Effective protection of the N-sulfate of glucosamine derivatives with the 2,2,2-trichloroethyl group

Article abstract of DOI:10.1016/j.tetlet.2007.12.132

The 2,2,2-trichloroethyl (TCE) group was utilized as the first protecting group for N-sulfates (chlorosulfuric acid TCE ester, Et₃N, DMAP, DMF). Glycosylation with 3,4,6-tri-O-acetyl-N-trichloroethylsulfuryl-α-d-glucosaminosyl trichloroacetimid

Full text of DOI:10.1016/j.tetlet.2007.12.132

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1682–1685
Effective protection of the N-sulfate of glucosamine derivatives
with the 2,2,2-trichloroethyl group
Jianfang Chen, Biao Yu *
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Received 27 November 2007; revised 24 December 2007; accepted 25 December 2007
Available online 10 January 2008
Abstract
The 2,2,2-trichloroethyl (TCE) group was utilized as the first protecting group for N-sulfates (chlorosulfuric acid TCE ester, Et3N,
DMAP, DMF). Glycosylation with 3,4,6-tri-O-acetyl-N-trichloroethylsulfuryl-a-D-glucosaminosyl trichloroacetimidate provided the
corresponding b-glucosaminosides stereoselectively and in excellent yields. The TCE protection stayed stable under a variety of condi-
tions for the manipulation of other protecting groups, and was readily removable with zinc in the presence of ammonium chloride in
methanol.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: 2,2,2-Trichloroethyl (TCE) group; N-Sulfate; Glucosamine; Protecting group; Glycosylation
The O- and N-sulfate decoration is a prominent feature
of the heparin-like glycosaminoglycans, which are found
protein-conjugated in the extracellular matrix and free in
the circulatory system. These sulfated polysaccharides are
involved in a number of signaling functions, such as regu-
lation of the coagulation cascade, growth factor interac-
tions, and viral entry into cells, via binding to the
corresponding functional proteins.1 The ‘sulfo-form’ of
the integral fragments of the polysaccharides determines
the specific binding.2 Chemical synthesis of these oligosac-
charide fragments is highly demanding but notoriously dif-
ficult.3 Introduction of the sulfate substitutions is among
one of the major challenges in the synthesis. Convention-
ally, the sulfonation is performed at a later stage of the syn-
thesis with a sulfur trioxide-amine or -amide complex, that
requires an additional level of protective group manipula-
tion to distinguish the hydroxyl and amino groups requir-
ing sulfonation. In addition, the resulting sulfonated
products are highly polar and are difficult to manipulate
for the subsequent transformations. And multiple O- and
N-sulfonation is always difficult to complete. To by-pass
these difficulties, the sulfate substitution could be intro-
duced in a masked sulfate ester form at an early stage
and then be released at the final step. Perlin and Penney
tried phenyl as a protecting group for sulfate,4 Flitsch
et al. introduced trifluoroethyl group.5 However, deprotec-
tion of these two groups, requiring harsh conditions, is
problematic in the synthesis of complex targets.6 Recently,
Simpson and Widlanski showed that a variety of the alkyl
groups (e.g., neopentyl and isobutyl groups) could serve
the purpose.7 Taylor et al. disclosed that 2,2,2-trichloroeth-
yl (TCE) group was an ideal choice as a sulfate protecting
group for the synthesis of aryl and carbohydrate sulfates.8
Here, we report for the first time the use of TCE group as
an N-sulfate protecting group and its applicability in the
synthesis of glucosamine-N-sulfate derivatives.
Treatment of the readily available 1,3,4,6-tetra-O-acetyl-
b-D-glucosamine hydrochloride (1)9 with chlorosulfuric
acid TCE ester 28,10 in the presence of DMAP and Et3N
gave the TCE-protected D-glucosamine N-sulfate 3 in
82% yield (Scheme 1). Subjection of acetate 3 to ammonia
in THF/MeOH led to the selective removal of the anomeric
*
Corresponding author. Tel.: +86 21 54925131; fax: +86 21 64166128.
E-mail address: byu@mail.sioc.ac.cn (B. Yu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.132

