Hz), 5.23 (2H, s), 5.24 (2H, d, J = 3.2 Hz), 5.32 (1H, dd,
J = 13.6, 3.2 Hz), 5.92 (1H, ddt, J = 17.2, 10.4, 6.0 Hz), 6.27 (1H, s),
7.02 (1H, dd, J = 8.4, 2.0 Hz), 7.18 (1H, d, J = 8.4 Hz), 7.24 (1H, d,
J = 2.0 Hz), 12.10 (1H, s); 13C NMR (100 MHz CDCl3) δ: 26.16, 43.36,
56.17, 56.25, 56.36, 78.93, 93.42, 93.74, 95.26, 95.44, 103.34, 108.74,
114.23, 114.73, 116.57, 120.30, 132.52, 136.07, 147.40, 147.53,
340.1311 (M+); Found 340.1327.
4.1.3.8. 5-Allyloxy-7-methoxymethoxy-2-(2-methoxymethoxy-phenyl)chro
man-4-one (3h). Yield: 55%; 1H NMR (400 MHz CDCl3) δ: 2.67 (2H, d,
J = 7.2 Hz), 3.45 (3H, s), 3.48 (3H, s), 4.62 (2H, dd, J = 4.8, 1.6 Hz),
5.18 (2H, s), 5.19 (2H, s), 5.35 (1H, dd, J = 10.8, 1.6 Hz), 5.69 (1H, dd,
J = 17.2, 1.6 Hz), 5.80 (1H, t, J = 7.2 Hz), 6.09 (1H, ddt, J = 17.2,
10.8, 4.8 Hz), 6.20 (1H, d, J = 2.4 Hz), 6.45(1H, d, J = 2.4 Hz), 7.09
(1H, t, J = 8.0 Hz), 7.13 (1H, d, J = 8.0 Hz), 7.30 (1H, td, J = 8.0,
2.0 Hz), 7.61 (1H, dd, J = 8.0, 2.0 Hz); 13C NMR (100 MHz CDCl3) δ:
8

H. Du Nguyen et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
160.68, 161.21, 162.87, 196.17; IR (KBr): 1653, 1636, 1577, 1559,
1521, 1516, 1507, 1433, 1261, 1157, 1130, 1091, 1076, 1057, 993,
962, 923 cm−1; mp: 79–80 °C; MS (EI): m/z 460 (M+); HRMS (EI) Calcd
for C24H28O9 460.1733 (M+); Found 460.1728.
280 (M+); HRMS (EI) Calcd for C18H16O3 280.1099 (M+); Found
280.1112.
4.1.4.2. 6-Allyl-5-hydroxy-2-p-tolylchroman-4-one (4b). Yield: 95%; 1H
NMR (400 MHz CDCl3) δ: 2.38 (3H, s), 2.86 (1H, dd, J = 17.2, 2.8 Hz),
3.14 (1H, dd, J = 17.2, 13.0 Hz), 3.34 (2H, d, J = 6.8 Hz), 5.07 (1H, d,
J = 10.4 Hz), 5.08 (1H, d, J = 17.2 Hz), 5.41 (1H, dd, J = 13.0,
2.8 Hz), 5.97 (1H, ddt, J = 17.2, 10.4, 6.8 Hz), 6.47 (1H, d,
J = 8.8 Hz), 7.23 (1H, d, J = 8.8 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.35
(2H, d, J = 8.0 Hz), 11.99 (1H, s); 13C NMR (100 MHz CDCl3) δ: 21.18,
32.58, 43.81, 78.97, 106.97, 107.73, 115.68, 120.13, 126.12, 129.48,
135.36, 136.32, 138.65, 138.78, 159.43, 159.89, 198.37; IR (KBr):
1641, 1583, 1517, 1481, 1474, 1441, 1373, 1339, 1263, 1238, 1117,
1063, 999, 912, 814 cm−1; mp: 75–77 °C; MS (EI): m/z 294 (M+);
HRMS (EI) Calcd for C19H18O3 294.1256 (M+); Found 294.1244.
4.1.3.13. 5-Allyloxy-2-(3,5-bismethoxymethoxyphenyl)-7-methoxymethox
ychroman-4-one (3m). Yield: 53%; 1H NMR (400 MHz CDCl3) δ: 2.77
(1H, dd, J = 17.2, 2.4 Hz), 2.98 (1H, dd, J = 17.2, 13.6 Hz), 3.48 (9H,
s), 4.62 (2H, d, J = 5.2 Hz), 5.18 (6H, s), 5.32 (1H, dd, J = 17.2,
2.4 Hz), 5.35 (1H, dd, J = 10.4, 1.2 Hz), 5.66 (1H, dd, J = 13.6,
1.6 Hz), 6.09 (1H, ddt, J = 17.2, 10.4, 5.2 Hz), 6.19 (1H, d,
J = 2.4 Hz), 6.34 (1H, d, J = 2.4 Hz), 6.74 (1H, t, J = 2.4 Hz), 6.80
(2H, d, J = 2.4 Hz); 13C NMR (100 MHz CDCl3) δ: 45.70, 56.07, 56.38,
69.37, 78.88, 94.13, 94.54, 95.15, 96.27, 104.60, 106.73, 107.36,
117.65, 132.09, 141.13, 158.51, 161.04, 163.28, 164.44, 188.90; IR
(neat): 1685, 1680, 1676, 1609, 1570, 1437, 1260, 1237, 1148, 1125,
1105, 1085, 1057, 1035, 924 cm−1; MS (EI): m/z 460 (M+); HRMS (EI)
Calcd for C24H28O9 460.1733 (M+); Found 460.1739.
4.1.4.3. 6-Allyl-5-hydroxy-2-(2-methoxymethoxyphenyl)chroman-4-one (4c).
Yield: 87%; 1H NMR (400 MHz CDCl3) δ: 2.96 (1H, d, J = 4.8 Hz), 2.98
(1H, d, J = 12.4 Hz), 3.33 (2H, d, J = 6.0 Hz), 3.45 (3H, s), 5.05 (1H, dd,
J = 10.0, 1.6 Hz), 5.07 (1H, dd, J = 17.2, 1.6 Hz), 5.20 (2H, d, J = 3.2 Hz),
5.80 (1H, dd, J = 12.4, 4.8 Hz), 5.96 (1H, ddt, J = 17.2, 10.0, 6.0 Hz), 6.47
(1H, d, J = 8.4 Hz), 7.09 (1H, t, J = 7.2 Hz), 7.14 (1H, d, J = 7.2 Hz), 7.26
(1H, d, J = 8.4 Hz), 7.31 (1H, td, J = 7.2, 1.2 Hz), 7.61 (1H, dd, J = 7.2,
1.2 Hz), 12.03 (1H, s); 13C NMR (100 MHz CDCl3) δ: 32.61, 43.12, 56.23,
74.23, 94.30, 106.95, 107.81, 113.92, 115.56, 120.09, 122.07, 126.47,
127.66, 129.54, 136.36, 138.55, 153.49, 159.50, 160.28, 198.88; IR (neat):
1651, 1644, 1639, 1634, 1494, 1455, 1442, 1435, 1362, 1234, 1154, 1080,
1061, 995, 755 cm−1; MS (EI): m/z 340 (M+); HRMS (EI) Calcd for
4.1.3.14. 5-Allyloxy-7-methoxymethoxy-2-(4-methoxyphenyl)-chroman-4-
one (3n). Yield: 28%; 1H NMR (400 MHz CDCl3) δ: 2.76 (1H, dd,
J = 16.8, 2.6 Hz), 3.03 (1H, dd, J = 16.8, 13.2 Hz), 3.47 (3H, s), 3.83
(3H, s), 4.60 (2H, dd, J = 5.2, 1.2 Hz), 5.17 (2H, d, J = 1.6 Hz), 5.34
(1H, dd, J = 9.2, 1.2 Hz), 5.38 (1H, dd, J = 13.2, 2.6 Hz), 5.67 (1H, dd,
J = 17.2, 1.2 Hz), 6.07 (1H, ddt, J = 17.2, 9.2, 5.2 Hz), 6.19 (1H, d,
J = 2.4 Hz), 6.31 (1H, d, J = 2.4 Hz), 6.94 (2H, d, J = 6.8 Hz), 7.38
(2H, d, J = 6.8 Hz); 13C NMR (100 MHz CDCl3) δ: 45.48, 55.27, 56.36,
69.34, 78.84, 94.01, 95.01, 96.20, 106.72, 114.02, 117.62, 127.61,
130.73, 132.10, 159.78, 161.05, 163.25, 164.64, 189.29; IR (KBr):
1672, 1611, 1587, 1572, 1516, 1437, 1421, 1337, 1271, 1254, 1227,
1207, 1180, 1157, 1146, 1111, 1087, 1065, 1034, 947, 835 cm−1; mp:
95–97 °C; MS (EI): m/z 370 (M+); HRMS (EI) Calcd for C21H22O6
370.1416 (M+); Found 370.1400.
C
20H20O5 340.1311 (M+); Found 340.1327.
4.1.4.4. 6-Allyl-5-hydroxy-2-(4-methoxyphenyl)chroman-4-one (4d). Yield:
89%; 1H NMR (400 MHz CDCl3) δ: 2.85 (1H, dd, J = 17.0, 2.8 Hz), 3.15
(1H, dd, J = 17.0, 13.2 Hz), 3.35 (2H, d, J = 6.8 Hz), 3.84 (3H, s), 5.07
(1H, d, J = 8.8 Hz), 5.08 (1H, d, J = 17.8 Hz), 5.39 (1H, dd, J = 13.2,
2.8 Hz), 597 (1H, ddt, J = 17.8, 8.8, 6.8 Hz), 6.47 (1H, d, J = 8.4 Hz),
6.96 (2H, d, J = 7.8 Hz), 7.27 (1H, d, J = 8.4 Hz), 7.40 (2H, d,
J = 7.8 Hz), 12.00 (1H, s); 13C NMR (100 MHz CDCl3) δ: 32.59, 43.75,
55.35, 78.83, 106.98, 107.74, 114.19, 115.68, 120.15, 127.69, 130.38,
136.33, 138.68, 159.45, 159.93, 160.01, 198.46; IR (neat): 1683, 1670,
1647, 1616, 1603, 1516, 1472, 1456, 1256, 1231, 1121, 1069,
1032 cm−1; MS (EI): m/z 310 (M+); HRMS (EI) Calcd for C19H18O4
310.1205 (M+); Found 310.1198.
4.1.3.15. 5-Allyloxy-2-(4-chlorophenyl)-7-methoxymethox-ychroman-4-one (3o).
Yield: 48%; 1H NMR (400 MHz CDCl3) δ: 2.77 (1H, dd, J= 16.4, 2.8 Hz), 2.95
(1H, dd, J = 16.4, 13.0 Hz), 3.47 (3H, s), 4.60 (2H, dd, J = 4.8, 1.2 Hz), 5.18
(2H, d, J = 1.2 Hz), 5.34 (1H, dd, J = 9.2, 1.2 Hz), 5.38 (1H, dd, J= 13.0,
2.8 Hz), 5.65 (1H, dd, J= 16.8, 1.2 Hz), 6.07 (1H, ddt, J= 16.8, 9.2, 4.8 Hz),
6.19 (1H, d, J = 2.4 Hz), 6.31 (1H, d, J= 2.4Hz), 7.35–7.42 (4H, br); 13C
NMR (100 MHz CDCl3) δ: 45.60, 56.42, 69.40, 78.31, 94.05, 95.23, 96.19,
106.70, 117.71, 127.39, 128.88, 132.04, 134.33, 137.27, 161.10, 163.38,
164.30, 188.56; IR (KBr): 1680, 1608, 1570, 1495, 1437, 1423, 1337, 1269,
1223, 1207, 1149, 1109, 1086, 1063, 1032, 1015, 936, 814 cm−1; mp:
90–92 °C; MS (EI): m/z 374 (M+); HRMS (EI) Calcd for C20H19ClO5 374.0921
(M+); Found 374.0937.
4.1.4.5. 6-Allyl-2-(4-ethoxyphenyl)-5-hydroxychroman-4-one (4e). Yield:
83%; 1H NMR (400 MHz CDCl3) δ: 1.41 (3H, t, J = 7.0 Hz), 2.83 (1H,
dd, J = 17.2, 2.6 Hz), 3.13 (1H, dd, J = 17.2, 13.0 Hz), 3.32 (2H, d,
J = 6.8 Hz), 4.04 (2H, q, J = 7.0 Hz), 5.05 (1H, d, J = 9.6 Hz), 5.06 (1H,
d, J = 17.2 Hz), 5.36 (1H, dd, J = 13.0, 2.6 Hz), 597 (1H, ddt, J = 17.2,
9.6, 6.8 Hz), 6.44 (1H, d, J = 8.2 Hz), 6.92 (2H, d, J = 8.8 Hz), 7.27 (1H,
d, J = 8.2 Hz), 7.36 (2H, d, J = 8.8 Hz), 11.98 (1H, s); 13C NMR (100 MHz
CDCl3) δ: 14.76, 32.56, 43.75, 63.54, 78.87, 106.98, 107.75, 114.72,
115.67, 120.13, 127.69, 130.19, 136.34, 138.66, 159.39, 159.45, 159.95,
198.49; IR (KBr): 1636, 1614, 1585, 1520, 1515, 1473, 1456, 1429, 1396,
1362, 1340, 1302, 1263, 1256, 1234, 1188, 1177, 1119, 1059, 1045, 993,
839, 820, 772 cm−1; mp: 99–101 °C; MS (EI): m/z 324 (M+); HRMS (EI)
Calcd for C20H20O4 324.1362 (M+); Found 324.1377.
4.1.4. General procedure for the synthesis of C-6 allylated flavanone
intermediates 4a–o
To a stirred solution of 3a–o (0.69 mmol) in ClCH2CH2Cl (5 mL) was
added Eu(fod)3 (0.07 mmol) under argon atmosphere, and the resulting
solution was heated at 100 °C in a sealed tube for 12 h. After cooling,
the solvent was evaporated and the residue was chromatographed on
SiO2 (10 g, acetone/n-hexane = 1/10) to give the corresponding pro-
duct 4a–o.
4.1.4.1. 6-Allyl-5-hydroxy-2-phenylchroman-4-one (4a). Yield: 92%; 1H
NMR (400 MHz CDCl3) δ: 2.89 (1H, dd, J = 17.2, 3.0 Hz), 3.14 (1H, dd,
J = 17.2, 13.2 Hz), 3.34 (2H, d, J = 6.4 Hz), 5.07 (1H, d, J = 10.4 Hz),
5.08 (1H, d, J = 17.2 Hz), 5.44 (1H, dd, J = 13.2, 3.0 Hz), 5.97 (1H,
ddt, J = 17.2, 10.4, 6.4 Hz), 6.49 (1H, d, J = 8.8 Hz), 7.28 (1H, d,
J = 8.8 Hz), 7.39–7.50 (5H, m), 11.98 (1H, s); 13C NMR (100 MHz
CDCl3) δ: 32.60, 43.93, 79.06, 106.98, 107.76, 115.72, 120.28, 126.09,
128.85, 136.31, 138.37, 138.71, 159.45, 159.82, 198.19; IR (KBr):
1636, 1583, 1498, 1474, 1456, 1427, 1364, 1340, 1261, 1232, 1103,
1061, 1005, 924, 820, 779, 752, 700 cm−1; mp: 90–92 °C; MS (EI): m/z
4.1.4.6. 6-Allyl-2-(4-chlorophenyl)-5-hydroxychroman-4-one (4f). Yield:
90%; 1H NMR (400 MHz CDCl3) δ: 2.87 (1H, dt, J = 17.0, 2.0 Hz), 3.07
(1H, ddd, J = 17.0, 13.0 Hz), 3.33 (2H, d, J = 6.0 Hz), 5.07 (1H, d,
J = 10.4 Hz), 5.08 (1H, d, J = 16.8 Hz), 5.41 (1H, dt, J = 13.0, 2.0 Hz),
5.95 (1H, ddt, J = 16.8, 10.4, 6.0 Hz), 6.47 (1H, dd, J = 8.0 Hz), 7.28
(1H, d, J = 8.0 Hz), 7.40 (4H, d, J = 2.8 Hz), 11.94 (1H, s); 13C NMR
(100 MHz CDCl3) δ: 32.59, 43.86, 78.28, 106.94, 107.70, 115.79,
120.54, 127.45, 129.05, 134.67, 136.23, 136.90, 138.78, 159.48,
159.51, 197.74; IR (KBr): 1635, 1585, 1491, 1445, 1429, 1362, 1338,
9

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1304, 1261, 1238, 1190, 1168, 1107, 1079, 1062, 1056, 1015, 993,
906, 897, 831, 789 cm−1; mp: 75–77 °C; MS (EI): m/z 314 (M+); HRMS
(EI) Calcd for C18H15ClO3 314.0710 (M+); Found 314.0715.
