Synthesis of optically pure lactone metabolites of tea catechins

Article abstract of DOI:10.1055/s-0029-1218671

Catechins and epicatechins are extremely useful compounds in the context of biological activities. These compounds afford many metabolites, including γ-valerolactone derivatives, through metabolic pathways in the human body. Several of these γ-valerolacto

Full text of DOI:10.1055/s-0029-1218671

1512
PAPER
Synthesis of Optically Pure Lactone Metabolites of Tea Catechins
L
actone Metabolites of
a
T
ea
C
ate
c
s
hins ahiro Hamada, Ai Furuno, Sousuke Nakano, Takao Kishimoto, Noriyuki Nakajima*
Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939-0398, Japan
Fax +81(766)562498; E-mail: nori@pu-toyama.ac.jp
Received 11 December 2009; revised 8 January 2010
tea catechin metabolites 5a and 5d.19 We have also report-
ed the first synthesis of optically pure (5R)-5-phenyldihy-
drofuran-2(3H)-one and (S)-5a from optically active (R)-
and (S)-benzyl glycidyl ethers,20 and we showed that the
Abstract: Catechins and epicatechins are extremely useful com-
pounds in the context of biological activities. These compounds af-
ford many metabolites, including g-valerolactone derivatives,
through metabolic pathways in the human body. Several of these g-
valerolactone metabolites were synthesized as optically pure au- metabolite has an R-configuration because the specific ro-
thentic standards.
tation of the synthetic (S)-5a was opposite to that of the
metabolite form of 5a derived from (–)-epicatechin.
Key words: tea catechins, polyphenols, stereoselective synthesis,
lactones, cyclizations
Here we report efficient syntheses of four optically pure
(R)-type metabolite lactone derivatives 5a–d to confirm
their stereochemistry.
The tea catechins (–)-epicatechin (1), (–)-epigallocatechin
(2), (–)-epicatechin gallate (3), and (–)-epigallocatechin
gallate (4) are among a group of polyphenols that have a
diverse range of biological activities including scaveng-
ing of free radicals,1 antibacterial properties,2 antiviral
properties,3 anticancer properties,4 anti-inflammatory ac-
tivities,5 and inhibitory activities against DNA polymer-
ases.6 Orally administered tea catechins and procyanidins
are metabolized to afford ring-fission metabolites, includ-
ing 5-(3,4-dihydroxybenzyl)dihydrofuran-2(3H)-one [5a;
5-(3,4-dihydroxyphenyl)-g-valerolactone], 5-(3-hydroxy-
phenyl)dihydrofuran-2(3H)-one (5b), 5-(3,5-dihydroxy-
phenyl)dihydrofuran-2(3H)-one (5c), and 5-(3,4,5-tri-
hydroxyphenyl)dihydrofuran-2(3H)-one (5d) (Figure 1),7–13
which show the same biological activities as the tea cat-
echins.14–17 These lactone derivatives each contain one
stereogenic center at the C4 position that is derived from
the C3 position of the corresponding catechin; however,
there are no reports on the stereochemistry and optical pu-
rity of these lactones.
The problem in our previous synthesis of (S)-5a was the
final lactonization step. We examined various continuous
deprotection and lactonization conditions, but the isolated
yield remained less than 20%. We therefore carefully re-
investigated the synthetic route. In the previous route
(Scheme 1), (S)-benzyl glycidyl ether 7 was coupled with
four aryl bromides 6a–d, and subsequent acetylation with
acetic anhydride, triethylamine, and 4-(N,N-dimethylami-
no)pyridine gave the corresponding acetates 8a–d in 49–
68% yields. The protecting benzyl group was removed by
hydrogenolysis to give the corresponding alcohols 9a–d,
which were oxidized to aldehydes by Swern oxidation.
Subsequent one-pot Wittig olefination gave the a,b-unsat-
urated esters 10a–d in 79–96% yields. Hydrolysis of the
acetyl groups with ethanolic potassium carbonate gave the
allylic alcohols 11a–d which were reduced to the saturat-
ed g-hydroxy esters 12a–d by hydrogenation. When esters
12a–c were treated with an excess of p-toluenesulfonic
acid monohydrate under conditions designed to remove
ethanol, lactonization and desilylation occurred smoothly
to give the desired lactones 5a–c in 81–83% yields. The
In 1959, Watanabe reported the synthesis of racemic 5a
and 5b.18 Recently, Lambert and co-workers have report-
ed the synthesis and biological activities of the racemic
1
experimental H and 13C NMR spectra and mass spectra
agreed with the reported values. However, the optical ro-
OH
R1
5
3
3'
4'
OH
R1
4
O
HO
2
R2
O
5'
R2
OR3
O
OH
1 (–)-epicatechin: R1 = OH, R2 = R3 = H
5a R1 = OH, R2 = H
5b R1 = R2 = H
2 (–)-epigallocatechin: R1 = R2 = OH, R3 = H
3 (–)-epicatechin gallate: R1 = OH, R2 = H, R3 = galloyl
4 (–)-epigallocatechin gallate: R1 = R2 = OH, R3 = galloyl
5c R1 = H, R2 = OH
5d R1 = R2 = OH
Figure 1 The structures of tea catechins and their lactone metabolites
SYNTHESIS 2010, No. 9, pp 1512–1520
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x
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x
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Advanced online publication: 05.02.2010
DOI: 10.1055/s-0029-1218671; Art ID: F23809SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Lactone Metabolites of Tea Catechins
1513
OTBS
OTBS
R1
Br
OTBS
R1
BnO
a
BnO
b
R1
OAc
OH
OBn
R2
R2
R2
O
6a R1 = OTBS, R2 = H
6b R1 = R2 = H
8a R1 = OTBS, R2 = H (75%)
8b R1 = R2 = H (63%)
7
6c R1 = H, R2 = OTBS
6d R1 = R2 = OTBS
8c R1 = H, R2 = OTBS (73%)
8d R1 = R2 = OTBS (57%)
OTBS
R1
EtO2C
OTBS
e
d
c
HO
R1
OAc
OAc
R2
R2
9a: R1 = OTBS, R2 = H (96%)
9b: R1 = R2 = H (92%)
10a: R1 = OTBS, R2 = H (94%)
10b: R1 = R2 = H (95%)
9c: R1 = H, R2 = OTBS (79%)
9d: R1 = R2 = OTBS (86%)
10c: R1 = H, R2 = OTBS (95%)
10d: R1 = R2 = OTBS (97%)
EtO2C
OTBS
c
OH
R1
EtO2C
OTBS
f
O
R1
R1
OH
OH
O
R2
R2
R2
11a R1 = OTBS, R2 = H (74%)
11b R1 = R2 = H (74%)
12a R1 = OTBS, R2 = H (83%)
12b R1 = R2 = H (90%)
5a: R1 = OH, R2 = H (87%)
5b: R1 = R2 = H (81%)
11c R1 = H, R2 = OTBS (75%)
11d R1 = R2 = OTBS (83%)
12c R1 = H, R2 = OTBS (91%)
12d R1 = R2 = OTBS (97%)
5c: R1 = H, R2 = OH (83%)
5d: R1 = R2 = OH (0%)
Scheme 1 Reagents and conditions: (a) BuLi, THF then 7, BF3·OEt2, THF, –78 °C to r.t.; (b) Ac2O, Et3N, DMAP, CH2Cl2; (c) H2, 10% Pd/C,
EtOAc; (d) (ClCO)2, DMSO, Et3N, CH2Cl2 then Ph3P=CHCO2Et; (e) K2CO3, EtOH; (f) TsOH·H2O, 4 Å MS, benzene, reflux.
26
tations for 5a {[a]D28 –16.7 (c 0.70, MeOH)}, 5b {[a]D
ic bacteria. We attempted to identify suitable conditions
–29.2 (c 1.00, MeOH)}, and 5c {[a]D27 –20.6 (c 0.97, for separation by HPLC using several chiral columns, but
MeOH)} were greater than the literature values {5a: complete separation could not be achieved. We therefore
[a]D28 –8.6 (c 0.5, MeOH),8a 5b: [a]D26 –11.6 (c 0.1, converted both (R)-5b and (S)-5b21 into the corresponding
MeOH),8a,11b and 5c: [a]D27 –12.9 (c 0.4, MeOH)11a}.
(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate es-
ters, (S,S)-14 and (R,S)-14, in 96% and 98% yields, re-
spectively (Scheme 3). In the 13C NMR spectrum, the
peaks of the two diastereomers at the C3, C4, and C5 po-
sitions could be differentiated,22 and the ee values for both
the (R)-5b and (S)-5b enantiomers were therefore >96%.
Under the same conditions, we obtained the trihydroxy-
phenyl lactone 5d as a complex mixture, because the
pyrogallol part was unstable in the presence of p-toluene-
sulfonic acid monohydrate in refluxing benzene. The de-
sired lactone 5d was, however, obtained via the silyl-
protected lactone 13. Treatment of the g-hydroxy ester In conclusion, we synthesized optically pure forms of four
12d with pyridinum p-toluenesulfonate in refluxing ben- tea catechin lactone metabolites in seven steps for 5a–c,
zene gave 13 in 98% yield. This product was desilylated and in eight steps for 5d, in 30–37% overall yields. The
by treatment with concentrated hydrogen chloride in tet- specific rotations of the synthetic products were larger
rahydrofuran–methanol (5:1) at 0 °C to afford 5d in 81% than those previously reported for these metabolites.
yield (Scheme 2).
These results suggest that the epimerization step at the C3
position in epicatechin is vital to the metabolic pathway of
enteric bacteria. It is therefore important to clarify this
pathway in studying the medicinal chemistry of catechins.
