Enantioselective synthesis of (2R,3S)-(+)-catechin

Article abstract of DOI:10.1016/S0957-4166(02)00182-9

A new enantioselective synthetic method for catechin from trans-methyl cinnamate derivative was developed via asymmetric dihydroxylation (ADH), the addition of an aryllithium species, followed by the Barton-McCombie reaction and an intramolecular Mitsunobu reaction as key steps.

Full text of DOI:10.1016/S0957-4166(02)00182-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 715–720
Enantioselective synthesis of (2R,3S)-(+)-catechin
Sang-sup Jew,* Doo-yeon Lim, So-young Bae, Hyun-ah Kim, Jeong-hoon Kim, Jihye Lee and
Hyeung-geun Park*
Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, South Korea
Received 1 March 2002; accepted 11 April 2002
Abstract—A new enantioselective synthetic method for catechin from trans-methyl cinnamate derivative was developed via
asymmetric dihydroxylation (ADH), the addition of an aryllithium species, followed by the Barton–McCombie reaction and an
intramolecular Mitsunobu reaction as key steps. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
cyclization, afforded a mixture of catechin 1a and the
C(2)-epimer 2b of catechin (in a 3:1 ratio), as a result of
C(2)-epimerization under the acidic cyclization condi-
tions.6 Recently, we reported a new and efficient syn-
thetic method for (2R,3S)-3-hydroxyflavanone, which
has a similar structure to the 3-flavanols, using asym-
metric dihydroxylation7 and an intramolecular Mit-
The catechins are a group of 3-flavanols including
catechin 1a, epicatechin 1b, enti-catechin 2a, enti-epi-
catechin 2b, and their derivatives. Catechins are widely
distributed in a variety of plants. Green tea leaves,
Camellia sinensis (family Theaceae) contain catechin as
a major component, comprising up to 30% of the
weight of dry leaves.1 Historically, green tea has been
popular in Asia.
sunobu reaction.8,9 We now describe
a
highly
enantioselective synthetic method (>99% ee) for the
catechin 1a using catalytic asymmetric dihydroxylation7
and an intramolecular Mitsunobu reaction8 as key
reactions.
Recently, extensive biological activity studies have
shown that catechin possesses various important bio-
logical activities, such as antitumor activity,2 antimuta-
genic activity,3 and antioxidant properties.4 As part of
our program to find new candidates for anticancer or
psychoactive agents, we wanted to perform a structure–
activity relationship (SAR) study by catechin modifica-
tions. Since a synthetic method for catechin should be
established ahead of the SAR study, we first had to
develop an efficient synthetic method for catechin.
2. Results and discussion
Based on the retrosynthetic analysis depicted in Scheme
1, we planned to prepare (2R,3S)-(+)-catechin 1a by
three steps: the asymmetric dihydroxylation of methyl
cinnamate derivative 5, the addition of a functionalized
aryllithium to the chiral dihydroxyaldehydes 4 followed
OH
OH
HO
O
2
HO
O
OH
OH
3
X
X
Y
Y
OH
OH
2a (enti-catechin): X=H, Y=OH
1a (catechin): X=OH, Y=H
2b (enti-epicatechin): X=OH, Y=H
1b (epicatechin): X=H, Y=OH
Thus far, several synthetic methods have been reported:
Vercanteren and Brown prepared catechin enantioselec-
tively by chemical resolution.5 Ferreira’s method, using
asymmetric dihydroxylation followed by acid-catalyzed
by deoxygenation via Barton–McCombie reaction,10
and the intramolecular Mitsunobu reaction.8
As shown in Scheme 2, the catechol 5 was protected at
both phenols with a methoxymethyl (MOM) group by
treatment with MOMCl under basic conditions to
* Corresponding authors.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00182-9

716
S. Jew et al. / Tetrahedron: Asymmetry 13 (2002) 715–720
enantioselectivity mnemonic of the ADH reactions.7
The two hydroxy groups at C(2) and C(3) of 7 were
protected by treating 7 with MOMCl and diisopropyl-
ethylamine to give 8 (89%). Compound 11 was pre-
pared by the addition of aryllithium 10 derived from
1,3,5-tris(methoxymethoxy)benzene and n-butyllithium
to 9, obtained by reduction of 8 with diisobutylalu-
minum hydride (87%). The deoxygenation could be
accomplished by a Barton–McCombie reaction. Treat-
ment of 11 with sodium hydride, carbon disulfide, and
imidazole in THF produced the xanthate, which was
reduced to 12 by using tributyltin hydride and 2,2%-azo-
bisisobutyronitrile (AIBN) (91%). Removal of all
MOM groups was carried out using 2% HCl in
methanol to afford 13 (49%).
