Solid-phase synthesis of a combinatorial methylated (±)- epigallocatechin gallate library and the growth-inhibitory effects of these compounds on melanoma B16 cells

DOI: 10.1002/asia.201000372

Solid-Phase Synthesis of a Combinatorial Methylated (Æ)-Epigallocatechin

Gallate Library and the Growth-Inhibitory Effects of these Compounds on

Melanoma B16 Cells

Hiroshi Tanaka,*^[a]Maasa Yamanouchi,^[a]Haruko Miyoshi,^[a]Keisuke Hirotsu,^[b]

Hirofumi Tachibana,^[b]and Takashi Takahashi*^[a]

Abstract: We report on the solid-phase

synthesis of a combinatorial methylat-

with a ketone and an acid. The subse-

quent release and reductive etherifica-

tion reaction of the solid-supported a-

acyloxyketone provide the protected

EGCG in good total yields. Sixty-four

methylated EGCGs were successfully

prepared. The growth-inhibitory effects

of the methylated EGCG library were

also examined. Although methylation

of EGCG generally causes reduced

growth inhibition, the growth-inhibito-

ry effect of 7-OMe EGCGs was com-

parable to that of EGCG. The 7-OMe

EGCGs are attractive drug candidates

because of their enhanced bioavailabil-

ity.

ed

(EGCG) library and its biological eval-

uation. Epigallocatechin gallate

(Æ)-epigallocatechin

gallate

(EGCG) and its methylated deriva-

tives, which are members of the cate-

chin family, exhibit various anti-cancer

effects. The solid-phase synthesis of

methylated EGCG involves the prepa-

ration of the a-acyloxyketone by the

coupling of a solid-supported aldehyde

Keywords: combinatorial chemis-

try · microreactors · phytochem-

istry

·

receptors

·

solid-phase

synthesis

Introduction

advantages for the combinatorial synthesis of small mole-

cules. In particular, the use of solid-supported substrates re-

sults in easy manipulation and adaptability of the split-and-

pool strategy. An effective application of combinatorial

chemistry is the synthesis of combinatorial libraries based

on the unique structures of natural products with biological

activities;^[1]these libraries serve as attractive drug candi-

dates and biochemical probes. We have already reported the

synthesis of natural-product-based combinatorial libraries,

such as terpenoids, macrolides, peptides, heterocycles, and

glycoconjugates.^[2]

Combinatorial chemistry greatly facilitates the systematic

syntheses of small molecules that involve a common core

structure. Solid-phase syntheses that are based on the reac-

tions of solid-supported substrates and the release of prod-

ucts from the solid-support during the final stage have many

[a] Prof. Dr. H. Tanaka, M. Yamanouchi, H. Miyoshi,

Prof. Dr. T. Takahashi

Polyphenols, such as (À)-catechin (1) and (À)-epigalloca-

techin-3-O-gallate (EGCG, (À)-2aa), are phytochemicals

found in tea leaves that exhibit various biological activities

(Scheme 1).^[3]The 67 kDa laminin receptor (67LR)^[4]is a re-

ceptor for EGCG that mediates its anti-cancer^[5]and anti-al-

lergic^[6]actions. However, because EGCGs are highly hydro-

philic, they have low bioavailability, which makes them inef-

fective when administered orally. On the other hand, methy-

lated EGCGs, the phenols of which are partially capped

with methyl ethers, have recently attracted considerable at-

tention because the hydrophilicity of the methyl groups im-

proves the bioavailability of the methylated compounds.^[7]

However, methylated EGCGs isolated from natural sources

Department of Applied Chemistry

Graduate School of Science and Engineering

Tokyo Institute of Technology

2-12-1 Ookayama, Meguro, Tokyo 152-8552 (Japan)

Fax : (+81)3-5734-2471

E-mail: thiroshi@apc.titech.ac.jp

ttak@apc.titech.ac.jp

[b] K. Hirotsu, Prof. Dr. H. Tachibana

Department of Bioscience and Biotechnology

Faculty of Agriculture

Kyushu University

Hakozaki 6-10-1, Fukuoka, 812-8581 (Japan)

Fax : (+81)92-642-3008

Supporting information for this article is available on the WWW

under http://dx.doi.org/10.1002/asia.201000372.

Chem. Asian J. 2010, 5, 2231 – 2248

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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(Scheme 2). H-Cube is a continuous-flow hydrogenation re-

actor with endogenous on-demand hydrogen generation and

a disposable catalyst-cartridge system, and allows precise

tuning of the reaction conditions to minimize over-reac-

tion.^[12]The solid-phase synthesis of the protected library 6–

9 involved four steps: 1) loading of phenol 15 on the poly-

styrene resin through para-alkyloxybenzyl linker (Wang

resin) 16 to prepare the solid-supported aldehyde 13;

2) aldol condensation of ketone 14 with the solid-supported

aldehyde 13, followed by epoxidation of the resulting enone

to 12; 3) regioselective opening of the epoxide 12, followed

by the acylation of the resulting alcohol with acid 11; and,

4) the construction of the epicatechin skeleton by one-pot

release and reductive etherification of the solid-supported

a-acyloxyl ketone 10. The reductive etherification of the a-

acyloxyl ketone 10 provided the cis-substituted benzopyran

by neighboring-group participation.^[13]The bromide at the

C8 position prevented Friedel–Craft alkylation of the

cleaved para-alkyloxybenzyl linker at the C8 position.^[14]The

three-component coupling strategy was effective for the syn-

thesis of combinatorial epicatechin libraries with three dif-

ferent aromatic rings. Furthermore, the solid-phase synthesis

allowed the synthesis of all possible methylated EGCGs be-

cause the phenol group that is used to link to the solid sup-

port becomes an element of the pyran ring. We used this

method to synthesize 64 methylated EGCGs from aldehydes

15a–d, ketones 14a–d, and carboxylic acids 11a–d

(Scheme 3).

We first examined the solution-phase synthesis of (Æ)-

EGCG 2aa using para-methoxybenzyl ether instead of a

Wang resin (Scheme 4). Treatment of triphenol 17 with

2.0 equivalents of para-fluorobenzyl bromide under basic

conditions provided the dibenzylated product 18 in 81%

yield. Subsequent bromination at the ortho position of the

remaining free phenol group provided the phenyl bromide

15a in 87% yield. ¹H NOESY experiments showed 9.5%

and 11% NOEs between the hydrogens at the C5 position

and the two benzylic positions, respectively, thus indicating

that the remaining proton of 19 was located at the C5 posi-

tion. Protection of the free phenol group of 19 with para-

methoxybenzyl chloride, followed by aldol condensation

with 3,4,5-tribenzyloxyphenylmethyl ketone (14a) afforded

the E-enone 20 in 82% yield in two steps.

Scheme 1. Structures of catechin and epigallocatechin gallate.

frequently show reduced biological activity in vitro in com-

parison with EGCG.^[8]Furthermore, the structural diversity

of both the methylated EGCGs and the catechins is limited.

In particular, naturally occurring EGCG derivatives methy-

lated at the phenol on the A ring have not been isolated.

Therefore, the systematic chemical synthesis of both natural

and unnatural methylated EGCGs, and a survey of the bio-

logical activities of these compounds is highly desirable.

However, although several reports on the solid-phase syn-

theses of pyran natural products have been reported,^[9]most

of the syntheses of acylated epicatechins reported to date

have been based on a target-oriented synthesis which in-

volves the preparation of cis-benzopyran derivatives, fol-

lowed by the acylation of the C3 hydroxyl group.^[10]There-

fore, the goal of this study was to develop an effective

method for the synthesis of methylated EGCG deriva-

tives.^[11]Herein, we report the solid-phase synthesis of a me-

thylated (Æ)-EGCG library and the biological evaluation of

these compounds.

Results and Discussion

We planned to synthesize the racemic methylated EGCG li-

brary 2–5 involving the natural dihydroxyl A ring (in 2) and

the three unnatural methylated A rings (in 3–5). Our strat-

egy for the synthesis of methylated EGCG library 2–5 in-

volved the combinatorial synthesis of benzyl-protected, me-

thylated EGCG library 6–9 in the solid-phase from aldehyde

15, ketone 14, and carboxylic acid 11, and the deprotection

of the benzyl-protected library 6–9 by utilizing the H-Cube

Synthesis of precursor 25a for reductive etherification

was examined (Scheme 5). Enone 20 was treated with H₂O₂

under basic conditions. After a conventional workup of the

reaction, the crude material, which included the epoxide 22,

Abstract in Japanese:

was exposed to methanol in the presence of ScACTHNUGTRENUNG(OTf)₃to

provide the alcohol 24 in 81% yield from 20 as a mixture of

diastereomers. Purification of the epoxide 22 using column

chromatography on silica gel was difficult. The correspond-

ing benzyl ether derivative 21 was not converted into the

corresponding epoxide 23 under the same reaction condi-

tions. These results suggested that the fluoro substituents

might reduce the LUMO level, thereby, enhancing the reac-

tivity of the enone towards nucleophilic epoxidation. The

relative stereochemistry of 24 was not determined, but the

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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Asian J. 2010, 5, 2231 – 2248

Solid-Phase Synthesis of a Combinatorial Methylated EGCG Library

Scheme 2. Strategy for the solid-phase synthesis of methylated EGCG derivatives 2–5.

Scheme 3. Building blocks 15, 14, and 11 for the synthesis of the 64-

member combinatorial library.

Scheme 4. Reagents and conditions: a) para-fluorobenzyl bromide,

Cs₂CO₃, DMF, 81%; b) bromine, CH₂Cl₂, 08C, 82%; c) para-methoxy-

benzyl chloride, K₂CO₃, DMF; d) 3’,4’,5’-tris(benzyloxy)acetophenone

(14a), NaOMe, THF, 82% based on 15a. DMF=N,N-dimethylforma-

mide.

methyl ether was reduced at the final stage. Acylation of the

resulting alcohol 24 with the tribenzyl-protected gallic acid,

provided the precursor 25a in 96% yield.

Table 1. Reductive cyclization of the a-acyloxy ketone 25.

Entry TFA [VV^À1%] Et₃SiH [VV^À1%] t [h] T [8C] Yield [%]

Cyclization of 25a by reductive etherification was exam-

ined (Table 1). Exposure of the precursor 25a to our previ-

ously reported reaction conditions for reductive cyclization

of thioether 25b (15% TFA and 10% Et₃SiH in CH₂Cl₂

À208C) resulted in a high yield of the starting material 25a

and a trace amount of the product 6aa (Table 1 entry 3).

1

2

5

10

2

0

-20

72

28

trace

68

15

10

5

3

4^[a]

[a] Addition of decanethiol to the reaction mixture.

Chem. Asian J. 2010, 5, 2231 – 2248

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T. Takahashi et al.

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Scheme 5. Reagents and conditions: a) KOH, H₂O₂(aq.), Bu₄N·HSO₄, CH₂Cl₂, room temperature, 30 hours; b) Sc

temperature, 3 hours, 81% based on 20; c) 10a, EDCI, DMAP, pyridine, 12 h, 96%.

ACHTUGNTREN(NUNG OTf)₃, MeOH/CH₂Cl₂(1:1), room

The addition of thiol to the reaction of 25a under the previ-

ously reported conditions provided the protected EGCG

6aa in 68% yield (Table 1 entry 4). These results suggested

that the thiol accelerates cyclization by the removal of the

para-methoxybenzyl ether. After further optimization of the

reaction conditions, we found that treatment of 25a with tri-

fluoroacetic acid (TFA, 15%) and triethylsilane (Et₃SiH,

5%) in dichloromethane at 08C for 2 hours provided the

protected EGCG 6aa in 72% yield as a single diastereomer

(Table 1, entry 1). Both the bromide at the 8-position and a

methyloxy group at the 4-position were reduced under the

release-and-cyclization conditions. Based on the coupling

constant between H2 and H3 (J_H2ÀH3=<1 Hz), the relative

stereochemistry between the C2 and C3 positions was deter-

mined to be cis.

Deprotection of the protected EGCG 6aa using a contin-

uous-flow hydrogenation reactor (H-Cube) was examined

(Table 2). CatCart (70 mm) containing 20% Pd(OH)₂/C was

used as the catalyst. A solution of the protected EGCG 6aa

(1 mgmL^À1in 1% formic acid in THF/MeOH=1:1) was in-

jected into the device (the flow ratio was 1 mLmin^À1) at

508C and 20 bar to provide (Æ)-EGCG (2aa) in 72% yield

(Table 2 entry 2). Cleavage of the fluorobenzyl groups was

difficult without formic acid (Table 2, entry 1). However, the

use of a 5% formic acid solution as a solvent reduced the

yield of (Æ)-EGCG (2aa) (28%; Table 2, entry 3). TLC

analysis of the reaction mixture indicated that a significant

amount of (Æ)-EGCG (2aa) had decomposed under these

reaction conditions. The use of the protected EGCG 6aa

from 25b reduced the recyclability of the catalyst. A trace

amount of thiol remaining in 6aa would poison the catalyst.

The solid-phase synthesis of EGCG is shown in Scheme 6.

Treatment of a solution of the aldehyde 15a (2.0m) with the

para-alkyloxybenzyl bromide on polystyrene resin 16 (PS-

Wang bromide, 1.6 mmolg^À1) provided the solid-supported

aldehyde 26.^[15]The loading yield was 67%, as estimated by

the cleavage from the resin. Treatment of the solid-support-

ed aldehyde 26 with ketone 14a under basic conditions pro-

vided the solid-supported enone 27. Epoxidation of the

solid-supported enone 27 with tert-butyl hydrogen peroxide

(TBHP) under basic conditions, followed by the regioselec-

tive opening of the solid-supported epoxide 28 with metha-

nol in the presence of ScACTHNUTRGNE(UNG OTf)₃without cleavage of the

Wang linker afforded the solid-supported a-hydroxyl ketone

29. Acylation of the resulting alcohol 29 with 3,4,5-tribenzy-

loxybenzoic acid 11a afforded the precursor 30 for reductive

cyclization. Reactions 26–30 were monitored using infrared

analysis of the solid-supported compounds 26–30. A release

and cyclization reaction of 30 was then conducted. Exposure

of 30 to trifluoroacetic acid (1%) in dichloromethane in the

presence of Et₃SiH (10%) also in dichloromethane, provid-

ed the protected EGCG 6aa. The crude material, after pu-

rification by gel permeation chromatography, gave the pro-

tected EGCG 6aa in 47% yield based on the solid-support-

Table 2. Deprotection of protected EGCG 6aa using a continuous-flow

hydrogenation reactor (H-Cube).

Entry Cat. cartridge HCO₂H [VV ^À1%] T [8C] Cycles Yield [%]

1

2

3

Pd(OH)₂

–

1

5

50

3

1

42

72

28

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Chem. Asian J. 2010, 5, 2231 – 2248

Solid-Phase Synthesis of a Combinatorial Methylated EGCG Library

Scheme 6. Reagents and conditions: a) PS-Wang-Br (1.6 mmolg)^À1, Cs₂CO₃(0,2m), NaI (0.06m), DMF, room temperature, 24 hours, 58% based on the

resin; b) 11a (0.5m), NaOMe (0.1m), THF/MeOH (4:1), room temperature, 24 hours; c) TBHP (1.5m), KOH (0.2m), CH₂Cl₂/MeOH:decane (19:2:9),

room temperature, 72 hours; d) Sc

ACHTNUGTNERUN(GN OTf)₃(0.01m), MeOH/CH₂Cl₂(1:1), room temperature, 3 hours; e) 7a (0.2m), DIC (0.2m), DMAP (0.06m), CH₂Cl₂/

DMF (4:1), room temperature, 48 hours; f) TFA (5%), Et₃SiH (10%), CH₂Cl₂, 08C, 6 hours, 47% based on 26.

ed aldehyde 26. The previous reported method involving the

use of a thiol instead of methanol resulted in a total yield of

6aa of 19%. These results indicated that the second genera-

tion of the solid-phase synthesis of EGCG derivatives was

successfully optimized and clearly improved in comparison

with the previously reported one.

by trypan-blue staining. The growth-inhibitory effects of me-

thylated EGCGs 2–5 on the B16 cells were estimated by the

comparison with the number of the remaining cells. Methyl-

ation of phenols on the D rings reduced the biological activi-

ty of these compounds. On the other hand, most of the 7-

methoxy-methylated EGCGs 4 exhibited biological activity

comparable to that of the naturally occurring EGCG. These

results suggest that 7-OMe-methylated EGCGs 4 are attrac-

tive drug candidates because of their enhanced bioavailabil-

ity.

The synthesis of the methylated EGCG library 2–5 con-

taining 64 compounds was achieved based on the split-and-

pool strategy using 64 IRORI MiniKans. The polystyrene

Wang-Br resin (70 mg) and a radiofrequency tag were

packed in IRORI MiniKans.^[13]The content in each of Mini-

Kans^TMwas encoded by the radiofrequency tag. Coupling of

the building blocks 11a–d, 14a–d, and 15a–d was achieved

in separate vessels. The processes of workup and other reac-

tions were also achieved in a single vessel. Yields of the iso-

lated protected EGCG library compounds ranged from 29

to 58%. Deprotection of the protected EGCGs with para-

fluorobenzyl ethers was achieved by utilizing H-Cube under

the established conditions. Deprotection of the other

benzyl-protected EGCG derivatives did not require the ad-

dition of formic acid. The yields of the 64 methylated

EGCG derivatives ranged from 33 to 77%. Scheme 7 shows

the 64 compounds in the library.

Conclusions

The solid-phase synthesis of a combinatorial methylated epi-

gallocatechin gallate (EGCG) library and its biological eval-

uation has been performed. The solid-phase synthesis of me-

thylated EGCGs involved the preparation of the a-acyloxy-

ketone by coupling of the solid-supported aldehyde with a

ketone and an acid. The subsequent release and reductive

etherification reaction of the solid-supported a-acyloxyke-

tone provide protected EGCGs in good total yields. Depro-

tection of the protected EGCGs is achieved by utilizing a

continuous-flow hydrogenation reactor (H-Cube). Combina-

torial synthesis of 64 methylated EGCGs from four alde-

hydes, four ketones, and four carboxylic acids was success-

fully achieved using this method. The 7-OMe EGCGs 4 ex-

hibited growth-inhibitory effects which were comparable to

that of the naturally occurring EGCG. Thus, the 7-OMe

We next examined the effects of library compounds 2ab–

2dd, 3–5, and (À)-EGCG (2aa) on a sample of B16 cells (a

mouse melanoma cell line; Figure 1). The B16 cells were in-

cubated with each of the methylated EGCGs 2–5 (0, 1.0, or

5.0 mm) for 96 hours at 378C. The viability of the B16 cells

incubated with compounds 2–5 was almost 100% as assessed

Chem. Asian J. 2010, 5, 2231 – 2248

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T. Takahashi et al.

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Scheme 7. Structures of the representing compounds of the methylated EGCG library 2–5.

39.5 mmol) in DMF (5.00 mL) was added to the reaction mixture at the

same temperature. After being stirred at room temperature for 12 hours,

the reaction mixture was poured into a mixture of an aqueous solution of

HCl (1m) and ethyl acetate. The aqueous layer was extracted with ethyl

acetate. The combined organic layers were washed with H₂O and brine,

dried over MgSO₄, and concentrated in vacuo. The residue was purified

by column chromatography on silica gel (chloroform), and recrystallized

from CH₂Cl₂-hexane to afford 18 (5.93 g, 16.0 mmol, 81%) as a white

solid. R_f=0.48 (hexane/ethyl acetate=2/1); FTIR (solid): n˜ =3041, 2891,

EGCGs are attractive drug candidates because of their en-

hanced bioavailability. Synthesis of optically active EGCG

derivatives and further biological evaluation of the 7-OMe

EGCGs is in progress.

Experimental Section

1600, 1508, 1220, 1096, 814, 773, 646, 502, 494 cm^À1

CDCl₃): d=12.5 (s, 1H), 10.1 (s, 1H), 7.38 (dd, J=8.2 Hz, J_H,F=4.3 Hz,

2H), 7.37 (dd, J=8.2 Hz, J_H,F=4.3 Hz, 2H), 7.09 (dd, J=8.2 Hz, J_H,F

;

¹H NMR (400 MHz,

NMR spectra were recorded on a JEOL Model ECP-400 (400 MHz for

¹H, 100 MHz for ¹³C) instrument in the indicated solvent. Chemical shifts

are reported in units parts per million (ppm) relative to the signal

(0 ppm) for internal tetramethylsilane for solutions in deuterated chloro-

form (CDCl₃). ¹H NMR spectrum data are reported as follows: CDCl₃

(7.26 ppm) or perdeuterated methanol (CD₃OD, 3.30 ppm), [D₆]acetone

(2.00 ppm), dimethyl-d6 sulfoxide ([D₆]DMSO, 2.50 ppm). ¹³C NMR

spectrum data are reported as follows: CDCl₃(77.1 ppm) or [D₆]acetone

(30.3 ppm) as internal standard for deuterium oxide (D₂O). Multiplicities

are reported by using the following abbreviations: s, singlet; d, doublet; t,

triplet; q, quartet; m, multiplet; br, broad; J, coupling constants in Hertz.

=

8.7 Hz, 4H), 6.10 (s, 1H), 6.04 (s, 1H), 5.04 (s, 2H), 5.02 ppm (s, 2H);

¹³C NMR (100 MHz, CDCl₃): d=191.8, 166.8, 166.3, 162.7ꢁ2 (J_C,F

247 Hz), 162.4, 131.4 (J_C,F=3.0 Hz), 131.3 (J_C,F=3.0 Hz), 129.5 (J_C,F

=

7.6 Hz), 129.3 (J_C,F=8.4 Hz), 115.7 (J_C,F=21.3 Hz), 106.3, 94.1, 92.3, 69.9,

69.7 ppm; elemental analysis: calcd (%) for C₂₁H₁₆F₂O₄: C 68.11, H 4.35;

found: C 67.80, H 4.47.

15a: To a solution of 18 (2.79 g, 7.54 mmol) in CH₂Cl₂(20 mL) was

added dropwise a solution of bromine (385 mL, 7.54 mmol) in CH₂Cl₂

(5.0 mL) at 08C under argon. After being stirred at the same temperature

for 30 minutes, the reaction mixture was poured into a mixture of aque-

ous solution of Na₂S₂O₃(10%), saturated aqueous solution of NaHCO₃,

and ethyl acetate. The aqueous layer was extracted with ethyl acetate.

The combined organic layers were washed with brine, dried over MgSO₄,

and concentrated in vacuo. The residue was recrystallized from CH₂Cl₂-

hexane to afford 15a (2.97 g, 6.62 mmol, 87%) as a pale yellow solid.

R_f=0.40 (hexane:ethyl acetate=2:1); FTIR (solid): n˜ =3048, 2905, 1633,

Zodiac is a parallel synthesizer purchased by TOKYO RIKAKIKAI

CO., LTD.

Syntheses

18: To a solution of 17 (3.04 g, 19.7 mmol) in dimethylformamide (DMF,

55.0 mL) was added K₂CO₃(6.30 g, 45.4 mmol) at 08C under argon.

After 5 minutes,

a solution of 4-fluorobenzyl bromide (4.90 mL,

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Chem. Asian J. 2010, 5, 2231 – 2248

Solid-Phase Synthesis of a Combinatorial Methylated EGCG Library

Figure 1. Growth inhibitory effects of the methylated EGCG library 2–5 on the B16 cells.

1608, 1509, 1294, 1219, 1197, 1120, 1097, 981, 823, 814, 792, 716 cm^À1

;

(solid): n˜ =2941, 1642, 1585, 1513, 1319, 1251, 1183, 1158, 1093, 1030, 829,

749, 697 cm^À^{1 1}H NMR (400 MHz, CDCl₃): d=8.16 (d, J=15.8 Hz, 1H),

¹H NMR (400 MHz, CDCl₃): d=12.9 (s, 1H), 10.2 (s, 1H), 7.40 (dd, J=

8.1 Hz, J_H,F=5.3 Hz, 2H), 7.33 (dd, J=8.1 Hz, J_H,F=5.3 Hz, 2H), 7.09

(dd, J=8.1 Hz, J_H,F=8.8 Hz, 4H), 6.08 (s, 1H), 5.14 (s, 2H), 5.08 ppm (s,

2H); elemental analysis: calcd (%) for C₂₁H₁₅BrF₂O₄: C 56.14, H 3.37;

found: C 56.26, H 3.37.

;

7.92 (d, J=15.8 Hz, 1H), 7.31–7.46 (m, 21H, aromatic), 7.23 (s, 2H), 7.10

(dd, J=8.2 Hz, J_H,F=8.7 Hz, 2H), 7.04 (dd, J=8.2 Hz, J_H,F=8.7 Hz, 2H),

6.82 (d, J=8.7 Hz, 2H), 6.42 (s, 1H), 5.11 (s, 4H), 5.09 (s, 2H), 4.95 (s,

4H), 4.85 (s, 2H), 3.64 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=

189.7, 162.7 (J_C,F=248 Hz), 160.0, 158.9, 157.6, 157.5, 152.7, 142.5, 137.6,

136.7, 135.3, 133.8, 131.6ꢁ2 (J_C,F=3.0 Hz), 130.8, 129.1 (J_C,F=7.6 Hz),

19: To

a solution of 15a (1.36 g, 3.02 mmol) and Cs₂CO₃(1.97 g,

6.05 mmol) in DMF (15 mL) was added 4-methoxybenzyl bromide

(430 mL, 3.18 mmol) and sodium iodide (181 mg, 1.21 mmol) at room

temperature under argon. After being stirred at the same temperature

for 20 hours, the reaction mixture was poured into a mixture of H₂O and

ethyl acetate. The aqueous layer was extracted with ethyl acetate. The

combined organic layers were washed with H₂O and brine, dried over

MgSO₄, and concentrated in vacuo. The residue was recrystallized from

diethylether-hexane to afford 19 (1.14 g, 2.00 mmol, 66%) as a pale white

solid. R_f=0.36 (hexane:ethyl acetate=2:1); FTIR (solid): n˜ =2919, 1673,

128.9 (J_C,F=8.4 Hz), 128.5, 128.2ꢁ2, 128.0ꢁ2, 127.8, 123.9, 115.9 (J_C,F

=

21.3 Hz), 115.8 (J_C,F=21.3 Hz), 114.0, 113.8, 108.3, 101.1, 96.0, 75.3, 71.2,

70.6ꢁ2, 55.2 ppm.

