Design, Synthesis, and Structure–Activity Relationships of Bavachinin Analogues as Peroxisome Proliferator-Activated Receptor γ Agonists

Article abstract of DOI:10.1002/cmdc.201600554

Peroxisome proliferator-activated receptor γ (PPARγ) agonists have been used for the treatment of diabetes with the effect of lowering blood glucose levels and improving insulin sensitivity. Natural compounds such as flavones, flavanones, and isoflavones

Full text of DOI:10.1002/cmdc.201600554

Accepted Article
Title: Design, synthesis, and structure-activity relationships of
bavachinin analogues as peroxisome proliferator-activated
receptor γ agonists
Authors: Guoxin Du, Yuanyuan Zhao, Li Feng, Zhuo Yang, Jiye Shi,
Cheng Huang, Bo Li, Fujiang Guo, Weiliang Zhu, and Yiming
Li
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemMedChem 10.1002/cmdc.201600554
Link to VoR: http://dx.doi.org/10.1002/cmdc.201600554
A Journal of
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synthesis, and structure–activity relationships of
nin analogues as peroxisome proliferator-activated
r γ agonists
[a] Yuanyuan Zhao,1[a] Li Feng,[a] Zhuo Yang,[b] Jiye Shi,[c] Cheng Huang,[a] Bo Li,*[b] Fujiang
iang Zhu,[b] and Yiming Li[a]
Y. Zhao, L. Feng, C. Huang, F.J. Guo, Y.M. Li
armacy
niversity of Traditional Chinese Medicine
Road, Shanghai, 201203 (China)
shutcm.edu.cn
Li, W.L. Zhu
ory of Receptor Research & Drug Discovery and Design Center
stitute of Materia Medica, Chinese Academy of Sciences
gzhi Road, Shanghai, 201203 (China)
@simm.ac.cn
Department
a
ad, Slough SL1 4EN (United Kingdom)
rs (G.X. Du and Y.Y. Zhao) contributed equally to this work
g authors (B. Li and FJ. Guo).
nformation for this article is given via a link at the end of the document.
hinin analogues with systematic modifications at the A-, B-, and C-rings were designed, synthesized, and subjected to in vitro
peroxisome proliferator-activated receptor γ (PPAR-γ) agonists. In total, 30 molecules, including flavanone and flavone
evaluated by reporter gene assays for the PPAR-γ agonist activity. Preliminary structure–activity relationships of PPAR-γ
f bavachinin analogues were initially summarized and analogues 2b, 3, 4a, 4b, 11c, 11d, and 12b were found with higher
activities compared to bavachinin.
n
llitus is a chronic metabolic disorder characterized by a disruption in glucose homeostasis, manifesting as
abnormalities in lipid and protein metabolism, and the development of both acute- and long-term complications.[1]
ases the risk of ocular, renal, neurologic, cardiovascular, peripheral vascular, and metabolic conditions; these
ase the risk of premature mortality and lead to an excess increase in the body weight and physical inactivity.[2–4] In
announced that 347 million people worldwide have diabetes, an estimated 3.4 million people died from complications
a in 2004, and this mortality will double from 2005 to 2030.[5]
proliferator-activated receptors (PPARs) belong to a family of ligand-activated nuclear receptors that consist of three
R-α, PPAR-β/δ, and PPAR-γ.[6] PPAR-γ is a key regulator of gene expression of metabolism, inflammation, and other
rious types of cells, especially adipocytes.[7] The crucial role of PPAR-γ in lipid metabolism, adipogenesis, glucose
nd insulin sensitization is well documented.[8] PPAR-γ agonists, such as thiazolidinediones, including the widely used
ne, have been used in clinical practice to treat diabetes for several years and have been shown to lower blood
nd improve insulin sensitivity.[9–10]
ural compounds, including flavones, flavanones, and isoflavones, exhibited excellent PPAR-γ agonist activity.[11]
ure 1) is a naturally occurring flavanone isolated from the seeds of Psoralea Corylifolia.[12] It exhibits various biological
as inhibition of the production of nitric oxide and antiangiogenic, antitumor, antiallergic, and antibacterial activities.[13–16]
tudy showed that bavachinin exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on
nd lipid metabolism in db/db and diet-induced obese mice.[17] Meanwhile naturally occurring bavachinin is a mixture of
s with S and R configurations, and the value of enantiomeric excess is approximately 24.3%. A study of the two
ggested that (S)-bavachinin and (R)-bavachinin have similar PPAR-γ agonist activity.[188]
study, structural modifications of bavachinin were performed focus on its PPAR-γ agonist activity. A novel series of
inin analogues with systematic modifications at the A-, B-, and C-rings were designed and synthesized. Several
selected to perform the further study.
1
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d Discussion
exhibiting a conspicuous PPAR-γ agonist activity, was used as a lead compound for designing analogues (Figure 2).
ocking study showed that in the A-ring, an isopentenyl group at the C-6 position and a methoxyl group at the C-7
ve a remarkable effect on the PPAR-γ agonist activity of bavachinin 1. In the present study, those two groups at the
sitions were removed, and the isopentenyl side chain was substituted with an isopentyl or geranyl chain. Previous
y relationship studies have shown that a hydroxyl group at the C-4′ position in the B-ring is necessary for PPAR-γ
Therefore, this group was modified through esterification, etherification, and halogen substitution. A hydroxyl group
om were introduced at the C-3′ position in the B-ring to investigate the PPAR-γ agonist activity. To determine whether
a role in PPAR-γ agonist activity, the B-ring was removed and substituted with a heterocyclic ring. In the C-ring,
molecules with various substituents were designed through oxidation reaction. Flavones are distinguished from
y by the presence of the 2,3-double bond in the chromone ring.
es 2a–2g were synthesized through the esterification or Williamson ether reaction of bavachinin 1 with appropriate
alkyl/aromatic halides in acetone in the presence of K2CO3 (Scheme 1).[19–22] Oxidizing bavachinin 1 with iodine in
de (DMSO) yielded flavones 3.[23] The analogues 4a–4c were synthesized using the procedure used for preparing 2a–
g appropriate acyl halides or alkyl/aromatic halides.
nalogues, 11a–11f, were generated through the synthesis route outlined in Scheme 2. The 2'-hydroxy acetophenones
ated with prenyl bromide or geranyl bromide in acetone in the presence of K2CO3 to yield 6a–6c, which provided the
a, 7b, and 7d in N,N-diethyl aniline through Claisen rearrangement.[24]
iates 7a–7e were treated with appropriate aromatic aldehydes, 8b, 8d, and 8f, in ethyl alcohol in the presence of
thylsilanolate and then neutralized with saturated NH4Cl and extracted with ethyl acetate, yielding chalcones 9a–9f.[25]
e
cyclization of 9a–9f through reflux with potassium fluoride in methyl alcohol yielded corresponding
ated flavanones 10a–10f. The methoxymethylated flavanones were demethoxymethylated by hydrogen chloride in
to obtain the desired flavanones 11a–11f.[26] Oxidizing the corresponding flavanones 11b and 11d with iodine in
ed 12a and 12b.
nalogues, 14a–14f, were prepared through the synthesis route outlined in Scheme 3. The intermediate 7b was treated
heteroaromatic aldehydes in ethyl alcohol in the presence of sodium hydroxide to obtain chalcones 13a–13f.[27] The
13f were cyclized using KF as a base in methyl alcohol to yield flavanones 14a–14f. Oxidizing the flavanones14a–
n DMSO generated 15a–15c.
ate 7b was subjected to condensation with N,N-dimethylformamide dimethylacetal to obtain the intermediate 16 and
g glacial acetic acid to yield the corresponding chromone 17.[28]
ew PPAR-γ modulators, reporter gene assays were conducted to analyze the effects of analogues on the PPAR-γ
domain (LBD).[29] Commercially available PPAR-γ agonists, rosiglitazone, was used as positive controls for PPAR-γ
30 synthesized analogues of the bavachinin were analyzed. The results are summarized in Table 1.
e discovered that introducing an aromatic ester group at the 4'-hydroxyl position of the B-ring (2b–2d) resulted in
R-γ agonist activity; whereas introducing an aliphatic ester group (2a) resulted in reduced PPAR-γ agonist activity.
ucing an ether group at the same position (2e–2g) markedly reduced the PPAR-γ agonist activity compared with that
Changing the single bond at C-2 and C-3 position of the C-ring to double bond (3) and introducing an ester group at
position of the B-ring of 3 (4a–4b) significantly increased the PPAR-γ agonist activity compared with that of bavachinin.
ucing with steric hindrance at the 4'-hydroxyl position of the B-ring of 3 (4c) results in decreased PPAR-γ activity. The
us substitutions on the A-ring and B-ring of bavachinin were evaluated. A total of 19 analogues, 11a–11f, 12a–12b,
5c, and 16–17 were synthesized with different substituents on either the A-ring or the B-ring. Removing the methoxyl
7 position (11a) or the isopentenyl group at the C-6 position (11f) of the A-ring and substituting the isopentenyl chain
ion of the A-ring with a geranyl chain (11e) resulted in reduced PPAR-γ agonist activity. However, substituting the
n at the C-7 position of the A-ring with an isopentyl chain (11d) increased the PPAR-γ agonist activity. The presence
onating substituent at the C-3' position (3'-OH, 11b) or an electron-withdrawing substituent at the C-3' position (3'-F,
ng increased the PPAR-γ agonist activity. In the flavone series (12a–12b), oxidizing the C-ring of flavanone 11b (12a)
PAR-γ agonist activity and oxidizing the C-ring of flavanone 11d (12b) increased the PPAR-γ agonist activity.
hydroxyl group at the C-4' position of the B-ring with a fluorine atom (14a–14b, 15a–15b) markedly reduced the
t activity. Changing the phenyl ring of the B-ring to a heterocyclic ring, creating thiazole, pyridine, or imidazole
, 14e, 14f, 15c), markedly reduced the PPAR-γ agonist activity. Complete removal of the B-ring (17) markedly
-γ agonist activity. This demonstrates the importance of the B-ring in enhancing the PPAR-γ agonist activity.
