Synthesis and Biological Evaluation of 4-Substituted Kaempfer-3-ols

Article abstract of DOI:10.1021/acs.joc.9b03461

The synthesis of two series of five kaempfer-3-ols was described. The first set all have a C-3 hydroxyl group and the second has a carboxymethoxy ether at the C-3 position. Both series have variable substitution at the C-4 position (i.e., OH, Cl, F, H, OMe). Both kaempferols and carboxymethoxy ethers were evaluated for their ability to inhibit ribosomal s6 kinase (RSK) activity and cancer cell proliferation.

Full text of DOI:10.1021/acs.joc.9b03461

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Article
Synthesis and biological evaluation of 4’-substituted kaempfer-3-ols
Sugyeom Kim, Yu Li, Lin Lin, Peyton R Sayasith, Ariel T Tarr, Eric B
Wright, Sharia Yasmin, Deborah A Lannigan, and George A. O'Doherty
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03461 • Publication Date (Web): 14 Feb 2020
Downloaded from pubs.acs.org on February 16, 2020
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The Journal of Organic Chemistry
Synthesis and biological evaluation of 4’-substituted kaempfer-3-ols
Sugyeom Kim,† Yu Li†, Lin Lin,† Peyton R. Sayasith,† Ariel T. Tarr,† Eric B. Wright,$ Sharia Yasmin,‡
Deborah A. Lannigan,‡,#,$,* and George A. O’Doherty†,*
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‡ Departments of Pathology, Microbiology & Immunology and # Cell & Developmental Biology and $ Biomedical
Engineering, Vanderbilt University Medical Center and Vanderbilt University, Nashville, Tennessee 37232 US.
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† Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, US.
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deborah.lannigan@vumc.org
G.ODoherty@neu.edu
Supporting Information Placeholder
X
X
X
4’
3’
1
O
O
8
O
YO
2
3
O
7
HO
O
O
Br
BnO
OH
2’
OBn
4
OH
6
OH
O
OY
O
OH
O
OBn
X = OH, Cl, F, H, OMe, OBn
Y = H, Bn
OH
ABSTRACT: The synthesis of two series of five kaempfer-3-ols was described. The first set all have a C-3 hydroxyl group
and the second has a carboxymethoxy ether at the C-3 position. Both series have variable substitution at the C-4’ position (i.e.,
OH, Cl, F, H, OMe). Both kaempferols and carboxymethoxy ethers were evaluated for their ability to inhibit RSK kinase
activity and cancer cell proliferation.
As part of an effort to find selective inhibitors of the p90 ribosomal s6 kinases (RSK), the glycosylated
kaempfer-3-ol natural product, SL0101 (A) was identified as a relatively selective inhibitor for RSK1/2
(Ki ~ 1 µm).1,2 In a combination of molecular modeling and structure activity relationship studies (Figure
1),3, 4 we identified carbohydrate (1a-e) and cyclitol analogues (2a-e) of SL0101 (A) with improved kinase
and cancer cell inhibitory activity.5 , 6 These efforts focused on the synthesis of stereoisomers and
7
analogues with substitution at the aglycone (e.g., C-4’of the kaempfer-3-ol) and carbohydrate (e.g., C-6”
of the rhamnose ring) portions of the natural product. These efforts focused on the synthesis of non-
hydrolyzable alternatives to the pyranose (e.g., carbasugar)5 and C-3’/4’ acetate groups (e.g., amide and
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carbamate substitution at C-3’ and/or C-4’). These efforts culminated in the discovery of a pyranose
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analogue B (1a, R = Et) and a carbasugar analogue C (2a, R = Et) of SL0101 (A) that showed improved
efficacy in the in vitro kinase assays.
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There have been several natural and unnatural kaempferol type flavonoids reported with anticancer
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activity. For instance, the alvocidib, cyclin-dependent kinase (CDK) inhibitor, is currently under
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development for the treatment of acute myeloid leukemia. In an effort to differentiate the effects of the
sugar/cyclitol from the kaempferol aglycon, we decide to make and test a series of substituted kaempfer-
3-ols (3a-e) with variable substitution at the C-4’ position of the B-ring. In addition, we planned to prepare
a related series of C-3 alkylated analogues (4a-e) with a polar carboxylic acid to add polarity to the
molecule and to prevent metabolic oxidation of 3a to a vinylogous quinone.8,
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Figure 1. SL0101 and related flavan-3-ols
4’
X
4’
3’
A
X
1
O
8
1
8
7
2
3
HO
O
HO
HO
O
2’
4
6
3
O
OH
O
3”
OH
O
OH
O
OH
O
O
1”
OAc
OAc
Z
3a-e
6”R
OH
O
H
a: X = OH
b: X = Cl
c: X = F
1a-e (Z = O)
2a-e (Z = CH2)
4a-e
d: X = H
e: X = OMe
Aglycon–OH = 3a
Aglycon
Aglycon
Aglycon
O
O
O
H
3”
1”
OAc
OAc
OAc
OAc
OAc
OAc
O
O
O
O
O
6”
H
H
SL0101
1st Gen Analogue
2nd Gen Analogue
(1a, R = H)
(1a, R = Et)
(2a, R = Et)
A
B
C
The list of desired aglycones 3a-e,13 3a,14 3d,15 and 3e16 are either part of a class of naturally occurring
compounds kaempferols or related congeners17 that have been evaluated over the years for their anti-
cancer, anti-inflammatory and antioxidant properties. There have been several other approaches to the
kaempfer-3-ol ring system and variants with substitution at the C-4’ position (Scheme 1). These include
direct condensations between a-methoxyacetophenone 5 with free phenols and carboxylic acids 6d and
9a-e,18,19 as well as, biosynthetic routes from 4’-hydroxycinnanic acid 8.20 In addition, the naturally
occurring kaempfer-3-ols, aka kaempferol, 3a has been prepared from the benzyl protected acetophenone
7 and 4’-hydroxycinnanic acid 6f.21 Of these approaches, our approach most similarly matches the work
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by Yu which was most compatible with our synthetic and structure activity relationship (SAR) design
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needs to access 3a-e and 4a-e. Key to their approach is the use of bis-benzyl protected acetophenone 7.
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Scheme 1. Previous approaches to substituted flavan-3-ols
7
8
9
OH
O
O
a: X = OH
b: X = Cl
c: X = F
d: X = H
e: X = OMe
f : X = OBn
OCH3
HO
+
HO
OH
H
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5
6d
X
ref. 8
BnO
OH
3 steps, 41% yield
4’
3’
O
1
8
3
2
3
HO
7
O
4
2
4’
OBn O
HO
OH
2’
ref. 5
4
7
ref. 21
7 Steps
13% yield
6
8
OH
O
+
3a: 4 steps, 11.5% (biosynthesis)
3c: ≈ 0%
3d: 4 steps, 0.17% (biosynthesis)
OH
O
3a-e
HO
ref. 1
3 steps, 71% yield
OBn
6f
OH
O
O
+
OCH3
Cl
HO
OH
X
5
9a-e
Retrosynthetically, we envisioned that methylcarboxylic acids 4a-c could be prepared from the per-
benzylated material 10b-f, which in turn could be prepared by the alkylation of enols 11b-f (Scheme 2).
The also desired aglycons 3a-e could similarly be prepared from the same intermediates 11b-f. The
common intermediate 11b-f could be prepared from carboxylic acids 6b-f and acetophenone 7 by an
acylation Claisen cyclization/dehydration reaction sequence. Finally, acetophenone 7 can be prepared by
a bis-benzylation/acylation of phloroglucinol 12.
Scheme 2. Our retrosynthetic approach to the flavan-3-ols
X
X
a: X = OH
b: X = Cl
c: X = F
d: X = H
e: X = OMe
f : X = OBn
PO
O
O
PO
O
OH
O
OP
OP
O
O
4a-e : P = H
3a-e : P = H
11b-f: P = Bn
OP
10b-f: P = Bn
O
HO
6b-f
BnO
OH
HO
OH
X
OBn O
OH
12
7
Our synthetic efforts began with the synthesis of key intermediate 17b-f from phloroglucinol 12 (Scheme
3). A Lewis acid catalyzed acylation of phloroglucinol 12 gave 2,4,6-trihydroxyacetophenone 13, which
can be bis-benzylated to give acetophenone 7. At this point the diversification is introduced by means of
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an EDCI coupling between 7 and carboxylic acids 6b-f to form phenol esters 14b-f. We next tuned to the
alpha-bromination of methylketone 14b-f to form 16b-f. To our surprise this was most easily
accomplished by a bis-bromination to form 15b-f and then selective reduction with diethylphosphite to
form mono-bromide 16b-f. Finally, the mono-bromide 16b-f can be displaced with potassium benzoate
to form esters 17b-f.
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Scheme 3. Synthesis of acetophenone 17b-f
HO
OH
HO
OH
CH3
BnO
OH
CH3
BnBr
K2CO3
BF3•Et2O
Ac2O
DMF
60oC
OH
OH
13
O
OBn O
12
7
X
X
O
O
BnO
O
6b-f
1.5 equiv
2.5 equiv PTT
OH
CH3
THF
OBn O
4 hr, rt
3 equiv EDCI
1 equiv DMAP
CH2Cl2, 8 hr, rt
14b = Cl, 85%
14c = F, 80%
PTT = (CH3)3N(Br3)C6H5
14d = H, 84%
14e = OMe, 85%
14f = OBn, 84%
X
O
X
BnO
O
1.5 equiv (EtO)2POH
1.5 equiv Et3N
O
BnO
O
Br
Br
THF
5 hr, rt (2 steps)
OBn O
Br
16b = Cl, 85%
16c = F, 71%
OBn O
16d = H, 87%
16e = OMe, 71%
16f = OBn, 87%
15b-f
X
O
BnO
O
b: X = Cl
c: X = F
1.5 equiv BzOK
d: X = H
OBz
Acetonitrile
12 hr, Reflux
e: X = OMe
f : X = OBn
OBn O
17b = Cl, 68%
17c = F, 76%
17d = H, 77%
17e = OMe, 76%
17f = OBn, 77%
With the series of a-benzoates 17b-f in hand, we next explored its dehydrative cyclization to form the
desired series of protected kaempferols 11b-f (Scheme 4). This began with a LiHMDS promoted
intramolecular Claisen condensation to form 1,3-diketone 18b-f. The crude THF solutions of 18b-f could
then be dehydrated upon heating in the presence of a slight excess of NaOAc/HOAc. Finally, the benzoate
esters 19b-f can be hydrolyzed to form the per-benzyl protected enol kaempferols 11b-f.