It is necessary to know the ee values for the synthesized
lactones to compare them with the authentic standard tea
catechin metabolites obtained by fermentation with enter-
EtO2C
OTBS
OTBS
OTBS
b
a
5d
O
HO
OTBS
O
OTBS
OTBS
12d
13
Scheme 2 Reagents and conditions: (a) PPTS, benzene, reflux, 1 h, 98%; (b) concd HCl, THF–MeOH (5:1), 0 °C to r.t., 6 h, 81%.
Synthesis 2010, No. 9, 1512–1520 © Thieme Stuttgart · New York

1514
M. Hamada et al.
PAPER
J1,2 = 23.5 Hz, JA,B = 12.1 Hz, 2 H, C6H5CH2), 3.52–3.45 (m, 2 H,
H-1), 2.86–2.77 (m, 2 H, H-3), 2.02 [s, 3 H, C(O)CH3], 0.97 (s, 18
H, t-Bu), 0.18 [s, 6 H, Si(CH3)2], 0.17 [s, 6 H, Si(CH3)2].
CF3
MeO
OH
a
4
O
4
13C NMR (100 MHz, CDCl3): d = 170.5, 146.6, 145.5, 138.1, 130.2,
128.4, 127.7, 127.6, 122.33, 122.30, 120.9, 73.6, 73.2, 70.1, 36.3,
25.9(6), 25.9(5), 21.2, 18.5, 18.4, –4.1.
98%
O
O
O
O
O
O
(R)-5b
(R,S)-14
MeO
MS (ESI): m/z (%) = 567 (20) [M + Na]+, 562 (39) [M + H2O]+, 485
CF3
(100), 467 (20).
OH
a
4
O
4
HRMS (ESI): m/z [M + Na]+ calcd for C30H48NaO5Si2: 567.2933;
found: 567.2927.
96%
O
O
O
O
(S)-5b
(S,S)-14
(1S)-1-Benzyloxy-1-(3-[tert-butyl(dimethyl)siloxy]benzyl}ethyl
Acetate [(S)-8b]
Scheme 3 Reagents and conditions: (a) (R)-PhC(OMe)(CF3)COCl,
Et3N, DMAP, CH2Cl2.
Colorless oil; yield: 62% (based on epoxide 7); Rf = 0.32 (hexane–
EtOAc, 4:1); [a]D27 –2.8 (c 1.01, CHCl3).
ATR-IR (neat): 3031, 2955, 2930, 2886, 2858, 1737 (C=O), 1602,
1585, 1485, 1472, 1463, 1443, 1371, 1271, 1233, 1158, 1126, 1096,
1050, 1028, 1003, 974, 939, 874, 836, 779, 734, 695, 665 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.36–7.26 (m, 5 H, Ph-H), 7.12
(td, J = 7.6 and 0.6 Hz, 1 H, H-5¢), 6.78, (d, J = 7.7 Hz, 1 H, H-4¢),
6.70 (d, J = 0.5 Hz, 1 H, H-2¢), 6.68 (dd, J = 2.2 and 0.8 Hz, 1 H, H-
4¢), 5.23–5.17 (m, 1 H, H-2), 4.52 (ABq, JA,B = 12.1 Hz, J1,2 = 24.6
Hz, 2 H, benzylic), 3.53–3.46 (m, 2 H, H-1), 2.92–2.84 (m, 2 H, H-
3), 2.03 [s, 3 H, C(O)CH3], 0.97 (s, 9 H, t-Bu), 0.18 [s, 6 H,
Si(CH3)2].
Melting points were measured with an MPJ3 micro melting-point
apparatus (Yanaco Co. Ltd., Kyoto, Japan) and are uncorrected.
ATR-IR spectra were recorded by using a PerkinElmer Spectrum
100 spectrometer equipped with a Universal ATR accessory. 1H and
13C NMR spectra were recorded on a Bruker Biospin Avance II 400
spectrometer and a JEOL JNM LA-400 spectrometer with TMS or
a solvent peak as the internal standard (chemical shifts are given in
ppm). Low-resolution ESI MS spectra were recorded on an Agilent
Technology 1100 LC-MSD spectrometer from solns in aq MeOH,
aq MeCN, or 0.5% aq HCO2H. We recorded the ESI HRMS spectra
on a Bruker Daltonics micrOTOF spectrometer. Specific rotations
were measured with a Horiba polarimeter. Analytical TLC was con-
ducted on precoated TLC plates (silica gel 60F254, Merck). Column
chromatography was conducted by using silica gel 60N (70–230
mesh, Kanto Chemical). All reagents used were of commercial
quality. Dehydrated-grade THF and CH2Cl2 (Kanto Chemical) were
used without purification. All air- and moisture-sensitive reactions
were performed under an inert gas (N2 or argon).
13C NMR (100 MHz, CDCl3): d = 170.5 (C=O), 155.6, 138.6,
138.0, 129.3, 128.4, 127.68, 127.65, 122.5, 121.3, 118.3, 73.4, 73.2,
70.1, 36.9, 25.7, 21.2, 18.2, –4.40, –4.42.
MS (ESI): m/z (%) = 453 (26) [M + K]+, 437 (41) [M + Na]+, 432
(17) [M + H2O]+, 415 (11) [M + H]+, 355 (50), 337 (100), 247 (22).
HRMS (ESI): m/z [M + Na]+ calcd for C24H34NaO4Si: 437.2119;
found: 437.2131.
(1S)-2-(Benzyloxy)-1-{3,5-bis[tert-butyl(dimethyl)silyloxy]ben-
zyl}ethyl Acetate [(S)-8c]
(1S)-2-(Benzyloxy)-1-{3,4-bis[tert-butyl(dimethyl)siloxy]ben-
zyl}ethyl Acetate [(S)-8a]; Typical Procedure
Colorless oil; yield: 73% (based on epoxide 7); Rf = 0.5 (hexane–
A 1.6 M soln of BuLi in hexane (1.78 mL, 2.83 mmol) was added
to a soln of bromo compound 6a (1.13 g, 2.70 mmol) in THF (15
mL) at –78 °C, and the mixture was stirred for 40 min at the same
temperature. BF3·OEt2 (402 mg, 2.83 mmol) and benzyl (S)-gly-
cidyl ether [(S)-7, 422 mg, 2.57 mmol] were added at –78 °C. The
mixture was stirred for 22 h at r.t. The reaction was quenched with
sat. aq NH4Cl (20 mL), and the mixed soln was extracted with
EtOAc (60 mL). The organic layer was washed with H2O and brine,
dried (Na2SO4), and filtered. The filtrate was concentrated in vacuo,
and the residual oil was purified by column chromatography [silica
gel, hexane–EtOAc (9:1)] to give the coupling product (936 mg) as
a colorless oil containing a small amount of 7. The coupling product
was dissolved in CH2Cl2 (19 mL) and mixed with Et3N (1.88 g, 18.6
mmol), DMAP (114 mg, 0.93 mmol), and Ac2O (570 mg, 5.58
mmol) at 0 °C. The mixture was stirred for 8 h at r.t. The reaction
was quenched with H2O (20 mL), and the mixture was extracted
with EtOAc (60 mL). The organic layer was washed with 1 M HCl,
H2O, and brine, then dried (Na2SO4) and filtered. The filtrate was
concentrated in vacuo, and the residual oil was purified by column
chromatography [silica gel, hexane–EtOAc (15:1)] to give (S)-8a as
a colorless oil; yield: 995 mg (72% from 7); Rf = 0.49 (hexane–
EtOAc, 4:1); [a]D27 +4.2 (c 0.40, CHCl3).
EtOAc, 4:1); [a]D24 –3.9 (c 0.45, CHCl3).
ATR-IR (neat): 3032, 2955, 2930, 2886, 2858, 1739 (C=O), 1588,
1496, 1471, 1451, 1390, 1371, 1362, 1336, 1251, 1234, 1160, 1096,
1040, 1006, 956, 939, 828, 814, 778, 736, 696, 669 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.36–7.26 (m, 5 H, Ph-H), 6.34 (d,
J = 2.2 Hz, 2 H, H-2¢ and 6¢), 6.20 (t, J = 2.2 Hz, 1 H, H-4¢), 5.21–
5.15 (m, 1 H, H-2), 4.51 (ABq, J1,2 = 21.1 Hz, JA,B = 12.1 Hz, 2 H,
benzylic), 3.53–3.45 (m, 2 H, H-1), 2.82 (d, J = 6.8 Hz, 2 H, H-3),
2.03 [s, 3 H, C(O)CH3], 0.96 (s, 18 H, t-Bu), 0.17 [s, 12 H,
Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 170.5, 156.4, 139.0, 138.0, 128.4,
127.7, 127.6, 114.7, 110.5, 73.3, 73.2, 70.2, 36.9, 25.7, 21.2, 18.2,
–4.38, –4.40.
MS (ESI): m/z (%) = 583 (29) [M + Na]+, 545 (100) [M + H]+, 81
(62).
HRMS (ESI): m/z [M + H]+ calcd for C30H49O5Si2: 545.3113;
found: 545.3110.
(1S)-2-(Benzyloxy)-1-{3,4,5-tris[tert-butyl(dimethyl)siloxy]ben-
zyl}ethyl Acetate [(S)-8d]
ATR-IR (neat): 3032, 2886, 2955, 2930, 2858, 1738 (C=O), 1605,
1576, 1509, 1472, 1463, 1421, 1390, 1372, 1289, 1250, 1232, 1159,
1126, 1095, 1051, 1028, 982, 904, 836, 779, 734, 696, 667 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.36–7.26 (m, 5 H, Ph-H), 6.71 (d,
J = 8.1 Hz, 1 H, H-2¢), 6.69 (d, J = 2.1 Hz, 1 H, H-5¢), 6.62 (dd,
J = 8.1 and 2.1 Hz, 1 H, H-6¢), 5.16 (m, 1 H, H-2), 4.52 (ABq,
Colorless oil; yield: 57% (based on epoxide 7); Rf = 0.56 (hexane–
EtOAc, 4:1); [a]D28 –1.7 (c 1.05, CHCl3).