3, 4a, 4b, 11c, 11d, and 12b (EC50 = 2.53, 1.13, 0.78, 0.43, 3.30, 13.61, and 3.55 μM, respectively) exhibited a
her PPAR-γ agonist activity compared to bavachinin 1 (EC50 = 18.74 μM).
s
ture–activity relationships trends of bavachinin 1 PPAR-γ agonist activity from the present study are listed as follows:
an isopentenyl group at the C-6 position and methoxyl group at the C-7 position are indispensable for the PPAR-γ
the results also suggest that an aliphatic chain in the C-6 position is crucial for the PPAR-γ agonist activity, and the
2
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hould not be too long; (ii) In the B-ring, changing hydroxyl group at C-4' position to aromatic ester group increases the
activity, meanwhile changing hydroxyl group to aliphatic ester group or ether group reduce PPAR-γ agonist activity.
g structure is essential for the PPAR-γ agonist activity, and replacing this phenyl ring with imidazole, thiazole, or
markedly reduce the PPAR-γ agonist activity; (iii) In the C-ring, changing the single bond at C-2 and C-3 position to
arkedly increases the PPAR-γ agonist activity. Analogues 2b, 3, 4a, 4b, 11c, 11d, and 12b were found with higher
t activity compared to bavachinin 1. In future studies, it might be useful to generate pan-PPAR agonists in order to
betic and antiobesity effects. Further in vitro pan-PPAR evaluation of these compounds is underway.
al Section
1
aterials were obtained from commercial suppliers and used without further purification. The H and 13C spectra were
Avance III 500 or 400, NMR spectrometer operating at 500 MHz or 400 MHz for 1H NMR, 150 MHz, 125 MHz or 100
MR, using TMS as the internal standard and CDCl3 or DMSO-d6 as the solvent. Chemical shifts were reported ind
lative to that of the internal TMS. The abbreviations s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet,
were used throughout. 13C NMR spectra were recorded with complete proton decoupling. The ESI-MS or EI-MS was
nnigan LCQ/DECA or Thermo-DFS, respectively. The HRMS were obtained from Mcromass Q-TOF Ultima (ESI) or
Scientific DFS (EI) spectrometer. Silica gel F254 was used in analytical thin-layer chromatography (TLC) and silica gel
umn chromatography, respectively, and the visualization was accomplished with UV light (254 nm).
ure for the preparation of 2a–2g
of bavachinin 1 and anhydrous potassium carbonate in acetone was added acyl halides or alkyl/aromatic halides. The
sing for obtaining 2a–2d was different from that of 2e–2g. For 2a–2d, the reaction mixture was stirred at room
2 h. For 2e–2g, the reaction mixture was stirred at reflux for 2 h. The reaction mixture was quenched with deionized
cted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried
fate, filtrated, and evaporated under vacuum. The crude material was purified by silica gel column chromatography
ether/ethyl acetate to afford 2a–2g.
y-7-methoxy-6-isopentenyl-flavanone (2a)
5 mmol), propionyl chloride (17.04 mg, 0.18 mmol) and anhydrous potassium carbonate (800 mg, 5.79 mmol) were
olorless solid 2a (46.2 mg, 79%). 2a: 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.18 (d, J =
8 (s, 1H), 5.47 (dd, J = 13.3, 3.0 Hz, 1H), 5.29 (t, J = 7.3 Hz, 1H), 3.88 (s, 3H), 3.27 (d, J = 7.3 Hz, 2H), 3.02 (dd, J =
H), 2.83 (dd, J = 16.9, 2.9 Hz, 1H), 2.63 (q, J = 7.4 Hz, 2H), 1.76 (s, 3H), 1.72 (s, 3H), 1.30 (t, J = 7.5 Hz, 3H). 13C
CDCl3) δ 190.5, 172.8, 164.1, 162.1, 150.9, 136.4, 133.1, 127.3, 127.1, 125.0, 122.0, 121.7, 114.0, 98.8, 79.5, 55.8,
, 25.9, 17.8, 9.1. ESI-MS m/z (%): 395.1 [M+H]+; 393.2 [M-H]-. HR ESI-MS calcd for C24H26O5Na 417.1678 [M+Na]+,
.
7-methoxy-6-isopentenyl-flavanone (2b)
5 mmol), benzoyl chloride (25.33 mg, 0.18 mmol) and anhydrous potassium carbonate (800 mg, 5.79 mmol) were
ale yellow solid 2b (39.4 mg, 60%). 2b: 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 7.7 Hz, 2H), 7.71 (s, 1H), 7.68 (t, J
.61–7.51 (m, 4H), 7.32 (d, J = 8.3 Hz, 2H), 6.50 (s, 1H), 5.51 (dd, J = 13.3, 2.9 Hz, 1H), 5.30 (t, J = 7.5 Hz, 1H), 3.89
J = 7.3 Hz, 2H), 3.05 (dd, J = 16.8, 13.3 Hz, 1H), 2.86 (dd, J = 16.8, 3.0 Hz, 1H), 1.77 (s, 3H), 1.73 (s, 3H). 13C NMR
Cl3) δ 190.5, 165.1, 164.2, 162.1, 151.1, 136.6, 133.7, 133.1, 130.2, 129.3, 128.6, 127.4, 127.1, 125.1, 122.2, 121.7,
.5, 55.8, 44.4, 27.8, 25.9, 17.8. ESI-MS m/z (%): 465.1 [M+Na]+; 441.2 [M-H]-. HR ESI-MS calcd for C28H26O5Na
a]+, found 465.1672.
y)-7-methoxy-6-isopentenyl-flavanone (2c)
5 mmol), p-toluoyl chloride (28.38 mg, 0.18 mmol) and anhydrous potassium carbonate (800 mg, 5.79 mmol) were
white solid 2c (32.1 mg, 48%). 2c: 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.9 Hz, 2H), 7.71 (s, 1H), 7.57 (d, J = 8.2
, J = 8.0 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 6.49 (s, 1H), 5.51 (dd, J = 13.4, 2.8 Hz, 1H), 5.30 (t, J = 7.3 Hz, 1H), 3.89
J = 7.3 Hz, 2H), 3.05 (dd, J = 16.9, 13.3 Hz, 1H), 2.86 (dd, J = 16.8, 3.0 Hz, 1H), 2.49 (s, 3H), 1.77 (s, 3H), 1.72 (s,
125 MHz, CDCl3) δ 190.5, 165.1, 164.1, 162.1, 151.2, 144.6, 136.5, 133.0, 130.3, 129.3, 127.4, 127.1, 126.6, 125.0,
4.0, 98.8, 79.5, 55.8, 44.4, 27.8, 25.9, 21.8, 17.8. ESI-MS m/z (%): 479.2 [M+Na]+. HR ESI-MS calcd for C29H28O5Na
a]+, found 479.1832.
y)-7-methoxy-6-isopentenyl-flavanone (2d)
5 mmol), p-anisoyl chloride (30.28 mg, 0.18 mmol) and anhydrous potassium carbonate (800 mg, 5.79 mmol) were
white solid 2d (39.4 mg, 56%). 2d: 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.6 Hz, 2H), 7.71 (s, 1H), 7.56 (d, J = 8.3
, J = 8.1 Hz, 2H), 7.02 (d, J = 8.5 Hz, 2H), 6.49 (s, 1H), 5.50 (dd, J = 13.1, 2.9 Hz, 1H), 5.30 (t, J = 7.5 Hz, 1H), 3.93
3H), 3.27 (d, J = 7.3 Hz, 2H), 3.05 (dd, J = 16.9, 13.3 Hz, 1H), 2.86 (dd, J = 16.9, 3.0 Hz, 1H), 1.77 (s, 3H), 1.72 (s,
150 MHz, CDCl3) δ 190.6, 164.8, 164.1, 164.0, 162.1, 151.2, 136.4, 133.1, 132.4, 127.4, 127.1, 125.0, 122.2, 121.7,
3
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3.9, 98.8, 79.5, 55.8, 55.6, 44.4, 27.8, 25.9, 17.8. ESI-MS m/z (%): 473.1 [M+H]+. HR ESI-MS calcd for C29H28O6Na
a]+, found 495.1778.
-methoxy-6-isopentenyl-flavanone (2e)
5 mmol), benzyl bromide (25.88 mg, 0.15 mmol) and anhydrous potassium carbonate (800 mg, 5.79 mmol) were
white solid 2e (20 mg, 32%). 2e: 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.52–7.31 (m, 7H), 7.05 (d, J = 8.6 Hz, 2H),
41 (dd, J = 13.4, 2.9 Hz, 1H), 5.30 (t, J = 7.5 Hz, 1H), 5.12 (s, 2H), 3.87 (s, 3H), 3.27 (d, J = 7.3 Hz, 2H), 3.06 (dd, J =
1H), 2.80 (dd, J = 16.8, 2.9 Hz, 1H), 1.77 (s, 3H), 1.72 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 190.9, 164.0, 162.2,
32.9, 131.2, 128.6, 128.0, 127.7, 127.4, 127.0, 124.8, 121.7, 115.1, 113.9, 98.7, 79.7, 70.0, 55.7, 44.1, 27.8, 25.8,
/z (%): 451.1 [M+Na]+. HR ESI-MS calcd for C28H29O4 429.2060 [M+H]+, found 429.2064.
oxy-7-methoxy-6-isopentenyl-flavanone (2f)
6 mmol), prenyl bromide (28.38 mg, 0.18 mmol) and anhydrous potassium carbonate (880 mg, 6.37 mmol) were used
solid 2f (41.3 mg, 63%). 2f: 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.41 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.6 Hz,
), 5.52 (t, J = 6.8 Hz, 1H), 5.41 (dd, J = 13.4, 2.8 Hz, 1H), 5.30 (t, J = 7.0 Hz, 1H), 4.56 (d, J = 6.7 Hz, 2H), 3.86 (s,
= 7.3 Hz, 2H), 3.06 (dd, J = 16.8, 13.4 Hz, 1H), 2.79 (dd, J = 16.8, 2.9 Hz, 1H), 1.83 (s, 3H), 1.78 (s, 3H), 1.76 (s, 3H),
C NMR (125 MHz, CDCl3) δ 191.0, 164.1, 162.3, 159.2, 138.5, 133.0, 130.8, 127.7, 127.1, 124.8, 121.8, 119.5, 114.9,
9, 64.8, 55.8, 44.1, 27.8, 25.9, 25.9, 18.2, 17.8. ESI-MS m/z (%): 429.2 [M+Na]+. HR ESI-MS calcd for C26H30O4Na
a]+, found 429.2049.
