Synthesis of glucuronic acid derivatives via the efficient and selective removal of a C6 methyl group

Article abstract of DOI:10.1016/j.tetlet.2016.12.055

This investigation is related to the development of a general strategy for the synthesis of certain glucuronic acid derivatives. In particular, we report exceptionally selective conditions for removing the C6 methyl protecting group by potassium hydroxide

Full text of DOI:10.1016/j.tetlet.2016.12.055

Accepted Manuscript
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
PII:
S0040-4039(16)31690-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.055
TETL 48467
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 October 2016
14 December 2016
19 December 2016
Please cite this article as: Hou, Z., Liu, Y., Zhang, X-x., Chang, X-w., Cheng, M-s., Guo, C., Synthesis of glucuronic
acid derivatives via the efficient and selective removal of a C6 methyl group, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.12.055
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1
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
(Received <Month> <Date>, <Year>; CL-<No>; E-mail: y.liu@syphu.edu.cn (Y. Liu), gc_66888@163.com (C. Guo))
Abstract
This investigation is related to the development of a general strategy for the synthesis of certain glucuronic
acid derivatives. In particular, we report exceptionally selective conditions for removing the C6 methyl
protecting group by potassium hydroxide without affecting the benzoyl protecting groups on the C2, C3 and C4
hydroxyl groups in high yields (95%–99%). The present method proves to be efficient and environmentally
friendly in terms of short reaction time, high yield and the single product.
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 synthesis of glucuronic acid is traditionally achieved by the oxidation of the C6 primary alcohol
6
of a monosaccharide to the corresponding C6 carboxylic acid . 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 days 7, 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 glucuronic acid derivative
1 by CH3ONa/CH3OH without affecting the C6 methyl ester. Conversely, to obtain a free C6 carboxyl group by
removing its methyl protecting group and keep all of the remaining acetyl groups, such as in glycosyl carboxylic
acid 2, is quite difficult. 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 multiple
disciplines, such as medicinal chemistry, drug metabolism, and natural product chemistry 9-11, it is necessary to
find alternative 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

2
12
such as MBHA resin
(Scheme 1, lower-right part). Therefore, this procedure can be widely used for the
synthesis and structural modification of glycoside relatives of glucuronic acid.
Scheme 1. Selective removal of the C6 methyl group on glucuronic acid derivatives.
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 benzoyl 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 center, which resulted in a corresponding β-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).
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%.
Scheme 2. Synthesis of glucuronic acid azide as a model compound

3
For the last step of demethylester reaction, we began the investigation 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 hydroxide 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 hydroxide (2.0 equiv.) as the base, which generated the desired product 8 in
only 5 minutes 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 investigations were carried out to
improve the product yields under various 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 molar 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 molar 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
molar 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 molar 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 aprotic solvents, such as acetonitrile, provided lower yields (Table 1, entries
13–14). As expected, polar protic solvents, such as methanol, 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.
Table 1. Optimization of the reaction conditions for selective removal of C6-methyl of glucuronic acid
Entry
1
Base
Solvent
acetone
Time
5 min
Equiv
2.0
Yielda
42%
LiOH
2
3
4
5
6
7
LiOH
LiOH
NaOH
NaOH
NaOH
KOH
acetone
acetone
acetone
acetone
acetone
acetone
5 min
5 min
5 min
5 min
5 min
5 min
2.5
3.0
2.0
2.5
3.0
2.0
51%
14%
74%
91%
23%
95%

4
8
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
acetone
acetone
10 min
30 min
5 min
30 min
3 h
2.0
2.0
3.0
1.0
1.0
2.0
3.0
2.0
2.0
93%
90%
82%
12%
17%
40%
80%
46%
10%
9
10
11
12
13
14
15
16
acetone
acetone
acetone
acetonitrile
acetonitrile
methanol
methanol
5 min
5 min
5 min
10 min
a Isolated yields.
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 provided
from intermediate 5 in a 95% yield by our method. In addition, 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 coumarin. Sugar amino acids (SAAs), the carbohydrate derivatives bearing both amino and
carboxylic acid functional groups, represent an important class of such new molecules that can be used to create
novel
materials
with
potential
applications
as
glycomimetics
and
peptidomimetics15-18
.
Considering the importance 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 alcohols. Compound 16 could be obtained by treatment of aromatic amine with isothiocyanate
intermediate in good yield (see supporting 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.

5
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 when dealing with
potassium hydroxide to remove the C6 methyl. Highly pure 21 and 23 can be isolated in excellent yields.
Moreover, this selective condition furnished the products without affecting either the sugar anomeric center or
the lactone ring.
OR
OR
OR
OR
O
O
O
O
O
O
O
O
AcO
AcO
BzO
BzO
BzO
BzO
BzO
BzO
N3
OBz
OCH3
NHAc
OAc
OBz
OBz
OBz
9: R=Me
10: R=H
5: R=Me
11: R=H
12: R=Me
13: R=H
14: R=Me
15: R=H
a
a
a
a
Yield=75%
Yield=95%
Yield=99%
Yield=97%
OR
O
O
OR
BzO
BzO
O
O
H
O
OBz
H
N
BzO
BzO
N
O
BzO
BzO
OBz
OBz
S
OBz
16: R=Me
17: R=H
a
18: R=Me
19: R=H
a
Yield=97%
Yield=98%
O
O
OR
OR
O
O
O
O
N
O
O
N
CH3
CH3
O
BzO
BzO
BzO
BzO
O
N
OBz
OBz
20: R=Me
21: R=H
22: R=Me
23: R=H
a
a
Yield=96%
Yield=98%
Reagents and conditions: (a) KOH (2.0 equiv.), acetone, 5 min.
Scheme 3. Selective removal of the C6 methyl group on different glucuronic acid substrates
Conclusion
In summary, an efficient and reliable procedure for the synthesis of C6-carboxyl glucuronyl acid and its
application in the preparation 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 centre and free C6
carboxyl group, the syntheses of further saccharide compounds may be expected, and their utilization in
carbohydrate chemistry can also undergo fast progress.
Acknowledgments

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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).
Supplementary data:
1
All the preparative procedures for the substrates descripted above and the H and 13C NMR spectra of
synthesized compounds are provided in supporting information.
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Graphical Abstract
A method for exceptionally selective removing the C6 methyl protecting group by potassium
hydroxide without affecting the benzoyl protecting groups on the C2, C3 and C4 hydroxyl
groups of certain glucuronic acid derivatives in high yields (95%–99%) was reported.

8
Highlights
•
•
•
•
Highly effective and efficient method for synthesis of glucuronic acid derivatives.
Exceptionally selective removing the C6 methyl from glucuronic acid ester.
Mild conditions; short reaction time; lower cost; easy operation; excellent yields.
Rapid access to relevant carbohydrates in a labor-saving and economical manner.