Tetrahedron Letters 58 (2017) 423–426

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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Synthesis of glucuronic acid derivatives via the efficient and selective

removal of a C6 methyl group
Zhuang Hou, Yang Liu ⇑, Xin-xin Zhang, Xiao-wei Chang, Mao-sheng Cheng, Chun Guo ⇑
Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang
110016, China

a r t i c l e i n f o a b s t r a c t

Article history: This investigation is related to the development of a general strategy for the synthesis of certain glu-
Received 24 October 2016 curonic acid derivatives. In particular, we report exceptionally selective conditions for removing the C6
Revised 14 December 2016 methyl protecting group by potassium hydroxide without affecting the benzoyl protecting groups on
Accepted 19 December 2016
the C2, C3 and C4 hydroxyl groups in high yields (95–99%). The present method proves to be efficient
Available online 23 December 2016
and environmentally friendly in terms of short reaction time, high yield and the single product.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Glucuronic acid
Potassium hydroxide
Selective deprotection

Introduction
Glucuronic acids are ubiquitous in many biological systems and
play a vital role in diverse physiological functions. What’s more,
functionalized glucuronic acid derivatives are used as valuable
building blocks in the synthesis of glycoproteins, glycolipids and
natural products which have biological function.1–5 As a result,
there are various efforts aiming at developing efficient and mild
methods for the synthesis of glucuronic acid derivatives. The syn-
thesis of glucuronic acid is traditionally achieved by the oxidation
of the C6 primary alcohol of a monosaccharide to the correspond-
ing C6 carboxylic acid.6 However, these methods are associated
with several limitations such as usage of oxidant, generation of
several side products, or unsatisfactory yields.
Recently, Murphy and co-workers reported that glucuronic acid
azide 2 can be prepared from azide 1 by saponification of all of the
esters and subsequent acetylation for six days7,8 (Scheme 1, upper
part). Although this method paved the way to prepare glycosides
with similar structural features, the disadvantages of the lower
yield and the generation of 3,6-lactone as the byproduct due to
the longer reaction time are obvious.
By inspecting the structure of compound 2, several clues were
obtained for the optimization of synthetic protocol. For example,
it is easy to remove C2, C3 and C4 acetyl protecting groups on glu-
curonic acid derivative 1 by CH3ONa/CH3OH without affecting the
C6 methyl ester. Conversely, to obtain a free C6 carboxyl group by
⇑ Corresponding author.
E-mail addresses: y.liu@syphu.edu.cn (Y. Liu), gc_66888@163.com (C. Guo).
removing its methyl protecting group and keep all of the remaining
acetyl groups, such as in glycosyl carboxylic acid 2, is quite diffi-
cult. The reason is that the carboxyl group and hydroxyl groups
in glucuronic acid tend to be protected or deprotected together.
Because glucuronic acid is quite important in the research of mul-
tiple disciplines, such as medicinal chemistry, drug metabolism,
and natural product chemistry9–11, it is necessary to find alterna-
tive protocol to fulfill the need of selective deprotection.
Herein, we report an efficient method that can selectively
remove the C6 methyl group from a glucuronic acid methyl ester
without influencing any benzoyl protecting groups (Scheme 1,
lower-left part). The resulting carboxyl group is ready to form
amides or esters to afford other modified structures or as more
complex donors such as MBHA resin12 (Scheme 1, lower-right
part). Therefore, this procedure can be widely used for the synthe-
sis and structural modification of glycoside relatives of glucuronic
acid.
Results and discussion
A typical example is introduced here when glucuronic acid
azide 8 with O-benzoyl protecting groups on the C2, C3 and C4
hydroxyl groups was prepared (Scheme 2). First, D-glucurono-6,3-
lactone 3 was hydrolyzed in a solution of CH3ONa in CH3OH to
afford methyl ester 4, which was then quantitatively converted
to per-O-benzoyl compound 5 by direct reaction with excess ben-
zoyl chloride. Compound 5 was brominated under the treatment of
the HBr–AcOH system in a high yield of 98%.13 To ensure a stable
model compound, an azide group was introduced at the anomeric

http://dx.doi.org/10.1016/j.tetlet.2016.12.055
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
424 Z. Hou et al. / Tetrahedron Letters 58 (2017) 423–426

Previous work: two steps, yield: P=Ac, 40%

OH O
1. LiOH, THF, H2O, MeOH
O 2. NaOAc, Ac2 O, 6 days 25% N3
O O
HO O
HO N3
OH
40% OP OP
R
NH
O
O
OH PO
OMe PO N3
O O
KOH (2 equiv.) OP
O O
PO PO
PO N3 PO N3
OP acetone, 5 min OP O
2 O
1
PO
PO N3
This work: one step, 5 min, yields: P=Ac, 75% OP
P=Bz, 95%

Scheme 1. Selective removal of the C6 methyl group on glucuronic acid derivatives.