methoxy-6-isopentenyl-flavanone (2g)
2 mmol), methyl iodide (34.2 mg, 0.24 mmol) and anhydrous potassium carbonate (600 mg, 4.34 mmol) were used to
1
oil 2g (32.6 mg, 78%). 2g: H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.43 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.6 Hz,
), 5.42 (dd, J = 13.4, 2.9 Hz, 1H), 5.30 (t, J = 7.2 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.26 (d, J = 7.3 Hz, 2H), 3.06 (dd,
Hz, 1H), 2.80 (dd, J = 16.8, 2.9 Hz, 1H), 1.76 (s, 3H), 1.72 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 191.0, 164.1, 162.3,
31.0, 127.7, 127.1, 124.8, 121.7, 114.2, 114.0, 98.8, 79.8, 55.8, 55.4, 44.2, 27.8, 25.9, 17.8. ESI-MS (ESI) m/z (%):
HR ESI-MS calcd for C22H25O4 353.1747 [M+H]+, found 353.1747.
methoxy-6-isopentenyl-flavone (3)
of bavachinin 1 (250 mg, 0.74 mmol) in DMSO (10 mL) was added iodine (94 mg, 0.74 mmol). The reaction mixture
0 ◦C for 3 h. After cooling, the reaction mixture was quenched with a saturated solution of sodium thiosulfate (10 mL)
with ethyl acetate (2 × 10 mL). The organic layers were combined, washed with deionized water (2 × 10 mL) and
m chloride solution (10 mL), dried over sodium sulfate, filtrated, and evaporated under vacuum. The crude material
silica gel column chromatography with petroleum ether/ethyl acetate to afford a pale yellow powder 3 (122 mg, 49%).
0 MHz, DMSO) δ 10.28 (s, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.70 (s, 1H), 7.29 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.78 (s,
7.5 Hz, 1H), 3.96 (s, 3H), 3.32 (d, J = 7.4 Hz, 2H), 1.74 (s, 3H), 1.68 (s, 3H). 13C NMR (125 MHz, DMSO) δ 176.2,
60.7, 156.0, 132.7, 128.0, 128.0, 123.9, 121.7, 121.4, 116.4, 115.8, 104.6, 99.3, 56.3, 27.6, 25.5, 17.6. ESI-MS m/z
H]+; 335.1 [M-H]-. HR ESI-MS calcd for C21H21O4 337.1440 [M+H]+, found 337.1441.
ure for the preparation of 4a–4c
of 3 and anhydrous potassium carbonate in acetone was added acyl halides or alkyl/aromatic halides. The reaction
btaining 4a–4b was different from that of 4c. For 4a–4b, the reaction mixture was stirred at room temperature for 2 h.
ction mixture was stirred at reflux for 2 h. The reaction mixture was quenched with deionized water and extracted with
he organic layers were combined, washed with saturated sodium chloride solution (10 mL), dried over sodium sulfate,
vaporated under vacuum. The crude material was purified by silica gel column chromatography with petroleum
ate to afford 4a–4c.
methoxy-6-isopentenyl-flavone (4a)
5 mmol), acetyl chloride (14.4 mg, 0.18 mmol) and anhydrous potassium carbonate (800 mg, 5.79 mmol) were used
solid 4a (47.9 mg, 85%). 4a: 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.96 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.6 Hz,
), 6.76 (s, 1H), 5.35 (t, J = 7.4 Hz, 1H), 3.99 (s, 3H), 3.40 (d, J = 7.4 Hz, 2H), 2.37 (s, 3H), 1.78 (s, 3H), 1.74 (s, 3H).
MHz, CDCl3) δ 177.9, 169.0, 162.2, 161.8, 156.7, 152.9, 133.5, 129.6, 129.4, 127.4, 125.3, 122.3, 121.3, 117.2, 107.6,
, 25.9, 21.2, 17.8. ESI-MS m/z (%): 379.1 [M+H]+. HR ESI-MS calcd for C23H23O5 379.1540 [M+H]+, found 379.1540.
oyloxy)-7-methoxy-6-isopentenyl-flavone (4b)
5 mmol), 4-nitrobenzoyl chloride (28 mg, 0.15 mmol) and anhydrous potassium carbonate (800 mg, 5.79 mmol) were
1
pale yellow solid 4b (37.5 mg, 52%). 4b: H NMR (400 MHz, CDCl3) δ 8.45–8.40 (m, 4H), 8.04 (d, J = 8.4 Hz, 2H),
4 (d, J = 8.5 Hz, 2H), 6.96 (s, 1H), 6.80 (s, 1H), 5.36 (t, J = 7.6 Hz, 1H), 4.00 (s, 3H), 3.40 (d, J = 7.2 Hz, 2H), 1.79 (s,
H). 13C NMR (125 MHz, CDCl3) δ 177.8, 162.9, 162.3, 161.6, 156.7, 152.7, 151.1, 134.5, 133.6, 131.4, 130.3, 129.6,
23.8, 122.2, 121.2, 117.2, 107.8, 98.2, 56.0, 28.3, 25.9, 17.8. ESI-MS m/z (%): 486.1 [M+H]+; 484.0 [M-H]-. HR ESI-
8H24O7N 486.1547 [M+H]+, found 486.1552.
benzyloxy)-7-methoxy-6-isopentenyl-flavone (4c)
4
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5 mmol), 3,4-difluorobenzyl bromide (32 mg, 0.15 mmol) and anhydrous potassium carbonate (800 mg, 5.79 mmol)
ve a white solid 4c (36.5 mg, 53%). 4c: 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.89 (d, J = 8.7 Hz, 2H), 7.36–7.17
, J = 8.7 Hz, 2H), 6.92 (s, 1H), 6.71 (s, 1H), 5.35 (t, J = 7.6 Hz, 1H), 5.11 (s, 2H), 3.98 (s, 3H), 3.39 (d, J = 7.4 Hz, 2H),
74 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 177.9, 162.4, 162.1, 160.7, 156.6, 150.50 (dd, J = 249.0, 12.8 Hz, 1C),
248.9, 12.5 Hz, 1C), 133.4, 133.37–133.20 (m, 1C), 129.2, 127.9, 125.3, 125.0, 123.35 (dd, J = 6.4, 3.6 Hz, 1C),
d, J = 17.4 Hz, 1C), 117.2, 116.50 (d, J = 17.9 Hz, 1C), 115.2, 106.4, 98.2, 68.9, 55.9, 28.2, 25.9, 17.8. ESI-MS m/z
H]+. HR ESIMS calcd for C28H25O4F2 463.1715 [M+H]+, found 463.1713.
ure for the preparation of 7a, 7b, 7d
of 5a–5b and anhydrous potassium carbonate in acetone was added alkyl halides. Then the reaction mixture was
for 5 h. The reaction mixture was quenched with deionized water and extracted with ethyl acetate. The organic layers
washed with saturated sodium chloride solution, dried over sodium sulfate, filtrated, and evaporated under vacuum
6a–c. The crude product was used for the next reaction step directly without further purification.
ssolved in diethylaniline and the solution was stirred at reflux under an inert atmosphere for 4 h. After cooling, the
e was quenched with 2N aqueous HCl and extracted with ethyl acetate. The organic layers were combined, washed
water and saturated sodium chloride solution, dried over sodium sulfate, filtrated, and evaporated under vacuum. The
ified by silica gel column chromatography with petroleum ether/ethyl acetate to afford 7a, 7b, 7d.
sopentenylacetophenone (7a)
etophenone 5a (3.0 g, 0.02 mol), prenyl bromide (3.62 g, 0.02 mol) and anhydrous potassium carbonate (9.12 g, 0.07
to give a colorless oil 6a. 6a and diethylaniline (20 mL) were used to give a yellow oil 7a (1.76 g, 39%). 7a: 1H NMR δ
l3) 12.14 (s, 1H), 7.51 (s, 1H), 7.31 (dd, J = 8.5, 1.6 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 5.31 (t, J = 7.5 Hz, 1H), 3.31 (d,
2.64 (s, 3H), 1.78 (s, 3H), 1.75 (s, 3H). ESI-MS m/z (relative intensity): 203.2 [M-H]-.
methoxyl-5'-isopentenylacetophenone (7b)
methoxylacetophenone 5b (3.00 g, 0.02 mol), prenyl bromide (3.23 g, 0.02 mol) and anhydrous potassium carbonate
mol) were used to give a yellow oil 6b. 6b and diethylaniline (20 mL) were used to give a yellow oil 7b (2.37 g, 56%).
