Enantioselective synthesis of orthogonally protected (2R,3R)-(-)- epicatechin derivatives, key intermediates in the de novo chemical synthesis of (-)-epicatechin glucuronides and sulfates

Article abstract of DOI:10.1016/j.tetasy.2013.02.012

Ten orthogonally protected (-)-epicatechin and 3′- or 4′-O-methyl-(-)-epicatechin derivatives were prepared in a regiospecific and enantioselective manner. For each orthogonally protected (-)-epicatechin derivative, one specific phenolic hydroxyl was protected with a methoxymethyl (MOM) or p-methoxybenyzl (PMB) group and the remainder were protected as benzyl ethers. These uniquely protected (-)-epicatechin derivatives were designed to facilitate the regiospecific installation of a glucuronic acid or sulfate unit onto (-)-epicatechin after selective removal of the MOM or PMB protecting group to provide authentic standards of (-)-epicatechin glucuronides and sulfates.

Full text of DOI:10.1016/j.tetasy.2013.02.012

Tetrahedron: Asymmetry 24 (2013) 362–373
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective synthesis of orthogonally protected
(2R,3R)-(ꢀ)-epicatechin derivatives, key intermediates in the de novo
chemical synthesis of (ꢀ)-epicatechin glucuronides and sulfates
Mingbao Zhang a, , G. Erik Jagdmann Jr. a, Michael Van Zandt a, Paul Beckett a, Hagen Schroeter b
⇑
a The Institutes for Pharmaceutical Discovery, 23 Business Park Drive, Branford, CT 06405, USA
b MARS Symbioscience, 20425 Seneca Meadows Parkway, Germantown, MD 20876, USA
a r t i c l e i n f o
a b s t r a c t
Ten orthogonally protected (ꢀ)-epicatechin and 30- or 40-O-methyl-(ꢀ)-epicatechin derivatives were
prepared in a regiospecific and enantioselective manner. For each orthogonally protected (ꢀ)-epicatechin
Article history:
Received 25 December 2012
Accepted 28 February 2013
derivative, one specific phenolic hydroxyl was protected with
a methoxymethyl (MOM) or
p-methoxybenyzl (PMB) group and the remainder were protected as benzyl ethers. These uniquely
protected (ꢀ)-epicatechin derivatives were designed to facilitate the regiospecific installation of a
glucuronic acid or sulfate unit onto (ꢀ)-epicatechin after selective removal of the MOM or PMB protect-
ing group to provide authentic standards of (ꢀ)-epicatechin glucuronides and sulfates.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
OR4'
R7O
O
(ꢀ)-Epicatechin, its epimer (+)-catechin, and their oligomeric
derivatives are believed to be the most abundant flavan-3-ols
found in the plant kingdom.1 Ingestion of flavanol-rich foods, such
as red wines, green teas, apples, pears, and cocoa products has
been correlated with health benefits including neuroprotection
and reduced risk of cardiovascular disease.2–9 In general, once
ingested, these compounds undergo rapid and extensive metabo-
lism to form the corresponding glucuronide, sulfate, and O-methyl
ether products.10–15 The methylated metabolites can undergo addi-
tional glucuronidation and sulfation to facilitate their excretion
from the body.10 Due to the polyphenolic structures of the (epi)-
catechins, glucuronidation, sulfation, and methylation reactions
can produce a wide variety of metabolites. Although the structures
of several major metabolites have been tentatively assigned using
LC/MS and various NMR techniques, the determination of the spe-
cific positional isomeric forms has generally been equivocal due to
the lack of authentic standards.10
OR3'
OH
OR5
1
R3´
MOM
Bn
Bn
Bn
R4´
Bn
PMB
Bn
Bn
MOM
Bn
Bn
Me
Me
Me
R5
Bn
Bn
MOM
Bn
Bn
MOM
Bn
Bn
MOM
Bn
R7
Bn
Bn
Bn
MOM
Bn
Bn
MOM
Bn
Bn
MOM
1a
1b
1c
1d
1e
1f
Me
Me
Me
MOM
Bn
1g
1h
1i
1j
Bn
Chart 1. Structures of the orthogonally protected (ꢀ)-epicatechin intermediates
1a–1j.
Recently, we have undertaken the task of gaining access to all
possible mono-glucuronides and mono-sulfates (ten each16) of
(ꢀ)-epicatechin, 30-OMe and 40-OMe-(ꢀ)-epicatechin via unambig-
uous chemical synthesis.17,18 Key to our synthetic strategy is the
availability of a set of orthogonally protected (ꢀ)-epicatechin
intermediates 1a–1j (Chart 1) prepared de novo. The key feature
of these late stage intermediates is that one phenolic OH is
protected as
a methoxymethyl (MOM) or p-methoxybenzyl
(PMB) ether while all remaining OHs are protected as benzyl
ethers. Selective removal of the MOM or PMB group in the pres-
ence of the benzyl ethers permits the unmasking of a single pheno-
lic OH group where glucuronidation or sulfation is desired. These
orthogonally protected (ꢀ)-epicatechin derivatives are a unique
⇑
Corresponding author. Tel.: +1 203 570 8879; fax: +1 203 653 2803.
E-mail address: nengren@yahoo.com (M. Zhang).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.02.012

M. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 362–373
363
OR4'
OR3'
OR4'
OR3'
OR4'
R7O
OH
R7O
O
R7O
O
OR3'
OH
OH
OH
OH
OR5
OR5
OR5
1
2
3
OR4'
OR3'
OR4'
OR3'
OR4'
OR3'
R7O
OH
R7O
OH
R5O
OH
+
H
OR5
O
O
OR5
OR5
O
4
5
7
6
Scheme 1. Retro-synthetic analysis of orthogonally protected (ꢀ)-epicatechins.
set of precursors, which enable the unambiguous chemical synthe-
sis of (ꢀ)-epicatechin glucuronides and sulfates. Herein we report
the regiospecific and enantioselective synthesis of 1a–1j.
chin derivatives 1 bearing the appropriate orthogonal protecting
groups according to Scheme 2.
The successful development of this synthetic strategy required
highly efficient and scalable syntheses of the various protected
acetophenones 6a–c and 3,4-dihydroxy benzaldehydes 7a–g.
These methods are described below.
2. Results and discussion
2.1. Retro-synthetic analysis
2.2. Synthesis of acetophenones 6a–c
The retro-synthetic analysis of 1 is shown in Scheme 1. The key
step is the cyclization of optically active diol 3 to form the
trans-isomer catechin 2, from which 1 can be obtained after inver-
sion of the 3-OH. Diol 3 can be obtained via the Sharpless asym-
metric dihydroxylation19 of the (E)-olefin intermediate 4, which
is accessible from the reduction of chalcone 5. A similar approach
has been applied to the synthesis of a non-orthogonally protected
(ꢀ)-epicatechin analogue 5,7,30,40-tetra-O-benzyl epicatechin.20,21
Herein, chalcone 5 is a key intermediate which provides the stage
for setting the desired orthogonal protection patterns in the final
compound 1. The aldol condensation of the appropriately pro-
tected trihydroxy acetophenone derivatives 6 and 3,4-dihydroxy
benzaldehyde derivatives 7 affords the chalcone 5 with the desired
orthogonal protection patterns.
The synthetic scheme for making 6a–c is shown in Scheme 3.
Treatment of commercially available 2,4,6-trihydroxyacetophe-
none (phloroacetophenone) monohydrate 8 with benzyl chloride
in the presence of potassium carbonate in DMF at 70 °C afforded
4,6-bisbenzyl ether 6a in 46% yield. The structure of 6a was
unequivocally identified by its 1H NMR spectrum in which the
two aromatic protons H-3 and H-5 appeared as two weakly
coupled doublets (J = 2.3 Hz) at d 6.10 and 6.17 ppm, respectively.
The 1H NMR spectrum of 6a also showed the presence of an
intramolecularly H-bonded ortho OH group (d 14.02). The regiose-
lectivity of the benzylation likely results from the intramolecular
hydrogen-bonding between the ketone carbonyl group and an
adjacent phenolic OH. In the presence of a base, 6a can behave
like an enolate to react further, at the 3-position, with benzyl
chloride via a nucleophilic substitution reaction to form the by-
product
0
0
The selections of the protecting groups R3 , R4 , R5, and R7 are
shown in Table 1. Their combinations provide the desired epicate-
1-(3-benzyl-4,6-bis(benzyloxy)-2-hydroxyphenyl)ethanone.
Treatment of 8 with bromomethyl methyl ether in the presence
of Hunig’s base in dichloromethane at 0 °C afforded the 4,6-bis-
methoxymethylether 9 in 64% yield. The 1H NMR of 9 in which
the two aromatic protons H-3 and H-5 appeared as an AB quartet
at d 6.25 (JAB = 2.3 Hz) and the OH group was significantly down-
field shifted (d 13.70) is consistent with the 4,6-substitution pat-
tern. Benzylation of the free phenolic OH group with benzyl
chloride in DMF afforded the intermediate 10 in 91% yield. Treat-
ment of 10 with Montmorillonite K-1022 clay under refluxing con-
ditions in acetone/water selectively removed the ortho MOM group
to afford the desired orthogonally bis-protected 2-hydroxy aceto-
phenone 6b in 88% yield.
Treatment of 8 with TBDMS in DMF in the presence of imidazole
afforded a readily separable mixture of the mono-silylated 11
(22%) and bis-silylated 12 (77%) products. When the bis-silylated
product 12 was treated with 20 mol % pyridinum p-toluenesulfo-
nate (PPTS)23 under refluxing conditions in methanol for 4 h, the
mono-silylated product 11 was isolated in 94% yield. Based on this
Table 1
Protecting group selections
R5
R7
R7O
OH
O
6a
6b
6c
Bn
Bn
MOM
Bn
MOM
Bn
OR5
6
0
0
R3
R4
OR4'
OR3'
7a
Bn
Bn
MOM
Me
Me
Bn
Bn
PMB
Bn
Bn
MOM
Me
Me
7b
7c
7d
7e
7f
H
O
7g
MOM
7