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Scheme 4. Synthesis of protected 4’-substitued flavan-3-ols
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4
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6
7
8
X
X
O
3 equiv LiHMDS
1.5 equiv NaOAc
AcOH
O
BnO
O
THF
1 hr, -78 °C
BzO
HO
12hr, 100 o
C
O
OBz
OBn O
OBn
17b-f
BnO
9
18b-f
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X
X
BnO
O
BnO
O
i. 0.1 mol% NaOMe
MeOH/CH2Cl2
OBz
OH
ii. Dowex 50w 8 Resin
12 hr, rt (3 steps)
OBn O
OBn O
11b = Cl, 30%
11c = F, 33%
11d = H, 35%
11e = OMe, 40%
11f = OBn, 35%
19b-f
b: X = Cl
c: X = F
d: X = H
e: X = OMe
f: X = OBn
The desired kaempferol aglycons 3a-e can be easily prepared from kaempferols 11b-f, by a
hydrogenolysis/global deprotection (Scheme 5). In a related two-step process, kaempferols 11b-f can be
converted into the series of desired carboxylic acids by an alkylation of the phenol with benzyl
bromoacetate and K2CO3 to form benzyl esters 10b-f, which in turn can be per-deprotected by a similar
hydrogenolysis reaction to give carboxylic acids 4a-e (Scheme 6).
Scheme 5. Synthesis of 4’-substituted flavan-3-ols
X
X
10 mol% Pd/C
1 atm H2
BnO
O
HO
O
O
a: X = OH
b: X = Cl
c: X = F
OH
OH
OBn O
OH
d: X = H
3a = OH, 72%
3b = Cl, 71%
3c = F, 60%
3d = H, 73%
3e = OMe, 70%
e: X = OMe
f: X = OBn
11b-f
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Scheme 6. Synthesis of flavan-3-ols carboxylic acids
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3
4
X
X
O
5
BnO
O
Bn
Br
BnO
O
O
6
7
8
9
O
K2CO3
DMF
8hr, r.t.
OH
OBn O
O
OBn O
O
11b-f
10b = Cl, 77%
10c = F, 51%
10d = H, 79%
Bn
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10e = OMe, 80%
10f = OBn, 81%
X
HO
O
a: X = OH
b: X = Cl
c: X = F
d: X = H
e: X = OMe
f: X = OBn
10 mol% Pd/C
1 atm H2
O
OH
O
O
H
THF
O
4a = OH, 70%
4b = Cl, 54%
4c = F, 57%
4d = H, 68%
4e = OMe, 70%
The five SL0101 aglycons 3a-e and the five variants with carboxymethyl groups at the C-3 position 4a-e
were evaluated as RSK inhibitors and for inhibition of proliferation using a breast cancer cell line, MCF-
7 (Table 1). The aglycons and variants demonstrated reduced efficacy to inhibit RSK2 kinase activity in
an in vitro kinase assay compared to SL0101 (A) and its more potent analogue (C). However, the aglycons
were more effective at inhibiting proliferation than SL0101 (A) even though their efficacy to inhibit RSK2
in vitro kinase activity was diminished in comparison to SL0101 (A). However, the aglycons were less
effective at inhibiting MCF-7 proliferation than C. These results suggest that the aglycons inhibit MCF-
7 proliferation through a mechanism distinct from RSK. The variants with the carboxymethyl group at
the C-3 position did not inhibit MCF-7 proliferation and a possible explanation is that these compounds
are less cell permeable. These results further demonstrate that the rhamnose moiety present in SL0101
provides specificity in targeting RSK1/2.
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Table 1. Inhibition of in vitro kinase activity and MCF-7 cell proliferation
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2
3
4
% kinase
activity
%
proliferation
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6
7
8
Compound
(30 µM)
(50 µM)
50%1
A
C
10.5 ± 1.35
3.1 ± 0.69
36.4 ± 2.18
40.6 ± 2.19
25.7 ± 6.11
60.3 ± 1.36
89.2 ± 1.93
70.2 ± 1.54
69.1 ± 1.81
83.1 ± 1.7
76.8 ± 1.78
38.0 ± 1.39
9
–2.51 ± 3.2
89.6 ± 4.58
7.6 ± 3.67
9.24 ± 3.22
40.4 ± 3.62
12.9 ± 2.19
99.0 ± 6.01
91.3 ± 4.49
90.2 ± 2.46
90.1 ± 4.33
93.1 ± 3.87
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3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
Conclusions
In summary, a route to five kaempferols 3a-e and five variants 4a-e with carboxymethyl groups at the C-
3 position has been described. The route readily allows for variable C-4’ substitution of the kaempferol
substitution and provides material for biological activity (i.e., the ability to inhibit RSK kinase activity
and MCF-7 cell proliferation). This strategy and study will inform our further studies of the SAR of
SL0101. Efforts along these lines will be reported in due course.
Experimental Section
General Methods
RSK2 in vitro kinase assay
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Kinase activity in the presence or absence of inhibitors was determined using the LanthaScreenÒ Eu
kinase binding assay for RPS6KA3 according to the manufacturer’s instructions (Invitrogen). Inhibitors
were pre-incubated with purified kinase before addition of kinase tracer 236 for two h. Excitation
fluorescence was 330 ± 80 nm, background emission from Eu tag 620 ± 10 nm and fluorescence resonance
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energy transfer (FRET) emission 665 ± 8 nm. Fluorescence was measured using a Synergy Neo (BioTek
Instruments). FRET was calculated as the ratio of emission at 665 divided by emission at 620.
Cell proliferation assay
The MCF-7 line was obtained and cultured as direct by ATCC. Stocks were authenticated based on
growth rate, morphology, molecular markers and absence of mycoplasma. For proliferation assays 103
cells/well were plated in a 96-well. Inhibitor or vehicle was added, and luciferase measured at 42 h using
CellTiterGlo reagent (Promega Corp.) with a GLoMax Discover luminometer (Promega Corp.).
1-(2,4,6-trihydroxyphenyl)ethan-1-one (13)22
To the flask of mixture of phloroglucinol 12 (125 g, 0.99 mol) and acetic anhydride (95 mL, 1.09 mol)
was added dropwise boron trifluoride etherate (375 mL, 1.49 mol) over 1 h at 0 °C. The resulting mixture
was stirred at room temperature for 48 h. The reaction was quenched with 10% NaOAc solution and
extracted with ethyl acetate, the aqueous layers were extracted with ether. The combined organic layers
were washed with brine and dried over sodium sulfate. After concentrating in vacuo, the crude product
was loaded onto a silica gel column and flash with solvent (hexanes : ethyl acetate = 2 : 1) give acetyl
triol 13 light a yellow solid (128 g, 78%): Rf = 0.3 (hexanes : ethyl acetate = 1 : 1); 1H NMR (400 MHz,
13
DMSO-d6) δ 12.23 (s), 10.39 (s), 5.78 (s, 2H), 2.52 (s, 3H); C{1H} NMR (100 MHz, DMSO-d6) δ
203.2, 165.4, 165.0, 104.7, 95.2, 33.1
1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)ethan-1-one (7)23
To a solution of triol 13 (28 g, 0.17 mol) in 100 mL DMF, K2CO3 (97.2 g, 0.7 mol) was added portion
wise followed by the dropwise addition of benzyl bromide (84 mL, 0.7 mol) over 1 h period at 0 °C. The
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resulting mixture was heated to 65 °C for 72 h. Then the reaction was washed with water and the aqueous
layers were extracted with ether. The combined organic layers were washed with brine and dried over
sodium sulfate. After concentrating in vacuo, the crude product was loaded onto a silica gel column and
flash with solvent (Hexanes : CH2Cl2 = 2 : 1) to give 7 as a white solid (20 g, 35%): Rf = 0.12 (Hexane :
CH2Cl2= 1 : 1); 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.27 (m, 10H), 6.18 (d, J = 1.7 Hz, 1H), 6.12 (d, J
= 1.7 Hz, 1H), 5.06 (s, 2H), 5.06 (s, 2H), 2.57 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 203.4, 167.8,
165.3, 162.2, 136.1, 135.9, 129.0, 129.0, 128.7, 128.6, 128.3, 127.9, 106.6, 95.0, 92.6, 71.3, 70.5, 33.6.
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2-acetyl-3,5-bis(benzyloxy)phenyl 4-(benzyloxy)benzoate (14f)21
To a solution of phenol 7 (3.17 g, 9.1 mmol) and benzoic acid 6f (3.12 g, 13.6 mmol) in CH2Cl2 (74 mL)
at 0 °C was added EDCI (5.25 g, 27.3 mmol) and DMAP (1.11 g, 9.1 mmol). After stirring for 4 h at rt,
the mixture was diluted with EtOAc, and then washed with saturated NaHCO3 solution. The organic phase
was washed with brine, dried over Na2SO4 and then concentrated in vacuo. The residue was purified by
silica gel column chromatography (Hexanes : Ethyl Acetate = 1 : 1) to give 14f (4.27 g, 84%) as a white
solid: Rf = 0.32 (Hexanes : Ethyl Acetate = 4 : 1); 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.5 Hz, 2H),
7.48 – 7.31 (m, 15H), 7.04 (d, J = 8.5 Hz, 2H), 6.54 (d, J = 1.5 Hz, 1H), 6.47 (d, J = 1.4 Hz, 1H), 5.15 (s,
2H), 5.08 (s, 2H), 5.04 (s, 2H), 2.47 (d, J = 0.5 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 199.4, 164.6,
163.1, 161.1, 158.1, 149.8, 136.1, 136.0, 135.9, 132.5, 128.7, 128.3, 128.2, 127.6, 127.4, 127.4, 121.7,
118.1, 114.7, 101.4, 98.4, 70.9, 70.4, 70.2, 32.0.
