Semisynthesis of fluoro-substituted benzoates of Epi-gallocatechin

Article abstract of DOI:10.1080/00397911.2011.585269

In the present study, four fluoro-substituted benzoates of epi-gallocatechin (EGC) were prepared through a semisynthetic strategy, and the yield of benzylation of epi-gallocatechin gallate (-)-EGCG was improved by using freshly purified (-)-EGCG as starting material and a mild base of K ₂CO₃. All structures of new compounds were characterized by ¹H NMR, ¹³C NMR, high-resolution mass spectrometry, and optical rotation.

Full text of DOI:10.1080/00397911.2011.585269

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Semisynthesis of Fluoro-substituted
Benzoates of Epi-gallocatechin
Xu Long Qin a , Xue Min Li a , Jian Yuan a , Di Chen b , Tao Jiang a
Q. Ping Dou b , Tak Hang Chan c & Sheng Biao Wan a
,
a Key Laboratory of Marine Drugs , Ministry of Education, School of
Medicine and Pharmacy, Ocean University of China , Qingdao , China
b Developmental Therapeutics Program , Barbara Ann Karmanos
Cancer Institute, and Department of Oncology, School of Medicine,
Wayne State University , Detroit , Michigan , USA
c Department of Applied Biology and Chemical Technology and
the Open Laboratory for Chiral Technology , Institute of Molecular
Technology for Drug Discovery and Synthesis, Hong Kong Polytechnic
University , Hong Kong , China
Accepted author version posted online: 08 May 2012.Published
online: 02 Aug 2012.
To cite this article: Xu Long Qin , Xue Min Li , Jian Yuan , Di Chen , Tao Jiang , Q. Ping Dou , Tak Hang
Chan & Sheng Biao Wan (2012) Semisynthesis of Fluoro-substituted Benzoates of Epi-gallocatechin,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:23, 3524-3531, DOI: 10.1080/00397911.2011.585269
To link to this article: http://dx.doi.org/10.1080/00397911.2011.585269
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Synthetic Communications1, 42: 3524–3531, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.585269
SEMISYNTHESIS OF FLUORO-SUBSTITUTED
BENZOATES OF EPI-GALLOCATECHIN
Xu Long Qin,1 Xue Min Li,1 Jian Yuan,1 Di Chen,2 Tao
Jiang,1 Q. Ping Dou,2 Tak Hang Chan,3 and Sheng Biao Wan1
1Key Laboratory of Marine Drugs, Ministry of Education, School of
Medicine and Pharmacy, Ocean University of China, Qingdao, China
2Developmental Therapeutics Program, Barbara Ann Karmanos Cancer
Institute, and Department of Oncology, School of Medicine, Wayne State
University, Detroit, Michigan, USA
3Department of Applied Biology and Chemical Technology and the Open
Laboratory for Chiral Technology, Institute of Molecular Technology for
Drug Discovery and Synthesis, Hong Kong Polytechnic University, Hong
Kong, China
GRAPHICAL ABSTRACT
Abstract In the present study, four fluoro-substituted benzoates of epi-gallocatechin (EGC)
were prepared through a semisynthetic strategy, and the yield of benzylation of epi-
gallocatechin gallate (ꢀ)-EGCG was improved by using freshly purified (ꢀ)-EGCG as
starting material and a mild base of K2CO3. All structures of new compounds were charac-
terized by 1H NMR, 13C NMR, high-resolution mass spectrometry, and optical rotation.
Keywords (ꢀ)-EGCG; fluoro-substituted benzoates of epi-gallocatechin; proteasome
inhibitor; semi-synthesis
INTRODUCTION
Epi-gallocatechin gallate [(ꢀ)-EGCG, shown in Fig. 1] has displayed the great-
est potency against the growth of four selected human tumor cell lines.[1] In addition,
a series of O-acyl derivatives of (ꢀ)-EGCG have also been semisynthesized and
Received January 10, 2011.