ATR-IR (neat): 2953, 2930, 2886, 2858, 1740 (C=O), 1574, 1494,
1472, 1463, 1430, 1390, 1361, 1344, 1230, 1081, 1029, 1005, 939,
894, 827, 779, 735, 696, 670 cm–1.
Synthesis 2010, No. 9, 1512–1520 © Thieme Stuttgart · New York

PAPER
Lactone Metabolites of Tea Catechins
1515
1H NMR (400 MHz, CDCl3): d = 7.35–7.26 (m, 5 H, Ph-H), 6.35 (s,
2 H, H-2¢ and 6¢), 5.18–5.12 (m, 1 H, H-2), 4.51 (ABq, JA,B = 12.1
Hz, J1,2 = 17.2 Hz, 2 H, benzylic), 3.51–3.44 (m, 2 H, H-1), 2.77–
2.71 (m, 2 H, H-3), 2.02 [s, 3 H, C(O)CH3], 0.98 (s, 9 H, t-Bu), 0.92
(s, 18 H, t-Bu), 0.18 [s, 12 H, Si(CH3)2], 0.10 [s, 6 H, Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 170.5, 143.4, 138.1, 137.0, 128.9,
128.4, 127.6, 127.5, 115.4, 73.6, 73.1, 70.3, 36.7, 26.2(3), 26.1(8),
21.2, 18.8, 18.4, –3.6, –4.0.
(1S)-1-{3,5-Bis[tert-butyl(dimethyl)silyloxy]benzyl}-2-hydroxy-
ethyl Acetate [(S)-9c]
Colorless oil; yield: 79%; Rf = 0.27 (hexane–EtOAc, 3:1); [a]D
–5.3 (c 1.05, CHCl3).
26
ATR-IR (neat): 3494 (OH), 2955, 2930, 2886, 2859, 1739 (C=O),
1587, 1472, 1450, 1390, 1373, 1362, 1337, 1251, 1237, 1187, 1159,
1037, 1018, 1005, 939, 828, 814, 778, 743, 702, 669 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.34 (d, J = 2.1 Hz, 2 H, H-2¢ and
6¢), 6.21 (t, J = 2.1 Hz, 1 H, H-4¢), 5.05 (qd, J = 6.8 and 3.2 Hz, 1 H,
H-2), 3.74–3.68 (m, 1 H, H-1), 3.63–3.57 (m, 1 H, H-1), 2.79 (qd,
J = 13.7 and 6.9 Hz, 2 H, H-3), 2.06 [s, 3 H, C(O)CH3], 1.60 (br d,
J = 2.1 Hz, 1 H, OH), 0.97 (s, 18 H, t-Bu), 0.18 [s, 12 H, Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 171.0, 156.5, 138.7, 114.6, 110.6,
75.8, 63.7, 36.6, 25.7, 21.2, 18.2, –4.38, –4.40.
MS (ESI): m/z (%) = 477 (9) [M + Na]+, 455 (100) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C23H43O5Si2: 455.2644;
MS (ESI): m/z (%) = 713 (18) [M + K]+, 697 (33) [M + Na]+, 675
(100) [M + H]+, 615 (74).
HRMS (ESI): m/z [M + H]+ calcd for C36H63O6Si3: 675.3927;
found: 675.3946.
(1S)-1-{3,4-Bis[tert-butyl(dimethyl)silyloxy]benzyl}-2-hydroxy-
ethyl Acetate [(S)-9a)]; Typical Procedure
10% Pd/C (145 mg) was added to a soln of (S)-8a (1.62 g, 2.97
mmol) in EtOAc (30 mL) added at r.t. The mixture was stirred for
10 h at r.t. under H2 (1 atm), and then filtered. The filtrate was con-
centrated in vacuo and the residual oil was purified by column chro-
matography [silica gel; hexane–EtOAc (4:1)] to give a colorless oil;
yield: 1.28 g (95%); Rf = 0.15 (hexane–EtOAc, 4:1); [a]D26 –6.5 (c
0.78, CHCl3).
found: 455.2647.
(1S)-2-Hydroxy-1-{3,4,5-tris[tert-butyl(dimethyl)silyloxy]ben-
zyl}ethyl Acetate [(S)-9d]
White powder; yield: 86%; mp = 94–95 °C (hexane–EtOAc);
Rf = 0.36 (hexane–EtOAc, 7:3); [a]D26 –4.8 (c 1.02, CHCl3).
ATR-IR (neat): 3460 (OH), 2955, 2930, 2886, 2858, 1738 (C=O),
1605, 1576, 1509, 1472, 1463, 1421, 1390, 1373, 1362, 1288, 1251,
1232, 1159, 1126, 1033, 1006, 982, 938, 905, 836, 778, 695, 666
cm–1.
ATR-IR (neat): 3488 (OH), 2950, 2929, 2896, 2857, 1740 (C=O),
1574, 1495, 1472, 1463, 1428, 1389, 1361, 1346, 1249, 1229, 1146,
1086, 1035, 1004, 939, 893, 827, 803, 779, 758, 736, 707, 673 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.36 (s, 2 H, H-2¢ and 6¢), 5.01
(octet, J = 3.2 Hz, 1 H, H-2), 3.71–3.54 (m, 2 H, H-1), 2.77–2.67
(m, 2 H, H-3), 2.05 [s, 3 H, C(O)CH3], 1.75 (br t, J = 6.2 Hz, 1 H,
OH), 0.98 (s, 9 H, t-Bu), 0.93 (s, 18 H, t-Bu), 0.20 [s, 12 H,
Si(CH3)2], 0.11 (s, 6 H, t-Bu).
13C NMR (100 MHz, CDCl3): d = 171.0, 148.5, 137.1, 128.6, 115.3,
63.7, 36.3, 26.22, 26.17, 21.2, 18.8, 18.4, –3.60, –3.62, –4.0.
1H NMR (400 MHz, CDCl3): d = 6.74 (d, J = 8.1 Hz, 1 H, H-2¢),
6.70 (d, J = 2.1 Hz, 1 H, H-5¢), 6.65 (dd, J = 8.1 and 2.1 Hz, 1 H, H-
6¢), 5.03 (qd, J = 6.9 and 3.2 Hz, 1 H, H-2), 3.70 (one of ABqd,
J = 2.6 Hz, JA,B = 11.9 Hz, 1 H, H-1), 3.59 (one of ABqd, J = 5.6
Hz, JA,B = 11.9 Hz, 1 H, H-1), 2.84–2.73 (m, 2 H, H-3), 2.05 [s, 3
H, C(O)CH3], 0.99 (s, 9 H, t-Bu), 0.98 (s, 9 H, t-Bu), 0.19 [s, 6 H,
Si(CH3)2], 0.18 [s, 6 H, Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 171.0, 146.7, 145.6, 129.8, 122.2,
MS (ESI): m/z (%) = 607 (42) [M + Na]+, 585 (100) [M + H]+, 525
(6).
HRMS (ESI): m/z [M + H]+ calcd for C29H57O6Si3: 585.3458;
found: 585.3463.
121.0, 76.1, 63.6, 36.1, 25.9, 21.2, 18.4, –4.07, –4.11.
MS (ESI): m/z (%) = 493 (37) [M + K]+, 477 (100) [M + Na]+, 472
(18) [M+ + H2O], 395 (40).
HRMS (ESI): m/z [M + Na]+ calcd for C23H42NaO5Si2: 477.2463;
Ethyl (2E,4S)-4-(Acetoxy)-5-{3,4-bis[tert-butyl(dimethyl)silyl-
oxy]phenyl}pent-2-enoate [(S)-10a]; Typical Procedure
(ClCO)2 (715 mg, 5.63 mmol) was added to a soln of DMSO (880
mg, 11.3 mmol) in CH2Cl2 (28 mL) at –78 °C. The mixture was
stirred at this temperature for 20 min and then mixed with a soln of
alcohol (S)-9a (1.28 g, 2.81 mmol) in CH2Cl2 (28 mL). The mixture
was stirred for 40 min at –78 °C and then added to Et3N (2.85 g, 28.2
mmol). The resulting mixture was stirred at r.t. for 1 h. The soln was
cooled to 0 °C and Ph3P=CHCO2Et (1.96 g, 5.63 mmol) at 0 °C was
added. The mixture was stirred at r.t. for 2 h. The reaction was
quenched with sat. aq NH4Cl (30 mL) and extracted with EtOAc
(90 mL). The organic layer was washed with H2O and brine, and
then dried (Na2SO4) and filtered. The filtrate was concentrated in
vacuo. The residual oil was purified by column chromatography
[silica gel, hexane–EtOAc (12:1)] to give a colorless oil; yield: 1.38
g (94%); Rf = 0.67 (hexane–EtOAc, 7:3); [a]D27 +6.9 (c 0.98,
CHCl3).
found: 477.2484.
(1S)-1-{3-[tert-Butyl(dimethyl)silyloxy]benzyl}-2-hydroxyethyl
Acetate [(S)-9b]
Colorless oil; yield: 92%; Rf = 0.21 (hexane–EtOAc, 3:1); [a]D
–8.3 (c 1.10, CHCl3).