OH
OMe OMe OMe
O a O b O c O d
O O O O
O HO BzO BzO
HO OH BzO OBz BzO
OH OH OBz BzO
Br
HO 3 4 5 6

OMe OH
O e O
O O
BzO BzO
BzO N3 BzO N3
OBz OBz
7 8

Scheme 2. Synthesis of glucuronic acid azide as a model compound. Reagents and conditions: (a) CH3ONa, CH3OH, r.t., 5 h; (b) BzCl, pyridine, 5 h, 99%; (c) HBr-AcOH, DCM, r.
t., 5 h, 98%; (d) NaN3, DMF, 2 h, 80%; (e) KOH (2 equiv.), acetone, r.t., 5 min, 95%.

center, which resulted in a corresponding b-azide with the effect of
the participation of the C2 benzoyl. Finally, the reaction proceeded
with high selectivity, giving the corresponding sugar derivative
with the free carboxyl group at C6 in excellent yield (Scheme 2).
For the last step of demethylester reaction, we began the inves-
tigation by treatment of 7 in acetone using lithium hydroxide as
the base, which formed product 8 with lower yields on different
amount of base (Table 1, entry 1–3).
We reasoned that if a stronger base instead of lithium hydrox-
ide was used to remove the methyl group on compound 7 in a
quick-treatment manner, the hydrolysis of benzoyl esters would
not occur. Therefore, we treated 7 in acetone using sodium hydrox-
ide (2.0 equiv.) as the base, which generated the desired product 8
in only 5 min with a 74% yield (Table 1, entry 4). Although this
yield was not good enough, the much shorter reaction time
showed advantages compared to the previous work. Further inves-
tigations were carried out to improve the product yields under var-
ious conditions. A good yield of 91% was observed by increasing the
amount of sodium hydroxide to 2.5 equivalents (Table 1, entry 5).
However, 3.0 M equivalents of the base resulted in a great decrease
in the yield to 23% (Table 1, entry 6).
Subsequently, potassium hydroxide was applied instead as the
base. To our delight, product 8 was obtained in a higher yield as
high as 95% (Table 1, entry 7) when 2.0 M equivalents of base
was introduced, and the reaction time was not as crucial as
expected (Table 1, entries 7–9). If the amount of the base was
increased to 3.0 M equivalents, the influence on the yield was
not too serious (Table 1, entry 10). However, when the amount
of the base was decreased to 1.0 M equivalent, the results were
so bad even if longer reaction times were allowed (Table 1, entry
11–12). The effects of various solvents were also investigated
(Table 1, entries 13–16). The results showed that other polar apro-
tic solvents, such as acetonitrile, provided lower yields (Table 1,
entries 13–14). As expected, polar protic solvents, such as metha-
nol, helped hydroxylize the esters without selectivity (Table 1,
entries 15–16). Therefore, all of the preliminary experiments
clearly revealed that the best way to proceed with the hydrolysis
of 7 is the application of potassium hydroxide (2.0 equiv.) as the
base, acetone as the solvent and a reaction time of 5 min.
To verify the applicability of this protocol, we tested different
substrates (Scheme 3). First, compound 9 with acetyls as protective
groups was applied. Although the yield of product 10 is not as good
as product 8, it still shows some advantages compared with the
reported method in terms of much shorter reaction time and
higher yield.
Subsequently, several glucuronide compounds with different
substitutions on the anomeric center were utilized. Compound
11 is an important intermediate in the research of glycolipids. To
the best of our knowledge, 11 can only be obtained in four steps
from D-glucose by oxidation using TEMPO.8 This time it can be pro-
vided from intermediate 5 in a 95% yield by our method. In addi-
tion, glucuronides are interesting markers for the consumption of
alcohol such as compound 13 which was obtained by use of the
RuCl3–NaIO4 reagent system.14 Considering the relatively high cost
of RuCl3 as well as NaIO4 used in the reaction, we apply our
approach to the synthesis of such compounds. It was nice to see
that compound 13 was conveniently synthesized in excellent yield
by this means.
The scope of this methodology was further explored in the
synthesis of sugar amino acid and glucuronic acid containing cou-
marin. Sugar amino acids (SAAs), the carbohydrate derivatives
bearing both amino and carboxylic acid functional groups,
 Z. Hou et al. / Tetrahedron Letters 58 (2017) 423–426 425

Table 1
Optimization of the reaction conditions for selective removal of C6-methyl of glucuronic acid.