Address correspondence to Sheng Biao Wan, Key Laboratory of Marine Drugs, Ministry of
Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China. E-mail:
biaowan@ouc.edu.cn
3524

FLUORO-SUBSTITUTED BENZOATES
3525
Figure 1. (ꢀ)-EGCG and fluoro-substituted benzoates of EGC.
screened for their tumor inhibitory potential against 7,12-dimethylbenz[a]anthracene
(DMBA)=12-O-tetradecanoyl phorbol 13-acetate (TPA)-induced skin carcinogenesis
in Swiss albino mice.[2] Further more, the (ꢀ)-EGCG analogs of 3-O-octanoyl- or
3-O-(2-methyloctanoyl)-(ꢀ)-epi-gallo-catechins have been found to inhibit papilloma
formation 1.3 to 1.6-fold more strongly than (ꢀ)-EGCG.[3] One mechanism research
study has found that ester bond–containing green tea polyphenols, such as EGCG,
gallocatechin gallate (GCG), and epi-gallocatechin (ECG), possess the ability to
inhibit proteasome activity in vitro and in vivo.[1] The 26S proteasome is a multica-
talytic protease complex responsible for the degradation of most cellular proteins.[4,5]
Because the ubiquitin=proteasome-dependent degradation pathway plays an impor-
tant role in the up-regulation of cell proliferation and down-regulation of cell death
in human cancer cells, proteasome inhibitors have been considered as potential antic-
ancer drugs.[6] To study the structure–activity relationship of EGCG on the protea-
some inhibition, a number of (ꢀ)-EGCG analogs with various hydroxy or
methoxy substituents at B- or D-rings have been prepared and evaluated,[7] showing
that (ꢀ)-EGCG demonstrates superior proteasome-inhibitory activity among the
natural green tea polyphenols and the synthetic analogs.
In our previous study, four novel fluoro-substituted benzoates of -(EGC [1, 2, 3,
and 4 (Fig. 1)] were found to inhibit the proteasomal chymotrypsin-like activity with
potency similar to (ꢀ)-EGCG,[8] and the biological results have been reported. In this
article, we report the semisynthetic strategy and physical data of the four compounds.
RESULTS AND DISCUSSION
A semisynthetic strategy was developed in the preparation of the four
fluoro-substituted benzoates of EGC, shown in Scheme 1. First of all, freshly puri-
fied (ꢀ)-EGCG obtained through chemical modification and purification of tea poly-
phenols was used as starting material to replace commercial pure (ꢀ)-EGCG. In the
purification experiment, commercial tea polyphenols containing 40% (ꢀ)-EGCG

3526
X. L. QIN ET AL.
Scheme 1. Synthetic route of fluoro-substituted benzoates of EGC 1, 2, 3 and 4 (a): Ac2O=Py, 0 ꢁC-rt; (b):
saturated methanolic hydrogen chloride, rt; (c): BnBr=K2CO3=DMF, rt; (d): K2CO3=DME=MeOH, rt;
(e): 2-fluorobenzoyl chloride, 3-fluorobenzoyl chloride, 4-fluorobenzoyl chloride, or 3,4-difluorobenzoyl
chloride=DMAP=CH2Cl2, rt; and (f): H2=Pd=C=MeOH, rt.
were treated with acetic anhydride in pyridine at room temperature for 24 h, and a
mixture of acetylated tea polyphenols were obtained and then purified by column
chromatography on silica gel to afford pure (ꢀ)-EGCG peracetate with 81% yield
based on (ꢀ)-EGCG. Deprotection of (ꢀ)-EGCG peracetate in saturated HCl=
1
methanol provided quantitatively pure (ꢀ)-EGCG, with the same H NMR and
13C NMR spectra and optical rotation as natural (ꢀ)-EGCG. Subsequent benzyla-
tion of freshly obtained (ꢀ)-EGCG by benzyl bromide and K2CO3 in dry
dimethylformamide (DMF) at room temperature afforded key intermediate per-
benzylated (ꢀ)-EGCG 5. The yield of perbenzylated (ꢀ)-EGCG 5 from (ꢀ)-EGCG
peracetate was 45%, greater than the 25% yield of enantioselective synthesis,[9] 18%
yield of semisynthesis from commercial pure (ꢀ)-EGCG with NaH as a base, and
27% yield of semisynthesis from (ꢀ)-EGCG peracetate with NaH as a base.[10]
Then hydrolysis of 5 in K2CO3=DME=MeOH gave pentabenzylated epigallocate-
chin 6 with an 87% yield. The compounds 5 and 6 have the same configurations
as reported in total and semisynthesis.[9,10] Esterification of 6 with various fluoro-
substituted benzoyl chlorides afforded compounds 7, 8, 9, and 10. Subsequent
hydrogenolysis of 7, 8, 9, and 10 provided provided the four fluoro-substituted
benzoates of EGC 1, 2, 3, and 4, respectively, with the total yields of 28–32% based
on freshly obtained (ꢀ)-EGCG. All structures of new compounds were character-
ized by 1H NMR, 13C NMR, high-resolution mass spectrometry (HRMS), and
optical rotation.