For the final cyclization, in order to avoid the epimer-
ization accompanying Ferreira’s method using acidic
cyclization conditions, we chose the intramolecular
Mitsunobu reaction. Compound 13 was submitted to
the intramolecular Mitsunobu reaction using
triphenylphosphine and diethyl azodicarboxylate in
THF to afford the (2R,3S)-(+)-catechin, 1a [50%; >99%
ee; [h]2D2 +16.0 (c 0.1, acetone)]. The absolute configura-
tion of the new stereogenic center C(2) of 1a could be
assigned as R by the anti-relationship between C(2)H
and C(3)H (J=7.3 Hz), which is in accord with the SN2
mechanism of the Mitsunobu reaction, as expected.
Scheme 1.
afford 6 (99%). Sharpless asymmetric dihydroxylation7
of the ester 6 with AD-mix-a and methanesulfonamide
in tert-butanol–H2O (1:1) led to the diasteromerically
pure (2R,3S)-dihydroxy ester 7 (quant., >99% ee). The
enantiomeric excess was determined by 1H NMR analy-
sis of the diastereomeric Mosher’s esters11 of 7.12 The
absolute configuration was assigned as 2R,3S from the
Scheme 2. Reagents and conditions: (a) MOMCl (5.0 equiv.), NaH (5.0 equiv.), DMF, rt, 1 h, 99%; (b) AD-mix-a (1.4 g/mmol),
methanesulfonamide (1.0 equiv.), t-BuOH–H2O (1:1), rt, 5 h, 100%; (c) MOMCl (10.0 equiv.), i-Pr2NEt (2.5 equiv.), CH2Cl2, rt,
20 h, 89%; (d) DIBAL-H (1.3 equiv.), toluene, −78°C, 1 h, 87%; (e) 1,3,5-tris(methoxymethoxy)benzene (1.9 equiv.), n-BuLi (1.5
equiv.), THF, −78°C, 10 min, 53%; (f) (i) NaH (5.0 equiv.), imidazole, CS2, CH3I, THF, 60°C, 1 h, 99%, (ii) n-Bu3SnH (3.0
equiv.), AIBN (cat.), benzene, 80°C, 2 h, 91%; (g) 2% HCl (17.0 equiv.), MeOH, 50°C, 30 min, 49%; (h) PPh3 (1.5 equiv.), DEAD
(1.5 equiv.), THF, rt, 1.5 h, 50%.

S. Jew et al. / Tetrahedron: Asymmetry 13 (2002) 715–720
717
3. Conclusion
sodium sulfite was added to the reaction and the mix-
ture was allowed to stir for an additional 10 min. The
mixture was diluted with EtOAc and the layers were
separated. The organic phase was washed with water
and brine, dried over MgSO4, and concentrated in
vacuo. Purification of the residue by silica gel chro-
matography (hexanes:EtOAc=1:2) afforded the desired
product 7 as a white solid (493 mg, 100% yield): [h]D21
The highly enantioselective synthesis of catechin 1a has
been accomplished by employing the asymmetric dihyd-
roxylation, the addition of aryllithium followed by the
Barton–McCombie reaction, and the intramolecular
Mitsunobu reaction as the crucial steps, in eight steps
from 3%,4%-dihydroxymethyl cinnamate 5 (9%, >99% ee).
The efficient synthetic route can be applied to the
synthesis of other catechins, 1b and 2a,b by the combi-
nation of the (E)- or (Z)-a,b-unsaturated ester and the
AD-mix-a or AD-mix-b. We believe that this method
will be very useful to prepare various derivatives of
catechins for SAR studies to find new candidates for
anticancer and psychoactive drugs.