J. Chen, B. Yu / Tetrahedron Letters 49 (2008) 1682–1685
1683
AcO
AcO
AcO
AcO
a
O
O
AcO
AcO
OAc
OAc
O
S
NH2HCl
NHSO3TCE
O
Cl
CCl3
c
1
3
2
O
AcO
AcO
AcO
AcO
AcO
AcO
b
O
O
TCEO3SHN
TCEO3SHN
O
CCl3
NH
OH
4
5
Scheme 1. Reagents and conditions: (a) Et3N (3.5 equiv), DMAP (1 equiv), DMF, 0 °C, 2 h, 82%; (b) NH3, THF/MeOH (7:3), 0 °C, 15 min, 81%; (c)
CNCCl3 (3.0 equiv), K2CO3 (1.2 equiv), CH2Cl2, rt, 10 h, 88%.
11
˚
O-acetyl group, providing a-lactol 4 in good yield. Treat-
ment of lactol 4 with CCl3CN in the presence of K2CO3
in CH2Cl2 afforded a-trichloroacetimidate 5 in 88% yield,
which was found stable under storage. The corresponding
b-anomers were not detected in the last two steps.
(0.1 equiv of TMSOTf, 4 A MS, CH2Cl2, rt). The results
are listed in Table 1. All the coupling reactions gave the
corresponding b-glycosides (7a–f) in satisfactory yields
(76–92%). The reaction is highly stereoselective, with no
a-anomers being detected.
The donor properties of the TCE-protected N-sulfo-glu-
cosaminosyl imidate 5 were then explored using a series of
alcohols (6a–f) as acceptors under a typical set of condi-
tions for glycosylation with trichloroacetimidates
The stability of the TCE protecting group was further
examined in the subsequent protecting group manipula-
tions (Scheme 2). The three O-acetyl groups in glycoside
7b were removed quantitatively with K2CO3 in MeOH.
Table 1
Glycosylation of alcohols (6a–f) with 3,4,6-tri-O-acetyl-N-trichloroethylsulfuryl-a-D-glucosaminosyl trichloroacetimidate (5)a
OAc
OAc
TMSOTf (0.1 equiv), 4Å MS
CH2Cl2, -20 oC
O
O
AcO
AcO
TCEO3SHN
AcO
AcO
ROH
OR
NHSO3TCE
7a-f
+
OC(NH)CCl3
6a-f
(1.0 equiv)
5 (1.3 equiv)
Entry
1
ROH
Product
H-1 (ppm, J)
Yield (%)
92
OAc
O
4.51, 8.1 Hz
HO
6a
AcO
AcO
OAll
NHSO3TCE
7a
7b
OAc
O
AcO
AcO
HO
OMe
2
3
4.93, 8.4 Hz
86
81
OMP
6b
NHSO3TCE
OAc
O
O
AcO
AcO
4.64, 8.1 Hz
HO
NHSO3TCE
7c
6c
OH
O
O
O
O
OAc
O
O
4
4.83, 8.4 Hz
86
O
O
O
AcO
AcO
O
O
O
NHSO3TCE
6d
7d
(continued on next page)

