Regiospecific and enantioselective synthesis of methylated metabolites of tea catechins

Article abstract of DOI:10.1016/j.tet.2006.04.010

The regiospecific and enantioselective syntheses of various methylated regioisomers of epicatechin gallate (EGC) and epigallocatechin gallate (EGCG) have been achieved.

Full text of DOI:10.1016/j.tet.2006.04.010

Tetrahedron 62 (2006) 5897–5904
Regiospecific and enantioselective synthesis of methylated
metabolites of tea catechins
Sheng Biao Wan,a Q. Ping Doub and Tak Hang Chana,
*
aDepartment of Applied Biology and Chemical Technology and the State Key Laboratory of Chinese Medicine
and Molecular Pharmacology, The Institute of Molecular Technology for Drug Discovery and Synthesis,
The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China
bThe Prevention Program, Barbara Ann Karmanos Cancer Institute and Department of Pathology, School of Medicine,
Wayne State University, Detroit, MI, USA
Received 13 February 2006; revised 4 April 2006; accepted 6 April 2006
Available online 3 May 2006
Abstract—The regiospecific and enantioselective syntheses of various methylated regioisomers of epicatechin gallate (EGC) and epigallo-
catechin gallate (EGCG) have been achieved.
Ó 2006 Elsevier Ltd. All rights reserved.
R1
1. Introduction
OH
R2
R3
OH
R
Tea, produced from the plant Camellia sinensis, has been
consumed by humans for thousands of years. It is one of
the most popular beverages worldwide, second to water.
Tea catechins, which are polyphenols, constitute about
30–40% of the water-soluble compounds in brewed
green tea. The major tea catechins are: (ꢀ)-epicatechin
(1, EC), (ꢀ)-epigallocatechin (2, EGC), (ꢀ)-epicatechin
gallate (3, ECG), and (ꢀ)-epigallocatechin gallate (4,
EGCG).1 Of these, EGCG is by far the most abundant and
has been reported to have various biological activities, which
may account for the beneficial effects attributed to green
tea.2,3
O
HO
O
HO
O
OH
OH
R4
R5
OH
1: R=H, EC
O
2: R=OH, EGC
R6
3: R1=H, R2=R3=R4=R5=R6=OH; ECG
4: R1=R2=R3=R4=R5=R6=OH; EGCG
5: R3=H, R1=R2=R4=R5=OH, R6=OMe
6: R3=H, R1=R2=R4=R6=OH, R5=OMe
7: R3=H, R1=R2=R4=OH, R5=R6=OMe
8: R1=R2=R3=R4=R5=OH, R6=OMe
9: R1=R2=R3=R4=R6=OH, R5=OMe
10:R1=R2=R3=R4=OH, R5=R6=OMe
11:R1=R3=R4=R5=R6=OH, R2=OMe
12:R1=R3=R4=R6=OH, R2=R5=OMe
13:R1=R3=R4=OH, R2=R5=R6=OMe
Recently, the metabolic transformations of tea catechins
have been investigated. Catechins were found to be sub-
strates of human catechol-O-methyltransferase (COMT).
In humans, 40-O-methyl-EGC4 and 40,400-di-O-methyl-
EGCG (12)5 were detected after green tea and catechin
consumption. In rats, 40-O-methyl-EGCG (11), 400-O-methyl-
EGCG (9), 30-O-methyl-EGCG, 300-O-methyl-EGCG (8),
and 40,400-dimethyl-EGCG (12) were found to be the biliary
metabolites of EGCG.6 Indeed, some of these methylated
catechins have been found as minor components in tea infu-
sions.7 Methylated EGCG has been shown to inhibit type I
allergic reactions in mice.7a,8
Biomethylation of catechins may play a significant role in
affecting the biological effects of tea. Recently, it has been
reported that among women who carried at least one low
activity COMT allele, tea drinkers showed a significantly
reduced risk of breast cancer compared with nontea drinkers.
In contrast, risk of breast cancer did not differ between tea
drinkers and nontea drinkers among those who were homo-
zygous for the high activity COMT allele.9 These data sug-
gest that methylation of catechins may reduce the cancer
protecting activities of tea polyphenols. EGCG is known to
inhibit COMT10 as well as DNA methyltransferase.11
* Corresponding author. Tel.: +852 2766 5605; fax: +852 2364 9932;
e-mail: bcchanth@polyu.edu.hk
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.010

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S. B. Wan et al. / Tetrahedron 62 (2006) 5897–5904
Because of our interest in the synthesis of EGCG12 and its
role as proteasome inhibitors in cancer protection,13 we
became interested in the synthesis of various methylated
metabolites of catechins. Previously, (ꢀ)-EGCG had been
methylated in a nonregiospecific manner to give a mixture
of 400-methyl-EGCG (9), 40,400-dimethyl-EGCG (12), and
40,300,400-trimethyl-EGCG (13).5 Herein, we report a regio-
specific and enantioselective synthesis of the various
methylated ECG and EGCG (5–13).
but only characterized by its 1H NMR spectrum.5 With
both compounds 8 and 9 at hand, we have assigned their
regiochemistry unambiguously by the synthesis.
2.3. Syntheses of compounds 11–13
In order to obtain the methylated compounds 11–13, a total
synthesis starting from a properly protected B-ring precursor
is used (Scheme 3). 3,5-Bis(benzyloxy)-4-methoxybenzal-
dehyde (22) was converted to the cinnamyl alcohol 24 via
a Wittig–Horner reaction followed by DIBAL reduction.
Friedel–Craft alkylation of 3,5-dibenzyloxyphenol (25)
with 24 gave the alkylation product 26. Compound 26 was
first protected as the tert-butyldimethylsilyl ether and then
dihydroxylated with the Sharpless asymmetric dihydroxyla-
tion protocol followed by desilylation to give the optically
active diol 27. The (+)-(1S,2S)-diol 27 was obtained from
AD-mix a in agreement with our previous observation that
similar enantioselectivity was obtained in EGCG synthe-
sis.12a Cyclization of 27 under the orthoformate/acidic con-
ditions followed by base hydrolysis gave the protected
flavan-3-ol 28. The trans stereochemistry of 28 was evident
2. Results and discussion
2.1. Syntheses of compounds 5–7
Previously, we had reported on the enantioselective
synthesis of the benzylated epicatechin 14 [(ꢀ)-(2R,3R)-
5,7-Bis(benzyloxy)-2-[3,4-bis(benzyloxy)phenyl]-chroman-
3-ol].12b The same compound 14 can be obtained by the direct
benzylation of (ꢀ)-epicatechin isolated from nature.14 Acyl-
ation of 14 with 3,4-bis(benzyloxy)-5-methoxybenzoyl
chloride, 3,5-bis(benzyloxy)-4-methoxybenzoyl chloride or
3-benzyloxy-4,5-dimethoxybenzoyl chloride gave the pro-
tected esters 15–17, respectively. Hydrogenolysis of 15–17
afforded compounds 5–7 in good yields (Scheme 1). The syn-
thetic compounds 5 and 6 have optical rotations and spectro-
scopic data similar to those reported for the natural products.7
1
from its H NMR spectrum. Compound 28 was then oxi-
dized by Dess–Martin periodinane to the corresponding
ketone 29. Reduction of the carbonyl function in 29 with
L-Selectride at ꢀ78 ꢁC gave exclusively the cis-substituted
compound 30. The stereochemistry of 30 was also evident
from its 1H NMR where the coupling of H-2 and H-3 hydro-
gens is distinctly different from that of compound 28. Ester-
ification of 30 with 3,4-bis(benzyloxy)-5-methoxybenzoyl
chloride, 3,5-bis(benzyloxy)-4-methoxybenzoyl chloride or
3-benzyloxy-4,5-dimethoxybenzoyl chloride gave the pro-
tected esters 31–33, respectively. Hydrogenolysis of 31–33
afforded the methylated compounds 11–13. The spectro-
scopic data of compounds 11–13 are in agreement with those
reported previously for the metabolites.5,6
OBn
OBn
OBn
OBn
O
BnO
O
BnO
b
a
5 - 7
O
OH
OBn
R2
OBn
OBn
O
R1
14
15: R1=OMe, R2=OBn
16: R1=OBn, R2=OMe
17: R1=R2=OMe
The structure–activity relationships (SARs) of these methyl-
ated metabolites of tea catechins were also examined as
a function of inhibition of a purified 20S proteasome. We
found that addition of a methyl group to the B- and/or
D-ring led to diminished proteasome-inhibitory activity in
vitro and that as the number of methyl groups increased on
these catechin molecules, their effectiveness as proteasome
inhibitors decreased.15
Scheme 1. (a) Acid chloride/DMAP in CH2Cl2, rt; (b) H2/Pd(OH)2/MeOH/
THF.