OMe OH
O O
O O
BzO BzO
BzO N3 BzO N3
OBz OBz
7 8

Entry Base Solvent Time Equiv Yielda

1 LiOH Acetone 5 min 2.0 42%
2 LiOH Acetone 5 min 2.5 51%
3 LiOH Acetone 5 min 3.0 14%
4 NaOH Acetone 5 min 2.0 74%
5 NaOH Acetone 5 min 2.5 91%
6 NaOH Acetone 5 min 3.0 23%
7 KOH Acetone 5 min 2.0 95%
8 KOH Acetone 10 min 2.0 93%
9 KOH Acetone 30 min 2.0 90%
10 KOH Acetone 5 min 3.0 82%
11 KOH Acetone 30 min 1.0 12%
12 KOH Acetone 3h 1.0 17%
13 KOH Acetonitrile 5 min 2.0 40%
14 KOH Acetonitrile 5 min 3.0 80%
15 KOH Methanol 5 min 2.0 46%
16 KOH Methanol 10 min 2.0 10%
a
Isolated yields.

OR OR OR OR
O O O O
O O O O
AcO BzO BzO BzO
AcO N3 BzO OBz BzO OCH 3 BzO NHAc
OAc OBz OBz OBz

a 9: R=Me a 5: R=Me a 12: R=Me 14: R=Me

a
10: R=H 11: R=H 13: R=H 15: R=H
Yield=75% Yield=95% Yield=99% Yield=97%

OR
O
OR O
O BzO
BzO O
O H OBz
BzO H N
BzO N O
OBz BzO
S BzO OBz
OBz
a 16: R=Me
a 18: R=Me
17: R=H
19: R=H
Yield=97%
Yield=98%

O
OR OR O
O O
O
O O O N N O CH 3
BzO BzO
BzO O BzO N
OBz OBz CH 3

a 20: R=Me a 22: R=Me

21: R=H 23: R=H
Yield=96% Yield=98%

Scheme 3. Selective removal of the C6 methyl group on different glucuronic acid substrates. Reagents and conditions: (a) KOH (2.0 equiv.), acetone, 5 min.

represent an important class of such new molecules that can be
used to create novel materials with potential applications as gly-
comimetics and peptidomimetics.15–17,12c Considering the impor-
tance of this class of compounds, we choose 15 as a model
compound to explore applicability of this protocol. The new sugar
amino acid 15 can be synthesized from compound 14 in excellent
yield of 97%. Another example is compound 17 which is useful to
the structural modification of aromatic amines and aromatic alco-
hols. Compound 16 could be obtained by treatment of aromatic
amine with isothiocyanate intermediate in good yield (see Sup-
porting information). Conversion of 16 to 17 proceeded smoothly
in 98% yield by our method.
Further evaluation on complex structure, such as disaccharide
22, was also successful. The novel compound 22 was prepared in
nine steps with 23% overall yield (see Supporting information).
To our delight, the desired disaccharide 23 was formed in 98%
yield, showing broader range of application of this method.
We note that the hydrolysis of 20 and 22 requires great care, for
even a slight excess of base leads to irreversible lactone opening.
However, we found that these unique structures were still stable
426 Z. Hou et al. / Tetrahedron Letters 58 (2017) 423–426
when dealing with potassium hydroxide to remove the C6 methyl.
Highly pure 21 and 23 can be isolated in excellent yields. More-
over, this selective condition furnished the products without
affecting either the sugar anomeric center or the lactone ring.
Conclusion
In summary, an efficient and reliable procedure for the synthe-
sis of C6-carboxyl glucuronyl acid and its application in the prepa-
ration of corresponding glycosyl compounds are described. The
high yields up to 99% testified the feasibility and efficiency of this
protocol. Given other advantages of this protocol, including its
mild conditions, short reaction time, lower cost and easy operation,
it provides rapid access to biologically relevant carbohydrates in a
labor-saving and economical manner. With modifications in the
anomeric center and free C6 carboxyl group, the syntheses of fur-
ther saccharide compounds may be expected, and their utilization
in carbohydrate chemistry can also undergo fast progress.
Acknowledgments
This project was financially supported by National Natural
Science Foundation of China (No. 81473087 and 81573292).
Dr. Y. Liu wishes to express his thanks for the support by the
Program for Liaoning Excellent Talents in University (LJQ2014110).
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.12.
055.
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