1
+3.9 (c 1.7, CHCl3); H NMR (CDCl3, 300 MHz) l
2.65 (d, 1H, J=7.1 Hz), 3.07 (d, 1H, J=5.8 Hz), 3.51
(s, 3H), 3.53 (s, 3H), 3.87 (s, 3H), 4.36 (dd, 1H, J=5.8,
2.7 Hz), 4.97 (dd, 1H, J=7.1, 2.7 Hz), 5.23 (s, 2H), 5.24
(s, 2H), 7.02 (dd, 1H, J=8.5, 2.2 Hz), 7.16 (d, 1H,
J=8.5 Hz), 7.22 (d, 1H, J=2.2 Hz); IR (neat) 1741,
2954, 3469 cm−1; LRMS (EI) 316 [M]+.
4.4. Methyl (2R,3S)-2,3-bis(methoxymethoxy)-3-[3%,4%-
4. Experimental
4.1. General
bis(methoxymethoxy)phenyl]propionate 8
To a solution of diol 7 (1.25 g, 4.88 mmol) and i-
Pr2NEt (2.12 mL, 12.2 mmol) in anhydrous CH2Cl2 (20
mL) was added dropwise MOMCl (3.7 mL, 48.8 mmol)
at 0°C. The resulting solution was stirred for 10 min at
the same temperature and allowed to warm to room
temperature while stirring for 20 h. The reaction mix-
ture was diluted with EtOAc and washed with water
and brine. The organic phase was dried over MgSO4,
filtered and concentrated in vacuo. The residue was
purified by silica gel chromatography (hex-
anes:EtOAc=2:1) to afford the desired product 8 as a
colorless oil (1.79 g, 89%): [h]2D0 +110.0 (c 0.9, CHCl3);
1H NMR (CDCl3, 300 MHz) l 3.00 (s, 3H), 3.32 (s,
3H), 3.50 (s, 6H), 3.76 (s, 3H) 4.31 (d, 1H, J=3.4 Hz),
4.49 (d, 1H, J=6.8 Hz), 4.58 (s, 2H), 4.65 (d, 1H,
J=6.8 Hz), 5.09 (d, 1H, J=3.4 Hz), 5.21 (s, 4H), 7.01
(dd, 1H, J=8.6, 2.0 Hz), 7.12 (d, 1H, J=8.6 Hz), 7.24
(d, 1H, J=2.0 Hz); IR (neat) 1715, 2953 cm−1; LRMS
(EI) 404 [M]+.
Optical rotations were measured with a JASCO DIP-
1000 digital polarimeter. Infrared spectra were taken on
a Perkin–Elmer 1710 FT-IR spectrometer. Mass spectra
1
were obtained on a VG Trio-2 GC-MS instrument. H
and 13C NMR spectra were measured with a JEOL
JNM-LA 300, a JEOL JNM-GCX 400, using TMS as
the internal standard. All reactions were carried out
under an argon atmosphere using anhydrous solvents
except for those involving hydrolysis. Most reagents
were obtained from commercial suppliers and used
without further purification unless noted. Tetra-
hydrofuran was distilled from Na and benzophenone,
and methylene chloride from CaH2.
4.2. Methyl 3%,4%-bis(methoxymethoxy)cinnamate 6
To a suspension of NaH (95% in mineral oil, 3.0 g, 0.12
mol) and methyl 3%,4%-dihydroxycinnamate (4.73 g,
0.024 mol) in anhydrous DMF (100 mL) was added
dropwise MOMCl (9.24 mL, 0.12 mol) at 0°C. After
stirring for 1 h at room temperature, the reaction
mixture was quenched by the addition of water and
then the solvent was removed in vacuo. The residue was
diluted with EtOAc and washed with water and brine.