2.2. Syntheses of compounds 8–10
Compounds 8–10 were prepared from the perbenzylated epi-
gallocatechin 1812a according to the same acylation and
hydrogenolysis sequence (Scheme 2). Compound 8 showed
the same optical rotation and spectroscopic data as the natural
compound.6 Compound 9 had been previously synthesized,
3. Conclusion
We have synthesized nine different methylated catechins,
which are metabolites or potential metabolites of tea cate-
chins in biomethylation. The synthesis is regiospecific and
enantioselective. These compounds will allow us to evaluate
the role of biomethylation in affecting the biological effects
of tea consumption.
OBn
OBn
OBn
OBn
OBn
OBn
O
BnO
O
BnO
b
8 - 10
a
O
OH
OBn
R2
OBn
OBn
O
4. Experimental
4.1. General
R1
18
19: R1=OMe, R2=OBn
20: R1=OBn, R2=OMe
21: R1=R2=OMe
The starting materials and reagents, purchased commer-
cially, were used without further purification. Literature
Scheme 2. (a) Acid chloride/DMAP in CH2Cl2, rt; (b) H2/Pd(OH)2/MeOH/
THF.

S. B. Wan et al. / Tetrahedron 62 (2006) 5897–5904
5899
OH
25
BnO
CH2OH
CO2Et
CHO
BnO
MeO
BnO
MeO
BnO
MeO
a
b
OBn
c
OBn
OBn
OBn
O
24
23
22
OBn
OBn
OBn
OMe
OMe
OBn
OMe
OBn
BnO
OH
BnO
OH
OBn
BnO
e
d
OH
OH
OH
28
OBn
OBn
OBn
OBn
OBn
26
27
f
OBn
OMe
OBn
OMe
OBn
OMe
OBn
O
BnO
O
O
BnO
g
BnO
i
h
11 - 13
O
OH
O
OBn
R1
R2
OBn
OBn
O
29
30
31: R1=OBn, R2=OBn
32: R1=OBn, R2=OMe
33: R1=OMe, R2=OMe
OBn
Scheme 3. (a) Triethyl phosphonoacetate/NaH/THF, 0 ꢁC–rt; (b) DIBAL/THF, ꢀ78 ꢁC–rt; (c) H2SO4/SiO2/CH2Cl2, rt; (d) (i) TBSCl/imidazole/DMF, rt; (ii)
AD-mix a/CH3SO2NH2/H2O/t-BuOH/CH2Cl2, 0 ꢁC; (iii) TBAF/THF, rt; (e) (i) CH(OEt)3/PPTS/CH2Cl2, 60 ꢁC; (ii) K2CO3/MeOH/DME, rt; (f) Dess–Martin
periodinane/CH2Cl2, rt; (g) L-Selectride/THF, ꢀ78 ꢁC; (h) acid chloride/DMAP/CH2Cl2, rt; (i) H2/Pd(OH)2/MeOH/THF.
procedures were used for the preparation of 3,5-bis(benzyl-
oxy)phenol,16 3,4,5-tris(benzyloxy)benzoic acid,9 silica gel
supported H2SO4,12a and 3,5-bis(benzyloxy)-4-methoxy-
benzaldehyde.17
6.26 (B of AB, J¼15.9 Hz, 1H), 5.07 (s, 4H), 4.21 (q,
J¼7.1 Hz, 2H), 3.89 (s, 3H), 1.29 (t, J¼7.l Hz, 3H); 13C
NMR (CDCl3, 400 MHz): d 166.6, 152.4, 144.2, 141.2,
136.5, 129.5, 128.3, 127.7, 127.0, 117.2, 107.5, 70.8, 60.7,
60.2, 14.1; HRMS (ESI): calcd for C26H26O5Na (M+Na)
441.1678, found 441.1697.
Anhydrous THF was distilled under nitrogen from sodium
benzophenone ketyl. Anhydrous methylene chloride was
distilled under nitrogen from CaH2. Anhydrous DMF was
distilled under vacuum from CaH2. Reaction flasks were
flame-dried under a stream of N2. All moisture-sensitive re-
actions were conducted under a nitrogen atmosphere. Flash
chromatography was carried out using silica gel 60 (70–230
4.3. (E)-3,5-Bis(benzyloxy)-4-methoxycinnamyl alcohol
(24)
To a solution of ethyl-(E)-3,5-bis(benzyloxy)-4-methoxy-
cinnamate (23, 5.0 g, 11.9 mmol) in dry THF (100 mL) at
ꢀ78 ꢁC under a nitrogen atmosphere, DIBAL (18 mL, 1 M
solution in hexane, 18.0 mmol) was added dropwise. The
mixture was stirred at ꢀ78 ꢁC for 1 h and then at rt for
another 1 h. The mixture was cooled to 0 ꢁC and poured
into a stirred mixture of hexane (150 mL) and saturated
aqueous Na2SO4 solution (5 mL). The resulting mixture
was stirred until a large quantity of solid was formed. The
mixture was filtered, and the solid was thoroughly washed
with EtOAc. The organic solutions were combined and dried
(MgSO4). The residue after evaporation of the solvent was
washed again with hexane, and the solid was collected and
recrystallized in EtOAc and hexane to afford (E)-3,5-bis-
(benzyloxy)-4-methoxycinnamyl alcohol (4.1 g, 91% yield):
1
mesh). The melting points were uncorrected. H and 13C
NMR (400 MHz) spectra were measured with TMS as inter-
nal standard when CDCl3 and acetone-d6 were used as
solvent. High-resolution electrospray ionization (ESI)
mass spectra were recorded using a QTOF-2 Micromass
spectrometer.