In summary, a modified semisynthetic strategy was developed for the prep-
aration of the four fluoro-substituted benzoates of EGC. The yield of benzylation
of EGCG was improved by using freshly purified (ꢀ)-EGCG as starting material
and a mild base of K2CO3. This strategy may be helpful to synthesize more
(ꢀ)-EGCG analogs.

FLUORO-SUBSTITUTED BENZOATES
3527
EXPERIMENTAL
The starting materials and reagents, purchased from commercial suppliers,
were used without further purification. Anhydrous methylene chloride and DMF
were distilled under nitrogen from CaH2. Reaction flasks were flamedried under a
stream of N2. All moisture-sensitive reactions were conducted under a nitrogen
atmosphere. Flash chromatography was carried out using silicagel 60 (70–230 mesh).
The melting points were uncorrected. 1HNMR and 13C NMR spectra were measured
with tetramethylsilane (TMS) as an internal standard when CDCl3 and dimethylsulf-
oxide (DMSO-d6) were used as a solvent. HRMS (ESI) spectra were recorded using a
QTOF-2 micromass spectrometer.
(2 R,3 R)-5,7-Bis(acetoxy)-2-[3’,4’,5’-tris(acetoxy)phenyl]chroman-
3-yl 3,4,5-tris(acetoxy)benzoate [(ꢀ)-EGCG Peracetate]
Crude tea polyphenol (5 g) containing 40% (ꢀ)-EGCG was dissolved in a
solution of acetic anhydride (20 mL) and pyridine (18 mL) at 0 ꢁC. The mixture
was stirred at 0 ꢁC for 30 min and then was stirred at rt overnight until thin-layer
chromatography (TLC) showed the reaction had been completed. The solution
was poured into a stirred mixture of ice water (300 mL), and a solid was formed.
The mixture was filtered, and the solid was thoroughly washed by water. The solid
was then dissolved in ethyl acetate (120 mL) and washed by 2 M HCl (3 ꢂ 30 mL)
and distilled water (3 ꢂ 30 mL) respectively. The organic phase was dried by Na2SO4.
After filtration and evaporation, the residue was purified by column chromato-
graphy on silica gel to afford (ꢀ)-EGCG peracetate (2.79 g, 81% yield based on
(ꢀ)-EGCG). The spectroscopic data of the title compound were identical to those
reported in the literature.[11] Mp 110–111 ꢁC; [a]20 ꢀ44.6 (lit.[10] ꢀ42) (c ¼ 1.0,
D
CHCl3); 1H NMR (CDCl3, 600 MHz) d 7.62 (s, 2H), 7.24 (s, 2H), 6.74 (d, J ¼ 2.3 Hz,
Hz, 1H), 6.61 (d, J ¼ 2.3 Hz, 1H), 5.63 (m, 1H), 5.18 (bs, 1H), 3.06 (A of ABq,
J ¼ 17.9 Hz, 4.6 Hz, 1H), 3.00 (B of ABq, J ¼ 17.9 Hz, 2.3 Hz, 1H), 2.29 (m, 24H);
13C NMR (CDCl3, 150 MHz) d 168.8, 168.3, 167.9, 167.4, 166.2, 163.5, 154.9,
149.7, 143.3, 142.0, 141.9, 138.9, 135.3, 127.4, 124.3, 123.5, 122.2, 121.8, 109.4,
108.9, 108.0, 68.1, 25.9, 21.0, 20.7, 20.5, 20.1; HRMS (ESI) calcd for
(C38H34O19þH)þ 795.1773; found 795.1786.