28
ATR-IR (neat): 3452 (OH), 2956, 2930, 2886, 2858, 1737 (C=O),
1602, 1585, 1485, 1472, 1463, 1442, 1373, 1251, 1235, 1158, 1032,
1003, 974, 939, 871, 836, 779, 713, 695, 665 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.16–7.12 (m, 1 H, H-5¢), 6.81 (br
d, J = 7.6 Hz, 1 H, H-4¢), 6.71–6.69 (m, 2 H, H-2¢ and 4¢), 5.08 (oc-
tet, J = 3.3 Hz, 1 H, H-2), 3.75–3.58 (m, 2 H, H-1), 2.92–2.81 (m, 2
H, H-3), 2.06 [s, 3 H, C(O)CH3], 0.97 (s, 9 H, t-Bu), 0.19 [s, 6 H,
Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 171.0, 155.7, 138.3, 129.4, 122.4,
121.2, 118.4, 75.9, 36.6, 25.7, 21.2, 18.2, –4.39, –4.41.
ATR-IR (neat): 2956, 2930, 2896, 2858, 1745, 1723, 1662, 1604,
1577, 1509, 1472, 1464, 1422, 1390, 1368, 1301, 1272, 1252, 1227,
1160, 1127, 1086, 1026, 980, 904, 836, 779, 755, 695, 666 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.85 (dd, J = 15.8 and 5.3 Hz, 1
H, H-3), 6.74 (d, J = 8.1 Hz, 1 H, Ar-H), 6.65 (d, J = 2.1 Hz, 1 H,
Ar-H), 6.62 (dd, J = 8.1 and 2.2 Hz, 1 H, Ar-H), 5.88 (dd, J = 15.8
and 1.5 Hz, 1 H, H-2), 5.54 (qd, J = 6.7 and 1.5 Hz, 1 H, H-4), 4.18
(qd, J = 7.1 and 1.0 Hz, 2 H, OCH2CH3), 2.87 (one of AB, dd,
J = 13.9 and 7.2 Hz, 1 H, H-5), 2.81 (one of AB, dd, J = 13.9 and
MS (ESI): m/z (%) = 363 (19) [M + K]+, 347 (70) [M + Na]+, 307
(11), 265 (63), 247 (100).
HRMS (ESI): m/z [M + Na]+ calcd for C17H28NaO4Si: 347.1649;
found: 347.1648.
Synthesis 2010, No. 9, 1512–1520 © Thieme Stuttgart · New York

1516
M. Hamada et al.
PAPER
6.5 Hz, 1 H, H-5), 2.04 [s, 3 H, C(O)CH3], 1.27 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 0.98 (s, 9 H, t-Bu), 0.97 (s, 9 H, t-Bu), 0.18 [s, 12 H,
Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 169.8, 165.8, 146.7, 145.8, 144.6,
129.0, 122.4, 122.3, 121.9, 121.0, 73.2, 60.5, 39.7, 25.94, 25.93,
21.0, 18.5, 18.4, 14.2, –4.08, –4.11.
ATR-IR (neat): 2954, 2930, 2896, 2858, 1746 (OAc), 1725 (ethyl
ester), 1663, 1574, 1493, 1472, 1464, 1431, 1391, 1362, 1307,
1252, 1227, 1200, 1174, 1084, 1047, 1005, 977, 938, 893, 827, 779,
737, 705, 670 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.81 (dd, J = 15.7 and 5.3 Hz, 1
H, H-3), 6.32 (s, 2 H, H-2¢ and 6¢), 5.85 (dd, J = 15.7 and 1.5 Hz, 1
H, H-2), 5.52 (qd, J = 6.6 and 1.3 Hz, 1 H, H-4), 4.20–4.11 (m, 2 H,
OCH2CH3), 2.80 (one of ABqd, J = 6.9 Hz, JA,B = 13.9 Hz, 1 H, H-
5), 2.75 (one of ABqd, J = 6.5 Hz, JA,B = 13.9 Hz, 1 H, H-5), 2.05
[s, 3 H, C(O)CH3], 1.27 (t, J = 7.1 Hz, 3 H, OCH2CH3), 0.97 (s, 9
H, t-Bu), 0.92 (s, 18 H, t-Bu), 0.19 [s, 18 H, Si(CH3)2].
MS (ESI): m/z (%) = 545 (14) [M + Na]+, 540 (100) [M + H2O]+,
523 (8) [M + H]+, 463 (43).
HRMS (ESI): m/z [M + Na]+ calcd for C27H46NaO6Si2: 545.2725;
found: 545.27388.
13C NMR (100 MHz, CDCl3): d = 169.8, 165.8, 148.5, 144.5, 137.3,
127.8, 122.0, 115.4, 73.3, 60.5, 39.9, 26.21, 26.16, 21.0, 18.8, 18.4,
14.2, –3.62, –3.64, –4.0.
Ethyl (2E,4S)-4-(Acetoxy)-5-{3-[tert-butyl(dimethyl)silyl-
oxy]phenyl}pent-2-enoate [(S)-10b]
Colorless oil; yield: 95%; Rf = 0.62 (hexane–EtOAc, 3:1);
[a]D27 +4.0 (c 1.07, CHCl3).
MS (ESI): m/z (%) = 691 (24) [M + K]+, 675 (55) [M + Na]+, 670
(18) [M + H2O]+, 653 (100) [M + H]+, 593 (53).
ATR-IR (neat): 2956, 2931, 2898, 2859, 1744 (OAc), 1721 (ethyl
ester), 1662, 1602, 1585, 1486, 1472, 1442, 1390, 1368, 1307,
1270, 1226, 1159, 1086, 1026, 1003, 974, 938, 920, 836, 779, 695,
665 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C33H61O7Si3: 653.3720;
found: 653.3742.
Ethyl (2E,4S)-5-{3,4-Bis[tert-butyl(dimethyl)silyloxy]phenyl}-
4-hydroxypent-2-enoate [(S)-11a]; Typical Procedure
1H NMR (400 MHz, CDCl3): d = 7.14 (t, J = 7.8 Hz, 1 H, H-5¢),
6.85 (dd, J = 15.7 and 5.3 Hz, 1 H, H-3), 6.78 (d, J = 7.6 Hz, 1 H,
H-6¢), 6.72–6.66 (m, 2 H, H-2¢ and 4¢), 5.90 (dd, J = 15.7 and 1.5
Hz, 1 H, H-2), 5.61–5.56 (m, 1 H, H-4), 4.18 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 2.94 (one of ABqd, J = 7.3 Hz, JA,B = 13.8 Hz, 1 H, H-
5), 2.88 (one of ABqd, J = 6.4 Hz, JA,B = 13.8 Hz, 1 H, H-5), 2.05
[s, 3 H, C(O)CH3], 1.28 (t, J = 7.1 Hz, 3 H, OCH2CH3), 0.98 (s, 9
H, t-Bu), 0.18 [s, 6 H, Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 169.8, 165.9, 155.7, 144.4, 137.4,
129.4, 122.5, 122.0, 121.3, 118.7, 73.0, 60.6, 40.2, 25.7, 20.1, 18.2,
14.2, –4.41, –4.43.
MS (ESI): m/z (%) = 431 (18) [M + K]+, 415 (52) [M + Na]+, 333
(100), 259 (13).
K2CO3 (1.28 g, 9.26 mmol) was added to a soln of (S)-10a (1.21 g,
2.31 mmol) in EtOH (46 mL), and the mixture was stirred for 4 h.
The reaction was quenched with H2O (50 mL), and the mixture was
extracted with EtOAc (200 mL). The organic layer was washed with
H2O (90 mL) and brine (90 mL), dried (Na2SO4), and filtered. The
filtrate was concentrated in vacuo, and the residual oil was purified
by column chromatography [silica gel, hexane–EtOAc (4:1)] to
give a colorless oil; yield: 795 mg (72%); Rf = 0.46 (hexane–
EtOAc, 7:3); [a]D28 –0.8 (c 1.11, CHCl3).
ATR-IR (neat): 3456 (OH), 2955, 2930, 2896, 2858, 1721 (OC=O),
1657, 1605, 1576, 1509, 1472, 1463, 1421, 1390, 1364, 1295, 1271,
1252, 1229, 1159, 1125, 1097, 1040, 981, 905, 836, 778, 695, 666
cm–1.
HRMS (ESI): m/z [M + Na]+ calcd for C21H32NaO5Si: 415.1911;
1H NMR (400 MHz, CDCl3): d = 6.99 (dd, J = 15.7 and 4.5 Hz, 1
H, H-3), 6.78 (d, J = 8.0 Hz, 1 H, Ar-H), 6.68 (d, J = 2.1 Hz, 1 H,
Ar-H), 6.65 (dd, J = 8.0 and 2.1 Hz, 1 H, Ar-H), 6.05 (dd, J = 15.7
and 1.7 Hz, 1 H, H-2), 4.45 (br q, J = 3.5 Hz, 1 H, H-4), 4.20 (q,
J = 7.1 Hz, 2 H, OCH2CH3), 2.84 (one of AB, dd, J = 13.7 and 4.9
Hz, 1 H, H-5), 2.67 (one of AB, dd, J = 13.7 and 8.2 Hz, 1 H, H-5),
1.81 (br d, J = 4.1 Hz, 1 H, OH), 1.29 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 0.982 (s, 9 H, t-Bu), 0.981 (s, 9 H, t-Bu), 0.191 [s, 6 H,
Si(CH3)2], 0.186 [s, 6 H, Si(CH3)2].
found: 415.1916.
Ethyl (2E,4S)-4-(Acetoxy)-5-{3,5-bis[tert-butyl(dimethyl)silyl-
oxy]phenyl}pent-2-enoate [(S)-10c]
Colorless oil; yield: 95%; Rf = 0.73 (hexane–EtOAc, 7:3);
[a]D26 +4.7 (c 1.01, CHCl3).