3.48 (6H, s), 3.92 (1H, dd, J = 17.2, 14.0 Hz), 4.97 (1H, d,
J = 10.0 Hz), 5.04 (1H, dd, J = 17.2, 1.2 Hz), 5.20 (6H, s), 5.95 (1H,
ddt, J = 17.2, 10.0, 6.4 Hz), 6.10 (1H, dd, J = 14.0, 3.2 Hz), 6.21 (1H,
s), 6.85 (2H, d, J = 8.4 Hz), 7.26 (1H, t, J = 8.4 Hz), 12.32 (1H, s); 13
C
4.1.4.7. 6-Allyl-5-hydroxy-7-methoxymethoxy-2-phenylchroman-4-one (4g).
Yield: 96%; 1H NMR (400 MHz CDCl3) δ: 2.83 (1H, dd, J = 17.2, 3.0 Hz),
3.09 (1H, dd, J = 17.2, 13.6 Hz), 3.36 (2H, d, J = 6.0 Hz), 3.46 (3H, s),
4.97 (1H, dd, J = 10.2, 1.6 Hz), 5.03 (1H, dd, J = 17.2, 1.6 Hz), 5.21 (2H,
d, J = 2.8 Hz), 5.42 (1H, dd, J = 13.6, 3.0 Hz), 6.08 (1H, ddt, J = 17.2,
10.2, 6.0 Hz), 6.31 (1H, s), 7.37–7.48 (5H, m), 12.13(1H, s); 13C NMR
(100 MHz CDCl3) δ: 26.21, 43.52, 56.41, 79.24, 93.45, 93.81, 103.41,
108.85, 114.31, 126.08, 128.83, 136.09, 138.40, 160.75, 161.28, 162.95,
196.14; IR (KBr): 1636, 1576, 1448, 1439, 1300, 1283, 1213, 1155, 1103,
1090, 1059, 964 cm−1; mp: 101–103 °C; MS (EI): m/z 340 (M+); HRMS (EI)
Calcd for C20H20O5 340.1311 (M+); Found 340.1305.
NMR (100 MHz CDCl3) δ: 26.22, 39.90, 56.34, 56.40, 71.63, 93.08,
93.77, 94.66, 108.20, 108.62, 114.26, 115.26, 130.71, 136.28, 156.66,
160.88, 162.40, 162.63, 197.99; IR (KBr): 1653, 1635, 1601, 1577,
1558, 1506, 1472, 1447, 1153, 1124, 1099, 1082, 1048 cm−1; mp:
87–89 °C; MS (EI): m/z 460 (M+); HRMS (EI) Calcd for C24H28O9
460.1733 (M+); Found 460.1728.
4.1.4.12. 6-Allyl-2-(3,4-bismethoxymethoxyphenyl)-5-hydroxy-7-methoxy
methoxychroman-4-one (4l). Yield: 96%; 1H NMR (400 MHz CDCl3) δ:
2.77 (1H, dd, J = 17.2, 3.2 Hz), 3.07 (1H, dd, J = 17.2, 13.6 Hz), 3.33
(2H, d, J = 6.0 Hz), 3.43 (3H, s), 3.50 (3H, s), 3.51 (3H, s), 4.94 (1H,
dd, J = 10.4, 1.2 Hz), 4.99 (1H, dd, J = 17.2, 1.2 Hz), 5.18 (2H, d,
J = 3.2 Hz), 5.23 (2H, s), 5.24 (2H, d, J = 3.2 Hz), 5.32 (1H, dd,
J = 13.6, 3.2 Hz), 5.92 (1H, ddt, J = 17.2, 10.4, 6.0 Hz), 6.27 (1H, s),
7.02 (1H, dd, J = 8.4, 2.0 Hz), 7.18 (1H, d, J = 8.4 Hz), 7.24 (1H, d,
J = 2.0 Hz), 12.10 (1H, s); 13C NMR (100 MHz CDCl3) δ: 26.16, 43.36,
56.17, 56.25, 56.36, 78.93, 93.42, 93.74, 95.26, 95.44, 103.34, 108.74,
114.23, 114.73, 116.57, 120.30, 132.52, 136.07, 147.40, 147.53,
160.68, 161.21, 162.87, 196.17; IR (KBr): 1653, 1636, 1577, 1559,
1521, 1516, 1507, 1433, 1261, 1157, 1130, 1091, 1076, 1057, 993,
962, 923 cm−1; mp: 79–80 °C; MS (EI): m/z 460 (M+); HRMS (EI) Calcd
for C24H28O9 460.1733 (M+); Found 460.1739.
4.1.4.8. 6-Allyl-5-hydroxy-7-methoxymethoxy-2-(2-methoxy-methoxyphe
nyl)chroman-4-one (4h). Yield: 97%; 1H NMR (400 MHz CDCl3) δ: 2.92
(1H, d, J = 4.4 Hz), 2.94 (1H, d, J = 12.4 Hz), 3.36 (2H, d, J = 6.0 Hz),
3.46 (3H, s), 3.47 (3H, s), 4.97 (1H, dd, J = 10.0, 1.6 Hz), 5.02 (1H, dd,
J = 17.2, 1.6 Hz), 5.22 (4H, s), 5.78 (1H, dd, J = 12.4, 4.4 Hz), 5.95
(1H, ddt, J = 17.2, 10.0, 6.0 Hz), 6.32 (1H, s), 7.10 (1H, t, J = 8.0 Hz),
7.15 (1H, d, J = 8.0 Hz), 7.32 (1H, t, J = 8.0 Hz), 7.61 (1H, d,
J = 8.0 Hz), 12.19 (1H, s); 13C NMR (100 MHz CDCl3) δ: 26.18,
42.72, 56.20, 56.37, 74.36, 93.38, 93.76, 94.25, 103.40, 108.63,
113.83, 114.24, 122.02, 126.41, 127.67, 129.45, 136.10, 153.42,
160.77, 161.69, 162.79, 196.86; IR (KBr): 1644, 1578, 1506, 1497,
1448, 1437, 1311, 1292, 1285, 1240, 1223, 1155, 1128, 1083, 1049,
997, 960, 913, 763 cm−1; mp: 114–115 °C; MS (EI): m/z 400 (M+);
HRMS (EI) Calcd for C22H24O7 400.1522 (M+); Found 400.1529.
4.1.4.13. 6-Allyl-2-(3,5-bismethoxymethoxyphenyl)-5-hydroxy-7-methoxy
methoxychroman-4-one (4m). Yield: 75%; 1H NMR (400 MHz CDCl3) δ:
2.80 (1H, dd, J = 17.2, 3.2 Hz), 3.05 (1H, dd, J = 17.2, 13.6 Hz), 3.35
(2H, d, J = 6.0 Hz), 3.46 (3H, s), 3.48 (6H, s), 4.96 (1H, dd, J = 10.0,
1.2 Hz), 5.00 (1H, dd, J = 17.2, 1.6 Hz), 5.18 (4H, s), 5.21 (2H, d,
J = 2.4 Hz), 5.33 (1H, dd, J = 13.6, 3.2 Hz), 5.94 (1H, ddt, J = 17.2,
10.0, 6.0 Hz), 6.31 (1H, s), 6.75 (1H, t, J = 2.4 Hz), 6.79 (2H, d,
J = 2.4 Hz), 12.10 (1H, s); 13C NMR (100 MHz CDCl3) δ: 26.16, 43.48,
56.09, 56.36, 78.97, 93.47, 93.76, 94.42, 103.34, 104.80, 107.36,
108.81, 114.25, 136.05, 140.76, 158.59, 160.68, 161.09, 162.88,
195.97; IR (KBr): 1653, 1636, 1616, 1603, 1577, 1448, 1438, 1293,
1219, 1155, 1147, 1127, 1086, 1056, 968, 922 cm−1; mp: 98–100 °C;
MS (EI): m/z 460 (M+); HRMS (EI) Calcd for C24H28O9 460.1733 (M+);
Found 460.1739.
4.1.4.9. 6-Allyl-5-hydroxy-7-methoxymethoxy-2-(3-methoxy-methoxyphe
nyl)chroman-4-one (4i). Yield: 98%; 1H NMR (400 MHz CDCl3) δ: 2.91
(1H, dd, J = 17.2, 2.4 Hz), 3.16 (1H, dd, J = 17.2, 13.6 Hz), 3.37 (2H,
d, J = 6.4 Hz), 3.47 (3H, s), 3.49 (3H, s), 4.97 (1H, dd, J = 10.4,
1.2 Hz), 5.03 (1H, dd, J = 17.2, 1.2 Hz), 5.21 (2H, d, J = 1.2 Hz), 5.22
(2H, d, J = 2.4 Hz), 5.42 (1H, dd, J = 13.6, 2.4 Hz), 5.95 (1H, ddt,
J = 17.2, 10.4, 6.4 Hz), 6.33 (1H, s), 7.06 (1H, dd, J = 8.0, 2.0 Hz),
7.09 (1H, d, J = 8.0 Hz), 7.15 (1H, s), 7.34 (1H, t, J = 8.0 Hz), 12.31
(1H, s); 13C NMR (100 MHz CDCl3) δ: 26.23, 43.85, 56.05, 56.40,
79.15, 93.49, 93.81, 94.39, 103.22, 108.88, 114.08, 114.30, 116.40,
119.41, 129.93, 136.08, 140.01, 157.58, 160.93, 161.31, 163.04,
196.67; IR (KBr): 1635, 1576, 1558, 1486, 1440, 1297, 1287, 1221,
1155, 1127, 1093, 1078, 1055, 1033, 966, 926 cm−1; mp: 79–81 °C; MS
(EI): m/z 400 (M+); HRMS (EI) Calcd for C22H24O7 400.1522 (M+);
Found 400.1529.
4.1.4.14. 6-Allyl-5-hydroxy-7-methoxymethoxy-2-(4-methoxy-phenyl)chr
oman-4-one (4n). Yield: 84%; 1H NMR (400 MHz CDCl3) δ: 2.78 (1H,
dd, J = 17.0, 2.8 Hz), 3.10 (1H, dd, J = 17.0, 13.2 Hz), 3.35 (2H, d,
J = 6.0 Hz), 3.45 (3H, s), 3.83 (3H, s), 4.97 (1H, d, J = 9.6 Hz), 5.02
(1H, dd, J = 17.0, 1.2 Hz), 5.20 (2H, d, J = 3.6 Hz), 5.36 (1H, dd,
J = 13.2, 2.8 Hz), 5.94 (1H, ddt, J = 17.0, 9.6, 6.0 Hz), 6.29 (1H, s),
6.95 (2H, d, J = 8.8 Hz), 7.38 (2H, d, J = 8.8 Hz), 12.13 (1H, s); 13C
NMR (100 MHz CDCl3) δ: 26.20, 43.32, 55.34, 56.39, 79.00, 93.41,
93.79, 103.38, 108.72, 114.16, 114.28, 127.67, 130.41, 136.11,
159.97, 160.72, 161.37, 162.92, 196.38; IR (neat): 1636, 1578, 1516,
1489, 1448, 1437, 1339, 1310, 1285, 1256, 1221, 1151, 1124, 1090,
1051, 959, 830 cm−1; MS (EI): m/z 370 (M+); HRMS (EI) Calcd for
4.1.4.10. 6-Allyl-2-(2,3-bismethoxymethoxyphenyl)-5-hydroxy-7-methoxy
methoxychroman-4-one (4j). Yield: 87%; 1H NMR (400 MHz CDCl3) δ:
2.94 (1H, d, J = 3.6 Hz), 2.97 (1H, d, J = 12.8 Hz), 3.36 (2H, d,
J = 6.0 Hz), 3.45 (3H, s), 3.50 (3H, s), 3.51 (3H, s), 4.97 (1H, dd,
J = 10.4, 1.6 Hz), 5.04 (1H, dd, J = 17.2, 1.6 Hz), 5.15 (2H, s), 5.20
(2H, s), 5.21 (2H, s), 5.85 (1H, dd, J = 12.8, 3.6 Hz), 5.95 (1H, ddt,
J = 17.2, 10.4, 6.0 Hz), 6.30 (1H, s), 7.14 (1H, t, J = 7.2 Hz), 7.16 (1H,
d, J = 7.2 Hz), 7.27 (1H, dd, J = 7.2, 2.0 Hz), 12.18 (1H, s); 13C NMR
(100 MHz CDCl3) δ: 26.21, 42.88, 56.28, 56.36, 57.57, 74.43, 93.39,
93.77, 95.07, 99.34, 103.34, 108.68, 114.29, 116.48, 119.68, 124.87,
133.08, 136.11, 143.90, 149.48, 160.75, 161.56, 162.78, 196.62; IR
(KBr): 1653, 1640, 1577, 1477, 1448, 1438, 1296, 1287, 1275, 1219,
1156, 1128, 1089, 1060, 1040, 998, 962, 923 cm−1; mp: 88–89 °C; MS
(EI): m/z 460 (M+); HRMS (EI) Calcd for C24H28O9 460.1733 (M+);
Found 460.1728.
C
21H22O6 370.1416 (M+); Found 370.1410.
4.1.4.15. 6-Allyl-2-(4-chlorophenyl)-5-hydroxy-7-methoxy-methoxychrom
an-4-one (4o). Yield: 98%; 1H NMR (400 MHz CDCl3) δ: 3.43 (1H, d,
J = 16.6 Hz), 3.48 (2H, d, J = 6.4 Hz), 3.54 (3H, s), 3.69 (1H, t,
J = 16.6 Hz), 5.02 (1H, d, J = 10.4 Hz), 5.10 (1H, d, J = 17.2 Hz),
5.32 (2H, d, J = 3.6 Hz), 5.70 (1H, d, J = 12.8 Hz), 6.12 (1H, ddt,
J = 17.2, 10.4, 6.4 Hz), 6.47 (1H, s), 7.37–7.48 (4H, m), 13.54 (1H, br);
13C NMR (100 MHz CDCl3) δ: 26.31, 44.09, 56.48, 78.71, 93.54, 93.89,
103.11, 109.18, 114.40, 127.46, 129.01, 134.61, 136.05, 137.01,
161.19, 161.26, 163.25, 196.87; IR (KBr): 1636, 1576, 1508, 1495,
1447, 1437, 1418, 1339, 1304, 1288, 1223, 1215, 1186, 1155, 1105,
4.1.4.11. 6-Allyl-2-(2,6-bismethoxymethoxyphenyl)-5-hydroxy-7-methoxy
methoxychroman-4-one (4k). Yield: 80%; 1H NMR (400 MHz CDCl3) δ:
2.59 (1H, dd, J = 17.2, 3.2 Hz), 3.36 (2H, d, J = 6.4 Hz), 3.45 (3H, s),
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1090, 1057, 962, 831 cm−1; mp: 97–99 °C; MS (EI): m/z 374 (M+);
4.1.5.5. 6-Allyl-2-(2,3-dihydroxylphenyl)-5,7-dihydroxychroman-4-one (5j).
