Hafnium(IV) triflate as a potent catalyst for selective 1-O-deacetylation of peracetylated saccharides

Article abstract of DOI:10.1016/j.carres.2017.11.015

An efficient method for selective anomeric deacetylation of peracetylated mono-, di-, and trisaccharides has been developed by using 2 mol% Hf(OTf)₄ as catalyst in acetonitrile. Employment of ultrasonic irradiation could significantly accelerate the reaction rate. Mechanistic study confirmed the hydrolysis nature of this reaction, and NMR experimental data suggested that multiple peracetylated saccharide molecules may ligate to Hf(IV) cation primarily via the anomeric acetate to promote its specific hydrolysis.

Full text of DOI:10.1016/j.carres.2017.11.015

Accepted Manuscript
Hafnium(IV) triflate as a potent catalyst for selective 1-O-deacetylation of
peracetylated saccharides
Rui Wang, Ji-Zong Chen, Xiu-An Zheng, Rui Kong, Shan-Shan Gong, Qi Sun
PII:
S0008-6215(17)30781-4
10.1016/j.carres.2017.11.015
CAR 7493
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 17 October 2017
Revised Date: 23 November 2017
Accepted Date: 23 November 2017
Please cite this article as: R. Wang, J.-Z. Chen, X.-A. Zheng, R. Kong, S.-S. Gong, Q. Sun, Hafnium(IV)
triflate as a potent catalyst for selective 1-O-deacetylation of peracetylated saccharides, Carbohydrate
Research (2017), doi: 10.1016/j.carres.2017.11.015.
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Carbohydrate Research
journal homepage: www.elsevier.com
Hafnium(IV) triflate as a potent catalyst for selective 1-O-deacetylation of
peracetylated saccharides
Rui Wang, Ji-Zong Chen, Xiu-An Zheng, Rui Kong, Shan-Shan Gong, Qi Sun
Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science and Technology Normal University, 605 Fenglin Avenue, Nanchang, Jiangxi 330013, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient method for selective anomeric deacetylation of peracetylated mono-, di-, and
trisaccharides has been developed by using 2 mol% Hf(OTf)4 as catalyst in acetonitrile.
Employment of ultrasonic irradiation could significantly accelerate the reaction rate.
Mechanistic study confirmed the hydrolysis nature of this reaction, and NMR experimental data
suggested that the multiple peracetylated saccharide molecules may ligate to Hf(IV) cation
primarily via the anomeric acetate to promote its specific hydrolysis.
Available online
Keywords:
Deacetylation
2009 Elsevier Ltd. All rights reserved
.
Hafnium triflate
Peracetylated saccharides
Regioselectivity
Ultrasound
materials or multiple deacetylated byproducts were observed,
when the reactions were repeated exactly according to the
described conditions. Therefore, novel Lewis acid catalysts with
excellent catalytic activity, high regioselectivity, and low toxicity
are highly desired for anomeric deacetylation of peracetylated
saccharides.
1. Introduction
Selective 1-O-deacetylation of peracetylated saccharides plays
a crucial role in oligosaccharide synthesis to access reactive
glycosyl donors, such as glycosyl trichloroacetimidates,
phosphates, and halides.1 Moreover, chemical synthesis of many
bioactive glycoconjugates2 also involves functionalizations
specifically at the anomeric OH of carbohydrate acetate building
blocks.
Recently, we noticed that Group IVB transition metal-based
Lewis acids such as ZrCl4, HfCl4, and Hf(tOBu)4 have been
reported to promote direct esterification/amidation of non-
–
19
activated carboxylic acids and alcohols/amines.18 Earlier this
year, Adolfsson and coworkers revealed the mechanism of
zirconium-catalyzed amidation and their NMR data indicated that
carboxylate ligated to Zr(IV) cation in THF to form the reactive
species.20 Inspired by these reports, we speculated that certain
Group IVB transition metal-based Lewis acids may ligate to the
acetyl groups of the peracetylated carbohydrates and activate the
most labile anomeric acetate, thereby promoting selective
deprotection. Herein, we report the employment of Hf(OTf)4 as a
highly efficient catalyst for selective 1-O-deacetylation of
peracetylated carbohydrates. Compared to the reported metal
Lewis acids, only 2 mol% of Hf(OTf)4 is needed for high-
yielding anomeric deacetylation of a diversity of mono-, di-, and
Currently, the methods that enable selective anomeric
deacetylation of peracetylated carbohydrates can be mainly
categorized in two types. The first approach selectively cleaves
the anomeric acetate via transamidation by using a variety of
nitrogenous nucleophiles such as ammonia3, hydrazine acetate4,
benzylamine5, ethylene diamine6, piperidine7, guanidine8, 3-
(dimethylamino)-1-propylamine (DMAPA)9, etc. While excess
bases are typically needed, some of these reagents are toxic. In
additon, other basic reagents, such as alkali metal fluorides in
PEG 40010 and molecular seives in combination with methanol,11
have also been successfully employed for the same purpose.
Alternatively, the anomeric acetyl group could be selectively
removed by Brønsted or Lewis acid-catalyzed hydrolysis or
transesterification depending on the solvent used. The fact that
stoichiometric amounts or even a large excess of Lewis acids
such as tributyltin alkoxide12, Cu(OAc)213, FeCl3·6H2O14, and
trisaccharide substrates in acetonitrile in 6
Moreover, the reaction time could be remarkably shorten to only
4 h, when the reactions were assisted with sonication.
–8 h at 60 ºC.
3
–
15
HgO/HgCl2 are required indicates that the potency of these
2. Results and discussion
catalysts is far from satisfactory. Though it has been reported that
16
catalytic amounts of Ln(OTf)3 or Zn(OAc)2·2H2O17 were
In the preliminary experiments, 1,2,3,4-tetraacetyl-L-
sufficient for the desired transformations, however, we found that
rhamnose (1) was treated with 10 mol% of either reported metal
———
significant amounts of either unreacted peracetylated starting
Corresponding author. Tel.: +86-791-8380-5183; fax: +86-791-8382-6894; E-mail addresses: sunqi@jxstnu.edu.cn.