00 MHz, CDCl3) δ 12.74 (s, 1H), 7.42 (s, 1H), 6.41 (s, 1H), 5.27 (t, J = 7.3 Hz, 1H), 3.88 (s, 3H), 3.24 (d, J = 7.3 Hz,
), 1.78 (s, 3H), 1.73 (s, 3H) . LRMS (EI) m/z (%): 234 [M+].
methoxy-5'-isopentylacetophenone (7c)
of 7b (530 mg, 2.13 mmol) in ethanol (10 mL) was added 10% Pd-C (230 mg, 0.21 mmol). The flask was placed
en atmosphere. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was filtered and
deionized water (10 mL) and ethyl acetate (2 × 10 mL). The organic layers were combined, washed with saturated
solution (10 mL), dried over sodium sulfate, filtrated, and evaporated under vacuum. The residue was purified by
n chromatography with petroleum ether/ethyl acetate to afford a yellow oil 7c (508.8 mg, 95%). 7c: 1H NMR (400 MHz,
(s, 1H), 7.42 (s, 1H), 6.39 (s, 1H), 3.86 (s, 3H), 2.57 (s, 3H), 2.56–2.50 (m, 2H), 1.64–1.55 (m, 1H), 1.49–1.38 (m, 2H),
5 (s, 3H). ESI-MS m/z (%): 237.2 [M+H]+.
methoxyl-5'-geranylacetophenone (7d)
methoxylacetophenone 5b (2.0 g, 0.01 mol), geranyl bromide (2.6 g, 0.01 mol) and anhydrous potassium carbonate
l) were used to give a colorless oil 6c. 6c and diethylaniline (20 mL) were used to give a corlorless oil 7d (1.27 g,
MR δ (400 MHz, CDCl3) 12.73 (s, 1H), 7.43 (s, 1H), 6.41 (s, 1H), 5.32 – 5.27 (m, 1H), 5.16 – 5.12 (m, 1H), 3.88 (s,
= 7.2 Hz, 2H), 2.56 (s, 3H), 2.21 – 2.11 (m, 2H), 2.10 – 2.01 (m, 2H), 1.81 – 1.71 (m, 3H), 1.70 – 1.68 (m, 3H), 1.63 –
I-MS m/z (relative intensity): 301.2 [M-H]-.
ure for the preparation of 8b, 8d, 8f
of hydroxylbenzaldehydes 8a, 8c, 8e and anhydrous potassium carbonate in acetone was added chloromethyl methyl
fter that, the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with
and extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution,
um sulfate, filtrated, and evaporated under vacuum. The residue was purified by silica gel column chromatography
ether/ethyl acetate to afford 8b, 8d, 8f.
hoxylbenzaldehyde (8b)
.012 mol), chloromethyl methyl ether (1.25 g, 0.015 mol) and anhydrous potassium carbonate (6.80 g, 0.049 mol)
ve a colorless oil 8b (1.63 g, 79.95%). 8b: 1H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.17 (d,
5.27 (s, 2H), 3.51 (s, 3H). LRMS (EI) m/z (%): 166 [M]+.
methoxylbenzaldehyde (8d)
3.62 mmol), chloromethyl methyl ether (714 mg, 8.87 mmol) and anhydrous potassium carbonate (2.00 g, 0.014 mol)
ve a colorless oil 8d (646 mg, 79%). 8d: 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.53 (dd,
1H), 7.30 (d, J = 8.3 Hz, 1H), 5.35 (s, 2H), 5.31 (s, 2H), 3.54 (s, 3H), 3.54 (s, 3H).
hoxymethoxylbenzaldehyde (8f)
5
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10.1002/cmdc.201600554
ChemMedChem
PER
3.50 mmol), chloromethyl methyl ether (345 mg, 4.20 mmol) and anhydrous potassium carbonate (1.93 g, 0.014 mol)
ve a colorless oil 8f (285 mg, 43%). 8f: 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.65–7.63 (m, 2H), 7.37–7.33 (m,
), 3.55 (s, 3H). LRMS (ESI) m/z (%): 185.6 [M+H]+.
ure for the preparation of chalcones 9a–9f
of 7a–7e and 8b, 8d, 8f in ethanol was added potassium trimethylsilanolate. Then the reaction mixture was stirred at
inert atmosphere for 4 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl
ganic layers were combined, washed with deionized water and saturated sodium chloride solution, dried over sodium
and evaporated under vacuum. The crude material was purified by silica gel column chromatography with petroleum
ate to afford 9a–9f.
'-isopentenyl)-3-(4-methoxymethoxyphenyl)-2E-propen-1-one (9a)
01 mol), 8b (1.44 g, 0.01 mol) and potassium trimethylsilanolate (4.14 g, 0.03 mol) were used to give a bright yellow
7%). 9a: 1H NMR (400 MHz, CDCl3) δ 12.78 (s, 1H), 7.91 (d, J = 15.4 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.65 (d, J =
7 (d, J = 15.5 Hz, 1H), 7.34 (dd, J = 8.4, 1.5 Hz, 1H), 7.12 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 8.5 Hz, 1H), 5.34 (t, J = 7.4
, 2H), 3.52 (s, 3H), 3.36 (d, J = 7.3 Hz, 2H), 1.80 (s, 3H), 1.77 (s, 3H). ESI-MS m/z (%): 353.2 [M+H]+.
'-methoxy-5'-isopentenyl)-3-(3,4-dimethoxymethoxyphenyl)-2E-propen-1-one (9b)
2.78 mmol), 8d (630 mg, 2.78 mmol) and potassium trimethylsilanolate (1.32 g, 0.009 mol) were used to give a bright
9b (460.3 mg, 37%). 9b: 1H NMR (400 MHz, CDCl3) δ 13.50 (s, 1H), 7.83 (d, J = 15.4 Hz, 1H), 7.61 (s, 1H), 7.51 (s,
= 15.4 Hz, 1H), 7.30–7.21 (m, 2H), 6.46 (s, 1H), 5.32 (s, 4H), 5.30 (s, 1H), 3.90 (s, 3H), 3.58 (s, 3H), 3.55 (s, 3H), 3.28
H), 1.81 (s, 3H), 1.76 (s, 3H). ESI-MS m/z (%): 442.9 [M+H]+.
'-methoxy-5'-isopentenyl)-3-(3-fluorine-4-methoxymethoxyphenyl)-2E-propen-1-one (9c)
.55 mmol), 8f (285 mg, 1.55 mmol) and potassium trimethylsilanolate (668 mg, 4.65 mmol) were used to give a bright
9c (218.9 mg, 35%). 9c: 1H NMR (400 MHz, CDCl3) δ 13.41 (s, 1H), 7.79 (d, J = 15.4 Hz, 1H), 7.59 (s, 1H), 7.46 (d, J
7.45–7.42 (m, 1H), 7.37–7.35 (m, 1H), 7.26–7.24 (m, 1H), 6.47 (s, 1H), 5.32–5.28 (m, 3H), 3.90 (s, 3H), 3.56 (s, 3H),
Hz, 2H), 1.80 (s, 3H), 1.76 (s, 3H). ESIMS m/z (%): 401.1 [M+H]+.
'-methoxy-5'-isopentyl)-3-(4-methoxymethoxyphenyl)-2E-propen-1-one (9d)
2.12 mmol), 8b (352 mg, 2.12 mmol) and potassium trimethylsilanolate (1.00 g, 0.007 mol) were used to give a bright
1
(261 mg, 32%). 9d: H NMR (400 MHz, CDCl3) δ 13.51 (s, 1H), 7.88 (d, J = 15.6 Hz, 1H), 7.65 (d, J = 8.5 Hz, 2H),
50 (d, J = 15.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.46 (s, 1H), 5.26 (s, 2H), 3.89 (s, 3H), 3.52 (s, 3H), 2.63–2.55 (m,
(m, 1H), 1.53–1.42 (m, 2H), 1.00 (s, 3H), 0.98 (s, 3H). ESI-MS m/z (%): 385.3 [M+H]+.
'-methoxy-5'-geranyl)-3-(4-methoxymethoxyphenyl)-2E-propen-1-one (9e)
04 mol), 8b (0.7 g, 0.004 mol) and potassium trimethylsilanolate (1.9 g, 0.013 mol) were used to give a yellow oil 9e
: 1H NMR (400 MHz, CDCl3) δ 13.54 (s, 1H), 7.87 (d, J = 15.4 Hz, 1H), 7.63 (s, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.48 (d,
), 7.09 (d, J = 8.3 Hz, 2H), 6.47 (s, 1H), 5.34 (t, J = 7.3 Hz, 1H), 5.25 (s, 2H), 5.18 (t, J = 7.0 Hz, 1H), 3.90 (s, 3H),
29 (d, J = 7.3 Hz, 2H), 2.23–2.14 (m, 2H), 2.14–2.01 (m, 2H), 1.80–1.60 (m, 9H). ESI-MS m/z (%): 451.1 [M+H]+;
'-methoxy)-3-(4-methoxymethoxyphenyl)-2E-propen-1-one (9f)
06 mol), 8b (1.0 g, 0.006 mol) and potassium trimethylsilanolate (2.87 g, 0.02 mol) were used to give a yellow solid 9f
: 1H NMR (400 MHz, CDCl3) δ 13.56 (s, 1H), 7.89 (d, J = 15.7 Hz, 1H), 7.86 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.50 (d,
), 7.11 (d, J = 8.5 Hz, 2H), 6.52–6.50 (m, 2H), 5.25 (s, 2H), 3.89 (s, 3H), 3.52 (s, 3H). ESI-MS m/z (%): 315.3 [M+H]+.
ure for the preparation of methoxymethylated flavanones 10a–10f
of 9a–9f in methanol was added potassium fluoride. Then the reaction mixture was stirred at reflux for 8 h. The
e was quenched with deionized water and extracted with ethyl acetate. The organic layers were combined, washed
odium chloride solution, dried over sodium sulfate, filtrated, and evaporated under vacuum. The residue was purified
umn chromatography with petroleum ether/ethyl acetate to afford 10a–10f.
hoxy-6-isopentenyl-flavanone (10a)
0.98 mmol) and potassium fluoride (180 mg, 3.10 mmol) were used to give a pale yellow solid 10a (218 mg, 63%).
00 MHz, CDCl3) δ 7.74 (d, J = 1.7 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.35 (dd, J = 8.5, 2.3 Hz, 1H), 7.12 (d, J = 8.5 Hz,
= 8.5 Hz, 1H), 5.42 (dd, J = 13.4, 2.8 Hz, 1H), 5.31 (t, J = 7.5 Hz, 1H), 5.22 (s, 2H), 3.51 (s, 3H), 3.34 (d, J = 7.1 Hz,
= 16.9, 13.4 Hz, 1H), 2.86 (dd, J = 16.8, 2.7 Hz, 1H), 1.77 (s, 3H), 1.74 (s, 3H). ESI-MS m/z (%): 353.1 [M+H]+.
ymethoxy-7-methoxy-6-isopentenyl-flavanone (10b)
6
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10.1002/cmdc.201600554
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PER
, 1.04 mmol) and potassium fluoride (230 mg, 3.96 mmol) were used to give a white solid 10b (269.3 mg, 59%). 10b:
Hz, CDCl3) δ 7.69 (s, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.09 (dd, J = 8.6, 1.6 Hz, 1H), 6.48 (s,
= 13.6, 2.7 Hz, 1H), 5.31 (s, 1H), 5.29 (d, J = 4.8 Hz, 4H), 3.87 (s, 3H), 3.55 (s, 3H), 3.55 (s, 3H), 3.26 (d, J = 7.5 Hz,
= 16.8, 13.4 Hz, 1H), 2.80 (dd, J = 16.9, 2.9 Hz, 1H), 1.76 (s, 3H), 1.72 (s, 3H). ESI-MS m/z (%): 443.0 [M+H]+.
ethoxymethoxy-7-methoxy-6-isopentenyl-flavanone (10c)
, 0.55 mmol) and potassium fluoride (110 mg, 1.89 mmol) were used to give a pale yellow oil 10c (165.8 mg, 76%).