ATR-IR (neat): 2956, 2931, 2897, 2859, 1744 (OAc), 1724 (ethyl
ester), 1663, 1588, 1472, 1451, 1390, 1369, 1342, 1307, 1252,
1227, 1159, 1006, 978, 938, 917, 828, 814, 779, 743, 699, 676 cm–1.
13C NMR (100 MHz, CDCl3): d = 166.4, 148.8, 146.9, 146.0, 129.5,
122.4, 122.3, 121.2, 120.6, 71.8, 60.4, 42.6, 25.9, 18.4, 14.2, –3.8,
–4.1.
MS (ESI): m/z (%) = 503 (93) [M + Na]+, 498 (62) [M + H2O]+, 81
(100).
HRMS (ESI): m/z [M + H]+ calcd for C25H45O5Si2: 481.2800;
found: 481.2802.
1H NMR (400 MHz, CDCl3): d = 6.83 (dd, J = 15.7 and 5.3 Hz, 1
H, H-3), 6.30 (d, J = 2.1 Hz, 2 H, H-2¢ and 6¢), 6.22 (t, J = 2.1 Hz, 1
H, H-4¢), 5.88 (dd, J = 15.8 and 1.5 Hz, 1 H, H-2), 5.58–5.53 (m, 1
H, H-4), 4.17 (qd, J = 7.1 and 1.1 Hz, 2 H, OCH2CH3), 2.87 (one of
ABqd, J = 7.1 Hz, JA,B = 13.8 Hz, 1 H, H-5), 2.80 (one of ABqd,
J = 6.5 Hz, JA,B = 13.8 Hz, 1 H, H-5), 2.05 [s, 3 H, C(O)CH3], 1.27
(t, J = 7.1 Hz, 3 H, OCH2CH3), 0.97 (s, 18 H, t-Bu), 0.17 [s, 12 H,
Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 169.8, 165.8, 156.5, 144.4, 137.8,
Ethyl (2E,4S)-5-{3-[tert-Butyl(dimethyl)silyloxy]phenyl}-4-hy-
droxypent-2-enoate [(S)-11b]
Colorless oil; yield: 74%; Rf = 0.44 (hexane–EtOAc, 3:1); [a]D
–1.5 (c 1.12, CHCl3).
122.0, 114.7, 110.8, 60.6, 40.2, 25.7, 21.0, 18.2, 14.2, –4.40, –4.42.
27
MS (ESI): m/z (%) = 545 (5) [M + Na]+, 523 (100) [M + H]+, 463
(14).
HRMS (ESI): m/z [M + H]+ calcd for C27H47O6Si2: 523.2906;
found: 523.2910.
ATR-IR (neat): 3454 (OH), 2956, 2930, 2897, 2858, 1719 (C=O),
1702, 1657, 1602, 1584, 1486, 1472, 1464, 1442, 1390, 1367, 1304,
1271, 1253, 1157, 1098, 1039, 1003, 975, 939, 887, 836, 779, 707,
694, 665 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.18 (t, J = 7.8 Hz, 1 H, H-5¢),
7.00 (dd, J = 15.7 and 4.5 Hz, 1 H, H-3), 6.81 (d, J = 7.5 Hz, 1 H,
H-6¢), 6.76–6.70 (m, 2 H, H-2¢ and 4¢), 6.06 (dd, J = 15.7 and 1.8
Hz, 1 H, H-2), 4.53–4.49 (m, 1 H, H-4), 4.20 (q, J = 7.1 Hz, 2 H,
Ethyl (2E,4S)-4-(Acetoxy)-5-{3,4,5-tris[tert-butyl(dimethyl)silyl-
oxy]phenyl}pent-2-enoate [(S)-10d]
Colorless oil; yield: 97%; Rf = 0.24 (hexane–EtOAc, 9:1);
[a]D28 +5.8 (c 1.05, CHCl3).
Synthesis 2010, No. 9, 1512–1520 © Thieme Stuttgart · New York

PAPER
Lactone Metabolites of Tea Catechins
1517
OCH2CH3), 2.90 (one of ABqd, J = 4.8 Hz, JA,B = 13.6 Hz, 1 H, H-
5), 2.73 (one of ABqd, J = 8.4 Hz, JA,B = 13.6 Hz, 1 H, H-5), 1.78
(br d, J = 3.4 Hz, 1 H, OH), 1.29 (t, J = 7.1 Hz, 3 H), 0.98 (s, 9 H, t-
Bu), 0.19 [s, 6 H, Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 166.4, 156.0, 148.7, 138.2, 129.7,
122.4, 121.2, 120.7, 118.7, 71.7, 60.4, 43.2, 25.7, 18.2, 14.3, –4.4.
Ethyl (4R)-5-{3,4-Bis[tert-butyl(dimethyl)silyloxy]phenyl}-4-
hydroxypentanoate [(R)-12a]; Typical Procedure
A mixture of ester (S)-11a (795 mg, 1.65 mmol) and 10% Pd/C (65
mg) in EtOAc (16 mL) was stirred for 2 h at r.t. under H2 (1 atm).
The mixture was filtered and concentrated in vacuo to give a resid-
ual oil that was purified by column chromatography [silica gel, hex-
ane–EtOAc, (4:1)] to give a colorless oil; yield: 662 mg (83%);
Rf = 0.44 (hexane–EtOAc, 7:3); [a]D26 –0.3 (c 1.08, CHCl3).
MS (ESI): m/z (%) = 389 (10) [M + K]+, 373 (23) [M + Na]+, 368
(14) [M + H2O]+, 351 (3) [M + H]+, 333 (55), 259 (13), 73 (100).
ATR-IR (neat): 3455 (OH), 2955, 2930, 2896, 2858, 1735 (C=O),
1605, 1575, 1509, 1472, 1463, 1420, 1390, 1362, 1295, 1252, 1221,
1158, 1125, 1070, 1031, 1007, 981, 906, 836, 778, 695, 666 cm–1.
HRMS (ESI): m/z [M + Na]+ calcd for C19H30NaO4Si: 373.1806;
found: 373.1821.
1H NMR (400 MHz, CDCl3): d = 6.76 (d, J = 8.1 Hz, 1 H, H-2¢),
6.67 (d, J = 2.1 Hz, 1 H, H-5¢), 6.64 (dd, J = 8.1 and 2.1 Hz, 1 H, H-
6¢), 4.13 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.79–3.74 (m, 1 H, H-4),
2.69 (one of ABqd, J = 4.6 Hz, JA,B = 13.6 Hz, 1 H, H-5), 2.56 (one
of ABqd, J = 8.2 Hz, JA,B = 13.6 Hz, 1 H, H-5), 2.52–2.42 (m, 2 H,
H-2), 1.90–1.84 (m, 1 H, H-3), 1.81 (br d, J = 3.8 Hz, 1 H, OH),
1.78–1.71 (m, 1 H, H-3), 1.25 (t, J = 7.1 Hz, 3 H, OCH2CH3), 0.98
(s, 18 H, t-Bu), 0.19 [s, 12 H, Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 174.0, 146.8, 145.6, 131.0, 122.3,
122.2, 121.1, 72.0, 60.4, 43.4, 31.4, 30.9, 25.9, 18.4, 14.2, –4.06,
–4.09.
MS (ESI): m/z (%) = 521 (30) [M + K]+, 505 (100) [M + Na]+, 465
(60).
Ethyl (2E,4S)-5-{3,5-bis[tert-butyl(dimethyl)silyloxy]phenyl}-4-
hydroxypent-2-enoate [(S)-11c]
Colorless oil; yield: 75%; Rf = 0.35 (hexane–EtOAc, 4:1); [a]D
–4.1 (c 1.00, CHCl3).
28
ATR-IR (neat): 3465 (OH), 2956, 2930, 2887, 2858, 1721 (C=O),
1657, 1587, 1472, 1450, 1390, 1363, 1338, 1306, 1252, 1158, 1097,
1035, 1005, 936, 855, 828, 813, 778, 743, 717, 698, 676 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.97 (dd, J = 15.6 and 4.5 Hz, 1
H, H-3), 6.33, (d, J = 2.1 Hz, 2 H, H-2¢ and 6¢), 6.24 (t, J = 2.1 Hz,
1 H, H-4¢), 6.05 (dd, J = 15.7 and 1.7 Hz, 1 H, H-2), 4.49–4.45 (m,
1 H, H-4), 4.19 (q, J = 7.1 Hz, 2 H, OCH2CH3), 2.83 (one of ABqd,
J = 4.8 Hz, JA,B = 13.5 Hz, 1 H, H-5), 2.66 (one of ABqd, J = 8.3
Hz, JA,B = 13.5 Hz, 1 H, H-5), 1.80 (br d, J = 4.2 Hz, 1 H, OH), 1.29,
(t, J = 7.1 Hz, 3 H, OCH2CH3), 0.97 (s, 18 H, t-Bu), 0.18 [s, 12 H,
Si(CH3)2].
HRMS (ESI): m/z [M + Na]+ calcd for C25H46O5Si2Na: 505.2776;
found: 505.2767.
13C NMR (100 MHz, CDCl3): d = 166.4, 156.8, 148.6, 138.5, 120.7,
Ethyl (4R)-5-{3-[tert-Butyl(dimethyl)silyloxy]phenyl}-4-
hydroxypentanoate [(R)-12b]
Colorless oil; yield: 90%; Rf = 0.72 (hexane–EtOAc, 1:1); [a]D
–1.8 (c 1.10, CHCl3).
114.6, 110.8, 71.6, 60.4, 43.2, 25.7, 18.2, 14.2, –4.4.