Yield: 99%; 1H NMR (400 MHz Acetone-d6) δ: 2.81 (1H, dd, J = 17.2,
3.2 Hz), 3.12 (1H, dd, J = 17.2, 12.8 Hz), 3.30 (2H, dd, J = 6.0, 1.2 Hz),
4.89 (1H, dd, J = 10.4, 1.6 Hz), 5.00 (1H, dd, J = 17.2, 1.6 Hz), 5.79 (1H,
dd, J = 12.8, 3.2 Hz), 5.91 (1H, ddt, J = 17.2, 10.4, 6.0 Hz), 6.07 (1H, s),
6.76 (1H, t, J = 8.0 Hz), 6.87 (1H, dd, J = 8.0, 1.2 Hz), 7.02 (1H, dd,
J = 8.0, 1.2 Hz), 8.65 (1H, br), 12.49 (1H, s); 13C NMR (100 MHz Acetone-
d6) δ: 26.66, 42.43, 75.30, 95.24, 103.00, 107.19, 114.50, 115.74, 118.42,
120.38, 126.57, 136.99, 143.29, 145.41, 162.43, 164.78, 197.42; IR (KBr):
1653, 1636, 1617, 1604, 1509, 1490, 1481, 1457, 1452, 1339, 1308, 1287,
1210, 1156 cm−1; mp: 177–178 °C; MS (EI): m/z 328 (M+); HRMS (EI)
Calcd for C18H16O6 328.0947 (M+); Found 328.0947.
HRMS (EI) Calcd for C20H19ClO5 374.0921 (M+); Found 374.0937.
4.1.5. General procedure of deprotection of methoxymethyl group for 5c
and 5g–o
To a stirred solution of 4c or 4g–o (0.64 mmol) in MeOH (5 mL) was
added conc. HCl (5 drops). The reaction mixture was stirred at room
temperature for 3 days. The reaction mixture was evaporated, and the
crude product was chromatographed on SiO2 (10 g, MeOH/
CH2Cl2 = 1/50) to give the corresponding product 5c or 5g–o.
4.1.5.1. 6-Allyl-5-hydroxy-2-(2-hydroxylphenyl)chroman-4-one (5c). Yield:
93%; 1H NMR (400 MHz Acetone-d6) δ: 2.93 (1H, dd, J = 17.2, 2.4 Hz),
3.19 (1H, dd, J = 17.2, 13.6 Hz), 3.30 (2H, d, J = 5.2 Hz), 5.00 (1H, d,
J = 10.4 Hz), 5.06 (1H, d, J = 17.2 Hz), 5.84 (1H, dd, J = 13.6, 2.4 Hz),
5.95 (1H, ddt, J = 17.2, 10.4, 5.2 Hz), 6.49 (1H, d, J = 8.0 Hz), 6.93 (1H,
t, J = 8.0 Hz), 6.94 (1H, d, J = 8.0 Hz), 7.21 (1H, t, J = 8.0 Hz), 7.32 (1H,
d, J = 8.0 Hz), 7.54 (1H, d, J = 8.0 Hz), 8.77 (1H, s), 12.15 (1H, s); 13C
NMR (100 MHz Acetone-d6) δ: 33.11, 43.02, 75.36, 107.73, 108.47,
115.81, 116.27, 120.42, 120.69, 126.23, 127.63, 130.20, 137.39,
139.18, 154.72, 160.18, 161.37, 200.18; IR (KBr): 1625, 1609, 1490,
1462, 1437, 1348, 1234, 755, 736 cm−1; mp: 184–186 °C; MS (EI): m/z
296 (M+); HRMS (EI) Calcd for C18H16O4 296.1049 (M+); Found
296.1044.
4.1.5.6. 6-Allyl-2-(2,6-dihydroxylphenyl)-5,7-dihydroxychroman-4-one (5k).
Yield: 82%; 1H NMR (400 MHz Acetone-d6) δ: 2.51 (1H, dd, J = 17.2,
2.4 Hz), 3.28 (2H, d, J = 6.0 Hz), 3.89 (1H, dd, J = 17.2, 13.6 Hz), 4.87
(1H, d, J = 10.0 Hz), 4.98 (1H, d, J = 17.2 Hz), 5.89 (1H, ddt, J = 17.2,
10.0, 6.0 Hz), 6.00 (1H, s), 6.02 (1H, dd, J = 13.6, 2.4 Hz), 6.44 (2H, d,
J = 8.4 Hz), 7.00 (1H, t, J = 8.4 Hz), 8.55 (2H, s), 9.56 (1H, s), 12.57 (1H,
s); 13C NMR (100 MHz Acetone-d6) δ: 26.20, 39.74, 72.64, 94.46, 102.25,
106.29, 107.67, 110.95, 113.71, 130.17, 136.33, 156.99, 161.84, 162.17,
163.86, 197.69; IR (KBr): 1653, 1635, 1601, 1558, 1506, 1472, 1456, 1451,
1447, 1312 cm−1; mp: 214–216 °C; MS (EI): m/z 328 (M+); HRMS (EI)
Calcd for C18H16O6 328.0947 (M+); Found 328.0947.
4.1.5.7. 6-Allyl-2-(3,4-dihydroxylphenyl)-5,7-dihydroxychroman-4-one (5l).
Yield: 100%; 1H NMR (400 MHz Acetone-d6) δ: 2.70 (1H, dd, J = 17.2,
3.2 Hz), 3.13 (1H, dd, J = 17.2, 12.8 Hz), 3.28 (2H, dt, J = 6.0, 2.0 Hz),
4.88 (1H, dd, J = 10.0, 2.0 Hz), 4.98 (1H, dd, J = 17.2, 2.0 Hz), 5.36 (1H,
dd, J = 12.8, 3.2 Hz), 5.90 (1H, ddt, J = 17.2, 10.0, 6.0 Hz), 6.03 (1H, s),
6.86 (2H, s), 7.02 (1H, s), 8.08 (2H, br), 9.62 (1H, br), 12.46 (1H, s); 13C
NMR (100 MHz Acetone-d6) δ: 26.64, 43.57, 79.87, 95.19, 102.95, 107.09,
114.49, 114.63, 115.92, 119.15, 131.53, 137.00, 145.90, 146.27, 162.18,
162.34, 164.86, 197.30; IR (KBr): 1654, 1646, 1635, 1617, 1589, 1523,
1507, 1490, 1457, 1339, 1326, 1303, 1290, 1158, 1109 cm−1; mp:
165–167 °C; MS (EI): m/z 328 (M+); HRMS (EI) Calcd for C18H16O6
328.0947 (M+); Found 328.0947.
4.1.5.2. 6-Allyl-5,7-dihydroxy-2-phenylchroman-4-one (5g). Yield: 93%;
1H NMR (400 MHz CDCl3) δ: 2.83 (1H, dd, J = 17.0, 3.0 Hz), 3.14 (1H,
dd, J = 17.0, 12.8 Hz), 3.41 (2H, d, J = 6.0 Hz), 5.15 (1H, dd, J = 10.0,
1.2 Hz), 5.20 (1H, dd, J = 17.2, 1.2 Hz), 5.42 (1H, dd, J = 12.8,
3.0 Hz), 5.76 (1H, br), 5.98 (1H, ddt, J = 17.2, 10.0, 6.0 Hz), 6.03
(1H, s), 7.37–7.47 (5H, m), 12.39 (1H, s); 13C NMR (100 MHz Acetone-
d6) δ: 26.68, 43.32, 79.90, 95.30, 103.03, 107.36, 114.54, 127.25,
129.35, 129.42, 136.98, 140.08, 162.03, 162.42, 164.92, 196.92; IR
(KBr): 1651, 1630, 1585, 1485, 1452, 1304, 1252, 1219, 1182, 1161,
1124, 1086, 817 cm−1; mp: 201–203 °C; MS (EI): m/z 296 (M+); HRMS
(EI) Calcd for C18H16O4 296.1049 (M+); Found 296.1044.
4.1.5.3. 6-Allyl-5,7-dihydroxy-2-(2-hydroxylphenyl)chroman-4-one (5h).
Yield: 95%; 1H NMR (400 MHz Acetone-d6) δ: 2.82 (1H, dd, J = 17.2,
3.2 Hz), 3.10 (1H, dd, J = 17.2, 13.2 Hz), 3.30 (2H, d, J = 6.4 Hz), 4.90
(1H, dd, J = 10.4, 2.0 Hz), 5.00 (1H, dd, J = 17.2, 2.0 Hz), 5.78 (1H, dd,
J = 13.2, 3.2 Hz), 5.91 (1H, ddt, J = 17.2, 10.4, 6.4 Hz), 6.09 (1H, s), 6.93
(1H, d, J = 8.0 Hz), 6.93 (1H, t, J = 8.0 Hz), 7.21 (1H, td, J = 8.0,
2.0 Hz), 7.52 (1H, dd, J = 8.0, 2.0 Hz), 8.78 (1H, s), 9.62 (1H, s), 12.15
(1H, s); 13C NMR (100 MHz Acetone-d6) δ: 26.66, 42.50, 75.26, 95.25,
102.97, 107.21, 114.51, 116.21, 120.62, 126.34, 127.62, 130.10, 136.98,
154.70, 162.43, 164.77, 197.39; IR (KBr): 1653, 1646, 1635, 1616, 1591,
1558, 1506, 1497, 1490, 1472, 1457, 1340, 1312, 1300, 1218, 1158,
1118, 826 cm−1; mp: 174–176 °C; MS (EI): m/z 312 (M+); HRMS (EI)
Calcd for C18H16O5 312.0998 (M+); Found 312.0986.
4.1.5.8. 6-Allyl-2-(3,5-dihydroxylphenyl)-5,7-dihydroxychroman-4-one (5m).
Yield: 98%; 1H NMR (400 MHz Acetone-d6) δ: 2.75 (1H, dd, J = 17.2,
2.8 Hz), 3.06 (1H, dd, J = 17.2, 12.8 Hz), 3.28 (2H, d, J = 6.4 Hz), 4.88
(1H, dd, J = 10.0, 1.6 Hz), 4.99 (1H, dd, J = 17.2, 1.6 Hz), 5.38 (1H, dd,
J = 12.8, 2.8 Hz), 5.89 (1H, ddt, J = 17.2, 10.0, 6.4 Hz), 6.06 (1H, s), 6.35
(1H, t, J = 2.0 Hz), 6.50 (2H, d, J = 1.6 Hz), 8.55 (1H, br), 12.43 (1H, s);
13C NMR (100 MHz Acetone-d6) δ: 26.64, 43.61, 79.72, 95.23, 102.99,
103.34, 105.56, 107.21, 114.51, 136.97, 142.30, 159.56, 161.97, 162.34,
164.89, 196.97 cm−1; mp: 121–123 °C; MS (EI): m/z 328 (M+); HRMS (EI)
Calcd for C18H16O6 328.0947 (M+); Found 328.0947.
4.1.5.9. 6-Allyl-5,7-dihydroxy-2-(4-methoxyphenyl)chroman-4-one
(5n).
Yield: 79%; 1H NMR (400 MHz CDCl3) δ: 2.79 (1H, dd, J = 17.2,
3.0 Hz), 3.10 (1H, dd, J = 17.2, 12.8 Hz), 3.41 (2H, dd, J = 6.0,
1.6 Hz), 3.83 (3H, s), 5.14 (1H, dd, J = 10.0, 1.6 Hz), 5.19 (1H, dd,
J = 17.2, 1.6 Hz), 5.39 (1H, dd, J = 12.8, 3.0 Hz), 5.77 (1H, br), 5.97 (1H,
ddt, J = 17.2, 10.0, 6.0 Hz), 6.01 (1H, s), 6.95 (2H, d, J = 8.8 Hz), 7.38
(2H, d, J = 8.8 Hz), 12.40 (1H, s); 13C NMR (100 MHz Acetone-d6) δ:
26.20, 43.32, 55.34, 56.39, 79.00, 93.41, 93.79, 103.38, 108.72, 114.16,
114.28, 127.67, 130.41, 136.11, 159.97, 160.72, 161.37, 162.92, 196.38;
IR (KBr): 1651, 1630, 1616, 1585, 1520, 1506, 1489, 1464, 1425, 1362,
1329, 1300, 1261, 1213, 1173, 1161, 1086, 835, 818 cm−1; mp:
199–201 °C; MS (EI): m/z 326 (M+); HRMS (EI) Calcd for C19H18O5
326.1154 (M+); Found 326.1165.
4.1.5.4. 6-Allyl-5,7-dihydroxy-2-(3-hydroxylphenyl)chroman-4-one
(5i).
Yield: 91%; 1H NMR (400 MHz Acetone-d6) δ: 2.78 (1H, dd, J = 17.2,
3.2 Hz), 3.11 (1H, dd, J = 17.2, 12.8 Hz), 3.29 (2H, d, J = 6.0 Hz), 4.89
(1H, dd, J = 10.4, 1.6 Hz), 4.99 (1H, dd, J = 17.2, 1.6 Hz), 5.47 (1H, dd,
J = 12.8, 3.2 Hz), 5.90 (1H, ddt, J = 17.2, 10.4, 6.0 Hz), 6.07 (1H, s), 6.84
(1H, dd, J = 8.0, 2.4 Hz), 6.99 (1H, d, J = 8.0 Hz), 7.02 (1H, d,
J = 2.4 Hz), 7.25 (1H, t, J = 8.0 Hz), 8.55 (1H, br), 9.66 (1H, br), 12.44
(1H, s); 13C NMR (100 MHz Acetone-d6) δ: 26.66, 43.65, 79.74, 95.27,
103.02, 107.29, 114.09, 114.53, 116.22, 118.19, 130.52, 136.97, 141.59,
158.44, 161.99, 162.39, 164.88, 196.95; IR (KBr): 1635, 1593, 1558,
1506, 1490, 1472, 1456, 1339, 1303, 1280, 1215, 1154, 1120,
1078 cm−1; mp: 168–170 °C; MS (EI): m/z 312 (M+); HRMS (EI) Calcd
for C18H16O5 312.0998 (M+); Found 312.0986.
4.1.5.10. 6-Allyl-2-(4-chlorophenyl)-5,7-dihydroxychroman-4-one (5o). Yield:
77%; 1H NMR (400 MHz CDCl3) δ: 2.82 (1H, dd, J = 17.2, 3.0 Hz), 3.02
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(1H, dd, J = 17.2, 12.8 Hz), 3.41 (2H, d, J = 5.6 Hz), 5.14 (1H, dd,
J = 10.4, 1.2 Hz), 5.18 (1H, dd, J = 16.0, 1.2 Hz), 5.39 (1H, dd, J = 12.8,
3.0 Hz), 5.90–6.05 (3H, m), 7.34–7.45 (4H, m), 12.33 (1H, s); 13C NMR
(100 MHz CDCl3) δ: 26.20, 43.31, 78.343, 95.49, 102.95, 105.68, 106.16,
127.47, 129.05, 134.67, 135.78, 136.92, 160.98, 161.52, 163.46, 195.46; IR
(KBr): 1651, 1632, 1587, 1495, 1462, 1450, 1416, 1331, 1310, 1303, 1250,
1217, 1162, 1153, 1124, 1088, 825 cm−1; mp: 185–187 °C; MS (EI): m/z
330 (M+); HRMS (EI) Calcd for C18H15ClO4 330.0659 (M+); Found
330.0672.