(2 R,3 R)-5,7-Bis (benzyloxy)-2-[3’,4’,5’- tris(benzyloxy)phenyl]chroman-3-
yl 3,4,5-tris(benzyloxy)benzoate (5)
(ꢀ)-EGCG peracetate (2.00 g, 2.5 mmol) was dissolved in saturated methanolic
hydrogen chloride (50 mL) under an ice bath. After stirring at rt for 4 h, TLC showed
the reaction had been completed. Evaporation of solvent and hydrogen chloride
yielded a pale yellow solid (1.15 g, 99.6% yield). The spectroscopic data of the pale
yellow solid were identical to those of the synthetic (ꢀ)-EGCG reported in the litera-
ture.[9] The freshly obtained (ꢀ)-EGCG (1.15 g, 2.5 mmol) was dissolved in dry DMF
(50 mL). Potassium carbonate (7.5 g, 54.3 mmol) and benzyl bromide (6 mL,
50.4 mmol) were added successively. The mixture was stirred at rt for 48 h and then
was poured into ice water (200 mL). The mixture was extracted with EtOAc. The

3528
X. L. QIN ET AL.
organic layers were combined, dried (Na2SO4), and evaporated. The residue was
purified by flash chromatograph on silica gel and then recrystallized in petroleum
ether–EtOAc to afford 1.33 g (45% yield) of the title compound 5 as a white solid.
The spectroscopic data of compound 5 were identical to those reported in the litera-
ture.[9] Mp 117–118 ꢁC; [a]20D ꢀ44.6 (c ¼ 1.0, CHCl3) (lit.[9] ꢀ45); 1H NMR (CDCl3,
600 MHz) d 7.41 (m, 42H), 6.72 (bs, 2H), 6.39 (d, J ¼ 2.3 Hz, 1H), 6.34 (d, J ¼ 2.3 Hz,
1H), 5.67 (m, 1H), 5.05 (m, 17H), 3.12 (A of ABq, J ¼ 17.9 Hz, 4.6 Hz, 1H), 3.06 (B
of ABq, J ¼ 17.9 Hz, 2.3 Hz, 1H); 13C NMR (DMSO-d6, 150 MHz) d 158.8, 158.3,
155.1, 153.0, 138.3, 137.8, 136.9, 133.7, 128.6, 127.2, 106.1, 100.9, 94.6, 94.1, 78.5,
75.2, 71.3, 70.1, 69.9, 66.4, 28.1; HRMS (ESI) calcd. for (C78H66O11 þ H)þ
1179.4683; found 1179.4671.
(2R,3R)-5,7-Bis (Benzyloxy)-2-[3’,4’,5’-tris
(benzyloxy)phenyl]chroman-3-ol (6)
Compound 5 (0.5 g, 0.4 mmol) was dissolved in a solution of methanol (10 mL)
and ethylene glycol dimethyl ether (10 mL), and then potassium carbonate (0.2 g,
1.4 mmol) was added successively. The resulting mixture was stirred at rt for 1 h until
TLC showed the reaction had been completed. The solvent was evaporated, and the
residue was purified by flash chromatography on silica gel to afford the desired com-
pound 6 (0.28 g, 87% yield). The spectroscopic data of compound 6 were identical to
those reported in the literature.[9] Mp 131–132 ꢁC; [a]20 ¼ ꢀ9.60 (c ¼ 1.0, CHCl3);
D
1H NMR (CDCl3, 600 MHz) d 7.43 (m, 25H), 6.78 (s, 2H), 6.28 (s, 2H), 5.13 (m,
10H), 4.89 (bs, 1H), 4.21 (bs, 1H), 3.01 (A of ABq, J ¼ 17.5 Hz, 1.9 Hz, 1H), 2.93
(B of ABq, J ¼ 17.5 Hz, 4.6 Hz, 1H); 13C NMR (DMSO-d6, 150 MHz) d 158.8,
158.3, 155.1, 153.0, 138.3, 137.8, 136.9, 133.7, 128.6, 127.2, 106.1, 100.9, 94.6,
94.1, 78.5, 75.2, 71.3, 70.1, 69.9, 66.4, 28.1. HRMS (ESI) calcd. for (C50H44O7þH)þ
757.3165:found 757.3177.