MS (ESI): m/z (%) = 519 (15) [M + K]+, 503 (22) [M + Na]+, 481
26
(100) [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C25H45O5Si2: 481.2800;
found: 481.2809.
ATR-IR (neat): 3455 (OH), 2955, 2930, 2858, 1733 (C=O), 1602,
1584, 1485, 1472, 1463, 1442, 1390, 1373, 1348, 1252, 1157, 1083,
1069, 1031, 1003, 973, 939, 882, 836, 779, 711, 695, 665 cm–1.
Ethyl (2E,4S)-4-Hydroxy-5-{3,4,5-tris[tert-butyl(dimethyl)silyl-
oxy]phenyl}pent-2-enoate [(S)-11d]
1H NMR (400 MHz, CDCl3): d = 7.16 (t, J = 7.7 Hz, 1 H, H-5¢),
6.80 (d, J = 7.6 Hz, 1 H, H-6¢), 6.73–6.70 (m, 2 H, H-2¢ and 4¢), 4.14
(q, J = 7.1 Hz, 2 H, OCH2CH3), 3.83 (octet, J = 4.1 Hz, 1 H, H-4),
2.76 (one of ABqd, J = 4.6 Hz, JA,B = 13.5 Hz, 1 H, H-5), 2.65 (one
of ABqd, J = 8.2 Hz, JA,B = 13.5 Hz, 1 H, H-5), 2.54–2.43 (m, 2 H,
H-2), 1.94–1.86 (m, 1 H, H-3), 1.84 (br d, J = 4.0 Hz, 1 H, OH),
1.80–1.71 (m, 1 H, H-3), 1.25 (t, J = 7.1 Hz, 3 H, OCH2CH3), 0.98
(s, 9 H, t-Bu), 0.19 [s, 6 H, Si(CH3)2].
White powder; yield: 83%; mp = 91–92 °C (hexane–EtOAc);
Rf = 0.34 (hexane–EtOAc, 4:1); [a]D27 –0.3 (c 0.98, CHCl3).
ATR-IR (neat): 2954, 2930, 2896, 2858, 1746 (OAc), 1725 (ethyl
ester), 1663, 1574, 1493, 1472, 1464, 1431, 1391, 1362, 1307,
1252, 1227, 1200, 1174, 1084, 1047, 1005, 977, 938, 893, 827, 779,
737, 705, 670 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.95 (dd, J = 15.7 and 4.6 Hz, 1
H, H-3), 6.34 (s, 2 H, H-2¢ and 6¢), 6.02 (dd, J = 15.7 and 1.7 Hz, 1
H, H-2), 4.42–4.39 (m, 1 H, H-4), 4.19 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 2.76 (one of ABqd, J = 5.2 Hz, JA,B = 13.6 Hz, 1 H, H-
5), 2.61 (one of ABqd, J = 7.9 Hz, JA,B = 13.6 Hz, 1 H, H-5), 1.78
(d, J = 4.2 Hz, 1 H, OH), 1.28 (t, J = 7.1 Hz, 3 H, OCH2CH3), 0.98
(s, 9 H, t-Bu), 0.93 (s, 18 H, t-Bu), 0.20 [s, 12 H, Si(CH3)2], 0.11 [s,
6 H, Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 174.0, 155.9, 139.6, 129.6, 122.3,
121.2, 118.3, 72.0, 60.5, 44.1, 31.5, 30.9, 25.7, 18.2, 14.2, –4.4.
MS (ESI): m/z (%) = 391 (12) [M + K]+, 375 (42) [M + Na]+, 353
(32) [M + H]+, 335 (18), 81 (71), 73 (100).
HRMS (ESI): m/z [M + Na]+ calcd for C19H32NaO4Si: 375.1962;
found: 375.1954.
Ethyl (4R)-5-{3,5-Bis[tert-butyl(dimethyl)silyloxy]phenyl}-4-
hydroxypentanoate [(R)-12c]
Colorless oil; yield: 91%; Rf = 0.38 (hexane–EtOAc, 3:1); [a]D
–1.1 (c 1.02, CHCl3).
13C NMR (100 MHz, CDCl3): d = 3482 (OH), 2953, 2930, 2859,
2858, 1698 (C=O), 1653, 1572, 1489, 1473, 1463, 1429, 1390,
1352, 1323, 1301, 1274, 1250, 1226, 1197, 1176, 1166, 1155, 1093,
1068, 1047, 1033, 999, 977, 956, 940, 887, 869, 854, 829, 778, 743,
706, 672.
28
ATR-IR (neat): 3465 (OH), 2955, 2930, 2897, 2858, 1736 (C=O),
1586, 1472, 1449, 1390, 1362, 1335, 1252, 1158, 1068, 1014, 1005,
939, 854, 828, 814, 778, 743, 699, 676 cm–1.
MS (ESI): m/z (%) = 649 (14) [M + K]+, 633 (41) [M + Na]+, 611
(100) [M + H]+.
1H NMR (400 MHz, CDCl3): d = 6.32 (d, J = 2.2 Hz, 2 H, H-2¢ and
6¢), 6.22 (t, J = 2.2 Hz, 1 H, H-4¢), 4.13 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 3.79 (octet, J = 4.0 Hz, 1 H, H-4), 2.69 (one of ABqd,
J = 4.6 Hz, JA,B = 13.4 Hz, 1 H, H-5), 2.57 (one of ABqd, J = 8.2
Hz, JA,B = 13.4 Hz, 1 H, H-5), 2.52–2.41 (m, 2 H, H-2), 1.92–1.86
(m, 1 H, H-3), 1.84 (br d, J = 3.9 Hz, 1 H, OH), 1.79–1.70 (m, 1 H,
HRMS (ESI): m/z [M + H]+ calcd for C31H59O6Si3: 611.3614;
found: 611.3615.
Synthesis 2010, No. 9, 1512–1520 © Thieme Stuttgart · New York

1518
M. Hamada et al.
PAPER
(5R)-5-(3-Hydroxybenzyl)dihydrofuran-2(3H)-one [(R)-5b]
White powder; yield: 81%; Rf = 0.41 (hexane–EtOAc, 1:1); [a]D
–29.2 (c 1.00, MeOH).
H-3), 1.25 (t, J = 7.1 Hz, 3 H, OCH2CH3), 0.97 (s, 18 H, t-Bu), 0.18
[s, 12 H, Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 174.0, 156.7, 140.0, 114.5, 110.4,
71.9, 60.5, 44.1, 31.5, 30.9, 25.7, 18.2, 14.2, –4.4.
26
ATR-IR (neat): 3309 (OH), 3036, 2964, 2933, 1741, 1722, 1615,
1588, 1488, 1417, 1385, 1363, 1347, 1293, 1280, 1250, 1225, 1208,
1196, 1173, 1155, 1148, 1076, 1065, 1018, 992, 944, 926, 901, 877,
841, 804, 790, 750, 696 cm–1.
1H NMR (400 MHz, CD3OD): d = 7.10 (t, J = 7.8 Hz, 1 H, H-5¢),
6.72 (dd, J = 1.5, 7.6 Hz, 1 H, H-6¢), 6.69 (dd, J = 1.5, 2.1 Hz, 1 H,
H-2¢), 6.66 (ddd, J = 0.8, 2.5, 8.1 Hz, 1 H, H-4¢), 4.76 (quint, 6.8 Hz,
1 H, H-4), 2.95 (one of ABqd, J = 6.5 Hz, JA,B = 13.9 Hz, 1 H, H-
5), 2.87 (one of ABqd, J = 6.0 Hz, JA,B = 13.9 Hz, 1 H, H-5), 2.51
(ddd, J = 9.1, 9.7, 17.7 Hz, 1 H, H-2), 2.32 (ddd J = 4.5, 9.5, 17.7
Hz, 1 H, H-2), 2.26 (dddd, J = 4.8, 6.8, 9.7, 12.7 Hz, 1 H, H-3), 1.95
(dtd, J = 7.5, 9.2, 12.7 Hz, 1 H, H-3).
MS (ESI): m/z (%) = 521 (10) [M + K]+, 505 (20) [M + Na]+, 483
(100) [M + H]+, 437 (6).
HRMS (ESI): m/z [M + H]+ calcd for C25H47O5Si2: 483.2957;
found: 483.2963.
Ethyl (4R)-4-Hydroxy-5-{3,4,5-tris[tert-butyl(dimethyl)silyl-
oxy]phenyl}pentanoate [(R)-12d]
White powder; yield: 97%; mp = 45–46 °C (hexane–EtOAc);
Rf = 0.44 (hexane–EtOAc, 3:1); [a]D27 +0.8 (c 1.05, CHCl3).
ATR-IR (neat): 3518 (OH), 2953, 2930, 2896, 2858, 1736, 1574,
1493, 1472, 1463, 1429, 1390, 1345, 1252, 1230, 1182, 1151, 1084,
1005, 939, 895, 857, 827, 778, 738, 707, 669 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.33 (s, 2 H, H-2¢ and 6¢), 4.13 (q,
J = 7.1 Hz, 2 H, OCH2CH3), 3.73 (octet, J = 3.8 Hz, 1 H, H-4), 2.62
(one of ABqd, J = 4.8 Hz, JA,B = 13.5 Hz, 1 H, H-5), 2.52–2.39 (m,
3 H, H-2 and 5), 1.90–1.82 (m, 1 H, H-3), 1.81 (d, J = 3.8 Hz, 1 H,
OH), 1.77–1.67 (m, 1 H, H-3), 1.25 (t, J = 7.1 Hz, 3 H, OCH2CH3),
0.98 (s, 9 H, t-Bu), 0.92 (s, 18 H, t-Bu), 0.20 [s, 12 H, Si(CH3)2],
0.11 [s, 6 H, Si(CH3)2].