2
Lewis acids or a series of Group IVB transition metal Lewis
92%, when only 2 mol% Hf(OTf)4 was used. However, when the
amount of Hf(OTf)4 was decreased to 1 mol%, the catatyltic
effect drastically diminished.
ACCEPTED MANUSCRIPT
acids at room temperature. Due to the concerns that certain metal
Lewis acids may potentially promote the formation of methyl
glycoside or isomerization of pyranose into furanose14,20 in
methanol, we chose to perform the deacetylation in commercial
AR grade acetonitrile. The data listed in Table 1 showed that
Cu(OAc)2, FeCl3·6H2O, Zn(OAc)2·2H2O, and Nd(OTf)3 (entry
Table 3. The effect of the amount of Hf(OTf)4 on 1-O-deacetylation of 1.
Entry
The amount of
Hf(OTf)4 (mol%)
Reaction time
(h)
Isolated yield of 2
(%)
1
–
4) exhibited either no or very low catalytic activity at 10 mol%
level. A large amount of 1 was left unreacted after 12 h.
Surprisingly, addition of Zr(IV) salts (entry 5 7) showed no
1
2
3
4
10
5
1
2
88
91
–
2
6
92
catalytic activity at all, whereas the presence of Hf(IV) salts
(entry 8–10) resulted in the generation of significant amounts of
desired product 2. It is noteworthy that HfCl4- and Hf(OTf)4-
catalyzed reactions proceeded much faster and reached maximum
conversion in 6 h. However, other than the desired 2 (35%),
HfCl4 also led to the formation of rhamnosyl chloride byproduct
(~10%). In contrast, Hf(OTf)4-catalyzed 1-O-deacetylation of 1
afforded 2 in 60% yield without any byproduct.
1
12
45a
aThe reaction was quenched at the time point that it proceeded no further.
The solvent effect was also investigated at 60 ºC with 2 mol%
Hf(OTf)4. The results in Table 4 showed that when commercial
AR grade MeOH, THF, DCE, and toluene were used, a large
amount of 1 was left unreacted. In the first three cases, multiple
deacetylated byproducts were obtained. Hf(OTf)4 exhibited no
catalytic activity in DMF and iPrOH. These results indicated that
reactivity and regioselectivity of Hf(OTf)4 is quite solvent-
dependent. To prove the hydrolysis mechanism in acetonitrile,
the reaction was tested in freshly dried acetonitrile. As expected,
no reaction was observed even after 12 h. In contrast, the
acetonitrile with 0.3% (v/v) water, whose water content is
comparable to AR grade acetonitrile, led to similar reaction time
and yield. However, if the amount of water was further increased
to 1% (v/v) and above, the reaction proceeded notably faster, but
the regioselectivity was compromised.
Table 1. The effect of metal Lewis acid on 1-O-deacetylation of 1.
Entry
Catalyst
Cu(OAc)2
FeCl3·6H2O
Nd(OTf)3
Zn(OAc)2
ZrOCl2·8H2O
ZrCp2Cl2
ZrCl4
Reaction time (h)
Isolated yield of 2 (%)
1
2
12
12
12
12
12
12
12
12
6
n.r.
15a
12a
10a
n.r.
n.r.
n.r.
22a
35a
60a
3
Table 4. The solvent effect on Hf(OTf)4-catalyzed 1-O-deacetylation of 1.
4
Entry
Solvent
Reaction
time (h)
Isolated yield
of 2 (%)
5
6
1
2
MeOH
THF
4
10
8
36a,b
27a,b
25a,b
20a
n.r.
n.r.
92
7
8
HfCp2Cl2
HfCl4
3
DCE
9
4
Toluene
8
10
Hf(OTf)4
6
5
DMF
12
12
6
aThe reaction was quenched at the time point that it proceeded no further.
6
iPrOH
7
CH3CN (AR)
CH3CN (dry)
CH3CN/H2O (3.3×102:1, v/v)
CH3CN/H2O (100:1, v/v)
CH3CN/H2O (20:1, v/v)
As expected, increasing reaction temperature notably
accelerated the reaction rate of Hf(OTf)4-catalyzed 1-O-
deacetylation of 1 (Table 2). When the reaction with 10 mol%
Hf(OTf)4 was performed at 60 ºC, the reaction time was shorten
to only 1 h. More importantly, 1 was completely consumed, and
the yield of 2 was improved to 88%. However, elevation to 80 ºC
resulted in the formation of multiple deacetylated byproducts.
8
12
5
n.r.
9
92
10
11
4
86b
74b
2.5
aThe reaction was quenched at the time point that it proceeded no further.
bMultiple deacetylated byproducts were observed on TLC.
Table 2. The effect of temperature on Hf(OTf)4-catalyzed 1-O-deacetylation of 1.
Entry
Temp.
Reaction time
(h)
Isolated yield of 2
Since many previous reports have claimed that ultrasonic
irradiation may accelerate ester hydrolysis in binary solvent
systems,22 we performed the reaction in an ultrasonic bath (40
(%)
1
2
3
4
rt
6
3
1
1
60a
81a
88
o
KHz, power output 600W) at 60 C. Compared to the reaction
40
60
80
with mechanical agitation, the assistance of ultrasound
remarkably accelerated the reaction rate and shortened the
reaction time to only 3 h (Figure 1). It is worth noting that if the
temperature was further elevated to 70 ºC, multiple deacetylated
byproducts emerged again, indicating that 60 ºC was the
threshold for the regioselectivity of this method. It might be easy
to simply ascribe the rate enhancement to the cavitation
phenomena, such as violent temperature and pressure change
during the collapse of microbubbles. However, the temperature
threshold suggested that the changes in the molecular structure of
the solvent system and perturbation of hydrophobic solute-
75b
aThe reaction was quenched at the time point that it proceeded no further. bMultiple
deacetylated byproducts were observed on TLC.
In an attempt to optimize the quantity of catalyst required for
the reaction, we gradually reduced the amount of Hf(OTf)4 from
10 mol% to 1 mol% at 60 ºC. As shown in Table 3, the reaction
time was prolonged to 6 h, but the yield of 2 was improved to