J = 17.2, 9.6, 6.0 Hz), 6.30 (1H, s), 7.11 (1H, d, J = 8.0 Hz), 7.20 (1H,
s), 7.28 (1H, d, J = 8.0 Hz), 7.42 (1H, t, J = 8.0 Hz), 12.14 (1H, s); 13
C
NMR (100 MHz CDCl3) δ: 20.89, 21.06, 27.03, 43.61, 78.38, 102.23,
106.06, 113.24, 115.08, 119.29, 122.05, 123.27, 129.88, 135.09,
139.77, 150.92, 156.69, 159.78, 161.19, 168.26, 169.27, 196.84; IR
(KBr): 1768, 1652, 1640, 1635, 1586, 1436, 1371, 1198, 1138 cm−1
;
mp: 71-73 °C; MS (EI): m/z 396 (M+); HRMS (EI) Calcd for C22H20O7
396.1209 (M+); Found 396.1213
4.1.6.5. 7-Acetoxy-6-allyl-5-hydroxy-2-(2,3-diacetoxyphenyl)-chroman-4-
one (6j). Yield: 89%; 1H NMR (400 MHz CDCl3) δ: 2.28 (6H, s), 2.29
(3H, s), 2.82 (1H, dd, J = 17.2, 2.4 Hz), 3.09 (1H, dd, J = 17.2,
13.6 Hz), 3.24 (2H, d, J = 6.8 Hz), 4.97 (1H, dd, J = 10.4, 1.6 Hz),
5.00 (1H, dd, J = 17.2, 1.6 Hz), 5.52 (1H, dd, J = 13.6, 2.4 Hz), 5.83
(1H, ddt, J = 17.2, 10.4, 6.8 Hz), 6.25 (1H, s), 7.25 (1H, dd, J = 8.0,
1.6 Hz), 7.35 (1H, t, J = 8.0 Hz), 7.47 (1H, d, J = 8.0 Hz), 12.15 (1H,
s); 13C NMR (100 MHz CDCl3) δ: 20.29, 20.64, 20.87, 27.03, 42.46,
74.18, 102.21, 106.00, 113.47, 115.13, 124.03, 124.28, 126.93,
132.12, 135.04, 139.65, 142.65, 156.68, 159.74, 161.24, 167.84,
168.01, 168.23, 196.76; IR (KBr): 1772, 1654, 1638, 1586, 1472,
1437, 1374, 1278, 1200, 1164, 1141, 1114 cm−1; mp: 123–124 °C; MS
(EI): m/z 454 (M+); HRMS (EI) Calcd for C24H22O9 454.1264 (M+);
Found 454.1255.
4.1.6. General procedure of protection of acetyl group for 6c and 6g–o
To a stirred solution of 5c or 5g–o (0.46 mmol) in pyridine (5 mL)
was added dropwise Ac2O (2 eq. for the number of hydroxyl group on
5c or 5g–o) at room temperature. The reaction mixture was stirred for
12 h. The solvent was evaporated, and the residue was chromato-
graphed on SiO2 (10 g, EtOAc/hexane = 1/3) to give the corresponding
product 6c or 6g–o.
4.1.6.1. 6-Allyl-5-hydroxy-2-(2-acetoxyphenyl)chroman-4-one (6c). Yield:
99%; 1H NMR (400 MHz CDCl3) δ: 2.27 (3H, s), 2.83 (1H, dd, J = 17.2,
2.4 Hz), 3.10 (1H, dd, J = 17.2, 13.6 Hz), 3.32 (2H, d, J = 6.4 Hz), 5.05
(1H, dd, J = 10.4, 1.8 Hz), 5.06 (1H, dd, J = 17.2, 1.8 Hz), 5.53 (1H, dd,
J = 13.6, 2.4 Hz), 5.95 (1H, ddt, J = 17.2, 10.4, 6.4 Hz), 6.44 (1H, d,
J = 8.0 Hz), 7.13 (1H, dd, J = 8.0, 1.2 Hz), 7.25 (1H, d, J = 8.0 Hz),
7.32 (1H, td, J = 8.0, 1.2 Hz), 7.40 (1H, td, J = 8.0, 1.6 Hz), 7.62 (1H,
dd, J = 8.0, 1.6 Hz), 11.96 (1H, s); 13C NMR (100 MHz CDCl3) δ: 20.92,
32.59, 42.82, 74.32, 106.91, 107.66, 115.75, 120.49, 123.00, 126.55,
127.19, 129.76, 130.33, 136.22, 138.73, 147.72, 159.47, 159.72,
169.06, 198.02; IR (KBr): 1762, 1653, 1647, 1627, 1493, 1480, 1431,
4.1.6.6. 7-Acetoxy-6-allyl-5-hydroxy-2-(2,6-diacetoxyphenyl)-chroman-4-
one (6k). Yield: 65%; 1H NMR (400 MHz CDCl3) δ: 2.25 (6H, s), 2.29
(3H, s), 2.71 (1H, dd, J = 17.2, 3.2 Hz), 3.27 (2H, d, J = 6.4 Hz), 3.56
(1H, dd, J = 17.2, 14.0 Hz), 5.00 (1H, dd, J = 10.4, 1.2 Hz), 5.03 (1H,
dd, J = 17.2, 1.2 Hz), 5.59 (1H, dd, J = 14.0, 3.2 Hz), 5.85 (1H, ddt,
J = 17.2, 10.4, 6.4 Hz), 6.22 (1H, s), 7.05 (2H, d, J = 8.0 Hz), 7.44 (1H,
t, J = 8.0 Hz), 12.23 (1H, s); 13C NMR (100 MHz CDCl3) δ: 20.84,
27.08, 40.43, 72.23, 101.93, 105.79, 113.47, 115.19, 121.48, 122.48,
130.01, 135.04, 149.28, 156.77, 159.66, 161.36, 168.20, 168.96,
197.69; IR (KBr): 1771, 1653, 1646, 1635, 1616, 1558, 1507, 1436,
1192, 1139 cm−1; mp: 72–74 °C; MS (EI): m/z 454 (M+); HRMS (EI)
Calcd for C24H22O9 454.1264 (M+); Found 454.1255.
1369, 1356, 1340, 1226, 1202, 1186, 1175, 1166, 1060, 919, 815 cm−1
;
mp: 83–85 °C; MS (EI): m/z 338 (M+); HRMS (EI) Calcd for C20H18O5
338.1154 (M+); Found 338.1140.
4.1.6.2. 7-Acetoxy-6-allyl-5-hydroxy-2-phenylchroman-4-one (6g). Yield: 82%;
1H NMR (400 MHz CDCl3) δ: 2.30 (3H, s), 2.88 (1H, dd, J = 17.2, 3.0 Hz),
3.14 (1H, dd, J = 17.2, 13.2 Hz), 3.28 (2H, dd, J = 6.0, 1.6 Hz), 5.00 (1H,
dd, J = 10.4, 1.6 Hz), 5.02 (1H, dd, J = 17.0, 1.6 Hz), 5.42 (1H, dd,
J = 13.2, 3.0 Hz), 5.85 (1H, ddt, J = 17.0, 10.4, 6.0 Hz), 6.30 (1H, s),
7.37–7.47 (5H, m), 12.20 (1H, s); 13C NMR (100 MHz CDCl3) δ: 20.90, 27.05,
43.66, 79.13, 102.20, 106.12, 113.08, 115.06, 126.05, 128.84, 128.90,
135.16, 138.06, 156.69, 160.08, 161.21, 168.28, 197.23; IR (KBr): 1763,
1639, 1591, 1437, 1373, 1312, 1279, 1202, 1150, 1115, 1088, 1049, 993,
802 cm−1; mp: 102–104 °C; MS (EI): m/z 338 (M+); HRMS (EI) Calcd for
4.1.6.7. 7-Acetoxy-6-allyl-5-hydroxy-2-(3,4-diacetoxyphenyl)-chroman-4-
one (6l). Yield: 76%; 1H NMR (400 MHz CDCl3) δ: 2.28 (3H, s), 2.29
(3H, s), 2.29 (3H, s), 2.87 (1H, dd, J = 17.2, 3.2 Hz), 3.05 (1H, dd,
J = 17.2, 13.6 Hz), 3.26 (2H, d, J = 6.4 Hz), 4.98 (1H, d, J = 9.2 Hz),
4.99 (1H, d, J = 17.2 Hz), 5.41 (1H, dd, J = 13.6, 3.2 Hz), 5.83 (1H,
ddt, J = 17.2, 9.2, 6.4 Hz), 6.29 (1H, d, J = 2.4 Hz), 7.23 (1H, d,
J = 6.0 Hz), 7.24 (1H, d, J = 2.4 Hz), 7.30 (1H, d, J = 6.0 Hz), 12.13
(1H, s); 13C NMR (100 MHz CDCl3) δ: 20.57, 20.59, 20.89, 27.03,
43.60, 78.01, 102.21, 106.04, 113.35, 115.10, 121.30, 123.87, 124.07,
135.07, 136.86, 142.26, 142.30, 156.72, 159.69, 161.21, 168.04,
168.08, 168.24, 196.69; IR (KBr): 1769, 1751, 1653, 1647, 1637,
1507, 1436, 1374, 1262, 1216, 1201, 1137, 1115 cm−1; mp: 97–99 °C;
MS (EI): m/z 454 (M+); HRMS (EI) Calcd for C24H22O9 454.1264 (M+);
Found 454.1261.
C
20H18O5 338.1154 (M+); Found 338.1140.
4.1.6.3. 7-Acetoxy-6-allyl-5-hydroxy-2-(2-acetoxyphenyl)-chroman-4-one
(6h). Yield: 89%; 1H NMR (400 MHz CDCl3) δ: 2.30 (3H, s), 2.31 (3H,
s), 2.84 (1H, dd, J = 17.2, 3.2 Hz), 3.11 (1H, dd, J = 17.2, 13.6 Hz),
3.28 (2H, dd, J = 6.0, 1.2 Hz), 4.99 (1H, dd, J = 10.4, 1.2 Hz), 5.03
(1H, dd, J = 17.2, 1.2 Hz), 5.57 (1H, dd, J = 13.6, 3.2 Hz), 5.85 (1H,
ddt, J = 17.2, 10.4, 6.0 Hz), 6.28 (1H, s), 7.14 (1H, dd, J = 7.6, 1.2 Hz),
7.34 (1H, td, J = 7.6, 1.2 Hz), 7.42 (1H, td, J = 7.6, 2.0 Hz), 7.62 (1H,
dd, J = 7.6, 2.0 Hz), 12.19 (1H, s); 13C NMR (100 MHz CDCl3) δ: 20.85,
20.88, 27.01, 30.85, 42.52, 74.30, 102.19, 106.02, 113.30, 115.09,
122.95, 126.53, 127.10, 129.82, 135.06, 147.64, 156.64, 159.94,
161.21, 168.24, 169.06, 197.05; IR (KBr): 1771, 1653, 1635, 1587,
4.1.6.8. 7-Acetoxy-6-allyl-5-hydroxy-2-(3,5-diacetoxyphenyl)-chroman-4-
one (6m). Yield: 88%; 1H NMR (400 MHz CDCl3) δ: 2.28 (6H, s), 2.29
(3H, s), 2.88 (1H, dd, J = 17.2, 2.8 Hz), 3.04 (1H, dd, J = 17.2,
12.8 Hz), 3.26 (2H, d, J = 6.4 Hz), 4.98 (1H, dd, J = 10.4, 1.6 Hz),
5.00 (1H, dd, J = 17.2, 1.6 Hz), 5.41 (1H, dd, J = 12.8, 2.8 Hz), 5.83
(1H, ddt, J = 17.2, 10.4, 6.4 Hz), 6.30 (1H, s), 6.94 (1H, t, J = 1.6 Hz),
7.07 (2H, d, J = 2.4 Hz), 12.11 (1H, s); 13C NMR (100 MHz CDCl3) δ:
20.91, 21.05, 27.05, 43.58, 77.94, 102.24, 106.04, 113.43, 115.13,
115.80, 116.52, 135.08, 140.52, 151.30, 156.74, 159.57, 161.22,
168.25, 168.79, 196.51; IR (KBr): 1772, 1653, 1640, 1586, 1436,
1369, 1282, 1197, 1140, 1125, 1052, 1025, 911, 900 cm−1; mp:
145–147 °C; MS (EI): m/z 454 (M+); HRMS (EI) Calcd for C24H22O9
454.1264 (M+); Found 454.1255.
1558, 1505, 1436, 1373, 1270, 1192, 1178, 1138, 1083, 1055 cm−1
;
mp: 104–106 °C; MS (EI): m/z 396 (M+); HRMS (EI) Calcd for C22H20O7
396.1209 (M+); Found 396.1213.
4.1.6.4. 7-Acetoxy-6-allyl-5-hydroxy-2-(3-acetoxyphenyl)-chroman-4-one
(6i). Yield: 88%; 1H NMR (400 MHz CDCl3) δ: 2.28 (3H, s), 2.30 (3H,
s), 2.87 (1H, dd, J = 17.2, 3.2 Hz), 3.07 (1H, dd, J = 17.2, 13.2 Hz),
3.26 (2H, d, J = 6.0 Hz), 4.98 (1H, dd, J = 9.6, 1.6 Hz), 5.00 (1H, dd,
J = 17.2, 1.6 Hz), 5.43 (1H, dd, J = 13.2, 3.2 Hz), 5.83 (1H, ddt,
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4.1.6.9. 7-Acetoxy-6-allyl-5-hydroxy-2-(4-methoxyphenyl)-chroman-4-one
(6n). Yield: 81%; 1H NMR (400 MHz CDCl3) δ: 2.29 (3H, s), 2.84 (1H,
dd, J = 17.2, 2.6 Hz), 3.14 (1H, dd, J = 17.2, 13.2 Hz), 3.28 (2H, d,
J = 6.0 Hz), 3.83 (3H, s), 4.99 (1H, dd, J = 9.6, 1.2 Hz), 5.02 (1H, dd,
J = 16.8, 1.2 Hz), 5.39 (1H, dd, J = 13.2, 2.6 Hz), 5.85 (1H, ddt,
J = 16.8, 9.6, 6.0 Hz), 6.29 (1H, s), 6.95 (2H, d, J = 8.8 Hz), 7.37 (2H,
d, J = 8.8 Hz), 12.21 (1H, s); 13C NMR (100 MHz CDCl3) δ: 20.87, 27.02,
43.42, 55.28, 78.89, 102.14, 106.08, 112.93, 114.14, 115.01, 127.65,
130.02, 135.17, 156.62, 160.00, 160.17, 161.16, 168.26, 197.48; IR
(KBr): 1761, 1645, 1612, 1589, 1518, 1437, 1377, 1346, 1308, 1258,
1240, 1209, 1146, 1115, 1086, 1045 cm−1; mp: 145–147 °C; MS (EI): m/
z 368 (M+); HRMS (EI) Calcd for C21H20O6 368.1260 (M+); Found
368.1269.
7.34 (1H, td, J = 8.0, 1.2 Hz), 7.56 (1H, dd, J = 8.0, 1.2 Hz), 11.91
(1H, s); 13C NMR (100 MHz CDCl3) δ: 17.47, 20.93, 25.76, 26.83,
42.87, 74.30, 106.76, 107.63, 121.74, 122.12, 123.00, 126.55, 127.21,
129.74, 130.40, 133.15, 138.22, 147.73, 159.37, 159.48, 169.08,
198.06; IR (KBr): 1762, 1653, 1645, 1635, 1558, 1490, 1461, 1436,
1368, 1231, 1207, 1186, 1056, 790 cm−1; mp: 93–95 °C; MS (EI): m/z
366 (M+); HRMS (EI) Calcd for C22H22O5 366.1467 (M+); Found
366.1485.