00 MHz, CDCl3) δ 7.69 (s, 1H), 7.33– 7.21 (m, 2H), 7.16 (d, J = 9.0 Hz, 1H), 6.47 (s, 1H), 5.41 (dd, J = 13.1, 2.9 Hz,
7.2 Hz, 1H), 5.26 (s, 2H), 3.88 (s, 3H), 3.55 (s, 3H), 3.26 (d, J = 7.4 Hz, 2H), 2.99 (dd, J = 16.8, 13.2 Hz, 1H), 2.81
0 Hz, 1H), 1.76 (s, 3H), 1.71 (s, 3H). ESI-MS m/z (%): 401.3 [M+H]+.
hoxy-7-methoxy-6-isopentyl-flavanone (10d)
0.68 mmol) and potassium fluoride (180 mg, 3.10 mmol) were used to give a pale yellow oil 10d (160 mg, 62%). 10d:
Hz, CDCl3) δ 7.70 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.46 (s, 1H), 5.43 (dd, J = 13.5, 2.8 Hz,
H), 3.86 (s, 3H), 3.51 (s, 3H), 3.06 (dd, J = 16.9, 13.5 Hz, 1H), 2.80 (dd, J = 16.9, 2.9 Hz, 1H), 2.61–2.52 (m, 2H),
H), 1.49–1.43 (m, 2H), 0.96 (s, 3H), 0.95 (s, 3H). ESI-MS m/z (%): 385.2 [M+H]+.
hoxy-7-methoxy-6-geranyl-flavanone (10e)
1.55 mmol) and potassium fluoride (350 mg, 6.02 mmol) were used to give a pale yellow oil 10e (172 mg, 24.56%).
00 MHz, CDCl3) δ 7.70 (s, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 8.6 Hz, 2H), 6.47 (s, 1H), 5.42 (dd, J = 13.4, 2.8
J = 7.0 Hz, 1H), 5.22 (s, 2H), 5.13 (t, J = 7.2 Hz, 1H), 3.86 (s, 3H), 3.51 (s, 3H), 3.28 (d, J = 7.1 Hz, 2H), 3.06 (dd, J
, 1H), 2.80 (dd, J = 16.8, 2.9 Hz, 1H), 2.16–2.09 (m, 2H), 2.09–1.97 (m, 2H), 1.76–1.62 (m, 9H). ESI-MS m/z (%):
hoxy-7-methoxy-flavanone (10f)
04 mol) and potassium fluoride (0.6 g, 0.01 mol) were used to give a yellow solid 10f (0.6 g, 55%). 10f: 1H NMR δ (400
89 (d, J = 9.0 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 6.64 (dd, J = 8.7, 2.2 Hz, 1H), 6.51 (d, J = 2.3
d, J = 12.9, 2.6 Hz, 1H), 5.23 (s, 2H), 3.86 (s, 3H), 3.51 (s, 3H), 3.08 (dd, J = 16.8, 13.3 Hz, 1H), 2.82 (dd, J = 16.9,
I-MS m/z (%): 313.1 [M-H]-.
ure for the preparation of demethoxymethylated flavanones 11a–11f
of 10a–10f in methanol was added 3N aqueous HCl. Then the reaction mixture was stirred at reflux for 10 min. After
ction mixture was quenched with deionized water and extracted with ethyl acetate. The organic layers were combined,
aturated sodium chloride solution, dried over sodium sulfate, filtrated, and evaporated under vacuum. The crude
rified by silica gel column chromatography with petroleum ether/ethyl acetate to afford 11a–11f.
sopentenyl-flavanone (11a)
1
0.62 mmol) and 3N aqueous HCl (3.1 mL) were used to give a pale yellow solid 11a (130 mg, 68%). 11a: H NMR
l3) δ 7.75 (d, J = 2.1 Hz, 1H), 7.37–7.34 (m, 3H), 6.98 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 8.2 Hz, 2H), 6.12 (s, 1H), 5.41
7 Hz, 1H), 5.31 (t, J = 7.2 Hz, 1H), 3.33 (d, J = 7.3 Hz, 2H), 3.11 (dd, J = 16.9, 13.3 Hz, 1H), 2.87 (dd, J = 16.9, 2.8
, 3H), 1.74 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 192.9, 159.7, 155.8, 136.5, 134.7, 132.7, 130.3, 127.5, 125.5, 122.1,
15.3, 78.9, 44.0, 32.9, 25.3, 17.4. ESI-MS m/z (%): 309.2 [M+H]+. HR ESI-MS calcd for C20H19O3 307.1340 [M-H]-,
.
l-7-methoxy-6-isopentenyl-flavanone (11b)
0.45 mmol) and 3N aqueous HCl (2.26 mL) were used to give a pale yellow solid 11b (96.5 mg, 60%). 11b: 1H NMR
O) δ 9.07 (s, 1H), 9.02 (s, 1H), 7.47 (s, 1H), 6.90 (s, 1H), 6.78–6.73 (m, 2H), 6.60 (s, 1H), 5.40 (dd, J = 12.7, 3.0 Hz,
7.5 Hz, 1H), 3.84 (s, 3H), 3.18 (d, J = 7.4 Hz, 2H), 3.06 (dd, J = 16.8, 12.7 Hz, 1H), 2.63 (dd, J = 16.8, 3.0 Hz, 1H),
65 (s, 3H). 13C NMR (125 MHz, DMSO) δ 190.4, 163.4, 161.9, 145.6, 145.2, 132.2, 129.8, 126.0, 123.4, 121.9, 117.9,
3.5, 99.3, 79.2, 56.1, 43.2, 27.3, 25.6, 17.6. ESI-MS m/z (%): 355.1 [M+H]+. HR ESI-MS calcd for C21H23O5 355.1545
55.1535.
ydroxyl-7-methoxy-6-isopentenyl-flavanone (11c)
1
0.40 mmol) and 3N aqueous HCl (2.0 mL) were used to give a white solid 11c (89.2 mg, 63%). 11c: H NMR (400
7.69 (s, 1H), 7.25 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.07 (t, J = 8.5 Hz, 1H), 6.47 (s, 1H), 5.43–5.35 (m, 2H), 5.29 (t, J
3.88 (s, 3H), 3.26 (d, J = 7.4 Hz, 2H), 3.00 (dd, J = 16.9, 13.1 Hz, 1H), 2.80 (dd, J = 16.9, 3.0 Hz, 1H), 1.76 (s, 3H),
C NMR (125 MHz, CDCl3) δ 190.0, 163.7, 161.5, 150.44 (d, J = 238.2 Hz, 1C), 143.32 (d, J = 14.4 Hz, 1C), 132.6,
.7 Hz, 1C), 126.6, 124.6, 122.33 (d, J = 3.2 Hz, 1C), 121.1, 117.0, 113.36 (d, J = 12.5 Hz, 1C), 113.2, 98.3, 78.6, 55.3,
, 17.3. ESI-MS m/z (%): 357.4 [M+H]+. HR ESI-MS calcd for C21H22O4F 357.1497 [M+H]+, found 357.1495.
7
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10.1002/cmdc.201600554
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PER
methoxy-6-isopentyl-flavanone (11d)
0.42 mmol) and 3N aqueous HCl (2.1 mL) were used to give a pale yellow solid 11d (112.7 mg, 80%). 11d: 1H NMR
l3) δ 7.71 (s, 1H), 7.37 (d, J = 8.3 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.46 (s, 1H), 5.62 (s, 1H), 5.41 (dd, J = 13.5, 2.8
, 3H), 3.07 (dd, J = 16.7, 13.5 Hz, 1H), 2.80 (dd, J = 16.7, 2.7 Hz, 1H), 2.58– 2.54 (m, 2H), 1.65–1.55 (m, 1H), 1.51–
96 (s, 3H), 0.94 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 191.4, 164.4, 162.2, 156.2, 131.0, 128.0, 127.2, 126.3, 115.7,
8, 55.7, 44.1, 38.8, 28.0, 27.2, 22.6. ESI-MS m/z (%): 341.2 [M+H]+. HR ESIMS calcd for C21H25O4, 341.1753, [M+H]+,
.
methoxy-6-geranyl-flavanone (11e)
0.20 mmol) and 3N aqueous HCl (1 mL) were used to give a pale yellow oil 11e (25 mg, 31%). 11e: H NMR (400
1
7.71 (s, 1H), 7.37 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.3 Hz, 2H), 6.47 (s, 1H), 5.61 (s, 1H), 5.41 (dd, J = 13.3, 2.9 Hz,
7.0 Hz, 1H), 5.17–5.09 (m, 1H), 3.86 (s, 3H), 3.27 (d, J = 7.3 Hz, 2H), 3.06 (dd, J = 17.0, 13.3 Hz, 1H), 2.80 (dd, J =
H), 2.16–2.08 (m, 2H), 2.08–2.02 (m, 2H), 1.76–1.62 (m, 9H). 13C NMR (100 MHz, CDCl3) δ 190.9, 163.8, 161.9, 155.7,
30.5, 127.5, 126.7, 124.5, 123.8, 121.2, 115.2, 113.4, 98.3, 79.3, 55.3, 43.7, 39.3, 27.3, 26.2, 25.3, 17.3, 15.7. ESI-
7.0 [M+H]+; 405.1 [M-H]-. HR ESI-MS calcd for C26H30O4Na 429.2042 [M+Na]+, found 429.2030.