3,5-bis(benzyloxy)-2-(2-bromoacetyl)phenyl 4-(benzyloxy)benzoate (16f)21
To a solution of ester 14f (4.18 g, 7.5 mmol) in dry THF (15 mL) was added PTT (7.03 g, 18.7 mmol, 2.5
equiv) in portions at 0 °C. The reaction mixture was stirred for 4 h at rt, monitored by crude NMR. When
the reaction was completed, it was cooled down at 0 °C and treated with diethyl phosphate (1.44 mL, 11.3
mmol, 1.5 equiv) and Et3N (1.49 mL, 11.3 mmol, 1.5 equiv) dropwise. The resulting mixture was stirred
for 6 h at rt until complete. Then the reaction was washed with water and the aqueous layers were extracted
with dichloromethane. The combined organic layers were washed with brine and dried over sodium
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sulfate. After concentrating in vacuo, the crude product was loaded onto a silica gel column and flash with
solvent (Hexanes : CH2Cl2 = 1 : 2) to give 16f (4.1 g, 87%): Rf = 0.34 (Hexanes : Ethyl Acetate = 4: 1);
1H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 8.8 Hz, 2H), 7.47 – 7.35 (m, 15H), 7.04 (d, J = 8.8 Hz, 2H),
6.55 (s, 2H), 5.15 (s, 2H), 5.10 (s, 2H), 5.05 (s, 2H), 4.37 (s, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ
192.0, 164.6, 163.2, 162.1, 158.3, 151.1, 136.1, 135.7, 135.4, 132.6, 128.8, 128.7, 128.7, 128.5, 128.4,
128.2, 127.7, 127.6, 127.5, 121.4, 114.8, 114.1, 102.1, 98.3, 77.3, 77.0, 76.8, 71.3, 70.6, 70.2, 36.7
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2-(2-(benzoyloxy)acetyl)-3,5-bis(benzyloxy)phenyl 4-(benzyloxy)benzoate (17f)21
A mixture of 16f (2.79 g, 4.4 mmol) and BzOK (1.1 g, 6.6 mmol) was stirred in CH3CN (30 mL) at 82 oC
in a sand bath for 24 h. The reaction was diluted with CH2Cl2, washed with saturated sodium bicarbonate,
brine, dried over sodium sulfate, then concentrated in vacuo. The resulting crude was purified by silica
gel chromatography and flash with solvent (Hexane: Ethyl Acetate = 10 : 1) to afford the product 17f as
a light yellow solid (2.3 g, 77%): Rf = 0.40 (Hexane: Ethyl Acetate = 4: 1); mp 161 – 163 °C; 1H NMR
(400 MHz, CDCl3) δ 8.10 (d, J = 8.6 Hz, 2H), 7.99 (d, J = 7.7 Hz, 2H), 7.53 (dd, J = 7, 7 Hz, 1H), 7.46 –
7.31 (m, 17H), 7.00 (d, J = 8.6 Hz, 2H), 6.54 (d, J = 5.8 Hz, 2H), 5.23 (s, 2H), 5.12 (s, 2H), 5.10 (s, 2H),
5.05 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.9, 166.0, 164.9, 163.3, 162.3, 159.0, 151.5, 136.4,
136.1, 135.8, 133.2, 132.9, 130.1, 129.9, 129.0, 129.0, 128.9, 128.7, 128.6, 128.5, 128.5, 127.9, 127.8,
127.7, 121.9, 114.9, 114.5, 102.5, 98.5, 71.5, 70.8, 70.4, 69.9
5,7-bis(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-hydroxy-4H-chromen-4-one (11f)21
To a solution of benzoate 17f (2.19 g, 3.2 mmol) in THF (30 mL) added LiHMDS in hexanes (9.4 mL,
9.6 mmol) at -78 °C. The mixture was stirred at -78 °C for 1 h until the crude NMR confirmed completion
of the reaction. The cooled mixture was poured into water and was then extracted with Ethyl Acetate (3
x 80 mL). The combined organic layers were then washed with brine, dried over sodium sulfate and
concentrated in vacuo. Resulting residue was dissolved in AcOH (30 mL), then AcONa (0.34 g, 4.8 mmol)
was added. After being stirred at 100 °C for 12 h, the mixture was cooled to rt and then diluted with
CH2Cl2. The mixture was washed with water, saturated NaHCO3 solution and brine, successively. The
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The Journal of Organic Chemistry
organic phases were combined and concentrated in vacuo to give a solid residue, which was dissolved in
MeOH/ CH2Cl2 (12 mL, v/v1:1). After being stirred for 10 h in the presence of a catalytic amount of
NaOMe at rt, the mixture was neutralized with Dowex 50W-X 8 (H+) resin. The resins were filtered,
solvent was removed. The resulting solid was recrystallized from methanol to provide 11f (630 mg, 35%)
as a yellow solid. mp 167 – 169 °C; Rf = 0.41 (Hexane: Ethyl Acetate = 2: 1); 1H NMR (500 MHz, CDCl3)
δ 8.17 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 7.5 Hz, 2H), 7.46 – 7.33 (m, 13H), 7.09 (d, J = 8.5 Hz, 2H), 6.62
(s, 1H), 6.47 (s, 1H), 5.22 (s, 2H), 5.13 (s, 2H), 5.11 (s, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 171.7,
163.2, 159.8, 159.3, 158.7, 142.4, 137.6, 136.5, 136.2, 135.6, 128.9, 128.8, 128.7, 128.6, 128.5, 128.1,
127.8, 127.7, 127.5, 126.6, 123.8, 114.9, 106.7. 97.6, 93.7, 70.7, 70.6, 70.0.
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2-acetyl-3,5-bis(benzyloxy)phenyl 4-chlorobenzoate (14b)
To a suspension of phenol 7 (3.51 g, 0.01 mol), 4-chlorobenzoic acid 7b (2.37 g, 0.015 mol) in CH2Cl2
(50 mL) at 0 °C was added EDCI (5.79 g, 0.03 mol) and DMAP (1.23 g, 0.01 mol). After stirring for 4 h
at rt, the mixture was diluted with EtOAc, and then washed with saturated NaHCO3 solution. The organic
phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by
silica gel column chromatography (EtOAc-petroleum ether, 1 : 1) to give 14b (4.17 g, 85%) as a white
solid: Rf = 0.5 (Hexanes : Ethyl Acetate = 4: 1), mp 100 – 102 °C; IR (thin film, cm-1) 3063, 3010, 1736,
1683, 1608, 1573, 1497, 1487, 1454, 1431, 1400, 1377, 1352, 1327, 1254, 1150, 1088, 1012, 977, 910,
876, 845, 733, 695, 612, 524, 475; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.4 Hz, 2H), 7.52 – 7.29
(m, 10H), 6.56 (s, 1H), 6.47 (d, J = 1.2 Hz, 1H), 5.09 (s, 2H), 5.05 (s, 2H), 2.48 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 199.3, 164.5, 161.6, 158.7, 150.0, 140.4, 136.2, 136.0, 132.0, 129.2, 129.0, 128.6,
128.6, 128.0, 127.9, 127.8, 117.8, 101.7, 98.8, 71.3, 70.7, 32.4; HRMS (MALDI-TOF/CCA) calcd.
[C29H23ClO5+Na]+; 509.1126, found: 509.1096.
3,5-bis(benzyloxy)-2-(2-bromoacetyl)phenyl 4-chlorobenzoate (16b)
To a solution of ester 14b (5.70 g, 0.012 mol) in dry THF (40 mL) was added PTT (11 g, 0.03 mol, 2.5
equiv) in portions at 0 °C. The reaction mixture was stirred at rt for 4 h, the reaction progress was
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monitored by crude NMR. When the reaction was completed, it was cooled down to 0 °C and dropwise
treated with diethyl phosphate (2.27 mL, 0.018 mol, 1.5 equiv) and Et3N (2.45 mL, 0.018 mol, 1.5 equiv),
the resulting mixture was stirred for 6 h at rt until complete, the mixture was poured into water and
extracted with CH2Cl2 (3 x 100 mL). The combined organic phases were dried over NaSO4 and
concentrated in vacuo. The residue was purified by silica gel column chromatography (Hexanes : CH2Cl2=
1 : 2) to give 16b (4.81 g, 85%) as a light yellow solid: Rf = 0.47 (Hexanes : Ethyl Acetate = 4: 1), mp 98
-100 °C; IR (thin film, cm-1) 3064, 1933, 1740, 1691, 1690, 1574, 1497, 1487, 1454, 1435, 1400, 1380,
1330, 1257, 1153, 1089, 1058, 1013, 846, 828, 750, 698; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.2
Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 7.41 (s, 8H), 6.57 (d, J = 9.1 Hz, 2H), 5.10 (s, 2H), 5.06 (s, 2H), 4.36
(s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.0, 164.4, 162.5, 158.8, 151.3, 140.5, 135.9, 135.5, 132.0,
129.2, 129.1, 129.0, 128.9, 128.7, 127.9, 127.7, 114.0, 102.3, 98.7, 71.6, 70.9, 37.0; HRMS (MALDI-
TOF/CCA) calcd. [C29H22BrClO5+Na]+; 587.0231, found: 587.0238.
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2-(2-(benzoyloxy)acetyl)-3,5-bis(benzyloxy)phenyl 4-chlorobenzoate (17b)
A mixture of 16b (3 g, 5.3 mmol) and BzOK (1.27 g, 8.0 mmol) was stirred in CH3CN (53 mL) at 82 oC
in a sand bath for 24 h. The reaction was diluted with CH2Cl2, washed with saturated sodium bicarbonate
and brine, dried over sodium sulfate, then concentrated in vacuo. The resulting crude was purified by a
silica gel chromatography and flash with solvent (Hexane: Ethyl Acetate = 10 : 1) to afford the product
17b as a light yellow solid (2.19 g, 68%): m. 118 – 120 °C; Rf = 0.40 (Hexane: Ethyl Acetate = 4: 1); IR
(thin film, cm-1) 3064, 3033, 2932, 1724, 1692, 1607, 1488, 1452, 1434, 1401, 1365, 1329, 1315, 1265
,1152, 1089, 1014, 973, 939, 911, 878, 845, 738, 710, 699, 525; 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J
= 8.4 Hz, 2H), 7.99 (d, J = 7.5 Hz, 2H), 7.54 (dd, J = 7, 7 Hz, 1H), 7.44 – 7.34 (m, 14H), 6.56 (s, 2H),
5.22 (s, 2H), 5.11 (s, 2H), 5.06 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.6, 166.1, 164.5, 162.4,
159.3, 151.4, 140.2, 135.9, 135.6, 133.3, 132.1, 130.0, 129.8, 129.1, 129.1, 129.0, 128.8, 128.7, 128.6,
127.9, 127.9, 114.1, 102.6, 98.7, 71.5, 70.8, 70.0; HRMS (MALDI-TOF/CCA) calcd. [C36H27ClO7+Na]+;
629.1338, found: 629.1321.
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The Journal of Organic Chemistry
5,7-bis(benzyloxy)-2-(4-chlorophenyl)-3-hydroxy-4H-chromen-4-one (11b)
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To a solution of benzoate 17b (1.54 g, 2.5 mmol) in THF (25 mL) added LiHMDS in hexanes (7.6 mL,
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7.5 mmol). The mixture was stirred at -78 °C for 1 h until crude NMR analysis confirmed the reaction
was complete. The cooled reaction mixture was poured into water and then extracted with Ethyl Acetate
(3 x 80 mL). Combined organic layers were then washed with brine, dried over sodium sulfate and
concentrated in vacuo. Resulting residue was dissolved in AcOH (25 mL), then AcONa (0.52 g, 6.25
mmol) was added. After stirring at 100 °C for 12 h, the mixture was cooled to rt and then diluted with
CH2Cl2. The reaction mixture was washed with water, saturated NaHCO3 solution and brine, successively.