4.2. Ethyl-(E)-3,5-bis(benzyloxy)-4-methoxycinnamate
(23)
3,5-Bis(benzyloxy)-4-methoxybenzaldehyde (22, 3.48 g,
10.0 mmol) was dissolved in dry THF (100 mL) under a
nitrogen atmosphere and cooled in an ice bath. To this solu-
tion triethyl phosphonoacetate (3.3 g, 15.0 mmol) was
added. Sodium hydride (0.48 g, 60% dispersion in mineral
oil, 12.0 mmol) was then added in five batches. The mixture
was allowed to be stirred at rt for 2 h. Saturated aqueous
NaHCO3 solution was added. The organic phase was sepa-
rated, and the aqueous layer was extracted with EtOAc.
The organic phases were combined, dried (MgSO4), and
evaporated to afford a solid. The solid was washed with
hexane to remove the mineral oil to yield ethyl-(E)-3,5-
bis(benzyloxy)-4-methoxycinnamate (3.76 g, 90.0% yield):
1
mp 99–101 ꢁC; H NMR (CDCl3, 400 MHz): d 7.43–7.27
(m, 10H), 6.62 (s, 2H), 6.39 (A of AB, J¼15.8 Hz, 1H),
6.13 (B of ABt, J¼15.8, 5.6 Hz, 1H), 5.08 (s, 4H), 4.21 (d,
J¼5.6 Hz, 2H), 3.87 (s, 3H); 13C NMR (CDCl3,
400 MHz): d 152.4, 139.1, 136.9, 132.2, 130.5, 128.4,
128.0, 127.7, 127.1, 106.1, 71.0, 63.3, 60.9; HRMS (ESI):
calcd for C24H24O4Na (M+Na) 399.1572, found 399.1554.
4.4. (E)-3-[2,4-Bis(benzyloxy)-6-hydroxyphenyl]-1-[3,5-
bis(benzyloxy)-4-methoxyphenyl]propene (26)
1
mp 80–82 ꢁC; H NMR (CDCl3, 400 MHz): d 7.52 (A of
At rt under a N2 atmosphere, 25% H2SO4/SiO2 (1.6 g,
4 mmol) was added in one batch to a stirred mixture of
AB, J¼15.9 Hz, 1H), 7.42–7.25 (m, 10H), 6.77 (s, 2H),

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S. B. Wan et al. / Tetrahedron 62 (2006) 5897–5904
3,5-bis(benzyloxy)phenol (3.06 g, 10 mmol) and (E)-3,4-
bis(benzyloxy)cinnamyl alcohol (3.76 g, 10 mmol) in dry
CH2Cl2 (100 mL). The resulting mixture was stirred at rt
overnight. After filtration and evaporation, the residue was
purified by column chromatography on silica gel (benzene)
to afford the desired compound as white solid (3.0 g, 45.1%
yield): mp 96–98 ꢁC; 1H NMR (CDCl3, 400 MHz): d 7.43–
7.27 (m, 20H), 6.59 (s, 2H), 6.32 (A of AB, J¼15.8 Hz, 1H),
6.26 (d, J¼2.0 Hz, 1H), 6.16 (d, J¼2.0, 1H), 6.16–6.12 (B of
ABt, m, 1H), 5.29 (br s, 1H), 5.07 (s, 4H), 5.01 (s, 2H), 4.96
(s, 2H), 3.85 (s, 3H), 3.54 (d, J¼6.2 Hz, 2H); 13C NMR
(CDCl3, 400 MHz): d 158.6, 157.9, 155.5, 152.5, 138.6,
137.1, 137.0, 136.8, 133.1, 129.9, 128.5, 128.4, 128.3,
128.0, 127.9, 127.7, 127.5, 127.4, 127.2, 127.1, 106.9,
105.8, 95.0, 93.4, 71.0, 70.2, 70.0, 60.9, 26.2; HRMS
(ESI): calcd for C44H40O6Na (M+Na) 687.2723, found
687.2697.
1H), 3.90–3.85 (m, 1H), 3.81 (s, 3H), 2.89 (A of AB,
J¼14.6, 3.6 Hz, 1H), 2.73 (B of AB, J¼14.6, 8.5 Hz,
1H); 13C NMR (CDCl3, 400 MHz): d 158.9, 157.7, 157.1,
152.2, 138.6, 136.8, 136.7, 136.1, 128.5, 128.4, 128.3,
127.8, 127.7, 127.6, 127.5, 127.2, 127.0, 126.9, 126.4,
105.1, 95.7, 93.3, 76.4, 70.8, 69.9, 60.7, 26.6; HRMS
(ESI): calcd for C44H42O8Na (M+Na) 721.2777, found
721.2759.
4.6. (+)-(2R,3S)-5,7-Bis(benzyloxy)-2-[30,50-bis(benzyl-
oxy)-40-methoxyphenyl]chroman-3-ol ((+)-28)
To a suspension of compound (+)-27 (3.0 g, 4.3 mmol) in
1,2-dichloroethane (50 mL) was added triethyl ortho-
formate (2 mL), followed by PPTS (500 mg, 2.0 mmol).
The mixture was stirred at rt for 20 min and the solid
was dissolved. The mixture was heated to 50 ꢁC for 5 h
until TLC showed the reaction had been completed. After
evaporation of the solvent, the residue was redissolved in
DME (30 mL) and MeOH (30 mL), K2CO3 (600 mg) was
added, and the mixture was stirred at rt overnight. The sol-
vent was evaporated, and the residue was purified by flash
chromatography on silica gel (EtOAc/hexane, 1/3 v/v) to
afford the desired product as white solid (2.1 g, 71.8%
yield): mp 123–125 ꢁC; [a]D +5.5 (c 7.0, CH2Cl2); 1H
NMR (CDCl3, 400 MHz): d 7.41–7.23 (m, 20H), 6.67 (s,
2H), 6.26 (s, 1H), 6.20 (s, 1H), 5.05 (s, 2H), 5.04 (s,
2H), 4.97 (s, 2H), 4.95 (s, 2H), 4.54 (d, J¼8.1 Hz, 1H),
3.90–3.86 (m, 1H), 3.85 (s, 3H), 3.05 (A of ABq,
J¼16.4, 5.4 Hz, 1H), 2.61 (B of ABq, J¼16.4, 8.9 Hz,
1H); 13C NMR (CDCl3, 400 MHz): d 158.6, 157.6,
155.0, 152.4, 139.2, 136.7, 133.2, 128.3, 128.2, 128.1,
127.9, 127.8, 127.7, 127.4, 127.3, 127.2, 127.0, 126.9,
106.5, 102.1, 94.2, 93.7, 81.6, 70.8, 69.9, 69.7, 67.8,
60.7, 27.4; HRMS (ESI): calcd for C44H40O7Na (M+Na)
703.2672, found 703.2684.
4.5. (+)-(1S,2S)-3-[2,4-Bis(benzyloxy)-6-hydroxy-
phenyl]-1-[30,40-bis(benzyloxy)-40-methoxyphenyl]-
propane-1,2-diol ((+)-27)
The propene 26 (3.0 g, 4.5 mmol) was dissolved in dry DMF
(30 mL), and to this solution imidazole (1.0 g, 14.7 mmol)
and TBSCl (1.1 g, 7.2 mmol) were added successively.