The organic phase was dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by
silica gel chromatography (hexanes:EtOAc=1:1) to
afford the desired product 6 as a yellow oil (6.80 g, 99%
4.5. (2R,3S)-2,3-Bis(methoxymethoxy)-3-[3%,4%-bis-
(methoxymethoxy)phenyl]propionaldehyde 9
To a solution of compound 8 (4.2 g, 10.4 mmol) in
anhydrous toluene (80 mL) at −78°C was added
DIBAL-H dropwise (13.5 mL, 13.5 mmol, 1.0 M in
toluene). The resulting solution was stirred for 1 h at
−78°C. The reaction was quenched by dropwise addi-
tion of sat. NH4Cl, and was diluted with ethyl ether
(250 mL). After allowing the reaction mixture to reach
room temperature, a saturated solution of Rochelle salt
(250 mL) was added and the mixture was stirred for 18
h. The layers were separated and the organic phase was
washed with water and brine, dried over MgSO4 and
evaporated. The residue was purified by silica gel chro-
matography (hexanes:EtOAc=1:1) to afford the
desired product 9 as a colorless oil (3.39 g, 87%): [h]D21
1
yield). H NMR (CDCl3, 300 MHz) l 3.51 (s, 3H), 3.53
(s, 3H), 3.80 (s, 3H), 5.25 (s, 2H), 5.27 (s, 2H), 6.33 (d,
1H, J=15.8 Hz), 7.15 (s, 2H), 7.36 (s, 1H), 7.62 (d, 1H,
J=15.8 Hz); IR (neat) 1714, 2958 cm−1; LRMS (EI)
282 [M]+.
4.3. Methyl (2R,3S)-2,3-dihydroxy-3-[3%,4%-bis(methoxy-
methoxy)phenyl]propionate 7
1
+131.6 (c 0.95, CHCl3); H NMR (CDCl3, 300 MHz) l
3.20 (s, 3H), l.33 (s, 3H), 3.51 (s, 6H), 4.09 (dd, 1H,
J=3.2, 1.0 Hz), 4.44 (d, 1H, J=7.0 Hz), 4.56 (s, 2H),
4.69 (d, 1H, J=7.0 Hz), 5.08 (d, 1H, J=3.2 Hz), 5.23
(s, 4H), 6.99 (dd, 1H, J=8.3, 2.0 Hz), 7.14 (d, 1H,
J=8.3 Hz), 7.23 (d, 1H, J=2.0 Hz), 9.77 (d, 1H, J=1.0
Hz); IR (neat) 1734, 2953 cm−1; LRMS (EI) 374 [M]+.
To a solution of AD-mix-a (2.22 g) and methanesulfon-
amide (148 mg, 1.56 mmol) in tert-BuOH–H2O (1:1
v/v, 15 mL) was added the methyl cinnamate derivative
6 (439 mg, 1.56 mmol). The resulting solution was
stirred vigorously for 5 h at room temperature. Excess

718
S. Jew et al. / Tetrahedron: Asymmetry 13 (2002) 715–720
4.6. Methyl (2S,3R)-2,3-dihydroxy-3-[3%,4%-bis(methoxy-
methoxy)phenyl]propionate 7%
filtration of the reaction mixture, the filtrate was con-
centrated in vacuo to afford the desired product 14% as
1
a colorless oil (200 mg, 98%). H NMR (CDCl3, 300
To a solution of AD-mix-b (967 mg) and methanesul-
fonamide (656 mg, 0.69 mmol) in tert-BuOH–H2O (1:1
v/v, 6 mL) was added compound 6 (195 mg, 0.69
mmol). The resulting solution was stirred vigorously for
5 h at room temperature. Excess sodium sulfite was
added to the reaction mixture and the mixture was
allowed to stir for an additional 10 min. The mixture
was diluted with EtOAc and the layers were separated.
The organic phase was washed with water and brine,
dried over MgSO4, and concentrated in vacuo. The
purification of the residue by silica gel chromatography
(hexanes:EtOAc=1:2) afforded the desired product 7%
as a white solid (213 mg, 98%).
MHz) l 3.37 (s, 3H), 3.38 (s, 3H), 3.41 (s, 3H), 3.52 (s,
3H), 3.72 (s, 3H), 5.02 (d, 1H, J=6.6 Hz), 5.10 (d, 1H,
J=6.6 Hz), 5.23 (s, 2H), 5.50 (d, 1H, J=2.9 Hz), 6.51
(d, 1H, J=2.9 Hz), 6.84 (dd, 1H, J=6.6, 2.9 Hz),
7.07–7.12 (m, 2H), 7.25–7.42 (m, 10H).
