Benzylidene Acetal Protecting Group as Carboxylic Acid Surrogate: Synthesis of Functionalized Uronic Acids and Sugar Amino Acids

Article abstract of DOI:10.1002/chem.201503998

Direct oxidation of the 4,6-O-benzylidene acetal protecting group to C-6 carboxylic acid has been developed that provides an easy access to a wide range of biologically important and synthetically challenging uronic acid and sugar amino acid derivatives in good yields. The RuCl₃-NaIO₄-mediated oxidative cleavage method eliminates protection and deprotection steps and the reaction takes place under mild conditions. The dual role of the benzylidene acetal, as a protecting group and source of carboxylic acid, was exploited in the efficient synthesis of six-carbon sialic acid analogues and disaccharides bearing uronic acids, including glycosaminoglycan analogues.

Full text of DOI:10.1002/chem.201503998

DOI: 10.1002/chem.201503998
Communication
&
Synthetic Methods
Benzylidene Acetal Protecting Group as Carboxylic Acid
Surrogate: Synthesis of Functionalized Uronic Acids and Sugar
Amino Acids
Amit Banerjee, Soundararasu Senthilkumar, and Sundarababu Baskaran*[a]
fatty acid derivatives, retinoids, bile acids, and metabolism of
drugs in human body through glucuronidation.[5a] Sialic acids,
Abstract: Direct oxidation of the 4,6-O-benzylidene acetal
protecting group to C-6 carboxylic acid has been devel-
oped that provides an easy access to a wide range of bio-
logically important and synthetically challenging uronic
acid and sugar amino acid derivatives in good yields. The
RuCl3–NaIO4-mediated oxidative cleavage method elimi-
nates protection and deprotection steps and the reaction
takes place under mild conditions. The dual role of the
benzylidene acetal, as a protecting group and source of
carboxylic acid, was exploited in the efficient synthesis of
six-carbon sialic acid analogues and disaccharides bearing
uronic acids, including glycosaminoglycan analogues.
SAA analogues often located on the periphery of glycopro-
teins, are responsible for the various biological functions, such
as cell–cell recognition, adhesion, and intracellular signaling
events,[5b,c] whereas heparin plays crucial regulatory roles in
embryogenesis, cell adhesion, and viral invasion, and also in
the processes of tumor onset, growth, and metastasis.[5d,e]
Moreover, functionalized uronic acid derivatives are used as
valuable building blocks in the synthesis of glycoproteins, pro-
teoglycans, and functional polymers,[6] whereas sugar amino
acids are used as scaffolds in combinatorial chemistry and in
a template-directed synthesis of biopolymers as well as in pep-
tidomimetics.[7]
The synthesis of uronic acid is traditionally achieved by the
oxidation of the C-6 primary alcohol of a monosaccharide to
the corresponding C-6 carboxylic acid. The efficient synthesis
of uronic acid often relies on the choice of protecting groups,
oxidizing agent, and reaction conditions. Although, various oxi-
dation methods have been introduced for the conversion of
the C-6 primary alcohol of monosaccharides to uronic acid de-
rivatives, most of the approaches are not very general or effi-
cient. Among the reported methods, the TEMPO-mediated oxi-
dation is considered to be more general.[8] However, synthesis
of a free C-6 primary alcohol requires additional orthogonal
protection and deprotection protocols, which ultimately
reduce the efficiency of the overall synthesis (Scheme 1).
Recently, we developed a novel method for the direct oxida-
tive cleavage of a benzylidene acetal to the corresponding
benzoyloxy carboxylic acid using the RuCl3–NaIO4 reagent
system.[9,10] Since benzylidene acetal has been extensively used
Uronic acids and sugar amino acids (SAAs) are ubiquitous in
many biological systems and play a vital role in diverse physio-
logical functions.[1,2] Uronic acids are often found in various
naturally occurring polysaccharides, such as glycosaminogly-
cans and homoglycuronans (Figure 1).[3] Glycosaminoglycans,
Figure 1. Uronic acid and sugar amino acid (SAA) containing natural mole-
cules.
for example heparin, hyaluronan, and chondroitin, consist of
repeating disaccharide units of uronic acids and amino sugars,
whereas homoglycuronans, such as alginate and pectin, are
composed of only uronic acid moieties.[4] Uronic acids are
often responsible for the xenobiotic metabolism of many com-
pounds, such as pollutants, androgens, estrogens, bilirubin,
[a] Dr. A. Banerjee, S. Senthilkumar, Prof. Dr. S. Baskaran
Department of Chemistry
Indian Institute of Technology Madras
Chennai-600036 (India)
E-mail: sbhaskar@iitm.ac.in
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503998.