The resulting mixture was stirred at rt overnight, and
then saturated Na2CO3 solution was added to quench the re-
action. The mixture was extracted with EtOAc. The organic
layers were combined, dried (MgSO4), and evaporated. The
residue was purified by flash chromatography on silica gel
(n-hexane/EtOAc, 6/1 v/v) to afford [3,5-bis(benzyloxy)]-
2-[30-[300,500-bis(benzyloxy)-400-methoxyphenyl]allyl]phen-
oxy-tert-butyldimethylsilane (3.1 g). This material was used
in the next step without further purification.
AD-mix a (12.8 g) and methanesulfonamide (0.85 g) were
dissolved in a solvent mixture of t-BuOH (60 mL) and H2O
(60 mL). The resulting mixture was stirred at rt for 5 mm,
then the mixture was cooled to 0 ꢁC, and a solution of [3,5-
bis(benzyloxy)-2-[30-[300,500-bis(benzyloxy)-400-methoxy-
phenyl]allyl]phenoxy-tert-butyldimethylsilane (3.1 g) in
dichloromethane (60 mL) was added. After the mixture
had been stirred overnight, a total of four batches of AD-
mix a (6.4 g each) and methanesulfonamide (0.43 g each)
were added in 24 h intervals. After another 24 h of stirring
at 0 ꢁC, TLC showed that the reaction was completed. Then
a 10% aqueous Na2S2O3 solution was added to quench the
reaction. The mixture was extracted with EtOAc. The
organic phases were combined, dried (MgSO4), and evapo-
rated. The residue was purified by flash chromatography
on silica gel (n-hexane/EtOAc, 4/1 v/v). The product was
redissolved in THF (30 mL) and then TBAF (10 mL, 1 M
in THF) was added. The resulting mixture was stirred at
rt for 4 h, and saturated NaHCO3 solution was added. The
mixture was extracted with EtOAc and the organic layers
were combined, dried (MgSO4), and evaporated. The
residue was purified by flash chromatography on silica
gel (5% EtOAc/CH3Cl) and then recrystallized in EtOAc
to give a white solid (2.2 g, 69.7% yield): mp 125–
127 ꢁC; [a]D +7.0 (c 3, CH3Cl); 1H NMR (CDCl3,
400 MHz): d 7.38–7.14 (m, 20H), 6.57 (s, 2H), 6.26 (d,
J¼2.1 Hz, 1H), 6.21 (d, J¼2.1 Hz, 1H), 4.97 (s, 2H), 4.96
(s, 2H), 4.93 (s, 2H), 4.87 (s, 2H), 4.39 (d, J¼5.6 Hz,
4.7. (+)-(2R)-5,7-Bis(benzyloxy)-2-[30,50-bis(benzyloxy)-
40-methoxyphenyl]chroman-3-one ((+)-29)
Dess–Martin periodinane (19.7 mL, 15% g/mL in CH2Cl2,
4.6 mmol) was added in one batch to a stirred solution of
(+)-28 (2.1 g, 3.1 mmol) in CH2Cl2 (30 mL) under a N2
atmosphere. The mixture was stirred at rt for about 2 h till
TLC showed the absence of starting material. Subsequently,
saturated NaHCO3 solution (40 mL) and 10% aqueous
Na2S2O3 solution (40 mL) were added to quench the reac-
tion. The organic layer was separated, and the aqueous layer
was extracted with CH2Cl2. The combined organic phases
were dried (MgSO4) and evaporated. The residue was puri-
fied by flash chromatography on silica gel (benzene) and
then recrystallized in CHCl3 and ether to afford the desired
compound (1.8 g, 85.7%): mp 149–151 ꢁC; [a]D +20.2
1
(c 7, CHCl3); H NMR (CDCl3, 400 MHz): d 7.40–7.23
(m, 20H), 6.63 (s, 2H), 6.35 (d, J¼0.6 Hz, 1H), 6.33 (d,
J¼0.6 Hz, 1H), 5.18 (s, 1H), 5.03 (s, 2H), 5.02 (s, 2H),
4.98 (s, 2H), 4.97 (s, 2H), 3.84 (s, 3H), 3.58–3.35 (AB,
J¼21.5 Hz, 2H); 13C NMR (CDCl3, 400 MHz): d 204.4,
159.3, 156.9, 154.1, 152.5, 139.3, 136.7, 136.4, 136.2,
130.0, 128.5, 128.4, 128.3, 128.0, 127.9, 127.7, 127.3,
127.2, 127.0, 106.0, 101.6, 95.5, 94.8, 82.8, 70.8, 70.0,
69.9, 60.7, 33.3; HRMS (ESI): calcd for C44H39O7 (M+H)
679.2696, found 679.2700.

S. B. Wan et al. / Tetrahedron 62 (2006) 5897–5904
5901
4.8. (L)-(2R,3R)-5,7-Bis(benzyloxy)-2-[30,50-bis(benzyl-
4.10. (L)-(2R,3R)-cis-5,7-Bis(benzyloxy)-2-[30,40-bis-
oxy)-40-methoxyphenyl]chroman-3-ol ((L)-30)
(benzyloxy)phenyl]chroman-3-yl-300,500-bis(benzyloxy)-
400-methoxybenzoate (16)
Under a N2 atmosphere, the ketone (+)-29 (1.8 g,
2.6 mmol) was dissolved in dry THF (30 mL), and the
solution was cooled to ꢀ78 ꢁC. Then L-Selectride (4.0 mL,
1 M solution in THF, 4.0 mmol) was added dropwise. The
resulting solution was stirred at ꢀ78 ꢁC overnight. When
TLC showed the reaction was completed, saturated aque-
ous NaHCO3 solution (30 mL) was added to quench the
reaction. The organic layer was separated and the aqueous
layer was extracted with EtOAc. The combined organic
phases were dried (MgSO4) and evaporated. The residue
was purified by flash chromatography on silica gel
(EtOAc/hexane, 1/3 v/v) and then recrystallized with
EtOAc and n-hexane to afford the desired product (1.6 g,
88.8%) as a white solid: mp 107–109 ꢁC; [a]D ꢀ21.2
Following the procedure for the preparation of 15, the ester-
ification of (ꢀ)-14 with 3,5-dibenzyloxy-4-methoxybenzoic
acid gave the product 16 (86% yield): mp 126–128 ꢁC; [a]D
ꢀ76.5 (c 3.0, CHCl3); 1H NMR (CDCl3, 400 MHz): d 7.40–
7.21 (m, 31H), 7.00 (d, J¼1.8 Hz, 1H), 6.86 (A of ABq,
J¼8.3, 1.6 Hz, 1H), 6.81 (B of AB, J¼8.3 Hz, 1H), 6.37
(d, J¼2.0 Hz, 1H), 6.32 (d, J¼2.0 Hz, 1H), 5.60 (br s, 1H),
5.10–4.98 (m, 12H), 4.61 (AB, J¼11.6 Hz, 2H), 3.83
(s, 3H), 3.12 (A of ABq, J¼17.7, 4.4 Hz, 1H), 3.05 (B of
AB, J¼17.7 Hz, 1H); 13C NMR (CDCl3, 400 MHz):
d 164.8, 158.7, 157.9, 155.6, 151.9, 148.9, 148.8, 143.5,
137.1, 136.9, 136.7, 136.4, 130.9, 128.6, 128.5, 128.3,
128.2, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4,
127.3, 127.1, 124.6, 119.9, 114.6, 113.5, 109.1, 100.8,
94.5, 93.8, 77.6, 77.2, 71.1, 71.0, 70.9, 70.1, 69.9, 68.4,
60.8, 26.1; HRMS (ESI): calcd for C65H57O10 (M+H)
997.3952, found 997.3923.