4.10. Methyl 2,3-bis[(S)-a-methoxy-a-(trifluoromethyl)-
phenylacetoxy]-3-[3%,4%-bis(methoxymethoxy)phenyl]-
propionate 14¦
To a solution of diol 7¦ (40 mg, 0.13 mmol) and DMAP
(77 mg, 0.63 mmol) in anhydrous THF (1.5 mL) was
added (S)-MTPACl (118 mL, 0.63 mmol). The resulting
mixture was stirred for 2 h at room temperature. After
filtration of the reaction mixture, the filtrate was con-
centrated in vacuo to afford the desired product 14¦ as
4.7. Methyl 2,3-dihydroxy-3-[3%,4%-bis(methoxymethoxy)-
phenyl]propionate 7¦
1
a colorless oil (90 mg, 95%). H NMR (CDCl3, 300
To a solution of NMO (1.41 g, 3.20 mmol) in tert-
BuOH–H2O (1:1 v/v, 5 mL) was added dropwise
osmium tetroxide (1.5 mL, 0.32 mmol, 0.2 M in tolu-
ene). After stirring for 10 min, compound 6 (900 mg,
3.20 mmol) was added. The resulting solution was
stirred vigorously for 15 h at room temperature. Excess
sodium sulfite was added to the reaction and the mix-
ture was allowed to stir for an additional 10 min. The
mixture was diluted with EtOAc and the layers were
separated. The organic phase was washed with water
and brine, dried over MgSO4, and concentrated in
vacuo. The purification of the residue by silica gel
chromatography (hexanes:EtOAc=1:2) afforded the
desired product 7%% as a white solid (677 mg, 67%).
MHz) l 3.37–3.44 (m, 6H), 3.51–3.56 (m, 6H), 3.67 (s,
1.5H), 3.72 (s, 1.5H), 5.01–5.11 (m, 2H), 5.20 (s, 1H),
5.23 (s, 1H), 5.47 (dd, 1H, J=6.6, 2.9 Hz), 6.47 (dd,
1H, J=6.6, 2.7 Hz), 6.73–7.06 (m, 3H), 7.25–7.59 (m,
10H).
4.11. (2R,3S)-3-[3¦,4¦-Bis(methoxymethoxy)]phenyl-2,3-
bis(methoxymethoxy)-1-[2%,4%,6%-tris(methoxymethoxy)]-
phenylpropanol 11
To a solution of 1,3,5-tris(methoxymethoxy)benzene
(4.22 g, 16.3 mmol) in anhydrous THF (50 mL) was
added dropwise n-BuLi (8.13 mL, 13.0 mmol, 1.6 M in
hexane). The mixture was stirred for 2 h at 50°C before
a solution of aldehyde 9 (3.25 g, 8.7 mmol) in anhy-
drous THF (40 mL) was added dropwise at −78°C.
After the addition was completed, the reaction was
stirred for 10 min at −78°C, and then quenched by
addition of water. The solvent was removed in vacuo
and the residue was diluted with EtOAc and washed
with water and brine. The organic phase was dried over
MgSO4, filtered and evaporated. The residue was
purified by silica gel chromatography (hex-
anes:EtOAc=1:2) to afford the desired product 11 as a
colorless oil (2.92 g, 53%). 1H NMR (CDCl3, 400 MHz)
l 3.45 (s, 3H), 3.48 (s, 3H), 3.50 (s, 9H), 3.51 (s, 6H),
3.73 (d, 1H, J=6.8 Hz), 3.95 (d, 1H, J=6.8 Hz), 4.74
(d, 1H, J=6.4 Hz), 4.81 (d, 1H, J=6.4 Hz), 5.12–5.15
(m, 4H), 5.20–5.22 (m, 8H), 5.31 (s, 1H), 5.43–5.46 (m,
1H), 6.55 (s, 2H), 7.04–7.14 (m, 3H); IR (neat) 2954,
3545 cm−1; LRMS (CI) 615 [M−17]+.