methoxy-flavanone (11f)
0.48 mmol) and 3N aqueous HCl (2.4 mL) were used to give a yellow solid 11f (43 mg, 33%). 11f: 1H NMR (400 MHz,
s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 6.66 (dd, J = 8.7, 2.3 Hz, 1H), 6.60
H), 5.50 (dd, J = 13.1, 2.8 Hz, 1H), 3.81 (s, 3H), 3.18 (dd, J = 16.8, 13.1 Hz, 1H), 2.66 (dd, J = 16.8, 2.9 Hz, 1H). 13
C
, DMSO) δ 190.4, 165.6, 163.3, 157.7, 129.1, 128.3, 128.0, 115.1, 114.4, 109.9, 101.0, 79.2, 55.8, 43.1. ESI-MS m/z
H]+; 269.1 [M-H]-. HR ESI-MS calcd for C16H14O4Na 293.0790 [M+Na]+, found 293.0783.
ure for the preparation of demethoxymethylated flavones 12a–12b
of 11b, 11d in DMSO was added iodine. The reaction mixture was stirred at 90 ◦C for 3 h. After cooling, the reaction
enched with a saturated solution of sodium thiosulfate and extracted with ethyl acetate. The organic layers were
hed deionized water and saturated sodium chloride solution, dried over sodium sulfate, filtrated, and evaporated under
ude material was purified by silica gel column chromatography with petroleum ether/ethyl acetate to afford 12a–12b.
l-7-methoxy-6-isopentenyl-flavone (12a)
0.20 mmol) and iodine (25 mg, 0.20 mmol) were used to give a yellow powder 12a (50 mg, 72%). 12a: 1H NMR (400
7.70 (s, 1H), 7.43–7.41 (m, 2H), 7.24 (s, 1H), 6.89 (d, J = 8.7 Hz, 1H), 6.66 (s, 1H), 5.30 (t, J = 7.6 Hz, 1H), 3.96 (s,
(m, 2H), 1.73 (s, 3H), 1.68 (s, 3H). 13C NMR (125 MHz, DMSO) δ 176.2, 162.6, 161.5, 156.0, 149.1, 145.7, 132.7,
22.1, 121.5, 118.5, 116.4, 115.9, 113.3, 104.6, 99.2, 56.3, 27.6, 25.6, 17.6. ESI-MS m/z (%): 353.2 [M+H]+. HR ESI-
1H21O5 353.1389 [M+H]+, found 353.1384.
methoxy-6-isopentyl-flavone (12b)
0.19 mmol) and iodine (25 mg, 0.19 mmol) were used to give a pale yellow solid 12b (36.5 mg, 56%). 12b: 1H NMR
O) δ 10.29 (s, 1H), 7.95 (d, J = 8.6 Hz, 2H), 7.74 (s, 1H), 7.28 (s, 1H), 6.93 (d, J = 8.6 Hz, 2H), 6.77 (s, 1H), 3.95 (s,
(m, 2H), 1.61–1.51 (m, 1H), 1.48–1.42 (m, 2H), 0.94 (s, 3H), 0.92 (s, 3H). 13C NMR (125 MHz, DMSO) δ 176.7, 162.9,
56.4, 129.8, 128.5, 124.7, 122.3, 116.9, 116.3, 105.1, 99.8, 56.8, 38.8, 27.8, 27.5, 22.9. ESI-MS m/z (%): 339.3
-MS calcd for C21H23O4 339.1596 [M+H]+, found 339.1588.
ure for the preparation of chalcones 13a–13f
solution of 7b and aromatic/heteroaromatic aldehydes in ethanol was added sodium hydroxide. Then the reaction
red at room temperature for 72 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted
te. The organic layers were combined, washed with deionized water saturated sodium chloride solution, dried over
filtrated, and evaporated under vacuum. The residue was purified by silica gel column chromatography with
/ethyl acetate to afford 13a–13f.
'-methoxy-5'-isopentenyl)-3-(4-fluorinephenyl)-2E-propen-1-one (13a)
2.13 mmol), 4-fluorobenzaldehyde (265 mg, 2.13 mmol) and sodium hydroxide (256 mg, 6.40 mmol) were used to
eedles 13a (200 mg, 28%). 13a: 1H NMR (400 MHz, CDCl3) δ 13.40 (s, 1H), 7.86 (d, J = 15.4 Hz, 1H), 7.67 (dd, J =
, 7.60 (s, 1H), 7.51 (d, J = 15.4 Hz, 1H), 7.16 (t, J = 8.4 Hz, 2H), 6.47 (s, 1H), 5.30 (t, J = 7.3 Hz, 1H), 3.91 (s, 3H),
Hz, 2H), 1.80 (s, 3H), 1.76 (s, 3H). ESI-MS m/z (%): 341.2 [M+H]+.
'-methoxy-5'-isopentenyl)-3-(3,4-difluorinephenyl)-2E-propen-1-one (13b)
.28 mmol), 3,4-difluorobenzaldehyde (182 mg, 1.28 mmol) and sodium hydroxide (154 mg, 3.85 mmol) were used to
eedles 13b (118 mg, 26%). 13b: 1H NMR (400 MHz, CDCl3) δ 13.31 (s, 1H), 7.78 (d, J = 15.2 Hz, 1H), 7.58 (s, 1H),
3 Hz, 1H), 7.54–7.44 (m, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.27–7.19 (m, 1H), 6.47 (s, 1H), 5.29 (t, J = 7.3 Hz, 1H), 3.91
J = 7.2 Hz, 2H), 1.80 (s, 3H), 1.76 (s, 3H). ESI-MS m/z (%): 359.3 [M+H]+.
8
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'-methoxy-5'-isopentenyl)-3-(4-methylthiazole-5-yl)-2E-propen-1-one (13c)
1.49 mmol), 4-Methylthiazole-5-carboxaldehyde (190 mg, 1.49 mmol) and sodium hydroxide (180 mg, 4.50 mmol)
ve a yellow solid 13c (163.7 mg, 32%). 13c: 1H NMR (400 MHz, CDCl3) δ 13.32 (s, 1H), 8.77 (s, 1H), 8.04 (d, J = 15.0
, 1H), 7.27 (d, J = 15.4 Hz, 1H), 6.46 (s, 1H), 5.30 (t, J = 7.9 Hz, 1H), 3.91 (s, 3H), 3.28 (d, J = 7.3 Hz, 2H), 2.66 (s,
), 1.75 (s, 3H). ESI-MS m/z (%): 342.2 [M-H]-.
'-methoxy-5'-isopentenyl)-3-phenyl-2E-propen-1-one (13d)
.007 mol), benzaldehyde (0.69 g, 0.007 mol) and sodium hydroxide (0.84 g, 0.021 mol) were used to give a yellow
1
24 g, 59%). 13d: H NMR (400 MHz, CDCl3) δ 13.43 (s, 1H), 7.90 (d, J = 15.5 Hz, 1H), 7.70–7.60 (m, 2H), 7.62 (s,
= 15.5 Hz, 1H), 7.50–7.43 (m, 3H), 6.47 (s, 1H), 5.31 (t, J = 7.2 Hz, 1H), 3.91 (s, 3H), 3.29 (d, J = 7.2 Hz, 2H), 1.80 (s,
). ESI-MS m/z (%): 323.1 [M+H]+; 321.2 [M-H]-.
'-methoxy-5'-isopentenyl)-3-(pyridine-4-yl)-2E-propen-1-one (13e)
0.85 mmol), 4-pyridinecarboxaldehyde (91 mg, 0.85 mmol) and sodium hydroxide (102 mg, 2.56 mmol) were used to
edles 13e (96.7 mg, 35%). 13e: 1H NMR (400 MHz, CDCl3) δ 13.21 (s, 1H), 8.73 (d, J = 5.2 Hz, 2H), 7.78 (d, J = 15.6
, J = 15.6 Hz, 1H), 7.58 (s, 1H), 7.50 (d, J = 5.3 Hz, 2H), 6.48 (s, 1H), 5.29 (t, J = 7.4 Hz, 1H)., 3.92 (s, 3H), 3.29 (d, J
.80 (s, 3H), 1.76 (s, 3H). ESI-MS m/z (%): 324.2 [M+H]+.
'-methoxy-5'-isopentenyl)-3-(1-N,N-dimethylsulfuryl-imidazole-4-yl)-2E-propen-1-one (13f)
0.44 mmol), 1-N,N-dimethylsulfuryl-imidazole-4-aldehyde (90 mg, 0.44 mmol) and sodium hydroxide (54 mg, 1.35
d to give a yellow needles 13f (58.3 mg, 31%). 13f: 1H NMR (400 MHz, CDCl3) δ 13.44 (s, 1H), 7.98 (s, 1H), 7.88 (d,
), 7.72 (d, J = 15.0 Hz, 1H), 7.69 (s, 1H), 7.48 (s, 1H), 6.46 (s, 1H), 5.27–5.22 (m, 1H), 3.90 (s, 3H), 3.27 (d, J = 7.1
, 6H), 1.76 (s, 3H), 1.75 (s, 3H). EI-MS m/z (%): 419 [M+].
ure for the preparation of flavanones 14a–14f
of 13a–13f and potassium fluoride in methanol. The reaction mixture was stirred at reflux for 8 h. Then, the reaction
enched with deionized water and extracted with ethyl acetate. The organic layers were combined, washed with
m chloride solution, dried over sodium sulfate, filtrated, and evaporated under vacuum. The crude material was
gel column chromatography with petroleum ether/ethyl acetate to afford 14a–14f.
ethoxy-6-isopentenyl-flavanone (14a)
0.50 mmol) and potassium fluoride (85 mg, 1.46 mmol) were used to give a white solid 14a (121 mg, 71%). 14a: 1H
CDCl3) δ 7.70 (s, 1H), 7.48 (dd, J = 8.4, 5.3 Hz, 2H), 7.14 (t, J = 8.5 Hz, 2H), 6.48 (s, 1H), 5.45 (dd, J = 13.6, 3.1 Hz,
7.4 Hz, 1H), 3.88 (s, 3H), 3.27 (d, J = 7.4 Hz, 2H), 3.02 (dd, J = 16.8, 13.4 Hz, 1H), 2.81 (dd, J = 16.8, 2.9 Hz, 1H),
72 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 190.5, 164.2, 162.0, 162.79 (d, J = 247.6 Hz, 1C), 134.8, 133.1, 128.04 (d, J
27.1, 125.1, 121.7, 115.77 (d, J = 21.7 Hz, 2C), 113.9, 98.8, 79.4, 55.8, 44.4, 27.8, 25.9, 17.8. ESI-MS m/z (%) 341.2
-MS calcd for C21H22O3F 341.1547 [M+H]+, found 341.1553.
