Synthesis of 2-chloro-4-nitrophenyl α-L-fucopyranoside: A substrate for α-L-fucosidase (AFU)

Article abstract of DOI:10.1016/S0008-6215(03)00244-1

An effective method to prepare the substrate of α-L-fucosidase (AFU) is described. Ethyl 1-thiofucoside with a free 2-OH group was used as the glycosyl donor, and there was found no self-condensed side product. The use of the HF·pyridine reagent to remove

Full text of DOI:10.1016/S0008-6215(03)00244-1

Carbohydrate Research 338 (2003) 1603Á1607
/
www.elsevier.com/locate/carres
Note
Synthesis of 2-chloro-4-nitrophenyl a-
L
-fucopyranoside: a substrate
for a-
L
-fucosidase (AFU)
Guofeng Gu,a Yuguo Du,a,* Hongyan Hu,b Cheng Jinb
a Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Academia Sinica, 18 Shuangqing Road Haidian District, P.O. Box
2871, Beijing 100085, PR China
b Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080, PR China
Received 28 February 2003; accepted 8 May 2003
Abstract
An effective method to prepare the substrate of a-
L-fucosidase (AFU) is described. Ethyl 1-thiofucoside with a free 2-OH group
was used as the glycosyl donor, and there was found no self-condensed side product. The use of the HF×
/
pyridine reagent to remove
the silyl protecting group in the last step afforded a target molecule of high purity.
# 2003 Elsevier Ltd. All rights reserved.
Keywords: a-L-Fucosidase; Hepatocellular carcinoma; Glycosylation
Glycosidases are involved in the metabolism of a wide
range of biologically essential oligo- and polysacchar-
ides.1 What attracts chemists is how to control the
biological processes of the glycosidases through suitable
a new way to synthesize the target compound efficiently.
We present herein a method to prepare NCP a-L-
fucopyranoside in good overall yield and with complete
stereoselectivity.
substrates or potent inhibitors.2 a-
L-Fucosidase (AFU),
The synthetic route is as shown in Scheme 1. As
known, an a-glycosidic bond is best formed using a
glycosyl donor with a nonparticipating group on C-2.8
Following this idea, fully benzylated 1-thiofucopyran-
oside 19 and commercially available 2-chloro-4-nitro-
phenol was condensed in anhydrous CH2Cl2 in the
presence of TMSOTf to afford 2-chloro-4-nitrophenyl
which is one type of hydrolyase, is found widely
distributed in many organisms. Recent research has
demonstrated that AFU in blood serum plays an
important role in diagnosing hepatocellular carcinoma
(HCC).3Á6 In 1992, Kasai and coworkers first reported
the synthesis of 2-chloro-4-nitrophenyl a-
oside (NCP a- -fucopyranoside) as a substrate for
AFU.7 In a collaborative project, we needed to prepare
pure NCP a- -fucopyranoside for enzyme kinetic stu-
dies. When we tried the above-mentioned method for
the making of NCP a- -fucopyranoside, we found that
L-fucopyran-
2,3,4-tri-O-benzyl-a-
L-fucopyranoside (2) in 71% yield.
L
However, hydrogenation of compound 2 with 20%
Pd(OH)2-on-charcoal under an H2 atmosphere (1 atm)
for 10 h, yielded 2-chloro-4-aminophenyl 2,3,4-tri-O-
L
benzyl-a-
L-fucopyranoside (3, 77%), based on MAL-
L
1
DITOF-MS and H NMR spectral analysis. We found
no debenzylated product under these hydrogenation
conditions. 1H NMR spectra of compounds 2 and 3
showed that the chemical shifts of the aromatic protons
moved from downfield (d 8.29, 8.08, 7.30) to upfield (d
6.99, 6.48, 6.72, respectively). We then turned our
attention to the silyl-protected fucopyranosyl donors.
it was technically challenging, and we got only a
moderate yield of an a,b mixture of product, with the
a anomer predominating. This prompted us to look for
* Corresponding author. Tel.: ꢀ
10-62923563.