4.8. Methyl (2R,3S)-2,3-bis[(S)-a-methoxy-a-(trifluoro-
methyl)phenylacetoxy]-3-[3%,4%-bis(methoxymethoxy)-
phenyl]propionate 14
To a solution of diol 7 (35 mg, 0.11 mmol) and DMAP
(68 mg, 0.55 mmol) in anhydrous THF (1 mL) was
added
(S)-(+)-a-methoxy-a-(trifluoromethyl)phenyl-
acetyl chloride [(S)-MTPACl] (103 mL, 0.55 mmol). The
resulting mixture was stirred for 1 h at room tempera-
ture. After filtration of the reaction mixture, the filtrate
was concentrated in vacuo to afford the desired product
14 as a colorless oil (66 mg, 80% yield). 1H NMR
(CDCl3, 300 MHz) l 3.43 (s, 3H), 3.44 (s, 3H), 3.51 (s,
3H), 3.53 (s, 3H), 3.67 (s, 3H), 5.01 (dd, 2H, J=6.8, 2.0
Hz), 5.19 (s, 2H), 5.45 (d, 1H, J=2.6 Hz), 6.45 (d, 1H,
J=2.6 Hz), 6.73 (dd, 1H, J=8.3, 2.0 Hz), 6.90 (d, 1H,
J=8.3 Hz), 7.06 (d, 1H, J=2.0 Hz), 7.24–7.55 (m,
10H).
4.12. (2S,3S)-3-[3¦,4¦-Bis(methoxymethoxy)]phenyl-2,3-
bis(methoxymethoxy)-[2%,4%,6%-tris(methoxymethoxy)]-
phenylpropane 12
4.9. Methyl (2S,3R)-2,3-bis[(S)-a-methoxy-a-(trifluoro-
methyl)phenylacetoxy]-3-[3%,4%-bis(methoxymethoxy)-
phenyl]propionate 14%
To a suspension of NaH (460 mg, 18.2 mmol, 95% in
mineral oil) and imidazole (100 mg, 1.47 mmol) in
anhydrous THF (35 mL) was added a solution of
alcohol 11 (2.29 g, 3.63 mmol) in anhydrous THF (35
mL) at room temperature. After stirring for 30 min, the
To a solution of diol 7% (89 mg, 0.28 mmol) and DMAP
(172 mg, 1.41 mmol) in anhydrous THF (3 mL) was
added (S)-MTPACl (263 mL, 1.41 mmol). The resulting
mixture was stirred for 1 h at room temperature. After

S. Jew et al. / Tetrahedron: Asymmetry 13 (2002) 715–720
719
reaction mixture was cooled to 0°C, and then carbon
disulfide (8.0 mL) was added to the mixture dropwise.
The resulting mixture was stirred for 2 h at 60°C, and
the temperature was cooled to 0°C. Methyl iodide (1.4
mL) was added and the resulting solution was allowed
to warm to room temperature while stirring for 1 h.
The reaction mixture was quenched by addition of
water and the solvent was removed in vacuo. The
residue was diluted with EtOAc and washed with water
and brine. The organic phase was dried over MgSO4,
filtered and evaporated. The residue was purified by
silica gel chromatography (hexanes:EtOAc=1:1) to
afford the desired xanthate as a yellow oil (2.59 g,
99%). To a solution of xanthate (844 mg, 1.17 mmol)
and AIBN (19 mg, 0.12 mmol) in anhydrous benzene
was added n-Bu3SnH (0.9 mL, 3.50 mmol) at ambient
temperature. The resulting solution was stirred for 2 h
at 80°C. The solvent was removed in vacuo and the
residue was purified on silica gel chromatography (hex-
anes:EtOAc=1:1) to afford 658 mg (91%) of the
4.84 (br s, 1H), 5.67 (d, 1H, J=2.2 Hz), 5.87 (d, 1H,
J=2.2 Hz), 6.56–6.70 (m, 3H), 8.79 (s, 1H), 8.84 (s,
1H), 8.91 (s, 1H), 9.15 (s, 1H); 13C NMR (DMSO-d6,
100 MHz) l 28.3, 66.7, 81.4, 94.3, 95.5, 99.5, 114.9,
115.5, 118.9, 131.0, 145.2, 146.0, 155.8, 156.6, 156.9; IR
(KBr) 1469, 1521, 1625, 3345 cm−1; LRMS (EI) 290
[M]+.