7-methoxy-6-isopentenyl-flavanone (14b)
0.50 mmol) and potassium fluoride (50 mg, 1.46 mmol) were used to give a pale yellow solid 14b (46.3 mg, 46%).
400 MHz, CDCl3) δ 7.67 (s, 1H), 7.39–7.30 (m, 1H), 7.24–7.14 (m, 2H), 6.45 (s, 1H), 5.41 (dd, J = 13.0, 3.1 Hz, 1H),
H), 3.86 (s, 3H), 3.24 (d, J = 7.3 Hz, 2H), 2.94 (dd, J = 16.8, 13.0 Hz, 1H), 2.80 (dd, J = 16.8, 3.2 Hz, 1H), 1.74 (s,
). 13C NMR (125 MHz, CDCl3) δ 189.4, 163.7, 161.2, 150.00 (dd, J = 249.6, 13.1 Hz, 1C), 150.00 (dd, J = 249.6, 13.1
–135.43 (m, 1C), 132.7, 126.6, 124.8, 121.67 (dd, J = 6.3, 3.7 Hz, 1C), 121.1, 117.16 (d, J = 17.5 Hz, 1C), 114.91 (d,
C), 113.4, 98.2, 78.2, 55.3, 43.8, 27.3, 25.4, 17.3. ESI-MS m/z (%): 357.2 [M-H]-. HR ESI-MS calcd for C21H21O3F2
+, found 359.1446.
methoxy-2-(4-methylthiazole-5-yl)-6-isopentenyl-4H-1-benzopyran-4-one (14c)
0.17 mmol) and potassium fluoride (30 mg, 0.52 mmol) were used to give a pale yellow solid 14c (28.5 mg, 48%). 14c:
Hz, CDCl3) δ 8.77 (s, 1H), 7.71 (s, 1H), 6.45 (s, 1H), 5.76 (dd, J = 13.2, 3.1 Hz, 1H), 5.28 (t, J = 7.5 Hz, 1H), 3.88 (s,
= 7.4 Hz, 2H), 3.04 (dd, J = 16.8, 13.0 Hz, 1H), 2.88 (dd, J = 16.7, 3.1 Hz, 1H), 2.52 (s, 3H), 1.76 (s, 3H), 1.71 (s, 3H).
MHz, CDCl3) δ 189.4, 164.2, 161.7, 151.8, 151.0, 133.2, 129.5, 127.1, 125.5, 121.5, 113.8, 98.7, 73.4, 55.9, 44.9, 27.8,
. ESI-MS m/z (%): 344.2 [M+H]+. HR ESI-MS calcd for C19H22O3NS 344.1320 [M+H]+, found 344.1315.
opentenyl-flavanone (14d)
0.004 mol) and potassium fluoride (0.6 g, 0.010 mol) were used to give a white solid 14d (0.68 g, 60%). 14d: 1H NMR
Cl3) δ 7.71 (s, 1H), 7.53–7.38 (m, 5H), 6.49 (s, 1H), 5.47 (dd, J = 13.4, 2.9 Hz, 1H), 5.30 (t, J = 7.4 Hz, 1H), 3.88 (s,
9
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= 7.3 Hz, 2H), 3.05 (dd, J = 16.8, 13.4 Hz, 1H), 2.83 (dd, J = 16.9, 2.9 Hz, 1H), 1.77 (s, 3H), 1.72 (s, 3H). 13C NMR
l3) δ 190.7, 164.1, 162.2, 138.9, 133.0, 128.8, 128.7, 127.1, 126.2, 124.9, 121.7, 114.0, 98.8, 80.1, 55.8, 44.4, 27.8,
MS m/z (%): 323.2 [M+H]+; 321.2 [M-H]-. HR ESI-MS calcd for C21H22O3Na 345.1467 [M+Na]+, found 345.1459.
methoxy-2-(4-pyridine-4-yl)-6-isopentenyl -4H-1-benzopyran-4-one (14e)
, 0.30 mmol) and potassium fluoride (50 mg, 0.86 mmol) were used to give a white solid 14e (51.6 mg, 53%). 14e: 1H
CDCl3) δ 8.67 (d, J = 6.1 Hz, 2H), 7.67 (s, 1H), 7.40 (d, J = 6.9 Hz, 2H), 6.49 (s, 1H), 5.47 (dd, J = 12.0, 4.2 Hz, 1H),
H), 3.88 (s, 3H), 3.24 (d, J = 7.2 Hz, 2H), 2.98–2.80 (m, 2H), 1.74 (s, 3H), 1.69 (s, 3H). 13C NMR (125 MHz, CDCl3) δ
61.1, 149.8, 147.3, 132.7, 126.6, 125.0, 121.0, 120.0, 113.5, 98.2, 77.6, 55.4, 43.4, 27.3, 25.3, 17.3. ESI-MS m/z (%):
R ESI-MS calcd for C20H22O3N 324.1594 [M+H]+, found 324.1586.
methoxy-2-(1-N,N-dimethylsulfuryl-imidazole-4-yl)-6-isopentenyl-4H-1-benzopyran-4-one (14f)
.14 mmol) and potassium fluoride (29 mg, 0.50 mmol) were used to give a white solid 14f (30 mg, 52%). 14f: 1H NMR
l3) δ 7.94 (s, 1H), 7.68 (s, 1H), 7.34 (s, 1H), 6.48 (s, 1H), 5.53 (dd, J = 12.1, 3.4 Hz, 1H), 5.28 (t, J = 7.2 Hz, 1H), 3.87
J = 7.9 Hz, 2H), 3.16 (dd, J = 16.8, 12.1 Hz, 1H), 2.97 (dd, J = 16.9, 3.5 Hz, 1H), 2.91 (s, 6H), 1.76 (s, 3H), 1.71 (s,
125 MHz, CDCl3) δ 190.1, 164.1, 161.5, 141.6, 137.0, 133.1, 127.0, 125.1, 121.6, 115.4, 114.1, 98.8, 74.0, 55.8, 41.6,
, 17.8. EI-MS m/z (%): 419 [M+]. HR EI-MS calcd for C20H25SN3O5 419.1515 [M+], found 419.1509.
ure for the preparation of flavones 15a–15c
of 13a–13c in DMSO was added iodine. The reaction mixture was stirred at 90 ◦C for 3 h. After cooling, the reaction
enched with a saturated solution of sodium thiosulfate and extracted with ethyl acetate. The organic layers were
hed with deionized water and saturated sodium chloride solution, dried over sodium sulfate, filtrated, and evaporated
The crude material was purified by silica gel column chromatography with petroleum ether/ethyl acetate to afford
ethoxy-6-isopentenyl-flavone (15a)
0.60 mmol) and iodine (77 mg, 0.60 mmol) were used to give a white solid 15a (80 mg, 39%). 15a: H NMR (400
1
7.97 (s, 1H), 7.93 (dd, J = 8.7, 5.3 Hz, 2H), 7.23 (t, J = 8.5 Hz, 2H), 6.93 (s, 1H), 6.73 (s, 1H), 5.35 (t, J = 7.5 Hz, 1H),
39 (d, J = 7.6 Hz, 2H), 1.78 (s, 3H), 1.74 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 177.9, 164.56 (d, J = 252.7 Hz, 1C),
56.6, 133.6, 129.5, 128.29 (d, J = 8.9 Hz, 2C), 128.2, 125.3, 121.2, 117.1, 116.22 (d, J = 21.9 Hz, 2C), 107.4, 98.2,
, 17.8. ESI-MS m/z (%): 339.3 [M+H]+. HR ESI-MS calcd for C21H19O3FNa 361.1216 [M+Na]+, found 361.1207.
7-methoxy-6-isopentenyl-flavone (15b)
0.30 mmol) and iodine (38 mg, 0.30 mmol) were used to give a white solid 15b (49.1 mg, 47%). 15b: 1H NMR (400
7.96 (s, 1H), 7.82–7.72 (m, 1H), 7.67 (dd, J = 8.4, 3.6 Hz, 1H), 7.33 (q, J = 8.6 Hz, 1H), 6.93 (s, 1H), 6.71 (s, 1H),
Hz, 1H), 3.99 (s, 3H), 3.39 (d, J = 7.4 Hz, 3H), 1.78 (s, 3H), 1.73 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 177.6, 162.4,
52.15 (dd, J = 254.8, 12.6 Hz, 1C), 150.65 (dd, J = 249.9, 13.0 Hz, 1C), 133.7, 129.7, 129.13 (dd, J = 5.9, 3.9 Hz, 1C),
dd, J = 6.8, 3.5 Hz, 1C), 121.1, 118.12 (d, J = 18.0 Hz, 1C), 117.1, 115.46 (d, J = 19.4 Hz, 1C), 107.9, 98.2, 56.0, 28.2,
MS m/z (%): 357.3 [M+H]+. HR ESI-MS calcd for C21H18O3F2Na 379.1122 [M+Na]+, found 379.1132.
-methylthiazole-5-yl)-6- isopentenyl-4H-1-benzopyran-4-one (15c)
0.29 mmol) and iodine (37 mg, 0.29 mmol) were used to give a pale yellow powder 15c (61.1 mg, 61%). 15c: H
1
, CDCl3) δ 8.87 (s, 1H), 7.96 (s, 1H), 6.85 (s, 1H), 6.58 (s, 1H), 5.34 (t, J = 7.5 Hz, 1H), 3.98 (s, 3H), 3.39 (d, J = 7.4
, 3H), 1.78 (s, 3H), 1.73 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 177.2, 162.4, 157.2, 156.5, 154.2, 153.5, 133.7, 129.7,
21.1, 116.9, 110.3, 98.0, 56.0, 28.2, 25.9, 18.1, 17.8. ESI-MS m/z (%): 342.3 [M+H]+. HR ESI-MS calcd for
2.1164 [M+H]+, found 342.1155.
