A highly efficient deprotection of the 2,2,2-trichloroethyl group at the anomeric oxygen of carbohydrates

Article abstract of DOI:10.1016/j.carres.2011.08.007

Commercially available zinc dust in the presence of ammonium chloride in acetonitrile at reflux removes the 2,2,2-trichloroethyl (TCE) group at anomeric centers with excellent yields (>95%) in short reaction times. This present method is easily implemented on substrates containing acyl and benzyl groups and large-scale reactions also proceed in high yield.

Full text of DOI:10.1016/j.carres.2011.08.007

Carbohydrate Research 346 (2011) 2290–2293
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Note
A highly efficient deprotection of the 2,2,2-trichloroethyl group
at the anomeric oxygen of carbohydrates
a
a
a
b,
a
Jianbo Zhang a, , Jie Fu , Wenshuai Si , Xiaohu Wang , Zhongfu Wang , Jie Tang
⇑
⇑
a Department of Chemistry, East China Normal University, Shanghai 200062, China
b School of Life Sciences, Northwest University, Xi’an 710069, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Commercially available zinc dust in the presence of ammonium chloride in acetonitrile at reflux removes
the 2,2,2-trichloroethyl (TCE) group at anomeric centers with excellent yields (>95%) in short reaction
times. This present method is easily implemented on substrates containing acyl and benzyl groups and
large-scale reactions also proceed in high yield.
Received 18 January 2011
Received in revised form 5 August 2011
Accepted 6 August 2011
Available online 16 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
2,2,2-Trichloroethyl
Anomeric center
Carbohydrates
Deprotection
Zinc dust
Table 1
In the course of synthesizing oligosaccharides and glycoconju-
gates, manipulations of the anomeric protection of a sugar moiety
usually play a key role.1 To date, various groups have been devel-
oped to achieve chemoselective transformations or activations,
such as acetyl, benzoyl, allyl, trimethylsilylethyl and phenylthiol.2
Since Woodward first highlighted the elegance of the 2,2,2-trichlo-
roethyl (TCE) ester group in his classical cephalosporin synthesis in
1966,3 the TCE moiety has been the most widely used haloethyl
protecting group for carbon, sulfuric and phosphorus acids.4 Later,
Lemieux, Ogawa and other chemists successfully introduced the
TCE group for the protection of the anomeric center against stan-
dard reaction conditions in carbohydrate chemistry.5,6 Despite
these achievements, cleavage of TCE protection is sometimes still
capricious in the syntheses of polyfunctional molecules. Hence
the development of new methodologies for TCE deprotection re-
mains a challenging task.5a,7 For instance, in our continuous efforts
toward carbohydrate-targeted drug delivery, we have encountered
difficulties in selectively removing this group at the anomeric
center. At the beginning of our work, we first investigated the
TCE removal using the methods developed by other groups, such
as Zn–AcOH,5a Zn–AcOH–NaOAc,5a Zn–pentane-2,4-dione6b and
Zn/NMI.6a However, most methods have drawbacks. For example,
the Zn–AcOH system suffers from long reaction times and low
yields and the use of Zn–pentane-2,4-dione requires pre-activation
of the zinc dust (Table 1).
Comparison of the known methods of removal anomeric TCE on 2,2,2-trichloroethyl
2,3,4,6-tetra-O-acetyl-b-D-glucopyranoside 1a
Entry
System
Temperature (°C)
Time (h)
Yielda (%)
1
2
3
4
5
Zn/AcOH5a
25
25
25
25
50
29
4
8
1.5
39.8
74.6
<10
52.4
75.6
Zn/AcOH/AcONa5a
Zn/NMI6b
Zn/pentane-2,4-dione6c
Zn/pentane-2,4-dione6c
10 min
a
Isolated yields.
In our earlier research, Zn–NH4Cl–EtOH had been successfully
applied in the deprotection of 2-iodo-3-perfluoroalkyl group at
the anomeric center of carbohydrates and other complex com-
pounds.8 Because most protective groups including ethers, esters,
silyl ethers, and ketals all remained intact under refluxing condi-
tions, we tried this elegant reductive approach in the deprotection
of TCE groups at the anomeric center.9 When a solution of 2,2,
2-trichloroethyl 2,3,4,6-tetra-O-acetyl-b-D-glucopyranoside 1a in
ethanol was treated with non-activated Zn dust and NH4Cl, and al-
lowed to heat at reflux over a period of just 10 min, TLC revealed
only the presence of one new component, which was revealed as
the 2,3,4,6-tetra-O-acetyl-b-D-glucopyranose with the help of
NMR and MS (Table 2, entry 1). Inspired by the fact that the
2,2,2-trichloroethyl could be easily removed using this simple sys-
tem, we established optimal conditions. First, even if the reaction
time was prolonged to 60 min, the starting material was not fully
⇑
Corresponding authors. Tel.: +86 21 62233853; fax: +86 21 62232414. (J.Z.).
E-mail address: jbzhang@chem.ecnu.edu.cn (J. Zhang).
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.08.007