4.1.7.4. 5-Hydroxy-6-(3-ethylpent-2-enyl)-2-(2-acetoxyphenyl)-chroman-
4-one (7d). Yield: 80%; 1H NMR (400 MHz CDCl3) δ: 0.98 (3H, t,
J = 7.2 Hz), 1.00 (3H, t, J = 7.2 Hz), 2.05 (2H, q, J = 7.2 Hz), 2.12
(2H, q, J = 7.2 Hz), 2.27 (3H, s), 2.83 (1H, dd, J = 17.2, 3.2 Hz), 3.09
(1H, dd, J = 17.2, 13.4 Hz), 3.29 (2H, d, J = 7.2 Hz), 5.21 (1H, t,
J = 7.2 Hz), 5.52 (1H, dd, J = 13.4, 3.2 Hz), 6.42 (1H, d, J = 8.0 Hz),
7.12 (1H, d, J = 8.0 Hz), 7.25 (1H, d, J = 8.0 Hz), 7.32 (1H, t,
J = 8.0 Hz), 7.40 (1H, td, J = 8.0, 2.0 Hz), 7.62 (1H, dd, J = 8.0,
2.0 Hz), 11.96 (1H, s); 13C NMR (100 MHz CDCl3) δ: 12.80, 13.20,
20.93, 23.21, 26.13, 29.19, 42.87, 74.29, 106.76, 107.61, 119.61,
122.30, 123.00, 126.55, 127.21, 129.74, 130.42, 138.16, 144.47,
147.73, 159.36, 159.51, 169.10, 198.09; IR (KBr): 1771, 1768, 1653,
1646, 1635, 1490, 1456, 1436, 1368, 1226, 1201, 1187, 1111,
1064 cm−1; mp: 72–74 °C; MS (EI): m/z 394 (M+); HRMS (EI) Calcd
for C24H26O5 394.1780 (M+); Found 394.1794.
4.1.6.10. 7-Acetoxy-6-allyl-5-hydroxy-2-(4-chlorophenyl)-chroman-4-one
(6o). Yield: 32%; 1H NMR (400 MHz CDCl3) δ: 2.30 (3H, s), 2.86 (1H,
dd, J = 17.2, 3.0 Hz), 3.08 (1H, dd, J = 17.2, 13.0 Hz), 3.28 (2H, d,
J = 6.4 Hz), 5.00 (1H, dd, J = 10.4, 1.6 Hz), 5.02 (1H, dd, J = 17.2,
1.6 Hz), 5.43 (1H, dd, J = 13.0, 3.0 Hz), 5.85 (1H, ddt, J = 17.2, 10.4,
6.4 Hz), 6.31 (1H, s), 7.40 (4H, d, J = 4.4 Hz), 12.15 (1H, s); 13C NMR
(100 MHz CDCl3) δ: 20.90, 27.03, 43.56, 78.34, 102.20, 106.05,
113.31, 115.11, 127.41, 129.04, 134.71, 135.08, 136.59, 156.72,
159.76, 161.22, 168.26, 196.76; IR (KBr): 1753, 1655, 1635, 1628,
1591, 1495, 1433, 1415, 1373, 1302, 1290, 1223, 1204, 1142, 1117,
1090, 1080, 1049, 908, 825 cm−1; mp: 101–103 °C; MS (EI): m/z 372
(M+); HRMS (EI) Calcd for C20H17ClO5 372.0765 (M+); Found
372.0778.
4.1.7.5. 6-(3-Ethylpent-2-enyl)-5-hydroxy-2-(4-methoxyphenyl)-chroman-
4-one (7e). Yield: 54%; 1H NMR (400 MHz CDCl3) δ: 1.62 (3H, s), 1.65
(3H, s), 2.74 (1H, dd, J = 17.2, 2.4 Hz), 3.03 (1H, dd, J = 17.2,
13.2 Hz), 3.35 (2H, d, J = 7.4 Hz), 3.73 (3H, s), 5.19 (1H, t,
J = 7.4 Hz), 5.26 (1H, dd, J = 13.2, 2.4 Hz), 6.34 (1H, d, J = 8.4 Hz),
6.85 (2H, d, J = 8.4 Hz), 7.16 (1H, d, J = 8.4 Hz), 7.29 (2H, d,
J = 8.4 Hz), 11.90 (1H, s); 13C NMR (100 MHz CDCl3) δ: 17.73,
25.75, 26.80, 43.77, 55.32, 78.77, 106.79, 107.69, 114.18, 121.76,
121.84, 127.67, 130.46, 133.06, 138.13, 159.43, 159.55, 159.98
198.45; IR (KBr): 1647, 1624, 1587, 1518, 1474, 1456, 1435, 1429,
1373, 1362, 1352, 1337, 1308, 1256, 1229, 1178, 1159, 1096, 1055,
1032, 833, 777 cm−1; mp: 54–56 °C; MS (EI): m/z 338 (M+); HRMS (EI)
Calcd for C21H22O4 338.1518 (M+); Found 338.1508.
4.1.7. General procedure of cross-metathesis for 7a–q
To a stirred solution of 4a–b, 6c, 4d–f or 6g–o (0.27 mmol) in
benzene (5 mL) were added corresponding olefin (5.40 mmol) and
Grubbs catalyst, 2nd Generation (11 mg, 0.014 mmol) under argon at-
mosphere. The reaction mixture was heated in the sealed tube at 100 °C
for 20 h. After cooling, the solvent was removed under vacuum, the
crude product was chromatographed on SiO2 (10 g, EtOAc/
hexane = 1/7) to give the corresponding product 7a–q.
4.1.7.1. 5-Hydroxy-6-(3-methylbut-2-enyl)-2-phenylchroman-4-one (7a). Yield:
98%; 1H NMR (400 MHz CDCl3) δ: 1.72 (3H, s), 1.75 (3H, s), 2.88 (1H, dd,
J = 17.2, 3.0 Hz), 3.14 (1H, dd, J = 17.2, 13.2 Hz), 3.28 (2H, d, J = 7.2 Hz),
5.28 (1H, tt, J = 7.2, 1.2 Hz), 5.43 (1H, dd, J = 13.2, 3.0 Hz), 6.46 (1H, d,
4.1.7.6. 2-(4-Ethoxyphenyl)-6-(3-ethylpent-2-enyl)-5-hydroxy-chroman-
4-one (7f). Yield: 64%; 1H NMR (400 MHz CDCl3) δ: 1.43 (3H, t,
J = 7.0 Hz), 1.71 (3H, s), 1.75 (3H, s), 2.83 (1H, dd, J = 17.2, 2.4 Hz),
3.13 (1H, dd, J = 17.2, 13.2 Hz), 3.27 (2H, d, J = 7.0 Hz), 4.05 (2H, q,
J = 7.0 Hz), 5.28 (1H, t, J = 7.0 Hz), 5.36 (1H, dd, J = 13.2, 2.4 Hz),
6.44 (1H, d, J = 8.0 Hz), 6.94 (2H, d, J = 8.4 Hz), 7.25 (1H, d,
J = 8.0 Hz), 7.37 (2H, d, J = 8.4 Hz), 11.99 (1H, s); 13C NMR
(100 MHz CDCl3) δ: 14.77, 17.75, 25.76, 26.81, 43.80, 63.55, 78.84,
106.81, 107.71, 114.72, 121.77, 121.85, 127.67, 130.28, 133.08,
138.15, 159.38, 159.44, 159.60 198.52; IR (KBr): 1626, 1616, 1599,
1520, 1489, 1474, 1456, 1437, 1375, 1364, 1340, 1273, 1231, 1171,
1101, 1057, 831 cm−1; mp: 105–107 °C; MS (EI): m/z 352 (M+);
HRMS (EI) Calcd for C22H24O4 352.1675 (M+); Found 352.1666.
J = 8.4 Hz), 7.27 (1H, d, J = 8.4 Hz), 7.39–7.49 (5H, m), 11.98 (1H, s); 13
C
NMR (100 MHz CDCl3) δ: 17.75, 25.77, 26.81, 43.98, 79.03, 106.81, 107.72,
121.80, 121.92, 126.10, 128.85, 128.90, 133.13, 135.68, 138.20, 138.43,
159.45, 198.23; IR (KBr): 1683, 1635, 1607, 1578, 1474, 1439, 1367, 1340,
1252, 1231, 1186, 1109, 1065, 698 cm−1; mp: 72–74 °C; MS (EI): m/z 308
(M+); HRMS (EI) Calcd for C20H20O3 308.1412 (M+); Found 308.1404.
4.1.7.2. 5-Hydroxy-6-(3-methylbut-2-enyl)-2-p-tolylchroman-4-one (7b). Yield:
1
56%; H NMR (400 MHz CDCl3) δ: 1.71 (3H, s), 1.74 (3H, s), 2.38 (3H, s),
2.84 (1H, dd, J = 17.2, 3.0 Hz), 3.12 (1H, dd, J = 17.2, 13.2 Hz), 3.27 (2H,
d, J = 7.6 Hz), 5.28 (1H, tt, J = 7.6, 1.6 Hz), 5.37 (1H, dd, J = 13.2, 3.0 Hz),
6.44 (1H, d, J = 8.4 Hz), 7.23 (2H, d, J = 7.8 Hz), 7.26 (1H, d, J = 8.4 Hz),
7.35 (2H, d, J = 7.8 Hz), 11.98 (1H, s); 13C NMR (100 MHz CDCl3) δ: 17.75,
21.19, 25.76, 26.80, 43.86, 78.96, 106.81, 107.71, 121.78, 121.83, 126.13,
129.48, 133.08, 135.44, 138.15, 138.76, 159.43, 159.54, 198.40; IR (KBr):
1639, 1582, 1518, 1474, 1443, 1369, 1313, 1263, 1238, 1107, 1063,
814 cm−1; mp: 57–59 °C; MS (EI): m/z 322 (M+); HRMS (EI) Calcd for
4.1.7.7. 2-(4-Chlorophenyl)-5-hydroxy-6-(3-methylbut-2-enyl)chroman-4-
one (7g). Yield: 64%; 1H NMR (400 MHz CDCl3) δ: 1.72 (3H, s), 1.75
(3H, s), 2.86 (1H, dd, J = 17.2, 2.8 Hz), 3.12 (1H, ddd, J = 17.2,
12.8 Hz), 3.27 (2H, d, J = 7.2 Hz), 5.28 (1H, t, J = 7.2 Hz), 5.40 (1H,
dd, J = 12.8, 2.8 Hz), 6.45 (1H, dd, J = 8.2, 3.2 Hz), 7.27 (1H, d,
J = 8.2 Hz), 7.40 (4H, d, J = 3.2 Hz), 11.94 (1H, s); 13C NMR (100 MHz
CDCl3) δ: 17.75, 25.76, 26.81, 43.88, 78.23, 106.76, 107.66, 121.72,
122.17, 127.45, 129.03, 133.20, 134.62, 136.97, 138.25, 159.15,
159.47, 197.75; IR (KBr): 1647, 1628, 1495, 1475, 1435, 1362, 1339,
1259, 1228, 1097, 1055, 1016, 831, 820, 793 cm−1; mp: 67–69 °C; MS
(EI): m/z 342 (M+); HRMS (EI) Calcd for C20H19ClO3 342.1023 (M+);
Found 342.1038.
C
21H22O3 322.1569 (M+); Found 322.1557.
4.1.7.3. 5-Hydroxy-6-(3-methylbut-2-enyl)-2-(2-acetoxyphenyl)-chroman-
4-one (7c). Yield: 85%; 1H NMR (400 MHz CDCl3) δ: 1.64 (3H, s), 1.68
(3H, s), 2.22 (3H, s), 2.77 (1H, dd, J = 17.2, 3.2 Hz), 3.04 (1H, dd,
J = 17.2, 13.2 Hz), 3.20 (2H, d, J = 7.6 Hz), 5.21 (1H, td, J = 7.6,
2.8 Hz), 5.46 (1H, dd, J = 13.2, 3.2 Hz), 6.36 (1H, d, J = 8.0 Hz), 7.07
(1H, d, J = 8.0 Hz), 7.19 (1H, d, J = 8.0 Hz), 7.27 (1H, t, J = 8.0 Hz),
13

H. Du Nguyen et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
4.1.7.8. 7-Acetoxy-5-hydroxy-6-(3-methylbut-2-enyl)-2-phenyl-chroman-
4-one (7h). Yield: 51%; 1H NMR (400 MHz CDCl3) δ: 1.68 (3H, s), 1.75
(3H, s), 2.30 (3H, s), 2.88 (1H, dd, J = 17.2, 2.8 Hz), 3.11 (1H, dd,
J = 17.2, 13.0 Hz), 3.22 (2H, d, J = 6.8 Hz), 5.11 (1H, t, J = 6.8 Hz),
5.44 (1H, dd, J = 13.0, 2.8 Hz), 6.29 (1H, s), 7.38–7.45 (5H, m), 12.20
(1H, s); 13C NMR (100 MHz CDCl3) δ: 17.75, 20.90, 21.98, 25.67,
43.70, 79.09, 102.05, 106.18, 114.98, 115.06, 121.28, 126.05, 128.84,
132.16, 138.13, 156.44, 159.72, 161.22, 168.37, 197.23; IR (KBr):
1763, 1632, 1589, 1454, 1431, 1373, 1310, 1281, 1202, 1169, 1146,
1090, 1067, 999, 903, 793 cm−1; mp: 82–84 °C; MS (EI): m/z 366 (M+);
HRMS (EI) Calcd for C22H22O5 366.1467 (M+); Found 366.1485.
1374, 1205, 1171, 1160, 1137 cm−1; mp: 56–58 °C; MS (EI): m/z 482 (M+);
HRMS (EI) Calcd for C26H26O9 482.1577 (M+); Found 482.1576.
4.1.7.13. 7-Acetoxy-5-hydroxy-6-(3-methylbut-2-enyl)-2-(2,6-diacetoxyp
henyl)chroman-4-one (7m). Yield: 89%; 1H NMR (400 MHz CDCl3) δ:
1.68 (3H, s), 1.75 (3H, s), 2.24 (6H, s), 2.29 (3H, s), 2.70 (1H, dd,
J = 17.2, 3.2 Hz), 3.20 (2H, d, J = 7.6 Hz), 3.54 (1H, dd, J = 17.2,
14.0 Hz), 5.10 (1H, t, J = 7.6 Hz), 5.57 (1H, dd, J = 14.0, 3.2 Hz), 6.19
(1H, s), 7.05 (2H, d, J = 8.0 Hz), 7.43 (1H, t, J = 8.0 Hz), 12.21 (1H, s);
13C NMR (100 MHz CDCl3) δ: 17.71, 20.79, 20.83, 21.96, 25.65, 40.47,
72.20, 101.80, 105.85, 115.29, 121.09, 121.47, 122.51, 129.97,
132.25, 149.27, 156.50, 159.32, 161.36, 168.27, 168.97, 197.09; IR
(KBr): 1771, 1653, 1646, 1635, 1616, 1558, 1506, 1472, 1465, 1436,
1373, 1192, 1138, 1032 cm−1; mp: 68–70 °C; MS (EI): m/z 482 (M+);
HRMS (EI) Calcd for C26H26O9 482.1577 (M+); Found 482.1576.