1684
J. Chen, B. Yu / Tetrahedron Letters 49 (2008) 1682–1685
Table 1 (continued)
Entry
ROH
Product
H-1 (ppm, J)
Yield (%)
76
AllO
OAll
OAc
O
5
O
4.93, 8.1 Hz
HO
O
AcO
AcO
O
O
O
O
O
6e
NHSO3TCE
7e
O
O
O
O
O
O
OH
O
6
4.75, 8.4 Hz
82
OAc
O
O
O
AcO
AcO
O
O
6f
NHSO3TCE
7f
a
˚
For a typical procedure: To a stirred mixture of 5 (220 mg, 0.33 mmol), alcohol 6b (33 mg, 0.26 mmol), and pulverized 4 A molecular sieves (300 mg) in
CH2Cl2 (3 mL) at ꢀ20 °C, was added dropwise a solution of TMSOTf in CH2Cl2 (0.1 M, 0.33 mL) under an atmosphere of Ar. After stirring for 0.5 h, the
temperature was allowed to warm up naturally to room temperature and the stirring continued for another 1.5 h. The mixture was then filtered through a
pad of Celite and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc 1.8:1) to afford 7b
(143 mg, 86%) as a white solid.
OH
O
OAc
O
a
HO
HO
AcO
AcO
OMP
OMP
NHSO3TCE
NHSO3TCE
7b
8
O
O
AcO
O
O
HO
Ph
Ph
b
O
c
O
OMP
OMP
N(Ac)SO3TCE
NHSO3TCE
10
9
Scheme 2. Reagents and conditions: (a) K2CO3 (1.0 equiv), MeOH, rt, 1 h, 100%; (b) benzaldehyde dimethyl acetal (1.2 equiv), TsOH (0.1 equiv), DMF,
40 °C, 8 h, 82%; (c) Ac2O (3.0 equiv), Et3N (5.0 equiv), DMAP, CH2Cl2, rt, 3 h, 86%.
Treatment of triol 8 with benzaldehyde dimethyl acetal
in the presence of TsOH in DMF at 40 °C provided
4,6-O-benzylidene derivative 9 in high yield. Acetylation
of 9 with Ac2O gave 10, where both the –OH and
–NH were acetylated. The N-sulfate TCE protecting
group survived well in the above acidic and basic
conditions.
Finally, the literature conditions (i.e., Zn, NH4Cl,
MeOH, rt) were found to work well on the deprotection
of the TCE group (on 8 and 12), providing the N-sulfate
derivatives (11 and 13, respectively) in excellent yields
(Scheme 3).12
In summary, the 2,2,2-trichloroethyl (TCE) group was
utilized as the first protecting group for N-sulfates. The
OH
OH
a
O
O
HO
HO
HO
HO
OMP
NHSO3TCE
OMP
-
+
NHSO3 NH4
8
11
O
O
O
O
O
OH
O
OH
O
a
b
O
7d
O
HO
HO
O
HO
HO
O
O
O
O
-
+
NHSO3TCE
NHSO3 NH4
12
13
Scheme 3. Reagents and conditions: (a) Zn dust (4 equiv), NH4Cl (7 equiv), MeOH, rt, 88% (for 11); 92% (for 13); (b) K2CO3 (1.0 equiv), MeOH, rt, 1 h,
100%.