364
M. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 362–373
R3´
R4´
R5
R7
6a + 7c
6a + 7b
6c + 7a
6b + 7a
6a + 7e
6c+ 7d
6b + 7d
6a + 7g
6c + 7f
6b + 7f
5a
MOM
Bn
Bn
Bn
5b Bn
5c
Bn
5d Bn
Me
Me
5g Me
5h MOM
PMB
Bn
Bn
MOM
Bn
Bn
Me
Me
Me
Bn
MOM
Bn
Bn
MOM
Bn
Bn
MOM
Bn
Bn
Bn
MOM
Bn
Bn
MOM
Bn
Bn
MOM
5e
5f
5i
5j
Bn
Bn
Scheme 2. Synthesis of the orthogonally protected chalcones 5a–j.
O
O
OH
O
OH
OH
O
OH
e
a
+
f
OH
OH
BnO
OBn
HO
TBSO
OTBS
TBSO
6a
12
11
8
46%
85% (2 steps)
g
b
OR
O
OBn
O
OH
O
OH
O
d
h
OH
OMOM
OMOM
MOMO
c
OMOM
MOMO
OR'
TBSO
9
6b
13
, R = H (64%)
(91%)
88%
14, R' = H (90% over 2 steps)
6c
10, R = Bn
i
, R' = Bn (86%)
Scheme 3. Synthesis of orthogonally protected 2,4,6-trihydroxyacetophenone 6a–c. Reagents and conditions: (a) BnCl (2.2 equiv), K2CO3 (2.2 equiv), DMF, 70 °C, 3 h; (b)
EtN(iPr)2 (5 equiv), BrCH2OCH3 (2.1 equiv), CH2Cl2, 0 °C, 3 h; (c) BnCl (1.3 equiv), K2CO3 (1.5 equiv), DMF, 90 °C, 20 h; (d) Montmorillonite K-10 clay, acetone/water (9:1),
reflux, 4 h; (e) imidazole (3 equiv), TBDMSCl (2.2 equiv), DMF, rt, 1 h; (f) PPTS (0.2 equiv), MeOH, reflux, 3 h; (g) EtN(iPr)2 (1.5 equiv), BrCH2OCH3 (1.1 equiv), CH2Cl2, 0 °C,
30 min; (h) TBAF (1.2 equiv), AcOH (1.2 equiv), THF, 0 °C, (i) BnCl (1.1 equiv), K2CO3 (1.3 equiv), DMF, 75 °C, 3 h.
observation, in a subsequent experiment, the mixture of 11 and 12
was not separated prior to treatment with PPTS to afford the de-
sired product 11 in 85% yield. Treatment of 11 with bromomethyl
methyl ether followed by de-silylation with TBAF afforded 2-MOM
protected phloroacetophenone 14 in 90% yield over two steps. Reg-
ioselective benzylation of 14 with benzyl chloride gave orthogo-
nally bis-protected phloroacetophenone 6c in 86% yield. The
structure of 6c was confirmed by the presence of an intramolecu-
larly H-bonded ortho OH group with a large downfield shift (d
13.86 ppm) by 1H NMR. This synthesis is better than that reported
in the literature where either expensive starting materials or low
yielding steps were involved.14,24,25
2.3. Synthesis of benzaldehydes 7a–g
The di-benzylated benzaldehyde 7a was commercially avail-
able. The orthogonally protected 3,4-dihydroxybenzaldehydes 7b
and 7c were synthesized according to Scheme 4. Treatment of
the commercially available 3,4-dihydroxybenzaldehyde 8a with
2 equiv of sodium hydride followed by 1.25 equiv of benzyl chlo-
ride in DMF afforded the 3-O-benzyl intermediate 15 which was
readily converted into 7b (p-anisyl chloride/NaH, DMF). It is note-
worthy that treatment of 8a with only 1.1 equiv of sodium hydride
followed by 1.1 equiv of benzyl bromide led to the formation of
4-O-benzyl intermediate 16. The structures of 15 and 16 were as-

M. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 362–373
365
HO
HO
CHO
c
3-methoxy-4-hydroxy-or 4-methoxy-3-hydroxybenzadehyde with
benzyl bromide or methoxymethyl bromide.14
2.4. Synthesis of chalcones 5a–j
8a
a
With the appropriately protected acetophenones 6a–c and
benzaldehydes 7a–g in hand, the orthogonally protected chalcones
5a–j were prepared by condensing acetophenone 6a–c and benzal-
dehyde 7a–j according to Scheme 2 with sodium hydride in DMF at
room temperature. Upon pouring the reaction in ice water and
acidification to pH 3–4, a crystalline suspension was obtained in
all cases, which thus allowed the convenient isolation of the ana-
lytically pure chalcone 5a–j by simple filtration in near quantita-
tive yields.
HO
CHO
BnO
HO
CHO
BnO
16 (49%)
15 (66%)
d
b
2.5. Synthesis of the protected (ꢀ) epicatechins 1a–j
MOMO
BnO
CHO
BnO
CHO
With the orthogonally protected chalcones 5a–j in hand, we
were ready to synthesize the (ꢀ)-epicatechin derivatives bearing
the desired orthogonal protecting groups 1a–j. For clarity, the syn-
thesis is illustrated by the preparation of 30-O-methyl-40,5-di-O-
benzyl-7-O-methoxymethoxy-(ꢀ)-epicatechin 1g. Chalcone 5g
was converted into the olefin intermediate 4g via reduction by
NaBH4 in the presence of cerium chloride in a mixture of THF
and ethanol at a low temperature (0 °C).18 Both visual observation
(yellow color fading away) and TLC analysis indicated the rapid
disappearance of the chalcone 5g (<1 h) under the reaction condi-
tions. However, quenching the reaction with 5% citric acid shortly
after the total consumption of 5g resulted in low yields of the de-
sired product 4g and the by-product 22g was isolated as the major
PMBO
7b (95%)
7c (99%)
Scheme 4. Synthesis of orthogonally protected 3,4-dihydroxybenzaldehydes 7b
and 7c. Reagents and conditions: (a) NaH (2.0 equiv), BnCl (1.25 equiv), DMF; (b)
NaH, DMF, p-anisyl chloride (1.2 equiv); (c) NaH (1.1 equiv), BnBr (1.1 equiv), DMF;
(d) EtN(iPr)2 (2 equiv), BrCH2OCH3 (1.1 equiv), CH2Cl2.
signed based on their 1H NMR spectra. The chemical shift of the
aromatic proton H-2 was larger for 15 (d 6.32 ppm) than 16 (d
5.92 ppm) due to the benzylation of the adjacent OH group. The
regioselectivity observed can be explained by relative stability of
the 4-phenoxy anion versus 3-phenoxy anion. With 1 equiv of
NaH, the more stable 4-phenoxy anion (para to the CHO group)
is formed; the 3-phenoxy anion is formed with the second equiva-
lent base and is more reactive toward alkylation because it is not
stabilized by the para aldehyde group. The intermediate 16 was
converted into 7c via treatment with bromomethyl methyl ether
in the presence of the Hünig’s base in dichloromethane. The pro-
tected methoxyl benzaldehydes 7d–7g were prepared according
to known procedures by the reaction of commercially available
product (Scheme 5). Apparently, the reduction of the carbonyl
26,27
group with NaBH4/CeCl3
occurred in two steps: the rapid first
step to the alcohol intermediate 21g, which was followed by a
much slower de-oxygenation step to form the desired product
4g. The position and the E-configuration of the double bond in 4g
were determined based on 1H NMR. The coupling constant be-
tween the two olefin protons was large (J = 16.0 Hz), which is char-
acteristic of the E-configuration. When the reaction was quenched
prematurely with an acid, the alcohol intermediate 21g underwent
an acid-catalyzed intra-molecular cyclization to form the by-prod-
OBn
OBn
H
NaBH4
H+
CeCl3.7H2O
MOMO
O
MOMO
O
OCH3
5g
OCH3
THF/EtOH
0
oC
OBn
OBn OH
22g (13%)
21g
NaBH4
OBn
H
O
MOMO
OCH3
OBn
4g (73%)
Scheme 5. Reduction of chalcone 5g.

366
M. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 362–373
OBn
OBn
OMe
TBS
O
TBS
MOMO
MOMO
O
c
b
a
OMe
4g
OH
OH
OBn
17g
OBn
18g (93%)
(88%)
OBn
OMe
OBn
OMe
OBn
MOMO
O
MOMO
O
MOMO
OH
e
d
OMe
OH
OH
OH
O
OBn
OBn
OBn
3g
O
19g (100%)
2g
(87%, 66%ee)
(84%)
OBn
OMe
OBn
OMe
MOMO
O
MOMO
O
g
h
f
2g (61%, 96% ee)
OH
O
OBn
OBn
20g
(79%, 93% ee)
1g
(66%)
Scheme 6. Synthesis of orthogonally protected (ꢀ)-epicatechin derivative 1g. Reagents and conditions: (a) TBDMSCl, imidazole, DMF; (b) AD-mix-
a
, MeSO2NH2/K2CO3,
t-BuOH/water/THF, 0 °C; (c) TBAF, AcOH, THF, 0 °C; (d) EtC(OEt)3, PPTS, CH2Cl2, 65 °C; (e) K2CO3, MeOH; (f) Mosher’s acid (0.2 equiv), DCC (0.2 equiv), DMAP (3.3 mol %),
CH2Cl2, 0 °C, 30 min; (g) Dess–Martin periodinane, CH2Cl2, rt; (h) Al(O-iPr) 3, 2-propanol/toluene, reflux.
uct 22g. Prolonged stirring (overnight to 24 h) after disappearance
of the chalcone was thus required to minimize the formation of the
by-product 22g (<15%).
Table 2
Enantiomeric excess values of some selected diols and the corresponding catechins
Diol precursora (ee %)
Catechinb (ee %)
The Sharpless asymmetric dihydroxylation of olefin intermedi-
ate 17g after the phenolic OH was protected as a silyl ether
(TBDMSCl, imidazole in DMF) afforded the optically active 2,3-cis
diol 18g in 93% yield (Scheme 6).19 The ee of diol 18g was assessed
by 1H NMR using (R)-(ꢀ)-1-(9-anthryl)-2,2,2-trifluoroethanol
(Pirkle’s alcohol) as a chiral shift reagent.28 In the presence of
68 equiv of Pirkle’s alcohol, the aromatic OCH3 protons of the race-
mic diol 18g appeared as baseline-resolved doublets in CDCl3 (d
3.701, 3.724 ppm). The enantiomeric purity of the optically active
18g was determined to be 67% ee. Removal of the TBS group fol-
lowed by cyclization, effected by triethyl orthopropionate in the
presence of catalytic amount of PPTS,18,29 afforded the catechin
intermediates 19g with the 3-OH protected as a propionate (84%
yield over two steps). Saponification of 19g (K2CO3, MeOH) re-
sulted in the formation of the (+)-catechin intermediate 2g in
87% yield with 66% ee as determined by chiral HPLC.
The enantioselectivity of the asymmetric dihydroxylation reac-
tions of the olefin intermediate 17a–j was variable and generally
lower than expected, except for 18i, based on ee assessments of
the selected diols 18e, 18g, 18h, and 18i using Pirkle’s alcohol
(8–68 equiv). The enantiomeric excess values of the corresponding
catechin intermediates 2 correlate very closely to those of the diol
precursors (Table 2), thus suggesting minimal loss of enantiomeric
purity during these transformations.
18e (60%)
18g (67%)
18h (50%)
18i (90%)
2e (59%)
2g (66%)
2h (50%)
2i (89%)
Estimated based on 1H NMR integration values in the presence of Pirkle’s
alcohol in CDCl3.
a
b
Determined by chiral HPLC.
(Scheme 7). Under these conditions, the minor enantiomer of the
catechin intermediate 2 undergoes a faster (3–7 fold) esterification
reaction with the (R)-Mosher’s acid. The unreacted catechin
starting materials were conveniently recovered by flash chroma-
tography on silica gel with 95–98% ee. The catechin intermediates
2a–2d, 2f, and 2j were not treated with the (R)-Mosher’s acid be-
cause they had already been converted into the final epicatechin
targets before this procedure was discovered. It is noteworthy that
the two enantiomers of the corresponding epicatechins reacted at a
similar rate with Mosher’s acid under the reaction conditions, thus
no ee enhancement was observed for the epicatechin compounds.
The Mitsunobu reaction failed to effect the required inversion of
the stereochemistry of the 3-ol.30 The best method reported to date
is an oxidation/stereoselective reduction sequence, converting the
3-OH into the 3-one via Dess–Martin periodinane oxidation fol-
lowed by Meerwein–Ponndorf–Verley reduction with aluminum
isopropoxide/propanol in refluxing toluene.31 Thus, the enatiomer-
ically enriched catechin intermediate 2g (96% ee) was converted
into the 3-one 20g in 66% yield by the treatment of the Dess–Mar-
The enantiomeric excess values of catechin intermediates 2e,
2g, 2h, and 2i were further enhanced by treatment with 0.2–
0.5 equiv of (R)-(+)-a-methoxy-a-trifluoromethylphenylacetic acid
(Mosher’s acid) in the presence of DCC and DMAP in CH2Cl2

M. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 362–373
367
OR4'
R7O
O
OR3'
CF3
MeO
O
OR4'
OR3'
O
O
OR5
CF3
O
R7O
O
MeO
DCC (0.2-0.5 eq)
DMAP (0.2-0.5 eq)
OH
+
OH
separation by flash column
CH2Cl2
OR4'
OR3'
OR5
50-89% ee
0.2-0.5 eq.
R7O
OH
OR5
95-98% ee
Scheme 7. Enantiomeric excess enhancement of the catechin intermediate 2 via kinetic resolution with (R)-(+)-
a
-methoxy-a-trifluoromethylphenylacetic acid.
tin periodinane in CH2Cl2 at room temperature. Reduction of 20g
with aluminum isopropoxide/propanol in refluxing toluene affor-
ded the final target 1g in 79% yield with 93% ee by Chiral HPLC
(Table 3). The data suggest that there was a slight loss of enantio-
meric purity after the conversion.
pared according to Scheme 8. For the sake of clarity, the synthesis
is illustrated by the preparation of racemic 2g and 1g. The cyclic
olefin intermediate 22g obtained as
a by-product from the
NaBH4/CeCl3 reduction of the chalcone 5g (vide supra) was dihy-
droxylated using a non asymmetric dihydroxylation protocol
reported in the literature32 to afford the racemic diol 23g.
Reduction of 23g with sodium cyanoborohydride in acetic acid at
50 °C afforded a 9:1 mixture of the racemic catechin 2g and race-
mic epicatechin 1g as determined by 1H NMR in 57% overall yield.
Both the racemic 2g and 1g were baseline resolved by chiral HPLC
using a Chiralpack AD-RH column.
Table 3
Summary data of orthogonally protected epicatechin intermediates 1a–1ja
Yieldb (%)
Mp (°C)
eed (%)
½ ꢁ
a 2D0
Entry
1a
1b
1c
1d
1e
1f
1g
1h
1i
67
61
63
30
22
57
12
26
26
35
129–130
131–132
106–108
102–103
94–95
150–152
110–111
74–75
57c
ꢀ10.3 (c 6.69)
ꢀ9.8 (c 7.06)
ꢀ22.4 (c 4.93)
ꢀ15.4 (c 5.30)
ꢀ18.2 (c 4.95)
ꢀ19.5 (c 6.08)
ꢀ15.8 (c 5.10)
ꢀ17.7 (c 5.60)
ꢀ24.4 (c 4.44)
ꢀ14.8 (c 5.33)
70c
86 (90)c
81 (84)c
96 (98)
3. Conclusion
c
75
In conclusion, we have developed an enantioselective synthesis
of orthogonally protected (ꢀ)-epicatechins and 30/40-O-methyl
epicatechins in whichone phenolic hydroxylgroup is protectedwith
a MOM or PMB protecting group and the remaining phenolic hydro-
xyl groups are protected as benzyl ethers. These orthogonally
protected (ꢀ)-epicatechins are useful precursors to the unambigu-
ous chemical synthesisof (ꢀ)-epicatechinsulfates and glucuronides,
important metabolites of (ꢀ)-epicatechin in vivo. The syntheses and
characterization of these metabolites will be reported separately.18
93 (97)
93 (95)
94 (96)
74 (76)c
130–132
114–115
1j
a
All compounds were fully characterized by 1H and 13C NMR, LC/MS and gave
satisfactory combustion analysis.
b
Overall yield from chalcone.
The corresponding (+)-catechin intermediates 2 were not treated with Mosher’s
c
acid to enhance the ee.
d
The ee values were determined by chiral HPLC (ChiralpakÒ AD-RH 5
l particle
size 4.6 ꢂ 150 mm with acetonitrile/water 60:40 as the mobile phase at 60 °C).
Numbers in parenthesis are the ee values of the corresponding catechin precursors.
4. Experimental
4.1. General
The rest of the orthogonally protected (ꢀ)-epicatechin deriva-
tives were prepared in a manner similar to 1g. The overall yields,
melting points, enantiomeric excess values, and specific rotations
are summarized in Table 3.
Racemic versions of the catechin intermediates 2a–j and epicat-
echin final targets 1a–j required for Chiral HPLC analyses were pre-
Reagents and solvents were obtained from commercial sources
and used without further purification. All reactions were run under
a nitrogen atmosphere at room temperature unless specified
otherwise. 1H and 13C NMR spectra were obtained on a 400 MHz
OBn
MOMO
O
OCH3
b
a
22g
1g
rac-
rac-2g
9:1 mixture
57% over two steps
+
OH
OBn OH
rac--23g
Scheme 8. Synthesis of the racemates of the catechin intermediate 2g and (ꢀ)-epicatechin final target 1g. Reagents and conditions: (a) K3Fe(CN)6 (3.0 equiv), K2CO3
(3.1 equiv), OsCl3.H2O (2.2 mol %), quinuclidine (7.2 mol %), methane sulfonamide (1.1 equiv), t-butanol/H2O/THF (1:1:2), rt, 18 h; (b) NaBH3CN (2.4 equiv), HOAc, 50 °C, 2 h.