The combined organic phases were and concentrated to give a solid residue, which was dissolved in
MeOH/CH2Cl2 (20 mL, v/v1:1). After being stirred for 10 h in the presence of a catalytic amount of
NaOMe at rt, the mixture was neutralized with Dowex 50W-X 8 (H+) resin. The resins were filtered off,
the solvent was removed in vacuo. The resulting solid was recrystallized from methanol to provide 11b
(330 mg, 30%) as a yellow solid. mp 178 – 180 °C; Rf = 0.48 (Hexane: Ethyl Acetate = 2: 1); IR (thin
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film, cm-1) 3407-3190 (br), 2923, 2853, 1615, 1491, 1452, 1401, 1332, 1213, 1170, 1135, 1092, 1050,
1013, 832, 801, 735, 697, 596; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 7.3
Hz, 2H), 7.50 – 7.39 (m, 9H), 7.34 (dd, J = 8, 8 Hz, 1H), 6.64 (s, 1H), 6.49 (s, 1H), 5.23 (s, 2H), 5.13 (s,
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2H); C{1H} NMR (100 MHz, CDCl3) δ 172.1, 163.8, 159.7, 159.1, 140.9, 138.7, 136.3, 135.7, 129.8,
129.0, 129.0, 128.9, 128.9, 128.8, 128.7, 128.6, 128.1, 127.9, 126.9, 106.9, 97.9, 94.7, 93.9, 71.0, 70.9;
HRMS (MALDI-TOF/CCA) calcd. [C29H21ClO5+Na]+: 507.0970, found: 507.0955
2-acetyl-3,5-bis(benzyloxy)phenyl 4-fluorobenzoate (14c)
To a solution of phenol 7 (5.03 g, 0.014 mol) and 4-fluorobenzoic acid 6c (3.03 g, 0.02 mol) in CH2Cl2
(30 mL) at 0 °C added EDCI (8.30 g, 0.04 mol) and DMAP (1.76 g, 0.014 mol). After stirring for 4 h at
rt, the mixture was diluted with EtOAc, and then washed with saturated NaHCO3 solution. The organic
phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified
by silica gel column chromatography (EtOAc-petroleum ether, 1 : 1) to give 14c (5.80 g, 83%) as a white
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solid: Rf = 0.24 (Hexanes : Ethyl Acetate = 6 : 1); mp 115 – 117 °C; IR (thin film, cm-1) 2953, 1739,
1686, 1610, 1577, 1506, 1433, 1413, 1377, 1352, 1329, 1257, 1204, 1153, 1100, 1053, 1028, 1013, 912,
878, 852, 828, 758, 740, 697, 630, 612; 1H NMR (500 MHz, CDCl3) δ 8.16 (dd, J = 8.6, 5.5 Hz, 2H), 7.44
– 7.31 (m, 10H), 7.16 (dd, J = 9, 9 Hz, 2H), 6.56 (d, J = 1.8 Hz, 1H), 6.47 (d, J = 1.8 Hz, 1H), 5.09 (s,
2H), 5.05 (s, 2H), 2.48 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 199.2, 166.2 (d, J = 203.1 Hz, 1C),
164.2, 161.3, 158.4, 149.7, 135.9, 135.8, 133.0, 132.9, 128.7, 128.4, 128.3, 127.6, 127.5, 125.5, 125.4,
117.7, 115.8 (d, J = 17.6 Hz, 2C), 101.4, 101.4, 98.6, 71.0, 70.5, 32.1; HRMS (MALDI) calcd for
[C29H23FO5+Na]+: 493.1422, found: 493.1433.
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3,5-bis(benzyloxy)-2-(2-bromoacetyl)phenyl 4-fluorobenzoate (16c)
To a solution of ester 14c (5.80 g, 0.012 mol) in dry THF (25 mL) was added PTT (11.6 g, 0.03 mol, 2.5
equiv) in portions at 0 °C. The reaction mixture was stirred at rt for 4 h, the reaction was monitored by
crude NMR. When the reaction was completed, it was cooled down to 0 °C and dropwise treated directly
with diethyl phosphate (2.39 mL, 0.018 mol, 1.5 equiv) and Et3N (2.58 mL, 0.018 mol, 1.5 equiv), the
resulting mixture was stirred for 6 h at rt until complete, then mixture was poured into water and extracted
with CH2Cl2 (3 x 100 mL). The combined organic phases were dried over NaSO4 and concentrated in
vacuo. The residue was purified by silica gel column chromatography (Hexanes : CH2Cl2 = 1 : 2) to give
16c (4.81 g, 71%) as a light yellow solid: Rf = 0.47 (Hexanes : Ethyl Acetate = 4: 1), mp : 122 – 124 °C;
IR (thin film, cm-1) 3065, 2932, 1739, 1691, 1605, 1576, 1506, 1454, 1435, 1413, 1379, 1330, 1294, 1255,
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1152, 1098, 1056, 1028, 1013, 851, 828, 756, 738, 698, 630, 612, 574; H NMR (500 MHz, CDCl3) δ
8.16 (dd, J = 8.2, 5.6 Hz, 2H), 7.47 – 7.32 (m, 11H), 7.17 (dd, J = 9, 9 Hz, 2H), 6.58 (s, 1H), 6.56 (s, 1H),
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5.11 (s, 2H), 5.07 (s, 2H), 4.37 (s, 2H); C{1H} NMR (126 MHz, CDCl3) δ 191.8, 166.2 (d, J = 203.1
Hz, 1C), 164.0, 162.3, 158.5, 151.1, 135.6, 135.2, 133.1, 133.0, 128.9, 128.8, 128.6, 128.5, 127.7, 127.7,
125.2, 125.2, 115.8 (d, J = 17.6 Hz, 2C), 113.8, 102.1, 98.4, 71.4, 70.6, 36.7; HRMS (MALDI) calcd for
[C29H22BrFO5+Na]+: 571.0527, found: 571.0532.
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The Journal of Organic Chemistry
2-(2-(benzoyloxy)acetyl)-3,5-bis(benzyloxy)phenyl 4-fluorobenzoate (17c)
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oC in a sand bath for 24 h. The reaction was diluted with CH2Cl2, washed with saturated sodium
bicarbonate and brine. The combined organic layers were dried over sodium sulfate, and then concentrated
in vacuo. The resulting crude was purified by a silica gel chromatography and flash with solvent (Hexane:
Ethyl Acetate = 10 : 1) to afford the product 17c as a light yellow solid (3.08 g, 76%): mp 104 – 106 °C;
Rf = 0.40 (Hexane: Ethyl Acetate = 4: 1); IR (thin film, cm-1) 2921, 2852, 1743, 1644, 1611, 1508, 1498,
1451, 1439, 1349, 1288, 1238, 1173, 1112, 1097, 1044, 1021, 840, 823, 736, 699, 624, 508, 488, 454; 1H
NMR (500 MHz, CDCl3) δ 8.19 (dd, J = 8.8, 5.5 Hz, 2H), 8.04 – 7.97 (m, 2H), 7.55 (dd, J = 7, 7 Hz, 1H),
7.44 – 7.35 (m, 12H), 7.12 (dd, J = 9, 9 Hz, 2H), 6.59 (d, J = 1.1 Hz, 2H), 5.26 (s, 2H), 5.12 (s, 2H), 5.06
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(s, 2H); C{1H} NMR (100 MHz, CDCl3) δ 193.4, 166.1 (d, J = 253.8 Hz, 1C), 165.8, 164.1, 162.2,
159.0, 151.2, 135.8, 135.4, 133.2, 133.1, 133.1, 129.8, 129.7, 128.8, 128.7, 128.5, 128.4, 128.3, 127.7,
127.7, 127.6, 125.5, 125.5, 115.8 (d, J = 22 Hz, 2C), 114.0, 102.5, 98.4, 71.3, 70.6, 69.8; HRMS (MALDI)
calcd for [C36H27FO7+Na]+: 613.1633, found: 613.1612.
5,7-bis(benzyloxy)-2-(4-fluorophenyl)-3-hydroxy-4H-chromen-4-one (11c)
To a solution of benzoate 17c (2.32 g, 3.9 mmol) in THF (39 mL) was added LiHMDS in hexanes (11.8
mL, 11.8 mmol) at – 78 °C. The mixture was stirred at – 78 °C for 1 h until the crude NMR analysis
confirmed the reaction was completed. The cooled mixture was poured into water and was then extracted
with Ethyl Acetate (3 x 80 mL). The combined organic layers were then washed with brine, dried over
sodium sulfate and concentrated in vacuo. Resulting residue was dissolved in AcOH (38 mL), then
AcONa (0.81 g, 9.8 mmol) was added. After stirring at 100 °C for 12 h, the mixture was cooled to rt and
then diluted with CH2Cl2. The mixture was washed with water, saturated NaHCO3 solution and brine,
successively. The organic phase was combined and concentrated in vacuo to give a solid residue, which
was then dissolved in MeOH/CH2Cl2 (20 mL, v/v1:1). After stirring for 10 h in the presence of a catalytic
amount of NaOMe at rt, the mixture was neutralized with Dowex 50W-X 8 (H+) resin. The resins were
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filtered off, the solvent was removed. The resulting solid was recrystallized from methanol to provide 11c
(600 mg, 33%) as a yellow solid. mp 179 – 181 °C; Rf = 0.45 (Hexane: Ethyl Acetate = 2: 1); IR (thin
film, cm-1) 2946, 1754, 1617, 1507, 1453, 1375, 1258, 1234, 1214, 1198, 1163, 1030, 736, 702, 471, 410;
1H NMR (500 MHz, CDCl3) δ 8.21 (dd, J = 8.8, 5.4 Hz, 2H), 7.60 (d, J = 7.5 Hz, 2H), 7.49 – 7.36 (m,
7H), 7.33 (dd, J = 7, 7 Hz, 1H), 7.19 (dd, J = 9, 9 Hz, 2H), 6.64 (d, J = 1.8 Hz, 1H), 6.50 (d, J = 1.8 Hz,
1H), 5.24 (s, 2H), 5.13 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.9, 163.5, 163.3 (d, J = 250.1 Hz,
1C), 159.5, 158.8, 141.0, 138.1, 136.1, 135.5, 129.4, 129.3, 128.9, 128.8, 128.8, 128.7, 128.6, 128.5,
127.8, 127.6, 127.3, 127.3, 126.7, 126.7, 126.6, 115.6 (d, J = 21.6 Hz, 2C), 106.7, 97.7, 93.7, 70.8, 70.6;
HRMS (MALDI-TOF/CCA) calcd. [C29H21FO5+Na]+: 491.1265, found: 491.1257
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2-acetyl-3,5-bis(benzyloxy)phenyl benzoate (14d)
To a solution of phenol 7 (7.81 g, 0.022 mol) and benzoic acid 6d (4.10 g, 0.034 mol) in CH2Cl2 (30 mL)
at 0 °C was added EDCI (12.90 g, 0.066 mol) and DMAP (2.74 g, 0.022 mol). After stirring for 4 h at rt,
the mixture was diluted with EtOAc, and then washed with saturated NaHCO3 solution. The organic
phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified
by silica gel column chromatography (EtOAc-Hexanes, 1 : 1) to give 14d (8.5 g, 84%) as a white solid:
Rf = 0.32 (Hexanes : Ethyl Acetate = 4 : 1); mp 108 – 110 °C; IR (thin film, cm-1) 3063, 2922, 1737, 1686,
1610, 1576, 1497, 1452, 1432, 1377, 1351, 1327, 1289, 1250, 1204, 1153, 1096, 1069, 1027, 1002, 827,
738, 703; 1H NMR (500 MHz, CDCl3) δ 8.15 (d, J = 7.9 Hz, 2H), 7.62 (dd, J = 7, 7 Hz, 1H), 7.50 (dd, J
= 7, 7 Hz, 2H), 7.43 – 7.31 (m, 10H), 6.56 (s, 1H), 6.49 (s, 1H), 5.10 (s, 2H), 5.05 (s, 2H), 2.49 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 199.3, 165.0, 161.2, 158.2, 149.8, 135.9, 135.8, 133.7, 130.3, 129.2,
128.7, 128.7, 128.6, 128.3, 128.3, 127.6, 127.5, 117.9, 101.4, 98.5, 71.0, 70.5, 32.1; HRMS (MALDI-
TOF/CCA) calcd. [C29H24O5+Na] +: 475.1516, Found: 475.1494.