4.1.7.9. 7-Acetoxy-5-hydroxy-6-(3-methylbut-2-enyl)-2-(2-acetoxyphenyl)
chroman-4-one (7i). Yield: 78%; 1H NMR (400 MHz CDCl3) δ: 1.64 (3H,
s), 1.68 (3H, s), 2.28 (6H, s), 2.81 (1H, dd, J = 17.2, 3.2 Hz), 3.08 (1H,
dd, J = 17.2, 13.2 Hz), 3.19 (2H, d, J = 7.2 Hz), 5.09 (1H, t, J = 7.2 Hz),
5.53 (1H, dd, J = 13.2, 3.2 Hz), 6.23 (1H, s), 7.12 (1H, d, J = 7.2 Hz),
7.32 (1H, t, J = 7.2 Hz), 7.40 (1H, td, J = 7.2, 1.6 Hz), 7.59 (1H, dd,
J = 7.2, 1.6 Hz), 12.16 (1H, s); 13C NMR (100 MHz CDCl3) δ: 17.73,
20.85, 20.89, 21.95, 25.65, 42.58, 74.28, 102.06, 106.10, 115.20,
121.18, 122.97, 126.54, 127.13, 129.81, 130.10, 132.19, 147.68,
156.41, 159.61, 161.25, 168.34, 169.08, 197.08; IR (KBr): 1771, 1683,
1653, 1646, 1635, 1558, 1540, 1506, 1490, 1456, 1436, 1373, 1195,
1139 cm−1; mp: 73–75 °C; MS (EI): m/z 424 (M+); HRMS (EI) Calcd for
4.1.7.14. 7-Acetoxy-5-hydroxy-6-(3-methylbut-2-enyl)-2-(3,4-diacetoxyp
henyl)chroman-4-one (7n). Yield: 90%; 1H NMR (400 MHz CDCl3) δ:
1.66 (3H, s), 1.73 (3H, s), 2.28 (6H, s), 2.29 (3H, s), 2.86 (1H, dd,
J = 17.2, 3.2 Hz), 3.04 (1H, dd, J = 17.2, 13.6 Hz), 3.19 (2H, d,
J = 7.6 Hz), 5.09 (1H, tt, J = 7.6, 1.2 Hz), 5.40 (1H, dd, J = 13.6,
3.2 Hz), 6.26 (1H, s), 7.23 (1H, d, J = 8.0 Hz), 7.24 (1H, s), 7.29 (1H, d,
J = 8.0 Hz), 12.11 (1H, s); 13C NMR (100 MHz CDCl3) δ: 17.73, 20.57,
20.59, 20.87, 21.96, 25.65, 43.64, 77.95, 102.05, 106.09, 115.23,
121.18, 121.28, 123.85, 124.06, 132.20, 136.93, 142.23, 142.29,
156.45, 159.33, 161.21, 168.05, 168.09, 168.34, 196.68; IR (KBr):
1772, 1654, 1646, 1635, 1507, 1430, 1374, 1270, 1205, 1197,
1138 cm−1; mp: 121–123 °C; MS (EI): m/z 482 (M+); HRMS (EI)
Calcd for C26H26O9 482.1577 (M+); Found 482.1597.
C
24H24O7 424.1522 (M+); Found 424.1505.
4.1.7.10. 7-Acetoxy-5-hydroxy-6-(3-ethylpent-2-enyl)-2-(2-acetoxyphenyl)
chroman-4-one (7j). Yield: 77%; 1H NMR (400 MHz CDCl3) δ: 0.94 (3H,
t, J = 7.2 Hz), 1.03 (3H, t, J = 7.2 Hz), 2.00 (2H, q, J = 7.2 Hz), 2.18
(2H, q, J = 7.2 Hz), 2.22 (3H, s), 2.30 (3H, s), 2.84 (1H, dd, J = 17.2,
3.2 Hz), 3.10 (1H, dd, J = 17.2, 13.6 Hz), 3.25 (2H, d, J = 6.8 Hz), 5.04
(1H, t, J = 6.8 Hz), 5.55 (1H, dd, J = 13.6, 3.2 Hz), 6.25 (1H, s), 7.14
(1H, dd, J = 7.6, 1.2 Hz), 7.34 (1H, td, J = 7.6, 1.2 Hz), 7.42 (1H, td,
J = 7.6, 2.0 Hz), 7.61 (1H, dd, J = 7.6, 2.0 Hz), 12.18 (1H, s); 13C NMR
(100 MHz CDCl3) δ: 12.59, 13.07, 20.90, 20.94, 21.39, 23.27, 29.05,
42.65, 74.30, 102.12, 106.15, 115.45, 119.21, 122.98, 126.58, 127.15,
129.84, 130.15, 143.46, 147.70, 156.56, 159.65, 161.29, 168.36,
169.11, 197.11; IR (KBr): 1771, 1768, 1762, 1653, 1646, 1635, 1558,
1506, 1490, 1457, 1437, 1368, 1207, 1197, 1141, 1100, 1062 cm−1; mp:
83–85 °C; MS (EI): m/z 452 (M+); HRMS (EI) Calcd for C26H28O7
452.1835 (M+); Found 452.1813.
4.1.7.15. 7-Acetoxy-5-hydroxy-6-(3-methylbut-2-enyl)-2-(3,5-diacetoxyp
henyl)chroman-4-one (7o). Yield: 84%; 1H NMR (400 MHz CDCl3) δ:
1.66 (3H, s), 1.73 (3H, s), 2.29 (9H, s), 2.89 (1H, dd, J = 17.2, 2.8 Hz),
3.02 (1H, dd, J = 17.2, 13.2 Hz), 3.19 (2H, d, J = 7.6 Hz), 5.09 (1H, t,
J = 7.6 Hz), 5.39 (1H, dd, J = 13.2, 2.8 Hz), 6.27 (1H, s), 6.94 (1H, t,
J = 1.2 Hz), 7.06 (2H, d, J = 1.2 Hz), 12.10 (1H, s); 13C NMR (100 MHz
CDCl3) δ: 17.78, 20.92, 21.09, 22.00, 25.68, 43.66, 77.91, 102.21,
106.13, 115.35, 115.80, 116.53, 121.18, 132.28, 140.61, 151.31,
156.50, 159.22, 161.25, 168.36, 168.83, 196.52; IR (KBr): 1772,
1653, 1646, 1635, 1507, 1435, 1369, 1195, 1138, 1062, 1025 cm−1
;
mp: 130–132 °C; MS (EI): m/z 482 (M+); HRMS (EI) Calcd for C26H26O9
482.1577 (M+); Found 482.1576.
4.1.7.11. 7-Acetoxy-5-hydroxy-6-(3-methylbut-2-enyl)-2-(3-acetoxyphenyl)
chroman-4-one (7k). Yield: 94%; 1H NMR (400 MHz CDCl3) δ: 1.68 (3H,
s), 1.75 (3H, s), 2.30 (3H, s), 2.32 (3H, s), 2.88 (1H, dd, J = 17.2,
3.2 Hz), 3.07 (1H, dd, J = 17.2, 13.2 Hz), 3.21 (2H, d, J = 7.2 Hz), 5.11
(1H, td, J = 7.2, 1.2 Hz), 5.43 (1H, dd, J = 13.2, 3.2 Hz), 6.29 (1H, s),
7.13 (1H, dd, J = 8.0, 1.2 Hz), 7.21 (1H, t, J = 1.2 Hz), 7.29 (1H, d,
J = 8.0 Hz), 7.44 (1H, t, J = 8.0 Hz), 12.14 (1H, s); 13C NMR (100 MHz
CDCl3) δ: 17.73, 20.87, 21.07, 21.96, 25.65, 43.66, 78.34, 102.06,
106.13, 115.15, 119.29, 121.21, 122.02, 123.27, 129.87, 132.19,
139.86, 150.93, 156.45, 159.43, 161.20, 168.34, 169.27, 196.84; IR
4.1.7.16. 7-Acetoxy-5-hydroxy-6-(3-methylbut-2-enyl)-2-(4-methoxyphenyl)
chroman-4-one (7p). Yield: 40%; 1H NMR (400 MHz CDCl3) δ: 1.68 (3H,
s), 1.75 (3H, s), 2.30 (3H, s), 2.83 (1H, dd, J = 17.0, 2.6 Hz), 3.13 (1H,
dd, J = 17.0, 13.4 Hz), 3.21 (2H, d, J = 6.8 Hz), 3.83 (3H, s), 5.11 (1H, t,
J = 6.8 Hz), 5.38 (1H, dd, J = 13.4, 2.6 Hz), 6.26 (1H, s), 6.95 (2H, d,
J = 8.8 Hz), 7.37 (2H, d, J = 8.8 Hz), 12.19 (1H, s); 13C NMR (100 MHz
CDCl3) δ: 17.74, 20.88, 21.97, 25.66, 43.50, 55.31, 78.86, 102.02,
106.17, 114.16, 114.84, 121.30, 127.66, 130.12, 132.13, 156.40,
159.84, 160.00, 161.19, 168.38, 197.50; IR (KBr): 1751, 1634, 1587,
1520, 1433, 1369, 1348, 1308, 1277, 1261, 1213, 1177, 1140, 1084,
1063 cm−1; mp: 105–107 °C; MS (EI): m/z 396 (M+); HRMS (EI) Calcd
for C23H24O6 396.1573 (M+); Found 396.1559.
(KBr): 1768, 1635, 1587, 1433, 1371, 1202, 1171, 1137, 1066 cm−1
;
mp: 84–86 °C; MS (EI): m/z 424 (M+); HRMS (EI) Calcd for C24H24O7
424.1522 (M+); Found 424.1505.
4.1.7.12. 7-Acetoxy-5-hydroxy-6-(3-methylbut-2-enyl)-2-(2,3-diacetoxyphenyl)
chroman-4-one (7l). Yield: 89%; 1H NMR (400 MHz CDCl3) δ: 1.65 (3H, s),
1.73 (3H, s), 2.27 (3H, s), 2.28 (6H, s), 2.81 (1H, dd, J = 17.2, 3.2 Hz), 3.07
(1H, dd, J = 17.2, 13.6 Hz), 3.19 (2H, d, J = 7.6 Hz), 5.08 (1H, tt, J = 7.6,
1.2 Hz), 5.50 (1H, dd, J = 13.6, 3.2 Hz), 6.22 (1H, s), 7.24 (1H, dd, J = 8.0,
1.6 Hz), 7.34 (1H, t, J = 8.0 Hz), 7.46 (1H, dd, J = 8.0, 1.6 Hz), 12.13 (1H,
s); 13C NMR (100 MHz CDCl3) δ: 17.88, 20.29, 20.64, 20.87, 22.09, 25.79,
42.62, 74.29, 102.21, 106.21, 115.48, 121.29, 124.16, 124.45, 127.07,
132.32, 132.37, 139.81, 142.81, 156.58, 159.54, 161.39, 168.00, 168.16,
168.48, 196.93; IR (KBr): 1772, 1654, 1646, 1635, 1629, 1507, 1470, 1431,
4.1.7.17. 7-Acetoxy-5-hydroxy-6-(3-methylbut-2-enyl)-2-(4-chlorophenyl)
chroman-4-one (7q). Yield: 56%; 1H NMR (400 MHz CDCl3) δ: 1.69
(3H, s), 1.75 (3H, s), 2.31 (3H, s), 2.85 (1H, dd, J = 17.0, 3.0 Hz), 3.06
(1H, dd, J = 17.0, 13.2 Hz), 3.21 (2H, d, J = 6.8 Hz), 5.10 (1H, t,
J = 6.8 Hz), 5.41 (1H, dd, J = 13.2, 3.0 Hz), 6.28 (1H, s), 7.39 (4H, d,
J = 4.8 Hz), 12.14 (1H, s); 13C NMR (100 MHz CDCl3) δ: 17.76, 20.90,
21.99, 25.68, 43.63, 78.33, 102.07, 106.13, 115.22, 121.19, 127.42,
129.05, 132.24, 134.71, 136.67, 156.48, 159.43, 161.25, 168.38,
196.78; IR (KBr): 1763, 1636, 1589, 1497, 1433, 1373, 1304, 1211,
1165, 1138, 1088, 1063, 822 cm−1; mp: 105–107 °C; MS (EI): m/z 400
14

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Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
(M+); HRMS (EI) Calcd for C22H21ClO5 400.1078 (M+); Found
400.1083.
4.1.8.5. 6-(3-Ethylpent-2-enyl)-5,7-dihydroxy-2-(2-hydroxy-phenyl)chro
man-4-one (8j). Yield: 80%; 1H NMR (400 MHz Acetone-d6) δ: 0.94
(3H, t, J = 7.2 Hz), 1.01 (3H, t, J = 7.2 Hz), 1.98 (2H, q, J = 7.2 Hz),
2.24 (2H, q, J = 7.2 Hz), 2.82 (1H, dd, J = 17.2, 3.2 Hz), 3.08 (1H, dd,
J = 17.2, 12.8 Hz), 3.29 (2H, d, J = 7.2 Hz), 5.21 (1H, t, J = 7.2 Hz),
5.77 (1H, dd, J = 12.8, 3.2 Hz), 6.08 (1H, s), 6.91 (1H, t, J = 7.6 Hz),
6.94 (1H, d, J = 7.6 Hz), 7.20 (1H, td, J = 7.6, 1.2 Hz), 7.52 (1H, dd,
J = 7.6, 1.2 Hz), 8.77 (1H, s), 9.62 (1H, s), 12.49 (1H, s); 13C NMR
(100 MHz Acetone-d6) δ: 13.11, 13.47, 21.01, 23.62, 42.57, 75.26,
95.31, 103.07, 109.14, 116.25, 120.64, 121.55, 126.44, 127.64,
130.11, 142.61, 154.75, 162.17, 162.31, 164.73, 197.41; IR (KBr):
2964, 1653, 1635, 1616, 1595, 1559, 1507, 1496, 1490, 1472, 1457,
1339, 1309, 1302, 1272, 1156, 1082, 752 cm−1; mp: 154–156 °C; MS
(EI): m/z 368 (M+); HRMS (EI) Calcd for C22H24O5 368.1624 (M+);
Found 368.1637.
4.1.8. General procedure for the synthesis of 6-PNG derivatives 8c–d and
8h–q
To a stirred solution of 7c–d or 7h–q (0.12 mmol) in MeOH (3 mL)
was added K2CO3 (0.36 mmol) under argon atmosphere. The resulting
solution was stirred at room temperature for 30 min. The reaction
mixture was neutralized and evaporated. The crude product was
chromatographed on SiO2 (5 g, EtOAc/hexane = 1/1) to give the cor-
responding product 8c–d or 8h–q.