1
(c 4, CHCl3); H NMR (CDCl3, 400 MHz): d 7.43–7.26
(m, 20H), 6.76 (s, 2H), 6.26 (s, 2H), 5.11 (s, 4H), 4.98
(s, 4H), 4.81 (s, 1H), 4.13 (br s, 1H), 3.88 (s, 3H), 2.96
(A of AB, J¼17.1 Hz, 1H), 2.87 (B of ABq, J¼17.1,
3.8 Hz, 1H); 13C NMR (CDCl3, 400 MHz): d 158.6,
158.1, 155.0, 152.5, 139.1, 136.9, 136.8, 136.7, 133.5,
128.4, 128.3, 128.2, 127.8, 127.7, 127.4, 127.3, 127.2,
127.0, 126.9, 106.0, 100.8, 94.5, 93.9, 78.3, 70.9, 69.9,
69.7, 66.1, 60.7, 27.9; HRMS (ESI): calcd for
C44H40O7Na (M+Na) 703.2672, found 703.2659.
4.11. (L)-(2R,3R)-cis-5,7-Bis(benzyloxy)-2-[30,40-bis-
(benzyloxy)phenyl]chroman3-yl-300-benzyloxy-400,
500-dimethoxybenzoate (17)
Following the procedure for the preparation of 15, the
esterification of (ꢀ)-14 with 3-benzyloxy-4,5-dimethoxy-
benzoic acid gave the product 17 (83% yield): mp 72–
74 ꢁC; [a]D ꢀ72.0 (c 2.5, CHCl3); 1H NMR (CDCl3,
400 MHz): d 7.40–7.25 (m, 25H), 7.16 (s, 1H), 7.06
(s, 1H), 6.88 (AB, J¼8.3 Hz, 2H), 6.36 (s, 1H), 6.31
(s, 1H), 5.61 (br s, 1H), 5.08–5.00 (m, 10H), 4.75 (AB,
J¼11.6 Hz, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.09 (br s,
2H); 13C NMR (CDCl3, 400 MHz): d 165.0, 158.8,
157.9, 155.6, 153.0, 151.6, 148.9, 148.8, 142.8, 137.1,
136.9, 136.8, 136.4, 131.0, 128.6, 128.5, 128.4, 128.3,
128.0, 127.9, 127.8, 127.7, 127.4, 127.3, 127.1, 124.8,
120.0, 114.6, 113.6, 108.8, 107.1, 100.8, 94.5, 93.8, 77.5,
71.2, 71.1, 70.8, 70.1, 69.9, 68.6, 60.8, 56.1, 26.0;
HRMS (ESI): calcd for C59H53O10 (M+H) 921.3639, found
921.3677.
4.9. (L)-(2R,3R)-5,7-Bis(benzyloxy)-2-[3,4-bis(benzyl-
oxy)-phenyl]chroman-3-yl-3,4-dibenzyloxy-5-methoxy-
benzoate ((L)-15)
Under a N2 atmosphere, a solution of 3,4-dibenzyloxy-5-
methoxybenzoic acid (246 mg, 0.67 mmol) was refluxed
with oxalyl (1 mL) in dry CH2Cl2 (10 mL) and one drop
of DMF for 3 h. The excess oxally chloride and solvent
were removed by distillation and the residue was dried
under vacuum for 3 h and dissolved in CH2Cl2 (2 mL).
This solution was added dropwise to a solution of (ꢀ)-14
(220 mg, 0.34 mmol)12b and DMAP (75 mg, 0.62 mmol)
in CH2Cl2 (15 mL) at 0 ꢁC. The mixture was stirred at
rt overnight, then saturated aqueous NaHCO3 solution
was added. The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2. The organic
phases were combined, dried (MgSO4), and evaporated.
The residue was purified by flash chromatography on silica
gel (n-hexane/EtOAc, 3/1 v/v) to afford the desired
compound (300 mg, 88.9% yield). Recrystallization in
CHCl3 and ether gave a white powder: mp 129–131 ꢁC;
[a]D ꢀ37.5 (c 2.5, CH2Cl2); 1H NMR (CDCl3,
400 MHz): d 7.39–7.26 (m, 30H), 7.22 (s, 1H), 7.16
(s, 1H), 6.88 (AB, J¼8.2 Hz, 2H), 6.34 (s, 1H), 6.30 (s,
1H), 5.60 (br s, 1H), 5.08 (s, 4H), 5.01 (s, 6H), 4.97
(s, 2H), 4.77 (AB, J¼11.7 Hz, 2H), 3.76 (s, 3H), 3.08
(br s, 2H); 13C NMR (CDCl3, 400 MHz): d 164.9, 158.6,
157.8, 155.5, 153.2, 151.9, 148.7, 141.7, 137.2, 136.9,
136.8, 136.7, 136.6, 136.3, 130.9, 128.4, 128.3, 128.2,
128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.3, 127.2,
127.0, 124.9, 119.8, 114.4, 113.5, 108.6, 107.1, 100.7,
94.4, 77.3, 74.8, 71.1, 70.9, 70.7, 69.9, 69.7, 56.0,
25.8; HRMS (ESI): calcd for C65H56O10Na (M+Na)
1019.3771, found 1019.3782.
4.12. (L)-(2R,3R)-cis-5,7-Bis(benzyloxy)-2-[30,40,50-tris-
(benzyloxy)phenyl]chroman-3-yl-300,400-bis(benzyloxy)-
500-methoxybenzoate (19)
Following the procedure for the preparation of 15, the ester-
ification of (ꢀ)-1812a with 3,4-dibenzyloxy-5-methoxy-
benzoic acid gave the product 19 (82% yield): mp 120–
1
121 ꢁC; [a]D ꢀ41.7 (c 2.3, CH2Cl2); H NMR (CDCl3,
400 MHz): d 7.40–7.25 (m, 35H), 7.20 (s, 2H), 6.75 (s,
2H), 6.37 (s, 1H), 6.32 (s, 1H), 5.65 (br s, 1H), 5.03–4.96
(m, 9H), 4.90 (s, 2H), 4.78 (AB, J¼11.5 Hz, 4H), 3.74 (s,
3H), 3.09 (br s, 2H); 13C NMR (CDCl3, 400 MHz):
d 164.8, 158.7, 157.8, 155.5, 153.3, 152.7, 152.0, 141.9,
138.3, 137.6, 137.3, 136.8, 136.7, 136.6, 136.2, 133.2,
128.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.7,
127.6, 127.3, 127.1, 124.9, 108.7, 107.3, 106.4, 100.8,
94.5, 93.8, 77.7, 75.0, 74.8, 71.1, 70.9, 70.0, 69.9, 68.3,
56.1, 26.0; HRMS (ESI): calcd for C72H62O11Na (M+Na)
1125.4190, found 1125.4204.