(2 R,3 R)-5,7-Bis(benzyloxy)-2-[3’,4’,5’-tris(benzyloxy)phenyl]chroman-
3-yl 2-Fluorobenzoate (7)
Oxalyl chloride (5 mL) was added, to a solution of 2-fluorobenzoic acid (1.4 g,
10.0 mmol) in dry CH2Cl2(50 mL), and then one drop of DMF was added. The mix-
ture was refluxed for 5 h. After evaporation of oxalyl chloride, the resulting oil was
dried completely under a reduced pressure for 2 h. The desired solid was dissolved in
dry CH2Cl2(10 mL) and then added dropwise into a solution of compound 6 and
dimethylaminopgridine (DMAP) (0.40 g) in CH2Cl2(20 mL) at 0 ꢁC. The mixture
was stirred at rt overnight, the solvent was evaporated, and the resulting mixture
was purified by flash chromatography on silica gel to give the desired compound 7
(0.90 g, 89% yield). Mp 113–115 ꢁC; [a]20D ꢀ56.8 (c ¼ 1.0, CHCl3); 1H NMR (CDCl3,
600 MHz) d 7.84 (m, 1H), 7.45 (m, 2H), 7.41 (m, 21H), 7.22 (m, 3H), 7.12 (m, 1H),
7.06 (m, 1H), 6.85 (bs, 2H), 6.34 (d, J ¼ 2.3 Hz, 1H), 6.29 (d, J ¼ 2.3 Hz, 1H), 5.67 (m,
1H), 5.06 (m, 11H), 3.13 (d, J ¼ 3.7 Hz, 2H); 13C NMR (CDCl3, 150 MHz) d 163.2,
161.2, 158.8, 157.9, 155.5, 152.8, 138.2, 137.8, 137.0, 136.8, 136.8, 134.7, 134.7, 133.2,
132.3, 128.4, 128.1, 127.2, 123.9, 118.4, 117.0, 106.5, 100.7, 94.7, 93.9, 77.6, 75.1,

FLUORO-SUBSTITUTED BENZOATES
3529
71.2, 70.1, 69.9, 68.9, 58.5, 26.0, HRMS (ESI) calcd. for (C57H47FO8þH)þ 879.3333;
found 879.3345.
(2 R,3 R)-5,7-Bis(benzyloxy)-2-[3’,4’,5’-tris(benzyloxy)
phenyl]chroman-3-yl 3-Fluorobenzoate (8)
Following the procedure used for the preparation of compound 7, but with
3-fluorobenzoic acid as starting material, the title compound 8 was obtained (91%
1
yield) as a white solid. Mp 113–115 ꢁC; [a]20 ꢀ72.9 (c ¼ 1.0, CHCl3); H NMR
D
(CDCl3, 600 MHz) d 7.76 (d, J ¼ 7.8 Hz, 1H), 7.65 (d, J ¼ 8.7 Hz, 1H), 7.45 (m,
2H), 7.41 (m, 25H), 6.79 (bs, 2H), 6.34 (d, J ¼ 2.3 Hz, 1H), 6.30 (d, J ¼ 2.3 Hz,
1H), 5.65 (m, 1H), 5.08 (m, 11H), 3.14 (A of ABq, J ¼ 17.9 Hz, 4.6 Hz, 1H), 3.09
(B of ABq, J ¼ 17.9 Hz, 2.3 Hz, 1H); 13C NMR (CDCl3, 150 MHz) d 164.2, 163.2,
158.8, 157.8, 155.3, 152.8, 138.1, 137.6, 136.8, 136.7, 136.7, 133.0, 132.1, 130.0,
128.5, 128.0, 127.3, 127.1, 125.5, 120.1, 116.5, 106.3, 100.6, 94.7, 94.0, 75.0, 71.1,
70.0, 69.9,68.9, 25.9, HRMS (ESI) calcd. for (C57H47FO8 þ H)þ 879.3333; found
879.3339.
(2 R,3 R)-5,7-Bis(benzyloxy)-2-[3’,4’,5’-tris(benzyloxy)
phenyl]chroman-3-yl 4-Fluorobenzoate (9)
Following the procedure used for the preparation of 7, but with 4-fluoroben-
zoic acid as starting material, the title compound 9 was obtained (90% yield) as a
white solid. Mp 102–104 ꢁC: [a]20 ꢀ61.1 (c ¼ 1.0, CHCl3); 1H NMR (CDCl3,
D
600 MHz) d 7.97 (m, 2H), 7.45 (m, 2H), 7.41 (m, 23H), 7.05 (m, 2H), 6.79 (bs,
2H), 6.34 (d, J ¼ 2.3 Hz, 1H), 6.30 (d, J ¼ 2.3 Hz, 1H), 5.67 (m, 1H), 5.08 (m,
11H), 3.13 (A of ABq, J ¼ 17.9 Hz, 4.6 Hz, 1H), 3.08 (B of ABq, J ¼ 17.9 Hz,
2.3 Hz, 1H); 13C NMR (CDCl3, 150 MHz) d 166.6, 164.9, 164.4, 158.8, 158.0,
155.4, 152.8, 138.2, 137.7, 136.9, 136.8, 136.7, 133.2, 132.3, 132.2, 128.6, 127.2,
126.2, 115.6, 115.4,106.5, 100.8, 94.7, 93.9, 77.6, 75.1, 71.2, 70.1, 69.9, 68.5, 26.1,
HRMS (ESI) calcd. for (C57H47FO8þH)þ 879.3333; found 879.3325.