3,5-bis(benzyloxy)-2-(2-bromoacetyl)phenyl benzoate (16d)
To a solution of ester 14d (8.47 g, 0.019 mol) in dry THF (40 mL) was added PTT (17.6 g, 0.047 mol,
2.5 equiv) in portions at 0 °C. The reaction mixture was stirred at rt for 4 h, and monitored by crude NMR.
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When the reaction completed, it was cooled down to 0 °C and dropwise treated directly with diethyl
phosphate (3.62 mL, 0.028 mol, 1.5 equiv) and Et3N (3.91 mL, 0.028 mol, 1.5 equiv), the resulting
mixture was stirred for 6 h at rt until complete, then mixture was poured into water and extracted with
CH2Cl2 (3 x 100 mL). The combined organic phases were dried over NaSO4 and concentrated in vacuo.
The residue was purified by silica gel column chromatography (Hexanes : Ethyl Acetate = 10 : 1) to give
16d ( 8.6 g, 87%) as a light yellow solid: Rf = 0.45 (Hexanes : Ethyl Acetate = 4: 1), mp 106 – 108 °C;
IR (thin film, cm-1) 3064, 3032, 1738, 1693, 1608, 1574, 1497, 1452, 1434, 1379, 1329, 1257, 1150, 1091,
1056, 1026, 827, 737, 699, 613, 590; 1H NMR (500 MHz, CDCl3) δ 8.14 (d, J = 7.4 Hz, 2H), 7.63 (dd, J
= 7, 7 Hz, 1H), 7.50 (dd, J = 8, 8 Hz, 2H), 7.48 – 7.33 (m, 10H), 6.56 (d, J = 2.0 Hz, 1H), 6.55 (d, J = 2.0
Hz, 1H), 5.11 (s, 2H). 5.06 (s, 2H). 4.36 (s, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 191.8, 165.0, 162.2,
158.4, 151.1, 135.7, 135.3, 133.8, 130.4, 129.0, 128.9, 128.8, 128.6, 128.6, 128.5, 127.7, 127.7, 114.0,
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110.0, 102.1, 98.4, 71.3, 70.6, 36.7; HRMS (MALDI-TOF/CCA) calcd. [C29H23BrO5+H] : 553.0621,
Found: 553.0607.
2-(2-(benzoyloxy)-4,6-bis(benzyloxy)phenyl)-2-oxoethyl benzoate (17d)
A mixture of 16d (8 g, 15 mmol) and BzOK (3.62 g, 22.5 mmol) was stirred in CH3CN (30 mL) at 82 oC
in a sand bath for 24 h. Reaction was diluted with CH2Cl2, washed with saturated sodium bicarbonate and
brine, dried over sodium sulfate, then concentrated in vacuo. The resulting crude was purified by silica
gel chromatography and flash with solvent (Hexane: Ethyl Acetate = 10 : 1) to afford the product 17d as
a light yellow solid (8.6 g, 77%): mp 114 – 116 °C; Rf = 0.48 (Hexane: Ethyl Acetate = 5 : 1); 1H NMR
(500 MHz, CDCl3) δ 8.15 (d, J = 7.5 Hz, 2H), 8.01 – 7.95 (d, J = 7.5 Hz, 2H), 7.59 (dd, J = 8, 8 Hz, 1H),
7.53 (dd, J = 7, 7 Hz, 1H), 7.47 (d, J = 8, 8 Hz, 2H), 7.44 – 7.32 (m, 13H), 6.56 (dd, J = 5.3, 1.9 Hz, 2H),
5.23 (s, 2H), 5.11 (s, 2H), 5.06 (s, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 193.6, 165.8, 165.0, 162.1,
158.9, 151.2, 135.7, 135.4, 133.5, 133.0, 130.5, 129.8, 129.6, 129.2, 128.8, 128.7, 128.5, 128.4, 128.3,
127.7, 127.6, 114.1, 112.5, 102.3, 98.4, 71.3, 70.5, 69.7; IR (thin film, cm-1) 1724, 1606, 1582, 1497,
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1451, 1434, 1413, 1364, 1329, 1315, 1258, 1176, 1151, 1092, 1071, 1024, 1001, 972, 938, 911, 826, 797,
735, 699; HRMS (MALDI-TOF/CCA) calcd. [C36H28O7+H] +: 595.1727, Found: 595.1707.
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5,7-bis(benzyloxy)-3-hydroxy-2-phenyl-4H-chromen-4-one (11d)
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To a solution of benzoate 17d (2.5 g, 4.4 mmol) in THF (30 mL) was added LiHMDS in hexanes (13 mL,
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13.2 mmol) at – 78 °C. The mixture was stirred at – 78 °C for 1 h until crude NMR analysis confirmed
the reaction was completed. The cooled mixture was then poured into water and then extracted with Ethyl
Acetate (3 x 80 mL). The combined organic layers were then washed with brine, dried over sodium sulfate
and concentrated in vacuo. Resulting residue was dissolved in AcOH (13 mL), then AcONa (0.54 g, 6.6
mmol) was added. After stirring at 100 °C for 12 h, the mixture was cooled to rt and then diluted with
CH2Cl2. The mixture was washed with water, saturated NaHCO3 solution and brine, successively. The
organic phases were combined and concentrated in vacuo to give a solid residue, which was dissolved in
MeOH/CH2Cl2 (12 mL, v/v1:1). After stirring for 10 h in the presence of a catalytic amount of NaOMe
at rt, the mixture was neutralized with Dowex 50W-X 8 (H+) resin. The resins were filtered off, the solvent
was removed. The resulting solid was recrystallized from methanol to provide 11d (650 mg, 35%) as a
yellow solid. mp 167 – 169 °C; Rf = 0.41 (Hexane: Ethyl Acetate = 2: 1); IR (thin film, cm-1) 3266, 1740,
1615, 1495, 1452, 1375, 1303, 1264, 1213, 1169, 1134, 1109, 1097, 821, 736, 695; 1H NMR (500 MHz,
CDCl3) δ 8.21 (d, J = 7.7 Hz, 2H), 7.61 (d, J = 7.5 Hz, 2H), 7.51 (dd, J = 8, 8 Hz, 2H), 7.47 – 7.37 (m,
8H), 7.32 (dd, J = 7, 7 Hz, 1H), 6.65 (d, J = 1.9 Hz, 1H), 6.48 (d, J = 1.9 Hz, 1H), 5.23 (s, 2H), 5.12 (s,
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2H); C{1H} NMR (100 MHz, CDCl3) δ 171.9, 163.4, 159.4, 158.9, 141.8, 138.4, 136.1, 135.6, 131.1,
129.6, 128.8, 128.7, 128.5, 128.5, 127.8, 127.6, 127.2, 126.6, 106.8, 97.6, 93.7, 70.7, 70.6; HRMS
(MALDI-TOF/CCA) calcd. [C29H22O5+H] +: 473.1359, Found: 473.1348.
2-acetyl-3,5-bis(benzyloxy)phenyl 4-methoxybenzoate (14e)
To a suspension of phenol 7 (7.92 g, 0.023 mol) and 4-methoxybenzoic acid 6e (5.68 g, 0.034 mol) in
CH2Cl2 (120 mL) at 0 °C was added EDCI (13.07 g, 0.069 mol) and DMAP (2.78 g, 0.023 mol). After
stirring for 8 h at rt, the mixture was diluted with EtOAc, and then washed with saturated NaHCO3
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solution. The organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The
residue was purified by silica gel column chromatography (Hexanes : Ethyl Acetate = 1 : 1) to give 14e
(9.34 g, 85 %) as a white solid: Rf = 0.27 (Hexanes : Ethyl Acetate = 4 : 1), mp 100 – 102 °C; IR (thin
film, cm-1) 2872, 1729, 1687, 1605, 1578, 1510, 1454, 1433, 1421, 1377, 1351, 1329, 1252, 1204, 1165,
1153, 1095, 1028, 845, 827, 760, 738, 696, 612; 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 8.7 Hz, 2H),
7.50 – 7.28 (m, 10H), 6.97 (d, J = 8.8 Hz, 2H), 6.54 (d, J = 1.7 Hz, 1H), 6.49 (d, J = 1.7 Hz, 1H), 5.09 (s,
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2H), 5.04 (s, 2H), 3.88 (s, 3H), 2.48 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 199.4, 164.6, 164.0,
161.1, 158.0, 149.8, 136.0, 135.9, 132.4, 132.4, 132.4, 128.9, 128.9, 128.8, 128.8, 128.8, 128.8, 128.8,
128.7, 128.3, 128.2, 127.6, 127.4, 127.3, 121.5, 118.1, 113.9, 113.8, 101.5, 98.4, 70.9, 70.4, 55.5, 32.0;
HRMS (MALDI-TOF/CCA) calcd. [C30H26O6+Na]+:505.1622, found: 505.1652.