5902
S. B. Wan et al. / Tetrahedron 62 (2006) 5897–5904
4.13. (L)-(2R,3R)-cis-5,7-Bis(benzyloxy)-2-[30,40,50-tris-
(benzyloxy)phenyl]chroman-3-yl-300,500-bis(benzyloxy)-
400-methoxybenzoate (20)
acid gave the product 32 (85% yield): mp 65–67 ꢁC; [a]D
ꢀ49.8 (c 2.7, CHCl3); 1H NMR (CHCl3, 400 MHz):
d 7.38–7.21 (m, 32H), 6.68 (s, 2H), 6.38 (s, 1H), 6.34 (s,
1H), 5.63 (br s, 1H), 5.04–4.98 (m, 9H), 4.70 (AB,
J¼11.7 Hz, 4H), 3.79 (s, 3H), 3.77 (s, 3H), 3.08–3.05 (m,
2H); 13C NMR (CHCl3, 400 MHz): d 164.5, 158.7, 157.9,
155.5, 152.4, 151.8, 143.5, 139.3, 136.8, 136.6, 136.2,
132.8, 128.5, 128.4, 128.3, 128.2, 127.9, 127.8, 127.6,
127.3, 127.1, 127.0, 124.5, 109.0, 106.6, 100.8, 94.5, 93.8,
77.8, 70.9, 70.8, 70.0, 69.8, 68.0, 60.7, 26.1; HRMS (ESI):
calcd for C66H59O11 (M+H) 1027.4057, found 1027.4054.
Following the procedure for the preparation of 15, the esteri-
fication of (ꢀ)-18 with 3,5-dibenzyloxy-4-methoxybenzoic
acid gave the product 20 (87% yield): mp 49–51 ꢁC; [a]D
ꢀ54.7 (c 2.5, CHCl3); 1H NMR (CDCl3, 400 MHz): d 7.39–
7.20 (m, 37H), 6.70 (s, 2H), 6.40 (s, 1H), 6.34 (s, 1H), 5.65
(br s, 1H), 5.04–4.94 (m, 11H), 4.67 (AB, J¼11.5 Hz, 4H),
3.77 (s, 3H), 3.11 (A of ABq, J¼17.6, 4.2 Hz, 1H), 3.04 (B
of AB, J¼17.6 Hz, 1H); 13C NMR (CDCl3, 400 MHz):
d 164.6, 158.8, 158.0, 155.6, 152.8, 152.0, 151.9, 147.1,
143.6, 138.3, 137.7, 136.8, 136.7, 136.3, 133.1, 128.6,
128.5, 128.4, 128.3, 128.0, 127.9, 127.7, 127.6, 127.5,
127.4, 127.2, 124.6, 109.1, 106.6, 100.9, 77.9, 77.2, 75.0,
71.0, 70.9, 70.1, 69.9, 68.1, 60.8, 26.2; HRMS (ESI): calcd
for C72H63O11 (M+H) 1103.4370, found 1103.4425.
4.17. (L)-(2R,3R)-cis-5,7-Bis(benzyloxy)-2-[30,50-bis-
(benzyloxy)-40-methoxyphenyl]chroman-3-yl-
300-benzyloxy-400,500-dimethoxybenzoate (33)
Following the procedure for the preparation of 15, the ester-
ification of (ꢀ)-30 with 3-benzyloxy-4,5-dimethoxybenzoic
acid gave the product 33 (86% yield): mp 51–53 ꢁC; [a]D
ꢀ47.1 (c 3.5, CHCl3); 1H NMR (CHCl3, 400 MHz):
d 7.38–7.21 (m, 26H), 7.17 (s, 1H), 6.72 (s, 2H), 6.35 (s,
1H), 6.32 (s, 1H), 5.63 (br s, 1H), 5.05–5.01 (m, 7H), 4.79
(AB, J¼11.6 Hz, 4H), 3.81 (s, 3H), 3.77 (s, 3H), 3.76 (s,
3H), 3.08 (m, 2H); 13C NMR (CHCl3, 400 MHz): d 164.7,
158.7, 157.8, 155.4, 153.0, 152.4, 151.6, 142.9, 139.4,
136.8, 136.6, 136.2, 132.9, 128.5, 128.4, 128.3, 127.9,
127.8, 127.7, 127.6, 127.3, 127.1, 127.0, 124.7, 108.8,
107.1, 106.7, 100.7, 94.4, 93.8, 77.6, 71.0, 70.8, 70.0,
69.8, 68.2, 60.7, 60.6, 56.1, 26.0; HRMS (ESI): calcd for
C60H55O11 (M+H) 951.3744, found 951.3757.
4.14. (L)-(2R,3R)-cis-5,7-Bis(benzyloxy)-2-[30,40,50-tris-
(benzyloxy)phenyl]chroman-3-yl-300-benzyloxy-400,500-
dimethoxybenzoate (21)
Following the procedure for the preparation of 15, the esteri-
fication of (ꢀ)-18 with 3-benzyloxy-4,5-dimethoxybenzoic
acid gave the product 21 (82% yield): mp 57–59 ꢁC; [a]D
ꢀ52.5 (c 2.5, CHCl3); 1H NMR (CHCl3, 400 MHz):
d 7.41–7.21 (m, 32H), 6.74 (s, 2H), 6.38 (d, J¼2.0 Hz, 1H),
6.32 (d, J¼2.0 Hz, 1H), 5.65 (br s, 1H), 5.06–4.93 (m, 9H),
4.76 (AB, J¼11.5 Hz, 4H), 3.76 (s, 6H), 3.10–3.09 (m,
2H); 13C NMR (CHCl3, 400 MHz): d 164.8, 158.8, 158.0,
155.6, 153.1, 152.8, 151.7, 143.0, 138.4, 137.7, 136.8,
136.7, 136.3, 133.2, 128.6, 128.5, 128.4, 128.3, 128.0,
127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.2, 124.8,
108.9, 107.2, 106.7, 100.9, 94.6, 93.9, 77.8, 75.1, 71.3,
71.2, 70.9, 70.1, 69.9, 68.3, 60.8, 56.2, 26.1; HRMS (ESI):
calcd for C65H59O11 (M+H) 1027.4057, found 1027.4100.
4.18. (L)-(2R,3R)-5,7-Dihydroxy-2-(30,40-dihydroxy-
phenyl)-chroman-3-yl-300,400-dihydroxy-500-methoxy-
benzoate (5)
Under a H2 atmosphere, Pd(OH)2/C (20%, 200 mg) was
added to a solution of 15 (280 mg, 0.28 mmol) in a solvent
mixture of THF/MeOH (1/1 v/v, 25 mL). The resulting reac-
tion mixture was stirred at rt under H2 for 6 h, TLC showed
that the reaction was completed. The reaction mixture was
filtered to remove the catalyst. The filtrate was evaporated,
and the residue was rapidly purified by flash chromato-
graphy on silica gel (10% MeOH/CH2Cl2, then 20%
MeOH/CH2Cl2) to afford 5 (100 mg, 80% yield): mp 248–
250 ꢁC (decomposed); [a]D ꢀ167 (c 1, EtOH), lit. 168 (c
1, EtOH);18 1H NMR (acetone-d6/D2O, 3/1 v/v, 400 MHz):
d 7.22 (d, J¼1.7 Hz, 1H), 7.18 (d, J¼1.8 Hz, 1H), 7.11 (d,
J¼1.7 Hz, 1H), 7.02 (A of ABq, J¼8.2, 1.8 Hz, 1H), 6.90
(B of AB, J¼8.2 Hz, 1H), 6.14 (AB, J¼2.0 Hz, 2H), 5.54
(br s, 1H), 5.22 (br s, 1H), 3.90 (s, 3H), 3.16 (A of ABq,
J¼17.3, 4.1 Hz, 1H), 3.04 (B of AB, J¼17.3 Hz, 1H); 13C
NMR (acetone-d6/D2O, 3/1 v/v, 400 MHz): d 166.9, 157.3,
157.2, 156.7, 148.6, 145.5, 145.3, 145.2, 140.1, 131.0,
120.9, 118.9, 115.9, 114.8, 111.6, 105.9, 98.7, 96.4, 95.5,
77.8, 70.3, 56.6, 26.3; HRMS (ESI): calcd for
C23H20O10Na (M+Na) 479.0954, found 479.0960.