13C NMR (100 MHz, CD3OD): d = 180.1 (C-1), 158.6 (C-3¢), 139.3
(C-1¢), 130.5 (C-5¢), 121.7 (C-6¢), 117.4 (C-2¢), 114.7 (C-4¢), 83.0
(C-4), 42.1 (C-5), 29.5 (C-2), 28.1 (C-3).
MS (ESI): m/z (%) = 407 (18) [2M + Na]+, 385 (15) [2M + H]+, 215
(49) [M + Na]+, 193 (100) [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C11H12O3Na: 215.0679;
found: 215.0671.
(5R)-5-(3,5-Dihydroxybenzyl)dihydrofuran-2(3H)-one [(R)-5c]
Amorphous powder; yield: 83%; Rf = 0.38 (toluene–EtOAc, 2:3);
[a]D27 –20.6 (c 0.97, MeOH).
13C NMR (100 MHz, CDCl3): d = 174.0, 148.7, 137.0, 129.7, 115.3,
72.1, 60.4, 43.7, 31.3, 30.9, 26.2(2), 26.1(8), 18.8, 18.4, 14.2, –3.6,
–4.0.
ATR-IR (neat): 3322, 2950, 1744, 1597, 1506, 1480, 1454, 1416,
1337, 1304, 1287, 1224, 1186, 1143, 998, 927, 836, 802, 721, 695
cm–1.
1H NMR (400 MHz, CD3OD): d = 6.20 (d, J = 2.2 Hz, 2 H, H-2¢ and
6¢), 6.16 (t, J = 2.2 Hz, 1 H, H-4¢), 4.72 (quint, J = 6.5 Hz, 1 H, H-
4), 2.86 (one of ABqd, J = 6.4 Hz, JA,B = 13.9 Hz, 1 H, H-5), 2.78
(one of ABqd, J = 6.0 Hz, JA,B = 13.9 Hz, 1 H, H-5), 2.49 (ddd,
J = 9.2, 9.5, 17.8 Hz, 1 H, H-2), 2.38 (ddd, J = 4.7, 9.5, 17.8 Hz, 1
H, H-2), 2.24 (dddd, J = 4.7, 6.8, 9.7, 12.7 Hz, 1 H, H-3), 1.94 (dtd,
J = 7.5, 9.2, 12.8 Hz, 1 H, H-3).
MS (ESI): m/z (%) = 651 (6) [M + K]+, 635 (30) [M + Na]+, 613
(100) [M + H]+, 595 (8), 567 (6).
HRMS (ESI): m/z [M + H]+ calcd for C31H61O6Si3: 613.3771;
found: 613.3777.
(5R)-5-(3,4-Dihydroxybenzyl)dihydrofuran-2(3H)-one
[(R)-5a]; Typical Procedure
A mixture of ester (R)-12a (661 mg, 1.37 mmol), TsOH·H2O (1.30
g, 6.84 mmol), and 4-Å MS (200 mg) in benzene (30 mL) was re-
fluxed for 4 h then cooled to r.t. The mixture was then filtered and
concentrated in vacuo to give a residue that was purified by column
chromatography [silica gel, toluene–EtOAc (3:2)] to give a white
powder; yield: 247 mg (87%); mp = 150–151 °C (toluene–EtOAc);
Rf = 0.07 (toluene–EtOAc, 3:1); [a]D28 –16.7 (c 0.70, MeOH).
13C NMR (100 MHz, CD3OD): d = 180.5 (C-1), 159.8 (C-3¢,5¢),
140.1 (C-1¢), 109.18 (C-2¢,6¢), 102.2 (C-4¢), 83.2 (C-4), 42.4 (C-5),
29.7 (C-2), 28.3 (C-3).
MS (ESI): m/z (%) = 231 (62) [M + Na]+, 226 (100) [M + H2O]+,
ATR-IR (neat): 3318 (OH), 3041, 2945. 2910, 1709 (OC=O), 1620,
1599, 1519, 1470, 1418, 1341, 1287, 1231, 1194, 1150, 1110, 1088,
1014, 987, 926, 905, 870, 844, 815, 804, 788, 752, 729 cm–1.
209 (93) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C11H13O4: 209.808; found:
209.0802.
1H NMR (400 MHz, CD3OD): d = 6.69 (d, J = 8.0 Hz, 1 H, H-5¢),
6.68 (d, J = 1.9 Hz, 1 H, H-2¢), 6.55 (dd, J = 8.0 and 2.1 Hz, 1 H, H-
6¢), 4.71 (quint, J = 6.5 Hz, 1 H, H-4), 2.86 (one of ABqd, J = 6.1
Hz, JA,B = 14.0 Hz, 1 H, H-5), 2.78 (one of ABqd, J = 6.1 Hz,
JA,B = 14.0 Hz, 1 H, H-5), 2.47 (ddd, J = 8.9, 9.7, 17.6 Hz, 1 H, H-
2), 2.32 (ddd, J = 4.8, 9.5, 17.7 Hz, 1 H, H-2), 2.22 (dddd, J = 4.8,
6.8, 9.8, 12.6 Hz, 1 H, H-3), 1.95 (dddd, J = 7.3, 8.9, 9.4, 12.6 Hz,
1 H, H-3).
(5R)-5-{3,4,5-Tris[tert-butyl(dimethyl)silyloxy]phenyl}dihydro-
furan-2(3H)-one [(R)-13]
A mixture of ester (R)-12d (1.36 g, 2.22 mmol) and PPTS (669 mg,
2.66 mmol) in benzene (44 mL) was refluxed for 1 h with azeotropic
removal of EtOH. The mixture was cooled to 0 °C and surplus
PPTS was removed by filtration. The filtrate was concentrated in
vacuo to give a residue that was purified by column chromatogra-
phy [silica gel, hexane–EtOAc (4:1)] to give white crystals; yield:
1.24 g (98%); mp = 69.5–71.0 °C (hexane–EtOAc); Rf = 0.59
(toluene–EtOAc, 4:1); [a]D28 +1.6 (c 1.04, CHCl3).
13C NMR (100 MHz, CD3OD): d = 180.5 (C-1), 146.5 (C-3¢), 145.4
(C-4¢), 129.3 (C-1¢), 122.1 (C-6¢), 117.9 (C-5¢), 116.6 (C-2¢), 83.5
(C-4), 41.7 (C-5), 29.7 (C-2), 28.1 (C-3).
ATR-IR (neat): 2955, 2930, 2896, 2858, 1767, 1570, 1494, 1473,
1463, 1430, 1381, 1360, 1341, 1316, 1255, 1235, 1199, 1170, 1143,
1093, 1044, 1004, 940, 920, 893, 835, 826, 780, 759, 735, 692, 673
cm–1.
1H NMR (400 MHz, CDCl3): d = 6.34 (s, 2 H, H-2¢ and 6¢), 4.62
(quint, J = 6.7 Hz, 1 H, H-4), 2.93 (one of ABqd, J = 5.5 Hz,
JA,B = 13.9 Hz, 1 H, H-5), 2.69 (one of ABqd, J = 7.0 Hz,
JA,B = 13.9 Hz, 1 H, H-5), 2.47 (td, J = 9.3, 17.7 Hz, 1 H, H-2), 2.40
(ddd, J = 4.8, 9.3, 17.7 Hz, 1 H, H-2), 2.17 (dddd, J = 4.8, 6.7, 9.3,
MS (ESI): m/z (%) = 439 (42) [2M + Na]+, 417 (14) [2M + H]+, 231
(95) [M + Na]+, 209 (100) [M + H]+ 439 (42) [2M + Na]+, 417 (14)
,
[2M + H]+, 231 (95) [M + Na]+, 209 (100) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C11H13O4: 209.0808 found:
209.0826.
Synthesis 2010, No. 9, 1512–1520 © Thieme Stuttgart · New York

PAPER
Lactone Metabolites of Tea Catechins
1519
12.8 Hz, 1 H, H-3), 1.90 (dtd, J = 7.8, 9.4, 12.8 Hz, 1 H, H-3), 0.98
(s, 9 H, t-Bu), 0.93 (s, 18 H, t-Bu), 0.20 [s, 12 H, Si(CH3)2], 0.11 [s,
6 H, Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 176.9 (C-1), 148.6 (C-3¢,5¢),
137.3 (C-4¢), 127.5 (C-1¢), 115.4 (C-2¢,6¢), 80.9 (C-4), 40.7 (C-5),
28.7 (C-2), 27.0 (C-3), 26.21, 26.16, 18.8, 18.4, –3.9, –4.0.
13C NMR (100 MHz, C6D6): d = 175.7 (C-1), 165.8, 150.9, 139.2,
132.9, 130.4, 130.2, 129.3, 129.0, 127.7, 124.6 (q, J = 286 Hz),
122.6, 120.1, 85.8 (q, J = 28.0 Hz), 79.5 (C-4), 55.9, 41.2 (C-5),
28.7 (C-2), 27.2 (C-3).