24: To a solution of 20 (214 mg, 216 mmol) in CH₂Cl₂(3.3 mL) was added

aqueous H₂O₂(30%, 2.40 mL, 21.6 mmol), aqueous KOH (1.1 mL, 3m),

and Bu₄N·HSO₄(147 mg, 432 mmol) at room temperature under argon.

After being stirred at the same temperature for 30 hours, the reaction

mixture was poured into a mixture of aqueous Na₂S₂O₃(10%) and ethyl

acetate. The aqueous layer was extracted with ethyl acetate. The com-

bined organic layers were washed with aqueous Na₂S₂O₃(10%) and

brine, dried over MgSO₄, and concentrated in vacuo. The residue was

used for the next reaction without further purification. To a solution of

the above residue in methanol (1.5 mL) and CH₂Cl₂(1.5 mL) was added

1604, 1584, 1510, 1367, 1249, 1186, 1079, 857, 829, 612 cm^À^{1 1}H NMR

;

(400 MHz, CDCl₃): d=10.3 (s, 1H), 7.52 (d, J=8.6 Hz, 2H), 7.37–7.43

(m, 4H), 7.05–7.13 (m, 4H), 6.92 (d, J=8.6 Hz, 2H), 6.38 (s, 1H), 5.12 (s,

2H), 5.10 (s, 2H), 4.98 (s, 2H), 3.82 ppm (s, 3H); ¹³C NMR (100 MHz,

CDCl₃): d=187.2, 164.0, 161.5, 160.7, 160.0, 159.7, 131.5, 131.2, 130.8,

ScACTHNUTRGEN(NUG OTf)₃(21.2 mg, 43.2 mmol) at room temperature under argon. After

129.0 (J_C,F=6.1 Hz), 128.9 (J_C,F=6.1 Hz), 128.6, 128.3, 115.9 (J_C,F

=

being stirred at the same temperature for 3 hours, the reaction mixture

was poured into a mixture of saturated aqueous solution of NaHCO₃and

ethyl acetate. The aqueous layer was extracted with ethyl acetate. The

combined organic layers were washed with saturated aqueous solution of

NaHCO₃and brine, dried over MgSO₄, and concentrated in vacuo. The

residue was purified by column chromatography on silica gel (2% ethyl

acetate in toluene) to afford 24 (180 mg, 174 mmol, 81% in 2 steps, a mix-

ture of diastereomers) as a white solid. R_f=0.23 (hexane:ethyl acetate=

2:1); FTIR (solid): n˜ =3474, 3033, 2934, 1674, 1604, 1587, 1513, 1455,

21.3 Hz), 115.9 (J_C,F=21.3 Hz), 115.2, 114.0, 101.1, 95.6, 76.7, 70.6, 70.6,

55.4 ppm; elemental analysis: calcd (%) for C₅₈H₄₇BrF₂O₈: C 70.37,

H 4.79; found: C 70.22, H 4.81.

20: To a solution of 19 (156 mg, 274 mmol) in tetrahydrofuran (THF,

1.9 mL) was added 14a (124 mg, 283 mmol) and sodium methoxide

(44.5 mg, 830 mmol) at room temperature under argon. After being

stirred at the same temperature for 5 hours, the reaction mixture was

poured into a mixture of H₂O and ethyl acetate. The aqueous layer was

extracted with ethyl acetate. The combined organic layers were washed

with brine, dried over MgSO₄, and concentrated in vacuo. The residue

was recrystallized from CH₂Cl₂-hexane to afford 20 (247 mg, 250 mmol,

91%) as a pale yellow solid. R_f=0.38 (hexane:ethyl acetate=2:1); FTIR

1427, 1372, 1332, 1250, 1226, 1158, 1103, 1031, 827, 751, 697 cm^À1

;

¹H NMR (400 MHz, CDCl₃): d=7.60 (d, J=8.2 Hz, 2H), 7.20–7.37 (m,

19H, aromatic), 7.10 (brt, J=8.2 Hz, 2H), 6.99 (s, 2H), 6.97 (brt, J=

8.2 Hz, 2H), 6.88 (d, J=8.2 Hz, 2H), 6.09 (s, 1H,), 5.83 (brt, J=7.3 Hz,

Chem. Asian J. 2010, 5, 2231 – 2248

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org

2237

T. Takahashi et al.

FULL PAPERS

1H), 4.72–5.06 (m, 13H), 3.77 (s, 3H), 3.52 (d, J=7.3 Hz, 1H), 3.39 ppm

(s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=200.2, 162.7 (J_C,F=247 Hz),

162.6 (J_C,F=247 Hz), 159.9, 157.3, 156.7, 152.3, 142.7, 137.5, 136.8, 132.1

(J_C,F=3.0 Hz), 131.7 (J_C,F=3.0 Hz), 131.1, 131.0, 129.1 (J_C,F=8.4 Hz),

d=167.3, 157.0, 156.9, 156.8, 146.0, 145.7, 139.3, 133.0, 130.6, 121.0, 110.2,

106.8, 99.0, 96.5, 95.8, 77.9, 70.3, 26.4 ppm.

26: PS-Wang-Br resin (Novabiochem, 1.60 mmolg^À1loading, 282 mg) was

placed in a syringe-shaped vessel. To this reaction vessel was added a sus-

pension of 15a (360 mg, 800 mmol, 200 mm) in DMF (4.00 mL), Cs₂CO₃

(260 mg, 800 mmol, 200 mm), and sodium iodide (30.0 mg, 240 mmol,

60.0 mm) at room temperature. After being shaken for 24 hours, the sol-

vent was removed and the resin was rinsed with DMF (5 min). The re-

maining resin was washed consecutively with DMF:H₂O (2:1, 5 min x3),

DMF (5 min x3), methanol (5 min x3), and CH₂Cl₂(5 min x3), and dried

under reduced pressure to afford polymer-supported benzaldehyde 26.

FTIR (solid): n˜ =3026, 2925, 1677, 1591, 1559, 1520, 1354, 1250, 1189,

128.9 (J_C,F=8.4 Hz), 128.5, 128.4, 128.2, 128.0, 127.5, 115.8 (J_C,F

=

21.4 Hz), 115.7 (J_C,F=21.4 Hz), 114.4, 114.1, 107.7, 101.5, 96.0, 79.4, 75.3,

75.1, 73.9, 70.9, 70.8, 70.4, 57.7, 55.3 ppm.

25: To a solution of 24 (484 mg, 466 mmol) in pyridine (3.30 mL) was

added 11a (226 mg, 513 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbo-

diimide hydrochloride (EDCI·HCl, 134 mg, 700 mmol, 1.50 equiv), and 4-

dimethylaminopyridine (DMAP, 11.0 mg, 93.3 mmol, 0.200 equiv) at room

temperature under argon. After being stirred at the same temperature

for 12 hours, the reaction mixture was poured into a mixture of aqueous

HCl (1m) and ethyl acetate. The aqueous layer was extracted with ethyl

acetate. The combined organic layers were washed with aqueous HCl

(1m), saturated aqueous solution of NaHCO₃, and brine, dried over

MgSO₄, and concentrated in vacuo. The residue was purified by column

chromatography on silica gel (15% ethyl acetate in hexane) to afford 26

(654 mg, 448 mmol, 96%) as a white solid. R_f=0.36 (hexane:ethyl ace-

tate=2:1); FTIR (solid): n˜ =3033, 2926, 1715, 1685, 1589, 1512, 1455,

1083, 855, 813, 734, 576 cm^À1

.

Procedure for Cleavage from PS Resins

Polymer-supported benzaldehyde 9 was placed in a syringe-shaped vessel.

To this reaction vessel was added a solution of trifluoroacetic acid

(50.0 mL) in CH₂Cl₂(950 mL) at room temperature. After being shaken at

the same temperature for 1 hour, the reaction mixture was filtered and

washed with CH₂Cl₂(5 min x3). The filtrate was concentrated in vacuo.

The residue was purified by short-pad column chromatography.

1428, 1372, 1327, 1227, 1112, 911, 827, 736, 697, 498 cm^À^{1 1}H NMR

;

(400 MHz, CDCl₃): d=7.59 (d, J=8.2 Hz, 2H), 7.52 (s, 2H), 7.08–7.44

(m, 38H, aromatic), 6.96 (brt, J=8.7 Hz, 2H), 6.81 (d, J=8.2 Hz, 2H),

6.09 (s, 1H), 5.38 (d, J=9.2 Hz, 1H), 4.74–5.20 (m, 19H), 3.69 (s, 3H),

27: 26 was placed in a syringe-shaped vessel. To this reaction vessel was

added 14a (330 mg, 750 mmol, 500 mm) in THF (1.20 mL) at room temper-

ature. After being shaken for 15 minutes, a solution of sodium methoxide

(8.10 mg, 150 mmol, 100 mm) in methanol (300 mL) was added to the reac-

tion mixture at room temperature. After being shaken for 24 hours, the

solvent was removed, and the resin was rinsed with THF (5 min). The re-

maining resin was washed consecutively with THF (5 min x3), methanol

(5 min x3), and CH₂Cl₂(5 min x3), and dried under reduced pressure to

afford polymer-supported chalcone 27. FTIR (solid): n˜ =3033, 2919, 1659,

3.42 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=166.0, 162.6ꢁ2 (J_C,F

=

247 Hz), 159.8, 157.0, 152.7, 152.4, 142.9, 138.0, 137.7, 137.5, 136.8ꢁ2,

132.3 (J_C,F=3.0 Hz), 131.7 (J_C,F=3.0 Hz), 130.8, 129.2 (J_C,F=8.4 Hz),

129.0 (J_C,F=8.4 Hz), 128.8, 128.7ꢁ2, 128.5, 128.4, 128.3, 128.2, 128.1ꢁ2,

127.9ꢁ2, 127.8, 127.7, 125.4, 124.7, 120.8, 115.9 (J_C,F=21.3 Hz), 115.6

(J_C,F=21.3 Hz), 114.0, 109.8, 107.8, 99.7, 95.9, 76.7, 76.6, 75.3, 71.4, 71.0,

70.7, 70.3, 58.0, 55.2, 21.6 ppm.

1591, 1555, 1337, 1287, 1188, 1148, 1083, 989, 857, 729, 693 cm^À1

.

6aa: To a solution of 25 (20.9 mg, 14.3 mmol) in CH₂Cl₂(850 mL) was

added triethylsilane (100 mL) and trifluoroacetic acid (50 mL) at 08C

under argon. After being stirred at the same temperature for 2 hours, the

28: 27 was placed in a syringe-shaped vessel. To this reaction vessel was

added tert-butyl hydrogen peroxide (TBHP, 5.5m) in decane (450 mL,

2.25 mmol, 1.50m), CH₂Cl₂(950 mL), and KOH (3m) in methanol

(100 mL, 300 mmol, 200 mm) at room temperature. After being shaken for

72 hours, the solvent was removed, and the resin was rinsed with CH₂Cl₂

(5 min). The remaining resin was washed consecutively with methanol

(5 min x4) and CH₂Cl₂(5 min x4), and dried under reduced pressure to

afford 28. FTIR (solid): n˜ =3028, 2928, 1675, 1608, 1512, 1168, 1113,

reaction mixture was poured into

a mixture of saturated aqueous

NaHCO₃and ethyl acetate at 08C. The aqueous layer was extracted with

ethyl acetate. The combined organic layers were washed with saturated

aqueous NaHCO₃and brine, dried over MgSO₄, and concentrated in va-

cuo. The residue was purified by column chromatography on silica gel

(15% ethyl acetate in hexane) to afford 6aa (12.5 mg, 103 mmol, 72%) as

a white solid. R_f=0.44 (hexane:ethyl acetate=2:1); FTIR (solid): n˜ =

3033, 2927, 1716, 1616, 1593, 1512, 1455, 1430, 1372, 1227, 1114, 911, 826,

1016, 825, 736 cm^À1

.

29: 28 was placed in a syringe-shaped vessel. To this reaction vessel was

added CH₂Cl₂(700 mL) at room temperature. After being shaken for

15 minutes, the reaction mixture was added with ScACTHNUGTRENUNG(OTf)₃(6.90 mg,

752, 697, 504 cm^À^{1 1}H NMR (400 MHz, CDCl₃): d=7.19–7.39 (m, 36H,

;

aromatic), 7.01–7.07 (m, 4H, aromatic), 6.73 (s, 2H), 6.38 (d, J=1.9 Hz,

1H), 6.30 (d, J=1.9 Hz, 1H), 5.66 (brs, 1H), 5.04 (s, 1H), 4.66–5.01 (m,

14.0 mg, 10.0 mm) in methanol (700 mL). After being shaken for 3 hours,

the solution was quenched with triethylamine. Then, the solvent was re-

moved and the resin was rinsed with CH₂Cl₂(5 min). The remaining

resin was washed consecutively with methanol (5 min x4) and CH₂Cl₂

(5 min x4), and dried under reduced pressure to afford 29. FTIR (solid):

n˜ =3368, 3027, 2927, 1677, 1604, 1512, 1453, 1427, 1376, 1233, 1158, 1030,

16H), 3.10 (dd,

J_gem=17.9 Hz, J=4.3 Hz, 1H), 3.03 ppm (dd, J_gem=

17.9 Hz, J=2.4 Hz, 1H, f); ¹³C NMR (100 MHz, CDCl₃): d=164.9, 162.7

(J_C,F=247 Hz), 162.6 (J_C,F=247 Hz), 158.8, 158.0, 155.8, 153.0, 152.5,

142.9, 138.6, 137.8, 137.5, 137.0, 136.5, 136.2, 133.2, 132.6 (J_C,F=3.0 Hz),

132.5 (J_C,F=3.0 Hz), 129.4 (J_C,F=8.4 Hz), 129.1 (J_C,F=8.4 Hz), 128.6ꢁ2,

128.5, 128.4, 128.3, 128.2ꢁ2, 128.0, 127.9, 127.8, 127.6ꢁ2, 125.0, 115.6

(J_C,F=21.8 Hz), 109.3, 106.9, 101.2, 94.8, 94.1, 78.1, 75.2, 75.1, 71.3, 71.2,

69.6, 69.5, 68.3, 26.3 ppm; HRMS (ESI-TOF): m/z (%) calcd for

C₇₈H₆₄F₂O₁₁: 1215.4495 [M+H]⁺; found: 1215.4495; elemental analysis:

calcd (%) for C₇₈H₆₄F₂O₁₁: C 77.08, H 5.31; found: C 76.76, H 5.41.

827, 730, 706 cm^À1

.

30: 29 was placed in a syringe-shaped vessel. To this reaction vessel was

added 11a (100 mg, 225 mmol, 150 mm), http://en.wikipedia.org/wiki/

N,N%27-Diisopropylcarbodiimide (DIC, 46.0 mL, 300 mmol, 200 mm), and

DMAP (11.0 mg, 90.0 mmol, 60.0 mm) in CH₂Cl₂:DMF (4:1, 1.50 mL) at

room temperature. After being shaken for 48 hours, the solvent was re-

moved, and the resin was rinsed with DMF (5 mL). The remaining resin

was washed consecutively with DMF:H₂O (2:1, 5 mL x3), DMF (5 mL

x3), methanol (5 mL x3), and CH₂Cl₂(5 mL x3), and dried under reduced

pressure to afford polymer-supported acyloxyketone 30. FTIR (solid):

n˜ =3029, 2926, 1720, 1686, 1592, 1513, 1453, 1427, 1364, 1326, 1219, 1116,

2aa: H-Cube system was charged with Pd(OH)₂:C CatCart column and

heated to 508C. The hydrogen pressure was set to 20 bar. 6aa (11.4 mg,

9.38 mmol) was dissolved in methanol:THF (1:1, 10.0 mL), and the solu-

tion was pumped through the system with a flow rate of 1 mLmin^À1

.

After passing through the instrument, the reaction mixture was collected,

and the column was washed with methanol (7.00 mL). The collected solu-

tions were combined and concentrated in vacuo. The residue was purified

by reverse-phase column chromatography (VARIAN Bond ELUT C18)

to afford 2aa (3.10 mg, 6.76 mmol, 72%) as a white solid. FTIR (solid):

915, 827, 738, 703, 592 cm^À1

.

6aa: To a suspension of 30 packed into MiniKan in CH₂Cl₂(8.50 mL)

was added a solution of trifluoroacetic acid (500 mL) and triethylsilane

(1.00 mL) at 08C. After being shaken at the same temperature for

6 hours, the reaction mixture was filtered. The remaining resin was rinsed

with ethyl acetate, and the filtrate was concentrated in vacuo. The residue

was purified by gel permeation chromatography (GPC) to afford chro-

man 6aa (9.20 mg, 7.57 mmol, 47% yield in 5 steps).

1

n˜ =3508, 1687, 1608, 1451, 1227, 1029, 730, 549 cm^À1; H NMR (400 MHz,

[D₆]acetone:D₂O=1:1): d=6.86 (s, 2H), 6.51 (s, 2H), 5.89 (s, 2H), 5.27

(brs, 1H), 4.89 (s, 1H), 2.87 (dd, J_gem=17.4 Hz, J=4.4 Hz, 1H), 2.76 ppm

(brd, J_gem=17.4 Hz, 1H); ¹³C NMR (100 MHz, [D₆]acetone:D₂O=1:1):

2238

www.chemasianj.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Asian J. 2010, 5, 2231 – 2248

Solid-Phase Synthesis of a Combinatorial Methylated EGCG Library

Solid-Phase Synthesis of the Protected Methylated EGCGs 6–9.

4.3 Hz, 1H), 3.04 ppm (dd,

(67.8 MHz, CDCl₃): d=165.0, 162.6ꢁ2 (¹J_C,F=247 Hz), 158.8, 158.0,

J

_gem=17.9 Hz, J=1.9 Hz, 1H); ¹³C NMR

Loading of building blocks 15: Each MiniKans contained PS-Wang-Br

resin (Novabiochem, 1.60 mmolg^À1loading, ca. 70.0 mg) and a radiofre-

quency tag. The 64 MiniKans were encoded and distributed into four

vials (A-1,2,3,4: 16 MiniKans in each). To a suspension of a set of Mini-

Kan and DMF solution of 15a–d (32.0 mL, 0.2m), was added Cs₂CO₃

(0.2m) and sodium iodide (0.06m) at room temperature. After being

shaken for 24 hours, the reaction mixture was filtered, and the Mini-

Kans^TMwere rinsed with DMF (80 mL). All MiniKans were pooled to-

gether, and washed consecutively with DMF:H₂O (2:1, 80 mL x3), DMF

(80 mL x3), methanol (80 mL x3), and CH₂Cl₂(80 mL x3), and dried

under reduced pressure.

155.8, 153.3, 153.0, 151.8, 143.3, 137.8, 137.0, 136.5, 133.3, 132.6 (⁴J_C,F

=

1.7 Hz), 129.4 (³J_C,F=8.4 Hz), 129.1 (³J_C,F=8.4 Hz), 128.7, 128.6, 128.5,

128.2, 128.0, 127.9, 127.8, 127.6, 127.5, 124.9, 115.6ꢁ2 (²J_C,F=22.1 Hz),

109.2, 107.5, 106.9, 101.2, 94.8, 94.7, 78.0, 75.2, 71.4, 71.1, 69.6, 68.4, 60.9,

56.4, 26.3 ppm.

6ad (43%): R_f=0.39 (hexane:ethyl acetate=2:1); ¹H NMR (400 MHz,

CDCl₃): d=7.19–7.42 (m, 26H, aromatic), 7.08 (t, J=8.7 Hz, 2H), 7.05

(t, J=8.7 Hz, 2H), 6.80 (s, 2H, c), 6.31 (d, J=1.9 Hz, 1H), 6.25 (d, J=

1.9 Hz, 1H), 5.63 (brs, 1H), 5.07 (s, 1H), 4.93–5.02 (m, 10H), 4.85 (d, J=

11.6 Hz, 2H), 3.76 (s, 6H), 3.11 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H),

3.06 ppm (dd,

J

_gem=17.9 Hz, J=2.9 Hz, 1H); ¹³C NMR (67.8 MHz,

Aldol condensation of ketone 14: The 64 MiniKans were sorted and dis-

tributed into four vials (B-1,2,3,4: 16 MiniKans in each). To a suspension

of each MiniKan and THF solution of 14a–d (22.4 mL, 0.3m) was added

a methanol solution of sodium methoxide (4.80 mL, 0.1m) at room tem-

perature. After being shaken for 24 hours, the reaction mixture was fil-

tered, and the MiniKans were rinsed with THF (80 mL). All MiniKans

were pooled together, and washed consecutively with THF (80 mL x3),

methanol (80 mL x3), CH₂Cl₂(80 mL x3), and dried under reduced pres-

sure.

CDCl₃): d=165.2, 164.4, 158.7, 157.9, 155.7, 153.3, 153.0, 141.7, 138.7,

137.5, 137.0, 133.4, 132.7 (⁴J_C,F=3.4 Hz), 132.6 (⁴J_C,F=3.9 Hz), 129.4

(³J_C,F=7.8 Hz), 129.1 (³J_C,F=7.8 Hz), 128.6, 128.5, 128.3, 128.2, 128.0ꢁ2,

127.9, 127.6, 127.5, 125.2, 115.6ꢁ2 (²J_C,F=21.8 Hz), 107.4, 107.0, 101.1,

94.8, 94.0, 77.8, 75.3, 75.0, 71.6, 69.6, 69.5, 68.7, 56.4, 26.3 ppm.

6ba (41%): R_f=0.46 (hexane:ethyl acetate=2:1); ¹H NMR (400 MHz,

CDCl₃): d=7.22–7.37 (m, 31H, aromatic), 7.04 (t, J=8.7 Hz, 2H), 7.02

(t, J=8.7 Hz, 2H), 6.71 (s, 2H), 6.36 (d, J=1.9 Hz, 1H), 6.29 (d, J=

1.9 Hz, 1H), 5.63 (brs, 1H, f), 5.05 (s, 1H), 4.92–5.03 (m, 10H), 4.82 (d,

Epoxidation: The 64 MiniKans in CH₂Cl₂(96.0 mL) were treated with a

decan solution of tert-butyl hydrogen peroxide (36.5 mL, 5.5m) and meth-

anol solution of KOH (17.3 mL, 2.5m) at room temperature. After being

shaken for 72 hours, the solvent was removed, and the MiniKans were

rinsed with CH₂Cl₂(480 mL). The MiniKans were washed consecutively

with methanol (480 mL x4) and CH₂Cl₂(480 mL x4), and dried under re-

duced pressure.

J=11.6 Hz, 2H), 4.71 (d, J=11.6 Hz, 2H), 3.80 (s, 3H), 3.09 (dd, J_gem

=

17.9 Hz, J=4.3 Hz, 1H, i), 3.02 ppm (dd, J_gem=17.9 Hz, J=2.4 Hz, 1H);

¹³C NMR (67.8 MHz, CDCl₃): d=164.3, 158.7, 157.9, 155.7, 152.6, 152.4,

142.8, 139.5, 137.4, 136.9, 136.4, 132.9, 132.5 (³J_C,F=3.4 Hz)„ 129.3 (³J_C,F

=

7.8 Hz), 129.0 (³J_C,F=7.8 Hz), 128.5ꢁ2, 128.4, 128.3, 128.2, 128.1, 127.9,

127.8, 127.4ꢁ2, 127.3, 124.8, 115.5 (²J_C,F=21.8 Hz), 109.2, 106.9, 101.1,

94.7, 94.0, 77.9, 75.0, 71.2, 71.1, 69.5, 69.4, 68.2, 60.9, 26.2 ppm.

Epoxide opening: The 64 MiniKans in CH₂Cl₂(64.0 mL) were treated

with a methanol suspension of ScACHTNUTRGENNG(U OTf)₃(64.0 mL, 0.01m). After being

6bb (58%): R_f=0.41 (hexane:ethyl acetate=2:1); ¹H NMR (400 MHz,

CDCl₃): d=7.21–7.38 (m, 26H, aromatic), 7.04 (t, J=8.7 Hz, 2H), 7.02

(t, J=8.7 Hz, 2H), 6.68 (s, 2H), 6.36 (d, J=1.4 Hz, 1H), 6.29 (d, J=

1.4 Hz, 1H), 5.63 (brs, 1H), 5.05 (s, 1H), 4.98–5.02 (m, 8H), 4.77 (d, J=

11.6 Hz, 2H), 4.66 (d, J=11.6 Hz, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 3.08

shaken for 3 hours, the solution was quenched by the addition of triethyl-

amine. Then, the solvent was removed, and the MiniKans were rinsed

with CH₂Cl₂(480 mL). The MiniKans was washed consecutively with

methanol (480 mL x4) and CH₂Cl₂(480 mL x4), and dried under reduced

pressure.

(dd,

J_gem=17.9 Hz, J=4.3 Hz, 1H), 3.01 ppm (dd, J_gem=17.9 Hz, J=

1.4 Hz, 1H); ¹³C NMR (67.8 MHz, CDCl₃): d=164.8, 162.5 (¹J_C,F

=

Esterification with 11: The 64 MiniKans were sorted and distributed into

four vials (D-1,2,3,4: 16 MiniKans in each). To a suspension of each

MiniKan and a CH₂Cl₂:DMF (4:1) solution of 11 (32.0 mL, 0.2m) was

added DIC (0.2m) and DMAP (0.06m) at room temperature. After being

shaken for 36 hours, the reaction mixture was filtered and rinsed with

DMF (80 mL). All MiniKans^TMwere pooled together, and washed con-

secutively with DMF:H₂O (2:1, 80 mL x3), DMF (80 mL x3), methanol

(80 mL x3), and CH₂Cl₂(80 mL x3), and dried under reduced pressure.