'-methoxy-5'-isopentenyl)-3-(dimethylamino)-2E-propen-1-one (16)
009 mol) was diluted with DMF/DMA (10 mL, 0.037 mol), and the reaction mixture was stirred at reflux under an inert
5 h. After cooling, the reaction mixture was quenched with deionized water (30 mL) and extracted with ethyl acetate
e organic layers were combined, washed with saturated sodium chloride solution (30 mL), dried over sodium sulfate,
aporated under vacuum to afford a yellow needle 16 (2.50 g, 96%). 16: 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 12.2
, 1H), 6.41 (s, 1H), 5.69 (d, J = 12.2 Hz, 1H), 5.29 (t, J = 7.2 Hz, 1H), 3.85 (s, 3H), 3.25 (d, J = 7.2 Hz, 2H), 2.99 (s,
). 13C NMR (125 MHz, CDCl3) δ 190.7, 164.0, 162.3, 153.8, 132.3, 128.6, 122.9, 120.3, 113.0, 99.4, 89.9, 55.5, 45.2,
, 17.8. ESI-MS m/z (%): 290.3 [M+H]+. HR ESI-MS calcd for C17H23NO3Na 312.1576 [M+Na]+, found 312.1567.
opentenyl-4H-1-benzopyran-4-one (17)
009 mol) was diluted with anhydrous acetic acid (10 mL, 0.175 mol), and the reaction mixture was stirred at reflux
tmosphere for 1 h. The reaction mixture was quenched with deionized water (20 mL) and extracted with ethyl acetate
e organic layers were combined, washed with saturated sodium chloride solution (20 mL), dried over sodium sulfate,
aporated under vacuum. The residue was purified by silica gel column chromatography with petroleum ether/ethyl
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d a yellow solid 17 (1.55 g, 73.36%). 17: 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.79 (d, J = 6.0 Hz, 1H), 6.81 (s,
= 6.0 Hz, 1H), 5.33 (t, J = 7.6 Hz, 1H), 3.95 (s, 3H), 3.37 (d, J = 7.4 Hz, 2H), 1.77 (s, 3H), 1.73 (s, 3H). 13C NMR (125
177.2, 162.1, 157.0, 154.6, 133.5, 129.4, 125.3, 121.2, 118.2, 112.9, 98.2, 55.9, 28.2, 25.9, 17.8. ESI-MS m/z (%):
R ESI-MS calcd for C15H17O3 245.1172 [M+H]+, found 245.1169.
assay
ne assays were performed using the Dual-Luciferase Reporter Assay System (Promega, USA) as previously described.[30] 293T cells
8-well plates at 5×104 per well. After cultured in 37 ℃ in DMEM (Gibco) containing 10% FBS for 20 h, cells were co-transfected with
asmids pCMX-Gal-mPPAR γ LBD, the Gal4 reporter vector MH100×4-TK-Luc and pREP7 reporter using FuGENE-HD (Roche,
transfection system containing 2 μg of Gal-mPPAR γ LBD and the Gal4 reporter vector MH100×4-TK-Luc, 0.3 μg of pREP7 reporter
μL FuGENE-HD per mL DMEM. After transfection for 24 h, the PPAR γ agonist rosiglitazone (0.01μM, 0.03μM, 0.1μM, 0.3μM, 1μM,
compounds (0.1μM, 0.3μM, 1μM, 3μM, 10μM, 30μM, 100μM) were added to the fresh medium, respectively. Then the luciferase
ere measured using the Dual-Luciferase Reporter Assay System (Promega, Madison, WI, USA). Renilla luciferase activity was used
ansfection efficiencies. All transfection experiments were repeated at least three times independently in triplicate or quadruplicate.
gements
s supported by the Excellent Academic Leaders Program of Shanghai (16XD1403500), the Shanghai Science and
mmittee funding (16401902000), Natural Science Foundation of Shanghai, China (14ZR1447800), and the program of
search Institute of Bioactive Constituents in Traditional Chinese Medicine.
achinin • PPAR-γ • Structure–activity relationships • Reporter–gene assay • Structural modification • Diabetes
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OH
O
O
O
1
Figure 1. Structure of the bavachinin 1.
13
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4'hydroxy: esterification; etherification;
OH
halogen substitution;
3'position: hydroxyll substitution;
halogen substitution;
B
O
O
C
B ring: heterocycle
A
pentyl substitution;
anyl substitution
O
ring opening;
double bond
Modification and Removal
Removal
Modification
Figure 2. Design rationale of the target PPAR-γ agonists.
14
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ts and conditions: (a) RCOX, K2CO3, Acetone, rt, 2 h (2a–2d) or RX, K2CO3, Acetone, reflux, 2 h (2e–2g)); (b) I2, DMSO, 90 ℃, 3 h; (c) Acyl
etone, rt, 2 h (4a–4b) or RX, K2CO3, Acetone, reflux, 2 h (4c).
15
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a
R1
O
O
OH
O
b
R1
R2
OH
O
R4
R3
e
R2
+
H
O
8a-8f
5a-5b
6a-6c
7a-7e
R1=H
R1=CH3O
6a: R1=H, R2=isopentenyl
6b: R1=CH3O, R2=isopentenyl
6c: R1=CH3O, R2=geranyl
7a: R1=H, R2=isopentenyl
8a: R3=H, R4=OH
d
d
d
8b: R3=H, R4=OMOMM
8c: R3=OH, R4=OH
8d: R3=OMOM, R4=OOMOM
8e: R3=F, R4=OH
7b: R1=CH3O, R2=isopentenyl
7c: R1=CH3O, R2=isopentyl
7d: R1=CH3O, R2=geranyl
7e: R1=CH3O, R2=H
c
8f: R3=F, R4=OMOM
R4
R4
R3
OH
O
R4
R3
R1
R2
O
R1
R2
OO
f
g
R3
O
OO
9a-9f
10a-10f
111a-11f
=H, R2=isopentenyl, R3=H, R4=OMOM
10a: R1=H, R2=isopentenyl, R3=H, R4=OMOM
11a: R1=H, R2=isoopentenyl, R3=H, R4=OH
11b: R1=CH3O, R22=isopentenyl, R3=OH, R4=OH
11c: R1=CH3O, R22=isopentenyl, R3=F, R4=OH
11d: R1=CH3O, R22=isopentyl, R3=H, R4=OH
11e: R1=CH3O, R22=geranyl, R3=H, R4=OH
11f: R1=CH3O, R2==H, R3=H, R4=OH
=CH3O, R2=isopentenyl, R3=OMOM, R4=OMOM
=CH3O, R2=isopentenyl, R3=F, R4=OMOM
=CH3O, R2=isopentyl, R3=H, R4=OMOM
=CH3O, R2=geranyl, R3=H, R4=OMOM
=CH3O, R2=H, R3=H, R4=OMOM
10b: R1=CH3O, R2=isopentenyl, R3=OMOM, R4=OMOM
10c: R1=CH3O, R2=isopentenyl, R3=F, R4=OMOM
10d: R1=CH3O, R2=isopentyl, R3=H, R4=OMOM
10e: R1=CH3O, R2=geranyl, R3=H, R4=OMOM
10f: R1=CH3O, R2=H, R3=H, R4=OMOM
R4
R1
R2
O
h
R3
O
12a-12b
12a: R1=CH3O, R2=isopentenyl, R3=OH, R4=OH
12b: R1=CH3O, R2=isopentyl, R3=H, R4=OH
nts and conditions: (a) RX, K2CO3, Acetone, reflux, 5 h; (b) PhNEt2, reflux, 4 h; (c) H2, Pd-C, C2H5OH, rt, 5 h; (d) MOMCl, K2CO3, Acetone, rt, 2
C2H5OH, reflux, 4 h; (f) KF, CH3OH, reflux, 8 h; (g) HCl, CH3OH, reflux, 10 min; (h) I2, DMSO, 90 ℃, 3 h.
16
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14a: R1= 1-fluuorine-Phenyl-4
O
O
O
R1
b
14b: R1= 1,2-ddifluorine-Phenyl-4
14c: R1= 4-meethylthiazole-5-yl
14d: R1= phennyl
14e: R1= pyriddine-4-yl
O
OH
O
14f: R1= 1-N,NN-dimethylsulfuryl -imidazole-4-yl
14a-14f
a
R1
O
O
O
R1
c
15a: R1= 1-fluuorine-Phenyl-4
15b: R1= 1,2-ddifluorine-Phenyl-4
15c: R1= 4-meethylthiazole-5-yl
13a-13f
O
OH
O
13a: R1= 1-fluorine-phenyl-4
13b: R1= 1,2-difluorine-phenyl-4
13c: R1= 4-methylthiazole-5-yl
13d: R1= phenyl
15a-15c
13e: R1= pyridine-4-yl
13f: R1= 1-N,N-dimethylsulfuryl -imidazole-4-yl
7b
O
O
O
O
OH
O
e
d
N
17
16
ts and conditions: (a) aromatic/heteroaromatic aldehyde , NaOH, C2H5OH, rt, 72 h; (b) KF, CH3OH, refluxx, 8 h; (c) I2, DMSO, 90 ℃, 3 h; (d)
5 h; (e) CH3COOH, reflux, 1 h
.
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Table 1. Effective concentrations (EC50) of test analogues for vitro PPAR-γ activity
PPAR-γ-LBD
EC50 (μM)
Relative Max
Activity (%)[b]
PPAR-γ-LBD
EC50 (μM)
Relative Max
Activity (%)
Analogue
Analogue
rosiglitazone
0.08
18.74
37.06
2.53
300%
100%
121%
92%
11d
11e
11f
12a
12b
14a
14b
14c
14d
14e
14f
15a
15b
15c
16
13.61
114.33
n.a.
65%
79%
bavachinin 1
2a
2b
2c
2d
2e
2f
42.53
3.55
57%
71%
18.25
11.03
n.a.[a]
n.a.
49%
54%
n.a.
n.a.
26.29
10.74
n.a.
39%
2g
3
n.a.
103%
1.13
79%
74%
84%
4a
4b
4c
11a
11b
11c
0.78
n.a.
0.43
29.38
n.a.
78%
30%
n.a.
47.07
11.25
3.30
79%
48%
78%
n.a.
n.a.
17
26.42
[a] n.a.: no activity.
[b]Relative Max Activity was normalized by Bavachinin.
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Entry for the Table of Contents
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