3,5-bis(benzyloxy)-2-(2-bromoacetyl)phenyl 4-methoxybenzoate (16e)
To a solution of ester 14e (9.34 g, 0.019 mol) in dry THF (50 mL) was added PTT (18.2 g, 0.048 mol, 2.5
equiv) in portions at 0 °C. The reaction mixture was stirred at rt for 4 h. The reaction was monitored by
crude NMR. When the reaction was complete, it was cooled down to 0 °C and dropwise treated directly
with diethyl phosphate (3.75 mL, 0.029 mol, 1.5 equiv) and Et3N (4.05 mL, 0.029 mol, 1.5 equiv), the
resulting mixture was stirred for 6 h at rt until complete, then mixture was poured into water and extracted
with CH2Cl2 (3 x 100 mL). The combined organic phases were dried over NaSO4 and concentrated in
vacuo. The residue was purified by silica gel column chromatography (Hexanes : CH2Cl2 = 1 : 2) to give
16e (4.81 g, 71%) as a light yellow solid: Rf = 0.34 (Hexanes : Ethyl Acetate = 4: 1), mp 141 – 143 °C;
IR (thin film, cm-1) 3064, 2910, 1731, 1694, 1605, 1577, 1510, 1498, 1435, 1422, 1381, 1331, 1252, 1166,
1152, 1092, 1028, 845, 759, 739, 697, 639, 613, 580; 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 8.9 Hz,
2H), 7.46 – 7.31 (m, 10H), 6.97 (d, J = 8.9 Hz, 2H), 6.56 (dd, J = 4.1, 1.9 Hz, 2H), 5.10 (s, 2H), 5.06 (s,
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2H), 4.37 (s, 2H), 3.88 (s, 3H); C{1H} NMR (126 MHz, CDCl3) δ 191.9, 164.6, 164.1, 162.1, 158.3,
151.1, 135.7, 135.4, 132.5, 128.8, 128.7, 128.5, 128.4, 127.7, 127.6, 121.2, 114.2, 113.9, 102.1, 98.3,
71.2, 70.6, 55.5, 36.8; HRMS (MALDI-TOF/CCA) calcd. [C30H25BrO6+Na]+:583.0727, found: 583.0715
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2-(2-(benzoyloxy)acetyl)-3,5-bis(benzyloxy)phenyl 4-methoxybenzoate (17e)
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A mixture of 16e (9.11 g, 0.016 mol) and BzOK (3.90 g, 0.024 mol) was stirred in CH3CN (100 mL) at
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bicarbonate and brine, dried over sodium sulfate, the combined organic layers were concentrated in vacuo.
The resulting crude was purified by silica gel column chromatography and flash with solvent (Hexane:
Ethyl Acetate = 10 : 1) to afford product 17e as a light yellow solid (7.40 g, 76%): mp 116 – 118 °C; Rf
= 0.40 (Hexane: Ethyl Acetate = 4: 1); IR (thin film, cm-1) 3033, 2935, 1724, 1602, 1577, 1510, 1452,
1434, 1364, 1330, 1315, 1249, 1150, 1089, 1024, 971, 939, 911, 878, 826, 793, 758, 734, 695, 642, 578,
506; 1H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 8.7 Hz, 2H), 8.01 (d, J = 7.4 Hz, 2H), 7.54 (dd, J = 7, 7
Hz, 1H), 7.48 – 7.31 (m, 12H), 6.93 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 1.8 Hz, 1H), 6.55 (d, J = 1.8 Hz, 1H),
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5.26 (s, 2H), 5.11 (s, 2H), 5.05 (s, 2H), 3.85 (s, 3H); C{1H} NMR (125 MHz, CDCl3) δ 193.7, 165.8,
164.7, 163.9, 162.1, 158.8, 151.3, 135.8, 135.5, 133.0, 132.6, 129.8, 129.7, 128.8, 128.7, 128.4, 128.4,
128.3, 127.7, 127.6, 121.5, 114.2, 113.8, 102.4, 98.2, 71.2, 70.5, 69.7, 55.5; HRMS (MALDI-TOF/CCA)
calcd. [C37H30O8+Na]+: 625.1833, found: 625.1815
5,7-bis(benzyloxy)-3-hydroxy-2-(4-methoxyphenyl)-4H-chromen-4-one (11e)
To a solution of benzoate 17e (2.52 g, 0.004 mol) in THF (30 mL) was added LiHMDS in hexanes (12.5
mL, 0.012 mol) at – 78 °C. The mixture was stirred at – 78 °C for 1 h until the crude NMR analysis
confirmed the reaction was complete. The cooled mixture was poured into water and was then extracted
with Ethyl Acetate (3 x 80 mL). The combined organic layers were then washed with brine, dried over
sodium sulfate and concentrated in vacuo. Resulting residue was dissolved in AcOH (30 mL), then
AcONa (0.51 g, 6.27 mmol) was added. After stirring at 100 °C for 12 h, the mixture was cooled to rt and
then diluted with CH2Cl2. The mixture was washed with water, saturated NaHCO3 solution and brine,
successively. The organic phases were combined and concentrated to give a solid residue, which was
dissolved in MeOH/CH2Cl2 (20 mL, v/v1:1). After being stirred for 10 h in the presence of a catalytic
amount of NaOMe at rt, the mixture was neutralized with Dowex 50W-X 8 (H+) resin. The resins were
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filtered off, solvent was concentrated in vacuo. The resulting solid was recrystallized from methanol to
provide 11e (800 mg, 40%) as a yellow solid. mp 188 – 190 °C; Rf = 0.42 (Hexane: Ethyl Acetate = 2: 1);
IR (thin film, cm-1) 3309 – 3234 (br), 2873, 1605, 1571, 1511, 1452, 1374, 1334, 1300, 1255, 1212, 1179,
1135, 1099, 1030, 976, 911, 8334, 819, 736, 696, 624; 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 9.0 Hz,
2H), 7.61 (d, J = 7.5 Hz, 2H), 7.46 – 7.36 (m, 9H), 7.02 (d, J = 9.0 Hz, 2H), 6.63 (d, J = 1.9 Hz, 1H), 6.48
(d, J = 1.9 Hz, 1H), 5.23 (s, 2H), 5.12 (s, 2H), 3.88 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 171.7,
163.2, 160.6, 159.3, 158.7, 142.4, 137.5, 136.2, 135.6, 130.0, 128.9, 128.8, 128.7, 128.7, 128.6, 128.5,
127.8, 127.7, 126.6, 123.6, 114.0, 106.7, 97.6, 93.7, 70.7, 70.6, 55.4; HRMS (MALDI-TOF/CCA) calcd.
[C30H24O6+Na]+ : 503.1465, found: 503.1442.
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3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one (3a)
To a solution of compound 11f (14 mg, 0.025 mmol) in 0.3 mL of a solvent mixture of THF and methanol
(1 : 1) was added Pd/C (2.6 mg, 10 mol%) and the resulting mixture was stirred under a H2 atmosphere
for 12 h. The reaction mixture was flashed through a celite column and crystalized by the addition of
acetone to give product 3a (5 mg, 72%) as a yellow solid. IR (thin film, cm-1) 3510 – 3060 (br), 1658,
1616, 1568, 1508, 1456, 1378, 1314, 1256, 1224, 1174, 1090, 1007, 977, 883, 797, 736, 641; 1H NMR
(500 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.11 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H), 6.43 (s, 1H),
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6.18 (s, 1H); C{1H} NMR (100 MHz, DMSO-d6) δ 176.3, 164.3, 161.1, 159.6, 156.6, 147.2, 136.1,
129.9, 122.1, 115.9, 103.5, 98.7, 93.9; HRMS (MALDI-TOF/CCA) calcd. [C15H10O6+Na]+: 309.0370,
Found: 309.0378.
2-(4-chlorophenyl)-3,5,7-trihydroxy-4H-chromen-4-one (3b)
To a solution of compound 11b (6.7 mg, 0.014 mmol) in 0.3 mL of a solvent mixture of THF and CH2Cl2
(1 : 1) was added Pd/C (0.7 mg, 5 mol%) and resulting mixture was stirred under a H2 atmosphere for 6
h. The reaction mixture was flashed through a celite column and crystalized by the addition of acetone to
give product 3b (3 mg, 71%) as a yellow solid. mp > 200 °C; IR (thin film, cm-1) 3407 – 3178(br), 2366,
2342, 1653, 1624, 1599, 1559, 1541, 1507, 1490, 1371, 1308, 1218, 1167, 1088, 1013, 878, 862, 831; 1H
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NMR (500 MHz, methanol-d4) δ 8.20 (d, J = 4.0 Hz, 2H), 7.51 (d, J = 4.0 Hz, 2H), 6.42 (s, 1H), 6.19 (s,
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1H); C{1H} NMR (150 MHz, methanol-d4) δ 176.2, 164.9, 161.3, 157.0, 144.2, 137.4, 135.3, 130.0,
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128.9, 128.3, 128.1, 127.4, 103.2, 98.1, 93.2; HRMS (MALDI-TOF/CCA) calcd.
[C15H9ClO5+Na]+:305.0211, found: 305.0217.
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2-(4-fluorophenyl)-3,5,7-trihydroxy-4H-chromen-4-one (3c)
To a solution of compound 11c (14.4 mg, 0.03 mmol) in 0.3 mL of a solvent mixture of THF and methanol
(1 : 1) was added Pd/C (3.3 mg, 10 mol%) and resulting mixture was stirred under a H2 atmosphere for
12 h. The reaction mixture was flashed through a celite column and crystalized by the addition of acetone
to give product 3c (60%) as a yellow solid. mp 196 – 198 °C; IR (thin film, cm-1) 3393 – 3201 (br), 2367,
2313, 1655, 1627, 1601, 1508, 1473, 1437, 1418, 1375, 1314, 1243, 1216, 1167, 1124, 1087, 1007, 978,
899, 882, 835; 1H NMR (500 MHz, acetone-d6) δ 12.06 (s, 1H), 8.31 (dd, J = 8.5, 5.5 Hz, 2H), 7.34 (dd,
J = 8.7 Hz, 2H), 6.57 (s, 1H), 6.29 (s, 1H); 13C{1H} NMR (100 MHz, acetone-d6) δ 176.0, 164.5, 163.4
(d, J = 248.6 Hz, 1C), 161.5, 157.0, 144.4, 136.8, 130.1, 130.0, 127.6, 115.5 (d, J = 21.9 Hz, 2C), 103.4,
98.5, 93.7; HRMS (MALDI-TOF/CCA) calcd. [C15H9FO5+Na]+: 289.0507, found: 289.0518.