J. Chen, B. Yu / Tetrahedron Letters 49 (2008) 1682–1685
1685
11. Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212–235.
3,4,6-tri-O-acetyl-N-trichloroethylsulfuryl-a-D-glucosamino-
syl trichloroacetimidate was readily prepared. Glycosyl-
ation with this donor provided the corresponding b-
glucosaminosides stereoselectively and in excellent yields.
The TCE protection on glucosamine-N-sulfate derivatives
stayed stable under a variety of conditions for the manipu-
lation of other protecting groups, and was readily remov-
able with zinc in the presence of ammonium chloride in
methanol.
23
12. Selected data for the new compounds. Compound 5: ½aꢁD 47.3 (c 1.0,
CHCl3); 1H NMR (CDCl3, 300 MHz): d 2.07 (s, 3H), 2.08 (s, 3H),
2.14 (s, 3H), 4.01 (dd, J = 10.8, 3.3 Hz, 1H), 4.09–4.15 (br m, 2H),
4.20–4.31 (m, 1H), 4.62 (2d, J = 11.1 Hz, 2H), 5.24 (t, J = 9.6 Hz,
1H), 5.35 (t, J = 9.9 Hz, 1H), 6.55 (d, J = 3.6 Hz, 1H), 8.91 (s, 1H);
13C NMR (CDCl3, 75 MHz): d 20.4, 20.57, 20.58, 56.1, 61.2, 67.4,
69.6, 69.9, 78.2, 90.4, 93.0, 94.4, 160.0, 169.1, 170.6, 171.6. Compound
23
7b: ½aꢁD ꢀ23.7 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): d 2.03 (s,
3H), 2.04 (s, 3H), 2.08 (s, 3H), 3.77 (s, 3H), 3.80–3.85 (m, 2H), 4.07–
4.16 (m, 2H), 4.28 (dd, J = 12.3, 5.1 Hz, 1H), 4.69 (s, 2H), 4.92 (d,
J = 5.4 Hz, 1H), 5.10 (t, J = 9.3 Hz, 1H), 5.22 (t, J = 9.9 Hz, 1H),
6.81–6.84 (m, 2H), 7.01–7.04 (m, 2H); 13C NMR (CDCl3, 75 MHz): d
20.5, 20.7, 20.8, 55.6, 58.7, 61.9, 68.5, 71.7, 72.6, 78.6, 93.2, 100.0,
114.6, 118.8, 150.4, 155.9, 169.5, 170.8, 171.6; ESIMS m/z 644.1
Acknowledgments
23
[M+Na]+. Compound 9: ½aꢁD ꢀ28.7 (c 1.0, CH3OH); 1H NMR
Financial support from the National Natural Science
Foundation of China (20572122 and 20621062) and the
Committee of Science and Technology of Shanghai
(06XD14026 and 04DZ19213) is gratefully acknowledged.
(CDCl3, 300 MHz): d 3.59–3.71 (br m, 3H), 3.75 (s, 3H), 3.83 (t,
J = 9.9 Hz, 1H), 3.99 (t, J = 9.3 Hz, 1H), 4.31 (dd, J = 10.2, 4.2 Hz,
1H), 4.93 (2d, J = 11.1 Hz, 2H), 5.15 (d, J = 8.1 Hz, 1H), 5.66 (s, 1H),
6.87 (d, J = 9.3 Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H), 7.37–7.42 (m, 3H),
7.50–7.52 (m, 2H); 13C NMR (CD3OD, 75 MHz): d 55.6, 62.1, 66.8,
68.7, 72.2, 78.8, 82.0, 94.8, 101.6, 101.9, 115.0, 118.9, 127.0, 128.6,
129.4, 138.6, 152.0, 156.1; ESIMS m/z 583.8 [M+H]+. Compound 10:
References and notes
23
½aꢁD ꢀ8.3 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): d 2.14 (s, 3H),
1. For a recent review on the heparin–protein interactions, see: Capila,
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2.60 (s, 3H), 3.68 (dd, J = 9.6, 4.5 Hz, 1H), 3.76 (s, 3H), 3.74–3.82 (m,
2H), 4.31 (dd, J = 10.5, 5.7 Hz, 1H), 4.44 (dd, J = 10.2, 7.5 Hz, 1H),
4.83 (2d, J = 10.8 Hz, 2H), 5.50 (s, 1H), 5.91 (t, J = 9.3 Hz, 1H), 6.07
(d, J = 8.1 Hz, 1H), 6.80–6.83 (m, 2H), 6.92–6.95 (m, 2H), 7.34–7.36
(m, 3H), 7.42–7.46 (m, 2H); 13C NMR (CDCl3,75 MHz): d 20.8, 20.4,
55.5, 64.9, 66.3, 68.45, 68.49, 79.4, 79.7, 92.1, 98.6, 101.6, 114.7, 119.1,
126.2, 128.2, 129.2, 136.7, 149.3, 156.1, 170.5, 170.9; ESIMS m/z 690.1
23
[M+Na]+. Compound 11: ½aꢁD ꢀ12.0 (c 1.0, CH3OH); 1H NMR
(CD3OD, 300 MHz): d 3.50–3.59 (br m, 5H), 3.69–3.74 (br m, 2H),
4.00–4.02 (br m, 5H), 4.13–4.20 (br m, 1H), 7.06–7.12 (m, 2H), 7.31–
7.37 (m, 2H); 13C NMR (CD3OD, 75 MHz): d 56.4, 62.1, 62.8, 71.9,
77.6, 78.0, 102.2, 115.7, 119.8, 153.4, 156.9; ESIMS m/z 364.1
23
[MꢀH]ꢀ. Compound 13: ½aꢁD ꢀ59.8 (c 1.0, CH3OH); 1H NMR
(CD3OD, 300 MHz): d 1.32 (s, 6H), 1.39 (s, 3H), 1.54 (s, 3H), 3.04 (t,
J = 8.7 Hz, 1H), 3.30–3.37 (br m, 3H), 3.62–3.78 (m, 3H), 3.87 (dd,
J = 15.3, 1.8 Hz, 1H), 3.97 (dd, J = 11.1, 4.5 Hz, 1H), 4.05–4.10 (br
m, 1H), 4.31–4.36 (m, 2H), 4.50 (d, J = 8.1 Hz, 1H), 4.61 (dd, J = 8.1,
2.4 Hz, 1H), 5.50 (d, J = 4.8 Hz, 1H); 13C NMR (CD3OD, 75 MHz):
d 24.8, 25.4, 26.6, 26.7, 61.9, 63.1, 69.3, 69.6, 72.1, 72.2, 72.3, 72.6,
78.2, 97.9, 103.1, 110.4, 110.7; ESIMS m/z 500.1 [MꢀH]ꢀ.
8. (a) Liu, Y.; Lien, I. F.; Ruttgaizer, S.; Dove, P.; Taylor, S. D. Org.
Lett. 2004, 6, 209–212; (b) Ingram, L. J.; Taylor, S. D. Angew. Chem.,
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