Acknowledgements
The work reported in this paper was supported by
grants from Aminogen Co., Korea, via the Research
Center of New Drug Development of Seoul National
University, and the Korea Health 21 R&D Project,
Ministry of Health & Welfare, Republic of Korea
(01-PJ2-PG6-01NA01-0002).
1
desired product 12 as a colorless oil. H NMR (CDCl3,
References
400 MHz) l 2.62 (dd, 1H, J=13.7, 3.6 Hz), 2.95–3.01
(m, 1H), 3.39 (s, 3H), 3.46 (s, 6H), 3.47 (s, 6H), 3.53 (d,
6H, J=3.6 Hz), 4.15–4.19 (m, 1H), 4.48 (dd, 2H,
J=9.3, 6.7 Hz), 4.62 (d, 1H, J=5.4 Hz), 4.66 (dd, 2H,
J=13.7, 6.7 Hz), 5.14 (d, 6H, J=9.3 Hz), 5.23 (s, 4H),
6.51 (s, 2H), 6.98 (dd, 1H, J=8.3, 1.7 Hz), 7.12 (d, 1H,
J=8.3 Hz), 7.22 (d, 1H, J=1.7 Hz); IR (neat) 1026,
1152, 1507, 3565 cm−1; LRMS (CI) 616 [M]+.
1. Bohm, B. A. In The Flavanoids—Advance in Research
Since 1986; Harnone, J. B., Ed.; Chapmane & Hall:
London, 1994; p. 23.
2. (a) Weyant, M. J.; Carothers, A. M.; Dannenberg, A.
J.; Bertagonolli, M. M. Cancer Res. 2001, 61, 118; (b)
Garbisa, S.; Biggin, S.; Cavallarin, N.; Sartor, L.;
Benelli, R.; Albini, A. Nat. Med. 1999, 5, 1216; (c)
Cao, Y.; Cao, R. Nature (Lond.) 1999, 38, 398.
3. Choi, J. S.; Park, K. Y.; Mon, S. H.; Rhee, S. H.;
Yound, H. S. Arch. Pharm. Res. 1994, 17, 71.
4. (a) Nakao, M.; Takio, S.; Ono, K. Phytochemistry
1998, 49, 2379; (b) Jovanovic, S. V.; Streenken, S.;
Tosic, M.; Mrjanovic, B.; Simic, M. G. J. Am. Chem.
Soc. 1994, 116, 4846.
4.13. 2-[(2S,3S)-3-(3¦,4¦-Dihydroxyphenyl)-2,3-dihyd-
roxypropyl]-1,3,5-benzenetriol 13
A solution of compound 12 (41 mg, 0.066 mmol) in 2%
HCl–MeOH (2 mL) was stirred for 30 min at 40°C. The
reaction mixture was diluted with EtOAc and washed
with brine. The organic phase was dried over MgSO4,
filtered and concentrated in vacuo. Purification of the
residue by silica gel chromatography (CH2Cl2:MeOH=
10:1) afforded the desired product 13 as a white solid
5. (a) Brown, B. R.; Fuller, M. J. J. Chem. Res. (S) 1986,
140; (b) Nay, B.; Monti, J.-P.; Nuhrich, A.; Deffieux,
G.; Merillon, J.-M.; Vercauteren, J. Tetrahedron Lett.
2000, 41, 9049.
1
(10 mg, 49%). H NMR (CD3OD, 400 MHz) l 2.52
6. (a) Reinier, J.; Nel, J.; Rensburg, H.; Heerden, P.; Fer-
reira, D. J. Chem. Res. (S) 1999, 606; (b) van Rens-
burg, H.; van Heerden, P. S.; Bezuidenhoudt, B. C. B.;
Ferreira, D. Tetrahedron Lett. 1997, 38, 3089; (c) Rens-
burg, H.; Heerden, P. S.; Ferreira, D. J. Chem. Soc.,
Perkin Trans. 1 1997, 3415.
7. Sharpless, K. B.; Amberg, W.; Bennni, Y. L.; Crispino,
G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.;
Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J.