246 Hz), 158.7, 158.0, 155.8, 152.7, 152.1, 143.9, 139.7, 137.0, 136.5, 132.9,

132.6 (⁴J_C,F=2.8 Hz), 129.4 (³J_C,F=8.4 Hz), 129.1 (³J_C,F=7.8 Hz), 128.7,

128.5ꢁ2, 128.2, 127.9, 127.8, 127.6, 127.5, 127.4, 124.7, 115.6 (²J_C,F

=

21.8 Hz), 109.3, 107.0, 101.2, 94.8, 94.0, 78.1, 71.2, 71.1, 69.6, 69.4, 68.2,

60.9, 26.4 ppm.

6bc (57%): R_f=0.32 (hexane:ethyl acetate=2:1); ¹H NMR (400 MHz,

CDCl₃): d=7.27–7.39 (m, 21H, aromatic), 7.04 (brt, J=8.7 Hz, 4H), 6.72

(s, 2H), 6.33 (d, J=1.9 Hz, 1H), 6.27 (d, J=1.9 Hz, 1H), 5.63 (brs, 1H),

5.00 (s, 1H), 4.98–5.04 (m, 6H), 4.86 (d, J=11.6 Hz, 2H), 4.74 (d, J=

11.6 Hz, 2H), 3.81 (s, 3H), 3.78 (s, 6H), 3.09 (dd, J_gem=17.9 Hz, J=

Release and reductive etherification: The 64 MiniKans were sorted and

distributed into 64 reaction vessels containing a magnetic stirring bar in

each. Then, each vessel was inserted into a Zodiac, and a solution of tri-

fluoroacetic acid (500 mL) and triethylsilane (1.00 mL) in CH₂Cl₂

(8.50 mL) was added at 08C. After being stirred for 6 hours, the reaction

mixtures were filtered, diluted with ethyl acetate, and concentrated in va-

cuo. The residues were purified by column chromatography (hexane:eth-

yl acetate) to afford EGCG analogues.

4.3 Hz, 1H), 3.02 ppm (dd,

J

_gem=17.9 Hz, J=2.4 Hz, 1H); ¹³C NMR

(67.8 MHz, CDCl₃): d=165.0, 161.4, 158.8, 158.0, 155.8, 153.3,152.7,

151.8, 143.3, 139.8, 137.0, 136.5, 133.0, 132.6, 129.4 (³J_C,F=7.6 Hz), 129.1

(³J_C,F=7.6 Hz), 128.7, 128.5, 128.2, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4,

124.9, 115.7 (²J_C,F=22.1 Hz), 115.5 (²J_C,F=21.3 Hz), 109.2, 107.5, 107.1,

101.2, 94.8, 94.1, 77.9, 77.6, 71.4, 71.1, 69.5ꢁ2, 68.4, 61.0, 56.4, 56.3,

25.7 ppm.

6ab (54%): R_f=0.43 (hexane:ethyl acetate=2:1); ¹H NMR (400 MHz,

CDCl₃): d=7.19–7.39 (m, 31H,aromatic), 6.99–7.07 (m, 4H, aromatic),

6.71 (s, 2H), 6.39(d, J=1.9 Hz, 1H), 6.30 (d, J=1.9 Hz,1H), 5.65 (brs,

1H), 4.94–5.03 (m, 11H), 4.74 (d, J=11.6 Hz, 2H), 4.62 (d, J=11.6 Hz,

2H), 3.77 (s, 3H), 3.09 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H), 3.03 ppm (dd,

6bd (57%): R_f=0.36 (hexane:ethyl acetate=2:1); ¹H NMR (270 MHz,

CDCl₃): d=7.29–7.42 (m, 19H, aromatic), 7.18 (s, 2H), 7.07 (t, J=

8.6 Hz, 2H7.04 (t, J=8.6 Hz, 2H), 6.78 (s, 2H), 6.29 (d, J=1.9 Hz, 1H),

6.25 (d, J=1.9 Hz, 1H), 5.61 (brs, 1H), 5.04 (s, 1H), 4.86–5.02 (m, 10H),

3.83 (s, 3H), 3.76 (s, 6H), 3.10 (dd, J_gem=17.9 Hz, J=4.4 Hz, 1H),

J

_gem=17.9 Hz, J=1.9 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): d=164.8,

162.6ꢁ2 (¹J_C,F=247 Hz), 158.8, 158.0, 155.8, 153.0, 152.1,143.9, 138.6,

3.04 ppm (dd,

J

_gem=17.9 Hz, J=2.4 Hz, 1H); ¹³C NMR (67.8 MHz,

137.8, 137.0, 136.6, 136.5, 133.2, 132.6 (⁴J_C,F=2.3 Hz), 129.4 (³J_C,F

=

CDCl₃): d=165.3, 162.6ꢁ2 (¹J_C,F=247 Hz), 158.7, 157.9, 155.7, 153.3,

152.7, 141.7, 139.8, 137.4, 137.0, 133.1, 132.7, 132.6 (⁴J_C,F=3.4 Hz), 129.4

(³J_C,F=7.8 Hz), 129.1 (³J_C,F=8.4 Hz), 128.6, 128.4, 128.3ꢁ2, 128.0ꢁ2,

127.5, 127.4, 125.2, 115.6ꢁ2 (²J_C,F=21.8 Hz), 107.4, 107.1, 101.1, 94.8,

94.0, 77.7, 75.0, 71.5, 69.6, 69.4, 68.6, 61.0, 56.4, 26.0 ppm.

8.4 Hz), 129.1 (³J_C,F=8.4 Hz), 128.7, 128.6, 128.5, 128.4, 128.3ꢁ2, 128.2,

127.8ꢁ2, 127.7, 127.6ꢁ2, 127.5, 124.7, 115.6 (²J_C,F=22.1 Hz), 109.3, 106.9,

101.2, 94.8, 94.1, 78.1, 75.2, 71.3, 71.1, 69.6, 69.5, 68.2, 60.9, 26.4 ppm.

6ac (56%): R_f=0.36 (hexane:ethyl acetate=2:1); ¹H NMR (400 MHz,

CDCl₃): d=7.18–7.38 (m, 26H, aromatic), 7.04ꢁ2 (t, J=8.7 Hz, 4H),

6.74 (s, 2H, c), 6.35(d, J=2.4 Hz, 1H), 6.28 (d, J=2.4 Hz, 1H), 5.65 (brs,

1H), 5.07 (s, 1H), 4.93–5.05 (m, 8H), 4.84 (d, J=11.6 Hz, 2H), 4.71 (d,

J=11.6 Hz, 2H), 3.78 (s, 3H), 3.77 (s, 3H), 3.11 (dd, J_gem=17.9 Hz, J=

6ca (52%): R_f=0.42 (hexane:ethyl acetate=2:1); ¹H NMR (400 MHz,

CDCl₃): d=7.26–7.43 (m, 26H, aromatic), 7.05 (t, J=8.7 Hz, 2H), 7.03

(t, J=8.7 Hz, 2H), 6.60 (s, 2H), 6.40 (d, J=1.9 Hz, 1H), 6.29 (d, J=

1.9 Hz, 1H), 5.66 (brs, 1H), 4.93–5.08 (m, 13H), 3.50 (s, 6H), 3.11 (dd,

Chem. Asian J. 2010, 5, 2231 – 2248

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org

2239

T. Takahashi et al.

FULL PAPERS

J

_gem=17.4 Hz, J=4.3 Hz, 1H), 3.05 ppm (dd, J_gem=17.4 Hz, J=2.4 Hz,

(¹J_C,F=247 Hz), 158.7, 157.9, 155.8, 153.3ꢁ2, 141.5, 138.1, 137.3, 133.3,

132.6 (⁴J_C,F=1.7 Hz), 132.5 (⁴J_C,F=1.7 Hz), 129.4 (³J_C,F=7.8 Hz), 129.1

(³J_C,F=7.8 Hz), 128.5, 128.3, 128.1, 125.2, 115.6ꢁ2 (²J_C,F=21.8 Hz), 107.4,

104.1, 101.1, 94.8, 94.0, 78.0, 69.6, 69.5, 68.6, 60.9, 56.4, 56.1, 26.2 ppm.

7aa (40%): R_f=0.68 (toluene:ethyl acetate=10:1); ¹H NMR (400 MHz,

CDCl₃): d=7.19–7.42 (m, 37H, aromatic), 6.73 (s, 2H), 6.38 (d, J=

1.9 Hz, 1H), 6.30 (d, J=1.9 Hz, 1H), 5.66 (brs, 1H), 4.95–5.04 (m, 9H),

4.90 (s, 2H, Bn), 4.80 (d, J_gem=11.6 Hz, 2H), 4.67 (d, J_gem=11.6 Hz, 2H),

1H); ¹³C NMR (67.8 MHz, CDCl₃): d=164.8, 162.5 (¹J_C,F=247 Hz),

158.7, 157.9, 155.7, 153.5, 152.3, 142.5, 137.7, 137.3, 137.0, 136.5, 133.4,

132.5, 129.3 (³J_C,F=8.4 Hz), 129.0 (³J_C,F=8.4 Hz), 128.6, 128.5, 128.4,

128.2, 128.1, 128.0, 127.8, 127.6, 124.9, 115.5 (²J_C,F=21.8 Hz), 109.2, 104.2,

101.1, 94.7, 94.0, 78.1, 75.1, 74.9, 71.1, 69.5, 69.4, 68.3, 55.9, 26.3 ppm.

6cb (56%): R_f=0.41 (hexane:ethyl acetate=2:1); ¹H NMR (400 MHz,

CDCl₃): d=7.27–7.42 (m, 21H, aromatic), 7.12 (t, J=8.7 Hz, 2H), 7.03

(t, J=8.7 Hz, 2H), 6.60 (s, 2H), 6.41 (d, J=1.9 Hz, 1H), 6.30 (d, J=

1.9 Hz, 1H), 5.66 (brs, 1H), 4.92–5.07 (m, 11H), 3.89 (s, 3H, h), 3.50 (s,

3.80 (s, 3H), 3.10 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H), 3.03 ppm (dd, J_gem

=

17.9 Hz, J=2.4 Hz, 1H); ¹³C NMR (67.8 MHz, CDCl₃): d=164.8, 158.9ꢁ

2, 155.5, 152,8, 152.3, 142.7, 138.4, 137.7, 137.4, 136.8ꢁ2, 136.4, 133.3,

128.6, 128.5, 128.4ꢁ2, 128.3, 128.2, 128.1, 128.0ꢁ3, 127.8, 127.7, 127.5ꢁ2,

127.4, 124.9, 109.1, 106.6, 100.5, 94.2, 92.7, 77.9, 75.1, 75.0, 71.1, 71.0, 70.1,

68.2, 55.4, 26.0 ppm; HRMS (ESI-TOF): m/z (%) calcd for C₇₂H₆₆NO₁₁:

1120.4636 [M+NH₄]⁺; found: 1120.4679.

6H), 3.11 (dd,

J_gem=17.9 Hz, J=4.8 Hz, 1H), 3.04 ppm (dd, J_gem=

17.9 Hz, J=2.4 Hz, 1H); ¹³C NMR (67.8 MHz, CDCl₃): d=164.9, 160.8,

158.8, 158.0, 155.8, 153.6, 152.3, 152.1, 144.0, 137.8, 137.1, 136.6, 133.3,

132.6, 129.4 (³J_C,F=8.4 Hz), 129.3 (³J_C,F=8.4 Hz), 128.7, 128.5, 128.2,

127.8ꢁ2, 127.6, 124.8, 115.6 (²J_C,F=21.8 Hz), 110.4, 109.5, 104.2, 101.2,

94.9, 94.1, 78.2, 75.0, 71.2, 69.6, 69.5, 68.3, 61.1, 56.0, 26.4 ppm.

7ab (38%): R_f=0.66 (toluene:ethyl acetate=10:1); FTIR (neat): n˜ =

6cc (47%): R_f=0.35 (hexane:ethyl acetate=2:1); ¹H NMR (400 MHz,

CDCl₃): d=7.16–7.43 (m, 16H, aromatic), 7.04 (brt, J=8.7 Hz, 4H), 6.63

(s, 2H), 6.38 (d, J=1.9 Hz, 1H), 6.28 (d, J=1.9 Hz, 1H), 5.67 (brs, 1H,

f), 4.93–5.06 (m, 9H), 3.88 (s, 3H), 3.81 (s, 3H), 3.57 (s, 6H, j), 3.12 (dd,

2964, 1716, 1621, 1591, 1496, 1427, 1370, 1261, 1213, 1102, 1047, 801, 736,

697 cm^À^{1 1}H NMR (400 MHz, CDCl₃): d=7.19–7.41 (m, 32H, aromatic),

;

6.71 (s, 2H), 6.38(d, J=2.4 Hz, 1H), 6.26 (d, J=2.4 Hz, 1H), 5.65 (brs,

1H), 4.94–5.06 (m, 9H), 4.75 (d, J_gem=11.6 Hz, 2H), 4.62 (d, J_gem

11.6 Hz, 2H, Bn), 3.80 (s, 3H), 3.77 (s, 3H), 3.05 (dd, J_gem=17.9 Hz, J=

4.3 Hz, 1H), 2.98 ppm (dd,

_gem=17.9 Hz, J=2.4 Hz, 1H); ¹³C NMR

=

J

_gem=17.9 Hz, J=4.9 Hz, 1H), 3.05 ppm (dd, J_gem=17.9 Hz, J=2.4 Hz,

1H); ¹³C NMR (67.8 MHz, CDCl₃): d=165.0, 164.4, 158.8, 158.0, 155.8,

153.6, 153.2, 151.9, 144.1, 143.4, 137.8, 137.1, 136.6, 133.4, 132.6, 129.4

(³J_C,F=8.4 Hz), 129.1 (³J_C,F=7.8 Hz), 128.7ꢁ2, 128.5, 128.2ꢁ2, 127.9,

124.9, 115.6 (²J_C,F=22.9 Hz), 109.3, 107.5, 104.2, 101.2, 94.9, 94.1, 78.1,

75.1, 71.2, 69.6, 69.5, 68.5, 61.0, 56.4, 56.1, 26.3 ppm.

J

(67.8 MHz, CDCl₃): d=164.8, 159.1, 159.0, 155.6, 152,9, 152.1, 143.7,

138.5, 137.8, 137.0, 136.9, 136.5, 133.3, 128.7, 128.6, 128.4, 128.1ꢁ2,

127.8ꢁ2, 127.6ꢁ3, 127.5, 124.8, 109.2, 106.7, 100.6, 94.3, 92.8, 78.0, 75.2,

71.2, 71.0, 70.2, 68.3, 60.9, 55.5, 26.2 ppm; HRMS (ESI-TOF): m/z

(%)calcd for C₆₆H₆₂NO₁₁: 1044.4323 [M+NH₄]⁺; found: 1044.4332.

6cd (55%): R_f=0.37 (hexane:ethyl acetate=2:1); FTIR (neat): n˜ =2939,

7ac (39%): R_f=0.61 (toluene:ethyl acetate=10:1); ¹H NMR (400 MHz,

CDCl₃): d=7.17–7.43 (m, 27H, aromatic), 6.75 (s, 2H), 6.35 (d, J=

2.4 Hz, 1H), 6.24 (d, J=2.4 Hz, 1H), 5.65 (brs, 1H), 4.96–5.14 (m, 7H),

4.84 (d, J_gem=11.6 Hz, 2H), 4.71 (d, J_gem=11.6 Hz, 2H), 3.79 (s, 3H), 3.77

(s, 3H), 3.77 (s, 3H), 3.07 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H), 3.03 ppm

(dd, J_gem=17.9 Hz, J=3.4 Hz, 1H); ¹³C NMR (67.8 MHz, CDCl₃): d=

165.0, 159.0ꢁ2, 155.5, 153,2, 152.9, 151.8, 137.8, 137.0, 136.9, 136.5, 133.4,

128.7, 128.6, 128.5, 128.4, 128.2ꢁ2, 128.1, 128.0, 127.9ꢁ2, 127.8, 127.6ꢁ3,

127.5, 124.9, 109.1, 107.3, 106.8, 100.5, 94.3, 92.8, 77.9, 75.2, 71.3, 71.0,

70.2, 68.5, 60.9, 56.3, 55.5, 26.1 ppm; HRMS (ESI-TOF): m/z (%) calcd

for C₆₀H₅₈NO₁₁: 968.4010 [M+NH₄]⁺; found: 968.4053.

1715, 1618, 1592, 1512, 1463, 1417, 1360, 1333, 1225, 1183, 1149, 1128,

1039, 826, 756, 734, 698 cm^À^{1 1}H NMR (400 MHz, CDCl₃): d=7.28–7.43

;

(m, 14H, aromatic), 7.16 (s, 2H), 7.03–7.10 (m, 4H, aromatic), 6.67 (s,

2H), 6.33 (d, J=1.9 Hz, 1H), 6.25 (d, J=1.9 Hz, 1H), 5.66 (brs, 1H),

5.08 (s, 1H), 5.05 (s, 2H, Bn), 5.00 (s, 2H, Bn), 4.98 (s, 2H, Bn), 4.95 (s,

2H, Bn), 3.78 (s, 6H), 3.65 (s, 6H), 3.12 (dd, J_gem=17.9 Hz, J=4.8 Hz,

1H), 3.06 ppm (d, J_gem=17.9 Hz, 1H).

6da (48%): R_f=0.38 (hexane:ethyl acetate=2:1); ¹H NMR (400 MHz,

CDCl₃): d=7.26–7.36 (m, 21H, aromatic), 7.00–7.06 (m, 4H, aromatic),

6.60 (s, 2H), 6.39 (d, J=1.9 Hz, 1H), 6.30 (d, J=1.9 Hz, 1H), 5.66 (brs,

1H), 4.98–5.08 (m, 11H), 3.78 (s, 3H), 3.52 (s, 6H), 3.11 (dd, J_gem

17.4 Hz, J=3.9 Hz, 1H), 3.04 ppm (dd, J_gem=17.4 Hz, J=1.4 Hz, 1H).

=

7ad (41%): R_f=0.63 (toluene:ethyl acetate=10:1); ¹H NMR (400 MHz,

CDCl₃): d=d 7.18–7.45 (m, 27H, aromatic), 6.80 (s, 2H), 6.30(d,

J=2.4 Hz, 1H), 6.21 (d, J=2.4 Hz, 1H,), 5.63 (brs, 1H), 4.84–5.06 (m,

11H), 3.78 (s, 3H), 3.75 (s, 6H), 3.06 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H),

6db (53%): R_f=0.36 (hexane:ethyl acetate=2:1); ¹H NMR (400 MHz,

CDCl₃): d=7.28–7.40 (m, 16H, aromatic), 7.04 (t, J=8.7 Hz, 2H), 7.02

(t, J=8.7 Hz, 2H), 6.60 (s, 2H), 6.40 (d, J=1.9 Hz, 1H), 6.30 (d, J=

1.9 Hz, 1H), 5.67 (brs, 1H), 5.02 (s, 1H), 4.99–5.06 (m, 8H, Bn), 3.89 (s,

3H), 3.78 (s, 3H), 3.53 (s, 6H), 3.11 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H),

3.02 ppm (dd,

J

_gem=17.9 Hz, J=2.4 Hz, 1H); ¹³C NMR (67.8 MHz,

CDCl₃): d=165.3, 159.0, 155.5, 153,3, 152.9, 141.5, 138.5, 137.8, 137.4,

137.0ꢁ2, 133.5, 128.7, 128.6, 128.5, 128.3ꢁ2, 128.2, 128.1, 128.0, 127.9,

127.8, 127.6ꢁ2, 127.5, 125.3, 107.3, 106.9, 100.5, 92.8, 77.0, 75.2, 75.0, 71.5,

70.2, 68.7, 56.4, 55.5, 25.9 ppm; HRMS (ESI-TOF): m/z (%) calcd for

C₆₀H₅₈NO₁₁: 968.4010 [M+NH₄]⁺; found: 968.4009.

7ba (44%): R_f=0.66 (toluene:ethyl acetate=10:1); ¹H NMR (400 MHz,

CDCl₃): d=7.25–7.41 (m, 32H, aromatic), 6.71 (s, 2H), 6.35 (d, J=

1.9 Hz, 1H), 6.25 (d, J=1.9 Hz, 1H), 5.63 (brs, 1H), 5.04 (s, 1H, e),

3.05 ppm (dd,

J

_gem=17.9 Hz, J=1.4 Hz, 1H); ¹³C NMR (67.8 MHz,

CDCl₃): d=164.9, 162.6, 158.8, 158.0, 155.8, 153.2, 152.1, 144.0, 140.5,

138.1, 136.6, 133.1, 132.6, 129.4 (³J_C,F=8.4 Hz), 129.1 (³J_C,F=8.4 Hz),

128.7, 128.2, 127.8, 124.8, 115.6 (²J_C,F=21.8 Hz), 109.4, 104.1, 101.2, 94.8,

94.1, 78.2, 71.1, 69.6, 69.5, 68.3, 61.1, 60.9, 56.0, 26.4 ppm.

6dc (49%): R_f=0.30 (hexane:ethyl acetate=2:1); ¹H NMR (400 MHz,

CDCl₃): d=7.26–7.40 (m, 11H, aromatic), 7.04 (t, J=8.7 Hz, 4H), 6.64

(s, 2H), 6.38 (d, J=2.4 Hz, 1H), 6.28 (d, J=2.4 Hz, 1H), 5.67 (brs, 1H),

4.99–5.08 (m, 7H), 3.88 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 3.60 (s, 6H),

3.12 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H), 3.06 ppm (dd, J_gem=17.9 Hz, J=

2.4 Hz, 1H); ¹³C NMR (67.8 MHz, CDCl₃): d=165.0, 160.7, 158.7, 158.0,

155.8, 153.2, 151.8, 143.3, 138.0, 136.5, 133.2, 132.6 (⁴J_C,F=2.2 Hz), 132.5

(⁴J_C,F=2.2 Hz), 129.4 (³J_C,F=8.4 Hz), 129.1 (³J_C,F=8.4 Hz), 128.7, 128.3,

127.9, 124.9, 115.6ꢁ2 (²J_C,F=21.2 Hz), 109.2, 107.5, 104.1, 101.2, 94.8,

94.1, 78.1, 71.1, 69.6, 69.5, 68.4, 61.0, 60.9, 56.4, 56.0, 26.4 ppm.

4.91–5.03 (m, 8H, Bn), 4.82 (d, J_gem=11.6 Hz, 2H, Bn), 4.71 (d, J_gem

11.6 Hz, 2H, Bn), 3.80 (s, 3H), 3.80 (s, 3H), 3.04 (dd, J_gem=17.9 Hz, J=

4.3 Hz, 1H), 2.98 ppm (dd,

_gem=17.9 Hz, J=2.4 Hz, 1H); ¹³C NMR

=

J

(67.8 MHz, CDCl₃): d=164.9, 159.0ꢁ2, 155.6, 152,7, 152.4, 142.8, 139.6,

137.5, 137.0, 136.9, 136.5, 133.1, 128.7, 128.6, 128.5, 128.3, 128.2, 128.1,

128.0, 127.9, 127.7, 127.6, 127.5, 127.4, 125.0, 109.2, 106.9, 100.6, 94.3,

92.8, 77.9, 75.1, 71.2, 71.1, 70.2, 68.3, 60.9, 55.5, 26.1 ppm; HRMS (ESI-

TOF): m/z (%) calcd for C₆₆H₆₂NO₁₁: 1044.4323 [M+NH₄]⁺; found:

1044.4333.

6dd (50%): R_f=0.31 (hexane:ethyl acetate=2:1); FTIR (neat): n˜ =3010,

7bb (49%): R_f=0.64 (toluene:ethyl acetate=10:1); ¹H NMR (400 MHz,

CDCl₃): d=7.25–7.46 (m, 27H, aromatic), 6.69 (s, 2H), 6.36 (d, J=

2.4 Hz, 1H), 6.25 (d, J=2.4 Hz, 1H), 5.63 (brs, 1H), 5.06 (s, 1H), 4.99–

5.03 (m, 6H), 4.77 (d, J_gem=11.6 Hz, 2H), 4.65 (d, J_gem=11.6 Hz, 2H),

3.80 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.03 (dd, J_gem=17.9 Hz, J=4.3 Hz,

1H), 2.97 ppm (dd, J_gem=17.9 Hz, J=2.4 Hz, 1H); ¹³C NMR (67.8 MHz,

CDCl₃): d=164.8, 159.1ꢁ2, 155.6, 152,7, 152.1, 143.9, 139.7, 137.1, 136.9,

136.6, 133.1, 128.7, 128.5ꢁ2, 128.1, 127.8ꢁ2, 127.6, 127.5ꢁ2, 127.4, 124.8,

2939, 2841, 1715, 1621, 1593, 1512, 1463, 1417, 1361, 1334, 1228, 1183,

1149, 1129, 1040, 1014, 827, 756, 699, 506 cm^À^{1 1}H NMR (400 MHz,

;

CDCl₃): d=7.28–7.44 (m, 9H, aromatic), 7.16 (s, 2H), 7.08 (t, J=8.7 Hz,

2H), 7.04 (t, J=8.7 Hz, 2H), 6.68 (s, 2H, d), 6.33 (d, J=2.4 Hz, 1H), 6.25

(d, J=2.4 Hz, 1H), 5.66 (brs, 1H), 5.08 (s, 1H), 5.05 (s, 2H), 5.00 (s,

2H), 4.98 (s, 2H), 3.80 (s, 3H), 3.78 (s, 6H), 3.69 (s, 6H), 3.12 (dd, J_gem

=

18.4 Hz, J=4.8 Hz, 1H), 3.06 ppm (dd, J_gem=18.4 Hz, J=2.9 Hz, 1H);

¹³C NMR (67.8 MHz, CDCl₃): d=165.2, 162.6 (¹J_C,F=247 Hz), 162.5

2240

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Chem. Asian J. 2010, 5, 2231 – 2248

Solid-Phase Synthesis of a Combinatorial Methylated EGCG Library

109.4, 107.0, 100.6, 94.4, 92.9, 78.0, 71.3, 71.1, 70.3, 68.3, 60.9, 55.5,

26.1 ppm; HRMS (ESI-TOF): m/z (%) calcd for C₆₀H₅₈NO₁₁: 968.4010

[M+NH₄]⁺; found: 968.4009.