solvent interactions might play a more important role on the
reduced. Alternatively, the reactions could be performed without
the assistance of ultrasonic irradiation. Both the yields and α:β
ACCEPTED MANUSCRIPT
sonochemical effect.23
Table 5. Hf(OTf)4-catalyzed 1-O-deacetylation of peracetylated mono-, di-, and trisaccharides under sonication conditions.
Entry
Substrate
Product
Reaction time
(h)
Isolated yield
(%)
α:βa
6.3:1
2.3:1
2.2:1
1
2
3
3
3
3
92
90
91
4
5
6
7
3
3
3
3
90
93
89
94
α only
α only
8.3:1
1:2
8
9
3
4
95
85
1:1
2:1
10
11
4
4
86
82
1.6:1
1.6:1
aThe α:β ratio was determined by 1H NMR.
To prove the generality of the Hf(OTf)4-based 1-O-
deacetylation method, a diverse number of peracetylated
saccharide substrates were subjected to the optimized conditions.
The results in Table 5 showed that the catalytic activity of
ratios were not affected except that longer reaction time (6
was required.
–8 h)
Driven by our curiosity about how Hf(OTf)4 catalyzes the 1-
O-deacetylation, we gradually added the catalyst to the CD3CN
solution of 1,2,3-triacetyl-5-deoxy-D-ribose (15), the structurally
simplest substrate, and monitored their interactions by both H
and 13C NMR. As shown in Figure 2A, addition of 2 mol%
Hf(OTf)4 resulted in the appearance of three new groups of peaks,
corresponding to different binding modes. When 5 mol%
Hf(OTf)4 exhibited no difference on
(entry 1 6). Similarly, Hf(OTf)4 also showed excellent potency
and regioselectivity on furanoses (entry 7 8). When disaccharide
L- or D-pyranose substrates
–
1
–
and trisaccharide substrates (entry 9–11) were employed, longer
reaction time (4 h) was required and the yields were only slightly