4.15. (L)-(2R,3R)-cis-5,7-Bis(benzyloxy)-2-[30,50-bis-
(benzyloxy)-40-methoxyphenyl]chroman-3-yl-300,400,500-
tris(benzyloxy)benzoate (31)
Following the procedure for the preparation of 15, the ester-
ification of (ꢀ)-30 with 3,4,5-tris(benzyloxy)benzoic acid
gave the product 31 (88% yield): mp 57–59 ꢁC; [a]D
ꢀ54.2 (c 5.0, CHCl3); 1H NMR (CHCl3, 400 MHz):
d 7.38–7.23 (m, 37H), 6.70 (s, 2H), 6.38 (d, J¼1.6 Hz,
1H), 6.33 (d, J¼1.6 Hz, 1H), 5.64 (br s, 1H), 5.02–4.99
(m, 9H), 4.91 (s, 2H), 4.74 (AB, J¼11.7 Hz, 4H), 3.80
(s, 3H), 3.08 (m, 2H); 13C NMR (CHCl3, 400 MHz):
d 164.7, 158.7, 157.9, 155.5, 152.5, 152.2, 142.6, 139.4,
137.3, 136.8, 136.6, 136.3, 132.9, 128.5, 128.4, 128.3,
128.1, 128.0, 127.9, 127.8, 127.7, 127.3, 127.2, 127.1,
124.8, 109.0, 106.7, 100.8, 94.5, 93.9, 77.8, 74.9, 71.0,
70.9, 70.0, 69.8, 60.7, 26.1; HRMS (ESI): calcd for
C72H62O11Na (M+Na) 1125.4190, found 1125.4181.
4.16. (L)-(2R,3R)-cis-5,7-Bis(benzyloxy)-2-[30,50-bis-
(benzyloxy)-40-methoxyphenyl]chroman-3-yl-300,500-bis-
(benzyloxy)-400-methoxybenzoate (32)
4.19. (L)-(2R,3R)-5,7-Dihydroxy-2-(30,40-dihydroxy-
phenyl)-chroman-3-yl-300,500-dihydroxy-400-methoxy-
benzoate (6)
Following the procedure for the preparation of 15, the ester-
ification of (ꢀ)-30 with 3,5-dibenzyloxy-4-methoxybenzoic
Following the preparation procedure for 5, the hydrogeno-
lysis of 16 afforded 6 (88% yield): mp 248–250 ꢁC

S. B. Wan et al. / Tetrahedron 62 (2006) 5897–5904
5903
(decomposed); [a]D ꢀ161.3 (c 4.0, Me2CO), lit. 160.1 (c
4.23. (L)-(2R,3R)-5,7-Dihydroxy-2-(30,40,50-trihydroxy-
1.1, Me2CO);18 1H NMR (acetone-d6, 400 MHz): d 7.25
(d, J¼1.8 Hz, 1H), 7.17 (s, 2H), 7.07 (A of ABq, J¼8.2,
1.8 Hz, 1H), 6.95 (B of AB, J¼8.2 Hz, 1H), 6.24 (d,
J¼2.2 Hz, 1H), 6.22 (d, J¼2.2 Hz, 1H), 5.73 (br s, 1H),
5.31 (br s, 1H), 3.98 (s, 3H), 3.23 (A of ABq, J¼17.4,
4.5 Hz, 1H), 3.11 (B of ABq, J¼17.4, 1.8 Hz, 1H); 13C
NMR (acetone-d6, 400 MHz): d 163.5, 155.4, 155.1,
154.7, 148.8, 143.2, 143.1, 138.1, 129.0, 124.1, 116.8,
113.4, 112.5, 107.6, 96.6, 94.2, 93.5, 75.6, 67.5, 58.3,
24.2; HRMS (ESI): calcd for C23H20O10Na (M+Na)
479.0954, found 479.0965.
phenyl)chroman-3-yl-300-hydroxy-400,500-dimethoxy-
benzoate (10)
Following the preparation procedure for 5, the hydrogeno-
lysis of 21 afforded 10 (83% yield): mp 229–231 ꢁC (decom-
posed); [a]D ꢀ128.3 (c 1.5, Me2CO); 1H NMR (acetone-d6,
400 MHz): d 7.24 (d, J¼1.9 Hz, 1H), 7.18 (d, J¼1.9 Hz,
1H), 6.81 (s, 2H), 6.20 (s, 1H), 6.19 (s, 1H), 5.69 (br s,
1H), 5.27 (br s, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 3.19 (A of
ABq, J¼17.4, 4.2 Hz, 1H), 3.12 (B of ABq, J¼17.4,
2.2 Hz, 1H); 13C NMR (acetone-d6, 400 MHz): d 163.5,
155.0, 154.9, 154.7, 154.0, 151.1, 148.3, 143.5, 138.8,
130.2, 127.9, 127.8, 123.6, 108.6, 103.6, 103.1, 95.7, 93.6,
92.7, 75.1, 67.8, 58.0, 53.6, 23.6; HRMS (ESI): calcd for
C24H22O11Na (M+Na) 509.1060, found 509.1069.
4.20. (L)-(2R,3R)-5,7-Dihydroxy-2-(30,40-dihydroxy-
phenyl)-chroman-3-yl-300-hydroxy-400,500-dimethoxy-
benzoate (7)
Following the preparation procedure for 5, the hydrogeno-
lysis of 17 afforded 7 (86% yield): mp 239–241 ꢁC (decom-
posed); [a]D ꢀ135.9 (c 4.0, Me2CO); 1H NMR (acetone-d6,
400 MHz): d 7.25 (AB, J¼1.9 Hz, 2H), 7.18 (d, J¼1.9 Hz,
1H), 7.07 (A of ABq, J¼8.2, 1.9 Hz, 1H), 6.94 (B of AB,
J¼8.2 Hz, 1H), 6.20 (AB, J¼2.2 Hz, 2H), 5.70–5.68 (m,
1H), 5.34 (br s, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.23 (A of
ABq, J¼17.5, 4.4 Hz, 1H), 3.15 (B of ABq, J¼17.5,
2.3 Hz, 1H); 13C NMR (acetone-d6, 400 MHz): d 164.6,
156.6, 156.2, 155.7, 152.5, 149.8, 144.4, 144.2, 140.2,
130.1, 125.1, 117.7, 114.4, 113.5, 110.0, 104.6, 97.5, 95.2,
94.4, 76.6, 68.9, 55.0, 25.1; HRMS (ESI): calcd for
C24H22O10Na (M+Na) 493.1111, found 493.1107.