7da (47%): R_f=0.40 (toluene:ethyl acetate=10:1); FTIR (neat): n˜ =

3031, 2937, 1716, 1620, 1592, 1499, 1455, 1429, 1367, 1328, 1214, 1148,

1123, 1029, 1006, 910, 814, 753, 697 cm^À^{1 1}H NMR (400 MHz, CDCl₃):

;

7bc (45%): R_f=0.57 (toluene:ethyl acetate=10:1); ¹H NMR (400 MHz,

CDCl₃): d=7.17–7.42 (m, 22H, aromatic), 6.72 (s, 2H), 6.33 (d, J=

2.4 Hz, 1H), 6.23 (d, J=2.4 Hz, 1H,), 5.63 (brs, 1H), 5.01–5.03 (m, 4H,

Bn), 5.00 (s, 1H), 4.86 (d, J_gem=11.6 Hz, 2H, Bn), 4.74 (d, J_gem=11.6 Hz,

d=7.25–7.41 (m, 22H, aromatic), 6.61 (s, 2H), 6.39 (d, J=2.4 Hz, 1H),

6.26 (d, J=2.4 Hz, 1H), 5.66 (brs, 1H), 4.99–5.07 (m, 9H), 3.80 (s, 3H),

3.78 (s, 3H), 3.53 (s, 6H), 3.06 (dd, J_gem=17.9 Hz, J=4.4 Hz, 1H),

3.01 ppm (dd,

J

_gem=17.9 Hz, J=1.9 Hz, 1H); ¹³C NMR (67.8 MHz,

CDCl₃): d=164.8, 158.9ꢁ2, 155.5, 153.1, 152,2, 142.3, 137.8, 137.2, 136.7,

136.4, 133.2, 128.5ꢁ2, 128.2, 128.1, 128.0, 127.7, 127.5, 124.9, 109.0, 103.9,

100.4, 94.2, 92.7, 78.0, 75.0, 71.0, 70.1, 68.3, 60.7, 55.8, 55.4, 26.1 ppm;

HRMS (ESI-TOF): m/z (%) calcd for C₅₄H₅₄NO₁₁: 892.3697 [M+NH₄]⁺;

found: 892.3724.

2H, Bn), 3.81ACHTUNGTRENNUNG(s, 3H), 3.79 (s, 3H), 3.78 (s, 6H), 3.04 (dd, J_gem=17.9 Hz,

J=4.3 Hz, 1H), 2.98 ppm (dd, J_gem=17.9 Hz, J=2.4 Hz, 1H); ¹³C NMR

(67.8 MHz, CDCl₃): d=165.0, 159.0, 155.6, 153.2, 152,7, 151.8, 143.2,

139.7, 137.0, 136.9, 136.5, 133.1, 128.7, 128.6, 128.5ꢁ2, 128.2, 128.1, 127.9,

127.5ꢁ2, 127.4, 124.9, 109.2, 107.4, 107.0, 100.6, 94.3, 92.8, 77.8, 71.3, 71.1,

70.2, 68.4, 60.9ꢁ2, 56.3, 55.5, 26.0 ppm; HRMS (ESI-TOF): m/z (%)

calcd for C₅₄H₅₄NO₁₁: 892.3697 [M+NH₄]⁺; found: 892.3698.

7db (46%): R_f=0.34 (toluene:ethyl acetate=10:1); FTIR (neat): n˜ =

2939, 1716, 1620, 1592, 1499, 1455, 1428, 1369, 1329, 1216, 1148, 1123,

1

1037, 1004, 814, 754, 698 cm^À1; H NMR (400 MHz, CDCl₃): d=7.28–7.41

7bd (48%): R_f=0.59 (toluene:ethyl acetate=10:1); ¹H NMR (400 MHz,

CDCl₃): d=7.26–7.45 (m, 20H, aromatic), 7.17 (s, 2H), 6.78 (s, 2H), 6.28

(d, J=1.9 Hz, 1H), 6.21 (d, J=1.9 Hz, 1H), 5.60 (brs, 1H), 4.87–5.04 (m,

9H), 3.83 (s, 3H), 3.78 (s, 3H), 3.75 (s, 6H), 3.05 (dd, J_gem=17.9 Hz, J=

(m, 15H, aromatic), 7.25 (s, 2H), 6.60 (s, 2H), 6.40 (d, J=2.4 Hz, 1H),

6.26 (d, J=2.4 Hz, 1H), 5.66 (brs, 1H), 5.01–5.09 (m, 7H), 3.88 (s, 3H),

3.80 (s, 3H), 3.78 (s, 3H), 3.53 (s, 6H), 3.06 (dd, J_gem=17.9 Hz, J=4.3 Hz,

1H), 3.00 ppm (dd, J_gem=17.9 Hz, J=2.4 Hz, 1H); ¹³C NMR (67.8 MHz,

CDCl₃): d=164.7, 159.0, 158.9, 155.5, 153.1, 151,9, 143.7, 137.8, 136.7,

136.4, 133.2, 128.6, 128.1, 128.0, 127.7, 127.5, 124.7, 109.1, 103.9, 100.5,

94.2, 92.7, 78.0, 70.9, 70.1, 68.2, 61.0, 60.7, 55.8, 55.4, 26.1 ppm; HRMS

(ESI-TOF): m/z (%) calcd for C₄₈H₅₀NO₁₁: 816.3384 [M+NH₄]⁺; found:

816.3384.

4.3 Hz, 1H), 3.01 ppm (dd,

J

_gem=17.9 Hz, J=2.4 Hz, 1H); ¹³C NMR

(67.8 MHz, CDCl₃): d=165.2, 158.8, 155.3, 153.2, 152,5, 141.4, 139.6,

137.3, 136.9, 136.8, 133.2, 128.6, 128.4, 128.3, 128.2, 128.0, 127.8, 127.5,

127.4, 127.3, 125.2, 107.2, 106.9, 100.4, 94.1, 92.6, 77.5, 74.9, 71.3, 70.1,

68.6, 60.9, 56.2, 55.4, 25.7 ppm; HRMS (ESI-TOF): m/z (%) calcd for

C₅₄H₅₄NO₁₁: 892.3697 [M+NH₄]⁺; found: 892.3697.

7dc (49%): R_f=0.27 (toluene:ethyl acetate=10:1); FTIR (neat): n˜ =

7ca (41%): R_f=0.57 (toluene:ethyl acetate=10:1); FTIR (neat): n˜ =

2939, 1716, 1620, 1593, 1500, 1455, 1421, 1358, 1331, 1219, 1148, 1123,

3031, 2938, 1716, 1621, 1593, 1499, 1455, 1429, 1369, 1328, 1214, 1148,

1

1037, 1005, 814, 756, 698 cm^À1; H NMR (400 MHz, CDCl₃): d=7.26–7.43

1124, 1030, 1002, 911, 815, 752, 697, 481 cm^À^{1 1}H NMR (400 MHz,

;

(m, 11H, aromatic), 7.15 (d, J=1.9 Hz, 1H), 6.64 (s, 2H), 6.37 (d, J=

1.9 Hz, 1H,), 6.24 (d, J=1.9 Hz, 1H), 5.67 (brs, 1H), 5.02–5.09 (m, 5H),

CDCl₃): d=7.25–7.42 (m, 27H, aromatic), 6.61 (s, 2H), 6.39 (d, J=

1.9 Hz, 1H), 6.25 (d, J=1.9 Hz, 1H), 5.66 (brs, 1H), 5.02–5.07 (m, 9H),

4.93 (s, 2H), 3.80 (s, 3H), 3.50 (s, 6H), 3.07 (dd, J_gem=17.9 Hz, J=4.3 Hz,

1H), 3.02 ppm (dd, J_gem=17.9 Hz, J=2.4 Hz, 1H); ¹³C NMR (67.8 MHz,

CDCl₃): d=164.6, 158.7ꢁ2, 155.3, 153.2, 152,1, 142.2, 137.5, 137.1, 136.6,

136.2, 133.1, 128.8, 128.3ꢁ2, 128.2, 128.0, 127.9, 127.8, 127.6, 127.3, 125.1,

124.7, 108.9, 103.8, 100.3, 94.0, 92.5, 77.8, 74.8, 74.7, 70.8, 69.9, 68.1, 55.7,

55.2, 25.9 ppm; HRMS (ESI-TOF): m/z (%) calcd for C₆₀H₅₈NO₁₁:

968.4010 [M+NH₄]⁺; found: 968.4010.

3.87 (s, 3H), 3.80 (s, 3H), 3.79ꢁ2 (s, 3H), 3.60 (s, 6H), 3.07 (dd, J_gem

=

17.4 Hz, J=4.4 Hz, 1H), 3.01 ppm (dd, J_gem=17.9 Hz, J=1.9 Hz, 1H);

¹³C NMR (67.8 MHz, CDCl₃): d=165.0, 159.0, 158.9, 155.5, 153.2, 151,7,

143.1, 137.9, 136.8, 136.5, 133.3, 128.7ꢁ2, 128.2, 128.1, 127.9, 127.6, 124.9,

109.0, 107.3, 103.9, 100.5, 94.2, 92.8, 78.0, 71.0, 70.2, 68.5, 61.0, 60.8, 56.3,

55.9, 55.5, 26.2 ppm; HRMS (ESI-TOF): m/z (%) calcd for C₄₂H₄₆NO₁₁:

740.3071 [M+NH₄]⁺; found: 740.3073.

7dd (43%): R_f=0.28 (toluene:ethyl acetate=10:1); ¹H NMR (400 MHz,

CDCl₃): d=7.25–7.43 (m, 10H, aromatic), 7.16 (s, 2H), 6.68 (s, 2H, b),

6.32 (d, J=1.9 Hz, 1H), 6.21 (d, J=1.9 Hz, 1H), 5.65 (brs, 1H), 5.07 (s,

1H), 5.05 (s, 4H, Bn), 3.80 (s, 3H), 3.78 (s, 3H), 3.77 (s, 6H), 3.69 (s, 6H

j), 3.05 (brs, 1H), 3.04 ppm (brs, 1H); ¹³C NMR (67.8 MHz, CDCl₃): d=

165.1, 158.8ꢁ2, 155.4, 153.1ꢁ2, 141.1, 137.8, 137.2, 136.8, 133.3, 128.6,

128.4, 128.2, 128.0ꢁ2, 127.5 125.1, 107.1, 103.8, 100.4, 94.1, 92.6, 77.8,

74.9, 70.1, 68.6, 60.8, 56.2, 55.9, 55.4, 25.9 ppm; HRMS (ESI-TOF): m/z

(%) calcd for C₄₂H₄₆NO₁₁: 740.3071 [M+NH₄]⁺; found: 740.3101.

7cb (43%): R_f=0.51 (toluene:ethyl acetate=10:1); FTIR (neat): n˜ =

3031, 2938, 1716, 1620, 1593, 1499, 1455, 1428, 1370, 1329, 1216, 1148,

1124, 1030, 1002, 910, 842, 814, 753, 698, 477 cm^À^{1 1}H NMR (400 MHz,

;

CDCl₃): d=7.27–7.42 (m, 22H, aromatic), 6.60 (s, 2H), 6.40 (d, J=

1.9 Hz, 1H), 6.26 (d, J=1.9 Hz, 1H), 5.66 (brs, 1H), 5.02–5.06 (m, 7H),

4.92 (s, 2H), 3.88 (s, 3H), 3.80 (s, 3H), 3.50 (s, 6H), 3.06 (dd, J_gem

=

17.9 Hz, J=4.3 Hz, 1H), 3.01 ppm (dd, J_gem=17.9 Hz, J=2.4 Hz, 1H);

¹³C NMR (67.8 MHz, CDCl₃): d=164.7, 159.0, 158.9, 155.5, 153.4, 151,9,

143.7, 137.7, 136.8, 136.4, 133.3, 128.6, 128.4, 128.1, 128.0, 127.7ꢁ2, 127.5,

124.7, 109.2, 103.9, 100.5, 94.2, 92.7, 78.0, 74.9, 71.0, 70.1, 68.3, 61.0, 55.8,

55.4, 26.1 ppm; HRMS (ESI-TOF): m/z (%) calcd for C₅₄H₅₄NO₁₁:

892.3697 [M+NH₄]⁺; found: 892.3697.

8aa (39%): R_f=0.66 (toluene:ethyl acetate=9:1); FTIR (neat): n˜ =3031,

2935, 1717, 1620, 1592, 1499, 1454, 1429, 1370, 1328, 1196, 1148, 1112,

1029, 909, 814, 736, 696, 476 cm^À^{1 1}H NMR (400 MHz, CDCl₃): d=7.19–

;

7.43 (m, 37H, aromatic), 6.74 (s, 2H), 6.32 (d, J=2.4 Hz, 1H), 6.25 (d,

7cc (40%): R_f=0.38 (toluene:ethyl acetate=10:1); FTIR (neat): n˜ =

J=2.4 Hz, 1H), 5.67 (brs, 1H), 4.91–5.06 (m, 11H), 4.81 (d, J_gem

11.6 Hz, 2H), 4.68 (d, J_gem=11.6 Hz, 2H), 3.78 (s, 3H), 3.12 (dd, J_gem

=

2936, 1715, 1620, 1592, 1500, 1454, 1421, 1358, 1330, 1218, 1147, 1122,

=

1

1029, 1001, 814, 753, 698 cm^À1; H NMR (400 MHz, CDCl₃): d=7.24–7.43

17.9 Hz, J=4.3 Hz, 1H), 3.06 ppm (dd, J_gem=17.9 Hz, J=1.9 Hz, 1H);

¹³C NMR (67.8 MHz, CDCl₃): d=164.8, 159.7, 158.0, 155.6, 152,8, 152.4,

142.7, 138.4, 137.7, 137.4, 136.9, 136.8, 136.4, 133.2, 128.5ꢁ3, 128.3ꢁ2,

128.2, 128.1, 128.0, 127.9, 127.8ꢁ2, 127.7, 127.6, 127,5, 127.2, 125.0, 109.1,

106.7, 100.7, 93.6, 93.3, 77.9, 75.1, 75.0, 71.2, 71.0, 70.0, 68.3, 55.4,

26.1 ppm; HRMS (ESI-TOF): m/z (%) calcd for C₇₂H₆₆NO₁₁: 1120.4636

[M+NH₄]⁺; found: 1120.4625.

(m, 16H), 7.16 (d, J=1.4 Hz, 1H), 6.63 (s, 2H), 6.37 (d, J=2.4 Hz, 1H),

6.24 (d, J=2.4 Hz, 1H), 5.66 (brs, 1H), 5.02–5.09 (m, 5H), 4.93 (s, 2H,

Bn), 3.87 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.57 (s, 6H), 3.07 (dd, J_gem

=

17.4 Hz, J=4.3 Hz, 1H), 3.02 ppm (dd, J_gem=17.4 Hz, J=2.4 Hz, 1H);

¹³C NMR (67.8 MHz, CDCl₃): d=164.9, 158.9ꢁ2, 155.5, 153.4, 153,0,

151.7, 143.0, 137.7, 136.8, 136.4, 133.4, 128.6ꢁ2, 128.4, 128.1ꢁ2, 128.0,

127.8, 127.5, 124.9, 109.0, 107.3, 103.9, 100.4, 94.2, 92.7, 77.9, 74.9, 71.0,

70.1, 68.4, 60.9, 56.2, 55.9, 55.4, 26.0 ppm; HRMS (ESI-TOF): m/z (%)

calcd for C₄₈H₅₀NO₁₁: 816.3384 [M+NH₄]⁺; found: 816.3380.

8ab (41%): R_f=0.61 (toluene:ethyl acetate=9:1); FTIR (neat): n˜ =3032,

2925, 1716, 1621, 1592, 1499, 1454, 1371, 1329, 1217, 1197, 1148, 1113,

1

1029, 1003, 909, 814, 737, 697, 477 cm^À1; H NMR (400 MHz, CDCl₃): d=

7cd (44%): R_f=0.39 (toluene:ethyl acetate=10:1); ¹H NMR (400 MHz,

CDCl₃): d=7.25–7.43 (m, 15H, aromatic), 7.16 (s, 2H), 6.67 (s, 2H), 6.33

(d, J=2.4 Hz, 1H), 6.21 (d, J=2.4 Hz, 1H), 5.65 (brs, 1H), 5.08 (s, 1H),

5.05 (s, 4H, Bn), 4.95 (s, 2H, Bn), 3.78 (s, 3H), 3.77 (s, 6H), 3.65 (s, 6H),

3.08 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H), 3.02 ppm (dd, J_gem=17.9 Hz, J=

2.4 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd for C₄₈H₅₀NO₁₁: 816.3384

[M+NH₄]⁺; found: 816.3384.

7.19–7.42 (m, 32H, aromatic), 6.72 (s, 2H), 6.33 (d, J=1.9 Hz, 1H), 6.25

(d, J=1.9 Hz, 1H), 5.66 (brs, 1H), 4.90–5.06 (m, 9H), 4.76 (d, J_gem

11.6 Hz, 2H), 4.63 (d, J_gem=11.6 Hz, 2H), 3.78 (s, 6H), 3.12 (dd, J_gem

=

17.9 Hz, J=4.3 Hz, 1H), 3.05 ppm (dd, J_gem=17.9 Hz, J=2.4 Hz, 1H);

¹³C NMR (67.8 MHz, CDCl₃): d=164.7, 159.7, 158.0, 155.7, 152,8, 152.0,

142.0, 137.7, 136.9, 136.8, 136.4, 133.2, 128.6, 128.5, 128.3, 128.0, 127.9,

127.7ꢁ2, 127.5, 127.4, 127.2, 124.7, 109.2, 106.7, 100.7, 93.6, 93.3, 77.9,

Chem. Asian J. 2010, 5, 2231 – 2248

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org

2241

T. Takahashi et al.

FULL PAPERS

75.1, 71.1, 71.0, 70.0, 68.2, 60.8, 55.4, 26.2 ppm; HRMS (ESI-TOF): m/z

(%) calcd for C₆₆H₆₂NO₁₁: 1044.4323 [M+NH₄]⁺; found: 1044.4319.

2.4 Hz, 1H), 6.25 (d, J=2.4 Hz, 1H), 5.67 (brs, 1H), 5.02–5.07 (m, 9H),

4.92 (s, 2H, Bn), 3.78 (s, 3H), 3.51 (s, 6H), 3.13 (dd, J_gem=17.9 Hz, J=

4.3 Hz, 1H), 3.07 ppm (dd, J_gem=17.9 Hz, J=1.9 Hz, 1H); HRMS (ESI-

TOF): m/z (%) calcd for C₆₀H₅₈NO₁₁: 968.4010 [M+NH₄]⁺; found:

968.4044.

8cb (38%): R_f=0.44 (toluene:ethyl acetate=10:1); ¹H NMR (400 MHz,

CDCl₃): d=7.27–7.42 (m, 22H, aromatic), 6.60 (s, 2H), 6.34 (d, J=

2.4 Hz, 1H), 6.25 (d, J=2.4 Hz, 1H), 5.67 (brs, 1H), 5.02–5.09 (m, 7H),

8ac (43%): R_f=0.49 (toluene:ethyl acetate=9:1); ¹H NMR (400 MHz,

CDCl₃): d=7.21–7.43 (m, 27H, aromatic), 6.75 (s, 2H), 6.29 (d, J=

1.9 Hz, 1H), 6.23 (d, J=1.9 Hz, 1H), 5.66 (brs, 1H), 4.96–5.15 (m, 7H),

4.85 (d, J_gem=11.6 Hz, 2H), 4.71 (d, J_gem=11.6 Hz, 2H), 3.78 (s, 3H, f),

3.77 (s, 3H), 3.75 (s, 3H), 3.12 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H),

3.05 ppm (dd, J_gem=17.9 Hz, J=2.4 Hz, 1H); HRMS (ESI-TOF): m/z

(%) calcd for C₆₀H₅₈NO₁₁: 968.4010 [M+NH₄]⁺; found: 968.4011.

4.92 (s, 2H), 3.88 (s, 3H), 3.78 (s, 3H), 3.50 (s, 6H), 3.13 (dd, J_gem

=

17.9 Hz, J=3.9 Hz, 1H), 3.07 ppm (dd, J_gem=17.9 Hz, J=1.9 Hz, 1H);

¹³C NMR (67.8 MHz, CDCl₃): d=164.8, 159.7, 158.0, 155.7, 153.4 152.0,

137.7, 136.8, 136.5, 133.3, 128.6, 128.5, 128.4, 128.1, 127.9, 127.7ꢁ2, 127.2,

124.8, 109.3, 104.0, 100.7, 93.6, 93.3, 78.0, 74.9, 71.0, 70.0, 68.3, 61.0, 55.9,

55.4, 26.3 ppm; HRMS (ESI-TOF): m/z (%) calcd for C₅₄H₅₄NO₁₁:

892.3697 [M+NH₄]⁺; found: 892.3690.

8ad (40%): R_f=0.53 (toluene:ethyl acetate=9:1); FTIR (neat): n˜ =3032,

2937, 1716, 1621, 1593, 1500, 1455, 1436, 1416, 1360, 1333, 1218, 1198,

1148, 1126, 1029, 911, 815, 751, 735, 697, 476 cm^À^{1 1}H NMR (400 MHz,

;

CDCl₃): d=7.19–7.44 (m, 27H, aromatic), 6.80 (s, 2H), 6.24 (d, J=

2.4 Hz, 1H), 6.20 (d, J=2.4 Hz, 1H), 5.64 (brs, 1H), 4.93–5.07 (m, 9H),

4.85 (d, J_gem=11.6 Hz, 2H, Bn), 3.78 (s, 3H), 3.76 (s, 6H), 3.12 (dd, J_gem

=

8cc (39%): R_f=0.31 (toluene:ethyl acetate=10:1); ¹H NMR (400 MHz,

CDCl₃): d=7.27–7.43 (m, 16H, a and aromatic), 7.16 (d, J=1.9 Hz, 1H),

6.64 (s, 2H), 6.32 (d, J=1.9 Hz, 1H), 6.23 (d, J=1.9 Hz, 1H), 5.68 (brs,

1H), 5.09 (s, 1H), 5.05 (s, 4H, Bn), 4.93 (s, 2H, Bn), 3.88 (s, 3H), 3.81 (s,

3H), 3.78 (s, 3H), 3.58 (s, 6H), 3.14 (dd, J_gem=17.9 Hz, J=4.4 Hz, 1H),

17.9 Hz, J=4.3 Hz, 1H), 3.05 ppm (dd, J_gem=17.9 Hz, J=2.4 Hz, 1H);

¹³C NMR (67.8 MHz, CDCl₃): d=165.2, 159.7, 157.9, 155.5, 153.2, 153,0,

152.8, 137.7, 137.4, 136.9, 136.8, 133.4, 128.5ꢁ2, 128.4, 128.2ꢁ2, 128.1,

127.9, 127.8, 127.7, 127.5ꢁ2, 127.4, 127.2, 125.2, 107.2, 106.8, 100.6, 93.6,

93.2, 77.6, 75.1, 74.9, 71.4, 69.9, 68.6, 56.3, 55.4, 25.9 ppm; HRMS (ESI-

TOF): m/z (%) calcd for C₆₀H₅₈NO₁₁: 968.4010 [M+NH₄]⁺; found:

968.4017.

3.08 ppm (dd,

J

_gem=17.9 Hz, J=2.4 Hz, 1H); ¹³C NMR (67.8 MHz,

CDCl₃): d=164.9, 159.7, 158.0, 155.7, 153.4, 153.1, 151.7, 143.1, 137.7,

136.8, 136.5, 133.3, 128.6, 128.5, 128.4, 128.1ꢁ2, 127.9, 127.7, 127.2, 124.9,

109.1, 107.3, 104.0, 100.6, 93.6, 93.3, 77.9, 74.9, 71.0, 70.0, 68.4, 60.9, 56.2,

55.9, 55.4, 26.2 ppm; HRMS (ESI-TOF): m/z (%) calcd for C₄₈H₅₀NO₁₁:

816.3384 [M+NH₄]⁺; found: 816.3392.

8ba (47%): R_f=0.51 (toluene:ethyl acetate=9:1); FTIR (neat): n˜ =3032,

2936, 1716, 1621, 1592, 1500, 1455, 1435, 1367, 1332, 1218, 1197, 1148,

1115, 1029, 814, 736, 697, 474 cm^À^{1 1}H NMR (400 MHz, CDCl₃): d=

;

7.22–7.42 (m, 32H, aromatic), 6.71 (s, 2H), 6.29 (d, J=2.4 Hz, 1H), 6.24

(d, J=2.4 Hz, 1H), 5.64 (brs, 1H), 5.01–5.05 (m, 7H), 4.92 (s, 2H, Bn),

4.83 (d, J_gem=11.6 Hz, 2H), 4.72 (d, J_gem=11.6 Hz, 2H), 3.81 (s, 3H), 3.77

8cd (39%): R_f=0.33 (toluene:ethyl acetate=10:1); ¹H NMR (400 MHz,

CDCl₃): d=7.17–7.35 (m, 15H, aromatic), 7.09 (s, 2H), 6.61 (s, 2H), 6.20

(d, J=2.4 Hz, 1H), 6.13 (d, J=2.4 Hz, 1H), 5.60 (brs, 1H), 5.02 (s, 1H),

4.97 (s, 2H, Bn), 4.96 (s, 2H, Bn), 4.87 (s, 2H, Bn), 3.85 (s, 6H), 3.76 (s,

3H), 3.73 (s, 3H), 3.04 (dd, J_gem=16.9 Hz, J=4.3 Hz, 1H), 2.84 ppm (dd,

(s, 3H), 3.11 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H), 3.04 ppm (dd, J_gem

=

17.9 Hz, J=1.9 Hz, 1H); ¹³C NMR (67.8 MHz, CDCl₃): d=164.8, 159.7,

158.0, 155.6, 152.6, 152.3, 142.7, 139.5, 137.4, 136.9, 136.8, 136.4, 133.0,

130.0, 128.5, 128.4ꢁ2, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.4,

127.3, 127.2, 124.9, 115.0, 109.2, 106.8, 100.6, 93.6, 93.2, 77.8, 75.0, 71.1,

71.0, 70.0, 68.2, 60.8, 55.4, 26.1 ppm; HRMS (ESI-TOF): m/z (%) calcd

for C₆₆H₆₂NO₁₁: 1044.4323 [M+NH₄]⁺; found: 1043.4330.