(2 R,3 R)-5,7-Bis(benzyloxy)-2-[3’,4’,5’-tris(benzyloxy)phenyl]
chroman-3-yl 3,4-Difluorobenzoate (10)
Following the procedure used for the preparation of 7, but with 3,4-difluoro-
benzoic acid as starting material, the title compound 10 was obtained (88% yield).
Mp 121–122 ꢁC; [a]20 ꢀ60.4 (c ¼ 1.0, CHCl3); 1H NMR (CDCl3, 600 MHz) d
D
7.67 (m, 1H), 7.64 (m, 1H), 7.43 (m, 25H), 7.27 (m, 1H), 6.74 (s, 2H), 6.30 (d,
J ¼ 2.3 Hz, 1H), 6.29 (d, J ¼ 2.3 Hz, 1H), 5.49 (m, 1H), 5.15 (d, J ¼ 11.8 Hz, 1H),
5.10 (d, J ¼ 11.8 Hz, 1H), 5.07 (s, 2H), 5.02 (d, J ¼ 1.8 Hz, 1H), 5.01 (d, J ¼ 1.8 Hz,
1H), 3.03–3.00 (m, 2H); 13C NMR (CDCl3, 150 MHz) d 164.2, 163.2, 160.0, 158.9,
157.9, 155.1, 152.7, 138.2, 137.7, 137.0, 136.7, 136.7, 132.8, 128.6, 128.5, 128.4,
128.1-127.2, 106.2, 100.2, 94.6, 94.1, 77.2, 77.0, 75.1, 71.1, 70.1, 69.9, 67.4, 26.1,
HRMS (ESI) calcd. for (C57H46F2O8þH)þ 897.3239; found 897.3227.

3530
X. L. QIN ET AL.
(2 R,3 R)-5,7-Bis(hydroxyl)-2-[3’,4’,5’-tris(hydroxy)phenyl]
chroman-3-yl 2-Fluorobenzoate (1)
Under a hydrogen atmosphere, 10% Pd=C (50 mg) was added to a solution of
compound 7 (0.50 g, 0.57 mmol) in methanol (20 mL) and ethyl acetate (20 mL). The
resulting mixture was stirred at room temperature for 5 h until TLC showed that the
reaction had been completed. Then the mixture was filtered to remove the catalyst.
The filtrate was evaporated in vacuum to afford the desired compound 1 (0.22 g, 91%
yield). Mp 157–159 ꢁC; [a]20 ꢀ74.3 (c ¼ 1.0, CH3OH); 1H NMR (DMSO-d6,
D
600 MHz) d 8.29 (s, 1H), 8.08 (s, 1H), 7.79 (s, 2H), 7.76 (m, 1H), 7.57 (m, 1 H),
7.29 (bs, 1H), 7.20 (m, 1H), 7.15 (m, 1H), 6.63 (bs, 2H), 6.04 (d, J ¼ 2.3 Hz, 1H),
6.00 (d, J ¼ 2.3 Hz, 1H), 5.64 (m, 1H), 5.11 (s, 1H), 3.08 (A of ABq, J ¼ 17.9 Hz,
4.6 Hz, 1H), 2.90 (B of ABq, J ¼ 17.9 Hz, 2.3 Hz, 1H); 13C NMR (DMSO-d6,
150 MHz) d 164.7, 162.2, 157.7, 157.6, 157.0, 146.7, 135.8, 133.7, 132.8, 130.6,
125.1, 119.6, 117.8, 106.6, 99.1, 96.5, 95.8, 78.2, 70.9, 26.6. HRMS (ESI) calcd. for
(C22H17FO8 þ H)þ 429.0986; found 429.0997.