3-[(2S)-(5-Oxotetrahydrofuran-2-yl)methyl]phenyl (2R)-3,3,3-
Trifluoro-2-methoxy-2-phenylpropanoate [(S,S)-14]
MS (ESI): m/z (%) = 605 (25) [M + K]+, 589 (48) [M + Na]+, 584
1H NMR (400 MHz, C6D6): d = 7.78 (d, J = 7.8 Hz, 2 H), 7.15 (t,
J = 7.4 Hz, 2 H), 7.07 (t, J = 7.2 Hz, 1 H, H-5¢), 6.94 (t, J = 7.5 Hz,
1 H), 6.86 (s, 1 H, H-2¢), 6.85 (d, J = 7.3 Hz, 1 H, H-6¢), 6.76 (d,
J = 7.5 Hz, 1 H, H-4¢), 3.79 (quint, 6.4 Hz, 1 H, H-4), 3.49 (s, 3 H),
2.41 (one of ABqd, J = 6.7 Hz, JA,B = 14.0 Hz, 1 H, H-5), 2.12 (one
of ABqd, J = 5.8 Hz, JA,B = 14.0 Hz, 1 H, H-5), 1.75 (ddd, J = 4.5,
9.4, 17.6 Hz, 1 H, H-2), 1.67 (td, J = 9.3, 17.4 Hz, 1 H, H-2), 1.14
(dddd, J = 4.6, 6.5, 9.3, 12.6 Hz, 1 H, H-3), 0.94 (dtd, J = 7.8, 9.4,
12.6 Hz, 1 H, H-3).
(68) [M + H2O]+, 567 (100) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C29H55O5Si3: 567.3352;
found: 567.3381.
(5R)-5-(3,4,5-Trihydroxyphenyl)dihydrofuran-2(3H)-one
[(R)-5d]
A soln of (R)-13 (199 mg, 0.35 mmol) and concd HCl (7 mL) in
THF (10 mL) and MeOH (2 mL) was stirred at 0 °C for 2 h and then
at r.t. for 4 h. The mixture was concentrated in vacuo and the residue
was diluted with H2O (5 mL) and extracted with EtOAc (30 mL).
The organic layer was washed with brine, dried (Na2SO4), and fil-
tered. The filtrate was concentrated in vacuo and the residue was pu-
rified by column chromatography [silica gel, toluene–EtOAc (1:1)];
to give a powder; yield: 68 mg (87%); mp = 142–143 °C (toluene–
13C NMR (100 MHz, C6D6): d = 175.7 (C-1), 165.8, 150.9, 139.3,
132.9, 130.4, 130.2, 129.3, 129.0, 127.7, 124.6 (q, J = 286 Hz),
122.6, 120.1, 85.8 (q, J = 28.0 Hz), 79.7 (C-4), 55.9, 41.3 (C-5),
28.7 (C-2), 27.4 (C-3).
27
EtOAc); Rf = 0.33 (toluene–EtOAc, 3:7); [a]D –12.6 (c 0.99,
Acknowledgment
MeOH).
We gratefully acknowledge the financial support by Grants-in-Aid
for Scientific Research (20590106) from the Ministry of Education,
Science, and Culture of Japan. M.H. thanks the Scholarship Found-
ation of the First Bank of Toyama for financial support. We
acknowledge the gift of (S)- and (R)-benzyl glycidyl ethers from
Sanyo Fine Co., Ltd.
ATR-IR (neat): 3422 (OH), 2955, 2926, 2867, 1724 (C=O), 1614,
1536, 1523, 1504, 1455, 1412, 1355, 1304, 1277, 1224, 1191, 1152,
1099, 1078, 1013, 989, 940, 898, 857, 827, 802, 773, 757, 729, 720,
673, 660 cm–1.
1H NMR (400 MHz, CD3OD): d = 6.24 (s, 2 H, H-2¢ and 6¢), 4.70
(quint, J = 6.6 Hz, 1 H, H-4), 2.81 (one of ABqd, J = 6.0 Hz,
JA,B = 14.0 Hz, 1 H, H-5), 2.71 (one of ABqd, J = 6.2 Hz,
JA,B = 14.0 Hz, 1 H, H-5), 2.48 (ddd, J = 8.9, 9.7, 17.7 Hz, 1 H, H-
2), 2.33 (ddd, J = 4.8, 9.5, 17.7 Hz, 1 H, H-2), 2.23 (dddd, J = 4.8,
6.8, 9.7, 12.8 Hz, 1 H, H-3), 1.95 (dtd, J = 7.3, 9.1, 12.8 Hz, 1 H, H-
3).
References
(1) Ariga, T.; Koshiyama, I.; Fukushima, D. Agric. Biol. Chem.
1988, 52, 2717.
(2) Fukai, T.; Ishigami, T.; Hara, Y. Agric. Biol. Chem. 1991,
55, 1895.
13C NMR (100 MHz, CD3OD): d = 180.6 (C-1), 147.2 (C-3¢,5¢),
133.2 (C-4¢), 128.6 (C-1¢), 109.7 (C-2¢,6¢), 83.5 (C-4), 41.9 (C-5),
29.7 (C-2), 28.1 (C-3).
(3) Nakayama, M.; Suzuki, K.; Toda, M.; Okubo, S.; Hara, Y.;
Shimamura, T. Antiviral Res. 1993, 21, 289.
(4) Xu, Y.; Ho, C.-T.; Amin, S. G.; Chung, F.-L. Cancer Res.
1992, 52, 3875.
(5) Yang, C. S.; Landau, J. M.; Huang, M.-T.; Newmark, H. L.
MS (ESI): m/z (%) = 471 (42) [2M + Na]+, 449 (14) [2M + H]+, 247
(95) [M + Na]+, 225 (100) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C11H13O5: 225.0758; found:
225.0771.
Annu. Rev. Nutr. 2001, 21, 381.
(6) Mizushina, Y.; Saito, A.; Tanaka, A.; Nakajima, N.;
Kuriyama, I.; Takemura, M.; Takeuchi, T.; Sugawara, F.;
Yoshida, H. Biochem. Biophys. Res. Commun. 2005, 333,
101.
(7) (a) Ohshima, Y.; Watanabe, H.; Isakari, S. J. Biochem. 1958,
45, 861. (b) Ohshima, Y.; Watanabe, H. J. Biochem. 1958,
45, 973. (c) Ohshima, Y.; Watanabe, H.; Kuwazuka, S. Bull.
Agric. Chem. Soc. Jpn. 1960, 24, 497.
(8) (a) Meselhy, M. R.; Nakamura, N.; Hattori, M. Chem.
Pharm. Bull. 1997, 45, 888. (b) Wang, L.-Q.; Meselhy, M.
R.; Li, Y.; Nakamura, N.; Min, B.-S.; Qin, G.-W.; Hattori,
M. Chem. Pharm. Bull. 2001, 49, 1640.
(9) (a) Li, C.; Lee, M.-J.; Sheng, S.; Meng, X.; Prabhu, S.;
Winnik, B.; Huang, B.; Chung, J. Y.; Yan, S.; Ho, C.-T.;
Yang, C. S. Chem. Res. Toxicol. 2000, 13, 177. (b) Li, C.;
Meng, X.; Winnik, B.; Lee, M.-J.; Lu, H.; Sheng, S.; Buckly,
B.; Yang, C. S. Chem. Res. Toxicol. 2001, 14, 702.
(c) Meng, X.; Sang, S.; Zhu, N.; Lu, H.; Sheng, S.; Lee, M.-
J.; Ho, C.-T.; Yang, C. S. Chem. Res. Toxicol. 2002, 15,
1042.
3-[(2R)-(5-Oxotetrahydrofuran-2-yl)methyl]phenyl (2R)-3,3,3-
Trifluoro-2-methoxy-2-phenylpropanoate [(R,S)-14]; Typical
Procedure
(S)-PhC(OMe)(CF3)COCl (29.7 mg, 0.122 mmol) was added to a
soln of lactone 5b (11.7 mg, 0.061 mmol), Et3N (33.4 mg, 0.366
mmol), and DMAP (0.6 mg, 0.005 mmol) in CH2Cl2 (1 mL) at 0 °C,
and the mixture was stirred for 1 h at r.t. The reaction was quenched
with H2O (2 mL) and extracted with EtOAc (20 mL). The combined
organic layer was washed with H2O and brine, dried (Na2SO4), fil-
tered, and concentrated in vacuo. The residual oil was purified by
preparative TLC (hexane–EtOAc, 1:1) to give a colorless oil; yield:
23.8 mg (98%); Rf = 0.45 (hexane–EtOAc, 1:1).
1H NMR (400 MHz, C6D6): d = 7.78 (d, J = 7.8 Hz, 2 H), 7.15 (t,
J = 7.4 Hz, 2 H), 7.07 (t, J = 7.2 Hz, 1 H, H-5¢), 6.93 (t, J = 7.5 Hz,
1 H), 6.85 (s, 1 H, H-2¢), 6.84 (d, J = 7.3 Hz, 1 H, H-6¢), 6.74 (d,
J = 7.4 Hz, 1 H, H-4¢), 3.79 (quint, 7.6 Hz, 1 H, H-4), 3.49 (s, 3 H),
2.39 (one of ABqd, J = 6.5 Hz, JA,B = 14.0 Hz, 1 H, H-5), 2.18 (one
of ABqd, J = 5.8 Hz, JA,B = 14.0 Hz, 1 H, H-5), 1.73 (ddd, J = 4.7,
9.6, 17.4 Hz, 1 H, H-2), 1.65 (td, J = 9.3, 17.4 Hz, 1 H, H-2), 1.12
(dddd, J = 4.8, 6.6, 9.1, 12.7 Hz, 1 H, H-3), 0.93 (dtd, J = 7.9, 9.5,
12.7 Hz, 1 H, H-3).
(10) Duweler, K. G.; Rohdewald, P. Pharmazie 2000, 55, 364.
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that used to prepare (R)-5b.
(22) The 13C NMR chemical shifts for the C3, C4 and C5 atoms
are observed at d = 27.23, d = 79.52, and d = 41.21,
respectively, for (R,S)-14 and at d = 27.36, d = 79.66, and
d = 41.31, respectively, for (S,S)-14.
Synthesis 2010, No. 9, 1512–1520 © Thieme Stuttgart · New York