J

_gem=17.4 Hz, J=2.4 Hz, 1H); ¹³C NMR (67.8 MHz, CDCl₃): d=165.3,

159.7, 157.9, 155.6, 153.4, 153.2, 141.3, 137.7, 137.2, 136.8, 133.4, 128.5,

128.4, 128.2, 128.1, 129.0, 127.9, 127.7, 127.2, 125.2, 107.2, 104.0, 100.6,

93.6, 93.2, 77.9, 74.9, 70.0, 68.6, 56.2, 56.0, 55.3, 25.7 ppm; HRMS (ESI-

TOF): m/z (%) calcd for C₄₈H₅₀NO₁₁: 816.3384 [M+H]⁺; found:

816.3383.

8da (52%): R_f=0.32 (toluene:ethyl acetate=10:1); ¹H NMR (400 MHz,

CDCl₃): d=7.25–7.42 (m, 22H, aromatic), 6.61 (s, 2H), 6.33 (d, J=

2.4 Hz, 1H), 6.25 (d, J=2.4 Hz, 1H), 5.68 (brs, 1H), 5.02–5.08 (m, 9H),

3.78 (s, 3H), 3.78 (s, 3H), 3.53 (s, 6H), 3.13 (dd, J_gem=17.9 Hz, J=4.3 Hz,

1H), 3.07 ppm (dd, J_gem=17.9 Hz, J=1.9 Hz, 1H); ¹³C NMR (67.8 MHz,

CDCl₃): d=164.8, 159.7, 158.0, 155.7, 153.1, 152.3, 142.4, 137.9, 137.3,

136.8, 136.5, 133.2, 128.5ꢁ2, 128.2, 128.1, 128.0ꢁ2, 127.9, 127.7, 127.2,

124.9, 109.1, 104.0, 100.7, 93.6, 93.3, 78.1, 75.0, 71.0, 70.0, 68.3, 60.7, 55.8,

55.4, 26.3 ppm; HRMS (ESI-TOF): m/z (%) calcd for C₅₄H₅₄NO₁₁

892.3697 [M+NH₄]⁺; found: 892.3719.

8bb (58%): R_f=0.43 (toluene:ethyl acetate=9:1); ¹H NMR (400 MHz,

CDCl₃): d=7.25–7.44 (m, 27H, aromatic), 6.69 (s, 2H, a), 6.30 (d, J=

1.9 Hz, 1H), 6.25 (d, J=1.9 Hz, 1H), 5.64 (brs, 1H), 5.03–5.05 (m, 6H,

Bn), 4.99 (s, 1H), 4.79 (d, J=11.6 Hz, 2H, Bn), 4.67 (d, J=11.6 Hz, 2H,

Bn), 3.80 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.10 (dd, J_gem=17.9 Hz, J=

4.3 Hz, 1H), 3.03 ppm (dd,

J

_gem=17.9 Hz, J=1.9 Hz, 1H); ¹³C NMR

(67.8 MHz, CDCl₃): d=164.7, 159.7, 158.0, 155.7, 152.6, 143.7, 139.5,

136.9, 136.8, 136.4, 133.0, 128.6, 128.5, 128.4, 128.0, 127.9, 127.7ꢁ2, 127.4,

127.3, 127.2, 124.7, 109.2, 106.8, 100.7, 93.6, 93.3, 77.9, 71.1, 71.0, 70.0,

68.2, 60.8, 55.4, 26.2 ppm; HRMS (ESI-TOF): m/z (%) calcd for

C₆₀H₅₈NO₁₁: 968.4010 [M+NH₄]⁺; found: 968.4034.

8bc (54%): R_f=0.29 (toluene:ethyl acetate=9:1); FTIR (neat): n˜ =2925,

8db (54%): R_f=0.28 (toluene:ethyl acetate=10:1); ¹H NMR (400 MHz,

CDCl₃): d=7.28–7.42 (m, 17H, aromatic), 6.60 (s, 2H), 6.34 (d, J=

2.4 Hz, 1H), 6.25 (d, J=2.4 Hz, 1H), 5.68 (brs, 1H), 5.02–5.09 (m, 7H),

3.88 (s, 3H), 3.78 (s, 6H), 3.53 (s, 6H), 3.13 (dd, J_gem=17.9 Hz, J=4.3 Hz,

1H), 3.06 ppm (dd, J_gem=17.9 Hz, J=1.9 Hz, 1H); ¹³C NMR (67.8 MHz,

CDCl₃): d=164.8, 159.7, 158.0, 155.7, 153.1, 152.0, 143.8, 137.9, 136.8,

136.5, 133.1, 128.6, 128.5, 128.1, 127.9, 127.6, 127.2, 124.7, 109.3, 104.0,

100.6, 93.6, 93.3, 78.0, 71.0, 70.0, 68.2, 60.9, 60.7, 55.8, 55.4, 26.3 ppm;

HRMS (ESI-TOF): m/z (%) calcd for C₄₈H₅₀NO₁₁: 816.3384 [M+NH₄]⁺;

found: 816.3375.

1716, 1620, 1592, 1500, 1434, 1373, 1331, 1219, 1147, 1115, 1029, 1006,

814, 772, 697 cm^À^{1 1}H NMR (400 MHz, CDCl₃): d=7.25–7.41 (m, 22H,

;

aromatic), 6.73 (s, 2H), 6.27 (d, J=1.9 Hz, 1H), 6.23 (d, J=1.9 Hz, 1H),

5.64 (brs, 1H), 5.03–5.05 (m, 4H), 5.00 (s, 1H), 4.87 (d, J_gem=11.6 Hz,

2H, Bn), 4.75 (d, J_gem=11.6 Hz, 2H, Bn), 3.81 (s, 3H), 3.78 (s, 3H), 3.78

(s, 6H), 3.11 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H), 3.04 ppm (dd, J_gem

=

17.9 Hz, J=1.9 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd for

C₅₄H₅₄NO₁₁: 892.3697 [M+NH₄]⁺; found: 892.3684.

8bd (51%): R_f=0.34 (toluene:ethyl acetate=9:1); ¹H NMR (400 MHz,

CDCl₃): d=7.29–7.44 (m, 20H, aromatic), 7.18 (s, 2H), 6.78 (s, 2H), 6.22

(d, J=1.9 Hz, 1H), 6.20 (d, J=1.9 Hz, 1H), 5.62 (brs, 1H), 5.05 (s, 1H),

5.03 (s, 2H), 4.99 (d, J_gem=11.6 Hz, 2H), 4.94 (s, 2H), 4.89 (d, J=

8dc (58%): R_f=0.15 (toluene:ethyl acetate=10:1); FTIR (neat): n˜ =

2927, 1716, 1621, 1593, 1502, 1456, 1422, 1357, 1331, 1221, 1149, 1124,

1004, 814, 756, 699 cm^À^{1 1}H NMR (400 MHz, CDCl₃): d=7.27–7.42 (m,

;

11.6 Hz, 2H, Bn), 3.83 (s, 3H), 3.78 (s, 3H), 3.76 (s, 6H), 3.12 (dd, J_gem

=

18.4 Hz, J=4.3 Hz, 1H), 3.05 ppm (dd, J_gem=18.4 Hz, J=2.9 Hz, 1H);

¹³C NMR (67.8 MHz, CDCl₃): d=165.2, 159.7, 157.9, 155.5, 153.2, 152.6,

141.5, 139.6, 137.3, 136.9, 136.8, 133.1, 128.5, 128.4, 128.2ꢁ2, 127.9ꢁ2,

127.8, 127.3, 127.1, 125.2, 107.2, 106.9, 100.6, 93.5, 93.1, 77.5, 74.9, 71.3,

69.9, 68.6, 60.9, 56.2, 55.4, 25.8 ppm; HRMS (ESI-TOF): m/z (%) calcd

for C₅₄H₅₄NO₁₁: 892.3697 [M+NH₄]⁺; found: 892.3695.

11H), 7.16 (d, J=1.9 Hz, 1H), 6.64 (s, 2H), 6.31 (d, J=1.9 Hz, 1H), 6.24

(d, J=1.9 Hz, 1H), 5.68 (brs, 1H), 5.08 (s, 1H), 5.06 (s, 2H, Bn), 5.05 (s,

2H, Bn), 3.87 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.61 (s,

6H), 3.14 (dd,

J_gem=17.9 Hz, J=4.3 Hz, 1H), 3.08 ppm (dd, J_gem=

17.9 Hz, J=2.4 Hz, 1H); ¹³C NMR (67.8 MHz, CDCl₃): d=164.9, 159.7,

158.0, 155.7, 153.1, 151.7, 143.1, 137.9, 136.8, 136.5, 133.2, 128.6, 128.5,

128.1, 127.9, 127.7, 127.5, 127.1, 124.8, 109.1, 107.3, 103.9, 100.6, 93.6,

93.2, 77.9, 71.0, 70.0, 68.4, 60.9, 60.7, 56.2, 55.9, 55.4, 26.2 ppm; HRMS

8ca (43%): R_f=0.49 (toluene:ethyl acetate=10:1); ¹H NMR (400 MHz,

CDCl₃): d=7.27–7.43 (m, 27H, aromatic), 6.61 (s, 2H), 6.34 (d, J=

2242

www.chemasianj.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Asian J. 2010, 5, 2231 – 2248

Solid-Phase Synthesis of a Combinatorial Methylated EGCG Library

(ESI-TOF): m/z (%) calcd for C₄₂H₄₆NO₁₁: 740.3071 [M+NH₄]⁺; found:

2H, Bn), 3.83 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H, g, h, or i), 3.76 (s, 6H, j),

740.3099.

3.05 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H), 3.03 ppm (brs, 1H).

8dd (53%): R_f=0.19 (toluene:ethyl acetate=9:1); ¹H NMR (400 MHz,

CDCl₃): d=7.28–7.44 (m, 10H, aromatic), 7.16 (s, 2H), 6.69 (s, 2H), 6.26

(d, J=2.4 Hz, 1H), 6.21 (d, J=2.4 Hz, 1H), 5.67 (brs, 1H), 5.09 (s, 1H),

5.05 (s, 2H, Bn), 5.04 (s, 2H, Bn), 3.80 (s, 3H), 3.79 (s, 3H), 3.78 (s, 6H),

9ca (34%): R_f=0.55 (hexane:ethyl acetate=1:1); ¹H NMR (400 MHz,

CDCl₃): d=7.24–7.34 (m, 27H, aromatic), 6.73 (s, 2H), 6.28 (d, J=

2.4 Hz, 1H), 6.17 (d, J=2.4 Hz, 1H), 5.64 (brs, 1H), 5.05 (s, 1H), 5.02 (s,

2H, Bn), 4.92 (s, 2H, Bn), 4.84 (d, J=11.6 Hz, 2H, Bn), 4.73 (d, J=

3.69 (s, 6H), 3.14 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H), 3.09 ppm (dd, J_gem

=

11.6 Hz, 2H, Bn), 3.81 (s, 6H), 3.79 (s, 3H), 3.75 (s, 6H), 3.05 (dd, J_gem

=

17.9 Hz, J=2.4 Hz, 1H); ¹³C NMR (67.8 MHz, CDCl₃): d=165.1, 159.6,

157.9, 155.6, 153.2, 153.1, 141.2, 137.9, 137.2, 136.8, 133.3, 128.5, 128.4,

128.2, 128.0, 127.9, 127.1, 125.2, 107.2, 103.9, 100.6, 93.6, 93.2, 77.9, 74.9,

69.9, 68.6, 60.8, 56.2, 56.0, 55.4, 26.1 ppm; HRMS (ESI-TOF): m/z (%)

calcd for C₄₂H₄₆NO₁₁: 740.3071 [M+NH₄]⁺; found: 740.3074.

9aa (45%): R_f=0.60 (hexane:ethyl acetate=1:1); ¹H NMR (400 MHz,

CDCl₃): d=7.19–7.36 (m, 32H, aromatic), 6.74 (s, 2H), 6.30 (d, J=

2.4 Hz, 1H), 6.17 (d, J=2.4 Hz, 1H), 5.66 (brs, 1H), 4.90–5.04 (m, 9H),

4.81 (d, J_gem=11.6 Hz, 2H), 4.68 (d, J_gem=11.6 Hz, 2H, Bn), 3.81 (s, 3H),

3.79 (s, 3H, f or g), 3.06 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H), 3.00 ppm

(dd, J_gem=17.9 Hz, J=1.9 Hz, 1H).

9ab (51%): R_f=0.58 (hexane:ethyl acetate=1:1); ¹H NMR (400 MHz,

CDCl₃): d=7.19–7.38 (m, 27H, aromatic), 6.72 (s, 2H), 6.30 (d, J=

1.9 Hz, 1H), 6.17 (d, J=1.9 Hz, 1H), 5.65 (brs, 1H), 4.95–5.06 (m, 7H),

4.77 (d, J_gem=11.6 Hz, 2H, Bn), 4.64 (d, J_gem=11.6 Hz, 2H, Bn), 3.81 (s,

3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.05 (dd, J_gem=17.9 Hz, J=3.9 Hz, 1H),

2.98 ppm (dd, J_gem=17.9 Hz, J=2.4 Hz, 1H).

9ac (38%): R_f=0.53 (hexane:ethyl acetate=1:1); ¹H NMR (400 MHz,

CDCl₃): d=7.14–7.38 (m, 22H, aromatic), 6.76 (s, 2H), 6.27 (d, J=

1.9 Hz, 1H), 6.15 (d, J=1.9 Hz, 1H), 5.65 (brs, 1H), 4.96–5.07 (m, 5H),

4.85 (d, J_gem=11.6 Hz, 2H, Bn), 4.72 (d, J_gem=11.6 Hz, 2H, Bn), 3.80 (s,

3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.06 (dd, J_gem=18.4 Hz, J=

4.3 Hz, 1H), 3.00 ppm (dd, J_gem=18.4 Hz, J=2.4 Hz, 1H).

17.9 Hz, J=4.3 Hz, 1H), 2.99 ppm (dd, J_gem=17.9 Hz, J=2.4 Hz, 1H).

9cb (39%): R_f=0.52 (hexane:ethyl acetate=1:1); ¹H NMR (400 MHz,

CDCl₃): d=7.24–7.42 (m, 17H, aromatic), 6.61 (s, 2H), 6.32 (d, J=

2.4 Hz, 1H), 6.17 (d, J=2.4 Hz, 1H), 5.66 (brs, 1H), 5.02–5.09 (m, 5H),

4.92 (s, 2H, Bn), 3.88 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 3.51 (s, 6H), 3.06

(dd, J_gem=17.9 Hz, J=4.3 Hz, 1H), 3.03 ppm (brs, 1H).

9cc (52%): R_f=0.47 (hexane:ethyl acetate=1:1); ¹H NMR (400 MHz,

CDCl₃): d=7.24–7.43 (m, 11H, a and aromatic), 7.16 (d, J=1.9 Hz, 1H),

6.64 (s, 2H), 6.30 (d, J=2.4 Hz, 1H), 6.15 (d, J=2.4 Hz, 1H), 5.67 (brs,

1H), 5.08 (d, J_gem=12.1 Hz, 1H, Bn), 5.08 (s, 1H, f), 5.04 (d, J_gem

=

12.1 Hz, 1H, Bn), 4.94 (s, 2H, Bn), 3.87 (s, 3H), 3.81 (s, 3H), 3.80 (s,

3H), 3.79 (s, 3H), 3.58 (s, 6H), 3.07 (dd, J_gem=17.4 Hz, J=3.9 Hz, 1H),

3.04 ppm (brs, 1H); ¹³C NMR (67.8 MHz, CDCl₃): d=164.9, 159.7, 158.9,

155.4, 153.4, 151.7, 143.0, 137.7, 136.8, 133.4, 128.6, 128.4, 128.1ꢁ2, 127.7,

127.6, 124.9, 109.0, 107.3, 100.2, 93.2, 77.9, 74.9, 71.0, 68.5, 60.9, 56.2, 55.9,

55.4ꢁ2, 26.0 ppm.

9cd (54%): R_f=0.49 (hexane:ethyl acetate=1:1); ¹H NMR (400 MHz,

CDCl₃): d=7.43 (d, J=6.8 Hz, 2H, aromatic), 7.26–7.34 (m, 8H, aromat-

ic), 7.16 (s, 2H), 6.68 (s, 2H), 6.25 (d, J=1.9 Hz, 1H), 6.13 (d, J=1.9 Hz,

1H), 5.65 (brs, 1H), 5.08 (s, 1H), 5.04 (s, 2H, Bn), 4.95 (s, 2H, Bn), 3.80

(s, 3H), 3.79 (s, 3H), 3.78 (s, 6H), 3.66 (s, 6H), 3.05 ppm (brs, 2H).

9da (48%): R_f=0.53 (hexane:ethyl acetate=1:1); ¹H NMR (400 MHz,

CDCl₃): d=7.25–7.38 (m, 17H, aromatic), 6.62 (s, 2H), 6.32 (d, J=

1.9 Hz, 1H), 6.17 (d, J=1.9 Hz, 1H), 5.67 (brs, 1H), 5.07–5.00 (m, 7H),

9ad (29%): R_f=0.54 (hexane:ethyl acetate=1:1); ¹H NMR (400 MHz,

CDCl₃): d=7.18–7.45 (m, 22H, aromatic), 6.81 (s, 2H), 6.22 (d, J=

1.9 Hz, 1H), 6.12 (d, J=1.9 Hz, 1H), 5.63 (brs, 1H, d), 4.97–5.08 (m,

5H), 4.94 (d, J_gem=11.6 Hz, 2H, Bn), 4.86 (d, J_gem=11.6 Hz, 2H, Bn),

3.80 (s, 3H), 3.79 (s, 3H), 3.76 (s, 6H), 3.07 (dd, J_gem=17.9 Hz, J=4.3 Hz,

1H), 3.01 ppm (dd, J_gem=17.9 Hz, J=2.4 Hz, 1H).

9ba (43%): R_f=0.58 (hexane:ethyl acetate=1:1); ¹H NMR (400 MHz,

CDCl₃): d=7.24–7.34 (m, 27H, aromatic), 6.73 (s, 2H), 6.28 (d, J=

2.4 Hz, 1H), 6.17 (d, J=2.4 Hz, 1H), 5.64 (brs, 1H), 5.05 (s, 1H), 5.02 (s,

3.81 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.54 (s, 6H), 3.06 (dd, J_gem

=

17.9 Hz, J=3.9 Hz, 1H), 3.01 ppm (d,

J

_gem=17.9 Hz, 1H); ¹³C NMR

(67.8 MHz, CDCl₃): d=164.8, 159.7, 158.9, 155.5, 153.1, 152.2, 142.3,

137.8, 137.2, 136.4, 133.2, 128.5ꢁ2, 128.2, 128.1, 128.0, 127.7, 124.9, 109.0,

103.9, 100.1, 93.2, 91.9, 78.0, 75.0, 71.0, 68.3, 60.7, 55.8, 55.4ꢁ2, 26.1 ppm.

9db (51%): R_f=0.50 (hexane:ethyl acetate=1:1); ¹H NMR (400 MHz,

CDCl₃): d=7.29–7.40 (m, 12H, aromatic), 6.61 (s, 2H), 6.32 (d, J=

1.9 Hz, 1H), 6.17 (d, J=1.9 Hz, 1H), 5.67 (brs, 1H), 5.08 (d, J_gem

11.6 Hz, 2H, Bn), 5.05 (s, 1H), 5.04 (d, J_gem=11.6 Hz, 2H, Bn), 3.88 (s,

3H), 3.81 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.54 (s, 6H), 3.06 (dd, J_gem

17.9 Hz, J=4.3 Hz, 1H), 3.00 ppm (d,

_gem=17.9 Hz, 1H); ¹³C NMR

=

4H, Bn), 4.92 (s, 2H, Bn), 4.84 (d, J_gem=11.6 Hz, 2H, Bn), 4.73 (d, J_gem

11.6 Hz, 2H, Bn), 3.81 (s, 6H), 3.79 (s, 3H), 3.05 (dd, J_gem=17.9 Hz, J=

4.3 Hz, 1H), 2.99 ppm (dd,

_gem=17.9 Hz, J=2.4 Hz, 1H); ¹³C NMR

=

J

(67.8 MHz, CDCl₃): d=164.8, 159.7, 158.9, 155.5, 152.5, 152.3, 142.7,

139.4, 137.4, 136.9, 136.4, 133.0, 128.5, 128.4ꢁ2, 128.2, 128.1, 128.0, 127.8,

127.7, 127.3, 124.9, 109.1, 106.7, 100.1, 93.2, 91.9, 77.8, 75.0, 71.1, 71.0,

68.2, 60.8, 55.4, 55.3, 26.0 ppm.

9bb (47%): R_f=0.56 (hexane:ethyl acetate=1:1); ¹H NMR (400 MHz,

CDCl₃): d=7.22–7.40 (m, 22H, aromatic), 6.70 (s, 2H), 6.28 (d, J=

2.4 Hz, 1H), 6.16 (d, J=2.4 Hz, 1H), 5.63 (brs, 1H), 5.06 (s, 1H), 5.03ꢁ2

(s, 4H, Bn), 4.79 (d, J_gem=12.1 Hz, 2H, Bn), 4.67 (d, J_gem=12.1 Hz, 2H,

Bn), 3.81 (s, 3H), 3.80 (s, 3H), 3.78ꢁ2 (s, 3H), 3.03 (dd, J_gem=17.9 Hz,

J=4.3 Hz, 1H), 2.97 ppm (dd, J_gem=17.9 Hz, J=2.4 Hz, 1H).

(67.8 MHz, CDCl₃): d=164.7, 159.7, 158.9, 155.5, 153.1, 151.9, 143.6,

137.8, 136.4, 133.2, 128.6, 128.1, 127.6, 124.7, 109.1, 103.8, 100.1, 93.2,

91.9, 78.0, 70.9, 68.2, 60.9, 60.7, 55.7, 55.4ꢁ2, 26.1 ppm.

9dc (47%): R_f=0.46 (hexane:ethyl acetate=1:1); FTIR (neat): n˜ =3031,

2938, 1716, 1621, 1593, 1499, 1455, 1429, 1369, 1328, 1214, 1148, 1124,

1030, 1002, 911, 843, 815, 752, 697, 481 cm^À^{1 1}H NMR (400 MHz,

;

CDCl₃): d=7.29–7.40 (m, 5H, aromatic), 7.27 (d, J=1.9 Hz, 1H), 7.15 (d,

J=1.9 Hz, 1H), 6.64 (s, 2H), 6.29 (d, J=2.4 Hz, 1H), 6.15 (d, J=2.4 Hz,

1H), 5.67 (brs, 1H), 5.08 (d, J_gem=11.6 Hz, 1H, Bn), 5.07 (s, 1H, f), 5.04

(d, J_gem=11.6 Hz, 1H, Bn), 3.87 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 3.79ꢁ

2 (s, 3H), 3.61 (s, 6H), 3.07 (dd, J_gem=17.9 Hz, J=4.8 Hz, 1H), 3.02 ppm

(dd, J_gem=17.9 Hz, J=2.4 Hz, 1H).

9dd ( 36%): R_f=0.48 (hexane:ethyl acetate=1:1); ¹H NMR (400 MHz,

CDCl₃): d=7.43 (d, J=6.8 Hz, 2H, aromatic), 7.28–7.34 (m, 3H, aromat-

ic), 7.16 (s, 2H), 6.69 (s, 2H), 6.24 (d, J=2.4 Hz, 1H), 6.12 (d, J=2.4 Hz,

1H), 5.66 (brs, 1H), 5.08 (s, 1H), 5.04 (s, 2H, Bn), 3.80ꢁ2 (s, 3H), 3.79

(s, 3H), 3.78 (s, 6H), 3.70 (s, 6H), 3.05 (s, 1H), 3.04 ppm (s, 1H);

¹³C NMR (67.8 MHz, CDCl₃): d=165.2, 159.8, 158.9, 155.6, 153.2ꢁ2,

141.3, 138.0, 137.3, 133.4, 128.4, 128.2, 128.0, 125.3, 107.3, 104.0, 100.2,

93.3, 91.9, 77.9, 75.0, 68.7, 60.8, 56.3ꢁ2, 56.0, 55.4, 26.0 ppm.

9bc (40%): R_f=0.51 (hexane:ethyl acetate=1:1); ¹H NMR (400 MHz,

CDCl₃): d=7.27–7.38 (m, 16H, a and aromatic), 7.17 (d, J=1.9 Hz, 1H),

6.73 (s, 2H), 6.25 (d, J=2.4 Hz, 1H), 6.14 (d, J=2.4 Hz, 1H), 5.63 (brs,

1H), 5.01–5.04 (m, 3H), 4.87 (d, J_gem=11.6 Hz, 2H, Bn), 4.76 (d, J_gem

=

11.6 Hz, 2H, Bn), 3.81 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.78 (s, 6H),

3.04 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H), 2.98 ppm (dd, J_gem=17.9 Hz, J=

2.4 Hz, 1H); ¹³C NMR (67.8 MHz, CDCl₃): d=165.0, 159.9, 159.0, 155.6,

153.2, 152.7, 151.9, 137.1, 136.6, 133.2, 128.7, 128.6, 128.5, 128.2, 127.9,

127.5, 127.4, 125.0, 109.2, 107.5, 100.3, 93.4, 92.0, 77.9, 71.4, 71.1, 68.5,

61.0, 60.9, 56.4, 55.5ꢁ2, 26.0 ppm.

9bd (32%): R_f=0.52 (hexane:ethyl acetate=1:1); ¹H NMR (400 MHz,

CDCl₃): d=7.28–7.42 (m, 15H, aromatic), 7.17 (s, 2H), 6.78 (s, 2H), 6.20

(d, J=2.4 Hz, 1H), 6.11 (d, J=2.4 Hz, 1H), 5.61 (brs, 1H), 5.04 (s, 1H),

5.00 (d, J_gem=11.6 Hz, 2H, Bn), 4.93 (s, 2H, Bn), 4.89 (d, J_gem=11.6 Hz,

Deprotection: deprotection of the protected methylated EGCG library

was achieved by the same procedure for the synthesis of 2aa.