E-mail address: duyuguo@mail.rcees.ac.cn (Y. Du).
/
86-10-62914475; fax: ꢀ86-
/
Silylation of ethyl 1-thio-b-
L-fucopyranoside with tert-
0008-6215/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0008-6215(03)00244-1

1604
G. Gu et al. / Carbohydrate Research 338 (2003) 1603Á1607
/
Scheme 1. Reagents and conditions: (a) NIS, TMSOTf, CH2Cl2; 71% for 2; 61% for 6; 8% for 7; 26% for 8; (b) H2, Pd(OH)2/C,
MeOHÁ
pyridine, CH3CN; 68% from 10.
/
EtOAc; 77% for 3; (c) TBDMSCl, imidazol, DMF, 78% for 4; (d) Ac2O, Py; 20% for 5; (e) TBAF, THF; 73% for 9; (f) HF×
/
butylchlorodimethylsilane (TBSCl, 3.0 equiv) and imi-
dazole (6.0 equiv) in dry DMF surprisingly afforded 3,4-
di-O-disilylated thiofucopyranoside (4). The correct
position of the TBSs on 4 was further confirmed by a
NMR spectra confirmed the structure assignments. As
for byproduct 8, we rationalized that it was generated
from the condensation of intermediates, i.e., 1,2-anhy-
dro-3,4-di-O-tert-butyldimethylsilyl-a-L-fucopyranose
and deiodinated NIS. Removal of TBS from compound
1
downfield shift of H-2 (d 5.34 ppm, J 9.4 Hz) in the H
NMR spectra of its acetylated derivative 5. It should be
noted that the complete acetylation of compound 4,
even with acetic anhydride in pyridine in the presence of
DMAP, was very difficult. Only about 20% of 4 was
converted to 5 at 60 8C for 20 h. We ascribed this to the
steric hindrance to OH-2 caused by adjacent b-thioethyl
and bulky TBS groups. Although we could not gain a
fully silylated donor,10 we thought that compound 4
might be a good donor extended from our former
project on 1,2-anhydrosugars.11 Coupling of disilylated
1-thiofucopyranoside 4 and 2-chloro-4-nitrophenol in
anhydrous CH2Cl2 with 1.1 equiv of NIS and a catalytic
amount of TMSOTf (5% equiv) under standard glyco-
sylation conditions afforded 2-chloro-4-nitrophenyl 3,4-
6 with TBAF in THF afforded 2-chloro-4-nitrophenyl
b-L-fucopyranoside (9) in a high yield. The chemical
shift of H-1 for 9 appears at d 4.80 in the H NMR
1
spectrum (J1,2 7.6 Hz), which confirms b-bond forma-
tion. HCl (gas, 3% w/v), AcOH and BF3×
tried, but none of these reagents gave satisfactory
pyridine complex12 was found
/
Et2O were also
results. Finally, the HF×
/
to be the best neutral reagent to thoroughly deprotect
TBS from 9 to smoothly give the desired 2-chloro-4-
nitrophenyl a-
age shown in the 1H NMR spectrum (d 5.71 ppm, J 3.1
Hz, H-1) and the MALDITOF-MS ([Mꢀ
Na]ꢀ: 342.3)
L
-fucopyranoside (10, 68%). The a-link-
/
of compound 10 confirmed the correct structure of the
target molecule.
In summary, we have described a method for prepar-
di-O-tert-butyldimethylsilyl-a-
L-fucopyranoside (6) as
the major component (61% of isolated yield), accom-
panied with 8% of isomer 2-chloro-4-nitrophenyl 3,4-di-
ing of pure AFU substrate, 2-chloro-4-nitrophenyl a-
fucopyranoside, using a partially silylated 1-thiofuco-
pyranoside as donor. The HF×pyridine complex was
L-
O-tert-butyldimethylsilyl-b-
L
-fucopyranoside (7) and
-fuco-
/
26% of N-(3,4-di-O-tert-butyldimethylsilyl-b-
L
shown to be the best reagent to remove TBS-protecting
groups in this case. Large-scale preparation of com-
pound 10 can be performed by this method.