Org. Chem. 1992, 57, 2768.
8. (a) Mitsunobu, O. Chem. Rev. 1981, 1; (b) Lee, B. H.;
Biwas, A.; Miller, M. J. J. Org. Chem. 1986, 51, 106;
(c) Mattingly, P. G.; Kerwin, J. K.; Miller, M. J. J.
Am. Chem. Soc. 1979, 101, 3983.
9. Jew, S.-s.; Kim, H.-a.; Bae, S.-y.; Kim, J.-h.; Park, H.-g.
Tetrahedron Lett. 2000, 41, 7925.
(dd, 1H, J=16.0, 8.3 Hz), 2.83–2.89 (m, 1H), 3.98–4.01
(m, 1H), 4.58 (d, 1H, J=8.3 Hz), 5.95 (s, 2H), 6.72–
6.85 (m, 3H); IR (neat) 1636, 1684, 2361, 2916 cm−1;
LRMS (EI) 308 [M]+.
4.14. (2R,3S)-(+)-2-(3,4-Dihydroxyphenyl)-3,4-dihydro-
2H-chromene-3,5,7-triol, (+)-catechin 1a
To a solution of compound 13 (78 mg, 0.252 mmol)
and triphenylphosphine (99 mg, 0.378 mmol) in anhy-
drous THF (2.5 mL) was added DEAD (59 mL, 0.378
mmol) dropwise. After stirring for 1.5 h at room tem-
perature, the reaction mixture was diluted with EtOAc
and washed with water and brine. The organic phase
was dried over MgSO4, filtered and concentrated in
vacuo. Purification of the residue by silica gel chro-
matography (CH2Cl2:MeOH=10:1) afforded the
desired product 1a as a white solid (37 mg, 50%). [h]D22
10. (a) Barton, D. H. R.; Jaszberenyi, J. Cs.; Tang, D.
Tetrahedron Lett. 1993, 34, 3381; (b) Robins, M. J.;
Wilson, J. S.; Hansske, F. J. Am. Chem. Soc. 1983,
105, 4059; (c) Barton, D. H. R.; McCombie, S. W. J.
Chem. Soc., Perkin Trans. 1 1975, 1574.
1
+16.0 (c 0.1, acetone); H NMR (DMSO-d6, 400 MHz)
l 2.33 (dd, 1H, J=15.9, 7.9 Hz), 2.64 (dd, 1H, J=16.0,
5.2 Hz), 3.74–3.85 (m, 1H), 4.46 (d, 1H, J=7.3 Hz),

720
S. Jew et al. / Tetrahedron: Asymmetry 13 (2002) 715–720
11. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512.
1
12. The enantiomeric excess was determined by the H NMR
analysis of the corresponding Mosher’s esters 14, 14%, and
14¦ derived from 7, 7%, and 7¦, respectively, as shown in
Scheme 3. It was based on the peaks at l 3.67 (CH3OCO
of 14) and l 3.72 (CH3OCO of 14%). Compounds 14 and
14% were prepared from 7 (vide supra) and 7%, which was
obtained by treatment of 6 with AD-mix-b, using (S)-(−)-
methylphenylacetyl chloride [(S)-MTPACl] and 4-
dimethylaminopyridine (DMAP) in DMF (80 and 98%,
respectively). Compound 14¦ was also obtained by the
same method from 7¦ in a 95% yield, which was derived
from the treatment of 6 with osmium tetroxide (OsO4)
and 4-methylmorpholine-N-oxide (NMO) (67%). In the
case of (R)-MTPACl, the corresponding Mosher esters
could not be formed.
Scheme 3. Reagents and conditions: (a) vide supra (Scheme 2);
(b) AD-mix-b (1.4 g/mmol), methanesulfonamide (1.0 equiv.),
t-BuOH–H2O (1:1), rt, 5 h, 7% (98%); (c) OsO4 (0.1 equiv.),
NMO (1.0 equiv.), t-BuOH–H2O (1:1), rt, 15 h, 7¦ (67%); (d)
(S)-MTPACl (5.0 equiv.), DMAP (5.0 equiv.), THF, rt, 0.5 h,
14 (80%), 14% (98%), 14¦ (95%).