Scheme 1. Direct oxidation of 4,6-O-benzylidene protecting group to uronic
acid.
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Communication
for the protection of a 4,6-diol of carbohydrate molecules, we
envisaged that the RuCl3–NaIO4 based direct oxidative cleav-
age method would provide a rare opportunity of converting
the 4,6-O-benzylidene acetal protecting group to a synthetically
challenging carboxylic acid group at the C-6 position. More-
over, the one-pot approach of converting a protecting group
to useful functional group would eliminate a number of differ-
ential protection and deprotection protocols. Thus, exposure
of 4,6-O-benzylidene glucopyranoside (1a) to the RuCl3–NaIO4
reagent system resulted in a smooth oxidative cleavage to fur-
nish the corresponding d-glucuronic acid derivative 1 in good
yield with a high degree of regioselectivity (Scheme 1). This
one-pot oxidative cleavage is found to be chemoselective and
furnishes the product without affecting the anomeric center.[11]
Moreover, under the reaction conditions, the newly formed
benzoate functional group does not undergo b-elimination to
a,b-unsaturated acid.
4,6-O-benzylidene pyranosides bearing an amino derivative
were prepared and subjected under RuCl3–NaIO4 oxidation
conditions. As expected, the benzylidene acetal protecting
group underwent a smooth oxidation to furnish the corre-
sponding sugar amino acid derivatives in very good yields
(Table 2). The structure and stereochemistry of the sugar
amino acid derivative 18 were confirmed by single-crystal X-
ray analysis (Figure 2).[14]
Table 2. Direct oxidation of 4,6-O-benzylidene pyranosides to sugar
amino acid derivatives.[a]
The generality of this methodology was tested with several
4,6-O-benzylidene pyranosides, which resulted in the isolation
of d-mannuronic and d-galacturonic acid derivatives in good
yields. This method is found to be equally effective for the
direct oxidation of various 3,5-O-benzylidene furanosides to
the corresponding penturonic acid derivatives in good yields
(Table 1). Intriguingly, the oxidative cleavage of 5,6-O-benzyli-
[a] Yield of the pure isolated product is given.
Table 1. Direct oxidation of benzylidene acetal protecting groups to
uronic acid and penturonic acid derivatives.[a]
Figure 2. ORTEP diagram of compound 18.
This oxidative cleavage method is also found to be effective
for the synthesis of azido uronic acid derivatives. Since the re-
gioselective introduction of an amino group at the C-2 or C-3
position of the sugar amino acid is very challenging, a simple
and efficient approach has been developed for the regioselec-
tive synthesis of 2-azido and 3-azido uronic acids from
-common intermediate 20 (Scheme 2).[15]
Similarly, the RuCl3–NaIO4-mediated oxidative cleavage of 1-
azido-4,6-O-benzylidene pyranosides furnished the correspond-
ing 1-azido uronic acid derivatives 26 and 27 as sugar amino
acid precursors (Scheme 3). Remarkably, the free hydroxyl
group of 26a was found to be stable under the oxidation con-
ditions that was further confirmed by single-crystal X-ray analy-
sis of 26 (Figure 3).[14]
The efficiency of this oxidative cleavage approach was fur-
ther shown in the synthesis of a six-carbon sialic acid frame-
work.[16] Thus, benzylidene acetals 28a[17a] and 29a,[17b] derived
from the l-sorbose on exposure to the RuCl3–NaIO4 reagent
system, underwent oxidative cleavage to give the correspond-
ing six-carbon sialic acid derivatives 28 and 29, respectively, in
good yields (Scheme 4).