pyranosyl)succinimide (8). Chemical shifts of H-1s (d
1
5.52, J 2.6 Hz of 6; d 5.05, J 7.3 Hz of 7) in the H

G. Gu et al. / Carbohydrate Research 338 (2003) 1603Á
/1607
1605
1. Experimental
1.1. General methods
(d, 1 H, 8.6 Hz, Ar), 7.23Á
Calcd for C33H34ClNO5: C, 70.77; H, 6.12. Found: C,
70.40; H, 6.09.
/
7.40 (m, 15 H, Ph). Anal.
Optical rotations were determined at 20 8C with a
PerkinÁElmer Model 241-Mc automatic polarimeter.
1.4. Ethyl 3,4-di-O-tert-butyldimethylsilyl-1-thio-b-L-
fucopyranoside (4)
/
1H and 13C NMR spectra were recorded with ARX 400
spectrometers for solutions in CDCl3. Chemical shifts
are given in d-units (ppm) downfield from internal
Me4Si. Mass spectra were measured using MALTITOF-
MS with dihydroxybenzoic acid (DHB) as matrix.
Thin-layer chromatography (TLC) was performed
on silica gel HF254 with detection by charring with
30% (v/v) H2SO4 in MeOH or in some cases by a UV
lamp.
Compound 1 (1.04 g, 5 mmol) was dissolved in N,N-
dimethylformamide (DMF, 5 mL). To the solution was
added imidazole (2.04 g, 30 mmol) and TBSCl (2.26 g,
15 mmol) at 0 8C. The mixture was stirred at 0 8C for 30
min, then it was heated to 40 8C, and stirred for another
12 h, diluted with water (50 mL) and extracted with
EtOAc (3ꢂ
anhyd Na2SO4 and concentrated. Purification of the
residue on a silica gel column (20:1 petroleum etherÁ
/50 mL). The organic phase was dried over
/
1.2. 2-Chloro-4-nitrophenyl 2,3,4-tri-O-benzyl-a-
fucopyranoside (2)
L
-
EtOAc) gave 4 (2.08 g, 78%) as a syrup: [a]D20
ꢀ258 (c 2,
/
CHCl3); 1H NMR (CDCl3): d 0.09, 0.14, 0.17 (3 s, 12 H,
2 (CH3)2Si), 0.92, 0.94 (2 s, 18 H, 2 (CH3)3C), 1.23 (d, 3
H, J5,6 6.4 Hz, H-6), 1.28 (t, 3 H, J 7.4 Hz, CH3CH2S),
To a solution of compound 1 (500 mg, 1.05 mmol) and
2-chloro-4-nitrophenol (200 mg, 1.16 mmol) in anhyd
CH2Cl2 (3 mL) was added NIS (260 mg, 1.16 mmol) and
TMSOTf (10 mL, 0.05 mmol) under an N2 atmosphere
2.60Á
J3,4 2.7 Hz, H-3), 3.56 (q, 1 H, J5,6 6.4 Hz, H-5), 3.64 (t,
1 H, J1,2 J2,3 9.1 Hz, H-2), 3.78 (d, 1 H, J3,4 2.7 Hz,
/2.75 (m, 2 H, CH3CH2S), 3.44 (dd, 1 H, J2,3 9.1,
ꢃ
/
ꢃ
/
at ꢁ
/
42 8C. The mixture was stirred for 30 min under
H-4), 4.22 (d, 1 H, J1,2 9.1 Hz, H-1). Anal. Calcd for
C20H44O4SSi2: C, 54.99; H, 10.15. Found: C, 55.26; H,
10.41.