4.1.8.1. 5-Hydroxy-2-(2-hydroxyphenyl)-6-(3-methylbut-2-enyl)chroman-
4-one (8c). Yield: 84%; 1H NMR (400 MHz Acetone-d6) δ: 1.70 (6H, s),
2.93 (1H, dd, J = 17.2, 2.4 Hz), 3.18 (1H, dd, J = 17.2, 12.8 Hz), 3.25
(2H, d, J = 7.2 Hz), 5.29 (1H, tt, J = 7.2, 1.2 Hz), 5.83 (1H, dd,
J = 12.8, 2.4 Hz), 6.47 (1H, d, J = 8.0 Hz), 6.92 (1H, t, J = 8.0 Hz),
6.94 (1H, d, J = 8.0 Hz), 7.21 (1H, t, J = 8.0 Hz), 7.31 (1H, d,
J = 8.0 Hz), 7.54 (1H, dd, J = 8.0, 1.2 Hz), 8.77 (1H, s), 12.15 (1H,
s); 13C NMR (100 MHz Acetone-d6) δ: 17.75, 25.82, 27.37, 43.07,
75.31, 107.57, 108.45, 116.26, 120.68, 121.93, 123.05, 126.30,
127.62, 130.17, 132.98, 138.73, 154.73, 160.18, 161.03, 200.19; IR
4.1.8.6. 5,7-Dihydroxy-2-(3-hydroxyphenyl)-6-(3-methylbut-2-enyl)chro
man-4-one (8k). Yield: 73%; 1H NMR (400 MHz Acetone-d6) δ: 1.63
(3H, s), 1.74 (3H, s), 2.77 (1H, dd, J = 17.2, 2.8 Hz), 3.10 (1H, dd,
J = 17.2, 12.8 Hz), 3.34 (2H, d, J = 7.2 Hz), 5.22 (1H, td, J = 7.2,
1.2 Hz), 5.46 (1H, dd, J = 12.8, 2.8 Hz), 6.06 (1H, s), 6.84 (1H, d,
J = 8.0 Hz), 6.99 (1H, d, J = 8.0 Hz), 7.02 (1H, s), 7.24 (1H, t,
J = 8.0 Hz), 12.43 (1H, s); 13C NMR (100 MHz Acetone-d6) δ: 17.06,
20.83, 25.09, 42.92, 78.94, 94.56, 102.33, 108.33, 113.33, 115.45,
117.45, 122.73, 129.78, 130.48, 140.88, 157.67, 160.93, 161.45,
163.99, 196.14; IR (KBr): 1635, 1589, 1485, 1455, 1327, 1305, 1283,
1182, 1166, 1155, 1085, 1076 cm−1; mp: 179–181 °C; MS (EI): m/z
340 (M+); HRMS (EI) Calcd for C20H20O5 340.1311 (M+); Found
340.1311.
(KBr): 1627, 1609, 1461, 1447, 1345, 1339, 1235, 1065, 735 cm−1
;
mp: 172–174 °C; MS (EI): m/z 324 (M+); HRMS (EI) Calcd for C20H20O4
324.1362 (M+); Found 324.1356.
4.1.8.2. 6-(3-Ethylpent-2-enyl)-5-hydroxy-2-(2-hydroxyphenyl)-chroman-
4-one (8d). Yield: 84%; 1H NMR (400 MHz Acetone-d6) δ: 0.99 (6H, t,
J = 8.0 Hz), 2.05 (2H, q, J = 8.0 Hz), 2.17 (2H, q, J = 8.0 Hz), 2.93
(1H, dd, J = 17.2, 2.4 Hz), 3.19 (1H, dd, J = 17.2, 13.2 Hz), 3.28 (2H,
d, J = 7.2 Hz), 5.25 (1H, t, J = 7.2 Hz), 5.84 (1H, dd, J = 13.2, 2.4 Hz),
6.48 (1H, d, J = 8.0 Hz), 6.93 (1H, t, J = 8.0 Hz), 6.94 (1H, d,
J = 8.0 Hz), 7.21 (1H, td, J = 8.0, 2.0 Hz), 7.33 (1H, d, J = 8.0 Hz),
7.54 (1H, dd, J = 8.0, 2.0 Hz), 8.80 (1H, br), 12.16 (1H, s); 13C NMR
(100 MHz Acetone-d6) δ: 13.16, 13.49, 23.65, 26.79, 43.08, 75.33,
107.61, 108.45, 116.28, 120.66, 121.09, 122.07, 126.31, 127.63,
130.18, 138.69, 144.44, 154.76, 160.21, 161.06, 200.23; IR (KBr):
2964, 1653, 1623, 1608, 1555, 1505, 1461, 1363, 1355, 1339, 1235,
1065, 740 cm−1; mp: 112–114 °C; MS (EI): m/z 352 (M+); HRMS (EI)
Calcd for C22H24O4 352.1675 (M+); Found 352.1673.
4.1.8.7. 2-(2,3-Dihydroxyphenyl)-5,7-dihydroxy-6-(3-methylbut-2-enyl)chro
man-4-one (8l). Yield: 95%; 1H NMR (400 MHz Acetone-d6) δ: 1.64 (3H,
s), 1.74 (3H, s), 2.81 (1H, dd, J = 17.2, 2.4 Hz), 3.10 (1H, dd, J = 17.2,
12.8 Hz), 3.25 (2H, d, J = 7.2 Hz), 5.23 (1H, t, J = 7.2 Hz), 5.78 (1H, dd,
J = 12.8, 2.4 Hz), 6.06 (1H, s), 6.76 (1H, t, J = 8.0 Hz), 6.87 (1H, dd,
J = 8.0, 1.2 Hz), 7.02 (1H, d, J = 8.0 Hz), 12.48 (1H, s); 13C NMR
(100 MHz Acetone-d6) δ: 17.80, 21.59, 25.83, 42.48, 75.28, 95.26,
103.04, 108.98, 115.76, 118.38, 120.38, 123.53, 126.66, 131.18,
143.28, 145.43, 162.13, 162.24, 164.68, 197.39; IR (KBr): 1653, 1635,
1624, 1617, 1596, 1577, 1563, 1507, 1481, 1476, 1457, 1448, 1338,
1305, 1284, 1156, 1120, 1085 cm−1; mp: 149–151 °C; MS (EI): m/z 356
(M+); HRMS (EI) Calcd for C20H20O6 356.1260 (M+); Found 356.1273.
4.1.8.3. 5,7-Dihydroxy-6-(3-methylbut-2-enyl)-2-phenylchroman-4-one
(8h). Yield: 84%; 1H NMR (400 MHz CDCl3) δ: 1.77 (3H, s), 1.83
(3H, s), 2.83 (1H, dd, J = 17.2, 2.4 Hz), 3.11 (1H, dd, J = 17.2,
12.8 Hz), 3.22 (2H, d, J = 7.0 Hz), 5.11 (1H, t, J = 7.0 Hz), 5.44 (1H,
dd, J = 12.8, 2.4 Hz), 6.01 (1H, s), 6.13 (1H, d, J = 1.6 Hz),
7.38–7.45 (5H, m), 12.40 (1H, s); 13C NMR (100 MHz Acetone-d6)
δ: 17.83, 21.60, 25.85, 43.68, 79.86, 95.33, 103.10, 109.16, 123.49,
127.25, 129.33, 129.43, 131.29, 140.14, 161.74, 162.24, 164.79,
196.89; IR (KBr): 1653, 1634, 1585, 1487, 1456, 1312, 1304, 1219,
1188, 1083, 1076 cm−1; mp: 197–199 °C; MS (EI): m/z 324 (M+);
HRMS (EI) Calcd for C20H20O4 324.1362 (M+); Found 324.1366.
4.1.8.8. 2-(2,6-Dihydroxyphenyl)-5,7-dihydroxy-6-(3-methylbut-2-enyl)
chroman-4-one (8m). Yield: 97%; 1H NMR (400 MHz Acetone-d6) δ:
1.63 (3H, s), 1.74 (3H, s), 2.51 (1H, dd, J = 17.2, 3.2 Hz), 3.24 (2H, d,
J = 7.2 Hz), 3.89 (1H, dd, J = 17.2, 14.0 Hz), 5.23 (1H, t, J = 7.2 Hz),
6.00 (1H, s), 6.01 (1H, dd, J = 14.0, 3.2 Hz), 6.46 (2H, d, J = 8.0 Hz),
7.02 (1H, t, J = 8.0 Hz), 8.57 (2H, s), 12.58 (1H, s); 13C NMR
(100 MHz Acetone-d6) δ: 17.79, 21.59, 25.82, 40.52, 73.38, 95.22,
103.03, 108.39, 108.84, 111.73, 123.62, 130.88, 131.09, 157.74,
162.39, 162.59, 164.51, 198.39; IR (KBr): 1653, 1635, 1603, 1559,
1506, 1472, 1456, 1451, 1447, 1309, 1150 cm−1; mp: 244–246 °C; MS
(EI): m/z 356 (M+); HRMS (EI) Calcd for C20H20O6 356.1260 (M+);
Found 356.1273.
4.1.8.4. 5,7-Dihydroxy-2-(2-hydroxyphenyl)-6-(3-methylbut-2-enyl)chro
man-4-one (8i). Yield: 87%; 1H NMR (400 MHz Acetone-d6) δ: 1.63
(3H, s), 1.74 (3H, s), 2.81 (1H, dd, J = 17.2, 3.2 Hz), 3.08 (1H, dd,
J = 17.2, 13.2 Hz), 3.24 (2H, d, J = 7.2 Hz), 5.23 (1H, tt, J = 7.2,
1.2 Hz), 5.77 (1H, dd, J = 13.2, 3.2 Hz), 6.08 (1H, s), 6.92 (1H, t,
J = 7.6 Hz), 6.93 (1H, d, J = 7.6 Hz), 7.20 (1H, t, J = 7.6 Hz), 7.51
(1H, d, J = 7.6 Hz), 12.47 (1H, s); 13C NMR (100 MHz Acetone-d6) δ:
17.80, 21.59, 25.82, 42.55, 75.24, 95.27, 103.01, 109.01, 116.22,
120.60, 123.52, 126.41, 127.60, 130.08, 131.18, 154.74, 162.13,
162.24, 164.72, 197.37; IR (KBr): 1653, 1635, 1616, 1601, 1576,
1558, 1540, 1506, 1496, 1490, 1472, 1457, 1339, 1312, 1272, 1155,
1083, 751 cm−1; mp: 174–176 °C; MS (EI): m/z 340 (M+); HRMS (EI)
Calcd for C20H20O5 340.1311 (M+); Found 340.1319.
4.1.8.9. 2-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-6-(3-methylbut-2-enyl)
chroman-4-one (8n). Yield: 80%; 1H NMR (400 MHz Acetone-d6) δ:
1.62 (3H, s), 1.73 (3H, s), 2.70 (1H, dd, J = 17.2, 3.2 Hz), 3.11 (1H,
dd, J = 17.2, 12.8 Hz), 3.23 (2H, d, J = 7.2 Hz), 5.22 (1H, t,
J = 7.2 Hz), 5.35 (1H, dd, J = 12.8, 3.2 Hz), 6.01 (1H, s), 6.85 (2H,
s), 7.01 (1H, s), 8.19 (1H, br) 12.45 (1H, s); 13C NMR (100 MHz
Acetone-d6) δ: 17.79, 21.56, 25.81, 43.60, 79.82, 95.24, 103.04,
108.92, 114.65, 115.95, 119.17, 123.51, 131.18, 131.64, 145.94,
146.28, 161.88, 162.17, 164.70, 197.26; IR (KBr): 1653, 1646, 1635,
1624, 1616, 1596, 1577, 1559, 1507, 1457, 1448, 1339, 1287, 1158,
15

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1120, 1090 cm−1; mp: 121–123 °C; MS (EI): m/z 356 (M+); HRMS (EI)
4.1.9.2. 7-Acetoxy-5-hydroxy-6-(3-propylhex-2-enyl)-2-(4-acetoxyphenyl)
chroman-4-one (10c). Yield: 23%; 1H NMR (400 MHz CDCl3) δ: 0.82
(3H, t, J = 7.2 Hz), 0.93 (3H, t, J = 7.2 Hz), 1.28–1.45 (4H, m), 1.90
(2H, t, J = 7.2 Hz), 2.11 (2H, t, J = 7.2 Hz), 2.27 (3H, s), 2.30 (3H, s),
2.79 (1H, dd, J = 17.2, 2.8 Hz), 3.08 (1H, dd, J = 17.2, 12.8 Hz), 3.22
(2H, d, J = 7.0 Hz), 5.06 (1H, t, J = 7.0 Hz), 5.41 (1H, dd, J = 12.8,
2.8 Hz), 6.25 (1H, s), 7.13 (2H, d, J = 8.8 Hz), 7.44 (2H, d, J = 8.8 Hz),
12.13 (1H, s); 13C NMR (100 MHz CDCl3) δ: 13.90, 14.31, 20.95, 21.11,
21.17, 21.57, 32.33, 38.99, 43.75, 78.52, 102.06, 106.16, 115.39,
121.23, 122.05, 127.28, 135.74, 140.28, 150.88, 156.55, 159.59,
161.27, 168.38, 169.33, 197.03; IR (KBr): 2959, 1768, 1752, 1647,
1628, 1587, 1507, 1431, 1373, 1219, 1194, 1163, 1142, 1086,
1065 cm−1; mp: 72–74 °C; MS (EI): m/z 480 (M+); HRMS (EI) Calcd
for C28H32O7 480.2148 (M+); Found 480.2151.
Calcd for C20H20O6 356.1260 (M+); Found 356.1273.
4.1.8.10. 2-(3,5-Dihydroxyphenyl)-5,7-dihydroxy-6-(3-methylbut-2-enyl)
chroman-4-one (8o). Yield: 93%; 1H NMR (400 MHz Acetone-d6) δ:
1.63 (3H, s), 1.74 (3H, s), 2.70 (1H, dd, J = 17.2, 2.4 Hz), 3.11 (1H, dd,
J = 17.2, 12.8 Hz), 3.23 (2H, d, J = 7.6 Hz), 5.22 (1H, t, J = 7.6 Hz),
5.34 (1H, dd, J = 12.8, 2.4 Hz), 6.01 (1H, s), 6.85 (2H, s), 7.01 (1H, s),
8.17 (1H, br), 12.45 (1H, s); 13C NMR (100 MHz Acetone-d6) δ: 25.37,
38.85, 43.71, 49.04, 74.80, 79.70, 95.36, 103.09, 103.36, 105.62,
109.99, 123.49, 142.42, 159.59, 161.62, 162.31, 164.90, 196.97; IR
(KBr): 1653, 1647, 1635, 1616, 1586, 1562, 1521, 1507, 1490, 1472,
1465, 1456, 1340, 1312, 1297, 1223, 1152, 1123, 833 cm−1; mp:
196–199 °C; MS (EI): m/z 356 (M+); HRMS (EI) Calcd for C20H20O6
356.1260 (M+); Found 356.1273.
4.1.9.3. 7-Acetoxy-5-hydroxy-6-(2-cyclopentylidenethyl)-2-(4-acetoxyphe
nyl)chroman-4-one (10d). Yield: 96%; 1H NMR (400 MHz CDCl3) δ:
1.57 (2H, quin, J = 6.8 Hz), 1.67 (2H, quin, J = 6.8 Hz), 2.18 (2H, t,
J = 6.8 Hz), 2.29 (3H, s), 2.30 (3H, s), 2.32 (2H, t, J = 6.8 Hz), 2.83
(1H, dd, J = 17.2, 3.2 Hz), 3.06 (1H, dd, J = 17.2, 13.6 Hz), 3.18 (2H,
d, J = 6.8 Hz), 5.21 (1H, t, J = 6.8 Hz), 5.40 (1H, dd, J = 13.6, 3.2 Hz),
6.25 (1H, s), 7.13 (2H, d, J = 8.4 Hz), 7.44 (2H, d, J = 8.4 Hz), 12.15
(1H, s); 13C NMR (100 MHz CDCl3) δ: 20.93, 21.10, 23.41, 26.33,
26.41, 28.68, 33.56, 43.70, 78.51, 102.02, 106.16, 115.16, 116.61,
122.03, 127.27, 135.71, 144.20, 150.85, 156.43, 159.54, 161.24,
168.40, 169.32, 197.02; IR (KBr): 2962, 1769, 1751, 1653, 1646,
1636, 1586, 1559, 1507, 1436, 1369, 1198, 1137, 1087 cm−1; mp:
67–69 °C; MS (EI): m/z 450 (M+); HRMS (EI) Calcd for C26H26O7
450.1679 (M+); Found 450.1682.