(2 R,3 R)-5,7-Bis(hydroxyl)-2-[3’,4’,5’-tris(hydroxy)phenyl]
chroman-3-yl 3-Fluorobenzoate (2)
Following the procedure used for the preparation of 1, but with compound 8 as
starting material, compound 2 was obtained (89% yield). Mp 131–133 ꢁC; [a]20
ꢀ
D
1
78.7 (c ¼ 1.0, CH3OH); H NMR (DMSO-d6, 600 MHz) d 7.68 (m, 1H), 7.51 (m,
1H), 7.41 (m, 1H), 7.26 (m, 1H), 6.49 (bs, 2H), 5.97 (d, J ¼ 2.3 Hz, 1H), 5.95 (d,
J ¼ 2.3 Hz, 1H), 5.56 (m, 1H), 5.00 (m, 1H), 3.01 (A of ABq, J ¼ 17.9 Hz, 4.6 Hz,
1H), 2.97 (B of ABq, J ¼ 17.9 Hz, 2.3 Hz, 1H); 13C NMR (DMSO-d6, 150 MHz) d
166.0, 164.5, 157.8, 157.7, 157.0, 146.7, 133.6, 133.5, 131.4, 130.6, 126.4, 121.0,
117.0, 107.0, 99.1, 96.5, 95.8, 78.2, 71.1, 26.5, HRMS (ESI) calcd for
(C22H17FO8þH)þ 429.0986; found 429.0995.
(2 R,3 R)-5,7-Bis(hydroxyl)-2-[3’,4’,5’-tris(hydroxy)phenyl]
chroman-3-yl 4-Fluorobenzoate (3)
Following the procedure used for the preparation of 1, but with compound 9 as
starting material, compound 3 was obtained (80% yield). Mp 134–136 ꢁC; [a]20
ꢀ
D
1
71.4 (c ¼ 1.0, CH3OH); H NMR (DMSO-d6, 600 MHz) d 7.95 (m, 2H), 7.18 (m,
2H), 6.62 (bs, 2H), 6.04 (d, J ¼ 2.3 Hz, 1H), 6.03 (d, J ¼ 2.3 Hz, 1H), 5.59 (m, 1H),
5.10 (s, 1H), 3.08 (A of ABq, J ¼ 17.9 Hz, 4.6 Hz, 1H), 2.95 (B of ABq, J ¼ 17.9 Hz,
Hz, 2.3 Hz, 1H); 13C NMR (DMSO-d6, 150 MHz) d 118.0, 116.3, 157.9, 157.1, 146.8,
133.7, 133.4, 133.3, 130.7, 127.8, 116.5, 116.3, 106.6, 99.1, 96.5, 95.8, 78.4, 70.9, 26.6,
HRMS (ESI) calcd. for (C22H17FO8þH)þ 429.0986; found 429.0976.
(2 R,3 R)-5,7-Bis(hydroxyl)-2-[3’,4’,5’-tris (hydroxy)phenyl]
chroman-3-yl 3,4-Difluoro-benzoate (4)
Following the procedure used for the preparation of 1, but with compound 10 as
starting material, compound 4 was obtained (88% yield). Mp 136–138ꢁC; [a]20D ꢀ72.3

FLUORO-SUBSTITUTED BENZOATES
3531
(c ¼ 1.0, CH3OH); 1H NMR (DMSO-d6, 600 MHz): d 8.35 (s, 1H), 8.15 (s, 1H), 7.74 (s,
1H), 7.73 (m, 2H), 7.43 (m, 2H), 7.29 (bs, 1H), 6.69 (bs, 2H), 6.05 (d, J ¼ 2.3 Hz, 1H),
6.03 (d, J ¼ 2.3, 1H), 5.61 (m, 1H), 5.11 (s, 1H), 3.03 (m, 2H); 13C NMR (DMSO-d6,
150 MHz) d 165.2, 158.0, 157.8, 157.1, 153.9, 150.4, 146.8, 133.7, 130.6, 128.8, 128.0,
119.0, 106.5, 99.0, 96.6, 95.8, 78.3, 71.3, 26.6, HRMS (ESI) calcd for
(C22H16F2O8þH)þ 447.0891; found 447.0882.
ACKNOWLEDGMENTS
This research is supported by Key International S&T Cooperation Projects
(2009DFA32080) of the Ministry of Science and Technology of the People’s Repub-
lic of China and by Shandong Provincial Key Laboratory of Glycoscience and
Glycotechnology. This project is also partly funded by the Special Fund for Marine
Scientific Research in the Public Interest (201005024), and the Program for
Changjiang Scholars and Innovative Research Team in University (IRT0944).
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