these conditions, neutralized with Et3N, and concen-
trated. The residue was subjected to a silica gel column
with 10:1 petroleum etherÁEtOAc as the eluent to
/
afford syrupy 2 (439 mg, 71%): [a]D20
ꢀ
/
1138 (c 1,
1.5. Ethyl 2-O-acetyl-3,4-di-O-tert-butyldimethylsilyl-1-
thio-b-L-fucopyranoside (5)
1
CHCl3); H NMR (CDCl3): d 1.23 (d, 3 H, J5,6 6.5
Hz, H-6), 3.67Á
H-3, H-4), 4.41Á
H, J 11.6 Hz, one proton of PhCH2), 4.61Á
three protons of PhCH2), 5.70 (d, 1 H, J1,2 1.3 Hz, H-1),
7.23Á7.35 (m, 16 H, Ph and Ar), 8.08 (dd, 1 H, J 2.7, 9.2
/
3.73 (m, 1 H, H-5), 4.11Á
4.47 (m, 3 H, H-2, PhCH2), 4.45 (d, 1
4.69 (m, 3 H,
/
4.17 (m, 2 H,
/
A mixture of compound 4 (22 mg, 0.05 mmol), py (2
mL) and Ac2O (1 mL) was stirred at 60 8C for 10 h, then
evaporated with toluene to dryness under reduced
pressure. Column chromatography (20:1 petroleum
/
/
Hz, Ar), 8.29 (d, 1 H, J 2.7 Hz, Ar). Anal. Calcd for
C33H32ClNO7: C, 67.17; H, 5.47. Found: C, 67.42; H,
5.39.
etherÁEtOAc) of the residue afforded recovered 4 and
/
1
syrupy product 5 (5 mg, 20%): H NMR (CDCl3): d
0.09, 0.14, 0.18 (3 s, 12 H, 2 (CH3)2Si), 0.92, 0.93 (2 s, 18
H, 2 (CH3)3C), 1.23 (d, 3 H, J5,6 6.4 Hz, H-6), 1.28 (t, 3
1.3. 2-Chloro-4-aminophenyl 2,3,4-tri-O-benzyl-a-
fucopyranoside (3)
L
-
H, J 7.4 Hz, CH3CH2S), 2.61Á2.74 (m, 2 H, CH3CH2S),
3.46 (dd, 1 H, J1,2 9.4, J2,3 2.7 Hz, H-3), 3.55 (q, 1 H, J5,6
6.4 Hz, H-5), 3.77 (d, 1 H, J3,4 2.7 Hz, H-4), 4.23 (d, 1 H,
/
To a solution of compound 2 (415 mg, 0.71 mmol) in 2:1
MeOHÁEtOAc (6 mL) was added Pd(OH)2/C (40 mg).
J1,2 9.4 Hz, H-1), 5.34 (t, 1 H, J1,2
ꢃ
/
J2,3
Anal. Calcd for C22H46O5SSi2: C, 55.18; H, 9.68.
ꢃ9.4 Hz, H-2).
/
/
The mixture was stirred under an H2 flow (80 mL/min)
for 10 h at room temperature, at the end of which time
TLC showed disappearance of the starting material. The
mixture was filtered, and the filtrate was concentrated
and purified on a silica gel column using 3:1 petroleum
Found: C, 55.53; H, 9.49.