368
M. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 362–373
spectrometer in CDCl3 unless otherwise specified. Chemical shifts
are expressed in ppm relative to TMS. Coupling constants are ex-
pressed in Hz. LC/MS was obtained on a LC/MS system equipped
with an autosampler and LC pump. Chiral analytical HPLC runs
were performed on a Chiralpack AD-RH column (150 ꢂ 4.6 mm,
4.4. Preparation of 6-benzyloxy-2,4-di(methoxymethoxy)aceto-
phenone 10
A stirred solution of 2,4-di(methoxymethoxy)-6-hydroxyace-
tophenone (14.09 g, 55 mmol) in N,N-dimethylformamide
(115 mL) was treated with solid potassium carbonate (11.4 g,
82.5 mmol) and benzyl chloride (7.95 mL, 69 mmol). The mix-
ture was heated to 75 °C for 16 h, cooled to room temperature,
diluted with water (500 mL), and stirred for an hour during
which time a precipitate formed. The suspension was cooled
in an ice bath, and filtered. The solid was rinsed with water
and partially air dried, before dissolving in dichloromethane
(150 mL). The solution was dried (Na2SO4), added directly to a
silica gel column, eluted with dichloromethane, then with 5%
ethyl acetate/dichloromethane to afford a pale yellow solid. Trit-
uration with petroleum ethers afforded 6-benzyloxy-2,4-
di(methoxymethoxy)acetophenone 10 (17.81 g, 94%) as a white
solid: mp 66–67 °C (lit.35 64–65 °C); LC/MS m/z 347 [M+1]; 1H
NMR (CDCl3, 400 MHz) d 2.48 (s, 3H), 3.46 (s, 6H), 5.05 (s,
2H), 5.13 (s, 2H), 5.14 (s, 2H), 6.38 (d, J = 1.9, 1H), 6.47 (d,
J = 1.9, 1H), 7.27–7.40 (m, 5H); 13C NMR (CDCl3, 100 MHz) d
32.7, 56.3, 56.5, 70.7, 94.7, 95.0, 95.6, 96.7, 116.7, 127.4,
128.1, 128.7, 136.5, 155.5, 157.0, 159.8, 201.5. Anal. Calcd for
5
l particle size). Mobile phase was an isocratic binary system con-
sisting of 60/40 acetonitrile and water at a flow rate of 1 ml/min.
The UV detection wavelength was 230 nm. The column tempera-
ture was 60 °C. Optical rotations were measured at 589 nm at room
temperature (20 °C) in chloroform.
4.2. Preparation of 2,4-dibenzyloxy-6-hydroxyacetophenone 6a
A 1 L 3-neck flask was charged with N,N-dimethylformamide
(180 mL) under nitrogen, heated to 35 °C, then phloroglycinol hy-
drate (37.23 g, 0.20 mol) was added in one portion, followed by
more DMF (120 mL). Potassium carbonate (60.8 g, 0.44 mol) was
added and the mixture was heated to 65 °C. Benzyl chloride
(50.6 mL, 0.44 mol) was introduced in one portion, and the mixture
was heated to 70 °C for 3 h, cooled to room temperature, and fil-
tered. The filter cake was then rinsed with methylene chloride.
The combined filtrates were concentrated in vacuo and the resid-
ual orange oil was taken up in dichloromethane (400 mL), stirred
for a few minutes, filtered, and the filtrate added to a pad of silica
gel and eluted with dichloromethane. The filtrate volume was
reduced to 150 mL, after which heptane (200 mL) was added, and
the mixture was stirred for 20 min. The resultant white crystalline
solid was collected by filtration, washed with heptane and air
dried. The filtrate solution was loaded directly onto a silica gel col-
umn (700 mL) and eluted with 1:1 dichloromethane/heptane, then
with 2:1 dichloromethane/heptane to yield additional product. The
two batches were combined to afford 32.22 g (46%) of 2,4-diben-
zyloxy-6-hydroxyacetophenone 6a as a white crystalline solid:
mp 103.5–105.5 °C (lit.33 103 °C); LC/MS m/z 349 [M+H]; 1H NMR
(CDCl3, 400 MHz) d 2.56 (s, 3H), 5.07 (m, 4H), 6.10 (d, J = 2.3, 1H),
6.17 (d, J = 2.3, 1H), 7.31–7.45 (m, 10H), 14.02 (s, 1H); 13C NMR
(CDCl3, 100 MHz) d 33.4, 70.4, 71.3, 92.5, 95.0, 106.6, 127.8,
128.1, 128.5, 128.6, 128.86, 128.9, 135.8, 136.1, 162.2, 165.3,
167.7, 203.3. Anal. Calcd for C22H20O4: C, 75.84; H, 5.79. Found:
C, 75.88; H, 5.79.
C19H22O6: C, 65.88; H, 6.40. Found: C, 65.69; H, 6.46.
4.5. Preparation of 2-benzyloxy-4-(methoxymethoxy)-6-hydro-
xyacetophenone 6b
A stirred solution of 6-benzyloxy-2,4-di(methoxymethoxy)ace-
tophenone (17.32 g, 50 mmol) in 9:1 acetone/water (180 mL) was
treated with Montmorillonite K-10 clay (50 g), heated at reflux
for 5 h, cooled to room temperature, and filtered through CeliteÒ.
The filter pad was rinsed with dichloromethane and acetone, and
the combined filtrate was concentrated in vacuo. The residue
was dissolved in dichloromethane (125 mL), dried (Na2SO4), added
directly to a silica gel column, and eluted with dichloromethane to
afford 2-benzyloxy-4-(methoxymethoxy)-6-hydroxyacetophenone
6b as a very pale yellow solid (13.15 g, 87%): mp 97–99 °C; LC/MS
m/z 303 [M+1]; 1H NMR (CDCl3, 400 MHz) d 2.56 (s, 3H), 3.47 (s,
3H), 5.09 (s, 2H), 5.17 (s, 2H), 6.14 (d, J = 2.2, 1H), 6.24 (d, J = 2.2,
1H), 7.33–7.45 (m, 5H), 13.84 (s, 1H); 13C NMR (CDCl3, 100 MHz)
d 33.5, 56.5, 71.3, 92.6, 94.2, 96.8, 107.0, 128.2, 128.6, 128.9,
135.8, 162.2, 163.7, 167.3, 203.5. Anal. Calcd for C17H18O5: C,
67.54; H, 6.00. Found: C, 67.27; H, 5.89.
4.3. Preparation of 2,4-di(methoxymethoxy)-6-hydroxyaceto-
phenone 9
To a stirred suspension of phloroglycinol hydrate (13.97 g,
75 mmol) in dichloromethane (300 mL) under nitrogen was added
N,N-diisopropylethylamine (65.3 mL, 375 mmol), while cooling in
an ice bath (3 °C). Bromomethyl methyl ether (14.3 mL, 158 mmol
corrected for 90% purity) was added dropwise at a rate to keep the
reaction temperature below 8 °C. The mixture was stirred at 3 °C
for 3 h, then quenched with saturated aqueous sodium bicarbonate
(250 mL). The mixture was stirred at room temperature for a few
minutes, after which the phases were separated, and the aqueous
solution extracted with dichloromethane (2 ꢂ 75 mL). The com-
bined organic solution was dried (Na2SO4), filtered, and concen-
trated in vacuo. The residue was dissolved in the minimal
amount of dichloromethane and then added to a silica gel column.
Elution with dichloromethane and then with 1.5% ethyl acetate/
dichloromethane afforded 2,4-di(methoxymethoxy)-6-hydroxy-
acetophenone 9 (14.32 g, 74.5%) as a white solid after evaporation:
mp 49–50 °C (lit.34 49–52 °C); LC/MS m/z 257 [M+H]; 1H NMR
(CDCl3, 400 MHz) d 2.65 (s, 3H), 3.47 (s, 3H), 3.51 (s, 3H), 5.16 (s,
4.6. Preparation of 2,6-dihydroxy-4-(t-butyldimethylsilyloxy)-
acetophenone 11
A stirred solution of phloroglucinol hydrate (13.96 g, 75 mmol)
and imidazole (15.32 g, 225 mmol) in anhydrous DMF (175 mL)
was treated in portions with t-butyldimethylsilyl chloride
(24.87 g, 165 mmol), then stirred at room temperature for 1 h
and diluted with water (700 mL). The mixture was extracted with
ethyl acetate (500 mL, then 2 ꢂ 100 mL), and the combined organic
extracts were washed with water (2 ꢂ 200 mL), dried (MgSO4), and
concentrated in vacuo. The residue was dissolved in a minimal vol-
ume of dichloromethane and loaded onto a silica gel column and
eluted with dichloromethane to afford a mixture of mono-11 and
disilylated 12 products after evaporation. This mixture was dis-
solved in methanol (250 mL) under nitrogen, treated with pyridini-
um p-toluene sulfonate (3.77 g, 15 mmol), and refluxed for 4 h,
then concentrated in vacuo. The residue was dissolved in a
minimal volume of dichloromethane and loaded onto a silica gel
column and eluted with dichloromethane to afford 2,6-dihy-
2H), 5.25 (s, 2H), 6.25 (ABq, JAB = 2.3,
DmAB = 8.3, 2H), 13.70 (s,
1H); 13C NMR (CDCl3, 100 MHz) d 33.1, 56.6, 56.8, 94.2, 94.7,
97.4, 107.2, 160.5, 163.6, 167.0, 203.3. Anal. Calcd for C12H16O6:
C, 56.25; H, 6.29. Found: C, 56.38; H, 6.23.
droxy-4-(t-butyldimethylsilyloxy)-acetophenone 11
(21.01 g,
99%) as a pale yellow solid: mp 97–98.5 °C; LC/MS m/z 283

M. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 362–373
369
[M+1]; 1H NMR (CDCl3, 400 MHz) d 0.22 (s, 6H), 0.95 (s, 9H), 2.69
(s, 3H), 5.89 (s, 2H); 13C NMR (CDCl3, 100 MHz) d -5.2, 17.3, 24.7,
31.9, 99.4, 104.9, 162.0, 162.4, 202.9. Anal. Calcd for C14H22O4Si:
C, 59.54; H, 7.85. Found: C, 59.70; H, 7.99.
volume. The solution was then added to a silica gel column and
eluted with dichloromethane to afford 4-benzyloxy-6-hydroxy-2-
(methoxymethoxy)acetophenone (18.98 g, 87%) as a pale yellow
solid: mp 82–83 °C; LC/MS m/z 303 [M+H]; 1H NMR (CDCl3,
400 MHz) d 2.65 (s, 3H), 3.51 (s, 3H), 5.06 (s, 2H), 5.23 (s, 2H),
6.18 (d, J = 2.4, 1H), 6.24 (d, J = 2.4, 1H), 7.31–7.45 (m, 5H), 13.86
(s, 1H); 13C NMR (CDCl3, 100 MHz) d 33.0, 56.8, 70.4, 94.0, 94.6,
95.7, 106.6, 127.7, 128.4, 128.8, 136.0, 160.5, 165.2, 167.3, 203.2.
Anal. Calcd for C17H18O5: C, 67.54; H, 6.00. Found: C, 67.82; H, 5.96.
4.7. Preparation of 4-(t-butyldimethylsilyloxy)-6-hydroxy-2-
(methoxymethoxy)acetophenone 13
To an ice cooled, stirred solution of 2,6-dihydroxy-4-(t-butyldi-
methylsilyloxy) acetophenone (20.9 g, 74 mmol) and N,N-diisopro-
pylethylamine
(19.3 mL,
111 mmol)
in
anhydrous
4.10. Preparation of 3-benzyloxy-4-hydroxybenzaldehyde 15
dichloromethane (250 mL), under a nitrogen atmosphere, was
added dropwise bromomethyl methyl ether (7.7 mL, 85 mmol cor-
rected for 90% purity). The reaction was stirred at 3 °C for 30 min,
then quenched with saturated aqueous sodium bicarbonate
(150 mL) and stirred at room temperature for 15 min. The layers
were separated, the aqueous solution extracted with dichloro-
methane (100 mL), and the combined organic solution was washed
with water (200 mL), dried (Na2SO4), and concentrated in vacuo.
The residue was dissolved in a minimum volume of dichlorometh-
An ice cooled stirred suspension of 60% sodium hydride/oil
(4.16 g, 104 mmol) in anhydrous DMF (100 mL) under nitrogen
was treated dropwise with a solution of 3,4-di-hydroxybenzalde-
hyde (6.91 g, 50 mmol) in anhydrous DMF (50 mL) and the mixture
was stirred at room temperature for 1 h and re-cooled on an ice
bath. Benzyl chloride (6.62 mL, 57.5 mmol) was added via syringe
and the mixture allowed to reach room temperature and stirred
overnight (18 h). The mixture was concentrated in vacuo to
remove most of the DMF, and ice water (300 mL) was added. The
aqueous solution was extracted with diethyl ether (3 ꢂ 100 mL),
acidified with concentrated hydrochloric acid (ꢃ10 mL), and stir-
red for 30 min, during which time a solid precipitated. The solid
was filtered, rinsed with water, partially air dried, and dissolved
in dichloromethane (125 mL) and dried (Na2SO4). The solution
was added directly to a silica gel column and eluted with dichloro-
methane to afford 3-benzyloxy-4-hydroxybenzaldehyde (7.52 g,
66%) as a white solid: mp 117–118 °C (lit.37 113–114 °C); LC/MS
m/z 229 [M+H]; 1H NMR (CDCl3, 400 MHz) d 5.17 (s, 2H), 6.32 (s,
1H), 7.06 (d, J = 8.1, 1H)), 7.35–7.46 (m, 6H), 7.51 (d, J = 1.6, 1H),
9.81 (s, 1H); 13C NMR (CDCl3, 100 MHz) d 71.5, 110.5, 114.8,
127.7, 128.2, 128.9, 129.0, 130.1, 135.6, 146.5, 152.0, 190.9. Anal.
Calcd for C14H12O3: C, 73.67; H, 5.30. Found: C, 73.93; H, 5.27.
ane and loaded onto
a silica gel column and eluted with
dichloromethane to afford 4-(t-butyldimethylsilyloxy)-6-hydro-
xy-2-(methoxymethoxy)acetophenone (23.20 g, 96%) as a pale yel-
low solid: mp 45–47 °C; LC/MS m/z 327 [M+1]; 1H NMR (CDCl3,
400 MHz) d 0.25 (s, 6H), 0.97 (s, 9H), 2.64 (s, 3H), 3.51 (s, 3H),
5.23 (s, 2H), 6.05 (d, J = 2.2, 1H), 6.10 (d, J = 2.2, 1H), 13.65 (s,
1H); 13C NMR (CDCl3, 100 MHz) d ꢀ4.2, 18.4, 25.7, 33.1, 56.7,
94.6, 97.9, 102.0, 107.1, 160.7, 163.0, 166.8, 203.3. Anal. Calcd for
C16H26O5Si: C, 58.87; H, 8.03. Found: C, 58.93; H, 8.04.
4.8. Preparation of 4,6-dihydroxy-2-(methoxymethoxy)aceto-
phenone 14
An ice cooled stirred solution of 4-(t-butyldimethylsilyloxy)-
6-hydroxy-2-(methoxymethoxy-oxy)acetophenone
(23.05 g,
70.6 mmol) in anhydrous THF (300 mL) under nitrogen was treated
with glacial acetic acid (4.9 mL, 85 mmol), then dropwise with 1 M
tetra-n-butylammonium fluoride/THF (85 mL, 85 mmol), and stir-
red for 1 h at 3 °C. Aqueous acetic acid (1 M, 150 mL) was then
added, and stirring continued for a few minutes, before diluting
with ethyl acetate (700 mL). The layers were separated, and the
aqueous solution extracted with ethyl acetate (2 ꢂ 100 mL). The
combined organic solution was dried (MgSO4), filtered, and con-
centrated in vacuo. The residue was dissolved in a minimum vol-
ume of dichloromethane and loaded onto a silica gel column and
eluted with 9:1 dichloromethane/ethyl acetate to afford 4,6-dihy-
4.11. Preparation of 3-benzyloxy-4-(4-methoxybenzyl)benzal-
dehyde 7b
An ice cooled stirred suspension of 60% sodium hydride/oil
(88 mg, 2.2 mmol) in anhydrous DMF (2 mL) under nitrogen was
treated with a solution of 3-benzyloxy-4-hydroxybenzaldehyde
(0.456 g, 2.0 mmol) in anhydrous DMF (2.0 mL) and the mixture
was stirred at room temperature for 30 min and re-cooled on an
ice bath.
A solution of 4-methoxybenzyl chloride (0.376 g,
2.4 mmol) in anhydrous DMF (1.0 mL) was added and the mixture
was allowed to reach room temperature and stirred overnight
(18 h). Water (50 mL) was added and after 30 min, a precipitate
formed. This was filtered, rinsed with water, partially air dried, dis-
solved in dichloromethane (40 mL), and dried (Na2SO4). The solu-
tion was added directly to a column of silica gel and eluted with
dichloromethane to afford 3-benzyloxy-4-(4-methoxybenzyl)-
benzaldehyde (0.665 g, 95%) as a white solid: mp 79–81 °C; LC/
MS m/z 349 [M+H]; 1H NMR (CDCl3, 400 MHz) d 3.81(s, 3H), 5.18
(s, 2H), 5.20 (s, 2H), 6.91 (d, J = 8.6, 2H), 7.04 (d, J = 8.2, 1H),
7.28–7.53 (m, 9H), 9.81 (s, 1H). 13C NMR (CDCl3, 100 MHz) d
55.4, 71.0, 71.2, 112.9, 113.5, 114.2, 126.7, 127.5, 128.1, 128.4,
128.7, 129.0, 130.5, 136.8, 149.5, 154.6, 159.7, 190.9. Anal. Calcd
for C22H20O4: C, 75.84; H, 5.79. Found: C, 75.59; H, 5.78.
droxy-2-(methoxymethoxy)acetophenone (13.78 g, 92%) as
a
white solid: mp 130–132 °C (lit.36 117–119 °C, EtOAc/hexane);
LC/MS m/z 213 [M+H]; 1H NMR (CDCl3, 400 MHz) d 2.65 (s, 3H),
3.52 (s, 3H), 5.24 (s, 2H), 6.04 (d, J = 2.2, 1H), 6.13 (d, J = 2.2, 1H),
6.27 (s, broad, 1H), 13.82 (s, 1H); 13C NMR (CDCl3, 100 MHz) d
33.0, 56.8, 93.7, 94.6, 97.6, 106.6, 161.2, 162.9, 167.1, 203.4. Anal.
Calcd for C10H12O5: C, 56.60; H, 5.70. Found: C, 56.72; H, 5.65.
4.9. Preparation of 4-benzyloxy-6-hydroxy-2-(methoxymeth-
oxy)acetophenone 6c
A stirred solution of 4,6-dihydroxy-2-(methoxymethoxy)aceto-
phenone (15.28 g, 72 mmol) in anhydrous DMF (200 mL) under
nitrogen, was treated with anhydrous potassium carbonate
(12.44 g, 90 mmol), then benzyl chloride (9.2 mL, 80 mmol) was
added via syringe. The mixture was heated to 75 °C for 4 h and
cooled to room temperature and combined with water (750 mL).
The aqueous suspension was stirred for 15 min, filtered, and the
solid rinsed with water, partially air dried, dissolved in dichloro-
methane (200 mL), dried (Na2SO4), and concentrated to a 100 mL
4.12. Preparation of 4-benzyloxy-3-hydroxybenzaldehyde 16
An ice cooled, stirred suspension of 60% sodium hydride/oil
(1.76 g, 44 mmol) in anhydrous DMF (40 mL) under nitrogen was
treated dropwise with a solution of 3,4-di-hydroxybenzaldehyde
(5.525 g, 40 mmol) in anhydrous DMF (40 mL) and the mixture
was stirred at room temperature for 30 min and recooled on an