J. Zhang et al. / Carbohydrate Research 346 (2011) 2290–2293
2291
Table 2
Initial studies of TCE removal
consumed and the yield of product scarcely increased. Then, sev-
eral solvents were tested. We found that the conversion proceeded
much better in aprotic polar solvents especially in acetonitrile (en-
try 5 in Table 2). In addition, the NH4Cl is indispensable to this
reaction. The reaction did not occur at all without NH4Cl (entry
7); moreover, the reaction times are shortened by using more
NH4Cl (entries 6 and 8–10).
OAc
O
OAc
Zn/NH4Cl
solvent
O
AcO
AcO
AcO
OH
OTCE
AcO
OAc
OAc
Entry Catalyst (Zn/NH4Cl)
(equiv)
Solvent
Temp
(°C)
Time
Yielda
(%)
(min)
These findings prompted us to examine if this novel method
could be effective with other trichloroethyl glycosides. The data
listed in Table 3 represent our preliminary results of the deprotec-
tion under the specified conditions (8 equiv Zn powder, 8 equiv
NH4Cl, CH3CN, reflux). All of the reactions of monosaccharide gly-
cosides with acyl protection went to completion within 5 min (en-
tries 1–6). Similarly, the deprotections are also nearly quantitative
in the presence of benzyl ether protection (entries 7–13). As well,
reactions of disaccharides proceeded smoothly in the presence of
more zinc dust and ammonium chloride (16 equiv Zn powder,
16 equiv NH4Cl, entries 14 and 15). The structure and stereochem-
istry of all products were elucidated by NMR and mass spectral
1
2
3
4
5
6
7
8
9
5/5
5/5
5/5
5/5
5/5
8/8
8/0
8/1
8/4
8/6
EtOH
AcOH
Toluene 90
78
90
10
10
10
10
10
5
120
90
40
15
63
56
Trace
84
89
THF
66
82
82
82
82
82
82
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
98
NRb
98
98
98
10
a
Isolated yields.
NR, no reaction.
b
Table 3
Deprotection of anomeric O-TCE glycosides in refluxing acetonitrilea
Entry
Starting material
Product
Time (min)
5
Yieldb (%)
9810
a
/bc
OAc
OAc
O
O
AcO
AcO
AcO
OTCE
1
2.7:1
1.7:1
OH
AcO
OAc
1a
OAc
1b
OAc
O
OAc
O
OAc
OAc
OH
2
5
9810
AcO
AcO
AcO
AcO
OTCE
2b
2a
AcO
AcO
AcO
AcO
AcO
AcO
OAc
O
OAc
O
OH
3
4
5
5
9610
>19:1
>19:1
3b
OTCE
OTCE
3a
OH
O
AcO
O
9614
AcO
AcO
AcO
OAc
AcO
OAc
4b
4a
O
O
AcO
OH
OH
AcO
AcO
5
6
5
5
9915
1.9:1
0.8:1
OAc
5b
AcO
5a
OTCE
OAc
O
OAc
O
AcO
AcO
9715
OAc OTCE
6a
OAc
6b
OBn
O
OBn
O
BnO
BnO
7
8
5
5
9711
1.8:1
1.7:1
OTCE
OH
OH
BnO
BnO
OBn
OBn
OBn
7a
7b
OBn
O
OBn
O
OBn
BnO
9810
BnO
OBn
8b
OBn
OTCE
8a
BnO
BnO
BnO
BnO
BnO
BnO
OBn
O
OBn
O
OH
9
5
9613
>19:1
9b
OTCE
9a
(continued on next page)