1.6. 2-Chloro-4-nitro-phenyl 3,4-di-O-tert-
butyldimethylsilyl-a-L-fucopyranoside (6), 2-chloro-4-
nitrophenyl 3,4-di-O-tert-butyldimethylsilyl-b-
L-
etherÁ
syrup: [a]2D0
1.24 (d, 3 H, J5,6 6.4 Hz, H-6), 3.50Á
NH2), 3.69Á3.73 (m, 1 H, H-5), 4.06 (dd, 1 H, J 3.6, 7.4
Hz, H-3), 4.25 (dd, 1 H, J 3.8, 7.4 Hz, H-2), 4.36 (dd, 1
H, J 1.2, 3.6 Hz, H-4), 4.42, 4.49, 4.54, 4.58, 4.61, 4.71 (6
d, 6 H, PhCH2), 5.51 (d, 1 H, J 3.8 Hz, H-1), 6.48 (dd, 1
H, J 2.7, 8.6 Hz, Ar), 6.72 (d, 1 H, J 2.7 Hz, Ar), 6.99
/
EtOAc as a eluent to give 3 (306 mg, 77%) as a
fucopyranoside (7) and N-(3,4-di-O-tert-
butyldimethylsilyl-b-L-fucopyranosyl)succinimide (8)
1
ꢀ
/
758 (c 0.8, CHCl3); H NMR (CDCl3): d
/3.56 (br s, 2 H,
/
Compound 4 (2.0 g, 3.73 mmol) and 2-chloro-4-nitro-
phenol (712 mg, 4.1 mmol) were placed in a pre-dried in
a flask under vacuum at 60 8C. The mixture was
dissolved in anhyd CH2Cl2 (10 mL), followed by the
addition of NIS (923 mg, 4.01 mmol) and TMSOTf (30

1606
G. Gu et al. / Carbohydrate Research 338 (2003) 1603Á1607
/
mL, 0.19 mmol) under an N2 atmosphere at ꢁ
/
42 8C. The
1.8. 2-Chloro-4-nitrophenyl a-L-fucopyranoside (10)
mixture was then stirred for 30 min under these
conditions, neutralized with Et3N, and concentrated to
dryness. The residue was purified on a silica gel column
Compound 6 (1.0 g, 1.54 mmol) was dissolved in py (4
mL) and MeCN (15 mL). To the solution was added
using 30:1Á
/
20:1 petroleum etherÁ
/
EtOAc as the eluent to
afford syrupy 6 (1.25 g, 61%), 7 (163 mg, 8%), and 8 (528
HF×
/
Py (15 mL, 70%), and the mixture was stirred at
0 8C for 20 h, at the end of which time TLC indicated
the completion of the reaction. The mixture was
evaporated to dryness under reduced pressure. Purifica-
tion of the residue on a silica gel column using EtOAc as
eluent afforded 10 (335 mg, 68%) as a white solid: [a]D20
mg, 26%).
1.6.1. Compound 6.
/
[a]2D0
ꢁ
1318 (c 0.5, CHCl3); 1H
/
NMR (CDCl3): d 0.02, 0.11, 0.12, 0.17 (4 s, 12 H,
(CH3)2Si), 0.85, 0.96 (2 s, 18 H, (CH3)3CSi), 1.18 (d, 3
H, J5,6 6.5 Hz, H-6), 3.92 (br s, 1 H, H-4), 3.97 (q, 1 H,
ꢁ
/
1538 (c 1, CHCl3); 1H NMR (CDCl3): d 1.31 (d, 3 H,
J5,6 6.6 Hz, H-6), 3.94 (br s, 1 H, H-4), 4.01Á4.10 (m, 3
/
H, H-2, H-3, H-5), 5.71 (d, 1 H, J1,2 3.1 Hz, H-1), 7.40
(d, 1 H, J 9.2 Hz, Ar), 8.18 (dd, 1 H, J 9.2, 2.7 Hz, Ar),
8.32 (d, 1 H, J 2.7 Hz, Ar); 13C NMR (CDCl3, 100
MHz): d 16.11, 68.25, 68.96, 71.15, 71.34, 98.86, 115.48,
124.06, 124.25, 126.00, 142.58, 157.14. MALDITOF-
MS Calcd for C12H14ClNNaO7 [Mꢀ
Found: 342.3 [Mꢀ Anal.
J5,6 6.5 Hz, H-5), 4.11Á4.13 (m, 2 H, H-2, H-3), 5.52 (d,
/
1 H, J1,2 2.6 Hz, H-1), 7.30 (d, 1 H, J 9.2 Hz, Ar), 8.13
(dd, 1 H, J 9.2, 2.7 Hz, Ar), 8.30 (d, 1 H, J 2.7 Hz, Ar).
Anal. Calcd for C24H42ClNO7Si2: C, 52.58; H, 7.72.
Found: C, 52.71; H, 7.59.
/
Na]ꢀ: 342.05.