3,5,7-trihydroxy-2-phenyl-4H-chromen-4-one (3d)
To a solution of compound 11d (12.7 mg, 0.028 mmol) in 0.3 mL of a solvent mixture of THF and CH2Cl2
(1 : 1) was added Pd/C (3 mg, 10 mol%) and resulting mixture was stirred under a H2 atmosphere for 6 h.
The reaction mixture was flashed through a celite column and crystalized by the addition of acetone to
give product 3d (5.4 mg, 73%) as a yellow solid. mp > 200 °C; IR (thin film, cm-1) 3412 – 3157(br), 2924,
2359, 2331, 1636, 1601, 1558, 1506, 1497, 1472, 1465, 1457, 1448, 1373, 1313, 1254, 1217, 1163, 1088,
1073, 1005, 990, 689; 1H NMR (500 MHz, acetone-d6) δ 8.25 (d, J = 7.9 Hz, 2H), 7.57 (dd, J = 7, 7 Hz,
2H), 7.51 (d, J = 7.1 Hz, 1H), 6.58 (s, 1H), 6.30 (s, 1H); 13C{1H} NMR (100 MHz, acetone-d6) δ 205.3,
176.1, 164.5, 161.5, 157.1, 145.2, 137.1, 131.2, 129.9, 128.5, 127.6, 103.4, 98.4, 93.7, 29.3, 29.1, 28.9,
28.7, 28.5; HRMS (MALDI-TOF/CCA) calcd. [C15H10O5+H]+: 271.0601, Found: 271.0574.
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3,5,7-trihydroxy-2-(4-methoxyphenyl)-4H-chromen-4-one (3e)
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To a solution of compound 11e (10 mg, 0.014 mmol) in 0.3 mL of a solvent mixture of THF and CH3OH
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(1 : 1) was added Pd/C (2 mg, 10 mol%) and the resulting mixture was stirred under a H2 atmosphere for
6 h. The reaction mixture was flashed through a celite column and crystalized by the addition of acetone
to give product 3e (4 mg, 70%) as a yellow solid. mp > 200 °C; IR (thin film, cm-1) 3648 – 3274(br),
2251, 2125, 1653, 1618, 1598, 1541, 1510, 1398, 1372, 1310, 1258, 1223, 1175 ,1052, 1003, 882, 821,
758, 622; 1H NMR (500 MHz, DMSO-d6) δ 8.11 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H), 6.43 (s,
1H), 6.18 (s, 1H), 3.82 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 176.4, 164.5, 161.2, 160.9, 156.7,
146.7, 136.5, 129.8, 123.7, 114.5, 103.5, 98.7, 94.0, 55.8; HRMS (MALDI-TOF/CCA) calcd.
[C16H12O6+Na]+: 323.0526, Found: 323.0518.
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benzyl 2-((5,7-bis(benzyloxy)-2-(4-(benzyloxy)phenyl)-4-oxo-4H-chromen-3-yl)oxy)acetate (10f)
To a solution of OBn-aglycon 11f (25 mg, 0.045 mmol) in DMF at 0 °C was added K2CO3 (8 mg, 0.058
mmol) portion-wise and dropwise of benzyl bromoacetate (7.9 µL, 0.049 mmol). The resulting solution
was stirred at rt for 6 h. The reaction solution was washed with water (3 x 4 mL) and extracted with ethyl
acetate, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash
silica gel column chromatography with CH2Cl2 and hexanes (CH2Cl2 : Hexanes = 5 : 1) to give benzyl
ester 10f (25 mg, 81%) as a yellow solid: mp 165 – 167 °C. Rf = 0.21 (CH2Cl2); IR (thin film, cm-1) 2955,
2922, 2852, 1749, 1627, 1603, 1508, 1497, 1454, 1437, 1375, 1351, 1295, 1254, 1176, 1124, 1107, 1038,
1026, 1015, 967, 835, 824, 736, 696, 406; 1H NMR (500 MHz, CDCl3) δ 8.15 (d, J = 8.5 Hz, 2H), 7.60
(d, J = 7.4 Hz, 2H), 7.39 (m, 18H), 7.02 (d, J = 8.5 Hz, 2H), 6.59 (s, 1H), 6.47 (s, 1H), 5.25 (s, 2H), 5.15
(s, 2H), 5.11 (s, 2H), 5.10 (s, 2H), 4.93 (s, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 173.4, 169.1, 162.8,
160.4, 159.7, 158.6, 152.8, 139.1, 136.5, 136.3, 135.6, 135.4, 130.3, 128.8, 128.7, 128.6, 128.5, 128.5,
128.3, 128.3, 128.2, 127.7, 127.6, 127.5, 126.6, 123.2, 114.6, 109.8, 98.1, 93.9, 70.8, 70.5, 70.0, 68.4,
66.5; HRMS (MALDI-TOF/CCA) calcd. [C45H36O8+Na]+: 727.2302, Found: 727.2274.
benzyl 2-((5,7-bis(benzyloxy)-2-(4-chlorophenyl)-4-oxo-4H-chromen-3-yl)oxy)acetate (10b)
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To a solution of chloro-aglycon 11b (16 mg, 0.033 mmol) in 0.3 mL of DMF at 0 °C added K2CO3 (5.9
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5
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7
8
9
mg, 0.043 mmol) portion-wise and benzyl bromoacetate (5.8 µL, 0.036 mmol) dropwise. The resulting
solution was stirred at rt overnight. The reaction solution was washed with water (3 x 4 mL) and extracted
with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The crude product was purified
by flash silica gel column chromatography with CH2Cl2 and hexanes (CH2Cl2 : Hexanes = 5 : 1) to give
benzyl ester 10b (16 mg, 77%) as a white solid; mp 132 – 134 °C. Rf = 0.21 (CH2Cl2); IR (thin film, cm-
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1
1) 2923, 1754, 1634, 1605, 1488, 1442, 1362, 1301, 1174, 1120, 1093, 1030, 749, 697, 455; H NMR
(500 MHz, CDCl3) δ 8.09 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 7.4 Hz, 2H), 7.45 – 7.27 (m, 15H), 6.59 (d, J
13
= 1.9 Hz, 1H), 6.48 (d, J = 1.9 Hz, 1H), 5.24 (s, 2H), 5.13 (s, 2H), 5.11 (s, 2H), 4.97 (s, 2H); C{1H}
NMR (100 MHz, CDCl3) δ 173.2, 168.9, 163.1, 159.8, 158.6, 151.5, 139.9, 136.4, 136.2, 135.6, 135.3,
129.9(2C), 129.1, 128.8(2C), 128.6(2C), 128.6(2C), 128.5(2C), 128.5, 128.4, 128.3(2C), 127.7, 127.6
(2C), 126.7, 126.6, 109.9, 98.3, 93.8, 70.8, 70.5, 68.3, 66.6; HRMS (MALDI-TOF/CCA) calcd.
[C38H29ClO7+Na]+:655.1494, found: 655.1467
benzyl 2-((5,7-bis(benzyloxy)-2-(4-fluorophenyl)-4-oxo-4H-chromen-3-yl)oxy)acetate (10c)
To a solution of fluoro-aglycon 11c (31.1 mg, 0.066 mmol) in DMF at 0 °C was added K2CO3 (11.9 mg,
0.86) portion-wise and benzyl bromoacetate (11.6 µL, 0.073 mmol) dropwise. The resulting solution was
stirred at rt for 6 h. The reaction solution was washed with water (3 x 4 mL) and extracted with ethyl
acetate, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash
silica gel chromatography column with CH2Cl2 and hexanes (CH2Cl2 : Hexanes = 5 : 1) to give a yellow
solid, 10c (20 mg, 51%), mp 132 – 134 °C. Rf = 0.21 (CH2Cl2); IR (thin film, cm-1) 2920, 1778, 1755,
1634, 1605, 1507, 1498, 1488, 1453, 1432, 1379, 1255, 1237, 1175, 1114, 736, 697, 454, 414; 1H NMR
(500 MHz, CDCl3) δ 8.16 (dd, J = 8.4, 5.7 Hz, 2H), 7.60 (d, J = 7.7 Hz, 2H), 7.46 – 7.28 (m, 14H), 7.09
(d, J = 8.5 Hz, 1H), 6.59 (s, 1H), 6.48 (s, 1H), 5.25 (s, 2H), 5.13 (s, 2H), 5.11 (s, 2H), 4.96 (s, 2H); 13C{1H}
NMR (100 MHz, CDCl3) δ 173.3, 169.0, 163.0, 163.7 (d, J = 251.0 Hz, 1C), 159.8, 158.6, 151.7, 139.5,
136.2, 135.6, 135.3, 130.9, 130.8, 128.9, 128.8, 128.8, 128.6, 128.6, 128.5, 128.5, 128.4, 128.3, 128.3,
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128.3, 127.7, 127.7, 127.6, 126.8, 126.8, 126.7, 126.6, 115.4 (d, J = 21.6 Hz, 2C), 109.9, 98.2, 93.8, 70.8,
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2
3
70.5, 68.3, 66.6; HRMS (MALDI-TOF/CCA) calcd. [C38H29FO7+Na]+: 639.1790, found: 639.1790.
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benzyl 2-((5,7-bis(benzyloxy)-4-oxo-2-phenyl-4H-chromen-3-yl)oxy)acetate (10d)
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To a solution of aglycon 11d (15.7 mg, 0.035 mmol) in 0.3 mL of DMF at 0 °C was added K2CO3 (6.3
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mg, 0.046 mmol) portion-wise and benzyl bromoacetate (6.1 µL, 0.039 mmol) dropwise. The resulting
solution was stirred at rt for 6 h. Reaction solution was washed with water (3 x 4 mL) and extracted with
ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by
flash silica gel column chromatography with CH2Cl2 and hexanes (CH2Cl2 : Hexanes = 5 : 1) to give a
yellow solid, benzyl ester 10d (16 mg, 79%), mp 50 – 52 °C. Rf = 0.21 (CH2Cl2); IR (thin film, cm-1)
1758, 1632, 1605, 1559, 1517, 1496, 1446, 1375, 1351, 1276, 1260, 1174, 1116, 1030, 822, 736, 695; 1H
NMR (500 MHz, CDCl3) δ 8.13 (dd, J = 3.0, 3.0 Hz, 2H), 7.60 (d, J = 7.6 Hz, 2H), 7.44 – 7.30 (m, 16H),
6.61 (d, J = 0.9 Hz, 1H), 6.48 (d, J = 1.0 Hz, 1H), 5.25 (s, 2H), 5.13 (s, 2H), 5.11 (s, 2H), 4.94 (s, 2H);
13C{1H} NMR (125 MHz, CDCl3) δ 173.4, 169.0, 163.0, 159.8, 158.7, 152.8, 139.8, 136.3, 135.6, 135.4,
130.6, 130.4, 128.8, 128.8, 128.7, 128.7, 128.6, 128.6, 128.5, 128.5, 128.4, 128.3, 128.3, 128.3, 127.7,
127.6, 126.6, 109.9, 98.2, 93.9, 70.8, 70.5, 68.3, 66.5; HRMS (MALDI-TOF/CCA) calcd.