370
M. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 362–373
ice bath. Benzyl bromide (5.25 mL, 44 mmol) was then added via
syringe and the mixture allowed to reach room temperature and
stirred overnight (18 h). The mixture was combined with 1% aque-
ous sodium hydroxide (300 mL) and the cloudy solution was ex-
tracted with ether (2 ꢂ 75 mL) and acidified with concentrated
hydrochloric acid. A precipitate soon formed, and the resulting sus-
pension was stirred for a few minutes and filtered. The solid was
rinsed with water, partially air dried, dissolved in dichloromethane
(100 mL), and dried (Na2SO4). The solution was added directly to a
column of silica gel and eluted with dichloromethane to yield a so-
lid, which was triturated from petroleum ethers to afford 4-benzyl-
oxy-3-hydroxybenzaldehyde (4.46 g, 49%) as a white solid: mp
122–123 °C (lit.38 121–122 °C); LC/MS m/z 229 [M+H]; 1H NMR
(CDCl3, 400 MHz) d 5.20 (s, 2H), 5.92 (s, 1H), 7.03 (d, J = 8.3, 1H),
7.35–7.44 (m, 6H), 7.46 (d, J = 1.9, 1H), 9.82 (s, 1H); 13C NMR
(CDCl3, 100 MHz) d 71.5, 111.7, 114.6, 124.4, 128.0, 128.9, 129.0,
131.0, 135.4, 146.5, 151.1, 191.1. Anal. Calcd for C14H12O3: C,
73.67; H, 5.30. Found: C, 73.91; H, 5.19.
4.15. Preparation of 4-methoxy-3-methoxymethoxybenzalde-
hyde 7g
An ice cooled stirred solution of 4-methoxy-3-hydroxybenzal-
dehyde (6.85 g, 45 mmol) and N,N-diisopropylethylamine
(15.75 mL, 90 mmol) in anhydrous dichloromethane (200 mL) un-
der nitrogen was treated dropwise with bromomethyl methyl
ether (5.0 mL, 55 mmol corrected for 90%) and stirred on an ice
bath for 1 h. Next, 1 M aqueous sodium hydroxide (125 mL) was
added and the mixture stirred for a few minutes and separated.
The aqueous solution was extracted with dichloromethane
(50 mL) and the combined organic solution washed with water
and brine (100 mL each), dried (Na2SO4), and concentrated in va-
cuo. The residue was dissolved in minimum dichloromethane
and loaded onto a silica gel column and eluted with 1:1 ethyl ace-
tate/heptane to afford 4-methoxy-3-methoxymethoxybenzalde-
hyde (8.74 g, 99%) as a pale yellow solid: mp 33–34 °C (lit.39 31–
32 °C); LC/MS m/z 197 [M+H]; 1H NMR (CDCl3, 400 MHz) d 3.51
(s, 3H), 3.95 (s, 3H), 5.27 (s, 2H), 7.00 (d, J = 8.3, 1H), 7.53 (dd,
J = 8.3, 1.9, 1H), 7.65 (d, J = 1.9, 1H), 9.84 (s, 1H); 13C NMR (CDCl3,
100 MHz) d 56.3, 56.5, 95.6, 111.3, 115.6, 126.9, 130.3, 147.1,
155.3, 190.8. Anal. Calcd for C10H12O4: C, 61.22; H, 6.16. Found:
C, 61.00; H, 6.07.
4.13. Preparation of 4-benzyloxy-3-methoxymethoxybenzal-
dehyde 7c
An ice cooled stirred solution of 4-benzyloxy-3-hydroxybenzal-
dehyde (6.85 g, 30 mmol) and N,N-diisopropylethylamine
(10.5 mL, 60 mmol) in anhydrous methylene chloride (200 mL) un-
der nitrogen was treated dropwise with bromomethyl methyl
ether (3.0 mL, 33 mmol corrected for 90%) and stirred on an ice
bath for 1 h. Aqueous sodium hydroxide (1 M, 75 mL) was added
and the mixture stirred a few minutes and separated. The aqueous
solution was extracted with dichloromethane (75 mL) and the
combined organic solution washed with water and brine (100 mL
each), dried (Na2SO4), and concentrated in vacuo. The residue
was dissolved in minimum dichloromethane and loaded onto a sil-
ica gel column and eluted with 2:1 heptane/ethyl acetate to afford
4-benzyloxy-3-methoxymethoxybenzaldehyde (8.09 g, 99%) as a
colorless viscous oil: LC/MS m/z 273 [M+H]; 1H NMR (CDCl3,
400 MHz) d 3.53 (s, 3H), 5.24 (s, 2H), 5.28 (s, 2H), 7.02 (d, J = 8.3,
1H), 7.30–7.46 (m, 5H), 7.48 (dd, J = 8.3, 1.9, 1H), 7.66 (d, J = 1.9,
1H), 9.84 (s, 1H); 13C NMR (CDCl3, 100 MHz) d 56.5, 71.0, 95.8,
113.4, 116.7, 126.8, 127.3, 128.4, 128.9, 130.6, 136.2, 147.5,
154.6, 190.8. Anal. Calcd for C16H16O4: C, 70.58; H, 5.92. Found:
C, 70.51; H, 6.01.
The experimental procedures for the preparation of the final
targets 1a–j are typified by those of (ꢀ)-30-OMe-40,5-di-O-benzyl-
7-O-MOM-epicatechin 1g.
4.16. Preparation of (E)-1-(2-benzyloxy-6-hydroxy-4-methoxy-
methoxy-phenyl)-3-(4-benzyloxy-3-methoxy-phenyl)-pro-
penone 5g
A dried 250 mL 3-necked round-bottomed flask was charged
with NaH (2.21 g, 55.31 mmol, 60% dispersion in mineral oil) under
nitrogen. Heptane (5 ml) was then added and the mixture was stir-
red for 5 min. Next, DMF (60 mL) was added and the white suspen-
sion was cooled in an ice-water bath for 10 min. A solution of the
acetophenone 6b (7.60 g, 25.14 mmol) in DMF (30 mL) was added
slowly via a syringe. The mixture was stirred for 30 min while cool-
ing in an ice-water bath. A solution of the 3-O-methyl 4-O-benzyl
benzaldehyde 7d (6.39 g, 26.39 mmol) in DMF (30 mL) was added
via syringe. The resultant orange mixture was stirred for an addi-
tional 10 min at 0 °C and at room temperature for 2 h. The reaction
was then poured onto crushed ice (350 g). The mixture was stirred
vigorously to obtain a yellow suspension. The solution pH was ad-
justed to neutral with 1 M HCl. The mixture was stirred until no
sticky droplets were visible and a homogenous yellow suspension
was obtained (ca 2 h). The yellow solid was collected by suction fil-
tration, rinsed with water (2 ꢂ 30 mL), and suction dried to afford
the title compound 5g (13.44 g, 100% yield): mp 138–139 °C; LC/
MS m/z 527 [M+H], 1H NMR (CDCl3, 400 MHz) d 3.52 (s, 3H), 3.69
(s, 3H), 5.11 (s, 2H), 5.02 (s, 4H), 6.22 (s, 1H), 6.32 (s, 1H), 6.66
4.14. Preparation of 3-methoxy-4-methoxymethoxybenzal-
dehyde 7e
An ice cooled stirred solution of 3-methoxy-4-hydroxybenzal-
dehyde (9.13 g, 60 mmol) and N,N-diisopropylethylamine (21 mL,
120 mmol) in anhydrous methylene chloride (400 mL) under
nitrogen was treated dropwise with bromomethyl methyl ether
(6.0 mL, 66 mmol corrected for 90%) and stirred on an ice bath
for 45 min. Aqueous sodium hydroxide (1 M, 150 mL) was added
and the mixture stirred for a few minutes and separated. The
aqueous solution was extracted with dichloromethane (100 mL)
and the combined organic solution washed with water
(200 mL), dried (Na2SO4), and concentrated in vacuo. The residue
was dissolved in minimum dichloromethane and loaded onto a
silica gel column and eluted with 1.5% ethyl acetate/dichloro-
methane to afford 3-methoxy-4-methoxymethoxybenzaldehyde
(11.56 g, 98%) as a colorless oil: LC/MS m/z 197 [M+H]; 1H NMR
(CDCl3, 400 MHz) d 3.52 (s, 3H), 3.95 (s, 3H), 5.32 (s, 2H), 7.27
(d, J = 8.2, 1H), 7.41–7.45 (m, 2H), 9.87 (s, 1H); 13C NMR (CDCl3,
100 MHz) d 56.2, 56.6, 95.2, 109.8, 115.0, 126.4, 131.3, 150.3,
152.2, 191.0. Anal. Calcd for C10H12O4: C, 61.22; H, 6.16. Found:
C, 60.94; H, 6.23.
(ABq, JAB = 8.2,
DmAB = 25.7, 2H), 7.21–7.51 (m, 10H), 7.75 (ABq,
JAB = 15.7,
D
m
AB = 27.3, 2H), 14.32 (s, 1H, OH); 13C NMR (CDCl3,
100 MHz) d 56.0, 56.6, 71.0, 71.4, 92.8, 94.2, 97.1, 107.2, 112.0,
113.8, 121.9, 125.9, 127.2, 128.1, 128.5, 128.75, 128.79, 128.9,
135.7, 136.9, 143.0, 149.6, 150.1, 161.8, 163.6, 168.1, 192.8. Anal.
Calcd for C32H30O7: C, 72.99; H, 5.74. Found: C, 72.88; H, 5.90.
4.17. Preparation of (E)-3-benzyloxy-2-[3-(3-benzyloxy-4-meth-
oxy-phenyl)-allyl]-5-methoxymethoxy-phenol 4g
A jacketed 1 L round-bottomed flask was charged with cerium
chloride heptahydrate (24.51 g, 65.8 mmol) and ethanol (92 mL).
The mixture was stirred at room temperature under nitrogen to
obtain a clear solution. Next, THF (224 mL) was added followed
by the addition of the chalcone 5g (13.30 g, 25.0 mmol). The reac-

M. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 362–373
371
tion was cooled to approximately 2 °C (internal temperature), after
which sodium borohydride (2.49 g, 65.8 mmol) was added in por-
tions. After completion of the addition, the reaction was stirred at
approximately 2 °C for 65 h, after which it was quenched by the
slow addition of 5 wt % citric acid solution. After vigorous gas re-
lease had subsided, the mixture was stirred for an additional
20 min, then extracted with ethyl acetate (300 mL). The solid
material in the aqueous layer was dissolved by adding 1 M HCl
(10 mL) and the aqueous phase was extracted with ethyl acetate
(300 mL). The combined organic layers were washed with satu-
rated sodium bicarbonate (200 mL ꢂ 3) and brine (200 mL). The
pH of the final aqueous wash was ca 4–5. The organic layer was
dried over anhydrous sodium sulfate. Removal of solvent in vacuo
afforded the crude as an orange solid. This was dissolved in dichlo-
romethane (30 mL) and purified by flash chromatography (silica
gel, heptane/ethyl acetate 3:1, v/v). Two fractions were collected.
The bottom fraction was concentrated in vacuo to obtain the de-
sired compound as a white solid (9.30 g, 73% yield). An analytical
sample was obtained by recrystallization from a mixture of hep-
tane and ethyl acetate (3:1, v/v): mp 129–130 °C; LC/MS m/z 513
[M+H]; 1H NMR (CDCl3, 400 MHz) d, 3.46 (s, 3H), 3.56 (d, J = 6.2,
2H), 3.85 (s, 3H), 5.04 (s, 2H), 5.11 (s, 2H), 5.12 (s, 2H), 5.26 (s,
1H), 6.11–6.22 (m, 1H), 6.25 (s, 1H), 6.32 (s, 1H), 6.38 (d, J = 15.8,
1H), 6.77 (m, 2H), 6.88 (s, 1H), 7.23–7.45 (m, 10H); 13C NMR
(CDCl3, 100 MHz) d 26.5, 56.1, 70.5, 71.3, 94.7, 94.8, 97.1, 108.4,
109.6, 114.4, 119.2, 126.7, 127.4, 127.5, 127.9, 128.0, 128.6,
130.3, 131.4, 137.25, 137.33, 147.7, 149.9, 155.8, 157.3, 158.1.
Anal. Calcd for C32H32O6: C, 74.98; H, 6.29. Found: C, 74.89; H, 6.33.
The less polar top fraction contained mainly a cyclized by-prod-
uct 5-benzyloxy-2-(4-benzyloxy-3-methoxy-phenyl)-7-methoxy-
methoxy-2H-chromene 22g and a small amount of the desired
product 4g. This was further purified by flash column (silica gel,
hepatane/ethyl acetate, 3:1, v/v) to obtain pure 22g (1.66 g, 13%)
as an orange oil: LC/MS m/z 511 [M+H]; 1H NMR (CDCl3,
400 MHz) d 3.45 (s, 3H), 3.89 (s, 3H), 5.06 (s, 2H), 5.10 (s, 2H),
5.16 (s, 2H), 5.62 (d, J = 9.9, 1H), 5.78 (s, 1H), 6.24 (d, J = 6.5, 2H),
6.83–6.97 (m, 3H), 7.05 (s, 1H), 7.27–7.49 (m, 10H); 13C NMR
(CDCl3, 100 MHz) d 56.2, 70.5, 71.2, 94.6, 94.7, 97.3, 106.0, 111.4,
114.1, 119.2, 120.0, 120.6, 127.4, 127.5, 127.9, 128.1, 128.66,
128.67, 134.1, 137.0, 137.3, 148.5, 150.0, 155.0, 155.4, 158.9;
4.19. Preparation of (1S,2S)-3-[2-benzyloxy-6-(tert-butyl-dimeth-
yl-silanyloxy)-4-methoxymethoxy-phenyl]-1-(4-benzyloxy-3-
methoxy-phenyl)-propane-1,2-diol 18g
To a cold mixture of ADMIX-a (56.7 g), t-butanol (150 mL), and
water (150 mL) cooled by a circulating chiller was added a solution
of 17g (9.51 g, 15.17 mmol) in THF (173 mL). The mixture was
cooled to ꢀ1 °C (internal temperature) followed by the addition
of methanesulfonamide (1.88 g, 19.72 mmol). The reaction was
stirred vigorously at ꢀ1 °C under nitrogen for 4 days, then
quenched by carefully adding a 10 wt % solution of sodium bisul-
fite (170 mL). The cooling was turned off and the mixture was stir-
red at room temperature overnight. The greenish bi-phasic
solution was transferred into a 1-L separatory funnel. The organic
layer was concentrated in vacuo. The aqueous layer was extracted
with ethyl acetate (250 ml ꢂ 2). The organic layers were combined
with the above residue from the initial organic phase, then washed
with water and brine (200 mL each) and dried over anhydrous
magnesium sulfate. Removal of the solvent afforded the crude
product as a yellow oil. The crude product was then dissolved in
10 mL of dichloromethane and purified by flash column (silica
gel, heptane/ethyl acetate 2:1, v/v) to obtain the desired product
(9.28 g, 93%) as a clear oil: LC/MS m/z 627 [M+H]; 1H NMR (CDCl3,
400 MHz) d 0.20 (s, 6H), 0.94 (s, 9H), 2.60 (s, broad, 1H,OH), 2.82 (d,
J = 7.1, 2H), 3.21 (s, broad, 1H, OH), 3.46 (s, 3H), 3.83 (s, 3H), 3.85
(m, partially overlaps with the aromatic OMe peak, 1H), 4.41 (d,
J = 5.2, 1H), 5.00 (s, 2H), 5.10 (s, 2H), 5.12 (s, 2H), 6.28 (d, J = 2.1,
1H), 6.36 (d, J = 2.2, 1H), 6.77 (s, 2H), 6.93 (s, 1H), 7.27–7.45 (m,
10H); 13C NMR (CDCl3, 100 MHz) d ꢀ4.1, ꢀ3.9, 18.4, 25.9, 27.8,
56.0, 70.7, 71.3, 75.7, 77.1, 94.9, 95.1, 100.7, 110.6, 110.9, 114.0,
119.2, 127.4, 127.5, 127.9, 128.2, 128.6, 128.8, 134.5, 136.6,
137.5, 147.8, 149.8, 155.4, 157.2, 158.4. Anal. Calcd for C38H48O8Si:
C, 69.06; H, 7.36. Found: C, 69.24; H, 7.27. The ee was determined
to be approximately 67% based on 1H NMR in the presence of
68 equivalents of (R)-(ꢀ)-1-(9-anthryl)-2,2,2-trifluoroethanol
(Pirkle’s alcohol) in CDCl3. Under these conditions, the OMe group
on the aromatic ring exhibited baseline-resolved doublets with d
3.70 [(S,S)-enantiomer] and 3.72 ppm [(R,R)-enantiomer],
respectively.
HRMS (ESI): Calcd for
511.2105.
C
32H30O6 ([M+H]+): 511.2115. Found:
4.20. Preparation of (1S,2S)-3-(2-benzyloxy-6-hydroxy-4-methoxy-
methoxy-phenyl)-1-(4-benzyloxy-3-methoxy-phenyl)-propane-
1,2-diol 3g
4.18. Preparation of (E)-{3-benzyloxy-2-[3-(4-benzyloxy-3-meth-
oxy-phenyl)-allyl]-5-methoxymethoxy-phenoxy}-tert-butyl-
dimethyl-silane 17g
To a solution of 18f (9.12 g, 14.7 mmol) in THF (70 mL) cooled in
an ice-water bath was added n-Bu4NF (29.4 mL, 1 M solution in
THF) containing acetic acid (1.77 g, 29.4 mmol) via an addition fun-
nel. After completion of the addition, the reaction was stirred in the
ice-water bath for 1 additional hour, then concentrated in vacuo to
remove the THF. The residue was dissolved in dichloromethane
(300 mL), washed with water (200 mL ꢂ 2), and then dried over
anhydrous magnesium sulfate. Removal of the solvent in vacuo
afforded the crude as a brown oil. The crude was dissolved in min-
imal volume of dichloromethane and purified by flash column (sil-
ica gel, heptane/EtOAc, 1:1, v/v) to obtain the desired product
(6.73 g, 84%) as a white solid. An analytical sample was obtained
by recrystallization from heptane/EtOAc (1:1, v/v): mp 136–
138 °C; LC/MS m/z 547 [M+H]; 1H NMR (CDCl3, 400 MHz) d 2.73
(dd, J = 14.6, 8.56, 1H), 2.93 (dd, J = 14.6, 3.4, 1H), 3.35 (s, 4H,
OMe plus OH), 3.80 (s, 3H), 3.95–4.02 (m, 1H), 4.45 (d, J = 6.8,
A
mixture of 4g (9.18 g, 17.9 mmol), imidazole (3.66 g,
53.7 mmol), and TBDMSCl (5.40 g, 35.8 mmol) in DMF (70 mL)
was stirred at room temperature under nitrogen overnight. Next,
it was poured onto 250 g of crushed ice. The milky mixture was ex-
tracted with ethyl acetate (250 mL ꢂ 2). The combined organic lay-
ers were washed with water and brine (200 mL each) and dried
over anhydrous magnesium sulfate. Removal of the solvent in va-
cuo afforded the crude product as an oil, which was purified by
flash chromatography (silica gel, heptane/ethyl acetate 3:1, v/v)
to give 17g (9.85 g, 88%) as a clear viscous oil: LC/MS, m/z 627
[M+H]; 1H NMR (CDCl3, 400 MHz) d 0.26 (s, 6H), 1.02 (s, 9H),
3.47 (s, 3H), 3.50 (d, J = 6.0, 2H), 3.86 (s, 3H), 5.04 (s, 2H), 5.11 (s,
2H), 5.13(s, 2H), 6.11–6.21 (m, 1H), 6.22–6.29 (m, 2H), 6.35 (s,
1H), 6.75 (ABq, JAB = 8.2,
D
m
AB = 21.2, 1H), 6.85 (s, 1H), 7.27–7.47
1H), 4.87 (ABq, JAB = 11.9,
DmAB = 16.6, 2H), 5.05 (s, 2H), 5.11 (s,
(m, 10H); 13C NMR (CDCl3, 100 MHz) d ꢀ3.9, 18.5, 26.0, 27.0,
56.0, 56.1, 70.3, 71.4, 94.9, 95.0, 100.3, 109.5, 113.5, 114.4, 119.0,
127.4, 127.5, 127.8, 127.86, 127.88, 128.58, 128.62, 129.4, 132.2,
137.47, 137.51, 147.4, 149.8, 154.9, 156.8, 158.4. Anal. Calcd for
4H), 6.24 (d, J = 2.3, 1H), 6.33 (d, J = 2.2, 1H), 6.73 (ABq, JAB = 8.3,
Dm
AB = 17.1, 2H),406.86 (d, J = 1.7, 1H), 8.10 (s, broad, 1H, phenolic
OH); 13C NMR (CDCl3, 100 MHz) d 26.7, 56.09, 56.14, 70.2, 71.0,
76.9, 77.0, 94.2, 94.7, 98.1, 107.4, 110.6, 113.8, 119.4, 127.0,
127.4, 127.8, 128.0, 128.6, 128.7, 133.6, 137.0, 137.2, 148.3,
C38H46O6Si: C, 72.81; H, 7.40. Found: C, 72.59; H, 7.51.