[a] Yield of the pure isolated product is given.
dene furanoside afforded d-glucuronic acid derivative 10,
which in turn can be converted to the l-iduronic acid deriva-
tive, a principal constituent of heparin and heparan sulfates.[12]
Evidently, this reaction takes place readily under mild condi-
tions and sensitive functional groups, such as OTs, OAc, OTBS
and isopropylidene acetal, were found to stable under the re-
action conditions.[13]
The usefulness of 4,6-O-benzylidene acetal protecting group
as a carboxylic acid surrogate was further tested in the synthe-
sis of functionalized sugar amino acid (SAA) derivatives. The
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step.[19] With the advent of direct oxidation of 4,6-O-benzyli-
dene acetal protecting group to C-6 carboxylic acid, this
method provides a viable alternative for the post-glycosylation
oxidation strategy, wherein the oxidation step could be carried
out after the assembly of the oligosaccharide chain. According-
ly, a simple two-step protocol was envisaged based on the
Schmidt glycosylation[20] and subsequent oxidation of 4,6-O-
benzylidene acetal with RuCl3–NaIO4. Based on this approach,
several uronic acids containing functionalized disaccharides, in-
cluding glycosaminoglycan analogues, were readily achieved
in good yields (Table 3).
Scheme 2. Synthesis of 2-azido and 3-azido uronic acid derivatives.
In conclusion, we have developed a mild and efficient
method for the synthesis of functionalized uronic acid and
sugar amino acid derivatives by direct oxidation of 4,6-O-ben-
zylidene pyranosides using the RuCl3–NaIO4 reagent system. In
this oxidative cleavage method, the benzylidene acetal pro-
tecting group serves as a carboxylic acid surrogate and pro-
vides an easy access to a wide range of biologically relevant
and synthetically useful azido uronic acids and six-carbon sialic
acid analogues. This single-step reaction is chemo- and regio-
selective, and tolerates many sensitive functional groups, such
as OTs, OAc, OTBS, N3, and isopropylidene acetal. The signifi-
cance of this method is further demonstrated in the efficient
synthesis of uronic acid containing disaccharides and glycos-
aminoglycan analogues. Further applications of such reactions
using this methodology are in progress.
Scheme 3. Synthesis of 1-azido uronic acid derivatives.
Experimental Section
General procedure for the oxidation of 4,6-O-benzylidene
pyranoside to uronic acid derivative
To a stirred solution of compound 1a (183 mg, 0.5 mmol) in
CH3CN:CCl4:H2O (1:1:0.5) (2.5 mL) solvent system was added
NaIO4 (1.07 g, 5.0 mmol) followed by RuCl3·3H2O (20 mg,
0.01 mmol) and the mixture was stirred at room temperature
for 3.5 h. After completion of the reaction as indicated by TLC,
IPA (2 mL) was added into the reaction mixture and the resul-
tant solid mass was filtered through a pad of Celite and
washed with EtOAc. The organic layers were collected, dried
over anhydrous Na2SO4 and concentrated under reduced pres-
sure. Purification of the crude product over silica gel using
column chromatography (gradient elution with 15–25% EtOAc
in hexane) yielded the pure compound 1 (120 mg, 61%) as
a colorless liquid.
Figure 3. ORTEP diagram of compound 26·H2O.
The scope of this methodology was further explored in the
synthesis of uronic acid containing oligosaccharides and glyco-
conjugates.[18] Since the introduction of a C-6 carboxylic acid
group in oligosaccharides at a later stage is a challenging task,
a pre-glycosylation oxidation approach is generally followed, in
which uronic acid building blocks are used in the glycosylation
Acknowledgements
We thank DST and CSIR, New Delhi for financial support and
DST-FIST, New Delhi for infrastructure facilities. A.B. and S.S.
thank CSIR-New Delhi and UGC-New Delhi, respectively, for re-
search fellowships. The authors thank V. Ramkumar for single-
crystal X-ray analysis.
Keywords: acetals · amino acids · carboxylic acids · oxidation ·
protecting groups · uronic acids
Scheme 4. Direct oxidation of benzylidene acetals to six-carbon sialic acid
analogues.
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Received: October 6, 2015
Published online on December 7, 2015
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