4
Hf(OTf)4 was added, the peaks of free 15 completely
In summary, we have developed an efficient and general
protocol for selective anomeric deacetylation of peracetylated
saccharides. Compared to previously reported metal Lewis acids,
Hf(OTf)4 is identified as a much more potent catalyst. Moreover,
it was found that the assistance of ultrasound may significantly
accelerate the deacetylation process. The mechanistic
investigations confirmed the hydrolysis nature of this reaction,
and suggested that peracetylated saccharides may coordinate with
Hf(IV) cation primarily via the anomeric acetate as reactive
intermediate species.
ACCEPTED MANUSCRIPT
disappeared. Interestingly, further addition of catalyst simplified
the spectra. When total 25 mol% Hf(OTf)4 was added, only one
major set of peaks was left (Figure 2A, inset). Due to the ligation
of 15 with Hf(IV) cation, the peaks of H-1, H-2, and one COCH3
upshifted, while those of H-3, H-4, and the other two COCH3
downshifted.
4. Experimental section
4.1 General methods
Chemical reagents and solvents were obtained from
commercial suppliers. Peracetylated saccharides were
synthesized according to a reported method.2a,24 Reactions were
sonicated at 60 °C in an ultrasonic bath (40 KHz, power output
600W). All reactions were monitored by thin layer
Figure 1. The sonochemical effect on Hf(OTf)4-catalyzed 1-O-deacetylation of 1.
aMultiple deacetylated byproducts were observed on TLC.
chromatography on plates coated with 0.25 mm silica gel 60 F254
.
Moreover, we experimentally determined that 25 mol%
Hf(OTf)4-catalyzed selective 1-O-deacetylation of 15 was
extremely fast (30 min) even at room temperature, indicating that
the 15-Hf(IV) complex observed should be the active
intermediate species. The 13C NMR data also confirmed the
formation of a dominant binding complex, when 25 mol%
Hf(OTf)4 was added to 15 (Figure 2B). The fact that one acetate
peak was remarkably upshifted from ~172 to ~183 ppm and only
0.25 equivalent catalyst was added suggested that multiple 15
possibly coordinated to the hafnium center primarily via the
anomeric acetate. In a control experiment, addition of up to 25
mol% Nd(OTf)3, a transition metal Lewis acid with almost no
TLC plates were visualized by charring with 20% H2SO4 in
EtOH. All NMR spectra were obtained with a 400 MHz
instrument with chemical shifts reported in parts per million
(ppm, δ) and referenced to CDCl3. Low-resolution mass spectra
were reported as m/z and obtained with an ion trap mass
spectrometer.
4.2 General procedures for Hf(OTf)4-catalyzed 1-O-deacetyl-
ation of peracetylated saccharides
To a solution of peracetylated saccharide (2.0 mmol) in
commerical AR grade acetonitrile (15 mL) was added Hf(OTf)4
(0.04 mmol). The reaction was sonicated at 60 °C for 3–4 h. The
reaction was cooled to room temperature and triethylamine (0.4
mmol) was added. Then the solution was concentrated under
vacuum. Flash column chromatography on silica gel (petroleum
ether:ethyl acetate = 3:1) afforded 1-O-deacetylated product in
pure form.
1
catalytic activity (Table 1), caused no change to the H NMR
spectra of free 15 in CD3CN (SI, Figure S1).
Supplementary Material
Supplementary data associated with this article can be found
at
Acknowledgments
We thank the National Natural Science Foundation of China
(21562021), Natural Science Foundation (20143ACB21014),
Fellowship for Young Scientists (2015BCB23009), and Sci &
Tech Project from Dept of Education (GJJ160763) of Jiangxi
Province, and Innovation Foundation of JXSTNU (YC2016-X05
for R.W.) for financial support.
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ACCEPTED MANUSCRIPT
ò Hf(OTf)4 is identified as a potent catalyst for selective anomeric deacetylation of
peracetylated mono-, di-, and trisaccharides.
ò Remarkable sonochemical effect on reaction rate is observed for
Hf(OTf)4-catalyzed regioselective deacetylation.
ò NMR experimental data suggest that multiple peracetylated saccharide molecules
may coordinate to Hf(IV) cation via the anomeric acetate as reactive intermediate
species.