372
M. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 362–373
149.8, 157.5, 157.6, 157.9. HRMS (ESI): Calcd for C32H34O8
([M+H]+): 547.2326. Found: 547.2321.
13C NMR (CDCl3, 100 MHz) d 28.1, 56.1, 56.2, 68.4, 70.1, 71.2,
81.9, 94.6, 94.8, 96.9, 103.6, 110.8, 114.2, 120.0, 127.3, 127.4,
128.0, 128.66, 128.71, 130.9, 137.1, 137.2, 148.7, 150.2, 155.5,
4.21. Preparation of 30-O-methyl-40,5-di-O-benzyl-7,-O-methoxy-
methoxy-(+)-catechin-3-O-propyl ester 19g
157.3, 157.9. ½a D20
¼ þ7:1 (c 5.4, CHCl3). Anal. Calcd for C32H32O7:
ꢁ
C, 72.71; H, 6.10. Found: C, 72.79; H, 6.19.
Evaporation of the top fraction afforded an approximately 1:1
diastereomeric ester of the Mosher’s acid by 1H NMR as an oil
which solidified upon standing (2.55 g, 86%).
A mixture of 3g (6.42 g, 11.75 mmol), triethyl orthopropionate
(3.73 g, 21.14 mmol), and pyridinium p-toluenesulfonate (1.59 g,
6.35 mmol) in 1,2-dichloroethane (150 mL) was heated in an oil
bath at 65 °C for 1 h, after which it was concentrated in vacuo.
The oily residue was dissolved in dichloromethane (20 ml) and
purified by flash chromatography (silica gel, heptane/ethyl acetate
4:1, v/v) to obtain the desired product 19g (6.80 g, 100%) as a clear
oil, which was solidified upon standing at room temperature. An
analytical sample was obtained by recrystallization from hep-
tane/EtOAc (4:1, v/v): mp 98–99 °C; LC/MS m/z 585 [M+H]; 1H
NMR (CDCl3, 400 MHz) d 0.97 (t, J = 7.6, 3H), 2.09–2.28 (m, 2H),
2.71 (dd, J = 16.8, 7.3, 1H), 3.00 (dd, J = 16.7, 5.6, 1H), 3.47 (s, 3H),
3.87 (s, 3H), 4.97 (d, J = 7.1, 1H), 5.02 (s, 2H), 5.13 (s, 2H), 5.15 (s,
2H), 5.36 (q, J = 6.4, 1H), 6.29 (d, J = 2.2, 1H), 6.35 (d, J = 2.2, 1H),
6.83 (s, 2H), 6.92 (s, 1H), 7.27–7.44 (m, 10H); 13C NMR (CDCl3,
100 MHz) d 9.1, 24.8, 27.7, 56.2, 69.0, 70.2, 71.2, 78.7, 94.5, 94.8,
96.9, 102.7, 110.5, 114.0, 119.5, 127.4, 127.5, 128.0, 128.1,
128.67, 128.68, 131.0, 137.0, 137.2, 148.3, 149.8, 155.1, 157.4,
4.23. Preparation of (2R)-5-benzyloxy-2-(4-benzyloxy-3-meth-
oxy-phenyl)-7-methoxymethoxy-chroman-3-one 20g
A
mixture of 30-O-methyl-40,5-di-O-benzyl-7-O-methoxy-
methyl-(+)-catechin 2g (3.10 g, 5.86 mmol) and Dess–Martin peri-
odinane (4.97 g, 11.71 mmol) in wet dichloromethane (60 mL) was
stirred at room temperature until completion of the reaction (ca.
3 h). Saturated NaHCO3 solution (60 mL) was then added and the
mixture was stirred at room temperature for 30 min. The organic
layer was separated and the aqueous layer was extracted with
dichloromethane (150 mL ꢂ 2). The combined organic layers were
washed with water (200 mL) and dried over anhydrous MgSO4. Re-
moval of the solvent afforded the crude product as a light yellow
oil, which was purified by flash chromatography (silica gel, hep-
tane/EtOAc, 3:1, v/v) to obtain the desired product (2R)-5-benzyl-
oxy-2-(4-benzyloxy-3-methoxy-phenyl)-7-methoxymethoxy-
chroman-3-one 20g (2.03 g, 66%) as a white solid: mp 120–121 °C;
LC/MS m/z 527 [M+H]; 1H NMR (CDCl3, 400 MHz) d 3.48 (s, 3H),
3.52 (d, J = 21.3, 1H), 3.66 (d, J = 21.3, 1H), 3.85 (s, 3H), 5.03 (s,
2H), 5.14 (s, 2H), 5.15 (s, 2H), 5.27 (s, 1H), 6.39 (d, J = 2.1, 1H),
6.50 (d, J = 2.1, 1H), 6.83 (m, 2H), 6.92 (s, 1H), 7.27–7.44 (m,
10H); 13C NMR (CDCl3, 100 MHz) d 34.0, 56.1, 56.2,70.3, 71.1,
83.3, 94.8, 95.9, 98.2, 103.3, 110.5, 114.0, 119.4, 127.3, 127.4,
128.0, 128.1, 128.2, 128.69, 128.73, 136.6, 137.1, 148.6, 149.9,
157.8, 173.6. ½a D20
¼ þ5:8 (c 5.2, CHCl3). Anal. Calcd for C35H36O8:
ꢁ
C, 71.90; H, 6.21. Found: C, 72.03; H, 6.27.
4.22. Preparation of 30-O-methyl-40,5-di-O-benzyl-7,-O-methoxy-
methoxy-(+)-catechin 2g
To a mixture of 19g (6.70 g, 11.46 mmol) in methanol (210 mL)
was added a solution of potassium carbonate (4.05 g, 29.34 mmol)
in water (16 mL). The mixture was stirred at room temperature for
24 h which gave a white suspension. This was filtered by suction to
obtain a wet cake. The filtrate was then concentrated in vacuo. The
residue was combined with the wet cake in dichloromethane
(500 mL). The dichloromethane solution was washed with water
(200 mL), brine (200 mL), and dried over anhydrous MgSO4. Re-
moval of the solvent in vacuo afforded the crude as an off-white so-
lid. The crude was stirred in methanol overnight, filtered, and dried
to obtain 5.10 g of pure product. The mother liquor was concen-
trated and the residue was purified by flash chromatography (silica
gel, heptane/EtOAc 2:1) to obtain 0.18 g of additional pure product.
The two crops of product were combined (5.28 g, 87% yield). The
enantiomeric excess was determined by chiral HPLC to be 66%.
The above enantiomerically enriched product (5.28 g, 10 mmol)
and Mosher’s acid (468 mg, 2.0 mmol) were dissolved in anhy-
drous dichloromethane (80 mL). The mixture was cooled in an
ice-water bath followed by the addition of N,N0-dicyclohexylcarbo-
diimide (412 mg, 2 mol) and a catalytic amount of 4-dimethylami-
nopyridine (40 mg, 0.33 mmol). The reaction was then stirred at
0 °C. After 30 min, chiral HPLC indicated 75% ee of the unreacted
catchin. After 60 min, additional Mosher’s acid (468 mg, 2 mmol)
and N,N0-dicyclohexylcarbodiimide (412 mg, 2 mol) were added
to the reaction. After 30 min, chiral HPLC showed 96% ee of the
unreacted catechin. The reaction was concentrated to a volume
of 20 mL. The residue (a suspension) was purified by flash chroma-
tography (silica gel, heptane/EtOAc, 2:1, v/v) to obtain two
fractions. Concentration of the bottom fraction afforded pure
30-O-methyl-40,5-di-O-benzyl-7-O-methoxymethyl-(+)-catechin
2g (3.22 g, 61% yield, 96% ee) as a white solid: mp 137–138 °C; LC/
MS m/z 529 [M+H]; 1H NMR (CDCl3, 400 MHz) d 2.67 (dd, J = 16.4,
9.20, 1H), 3.18 (dd, J = 16.4, 5.76, 1H), 3.47 (s, 3H), 3.91 (s, 3H), 4.06
154.8, 157.2, 158.0, 205.2 (C@O). ½a D20
¼ þ59:9 (c 5.0, CHCl3). Anal.
ꢁ
Calcd for C32H30O7: C, 72.99; H, 5.74. Found: C, 72.80; H, 5.76.
4.24. Preparation of 30-O-methyl-40,5-di-O-benzyl-7-O-methoxy-
methoxy-(ꢀ)-epicatechin 1g
A mixture of (2R)-5-benzyloxy-2-(4-benzyloxy-3-methoxy-phe-
nyl)-7-methoxymethoxy-chroman-3-one 20g (1.90 g, 3.61 mmol)
and aluminum isopropoxide (1.47 g, 7.22 mmol) in a mixed solvent
of toluene (60 mL) and 2-propanol (18 mL) was heated at reflux un-
der nitrogen. The distillate was collected via a Dean–Stark trap. After
ca. 13 mL of the distillate was collected (ca. 1 h), heating was
stopped, and the reaction was cooled to room temperature. The reac-
tion mixture was then concentrated in vacuo. The residue was dis-
solved in dichloromethane (100 mL). The dichloromethane
solution was washed with 1 M HCl (100 mL). The aqueous phase
was back extracted with dichloromethane (100 mL). The combined
dichloromethane layers were washed with saturated NaHCO3
(200 mL) and water (200 mL ꢂ 2) and dried over anhydrous MgSO4.
Removal of the solvent afforded the crude product as a light yellow
solid which was purified by flash chromatography (silica gel, hepa-
tene/EtOAc, 3:1, v/v) to obtain the desired product 30-O-methyl-40,5-
di-O-benzyl-7-O-methoxymethoxy-(ꢀ)-epicatechin 1g (1.51 g,
79%) as a white solid: mp 110–111 °C; LC/MS m/z 529 [M+H]; 1H
NMR (CDCl3, 400 MHz) d 3.00 (ABq, JAB = 17.4,
Dm ,
AB = 35.4, 2H)41
3.47 (s, 3H), 3.94 (s, 3H), 4.28 (s, br, 1H), 4.96 (s, 1H), 5.05 (s, 2H),
5.14 (s, 2H), 5.18 (s, 2H), 6.31 (d, J = 2.2, 1H), 6.40 (d, J = 2.2, 1H),
6.94 (ABq, JAB = 8.3,
Dm
AB = 17.2, 2H, H-50and H-60),42 7.11 (d,
J = 1.6, 1H, H-20), 7.27–7.47 (m, 10H); 13C NMR (CDCl3, 100 MHz) d
28.5, 56.1, 56.3, 66.5, 70.2, 71.3, 78.6, 94.8, 94.9, 97.1, 102.2, 110.4,
114.3, 118.7, 127.4, 127.97, 128.02, 128.66, 128.68, 131.5, 137.1,
(m, 1H), 4.65 (d, J = 8.4, 1H), 5.06 (ABq, JAB = 11.8,
5.12 (t, J = 7.0, 2H), 5.18 (s, 2H), 6.33 (ABq, JAB = 2.2,
2H), 6.88–6.96 (m, 2H), 7.00 (d, J = 1.2, 1H), 7.28–7.47 (m, 10H);
D
m
AB = 8.1, 2H),
D
m
AB = 10.7,
137.3, 148.2, 150.0, 155.4, 157.3, 158.4. ½a D20
¼ ꢀ15:8 (c 5.1, CHCl3).
ꢁ

M. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 362–373
373
10. Ottovani, J. I.; Momma, T. Y.; Kuhnle, G. K.; Keen, C. L.; Schroeter, H. Free Radic.
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Anal. Calcd for C32H32O7: C, 72.71; H, 6.10. Found: C, 72.73; H, 6.18. It
is 93% ee by Chiral HPLC.
The experimental procedures for the preparation of the racemic
chiral HPLC standards of the catechin 2a–j and epicatechin 1a–j are
illustrated by those of ( )-30-OMe-40,5-di-O-benzyl-7-O-methoxy-
methoxy-catechin 2g and the corresponding ( )-epicatechin 1g.
To a mixture of K3Fe(CN)6 (840 mg, 2.55 mmol), potassium car-
bonate (366 mg, 2.65 mmol), osmium trichloride monohydrate
(5.7 mg, 0.019 mmol), quinuclidine (6.9 mg, 0.062 mmol), and
methane sulfonamide (93.5 mg, 0.98 mmol) in t-butanol/water
(1:1, v/v, 12 mL) was added a solution of 22g (440 g, 0.86 mmol)
in tetrahydrofuran (12 mL). The resultant mixture was stirred at
room temperature for 18 h, after which it was quenched by adding
sodium bisulfite (1.2 g) and stirred for 1 h. The mixture was ex-
tracted with ethyl acetate (25 ml ꢂ 2). The combined organic lay-
ers were washed with water and brine (50 ml each), and dried
over anhydrous magnesium sulfate. Removal of the solvent affor-
ded an off-white solid (the crude product 23g). This solid was sus-
pended in acetic acid (20 mL) and treated with NaBH3CN (129 mg,
2.05 mmol) at 50 °C (oil bath) for 2 h. The light brown solution was
poured into a cold 2 M NaOH solution (100 mL). This gave a white
solid, which was collected by filtration, rinsed with water, suction
dried, and purified by flash chromatography (silica gel, heptane/
ethyl acetate 3:1, v/v) to obtain a 9:1 mixture of the desired race-
mic 2g and racemic 1g as a white solid (260 mg, 57% yield over two
steps). The ratio of 2g/1g was determined by both 1H NMR and chi-
ral HPLC. This mixture was used as a chiral HPLC standard without
first separating the racemic catechin from the racemic epicatechin.
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via the action of catechol-O-methyltransferase (COMT) and only one OH group
is methylated, thus limiting the total number of the epicatechin glucuronides/
sulfates that could be formed to ten each (4 non-methylated and 6 methylated
forms). For references on the enzymology of methylation of epicatechin and
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40. The higher field doublets were further split by the third proton at d 6.86 ppm
with a J = 1.8 Hz.
41. Each H-4 proton was split by H-3 with J = 4.4, 1.7 Hz, respectively.
42. H-60 was split by H-20 (J = 1.7 Hz).