2ab (49%): R_f=0.37 (CHCl₃:methanol=2:1); FTIR (solid): n˜ =1693,

1603, 1522, 1451, 1345, 1234, 1142, 1092, 1038, 882, 727, 636, 492 cm^À1

;

¹H NMR (400 MHz, [D₆]acetone:D₂O=2:1): d=6.93 (s, 2H), 6.59 (s,

Chem. Asian J. 2010, 5, 2231 – 2248

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org

2243

T. Takahashi et al.

FULL PAPERS

2H), 5.97 (d, J=2.4 Hz, 1H), 5.95 (d, J=1.9 Hz, 1H), 5.39 (brs, 1H),

4.97 (s, 1H), 3.72 (s, 3H), 2.95 (dd, J_gem=17.4 Hz, J=4.3 Hz, 1H),

2.84 ppm (d, J_gem=17.4 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd for

C₂₃H₂₁O₁₁: 473.1084 [M+H]⁺; found: 473.1088.

J

_gem=17.9 Hz, J=4.3 Hz, 1H), 2.86 ppm (d, J_gem=17.9 Hz, 1H); HRMS

(ESI-TOF): m/z (%) calcd for C₂₆H₂₇O₁₁: 515.1553 [M+H]⁺; found:

515.1552.

2cd (61%): R_f=0.43 (CHCl₃:methanol=4:1); FTIR (solid): n˜ =3386,

2ac (60%): R_f=0.49 (CHCl₃:methanol=2:1); FTIR (solid): n˜ =3282,

1693, 1602, 1512, 1461, 1423, 1328, 1211, 1146, 1108, 997, 955, 911, 864,

1696, 1603, 1607, 1510, 1455, 1340, 1226, 1146, 1112, 824, 803, 755, 645,

817, 759, 636 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone:D₂O=2:1): d=7.10

;

533 cm^À1

;

¹H NMR (400 MHz, [D₆]acetone:D₂O=2:1): d=7.00 (d, J=

(s, 2H), 6.79 (s, 2H), 6.00 (d, J=1.9 Hz, 1H), 5.98 (d, J=2.4 Hz, 1H),

5.51 (brs, 1H, e), 5.12 (s, 1H), 3.72 (s, 6H), 3.63 (s, 6H), 3.00 (dd, J_gem

1.9 Hz, 1H), 6.91 (d, J=1.9 Hz, 1H), 6.57 (s, 2H), 5.95 (d, J=1.9 Hz,

1H), 5.94 (d, J=1.9 Hz, 1H), 5.37 (brs, 1H), 4.98 (s, 1H), 3.73 (s, 3H),

=

17.9 Hz, J=4.8 Hz, 1H), 2.87 ppm (dd, J_gem=17.9 Hz, J=1.9 Hz, 1H);

HRMS (ESI-TOF): m/z (%) calcd for C₂₆H₂₇O₁₁: 515.1553 [M+H]⁺;

found: 515.1552.

3.68 (s, 3H), 2.94 (dd, J_gem=17.4 Hz, J=4.3 Hz, 1H), 2.85 ppm (dd, J_gem

=

17.4 Hz, J=1.4 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd for

C₂₄H₂₃O₁₁: 487.1240 [M+H]⁺; found: 487.1244.

2da (58%): R_f=0.38 (CHCl₃:methanol=4:1); FTIR (solid): n˜ =3287,

2ad (35%): R_f=0.49 (CHCl₃:methanol=2:1); FTIR (solid): n˜ =3357,

1682, 1598, 1533, 1505, 1459, 1421, 1368, 1329, 1234, 1193, 1146, 1117,

1611, 1510, 1456, 1339, 1146, 1003, 803, 755, 646, 524 cm^À1

;

¹H NMR

1031, 997, 968, 874, 818, 721, 586 cm^À1

;

¹H NMR (400 MHz,

(400 MHz, [D₆]acetone:D₂O=2:1): d=7.07 (s, 2H), 6.59 (s, 2H), 5.96 (s,

[D₆]acetone:D₂O=2:1): d=6.93 (s, 2H), 6.80 (s, 2H), 6.05 (s, 1H), 6.04

1H), 5.96 (s, 1H), 5.35 (brs, 1H), 5.01 (s, 1H), 3.74 (s, 6H), 2.94 (d,

(s, 1H), 5.43 (brs, 1H), 5.10 (s, 1H), 3.65 (s, 6H), 3.65 (s, 3H), 2.94 (dd,

J

_gem=18.4 Hz, 1H), 2.72 ppm (d, J_gem=18.4 Hz, 1H); HRMS (ESI-TOF):

J_gem=17.4 Hz, J=4.3 Hz, 1H), 2.79 ppm (d, J_gem=17.9 Hz, 1H); HRMS

m/z (%) calcd for C₂₄H₂₃O₁₁: 487.1240 [M+H]⁺; found: 487.1239.

(ESI-TOF): m/z (%) calcd for C₂₅H₂₅O₁₁: 501.1397 [M+H]⁺; found:

501.1397.

2ba (68%): R_f=0.43 (CHCl₃:methanol=2:1); FTIR (solid): n˜ =3299,

1689, 1605, 1529, 1506, 1441, 1315, 1233, 1195, 1143, 1116, 1029, 1007,

2db (52%): R_f=0.42 (CHCl₃:methanol=4:1); ¹H NMR (400 MHz,

[D₆]acetone:D₂O=2:1): d=6.95 (s, 2H), 6.83 (s, 2H), 6.02 (d, J=1.9 Hz,

1H), 5.99 (d, J=1.9 Hz, 1H), 5.51 (brs, 1H), 5.14 (s, 1H), 3.74 (s, 3H),

820, 766, 628 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone:D₂O=2:1): d=6.97

;

(s, 2H), 6.61 (s, 2H), 5.99 (d, J=2.4 Hz, 1H), 5.96 (d, J=2.4 Hz, 1H),

5.40 (brs, 1H), 4.99 (s, 1H), 3.67 (s, 3H), 2.95 (dd, J_gem=17.9 Hz, J=

4.4 Hz, 1H), 2.86 ppm (d, J_gem=17.9 Hz, 1H); HRMS (ESI-TOF): m/z

(%) calcd for C₂₃H₂₁O₁₁: 473.1084 [M+H]⁺; found: 473.1064.

3.67 (s, 6H), 3.61 (s, 3H), 3.01 (dd,

J_gem=17.9 Hz, J=4.3 Hz 1H),

2.87 ppm (d, J_gem=17.9 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd for

C₂₆H₂₇O₁₁: 515.1553 [M+H]⁺; found: 515.1556.

2bb (63%): R_f=0.32 (CHCl₃:methanol=3:1); FTIR (solid): n˜ =3283,

2dc (49%): R_f=0.54 (CHCl₃:methanol=4:1); ¹H NMR (400 MHz,

[D₆]acetone:D₂O=2:1): d=7.07 (d, J=1.9 Hz, 1H), 6.94 (d, J=1.9 Hz,

1H), 6.83 (s, 2H), 6.02 (d, J=2.4 Hz, 1H), 5.99 (d, J=2.4 Hz, 1H), 5.54

(brs, 1H), 5.16 (s, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 3.66 (s, 6H, j), 3.61 (s,

1693, 1601, 1600, 1510, 1435, 1372, 1193, 1145, 1050, 986, 823, 755, 713,

540 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone:D₂O=2:1): d=6.89 (s, 2H,

;

a), 6.59 (s, 2H, b), 5.95 (d, J=2.4 Hz, 1H, c or d), 5.94 (d, J=2.4 Hz, 1H,

c or d), 5.39 (brs, 1H, e), 4.98 (s, 1H, f), 3.70 (s, 3H, g or h), 3.64 (s, 3H,

3H), 3.01 (dd, J_gem=17.4 Hz, J=3.9 Hz, 1H), 2.89 ppm (dd, J_gem=

g or h), 2.94 (dd, J_gem=17.9 Hz, J=4.8 Hz, 1H, i), 2.82 ppm (dd, J_gem

17.9 Hz, J=1.9 Hz, 1H, i); HRMS (ESI-TOF): m/z (%) calcd for

C₂₄H₂₃O₁₁: 487.1240 [M+H]⁺; found: 487.1238.

=

16.4 Hz, J=0.97 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd for

C₂₇H₂₉O₁₁: 529.1710 [M+H]⁺; found: 529.1716.

2dd (50%): R_f=0.55 (CHCl₃:methanol=4:1); ¹H NMR (400 MHz,

[D₆]acetone:D₂O=2:1): d=7.06 (s, 2H), 6.82 (s, 2H), 6.08 (d, J=2.4 Hz,

1H), 6.05 (d, J=1.9 Hz, 1H), 5.54 (brs, 1H), 5.16 (s, 1H), 3.70 (s, 6H),

3.66 (s, 3H), 3.64 (s, 6H), 3.04 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H),

2.84 ppm (dd, J_gem=17.4 Hz, J=1.4 Hz 1H); HRMS (ESI-TOF): m/z

(%) calcd for C₂₇H₂₉O₁₁: 529.1710 [M+H]⁺; found: 529.1712.

2bc (51%): R_f=0.41 (CHCl₃:methanol=3:1); FTIR (solid): n˜ =3283,

1697, 1599, 1509, 1462, 1434, 1366, 1225, 1146, 1099, 1049, 1016, 1003,

824, 755, 714, 548 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone:D₂O=2:1): d=

;

7.00 (d, J=1.9 Hz, 1H, a), 6.91 (d, J=1.9 Hz, 1H, a), 6.58 (s, 2H, b), 5.95

(d, J=2.4 Hz, 1H, c or d), 5.93 (d, J=2.4 Hz, 1H, c or d), 5.39 (brs, 1H,

e), 5.00 (s, 1H, f), 3.72 (s, 3H, g, h, or i), 3.67 (s, 3H, g, h, or i), 3.63 (s,

3H, g, h, or i), 2.94 (dd, J_gem=17.4 Hz, J=4.3 Hz, 1H, j), 2.87 ppm (dd,

3aa (40%) R_f=0.37 (CHCl₃:methanol=3:1); FTIR (solid): n˜ =3271,

2962, 1654, 1601, 1513, 1432, 1370, 1200, 1145, 1118, 1042, 799, 668,

524 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone:D₂O=2:1): d=6.94 (d, J=

;

J

_gem=17.4 Hz, J=1.9 Hz, 1H, j); HRMS (ESI-TOF): m/z (%) calcd for

C₂₅H₂₅O₁₁: 501.1397 [M+H]⁺; found: 501.1390.

2.9 Hz, 2H), 6.58 (d, J=2.4 Hz, 2H), 6.03 (s, 1H), 6.01 (s, 1H), 5.33 (brs,

1H), 4.95 (s, 1H), 3.64 (s, 3H), 2.91 (dd, J_gem=17.9 Hz, J=1.9 Hz),

2.72 ppm (d, J_gem=17.4 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd for

C₂₃H₂₁O₁₁: 473.1084 [M+H]⁺; found: 473.1084.

2bd (34%): R_f=0.41 (CHCl₃:methanol=3:1); FTIR (solid): n˜ =3387,

1669, 1629, 1515, 1462, 1365, 1207, 1144, 1118, 1044, 960, 803, 755,

606 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone:D₂O=2:1): d=7.05 (s, 2H),

;

6.61 (s, 2H), 5.96 (s, 1H), 5.96 (s, 1H), 5.37 (brs, 1H), 5.04 (s, 1H), 3.74

(s, 6H), 3.64 (s, 3H), 2.98 (dd, J_gem=18.4 Hz, J=4.4 Hz, 1H), 2.84 ppm

(dd, J_gem=17.9 Hz, J=2.9 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd

for C₂₅H₂₅O₁₁: 501.1397 [M+H]⁺; found: 501.1400.

3ab (37%): R_f=0.46 (CHCl₃:methanol=3:1); FTIR (solid): n˜ =3401,

1627, 1444, 1371, 1212, 1043, 866, 621, 481 cm^À^{1 1}H NMR (400 MHz,

;

[D₆]acetone:D₂O=2:1): d=6.91 (s, 2H), 6.58 (s, 2H), 6.03 (s, 1H), 6.02

(s, 1H), 5.29 (brs, 1H), 5.13 (s, 1H), 3.71 (s, 3H), 3.65 (s, 3H), 2.83 (dd,

2ca (43%): R_f=0.38 (CHCl₃:methanol=3:1); FTIR (solid): n˜ =3301,

J_gem=17.4 Hz, J=4.4 Hz, 1H), 2.72 ppm (d, J_gem=17.4 Hz, 1H); HRMS

1689, 1612, 1517, 1462, 1340, 1213, 1146, 1117, 1036, 994, 824, 755, 649,

(ESI-TOF): m/z (%) calcd for C₂₄H₂₃O₁₁: 487.1240 [M+H]⁺; found:

535 cm^À1

;

¹H NMR (400 MHz, [D₆]acetone:D₂O=2:1): d=6.95 (s, 2H),

487.1230.

6.90 (s, 2H), 5.98 (d, J=2.4 Hz, 1H), 5.96 (d, J=2.4 Hz, 1H), 5.43 (brs,

1H), 5.05 (s, 1H), 3.64 (s, 6H), 2.96 (dd, J_gem=17.4 Hz, J=4.3 Hz, 1H),

2.81 ppm (d, J_gem=17.4 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd for

C₂₄H₂₃O₁₁: 487.1240 [M+H]⁺; found: 487.1235.

3ac (56%): R_f=0.55 (CHCl₃:methanol=4:1); FTIR (solid): n˜ =3332,

1693, 1595, 1534, 1506, 1463, 1426, 1364, 1338, 1195, 1140, 1111, 1029,

1003, 821, 761, 667, 524 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone:D₂O=

;

2:1): d=7.04 (d, J=1.9 Hz, 1H), 6.95 (d, J=1.9 Hz, 1H), 6.60 (s, 2H),

6.06 (d, J=1.9 Hz, 1H), 6.03 (d, J=1.9 Hz, 1H), 5.40 (brs, 1H), 5.02 (s,

1H), 3.76 (s, 3H) 3.71 (s, 3H), 3.66 (s, 3H), 2.83 (dd, J_gem=17.9 Hz, J=

4.4 Hz, 1H), 2.72 ppm (d, J_gem=17.9 Hz, 1H); ¹³C NMR (100 MHz, ace-

toned₆:D₂O=2:1): d=166.2, 159.4, 157.5, 156.0, 153.5, 150.6, 145.9, 141.3,

130.1, 125.8, 111.2, 106.1, 105.6, 99.1, 96.1, 92.7, 77.4, 70.2, 60.6, 56.2, 55.6,

25.9 ppm; HRMS (ESI-TOF): m/z (%) calcd for C₂₅H₂₅O₁₁: 501.1397

[M+H]⁺; found: 501.1394.

2cb (57%): R_f=0.52 (CHCl₃:methanol=3:1); FTIR (solid): n˜ =3337,

1697, 1606, 1517, 1461, 1433, 1372, 1223, 1147, 1113, 1057, 824, 755, 665,

531 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone:D₂O=2:1): d=6.92 (s, 2H),

;

6.75 (s, 2H), 5.97 (d, J=2.4 Hz, 1H), 5.95 (d, J=2.4 Hz, 1H), 5.44 (brs,

1H), 5.06 (s, 1H), 3.70 (s, 3H), 3.63 (s, 6H), 2.97 (dd, J_gem=17.9 Hz, J=

4.3 Hz, 1H), 2.81 ppm (dd, J_gem=17.9 Hz, J=1.4 Hz, 1H); HRMS (ESI-

TOF): m/z (%) calcd for C₂₅H₂₅O₁₁: 501.1397 [M+H]⁺; found: 501.1400.

2cc (60%): R_f=0.43 (CHCl₃:methanol=4:1); ¹H NMR (400 MHz,

[D₆]acetone:D₂O=2:1): d=7.06 (d, J=1.4 Hz, 1H), 6.94 (d, J=1.4 Hz,

1H), 6.78 (s, 2H), 6.00 (d, J=1.9 Hz, 1H), 5.97 (d, J=1.9 Hz, 1H), 5.50

(brs, 1H), 5.10 (s, 1H), 3.71 (s, 3H), 3.70 (s, 3H), 3.64 (s, 6H), 2.99 (dd,

3ad (33%): R_f=0.54 (CHCl₃:methanol=4:1); FTIR (solid): n˜ =3232,

1688, 1607, 1532, 1513, 1463, 1425, 1364, 1331, 1212, 1144, 1112, 1029,

1

958, 913, 821, 760, 738, 551 cm^À1; H NMR (400 MHz, [D₆]acetone:D₂O=

2:1): d=7.06 (s, 2H), 6.59 (s, 2H), 6.05 (s, 1H), 6.02 (s, 1H), 5.35 (brs,

2244

www.chemasianj.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Asian J. 2010, 5, 2231 – 2248

Solid-Phase Synthesis of a Combinatorial Methylated EGCG Library

1H), 5.02 (s, 1H), 3.74 (s, 6H), 3.65 (s, 3H), 2.94 (d, J_gem=18.4 Hz, 1H),

2.72 ppm (d, J_gem=18.4 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd for

C₂₅H₂₅O₁₁: 501.1397 [M+H]⁺; found: 501.1392.

17.9 Hz, J=4.3 Hz, 1H), 2.83 ppm (dd, J_gem=17.9 Hz, J=1.4 Hz, 1H);

¹³C NMR (100 MHz, [D₆]acetone:D₂O=2:1): d=165.7, 159.5, 157.7,

156.1, 153.7, 150.8, 148.1, 141.5, 135.7, 129.5, 125.7, 111.3, 105.5, 104.7,

99.0, 96.1, 92.7, 77.9, 69.9, 60.7, 56.2, 56.2, 55.6, 26.2 ppm; HRMS (ESI-

TOF): m/z (%) calcd for C₂₇H₂₉O₁₁: 529.1710 [M+H]⁺; found: 529.1727.

3ba (68%): R_f=0.47 (CHCl₃:methanol=4:1); FTIR (solid): n˜ =3299,

1689, 1605, 1529, 1506, 1441, 1315, 1233, 1195, 1143, 1116, 1029, 1007,

820, 766, 628 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone:D₂O=2:1): d=6.95

;

3cd (49%): R_f=0.54 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3386,

(s, 2H), 6.60 (s, 2H), 6.05 (d, J=2.4 Hz, 1H), 6.03 (d, J=2.4 Hz, 1H),

5.38 (brs, 1H), 4.99 (s, 1H), 3.66 (s, 3H), 3.65 (s, 3H), 2.93 (dd, J_gem

17.9 Hz, J=4.4 Hz, 1H), 2.82 ppm (d,

_gem=17.9 Hz, 1H); ¹³C NMR

(100 MHz, [D₆]acetone:D₂O=2:1): d=166.7, 159.3, 157.0, 155.7, 150.3,

145.4, 135.3, 134.8, 120.6, 109.7, 106.5, 99.2, 96.0, 92.7, 77.4, 69.4, 60.5,

55.6, 25.9 ppm; HRMS (ESI-TOF): m/z (%) calcd for C₂₄H₂₃O₁₁487.1240

[M+H]⁺; found: 487.1260.

1693, 1602, 1512, 1461, 1423, 1328, 1211, 1146, 1108, 997, 955, 911, 864,

817, 759, 636 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone): d=7.18 (s, 2H),

;

=

J

6.86 (s, 2H), 6.14 (d, J=1.9 Hz, 1H), 6.10 (d, J=1.9 Hz, 1H), 5.59 (brs,

1H), 5.20 (s, 1H), 3.79 (s, 6H), 3.74 (s, 3H), 3.69 (s, 6H), 3.04 (dd, J_gem

=

17.9 Hz, J=4.8 Hz, 1H), 2.84 ppm (dd, J_gem=17.9 Hz, J=1.9 Hz, 1H);

HRMS (ESI-TOF): m/z (%) calcd for C₂₇H₂₉O₁₁: 529.1710 [M+H]⁺;

found: 529.1689.

3bb (55%): R_f=0.57 (CHCl₃:methanol=4:1); FTIR (solid): n˜ =3315,

3da (55%): R_f=0.32 (CHCl₃:methanol=7:1); FTIR (solid): n˜ =3287,

1693, 1601, 1524, 1506, 1436, 1343, 1140, 1113, 1042, 990, 843, 816, 760,

1682, 1598, 1533, 1505, 1459, 1421, 1368, 1329, 1234, 1193, 1146, 1117,

714, 645, 530 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone:D₂O=2:1): d=6.87

;

1031, 997, 968, 874, 818, 721, 586 cm^À1

;

¹H NMR (400 MHz,

(s, 2H), 6.57 (s, 2H), 6.02 (d, J=2.4 Hz, 1H), 6.00 (d, J=2.4 Hz, 1H),

5.37 (brs, 1H), 4.97 (s, 1H), 3.68 (s, 3H), 3.62 (s, 3H), 3.62 (s, 3H), 2.93

(dd, J_gem=17.4 Hz, J=4.4 Hz, 1H), 2.82 ppm (d, J_gem=17.4 Hz, 1H);

¹³C NMR (100 MHz, [D₆]acetone:D₂O=2:1): d=166.2, 159.3, 157.2,

155.7, 150.7, 150.5, 140.4, 135.3, 134.8, 125.6, 109.5, 106.4, 99.0, 96.0, 92.6,

77.3, 69.7, 60.4, 55.5, 25.9 ppm; HRMS (ESI-TOF): m/z (%) calcd for

C₂₅H₂₅O₁₁: 501.1397 [M+H]⁺; found: 501.1397.

[D₆]acetone:D₂O=2:1): d=6.93 (s, 2H), 6.80 (s, 2H), 6.05 (s, 1H), 6.04

(s, 1H), 5.43 (brs, 1H), 5.10 (s, 1H), 3.65 (s, 6H), 3.65 (s, 3H),3.59 (s,

3H), 2.94 (dd, J_gem=17.4 Hz, J=4.3 Hz, 1H), 2.79 ppm (d, J_gem=17.9 Hz,

1H); HRMS (ESI-TOF): m/z (%) calcd for C₂₆H₃₀NO₁₁: 532.1819

[M+NH₄]⁺; found: 532.1842.

3db (53%): R_f=0.37 (CHCl₃:methanol=7:1); FTIR (solid): n˜ =3375,

1698, 1593, 1502, 1459, 1343, 1230, 1116, 1058, 995, 968, 922, 872, 815,

3bc (67%): R_f=0.65 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3401,

1

759, 731, 714, 670, 631 cm^À1; H NMR (400 MHz, [D₆]acetone:D₂O=2:1):

1686, 1598, 1512, 1459, 1425, 1358, 1326, 1201, 1139, 1110, 1044, 1002,

d=6.88 (d, J=3.4 Hz, 2H), 6.78 (d, J=2.9 Hz, 2H), 6.04 (s, 1H), 6.04 (s,

1H), 5.46 (brs, 1H), 5.10 (s, 1H), 3.68 (s, 3H), 3.64 (s, 6H), 3.59 (s, 3H),

3.58 (s, 3H), 2.95 (d, J_gem=17.9 Hz, 1H), 2.80 ppm (d, J_gem=17.9 Hz,

1H); ¹³C NMR (100 MHz, [D₆]acetone:D₂O=2:1): d=165.7, 159.4,157.5,

155.9, 153.3, 150.9, 140.5, 137.7, 125.5, 109.5, 104.5, 99.0, 96.1, 92.7, 78.8,

77.8, 69.5, 60.5, 60.4, 56.0, 55.6, 26.1 ppm; HRMS (ESI-TOF): m/z (%)

calcd for C₂₈H₃₁O₁₁: 529.1710 [M+H]⁺; found: 529.1732.

955, 911, 864, 819, 757, 717, 621 cm^À1

;

¹H NMR (400 MHz,

[D₆]acetone:D₂O=2:1): d=6.98 (d, J=1.9 Hz, 1H), 6.90 (d, J=1.9 Hz,

1H), 6.58 (s, 2H), 6.03 (d, J=2.4 Hz, 1H), 6.01 (d, J=1.9 Hz, 1H), 5.38

(brs, 1H), 5.01 (s, 1H), 3.72 (s, 3H), 3.68 (s, 3H), 3.63 (s, 3H), 3.63 (s,

3H), 2.93 (dd, J_gem=17.9 Hz, J=4.4 Hz, 1H), 2.84 ppm (d, J_gem=17.9 Hz,

1H); ¹³C NMR (100 MHz, [D₆]acetone:D₂O=2:1): d=166.2, 159.3,

157.4, 155.7, 153.4, 150.6, 150.5, 141.2, 135.3, 134.9, 125.6, 111.1, 106.2,

105.4, 98.9, 95.9, 92.6, 77.2, 70.1, 60.6, 60.4, 5 6.1, 55.5, 25.7 ppm; HRMS

(ESI-TOF): m/z (%) calcd for C₂₆H₂₇O₁₁: 515.1553 [M+H]⁺; found:

515.1567.

3dc (73%): R_f=0.53 (CHCl₃:methanol=9:1); FTIR (solid): n˜ =3368,

1709, 1591, 1503, 1458, 1421, 1366, 1343, 1196, 1145, 1119, 1035, 999, 945,

1

813, 757, 720, 671, 629 cm^À1; H NMR (400 MHz, [D₆]acetone:D₂O=2:1):

d=7.03 (d, J=1.9 Hz, 1H), 6.91 (d, J=1.9 Hz, 1H), 6.80 (s, 2H), 6.07 (d,

J=2.4 Hz, 1H), 6.05 (d, J=1.9 Hz, 1H), 5.51 (brs, 1H), 5.14 (s, 1H), 3.70

(s, 3H), 3.69 (s, 3H), 3.66 (s, 3H), 3.64 (s, 6H), 3.59 (s, 3H), 2.98 (dd,

3bd (61%): R_f=0.64 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3401,

1686, 1598, 1512, 1459, 1425, 1358, 1326, 1201, 1139, 1110, 1044, 1002,

955, 911, 864, 819, 757, 717, 621 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone):

;

J

_gem=17.9 Hz, J=4.3 Hz, 1H), 2.83 ppm (d,

J_gem=17.4 Hz, 1H);

d=7.10 (s, 2H), 6.63 (s, 2H), 6.08 (d, J=2.4 Hz, 1H), 6.05 (d, J=2.4 Hz,

1H), 5.40 (brs, 1H), 5.08 (s, 1H), 3.84 (s, 6H), 3.77 (s, 3H), 3.68 (s, 3H),

2.98 (dd, J_gem=17.9 Hz, J=4.4 Hz, 1H), 2.84 ppm (dd, J_gem=17.9 Hz, J=

2.9 Hz 1H); ¹³C NMR (100 MHz, [D₆]acetone:D₂O=2:1): d=166.6,

159.3, 157.4, 155.7, 150.6, 147.9,135.3, 135.0, 120.4, 107.3, 106.5, 106.1,

99.0, 95.9, 92.6, 77.1, 70.1, 60.4, 56.3, 55.5, 25.6 ppm; HRMS (ESI-TOF):

m/z (%) calcd for C₂₆H₂₇O₁₁: 515.1553 [M+H]⁺; found: 515.1555.