2292
J. Zhang et al. / Carbohydrate Research 346 (2011) 2290–2293
Table 3 (continued)
Entry
Starting material
OTCE
Product
Time (min)
Yieldb (%)
a
/bc
OH
O
BnO
O
BnO
10
5
9811
2.8:1
BnO
OBn
BnO
OBn
10b
10a
O
O
BnO
BnO
OTCE
OH
BnO
11
12
5
5
9916
0.8:1
0.5:1
BnO
OBn
OBn
11a
11b
OBn
O
OBn
O
BnO
BnO
OH
OH
9816
OTCE
OBn
12b
OBn
12a
OAc
OAc
O
O
BnO
BnO
13
14
5
9812
1.8:1
1.9:1
BnO
BnO
OBn
OBn
13b
OTCE
13a
OAc
OAc
OAc
O
OAc
O
OAc
O
OAc
O
AcO
O
AcO
O
OTCE
OTCE
OH
OH
20d
9710
OAc
OAc
AcO
AcO
OAc
OAc
14b
14a
OAc
O
OAc
O
OAc
O
OAc
O
AcO
AcO
O
AcO
O
AcO
OAc
AcO
20d
9610,17
1.9:1
OAc
AcO
15
OAc
AcO
15b
15a
a
Reaction conditions: 1 equiv O-TCE glycosides, 8 equiv Zn powder, 8 equiv NH4Cl, solvent, CH3CN (2 mL), reflux.
Isolated yields.
a
b
c
/b ratios were based on the integration of the corresponding anomeric protons in the 1H NMR (500 MHz) spectra.
d
16 equiv Zn powder, 16 equiv NH4Cl.
data.17 In addition, the same methodology was also shown to be
reliable on scales as large as 4.78 g (10 mmol) using 2,3,4,6-tetra-
1.2. General experimental procedure
O-acetyl-b-
D-glucopyranoside as the substrate; the yield was
To a solution of 2,2,2-trichloroethyl 2,3,4,6-tetra-O-acetyl-b-D-
excellent as well (98%).
glucopyranoside (96 mg, 0.2 mmol) in CH3CN (2 mL), were added
Zn powder (104 mg, 1.6 mmol) and NH4Cl (85 mg, 1.6 mmol). After
being heated at reflux for 5 min, the mixture was filtered. The fil-
trate was concentrated to a residue that was purified by silica gel
column chromatography (petroleum ether–EtOAc 3:1) to give
In summary, we have demonstrated a facile, highly efficient re-
moval of TCE protecting groups in the presence of either acetyl or
benzyl protection. The time required for the desired deprotective
reactions are remarkably short (5–20 min) and the yields are excep-
tionally high (>95%). All the applied reagents were directly applied
without any pretreatment. In particular, the zinc dust does not need
to be activated before use. Furthermore, the reaction could be done
in neutral media and in large scale; therefore, multiple bicarbonate
washes for removal of acetic acid are avoided. Thus, we expect that
this methodology will find widespread use in the deprotection of
this class of protecting group. Further exploration of this methodol-
ogy is currently under study in our laboratory.
2,3,4,6-tetra-O-acetyl-D-glucopyranose (69 mg, 98%).
Acknowledgments
We thank the analytic center of East China Normal University for
data measurement. The authors gratefully acknowledge helpful dis-
cussions with Professor Liangping Wu, Dr. Zhihong Zeng, Ms. Jiafen
Zhou and Mr. Guofang Yang. This project was financially supported
by Shanghai Rising-Star Program (06QA14018), National University
Students Innovative Experimental Projects (081026905), Natural
Science Foundation of Shanghai (11ZR1410400) and Open Founda-
tion of East China Normal University (2011-46).
1. Experimental
1.1. General experimental methods
1H NMR spectra were recorded on a Bruker DRX-500 MHz spec-
trometer using tetramethylsilane as internal standard and CDCl3 as
Supplementary data
solvent. Silica gel (10–40 l, Yantai, China) was used for column
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2011.08.007.
chromatography. TLC plates (10–40
l, Yantai, China) were used
to monitor the reactions.

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