4.24. (L)-(2R,3R)-5,7-Dihydroxy-2-(30,50-dihydroxy-40-
methoxyphenyl)chroman-3-yl-300,400,500-trihydroxy-
benzoate (11)
Following the preparation procedure for 5, the hydrogeno-
lysis of 31 afforded 11 (90% yield): mp 219–221 ꢁC (decom-
posed); [a]D ꢀ128.4 (c 2.0, Me2CO); 1H NMR (acetone-d6,
400 MHz): d 7.18 (s, 2H), 6.79 (s, 2H), 6.20 (AB, J¼2.2 Hz,
2H), 5.72 (br s, 1H), 5.24 (br s, 1H), 3.89 (s, 3H), 3.19 (A of
ABq, J¼17.4, 4.4 Hz, 1H), 3.07 (B of ABq, J¼17.4, 2.0 Hz,
1H); 13C NMR (acetone-d6, 400 MHz): d 164.5, 156.2,
155.9, 155.4, 149.4, 144.4, 137.3, 134.1, 133.8, 120.2,
108.4, 105.4, 97.5, 95.0, 94.3, 76.4, 67.6, 59.0, 25.1;
HRMS (ESI): calcd for C23H20O11Na (M+Na) 495.0903,
found 495.0924.
4.21. (L)-(2R,3R)-5,7-Dihydroxy-2-(30,40,50-trihydroxy-
phenyl)chroman-3-yl-300,400-dihydroxy-500-methoxy-
benzoate (8)
4.25. (L)-(2R,3R)-5,7-Dihydroxy-2-(30,50-dihydroxy-40-
methoxyphenyl)chroman-3-yl-300,500-dihydroxy-400-
methoxybenzoate (12)
Following the preparation procedure for 5, the hydrogeno-
lysis of 19 afforded 8 (83% yield): mp 221–223 ꢁC (decom-
posed); [a]D ꢀ160 (c 1, EtOH), lit. 162 (c 1, EtOH);18 1
H
Following the preparation procedure for 5, the hydrogeno-
lysis of 32 afforded 12 (90% yield): mp 228–230 ꢁC (decom-
posed); [a]D ꢀ131.1 (c 2.0, Me2CO); 1H NMR (acetone-d6,
400 MHz): d 7.15 (s, 2H), 6.80 (s, 2H), 6.21 (AB, J¼2.2 Hz,
2H), 5.75 (br s, 1H), 5.26 (br s, 1H), 3.96 (s, 3H), 3.89 (s,
3H), 3.19 (A of ABq, J¼17.4, 4.4 Hz, 1H), 3.11 (AB,
J¼17.4, 1.8 Hz, 1H); 13C NMR(acetone-d6, 400 MHz):
d 164.1, 156.1, 155.8, 155.2, 149.4, 149.3, 138.8, 134.0,
133.7, 124.7, 108.2, 105.1, 97.2, 94.9, 94.1, 76.1, 67.9,
58.9, 24.9; HRMS (ESI): calcd for C24H22O11Na (M+Na)
509.1060, found 509.1046.
NMR (acetone-d6/D2O, 3/1 v/v, 400 MHz): d 7.17 (d,
J¼1.9 Hz, 1H), 7.07 (d, J¼1.9 Hz, 1H), 6.71 (s, 2H), 6.09
(AB, J¼2.2 Hz, 2H), 5.47 (br s, 1H), 5.10 (br s, 1H), 3.85
(s, 3H), 3.07 (A of ABq, J¼17.4, 4.3 Hz, 1H), 3.01 (B of
AB, J¼17.4 Hz, 1H); 13C NMR (acetone-d6/D2O, 3/1 v/v,
400 MHz): d 167.0, 157.3, 157.2, 156.6, 148.6, 146.2,
145.5, 140.1, 133.0, 130.6, 121.0, 111.6, 106.5, 106.0,
98.7, 96.4, 95.5, 77.8, 70.5, 56.6, 26.3; HRMS (ESI): calcd
for C23H20O11Na (M+Na) 495.0903, found 495.0920.
4.22. (L)-(2R,3R)-5,7-Dihydroxy-2-(30,40,50-trihydroxy-
phenyl)chroman-3-yl-300,500-dihydroxy-400-methoxy-
benzoate (9)
4.26. (L)-(2R,3R)-5,7-Dihydroxy-2-(30,50-dihydroxy-
40-methoxyphenyl)chroman-3-yl-300-hydroxy-400,500-
dimethoxybenzoate (13)
Following the preparation procedure for 5, the hydrogeno-
lysis of 20 afforded 9 (89% yield): mp 226–228 ꢁC (decom-
Following the preparation procedure for 5, the hydrogeno-
lysis of 33 afforded 13 (89% yield): mp 199–201 ꢁC (decom-
posed); [a]D ꢀ139.0 (c 1.2, Me2CO); 1H NMR (acetone-d6,
400 MHz): d 7.24 (d, J¼1.9 Hz, 1H), 7.17 (d, J¼1.9 Hz,
1H), 6.82 (s, 2H), 6.18 (AB, J¼2.2 Hz, 2H), 5.65 (br s,
1H), 5.26 (br s, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.88 (s,
3H), 3.17 (A of ABq, J¼17.4, 4.3 Hz, 1H), 3.14 (B of
ABq, J¼17.4, 2.5 Hz, 1H); 13C NMR (acetone-d6,
400 MHz): d 163.9, 155.7, 155.3, 154.5. 151.7, 148.9,
139.3, 133.4, 133.3, 124.2, 109.1, 104.4, 103.6, 96.3, 94.2,
1
posed); [a]D ꢀ158.9 (c 1, Me2CO); H NMR (acetone-d6,
400 MHz): d 7.14 (s, 2H), 6.78 (s, 2H), 6.20 (AB,
J¼2.2 Hz, 2H), 5.72 (br s, 1H), 5.23 (br s, 1H), 3.97 (s,
3H), 3.20 (A of ABq, J¼17.3, 4.6 Hz, 1H), 3.07 (B of AB,
J¼17.4, 2.0 Hz, 1H); 13C NMR (acetone-d6, 400 MHz):
d 164.5, 156.5, 156.1, 155.7, 149.8, 144.9, 139.1, 131.8,
129.3, 125.1, 108.6, 105.3, 97.6, 95.1, 94.5, 76.6, 68.3,
59.2, 25.2; HRMS (ESI): calcd for C23H20O11Na (M+Na)
495.0903, found 495.0914.

5904
S. B. Wan et al. / Tetrahedron 62 (2006) 5897–5904
J. R. Magn. Reson. Chem. 1996, 34, 887; (c) Hashimoto, F.;
Nonaka, G.; Nishioka, I. Chem. Pharm. Bull. 1987, 35, 611.
8. Tachibana, H.; Sunada, Y.; Miyase, T.; Sano, M.; Maeda-
Yamamoto, M.; Yamada, K. Biosci. Biotechnol. Biochem.
2000, 64, 452.
93.3, 75.5, 68.1, 58.6, 58.5, 58.4, 58.3, 54.2, 54.1, 24.1;
HRMS (ESI): calcd for C25H24O11Na (M+Na) 523.1216,
found 523.1203.
9. Wu, A. H.; Tseng, C. C.; Van Den Berg, D.; Yu, M. C. Cancer
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Acknowledgements
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We thank the Areas of Excellence Scheme established under
the University Grants Committee of the Hong Kong Admin-
istrative Region, China (Project No. AoE/P-10/01) for finan-
cial support.
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