¹³C NMR (100 MHz, CDCl₃): d=165.2, 159.0, 155.6, 155.3, 153.0, 151.9,

148.7, 139.5, 137.6, 133.4, 125.4, 109.8, 105.9, 103.7, 99.8, 96.0, 92.1, 77.8,

68.7, 61.0, 60.8, 56.0, 55.9, 55.4, 25.9 ppm; HRMS (ESI-TOF): m/z (%)

calcd for C₂₈H₃₁O₁₁: 543.1866 [M+H]⁺; found: 543.1887.

3dd (69%): R_f=0.53 (CHCl₃:methanol=9:1); FTIR (solid): n˜ =3378,

1708, 1597, 1504, 1461, 1421, 1358, 1327, 1279, 1211, 1118, 1034, 1002,

955, 955, 914, 866, 819, 759, 721, 668, 632, 528 cm^À^{1 1}H NMR (400 MHz,

;

3ca (54%): R_f=0.29 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3335,

[D₆]acetone:D₂O=2:1): d=7.06 (s, 2H), 6.82 (s, 2H), 6.08 (d, J=2.4 Hz,

1H), 6.05 (d, J=1.9 Hz, 1H), 5.54 (brs, 1H), 5.16 (s, 1H), 3.70 (s, 6H),

3.66 (s, 3H), 3.64 (s, 6H), 3.60 (s, 3H), 3.04 (dd, J_gem=17.9 Hz, J=4.3 Hz,

1H), 2.84 ppm (dd, J_gem=17.4 Hz, J=1.4 Hz, 1H); ¹³C NMR (100 MHz,

CDCl₃): d=165.4, 158.8, 156.6, 155.3, 152.9, 146.8, 139.9, 133.5, 120.5,

106.9, 103.9, 99.1, 95.5„92.2, 77.6, 68.5, 60.7, 56.2, 55.8, 55.2, 50.2,

25.8 ppm; HRMS (ESI-TOF): m/z (%) calcd for C₂₈H₃₁O₁₁: 543.1866

[M+H]⁺; found: 543.1865.

1687, 1606, 1519, 1460, 1314, 1211, 1143, 1111, 1030, 996, 967, 911, 874,

1

819, 767, 663, 634, 544 cm^À1; H NMR (400 MHz, [D₆]acetone:D₂O=2:1):

d=6.96 (s, 2H), 6.77 (s, 2H), 6.05 (s, 1H), 6.04 (s, 1H), 5.43 (brs, 1H),

5.06 (s, 1H), 3.65 (s, 3H), 3.64 (s, 6H), 2.94 (dd, J_gem=17.4 Hz, J=4.3 Hz,

1H), 2.79 ppm (d, J_gem=17.4 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd

for C₂₅H₂₈NO₁₁: 518.1662 [M+NH₄]⁺; found: 518.1675.

3cb (60%): R_f=0.34 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3371,

1696, 1600, 1519, 1458, 1429, 1346, 1233, 1200, 1144, 1110, 1053, 996, 966,

1

912, 820, 744, 714, 624 cm^À1; H NMR (400 MHz, [D₆]acetone:D₂O=2:1):

4aa (36%): R_f=0.19 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3264,

1686, 1616, 1594, 1533, 1499, 1440, 1368, 1340, 1192, 1144, 1114, 1030,

d=6.91 (d, J=2.4 Hz, 2H), 6.75 (d, J=2.4 Hz, 2H), 6.05 (s, 1H), 6.05 (s,

1H), 5.45 (brs, 1H), 5.08 (s, 1H), 3.70 (s, 3H), 3.65 (s, 3H), 3.63 (s, 6H),

2.96 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H), 2.80 ppm (d, J_gem=17.9 Hz, 1H);

¹³C NMR (100 MHz, [D₆]acetone:D₂O=2:1): d=165.7, 159.6, 157.7,

156.2, 151.0, 148.1,140.4, 129.5, 125.7, 118.2, 109.5, 104.7, 99.1, 96.1, 92.7,

78.0, 69.6, 60.4, 56.2, 55.6, 26.2 ppm; HRMS (ESI-TOF): m/z (%) calcd

for C₂₆H₂₇O₁₁: 515.1553 [M+H]⁺; found: 515.1546.

1

884, 816, 737, 698, 630, 477 cm^À1; H NMR (400 MHz, [D₆]acetone:D₂O=

2:1): d=6.92 (s, 2H), 6.58 (s, 2H), 6.15 (s, 1H), 6.12 (s, 1H), 5.36 (brs,

1H), 4.99 (s, 1H), 3.67 (s, 3H), 2.91 (dd, J_gem=17.9 Hz, J=1.9 Hz, 1H),

2.72 ppm (d, J_gem=17.4 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd for

C₂₃H₂₁O₁₁: 473.1084 [M+H]⁺; found: 473.1070.

4ab (43%): R_f=0.31 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3304,

1694, 1619, 1596, 1516, 1438, 1373, 1342, 1231, 1192, 1142, 1039, 871, 759,

3cc (58%): R_f=0.54 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3379,

710, 668, 541 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone:D₂O=2:1): d=6.89

;

1697, 1603, 1503, 1459, 1427, 1341, 1213, 1144, 1107, 1029, 996, 957, 910,

871, 821, 761, 746, 720, 665, 632, 533 cm^À1

;

¹H NMR (400 MHz,

(s, 2H), 6.58 (s, 2H), 6.02 (d, J=1.9 Hz, 1H), 5.99 (d, J=2.4 Hz, 1H),

5.38 (brs, 1H), 4.98 (s, 1H), 3.69 (s, 3H), 3.62 (s, 3H), 2.95 (dd, J_gem

=

[D₆]acetone:D₂O=2:1): d=7.05 (d, J=1.9 Hz, 1H), 6.92 (d, J=1.9 Hz,

1H), 6.77 (s, 2H), 6.06 (s, 1H), 6.05 (s, 1H), 5.49 (brs, 1H), 5.10 (s, 1H),

17.9 Hz, J=4.3 Hz, 1H), 2.84 ppm (d, J_gem=17.9 Hz, 1H); HRMS (ESI-

TOF): m/z (%) calcd for C₂₄H₂₃O₁₁: 487.1240 [M+H]⁺; found: 487.1223.

3.71 (s, 3H), 3.70 (s, 3H), 3.70 (s, 3H), 3.63 (s, 6H), 2.97 (dd, J_gem

=

Chem. Asian J. 2010, 5, 2231 – 2248

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org

2245

T. Takahashi et al.

FULL PAPERS

4ac (45%): R_f=0.45 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3357,

2.82 ppm

(d,

J

_gem=16.9 Hz,

1H);

¹³C NMR

(67.8 MHz,

1686, 1619, 1595, 1514, 1448, 1426, 1362, 1330, 1196, 1145, 1112, 1039,

[D₆]acetone:D₂O=2:1): d=165.8, 159.8, 157.0, 156.4, 150.9, 148.0, 140.5,

135.4, 129.4, 125.6, 109.6, 104.6, 99.6, 95.0, 93.5, 78.0, 69.7, 60.4, 56.2, 55.3,

26.2 ppm; HRMS (ESI-TOF): m/z (%) calcd for C₂₆H₂₇O₁₁: 515.1553

[M+H]⁺; found: 515.1556.

868, 821, 765, 639, 626, 554, 503 cm^À1

;

¹H NMR (400 MHz,

[D₆]acetone:D₂O=2:1): d=7.06 (s, 1H), 7.06 (d, J=1.9 Hz, 0.5H), 6.95

(d, J=1.9 Hz, 0.5H), 6.60 (s, 2H), 6.06 (d, J=1.9 Hz, 1H), 6.03 (d, J=

1.9 Hz, 1H), 5.40 (brs, 1H), 5.02 (s, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.66

4cc (59%): R_f=0.50 (CHCl₃:methanol=9:1); FTIR (solid): n˜ =3372,

(s, 3H), 2.83 (dd, J_gem=17.9 Hz, J=4.4 Hz, 1H), 2.72 ppm (d, J_gem

=

1698, 1619, 1592, 1510, 1454, 1426, 1341, 1216, 1199, 1145, 1108, 1033,

995, 981, 913, 872, 821, 759, 728, 712, 526 cm^À^{1 1}H NMR (400 MHz,

;

17.9 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd for C₂₅H₂₅O₁₁: 501.1397

[M+H]⁺; found: 501.1394.

[D₆]acetone:D₂O=2:1): d=7.08 (d, J=1.9 Hz, 1H), 6.95 (d, J=1.9 Hz,

1H), 6.81 (s, 2H), 6.09 (d, J=1.9 Hz, 1H), 6.05 (d, J=1.9 Hz, 1H), 5.54

(brs, 1H), 5.15 (s, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 3.66 (s, 3H), 3.66 (s,

4ad (40%): R_f=0.44 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3366,

1686, 1618, 1597, 1514, 1460, 1425, 1325, 1183, 1144, 1112, 1035, 996, 962,

1

912, 818, 756, 734, 538 cm^À1; H NMR (400 MHz, [D₆]acetone:D₂O=2:1):

6H), 3.04 (dd,

J_gem=17.9 Hz, J=4.3 Hz, 1H), 2.90 ppm (dd, J_gem=

17.9 Hz, J=0.97 Hz, 1H); ¹³C NMR (67.8 MHz, CDCl₃): d=165.2, 159.4,

155.9, 155.0, 151.9, 148.7, 146.8, 139.5, 134.5, 128.8, 125.3, 109.8, 106.0,

103.5, 98.9, 95.5, 94.2, 77.9, 68.8, 61.0, 56.1, 56.0, 55.3, 25.7 ppm; HRMS

(ESI-TOF): m/z (%) calcd for C₂₇H₂₉O₁₁: 529.1710 [M+H]⁺; found:

529.1704.

d=7.04 (s, 2H), 6.59 (s, 2H), 6.03 (d, J=2.4 Hz, 1H), 6.02 (d, J=2.4 Hz,

1H), 5.36 (brs, 1H), 5.03 (s, 1H), 3.72 (s, 6H), 3.61 (s, 3H), 2.94 (d,

J

_gem=17.9 Hz, 1H), 2.72 ppm (dd, J_gem=17.9 Hz, J=2.4 Hz, 1H);

¹³C NMR (100 MHz, [D₆]acetone:D₂O=2:1): d=166.7, 159.7, 156.9,

156.2, 147.8, 145.8, 132.6, 130.2, 120.4, 120.3, 107.3, 105.9, 99.5, 94.9, 93.4,

77.4, 70.3, 56.3, 55.3, 25.7 ppm; HRMS (ESI-TOF): m/z (%) calcd for

C₂₅H₂₅O₁₁: 501.1397 [M+H]⁺; found: 501.1399.

4cd (62%): R_f=0.49 (CHCl₃:methanol=9:1); FTIR (solid): n˜ =3371,

1698, 1594, 1513, 1459, 1423, 1353, 1329, 1205, 1184, 1145, 1111, 1033,

962, 910, 868, 817, 756, 739, 587 cm^À^{1 1}H NMR (400 MHz, CDCl₃): d=

;

4ba (48%): R_f=0.29 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3340,

1686, 1596, 1512, 1444, 1317, 1193, 1144, 1034, 973, 819, 768, 684,

7.19 (s, 2H), 6.69 (s, 2H), 6.24 (d, J=2.4 Hz, 1H), 6.06 (d, J=2.4 Hz,

1H), 5.67 (brs, 1H), 5.09 (s, 1H), 3.85 (s, 6H), 3.76 (s, 3H), 3.73 (s, 6H),

3.04 (dd, J_gem=16.9 Hz, J=4.3 Hz, 1H), 2.84 ppm (dd, J_gem=17.4 Hz, J=

2.4 Hz, 1H); ¹³C NMR (67.8 MHz, CDCl₃): d=165.3, 159.5, 156.1, 155.0,

151.9, 146.9, 146.6, 139.6, 134.7, 128.8, 120.9, 107.0, 103.7, 99.1, 95.3, 94.2,

77.9, 68.4, 56.4, 56.2, 55.4, 25.7 ppm; HRMS (ESI-TOF): m/z (%) calcd

for C₂₇H₂₉O₁₁: 529.1710 [M+H]⁺_,found: 529.1708.

648 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone:D₂O=2:1): d=6.97 (s, 2H),

;

6.63 (s, 2H), 6.07 (d, J=2.4 Hz, 1H), 6.02 (d, J=2.4 Hz, 1H), 5.42 (brs,

1H), 5.03 (s, 1H), 3.68 (s, 3H), 3.65 (s, 3H), 2.99 (dd, J_gem=17.9 Hz, J=

4.4 Hz, 1H), 2.89 ppm (d,

J

_gem=17.9 Hz, 1H); ¹³C NMR (100 MHz,

[D₆]acetone:D₂O=2:1): d=166.7, 159.7, 156.9, 156.2, 150.4, 145.5, 138.9,

135.3,134.8, 120.6, 109.7, 106.5, 99.6, 95.0, 93.5, 77.5, 69.5, 60.5, 55.3,

26.0 ppm; HRMS (ESI-TOF): m/z (%) calcd for C₂₄H₂₃O₁₁: 487.1240

[M+H]⁺; found: 487.1250.

4da (50%): R_f=0.38 (CHCl₃:methanol=7:1); FTIR (solid): n˜ =3339,

1685, 1593, 1508, 1444, 1422, 1354, 1325, 1227, 1193, 1145, 1125, 1033,

1

995, 972, 874, 817, 729, 549 cm^À1; H NMR (400 MHz, [D₆]acetone:D₂O=

4bb (47%): R_f=0.55 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3333,

1692, 1624, 1592, 1513, 1434, 1376, 1233, 1194, 1145, 1044, 987, 818, 757,

2:1): d=6.96 (s, 2H), 6.83 (s, 2H), 6.08 (d, J=2.4 Hz, 1H), 6.03 (d, J=

2.4 Hz, 1H), 5.48 (brs, 1H), 5.14 (s, 1H), 3.67 (s, 6H), 3.60 (s, 3H), 3.22

711, 525 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone:D₂O=2:1): d=6.90 (s,

;

2H), 6.61 (s, 2H), 6.05 (d, J=2.4 Hz, 1H), 6.01 (d, J=2.4 Hz, 1H), 5.43

(brs, 1H), 5.02 (s, 1H), 3.71 (s, 3H), 3.66 (s, 3H), 3.64 (s, 3H), 2.98 (dd,

(s, 3H), 3.01 (dd, J_gem=17.4 Hz, J=4.3 Hz, 1H), 2.86 ppm (d, J_gem

=

16.4 Hz, 1H); ¹³C NMR (67.8 MHz, [D₆]acetone:D₂O=2:1): d=166.2,

159.8, 157.1, 156.3, 153.4, 145.7, 138.9, 137.8, 134.8, 120.6, 109.6, 104.7,

99.7, 95.1, 93.6, 78.1, 69.2, 60.5, 56.1, 55.3, 26.3 ppm; HRMS (ESI-TOF):

m/z (%) calcd for C₂₆H₂₇O₁₁: 515.1553 [M+H]⁺; found: 515.1553.

J

_gem=17.9 Hz, J=4.3 Hz, 1H), 2.87 ppm (d, J_gem=17.9 Hz, 1H); HRMS

(ESI-TOF): m/z (%) calcd for C₂₅H₂₅O₁₁: 501.1397 [M+H]⁺; found:

501.1405.

4bc (50%): R_f=0.36 (CHCl₃:methanol=9:1); FTIR (solid): n˜ =3357,

4db (73%): R_f=0.51 (CHCl₃:methanol=7:1); FTIR (solid): n˜ =3353,

1696, 1623, 1591, 1509, 1430, 1365, 1343, 1192, 1143, 1101, 1045, 998, 945,

1694, 1628, 1592, 1505, 1446, 1421, 1344, 1227, 1195, 1146, 1123, 1059,

815, 757, 712, 538 cm^À^{1 1}H NMR (270 MHz, [D₆]acetone:D₂O=2:1): d=

;

1042, 994, 972, 911, 873, 816, 758, 731, 713, 668, 634 cm^À^{1 1}H NMR

;

7.01 (d, J=1.9 Hz, 1H), 6.92 (d, J=1.9 Hz, 1H), 6.61 (s, 2H), 6.05 (d, J=

2.0 Hz, 1H), 6.01 (d, J=2.0 Hz, 1H), 5.42 (brs, 1H), 5.05 (s, 1H), 3.74 (s,

3H), 3.69 (s, 3H), 3.65 (s, 3H), 3.63 (s, 3H), 2.93 (dd, J_gem=17.1 Hz, J=

4.0 Hz, 1H), 2.84 ppm (d, J_gem=17.1 Hz, 1H); HRMS (ESI-TOF): m/z

(%) calcd for C₂₆H₂₇O₁₁: 515.1553 [M+H]⁺; found: 515.1578.

(400 MHz, [D₆]acetone:D₂O=2:1): d=6.94 (s, 2H), 6.84 (s, 2H), 6.09 (d,

J=2.4 Hz, 1H), 6.04 (d, J=2.4 Hz, 1H), 5.52 (brs, 1H), 5.16 (s, 1H), 3.73

(s, 3H), 3.67 (s, 6H), 3.65 (s, 3H), 3.61 (s, 3H), 3.03 (dd, J_gem=17.4 Hz,

J=4.3 Hz, 1H), 2.89 ppm (d, J_gem=17.4 Hz, 1H); ¹³C NMR (100 MHz,

[D₆]acetone:D₂O=2:1): d=165.5, 159.2, 155.9, 155.7, 153.0, 149.2, 139.0,

137.5, 133.4, 125.1, 109.3, 103.9, 99.1, 95.2, 93.3, 77.9, 68.6, 60.7, 60.6, 55.9,

55.2, 25.8 ppm; HRMS (ESI-TOF): m/z (%) calcd for C₂₇H₂₉O₁₁:

529.1710 [M+H]⁺; found: 529.1707.

4bd (39%): R_f=0.35 (CHCl₃:methanol=9:1); FTIR (solid): n˜ =3408,

1685, 1595, 1512, 1426, 1363, 1330, 1184, 1144, 1115, 997, 817, 752, 713,

554 cm^À^{1 1}H NMR (270 MHz, [D₆]acetone:D₂O=2:1): d=7.03 (s, 2H),

;

6.60 (s, 2H), 6.03 (d, J=1.9 Hz, 1H), 6.01 (d, J=1.9 Hz, 1H), 5.37 (brs,

1H), 5.06 (s, 1H), 3.72 (s, 6H), 3.62 (s, 3H), 3.61 (s, 3H), 2.96 (brs, 1H),

2.95 ppm (brs, 1H); ¹³C NMR (67.8 MHz, [D₆]acetone:D₂O=2:1): d=

166.6, 159.8, 157.0, 156.1, 150.6, 147.9, 135.3, 135.0, 120.5, 107.3, 106.1,

99.5, 94.9, 93.4, 77.3, 70.2, 60.4, 56.4, 55.3, 25.7 ppm; HRMS (ESI-TOF):

m/z (%) calcd for C₂₆H₂₇O₁₁: 515.1553 [M+H]⁺; found: 515.1567.

4dc (64%): R_f=0.53 (CHCl₃:methanol=9:1); FTIR (solid): n˜ =3385,

1711, 1625, 1590, 1504, 1458, 1420, 1342, 1218, 1198, 1145, 1121, 1098,

1035, 998, 872, 814, 759, 729, 668, 640 cm^À1

;

¹H NMR (67.8 MHz,

[D₆]acetone:D₂O=2:1): d=7.05 (d, J=2.0 Hz, 1H), 6.92 (d, J=2.0 Hz,

1H), 6.84 (s, 2H), 6.09 (d, J=2.3 Hz, 1H), 6.04 (d, J=2.3 Hz, 1H), 5.55

(brs, 1H), 5.18 (s, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 3.66 (s, 6H), 3.64 (s,

3H), 3.61 (s, 3H), 3.04 (dd, J_gem=17.4 Hz, J=4.3 Hz, 1H), 2.90 ppm (d,

4ca (55%): R_f=0.50 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3373,

J

_gem=17.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): d=165.2, 159.4, 155.8,

1681, 1619, 1595, 1517, 1430, 1348, 1195, 1144, 1111, 1056, 994, 914, 872,

822, 761, 713, 524 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone:D₂O=2:1): d=

;

155.1, 153.1, 151.9, 148.7, 139.6, 137.6, 133.3, 127.2, 125.3, 109.8, 105.9,

103.8, 98.9, 95.5, 94.2, 77.9, 68.7, 61.0, 60.8, 56.0, 55.3, 25.7 ppm; HRMS

(ESI-TOF): m/z (%) calcd for C₂₈H₃₁O₁₁: 543.1866 [M+H]⁺; found:

543.1866.

6.90 (s, 2H), 6.75 (s, 2H), 6.05 (d, J=2.4 Hz, 1H), 6.01 (d, J=1.9 Hz,

1H), 5.46 (brs, 1H), 5.09 (s, 1H), 3.69 (s, 3H), 3.63 (s, 6H), 2.99 (dd,

J

_gem=17.4 Hz, J=3.9 Hz, 1H), 2.83 ppm (d, J_gem=16.9 Hz, 1H); HRMS

(ESI-TOF): m/z (%) calcd for C₂₅H₂₅O₁₁: 501.1397 [M+H]⁺; found:

4dd (68%): R_f=0.52 (CHCl₃:methanol=9:1); FTIR (solid): n˜ =3360,

501.1388.

1708, 1626, 1592, 1510, 1460, 1421, 1355, 1329, 1207, 1185, 1146, 1115,

1035, 1002, 962, 914, 818, 761, 730, 712, 666 cm^À^{1 1}H NMR (67.8 MHz,

;

4cb (65%): R_f=0.56 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3343,

[D₆]acetone:D₂O=2:1): d=7.10 (s, 2H), 6.87 (s, 2H), 6.10 (s, 1H), 6.07

(s, 1H), 5.58 (brs, 1H), 5.21 (s, 1H), 3.73 (s, 6H), 3.66 (s, 3H), 3.66 (s,

6H), 3.62 (s, 3H), 3.05 (dd, J_gem=17.8 Hz, J=3.6 Hz, 1H), 2.93 ppm (d,

1685, 1619, 1592, 1514, 1448, 1434, 1344, 1212, 1144, 1113, 1056, 995, 973,

911, 872, 821,759, 739, 712, 585 cm^À1

;

¹H NMR (400 MHz,

[D₆]acetone:D₂O=2:1): d=6.89 (s, 2H), 6.75 (s, 2H), 6.04 (d, J=2.4 Hz,

1H), 6.02 (d, J=2.4 Hz, 1H), 5.45 (brs, 1H), 5.08 (s, 1H, f), 3.68 (s, 3H),

3.64 (s, 3H), 3.62 (s, 6H), 2.99 (dd, J_gem=17.9 Hz, J=4.4 Hz, 1H),

J

_gem=17.8 Hz, 1H); ¹³C NMR (67.8 MHz, CDCl₃): d=165.4, 159.5, 156.0,

155.1, 153.1, 146.6, 139.6, 137.9, 133.3, 120.9, 107.0, 104.0, 99.1, 95.4, 94.1,

2246

www.chemasianj.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Asian J. 2010, 5, 2231 – 2248

Solid-Phase Synthesis of a Combinatorial Methylated EGCG Library

77.8, 68.4, 60.8, 56.4, 56.0, 55.3, 25.7 ppm; HRMS (ESI-TOF): m/z (%)

calcd for C₂₈H₃₁O₁₁: 543.1866 [M+H]⁺; found: 543.1867.

3H), 3.78 (s, 3H), 3.76 (s, 3H), 3.07 (dd, J_gem=17.9 Hz, J=4.4 Hz, 1H),

3.00 ppm (d, J_gem=17.9 Hz, J=2.4 Hz, 1H); HRMS (ESI-TOF): m/z (%)

calcd for C₂₇H₂₉O₁₁: 529.1710 [M+H]⁺; found: 529.1699.

5aa (42%): R_f=0.46 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3315,

5ca (55%): R_f=0.49 (CHCl₃:methanol=9:1); FTIR (solid): n˜ =3230,

2943, 2851, 1678, 1602, 1514, 1460, 1434, 1347, 1191, 1144, 1113, 1054,

1016, 819, 800, 760, 663, 653, 511 cm^À1

;

¹H NMR (400 MHz,

2924, 2851, 1693, 1594, 1511, 1442, 1371, 1345, 1224, 1189, 1144, 1116,

1039, 823, 764, 721, 510 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone:D₂O=

;

[D₆]acetone:D₂O=2:1): d=7.04 (s, 2H), 6.84 (s, 2H), 6.07 (d, J=1.9 Hz,

1H), 6.04 (d, J=1.9 Hz, 1H), 5.57 (brs, 1H), 5.16 (s, 1H), 3.82 (s, 3H),

2:1): d=6.90 (s, 2H), 6.75 (s, 2H), 6.05 (d, J=2.4 Hz, 1H), 6.01 (d, J=

1.9 Hz, 1H), 5.46 (brs, 1H), 5.09 (s, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 3.79

3.71 (s, 3H), 3.07 (dd, J_gem=17.4 Hz, J=4.8 Hz), 2.98 ppm (dd, J_gem

=

(s, 6H), 2.99 (dd, J_gem=17.4 Hz, J=3.9 Hz, 1H), 2.83 ppm (d, J_gem

=

17.4 Hz, J=1.4 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd for

C₂₄H₂₃O₁₁: 487.1240 [M+H]⁺; found: 487.1247.