[C38H30O7+Na]+: 621.1884, Found: 621.1907.
benzyl 2-((5,7-bis(benzyloxy)-2-(4-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetate (10e)
To a solution of methoxyl-aglycon 11e (17.7 mg, 0.037 mmol) in 0.4 mL of DMF at 0 °C added K2CO3
(6.6 mg, 0.048 mmol) portion-wise and benzyl bromoacetate (6.4 µL, 0.041 mmol) dropwise. The
resulting solution was stirred at rt for 6 h. The reaction solution was washed with water (3 x 4 mL) and
extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. Crude was purified by
flash silica gel chromatography with CH2Cl2 and hexanes (CH2Cl2 : Hexanes = 5 : 1) to give yellow solid,
benzyl ester 10e (20 mg, 80%), mp 120 – 122 °C. Rf = 0.20 (CH2Cl2); IR (thin film, cm-1) 1757, 1604,
1509, 1487, 1453, 1440, 1351, 1298, 1258, 1178, 1123, 1106, 1062, 1029, 836, 737, 697; 1H NMR (500
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MHz, CDCl3) δ 8.15 (d, J = 8.9 Hz, 2H), 7.60 (d, J = 7.5 Hz, 2H), 7.44 – 7.30 (m, 13H), 6.94 (d, J = 8.9
Hz, 2H), 6.59 (d, J = 1.8 Hz, 1H), 6.47 (d, J = 1.7 Hz, 1H), 5.24 (s, 2H), 5.15 (s, 2H), 5.10 (s, 2H), 4.93
(s, 2H), 3.85 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.3, 169.0, 162.8, 161.2, 159.7, 158.6, 152.8,
139.1, 136.3, 135.7, 135.5, 130.3, 128.7, 128.7, 128.7, 128., 128.5, 128.4, 128.3, 128.3, 128.3, 127.7,
127.6, 126.6, 123.0, 113.8, 109.9, 98.1, 93.9, 70.8, 70.5, 68.3, 66.5, 55.3; HRMS (MALDI-TOF/CCA)
calcd. [C39H32O8+Na]+: 651.1989, Found: 651.1969.
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2-((5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetic acid (4a)
To a solution of alkylated aglycon 10f (12.4 mg, 0.018 mmol) in 0.2 mL of a mixture of CH2Cl2 and
MeOH (1 : 1) was added Pd/C (1.9 mg, 10 mol%) under H2 atmosphere and resulting solution was stirred
for 12 h. The resulting suspension solution was filtered by flashing through a celite column and then
concentrated in vacuo to give a yellow solid, acid 4a (4.5 mg, 70%), mp > 200 °C; IR (thin film, cm-1)
3316 – 3188(br), 2928, 1732, 1651, 1604, 1566, 1497, 1438, 1360, 1284, 1261, 1203, 1175, 1090, 1038,
1
1015, 999, 966, 844, 840, 732, 709, 691, 636, 581, 569, 517; H NMR (500 MHz, DMSO-d6) δ 8.16 (d,
J = 8.2 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 6.41 (d, J = 0.7 Hz, 1H), 6.15 (s, 1H), 4.36 (s, 2H); 13C{1H}
NMR (100 MHz, CD3OD) δ 178.0, 171.3, 164.5, 161.5, 160.3, 156.9, 156.4, 136.2, 130.3, 121.0, 115.1,
104.3, 98.5, 93.4, 68.3; HRMS (MALDI-TOF/CCA) calcd. [C17H12O8+Na]+: 367.0424, Found: 367.0413.
2-((2-(4-chlorophenyl)-5,7-dihydroxy-4-oxo-4H-chromen-3-yl)oxy)acetic acid (4b)
To a solution of alkylated aglycon 10b (13.2 mg, 0.021 mmol) in a mixture of CH2Cl2 and THF (1 : 1)
was added Pd/C (1.1 mg, 5 mol%) under H2 atmosphere and resulting solution was stirred for 12 h. The
resulting suspension solution was filtered through a celite column and then concentrated in vacuo to give
a yellow solid, acid 4b (4 mg, 54%), mp > 200 °C; IR (thin film, cm-1) 3421 – 3157(br), 2953, 2854,
1652, 1609, 1557, 1488, 1419, 1364, 1307, 1256, 1205, 1180, 1090, 1052, 1026, 1011, 837, 822, 807; 1H
NMR (500 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.16 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 6.47 (d,
13
J = 1.5 Hz, 1H), 6.21 (d, J = 1.6 Hz, 1H), 4.74 (s, 2H); C{1H} NMR (100 MHz, DMSO-d6) δ 178.1,
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170.3, 165.0, 161.6, 156.8, 153.6, 137.7, 136.1, 130.8, 129.0, 112.5, 104.7, 99.3, 94.3, 68.4; HRMS
(MALDI-TOF/CCA) calcd. [C17H11ClO7+Na]+:385.0086, found: 385.0102.
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2-((2-(4-fluorophenyl)-5,7-dihydroxy-4-oxo-4H-chromen-3-yl) oxy) acetic acid (4c)
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To a solution of alkylated aglycon 10c (7.4 mg, 0.012 mmol) in a mixture of CH2Cl2 and MeOH (1 : 1)
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was added Pd/C (1.3 mg, 10 mol%) under H2 atmosphere and resulting solution was stirred for 12 h. The
resulting suspension solution was filtered through a celite column and then concentrated in vacuo to give
a yellow solid, acid 4c (2.2 mg, 57%), mp 188 – 190 °C; IR (thin film, cm-1) 3212 – 3084 (br), 2923,
2366, 2342, 1741, 1698, 1653, 1559, 1506, 1473, 1416, 1397, 1364, 1340, 1310, 1238, 1167, 1090, 1073,
1050, 1040, 1024, 843, 776; 1H NMR (500 MHz, CD3OD) δ 8.31 – 8.16 (m, 2H), 7.25 (dd, J = 8.4, 8.4
Hz, 2H), 6.41 (s, 1H), 6.20 (s, 1H), 4.62 (s, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 178.4, 170.8,
164.9, 163.8 (d, J = 274.8 Hz, 1C), 161.6, 156.8, 153.5, 137.7, 131.7, 131.6, 127.3, 127.3, 115.9 (d, J =
21.6 Hz, 2C), 104.6, 99.3, 94.2, 69.4; HRMS (MALDI-TOF/CCA) calcd. [C17H11FO7+Na]+: 369.0381,
found: 369.0386.
2-((5,7-dihydroxy-4-oxo-2-phenyl-4H-chromen-3-yl) oxy) acetic acid (4d)
To a solution of alkylated aglycon 10d (16.4 mg, 0.027 mmol) in 0.3 mL mixture of CH2Cl2 and THF (1
: 1) added Pd/C (3 mg, 10 mol%) under H2 atmosphere and resulting solution was stirred for 12 h.
Suspension solution was filtered through a celite column and then concentrated in vacuo. The product
was crystallized from acetone to give yellow solid, acid 4d (6 mg, 68%), mp 160 – 162 °C; IR (thin film,
cm-1) 3308 – 3099 (br), 1732, 1651, 1606, 1567, 1491, 1447, 1363, 1306, 1256, 1203, 1175, 1092, 1075,
1039, 1000, 961, 881, 774, 690; 1H NMR (500 MHz, Methanol-d4) δ 8.12 (dd, J = 6.6, 2.8 Hz, 2H), 7.53
13
(m, 3H), 6.43 (d, J = 1.6 Hz, 1H), 6.22 (d, J = 1.7 Hz, 1H), 4.69 (s, 2H); C{1H} NMR (100 MHz,
Methanol-d4) δ 178.22, 170.99, 164.77, 161.67, 157.13, 155.74, 137.27, 130.77, 130.15, 128.32, 104.56,
98.62, 93.48, 68.11; HRMS (MALDI-TOF/CCA) calcd. [C17H12O7+Na]+: 351.0475, Found: 351.0452.
2-((5,7-dihydroxy-2-(4-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetic acid (4e)
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To a solution of alkylated aglycon 10e (14.2 mg, 0.023 mmol) in 0.3 mL of a mixture of CH2Cl2 and THF
(1 : 1) was added Pd/C (2.4 mg, 10 mol%) under H2 atmosphere and resulting solution was stirred for 12
h. The resulting suspension solution was filtered by flashing through celite column and concentrated in
vacuo. The product was crystallized from acetone to give a yellow solid, acid 4e (5.6 mg, 70%), mp 192
– 194 °C; IR (thin film, cm-1) 2357, 2149, 1603, 1541, 1520, 1507, 1435, 1361, 1339, 1303, 1261, 1202,
1179, 1125, 1074, 1026, 996; 1H NMR (500 MHz, DMSO-d6) δ 8.27 (d, J = 7.4 Hz, 2H), 7.03 (d, J = 8.5
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Hz, 2H), 6.43 (s, 1H), 6.16 (s, 1H), 4.35 (s, 2H), 3.81 (s, 3H); C{1H} NMR (100 MHz, DMSO-d6) δ
178.5, 171.1, 165.3, 161.6, 161.5, 156.7, 154.3, 137.5, 130.8, 123.2, 114.3, 104.3, 99.1, 94.1, 70.9, 55.8;
HRMS (MALDI-TOF/CCA) calcd. [C18H14O8+Na]+: 381.0581, Found: 381.0554.
Author Information
deborah.lannigan@vumc.org
G.ODoherty@neu.edu
Author contributions
§ Co-first authors, the order is alphabetical
ACKNOWLEDGMENTS
The authors gratefully acknowledge the National Science Foundation (CHE-1565788 (G.A.O.)), and the
National Institutes of Health (AI146485 (G.A.O.), AI144196 (G.A.O.), AI142040 (G.A.O.) and
CA213201 (D.A.L.)) for their support of this work.
Supporting Information
This material is available free of charge via the internet at http://pubs.acs.org
1H and 13C NMR spectra (PDF)
REFERENCES
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