Calcd for
/
Na]ꢀ.
1
1.6.2. Compound 7.
/
[a]2D0
(CDCl3): d 0.11, 0.12, 0.18, 0.21 (4 s, 12 H, (CH3)2Si),
0.87, 0.96 (2 s, 18 H, (CH3)3CSi), 1.28 (d, 3 H, J5,6 6.4
ꢁ
/
538 (c 1, CHCl3); H NMR
C12H14ClNO7: C, 45.08; H, 4.41. Found: C, 44.81; H,
4.57.
Hz, H-6), 3.58Á
3.78 (q, 1 H, J5,6 6.4 Hz, H-5), 3.87 (d, 1 H, J3,4 2.5 Hz,
H-4), 4.01 (t, 1 H, J1,2 J2,3 7.3 Hz, H-2), 5.05 (d, 1 H,
/
3.63 (dd, 1 H, J2,3 7.3, J3,4 2.5 Hz, H-3),
Acknowledgements
ꢃ
/
ꢃ
/
J1,2 7.3 Hz, H-1), 7.11 (d, 1 H, J 9.2 Hz, Ar), 8.11 (dd, 1
H, J 2.7, 9.2 Hz, Ar), 8.85 (d, 1 H, J 2.7 Hz, Ar).
This work was supported by students novelty fellowship
of CAS (G.G. and H.H.) and RCEES of CAS.
MALDITOF-MS Calcd for C24H42ClNNaO7Si2 [Mꢀ
/
Na]ꢀ: 570.22. Found: 570 [MꢀNa]ꢀ.
/
1
1.6.3. Compound 8.
(CDCl3): d ꢁ0.02, 0.08, 0.10, 0.15 ( 4 s, 12 H, (CH3)2Si),
0.79, 0.94 (2 s, 18 H, (CH3)3CSi), 1.13 (d, 3 H, J 6.4 Hz,
H-6), 2.62Á2.74 (m, 4 H, ÃCH2CH2Ã), 3.89 (d, 1 H, J
/
[a]2D0
ꢁ
/
468 (c 4, CHCl3); H NMR
References
/
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/
2.8 Hz, H-4), 4.15 (dd, 1 H, J 7.4, 9.1 Hz, H-2), 4.24 (q,
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/
C22H43NNaO6Si2 [Mꢀ
/
Na]ꢀ: 496.26. Found: 496 [Mꢀ
/
/
Na]ꢀ.
/
/
1.7. 2-Chloro-4-nitrophenyl b-L-fucopyranoside (9)
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To a solution of compound 6 (150 mg, 0.274 mmol) in
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892.
/
/
etherÁ
syrup: [a]2D0
1.13 (d, 3 H, J 6.6 Hz, H-6), 3.74Á
/
EtOAc) of the residue gave 9 (64 mg, 73%) as a
1
6. Takahashi, H.; Saibara, T.; Iwamura, S.; Tomita, A.;
Maeda, T.; Onishi, S.; Yamamoto, Y.; Enzan, H. Hepa-
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/
668 (c 0.1, CHCl3); H NMR (CDCl3): d
/
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tology 1994, 19, 1414Á1417.
/
5), 3.95 (dd, 1 H, J 3.6, 9.6 Hz, H-3), 4.33 (dd, 1 H, J
7.6, 9.6 Hz, H-2), 4.80 (d, 1 H, J 7.6 Hz, H-1), 7.31 (d, 1
H, J 9.2 Hz, Ar), 8.08 (dd, 1 H, J 2.6, 9.2 Hz, Ar), 8.85
(d, 1 H, J 2.6 Hz, Ar). MALDITOF-MS Calcd for
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/
Na]ꢀ: 342. Found: 342 [Mꢀ
/
Carbohydr. Res. 1997, 303, 39Á
/49;
Na]ꢀ.
(b) Geyer, A.; Reinhardt, S.; Bendas, G.; Rothe, U.;

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¨
/420.
12. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis; 3rd ed.; Wiley: New York, 1991; p 134.
38Á40.
/