17.4 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd for C₂₆H₂₇O₁₁: 515.1553

[M+H]⁺; found: 515.1569.

5ab (51%): R_f=0.50 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3260,

5cb (51%): R_f=0.61 (CHCl₃:methanol=9:1); FTIR (solid): n˜ =3387,

2923, 2851, 1693, 1619, 1594, 1525, 1498, 1453, 1437, 1375, 1341, 1215,

1190, 1145, 1120, 1039, 997, 976, 809, 761, 713, 668, 516 cm^À^{1 1}H NMR

;

2925, 2849, 1713, 1620, 1591, 1505, 1460, 1421, 1365, 1344, 1219, 1201,

1147, 1120, 1048, 1001, 948, 872, 814, 759, 732, 718, 669 cm^À^{1 1}H NMR

;

(400 MHz, [D₆]acetone:D₂O=2:1): d=6.98 (s, 2H), 6.64 (s, 2H), 6.17 (d,

J=2.0 Hz, 1H), 6.13 (d, J=2.0 Hz, 1H), 5.55 (brs, 1H), 5.09 (s, 1H), 3.81

(s, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 3.03 (dd, J_gem=17.8 Hz, J=4.6 Hz,

1H), 2.87 ppm (d, J_gem=17.8 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd

for C₂₅H₂₅O₁₁: 501.1397 [M+H]⁺; found: 501.1406.

(400 MHz, CDCl₃): d=7.13 (s, 2H), 6.72 (s, 2H), 6.25 (d, J=1.9 Hz, 1H),

6.12 (d, J=1.9 Hz, 1H), 5.58 (brs, 1H), 5.05 (s, 1H), 3.91 (s, 3H), 3.81 (s,

3H), 3.80 (s, 6H), 3.78 (s, 3H), 3.03 ppm (brd, J=2.9 Hz, 2H); HRMS

(ESI-TOF): m/z (%) calcd for C₂₇H₃₂NO₁₁: 546.1975 [M+H]⁺; found:

546.1987.

5ac (56%): R_f=0.56 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3279,

5cc (57%): R_f=0.55 (CHCl₃:methanol=12:1); FTIR (solid): n˜ =3394,

2924, 2851, 1707, 1617, 1594, 1512, 1456, 1427, 1364, 1344, 1198, 1146,

1113, 1034, 997, 810, 760, 653, 516 cm^À1

;

¹H NMR (400 MHz,

2919, 2849, 1709, 1618, 1592, 1499, 1460, 1427, 1361, 1344, 1217, 1202,

1146, 1111, 1045, 996, 982, 947, 818, 759, 717, 664, 532 cm^À^{1 1}H NMR

;

[D₆]acetone:D₂O=2:1): d=7.07 (d, J=1.9 Hz, 1H), 7.01 (d, J=1.9 Hz,

1H), 6.66 (s, 2H), 6.18 (d, J=2.4 Hz, 1H), 6.13 (d, J=2.4 Hz, 1H), 5.53

(brs, 1H), 5.13 (s, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.77 (s, 3H), 3.76 (s,

(400 MHz, CDCl₃): d=7.26 (d, J=1.9 Hz, 1H), 7.09 (d, J=1.9 Hz, 1H),

6.72 (s, 2H), 6.25 (d, J=2.4 Hz, 1H), 6.11 (d, J=2.4 Hz, 1H), 5.59 (brs,

1H), 5.05 (s, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H),

3.78 (s, 6H), 3.04 ppm (d, J=3.4 Hz, 2H, l); ¹³C NMR (67.8 MHz,

CDCl₃): d=165.1, 159.6, 158.8, 155.5, 151.9, 148.6, 146.8, 139.5, 134.4,

128.9, 125.4, 109.8, 106.0, 103.4, 100.0, 93.4, 92.0, 77.9, 77.2, 68.8, 61.0,

56.1, 56.0, 55.4ꢁ2, 25.9 ppm; HRMS (ESI-TOF): m/z (%) calcd for

C₂₈H₃₁O₁₁: 543.1866 [M+H]⁺; found: 543.1881.

3H), 3.04 (dd,

J_gem=17.9 Hz, J=2.4 Hz, 1H), 2.93 ppm (dd, J_gem=

17.9 Hz, J=2.4 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd for

C₂₆H₃₀NO₁₁: 532.1819 [M+H]⁺; found: 532.1816.

5ad (50%): R_f=0.56 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3354,

2923, 2850, 1685, 1593, 1512, 1455, 1425, 1363, 1330, 1183, 1144, 1110,

1030, 999, 816, 799, 761, 667, 652, 514, 501 cm^À^{1 1}H NMR (400 MHz,

;

5cd (53%): R_f=0.55 (CHCl₃:methanol=12:1); FTIR (solid): n˜ =3401,

[D₆]acetone:D₂O=2:1): d=7.04 (s, 2H), 6.59 (s, 2H), 6.03 (d, J=2.4 Hz,

1H), 6.02 (d, J=2.4 Hz, 1H), 5.36 (brs, 1H), 5.03 (s, 1H), 3.72 (s, 6H),

3.61 (s, 3H), 3.61 (s, 3H), 2.94 (d, J_gem=17.9 Hz, 1H), 2.72 ppm (dd,

2942, 2839, 1703, 1612, 1592, 1514, 1498, 1454, 1422, 1355, 1325, 1202,

1144, 1145, 1111, 1033, 962, 910, 868, 817, 756, 739, 587 cm^À^{1 1}H NMR

;

(400 MHz, CDCl₃): d=7.20 (s, 2H), 6.70 (s, 2H), 6.25 (d, J=1.9 Hz, 1H),

6.12 (d, J=1.9 Hz, 1H), 5.66 (brs, 1H), 5.07 (s, 1H), 3.85 (s, 6H), 3.80 (s,

3H), 3.79 (s, 3H), 3.73 (s, 6H) 3.06 (dd, J_gem=16.9 Hz, J=4.3 Hz, 1H),

J

_gem=17.9 Hz, J=2.4 Hz, 1H); HRMS (ESI-TOF): m/z (%) calcd for

C₂₆H₂₇O₁₁: 515.1553 [M+H]⁺; found: 515.1552.

5ba (55%): R_f=0.51 (CHCl₃:methanol=5:1); FTIR (solid): n˜ =3294,

2.99 ppm (d,

J

_gem=16.9 Hz, J=2.9 Hz, 1H); ¹³C NMR (67.8 MHz,

2942, 2840, 1687, 1595, 1530, 1499, 1452, 1438, 1372, 1335, 1312, 1191,

CDCl₃): d=165.2, 159.7, 158.9, 155.6, 146.9, 146.5, 139.4, 134.6, 128.9,

121.1, 107.0, 103.6, 100.2, 93.3, 91.9, 77.9, 77.2, 68.5, 56.4, 56.2, 55.4ꢁ2,

26.0 ppm; HRMS (ESI-TOF): m/z (%) calcd for C₂₈H₃₁O₁₁: 543.1866

[M+H]⁺; found: 543.1885.

1142,1119, 1034, 976, 874, 853, 817, 767, 715, 630, 491 cm^À^{1 1}H NMR

;

(400 MHz, [D₆]acetone:D₂O=2:1): d=6.96 (s, 2H), 6.63 (s, 2H), 6.13 (d,

J=2.4 Hz, 1H), 6.08 (d, J=2.4 Hz, 1H), 5.41 (brs, 1H), 5.03 (s, 1H), 3.70

(s, 3H), 3.68 (s, 3H), 3.25 (s, 3H), 2.96 (dd, J_gem=17.9 Hz, J=4.3 Hz,

5da (43%): R_f=0.24 (CHCl₃:methanol=12:1); FTIR (solid): n˜ =3338,

1H), 2.86 ppm (d,

J

_gem=17.9 Hz, 1H); ¹³C NMR (100 MHz,

1691, 1592, 1498, 1453, 1420, 1306, 1191, 1145, 1119, 1035, 972, 813, 758,

[D₆]acetone:D₂O=2:1): d=166.6, 160.2, 159.4, 156.0, 150.6, 145.6, 138.9,

135.4, 134.8, 120.8, 109.7, 106.6, 100.5, 94.1, 92.0, 77.7, 69.3, 60.4, 55.7,

55.5, 26.1 ppm; HRMS (ESI-TOF): m/z (%) calcd for C₂₅H₂₅O₁₁:

501.1397 [M+H]⁺; found: 501.1397.

631, 461 cm^À^{1 1}H NMR (400 MHz, [D₆]acetone:D₂O=2:1): d=6.96 (s,

;

2H), 6.84 (s, 2H), 6.14 (d, J=2.4 Hz, 1H), 6.11 (d, J=2.4 Hz, 1H), 5.49

(brs, 1H), 5.16 (s, 1H), 3.71 (s, 3H), 3.71 (s, 3H), 3.67 (s, 6H), 3.61 (s,

3H), 3.00 (dd, J_gem=17.9 Hz, J=4.4 Hz, 1H), 2.84 ppm (d, J_gem=17.9 Hz,

1H); ¹³C NMR (67.8 MHz, [D₆]acetone:D₂O=2:1): d=165.9, 159.4,

158.7, 155.2, 152.8, 144.5, 133.4, 109.1, 109.6, 104.7, 99.7, 95.1, 93.6, 78.1,

69.2, 60.5, 56.1, 55.3ꢁ2, 26.3 ppm; HRMS (ESI-TOF): m/z (%) calcd for

C₂₇H₃₂NO₁₁: 546.1975 [M+NH₄]⁺; found: 546.1995.

5bb (39%): R_f=0.43 (CHCl₃:methanol=7:1); FTIR (solid): n˜ =3349,

2935, 2844, 1693, 1619, 1594, 1499, 1453, 1435, 1348, 1267, 1216, 1192,

1141, 1117, 1050, 988, 977, 815, 757, 711, 616 cm^{À1 1}H NMR (400 MHz,

;

[D₆]acetone): d=6.98 (s, 2H), 6.65 (s, 2H), 6.18 (d, J=2.4 Hz, 1H), 6.14

(d, J=2.4 Hz, 1H,), 5.59 (brs, 1H), 5.12 (s, 1H), 3.81 (s, 3H), 3.77 (s,

3H), 3.76 (s, 3H), 3.74 (s, 3H), 3.03 (dd, J_gem=17.9 Hz, J=4.3 Hz, 1H),

2.90 ppm (dd, J_gem=17.9 Hz, J=1.4 Hz, 1H); HRMS (ESI-TOF): m/z

(%) calcd for C₂₆H₂₇O₁₁: 515.1553 [M+H]⁺; found: 515.1575.

5db (55%): R_f=0.34 (CHCl₃:methanol=12:1); FTIR (solid): n˜ =3379,

1707, 1618, 1591, 1499, 1454, 1420, 1345, 1219, 1194, 1145, 1116, 1053,

998, 975, 873, 838, 814, 759, 733, 712, 670, 631 cm^À^{1 1}H NMR (400 MHz,

;

[D₆]acetone:D₂O=2:1): d=6.91 (s, 2H), 6.83 (s, 2H), 6.14 (d, J=2.4 Hz,

1H), 6.11 (d, J=2.4 Hz, 1H), 5.51 (brs, 1H), 5.17 (s, 1H), 3.76 (s, 3H),

5bc (52%): R_f=0.55 (CHCl₃:methanol=7:1); FTIR (solid): n˜ =3344,

2929, 2849, 1697, 1619, 1592, 1500, 1453, 1427, 1365, 1343, 1217, 1197,

3.71 (s, 3H), 3.70 (s, 3H), 3.66 (s, 6H), 3.60 (s, 3H), 3.00 (dd, J_gem

=

1143, 1108, 1049, 997, 948, 814, 760, 714, 519 cm^À^{1 1}H NMR (400 MHz,

;

17.9 Hz, J=4.3 Hz, 1H), 2.85 ppm (d,

J

_gem=17.9 Hz, 1H); ¹³C NMR

CDCl₃): d=7.19 (d, J=1.9 Hz, 1H), 7.08 (d, J=1.9 Hz, 1H), 6.69 (s,

2H), 6.21 (d, J=1.9 Hz, 1H), 6.09 (d, J=1.9 Hz, 1H), 5.53 (brs, 1H),

5.03 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.79 (s, 3H), 3.76 (s,

3H), 3.03 ppm (brs, 2H); HRMS (ESI-TOF): m/z (%) calcd for

C₂₇H₂₉O₁₁: 529.1710 [M+H]⁺; found: 529.1721.

(100 MHz, [D₆]acetone:D₂O=2:1): d=165.5, 159.2, 155.9, 155.7, 153.0,

148.6, 138.6, 137.6, 133.4, 125.7, 109.8, 103.8, 100.0, 93.4, 92.1, 77.9, 68.8,

60.9, 60.8, 56.0, 55.4ꢁ2, 25.9 ppm; HRMS (ESI-TOF): m/z (%) calcd for

C₂₈H₃₁O₁₁: 543.1866 [M+H]⁺; found: 543.1891.

5dc (59%): R_f=0.66 (CHCl₃:methanol=15:1); FTIR (solid): n˜ =3386,

5bd (46%): R_f=0.55 (CHCl₃:methanol=7:1); FTIR (solid): n˜ =3341,

1710, 1619, 1589, 1503, 1455, 1420, 1362, 1342, 1216, 1196, 1145, 1120,

1048, 999, 982, 948, 872, 814, 758, 734, 717, 667, 631 cm^À^{1 1}H NMR

;

2917, 2851, 1709, 1618, 1594, 1513, 1499, 1462, 1426, 1362, 1338, 1260,

1216, 1203, 1145, 1113, 1052, 958, 816, 759, 720, 615 cm^À^{1 1}H NMR

;

(400 MHz, CDCl₃): d=7.26 (d, J=1.4 Hz, 1H), 7.09 (d, J=1.4 Hz, 1H),

6.72 (s, 2H), 6.25 (d, J=2.4 Hz, 1H), 6.12 (d, J=2.4 Hz, 1H), 5.61 (brs,

1H), 5.06 (s, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H),

(400 MHz, CDCl₃): d=7.20 (s, 2H), 6.70 (s, 2H), 6.22 (d, J=2.4 Hz, 1H),

6.10 (d, J=2.4 Hz, 1H), 5.49 (brs, 1H), 5.06 (s, 1H), 3.90 (s, 6H), 3.83 (s,

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3.78 (s, 3H), 3.76 (s, 6H), 3.04 ppm (d, J=3.4 Hz, 2H); HRMS (ESI-

TOF): m/z (%) calcd for C₂₉H₃₆NO₁₁: 574.2288 [M+NH₄]⁺; found:

574.2317.

Oe, M. Iwashima, K. Iguchi, T. Takahashi, Chem. Eur. J. 2006 , 12 ,

136 8 –1 376.

[3] a) T. Yamamoto, L. R. Juneja, D.-C. Chu, M. Kim, Chemistry and

Applications of Green Tea, CRC, Boca Raton, 1997; b) E. C. Stuart,

M. J. Scandlyn, R. J. Rosengren, Life Sci. 2006 , 79 , 232 9 –2 336.

[4] H. Tachibana, K. Koga, Y. Fujimura, K. Yamada, Nat. Struct. Mol.

Biol. 2004 , 11 , 38 0 –3 81.

5dd (68%): R_f=0.66 (CHCl₃:methanol=15:1); FTIR (solid): n˜ =3387,

1707, 1618, 1591, 1498, 1453, 1420, 1356, 1329, 1203, 1183, 1145, 1114,

1035, 1005, 954, 915, 816, 758, 717, 668, 633 cm^À^{1 1}H NMR (400 MHz,

;

CDCl₃): d=7.20 (s, 2H), 6.70 (s, 2H), 6.25 (d, J=2.4 Hz, 1H), 6.12 (d,

J=2.4 Hz, 1H), 5.66 (brs, 1H), 5.09 (s, 1H), 3.85 (s, 3H), 3.85 (s, 3H),

3.80 (s, 6H), 3.79 (s, 3H), 3.71 (s, 6H), 3.05 (brs, 1H), 3.04 (brs, 1H);

¹³C NMR (67.8 MHz, CDCl₃): d=165.3, 159.8, 158.9, 155.6, 153.2, 146.7,

139.5, 137.9, 133.5, 121.0, 107.0, 104.0, 100.3, 93.3, 91.9, 77.9, 68.5, 60.8,

56.5, 56.5, 56.1, 55.4, 26.0 ppm; HRMS (ESI-TOF): m/z (%) calcd for

C₂₉H₃₃O₁₁: 557.2023 [M+H]⁺; found: 557.2022.

[5] a) M. A. Shammas, P. Neri, H. Koley, R. B. Batchu, R. C. Bertheau,

V. Munshi, R. Prabhala, M. Fulciniti, Y. T. Tai, S. P. Treon, R. K.

Goyal, K. C. Anderson, N. C. Munshi, Blood 2006 , 108 , 280 4 –2 810;

b) D. Umeda, S. Yano, K. Yamada, H. Tachibana, J. Biol. Chem.

2008, 283, 3050–3058; c) D. Umeda, S. Yano, K. Yamada, H. Tachi-

bana, Biochem. Biophys. Res. Commun. 2008 , 371 , 17 2 –1 76; d) D.

Umeda, H. Tachibana, K. Yamada, Biochem. Biophys. Res.

Commun. 2005 , 333 , 62 8 –6 35; e) A. Britschgi, H.-U. Simon, A.

Tobler, M. F. Fey, M. P. Tschan, Br. J. Haematol. 2010 , 149 , 5 5 –6 4.

[6] a) Y. Fujimura, K. Yamada, H. Tachibana, Biochem. Biophys. Res.

Commun. 2005 , 336 , 67 4 –6 81; b) Y. Fujimura, D. Umeda, Y. Kiyo-

hara, Y. Sunada, K. Yamada, H. Tachibana, Biochem. Biophys. Res.

Commun. 2006 , 348 , 52 4 –5 31, c) Y. Fujimura, D. Umeda, K.

Yamada, H. Tachibana, Arch. Biochem. Biophys. 2008 , 476 , 13 3 –

138.

[7] M. Maeda-Yamamoto, K. Ema, I. Shibuichi, Cytotechnology 2007 ,

55 , 13 5 –1 42.

[8] S. Yano, Y. Fujimura, D. Umeda, T. Miyase, K. Yamada, H. Tachiba-

na, J. Agric. Food Chem. 2007 , 55 , 714 4 –7 148.

[9] a) K. C. Nicolaou, J. A. Pfefferkorn, A. J. Roecker, G.-Q. Cao, S.

Barluenga, H. J. Mitchell, J. Am. Chem. Soc. 2000 , 122 , 993 9 –9 953;

b) K. C. Nicolaou, J. A. Pfefferkorn, H. J. Mitchell, A. J. Roecker, S.

Barluenga, G.-Q. Cao, R. L. Affleck, J. E. Lillig, J. Am. Chem. Soc.

2000 , 122 , 995 4 –9 967; c) M. A. Sanz, T. Voigt, H. Waldmann, Adv.

Synth. Catal. 2006 , 348 , 151 1 –1 515.

Biological Evaluation

Cell culture: B16 cells (a mouse melanoma) were maintained in Dulbec-

coꢂs modified Eagleꢂs medium (DMEM) (COSMOBIO Co. Ltd., Tokyo,

Japan) supplemented with fetal bovine serum (FBS, 5%) (Biological In-

dustries, Kibbutz Beit Kaemek, Israel) in a humidified atmosphere with

CO₂(5%) at 37^oC. To assess cell proliferation, cells were plated in 24-

well plates at a density of 1ꢁ10⁴cells/well, and 24 hours later, they were

treated with the indicated concentrations of EGCG for 96 hours in

DMEM supplemented with FBS (1%), BSA (5 mgmL^À1), superoxide dis-

mutase (5 UmL^À1), and catalase (200 UmL^À1). Cell density is adhesive

cell number per well. Cell viability was evaluated by trypan blue dye ex-

clusion assay. Values are means ÆS.D. (n=3). Data containing star

marks are significantly different from the control group at p<0.05*, p<

0.01**, and p<0.001*** (Studentꢂs t-test).

Acknowledgements

[10] a) H. van Rensburg, P. S. Heerden, D. Ferreira, J. Chem. Soc. Perkin

Trans. 1 1997 , 341 5 –3 412; b) B. Nay, V. Arnaudinaud, J. F. Peyrat,

A. Nuhrich, G. Deffieux, J. M. Merillon, J. Vercauteren, Eur. J. Org.

Chem. 2000 , 127 9 –1 283; c) N. T. Zaveri, Org Lett. 2001 , 3 , 84 3 –8 46;

d) L. Li, T. H. Chan, Org. Lett. 2001 , 3 , 73 9 –7 41; e) S.-s. Jew, D.-y.

Lim, S.-y. Bae, H.-a. Kim, J.-h. Kim, J. Lee, H.-g. Park, Tetrahedro n :

Asymmetry 2002 , 13 , 71 5 –7 20; f) J. C. Anderson, C. Headley, P. D.

Stapleton, P. W. Taylor, Tetrahedron 2005 , 61 , 770 3 –7 712; g) S. B.

Wan, Q. P. Dou, T. H. Chan, Tetrahedron 2006 , 62 , 589 7 –5 904; h) T.

Furuta, Y. Hirooka, A. Abe, Y. Sugata, M. Ueda, K. Murakami, T.

Suzuki, K. Tanaka, T. Kan, Bioorg. Med. Chem. Lett. 2007 , 17 ,

309 5 –3 098; i) K. Ohmori, M. Takeda, T. Higuchi, T. Shono K.

Suzuki, Chem. Lett. 2009 , 38 , 93 4 –9 35; j) K. Ohmori, T. Yano, K.

Suzuki, Org. Biomol. Chem. 2010 , 8 , 269 3 –2 696.

[11] The preliminary communication of the solid-phase synthesis of acy-

lated epicatechin derivatives has been reported: H. Tanaka, H.

Miyoshi, Y.-C. Chuang, Y. Ando, T. Takahashi Angew. Chem. 2007,

119, 6038–6041; Angew. Chem. Int. Ed. 2007 , 46, 593 4 –5 937; Angew.

Chem. Int. Ed. 2007, 46, 5934–5937.

[12] H-Cube was purchased by ThalesNano: R. V. Jones, L. Godorhazy,

N. Varga, D. Szalay, L. Urge, F. Darvas, J. Comb. Chem. 2006 , 8 ,

11 0 –1 16.

This work was financially supported by the Naito Foundation and Grant-

in-Aid for Scientific Research (S) (Grant-in-aid No. 22228002) from the

Ministry of Education, Culture, Sports, Science, and Technology. We

thank EIWEISS Chemical Corporation for their kind supply of EDCI.

[1] a) J. P. Nandy, M. Prakesch, S. Khadem, P. T. Reddy, U. Sharma, P.

Arya, Chem. Rev. 2009 , 109 , 199 9 –2 060; b) K. Kumar, H. Wald-

mann, Angew. Chem. 2009 , 121 , 327 2 –3 290; Angew. Chem. Int. Ed.

2009 , 48 , 322 4 –3 242; c) T. Doi, H. Tanaka, T. Takahashi, J. Synth.

Org. Chem. Jpn. 2007, 65, 795–804; d) M. Mentel, R. Breinbauer,

Top. Curr. Chem. 2007 , 278 , 20 9 –2 41; e) D. S. Tan, Comb. Chem.

High Throughput Screening 2004, 7, 631–643; f) R. Breinbauer, I. R.

Vetter, H. Waldmann, Angew. Chem. 2002 , 114 , 300 2 –3 015; Angew.

Chem. Int. Ed. 2002 , 41 , 287 8 –2 890.

[2] a) T. Doi, I. Hijikuro, T. Takahashi, J. Am. Chem. Soc. 1999 , 121 ,

674 9 –6 750; b) A. Matsuda, T. Doi, H. Tanaka, T. Takahashi, Synlett

2001 , 110 1 –1 104; c) I. Hijikuro, T. Doi, T. Takahashi, J. Am. Chem.

Soc. 2001 , 123 , 371 6 –3 722; d) H. Ohno, K. Kawamura, A. Otake, H.

Nagase, H. Tanaka, T. Takahashi, Synlett 2002 , 009 3 –0 096; e) H.

Tanaka, T. Zenkoh, H. Setoi, T. Takahashi, Synlett 2002, 1427–1430;

f) T. Takahashi, H. Nagamiya, T. Doi, P. G. Griffiths, M. Andrew,

A. M. Bray, J. Comb. Chem. 2003 , 5 , 41 4 –4 28; g) H. Tanaka, H.

Ohno, K. Kawamura, A. Ohtake, H. Nagase, T. Takahashi, Org.

Lett. 2003 , 5 , 115 9 –1 162; h) H. Tanaka, M. Moriwaki, T. Takahashi,

Org. Lett. 2003 , 5 , 380 7 –3 809; i) T. Takahashi, S. Kusaka, T. Doi, T.

Sunazuka, S. Omura, Angew. Chem. 2003 , 115 , 538 8 –5 392; Angew.

Chem. Int. Ed. 2003 , 42 , 523 0 –5 234; j) H. Tanaka, T. Hasegawa, H.

Nakahara, N. Kita, T. Shibata, S. Oe, M. Ojika, K. Uchida, T. Taka-

hashi, Chem. Asian J. 2006 , 1 , 66 9 –6 77; k) M. Kitade, H. Tanaka, S.

[13] H. Tanaka, M. Kitade, Y. Ohno, H. Tanaka, T. Takahashi, Synlett

2006, 2827–2829.

[14] K. Ohmori, K. Ushimaru, K. Suzuki, Proc. Natl. Acad. Sci. USA

2004 , 101 , 1200 2 –1 2007.

[15] F. Micheli, F. Degiorgis, A. Feriani, A. Paio, A. Pozzan, P. Zaranto-

nello, P. Seneci, J. Comb. Chem. 2001 , 3 , 22 4 –2 28.

Received: May 21, 2010

Published online: August 16, 2010

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Article Doi

Solid-phase synthesis of a combinatorial methylated (±)- epigallocatechin gallate library and the growth-inhibitory effects of these compounds on melanoma B16 cells

DOI: 10.1002/asia.201000372

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