4.1.8.11. 5,7-Dihydroxy-2-(4-methoxyphenyl)-6-(3-methylbut-2-enyl)
chroman-4-one (8p). Yield: 98%; 1H NMR (400 MHz Acetone-d6) δ:
1.63 (3H, s), 1.74 (3H, s), 2.73 (1H, dd, J = 17.0, 3.0 Hz), 3.17 (1H,
dd, J = 17.2, 12.8 Hz), 3.24 (2H, d, J = 7.6 Hz), 3.81 (3H, s), 5.22
(1H, t, J = 7.6 Hz), 5.46 (1H, dd, J = 12.8, 3.0 Hz), 6.03 (1H, s),
6.98 (2H, d, J = 8.4 Hz), 7.47 (2H, d, J = 8.4 Hz), 9.59 (1H, br),
12.46 (1H, s); 13C NMR (100 MHz Acetone-d6) δ: 17.80, 21.59,
25.82, 43.54, 55.57, 79.65, 95.28, 103.05, 109.03, 114.71, 123.53,
128.83, 131.22, 132.02, 160.87, 161.87, 162.22, 164.81, 197.18; IR
(KBr): 1653, 1634, 1587, 1518, 1506, 1487, 1464, 1459, 1313,
1298, 1256, 1219, 1186, 1080, 1076, 827 cm−1; mp: 155–157 °C;
MS (EI): m/z 354 (M+); HRMS (EI) Calcd for C21H22O5 354.1467
(M+); Found 354.1463.
4.1.8.12. 2-(4-Chlorophenyl)-5,7-dihydroxy-6-(3-methylbut-2-enyl)chroman-
4-one (8q). Yield: 92%; 1H NMR (400 MHz Acetone-d6) δ: 1.63 (3H, s),
1.74 (3H, s), 3.14 (1H, dd, J = 17.2, 12.8 Hz), 3.24 (2H, d, J = 7.2 Hz),
5.22 (1H, t, J = 7.2 Hz), 5.57 (1H, dd, J = 12.8, 3.0 Hz), 6.07 (1H, s), 7.48
(2H, d, J = 8.4 Hz), 7.59 (2H, d, J = 8.4 Hz), 9.63 (1H, br), 12.42 (1H, s);
13C NMR (100 MHz Acetone-d6) δ: 17.80, 21.60, 25.82, 43.55, 79.08,
95.36, 103.04, 109.29, 123.45, 129.04, 129.51, 131.29, 134.59, 139.10,
161.52, 162.24, 164.87, 196.61; IR (KBr): 1653, 1634, 1587, 1495, 1458,
1417, 1364, 1312, 1300, 1217, 1186, 1088, 1082, 1076, 826 cm−1; mp:
183–185 °C; MS (EI): m/z 358 (M+); HRMS (EI) Calcd for C20H19ClO4
358.0972 (M+); Found 358.0971.
4.1.10. General procedure for the synthesis of 6-PNG derivatives 11b-d
To a stirred solution of 10b–d (0.14 mmol) in MeOH (2 mL) was
added K2CO3 (0.42 mmol) under argon atmosphere. The resulting so-
lution was stirred at room temperature for 30 min. The reaction mixture
was neutralized and evaporated. The crude product was chromato-
graphed on SiO2 (5 g, EtOAc/hexane = 1/1) to give the corresponding
product 11b–d.
4.1.10.1. 6-(3-Ethylpent-2-enyl)-5,7-dihydroxy-2-(4-hydroxy-phenyl)chro
man-4-one (11b). Yield: 86%; 1H NMR (400 MHz Acetone-d6) δ: 0.93
(3H, t, J = 7.2 Hz), 1.01 (3H, t, J = 7.2 Hz), 1.98 (2H, q, J = 7.2 Hz),
2.23 (2H, q, J = 7.2 Hz), 2.70 (1H, dd, J = 17.2, 3.2 Hz), 3.16 (1H, dd,
J = 17.2, 12.8 Hz), 3.28 (2H, d, J = 7.2 Hz), 5.19 (1H, t, J = 7.2 Hz),
5.42 (1H, dd, J = 12.8, 3.2 Hz), 6.02 (1H, s), 6.88 (2H, d, J = 8.4 Hz),
4.1.9. General procedure of cross-metathesis for 10b–d
To a stirred solution of 9 (0.1 g, 0.25 mmol) in benzene (5 mL) were
added corresponding olefin (5.04 mmol) and Grubbs catalyst, 2nd
Generation (11 mg, 0.012 mmol) under argon atmosphere. The reaction
mixture was heated in the sealed tube at 100 °C for 20 h. After the
solvent was removed under vacuum, the crude product was chroma-
tographed on SiO2 (10 g, EtOAc/hexane = 1/7) to give 10b–d.
7.38 (2H, d, J = 8.4 Hz), 8.53 (1H, br), 9.46 (1H, br), 12.48 (1H, s); 13
C
NMR (100 MHz Acetone-d6) δ: 12.35, 12.72, 20.32, 22.85, 28.94,
42.08, 79.07, 94.51, 102.30, 108.30, 115.34, 120.77, 128.20, 130.11,
141.84, 157.85, 161.20, 161.49, 164.00, 196.56; IR (KBr): 2965, 1653,
1646, 1635, 1616, 1587, 1558, 1521, 1517, 1507, 1490, 1457, 1447,
1337, 1309, 1297, 1170, 1153, 1085, 830 cm−1; mp: 208–210 °C; MS
(EI): m/z 368 (M+); HRMS (EI) Calcd for C22H24O5 368.1624 (M+);
Found 368.1637.
4.1.9.1. 7-Acetoxy-5-hydroxy-6-(3-ethylpent-2-enyl)-2-(4-acetoxyphenyl)
chroman-4-one (10b). Yield: 73%; 1H NMR (400 MHz CDCl3) δ: 0.96
(3H, t, J = 7.2 Hz), 1.03 (3H, t, J = 7.2 Hz), 2.00 (2H, q, J = 7.2 Hz),
2.20 (2H, q, J = 7.2 Hz), 2.29 (3H, s), 2.31 (3H, s), 2.85 (1H, dd,
J = 17.2, 2.8 Hz), 3.08 (1H, dd, J = 17.2, 13.2 Hz), 3.26 (2H, d,
J = 7.2 Hz), 5.04 (1H, t, J = 7.2 Hz), 5.43 (1H, dd, J = 13.2, 2.8 Hz),
6.28 (1H, s), 7.15 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.4 Hz), 12.17
(1H, s); 13C NMR (100 MHz CDCl3) δ: 12.55, 13.05, 20.89, 21.07,
21.37, 23.25, 29.02, 43.69, 78.49, 102.06, 106.14, 115.31, 119.23,
122.02, 127.25, 135.71, 143.40, 150.85, 156.55, 159.57, 161.23,
168.35, 169.29, 197.01; IR (KBr): 2964, 1769, 1752, 1646, 1633,
1585, 1511, 1431, 1371, 1303, 1219, 1193, 1141, 1086, 1065,
900 cm−1; mp: 70–72 °C; MS (EI): m/z 452 (M+); HRMS (EI) Calcd
for C26H28O7 452.1835 (M+); Found 452.1826.
4.1.10.2. 5,7-Dihydroxy-2-(4-hydroxyphenyl)-6-(3-propylhex-2-enyl)chro
man-4-one (11c). Yield: 90%; 1H NMR (400 MHz Acetone-d6) δ: 0.82
(3H, t, J = 7.4 Hz), 0.93 (3H, t, J = 7.4 Hz), 1.31–1.49 (4, m), 1.92 (2H,
t, J = 7.4 Hz), 2.18 (2H, t, J = 7.4 Hz), 2.69 (1H, dd, J = 17.2, 2.8 Hz),
3.15 (1H, dd, J = 17.2, 12.8 Hz), 3.28 (2H, d, J = 7.6 Hz), 5.25 (1H, t,
J = 7.6 Hz), 5.40 (1H, dd, J = 12.8, 2.8 Hz), 6.02 (1H, s), 6.88 (2H, d,
J = 8.4 Hz), 7.37 (2H, d, J = 8.4 Hz), 12.48 (1H, br); 13C NMR
(100 MHz Acetone-d6) δ: 14.11, 14.54, 21.29, 21.91, 22.33, 32.63,
39.72, 43.59, 79.83, 95.30, 103.35, 109.13, 116.11, 123.75, 128.97,
130.90, 139.29, 158.64, 161.88, 162.25, 164.77, 197.26; IR (KBr):
2959, 1638, 1616, 1601, 1518, 1491, 1456, 1340, 1310, 1252, 1215,
16

H. Du Nguyen et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
1153, 1086, 833 cm−1; mp: 130–132 °C; MS (EI): m/z 396 (M+); HRMS
224–226 °C; MS (EI): m/z 368 (M+); HRMS (EI) Calcd for C22H24O5
(EI) Calcd for C24H28O5 396.1937 (M+); Found 396.1920.
368.1624 (M+); Found 368.1637.
4.1.10.3. 6-(2-Cyclopentylidenethyl)-5,7-dihydroxy-2-(4-hydroxyphenyl)
chroman-4-one (11d). Yield: 98%; 1H NMR (400 MHz Acetone-d6) δ:
1.55 (2H, quin, J = 7.2 Hz), 1.65 (2H, quin, J = 7.2 Hz), 2.15 (2H, t,
J = 7.2 Hz), 2.39 (2H, t, J = 7.2 Hz), 2.70 (1H, dd, J = 17.2, 2.8 Hz),
3.15 (1H, dd, J = 17.2, 12.8 Hz), 3.22 (2H, d, J = 7.2 Hz), 5.32 (1H, tt,
J = 7.2, 2.0 Hz), 5.40 (1H, dd, J = 12.8, 2.8 Hz), 6.02 (1H, s), 6.88 (2H,
d, J = 8.4 Hz), 7.37 (2H, d, J = 8.4 Hz), 9.03 (2H, br), 12.47 (1H, s);
13C NMR (100 MHz Acetone-d6) δ: 23.02, 26.94, 27.04, 29.04, 34.08,
43.55, 79.81, 95.25, 103.06, 108.95, 116.10, 118.85, 128.96, 130.88,
143.13, 158.58, 161.92, 162.22, 164.70, 197.28; IR (KBr): 2969, 1653,
1646, 1635, 1616, 1586, 1559, 1521, 1517, 1507, 1497, 1490, 1472,
1457, 1448, 1437, 1339, 1310, 1296, 1245, 1220, 1160, 1085,
830 cm−1; mp: 217–219 °C; MS (EI): m/z 366 (M+); HRMS (EI) Calcd
for C22H22O5 366.1467 (M+); Found 366.1472.
4.2. Biology
4.2.1. Assessment of T-currents by a patch-clamp technique in Cav3.2-
expressing HEK293 cells
Measurements of T-type calcium channel-dependent membrane
currents were performed in HEK293 cells that stably express human
Cav3.2, using a whole cell patch-clamp technique, as described pre-
viously.26 The cell membrane voltage was held at −90 mV, and whole-
cell Ba2+ currents were elicited by a test pulse at 30 mV.
4.2.2. Animals, von Frey test and creation of
neuropathic pain model in mice
a surgically induced
Male ddY mice weighing 18–25 g (Kiwa Laboratory Animals Co.
Ltd., Wakayama, Japan) were used with approval by the Committee for
the Care and Use of Laboratory Animals at Kindai University, and all
procedures employed were in accordance with the NIH guidelines
(Guide for the Care and Use of Laboratory Animals, NIH Publication
86–23). Nociceptive threshold in the hindpaw was determined by von
Frey test, employing the up-down method.27 To create a surgically in-
duced neuropathic pain model, the right sciatic nerve of the mouse was
partially ligated under isoflurane anesthesia, according to the pre-
viously described method,28 and used to detect anti-allodynic activity
of test compounds one week after the surgery.
4.1.11. General procedure for the synthesis of 6-PNG derivatives 12a–c
To a stirred solution of 11a, b or 11d (0.05 mmol) in EtOAc (3 mL)
was added 10% Pd/C (5 mg), and the resulting mixture was hydro-
genated at 1 atm for 20 h. The catalyst was removed through a Celite
pad and washed with EtOAc (3 mL x 3). The filtrate and washings were
combined and evaporated to give the corresponding product 12a–c.
4.1.11.1. 5,7-Dihydroxy-2-(4-hydroxyphenyl)-6-(3-methylbutyl)-chroman-4-
one (12a). Yield: 100%; 1H NMR (400 MHz DMSO-d6) δ: 0.88 (6H, d,
J = 6.4 Hz), 1.28 (2H, q, J = 7.6 Hz), 1.42–1.54 (1H, m), 2.41 (1H, d,
J = 7.6 Hz), 2.43 (1H, d, J = 7.6 Hz), 2.63 (1H, dd, J = 17.2, 2.8 Hz),
3.22 (1H, dd, J = 17.2, 12.8 Hz), 5.38 (1H, dd, J = 12.8, 2.8 Hz), 5.93
(1H, s), 6.77 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz), 9.62 (1H, br),
12.41 (1H, s); 13C NMR (100 MHz DMSO-d6) δ: 19.47, 22.57, 27.59,
37.75, 42.12, 78.30, 94.41, 101.35, 108.59, 115.15, 128.31, 129.08,
157.70, 160.43, 160.74, 162.57, 196.28; IR (KBr): 2951, 1632, 1587,
1519, 1489, 1453, 1382, 1337, 1310, 1296, 1248, 1210, 1185, 1158,
1129, 1085, 1055, 830 cm−1; mp: 217–219 °C; MS (EI): m/z 342 (M+);
HRMS (EI) Calcd for C20H22O5 342.1467 (M+); Found 342.1475.
4.2.3. Drug administration to mice
All chemicals were suspended in 0.5% carboxymethyl cellulose so-
dium salt (CMC-Na) solution, and administered intraperitoneally (i.p.)
to mice.
4.2.4. Data analysis
Data are shown as the mean
S.E.M. Statistical significance was
evaluated by non-parametric procedures; i.e. the data were analyzed by
the Kruskal-Wallis H test followed by a least significant difference-type
test. Significance was set at a P < 0.05 level.
4.1.11.2. 6-(3-Ethylpentyl)-5,7-dihydroxy-2-(4-hydroxyphenyl)-chroman-
4-one (12b). Yield: 100%; 1H NMR (400 MHz Acetone-d6) δ: 0.87 (6H,
t, J = 7.2 Hz), 1.20–1.27 (1H, m), 1.31–1.41 (4H, m), 1.43–1.49 (2H,
m), 2.52 (1H, d, J = 8.0 Hz), 2.54 (1H, d, J = 8.0 Hz), 2.70 (1H, dd,
J = 17.2, 2.8 Hz), 3.16 (1H, dd, J = 17.2, 12.8 Hz), 5.41 (1H, dd,
J = 12.8, 2.8 Hz), 6.01 (1H, s), 6.88 (2H, d, J = 8.4 Hz), 7.38 (2H, d,
J = 8.4 Hz), 8.52 (1H, br), 9.55 (1H, br), 12.46 (1H, s); 13C NMR
(100 MHz Acetone-d6) δ: 11.16, 19.64, 26.06, 32.31, 41.33, 43.61,
79.84, 95.20, 103.01, 110.20, 116.10, 128.70, 130.90, 158.62, 161.83,
162.38, 164.89, 197.31; IR (KBr): 2960, 1635, 1587, 1518, 1489, 1458,
1338, 1308, 1296, 1261, 1244, 1186, 1161, 1105, 1084, 829 cm−1; mp:
206–208 °C; MS (EI): m/z 370 (M+); HRMS (EI) Calcd for C22H26O5
370.1780 (M+); Found 370.1765.
A. Supplementary data
Supplementary data associated with this article can be found, in the
online version, at https://doi.org/10.1016/j.bmc.2018.07.023.
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