Tetrahedron Letters 56 (2015) 5010–5012

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Tetrahedron Letters
jo urna l h o m epage: www.e lsevi er .co m /locat e/tetle t

A new set of orthogonal protecting groups on a monosaccharide

scaffold
Károly Ágoston a,⇑, Gregory M. Watt b, Péter Fügedi a
a
Institute of Organic Chemistry, RCNS-HAS, Magyar Tudósok Körútja 2, 1117 Budapest, Hungary
b
Carbosynth LTD, 8&9, Old Station Business Park, RG20 6NE Compton, UK

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

Article history: A monosaccharide unit was synthesized bearing four different temporary protecting groups. The protect-
Received 13 May 2015 ing groups used (Fmoc carbonate, NAP ether, levulinoyl and chloroacetyl esters) and the anomeric thio-
Revised 28 June 2015 glycoside form a new set of orthogonal protecting groups. The orthogonality of these groups has been
Accepted 4 July 2015
demonstrated on the monosaccharide scaffold.
Available online 9 July 2015
2015 Elsevier Ltd. All rights reserved.

Keywords:
Orthogonal protection
Protecting groups
Monosaccharide Scaffold
Full orthogonality

Introduction This orthogonality permits the selective modification of any posi-

The synthesis of small molecule libraries by creating diversity
around a rigid ring system is a well established strategy that is fre-
quently used by pharmaceutical companies during lead compound
identification. Monosaccharides could serve as an ideal scaffold for
these processes since they are cheap raw materials that contain
multiple chiral centers. These chiral centers fixed on a rigid ring
system provide a platform to create molecular diversity.1 The
diversity around a monosaccharide ring could be established for
two different purposes. Firstly, the targeted compound is a deco-
rated monosaccharide unit where their hydroxyl functional groups
have been modified to bear the appropriate pharmacophores for
the targeted drug candidate.2 Secondly, the modified monosaccha-
ride unit is used to build oligosaccharides. In this case the hydroxyl
functional groups of a monosaccharide unit are masked with pro-
tecting groups, while in the first case the hydroxyl functional
groups are permanently modified with the appropriate pharma-
cophore moieties. Although in both cases differentiation between
the hydroxyl functional groups of a monosaccharide unit is
required, this is not always straight-forward since the various
hydroxyl substituents often have similar reactivity.
In some cases all of the monosaccharide hydroxyl groups are
modified with protecting groups that are orthogonal to each-other.
⇑
Corresponding author at present address: Carbosynth LTD, 8&9, Old Station
Business Park, RG20 6NE Compton, UK. Tel.: +44 0 7840 347437; fax: +44 0 1635
579444.
E-mail address: karoly.agoston@carbosynth.com (K. Ágoston).
tion, allowing oligosaccharide synthesis or small molecule library
preparation from monosaccharides.
There are few literature examples where the hydroxyl func-
tional group of a monosaccharide residue is protected with 4 dif-
ferent orthogonal protecting groups.3 In the first example3a the
hydroxyl functional groups of a galactose thioglycoside were dec-
orated with two esters (chloroacetyl and levulinoyl) and two
ethers (p-methoxybenzyl and TBDPS). This monosaccharide unit
was then used as a scaffold to synthesize an oligosaccharide
library. Depending on the desired disaccharide linkage, the rele-
vant temporary protecting groups can be removed and the product
subsequently glycosylated. The deprotection-glycosylation steps
were repeated to create a library. Even though orthogonally-pro-
tected monosaccharides potentially have very broad use, since this
publication only two similarly protected monosaccharide deriva-
tives have been reported.3b,c Herein, we report the synthesis of
novel, orthogonally protected monosaccharide derivative with a
stable thio-ether group at the anomeric position that can be acti-
vated under specific conditions. This thioglycoside serves as a
model compound to test the orthogonality of the selected protect-
ing groups and potentially allows the preparation of diverse
oligosaccharide sets in a generalized fashion.
Results and discussion
The most common temporary protecting groups used in
carbohydrate chemistry are esters (acetyl, benzoyl, chloroacetyl,
and levulinoyl), carbonates (Fmoc) and ethers (benzyl, allyl,

http://dx.doi.org/10.1016/j.tetlet.2015.07.015
0040-4039/ 2015 Elsevier Ltd. All rights reserved.
 K. Ágoston et al. / Tetrahedron Letters 56 (2015) 5010–5012 5011

1 Naphth 1 Naphth 1 Naphth

O O O
O a O b O
O O O
SPh SPh SPh
HO ClAcO ClAcO
OH OH OFmoc
1 2 3

OLev OH
NAPO NAPO
d
O O
SPh SPh
ClAcO ClAcO
OFmoc OFmoc
5 4

Scheme 1. Reagents and conditions: (a) ClAcCl, CuCl 2, NaH, THF, 15 C, 1 h, 68%; (b) FmocCl, Pyridine, DCM, rt, 3 h, 60%; (c) BH3 THF, TMSOTf, DCM, rt, 3 h, 76%; (d) LevOH,
DCC, DMAP, DCM, rt, 2 h, 72%.

p-methoxybenzyl, and silyl). Several orthogonally protected
monosaccharides have been synthesized to date and their ability
to be selectively deprotected has been tested. Protecting group
combinations of levulinoyl ester, Fmoc carbonate, and diethyliso-
propylsilyl ether (DEIPS) were proven to be orthogonal,4 as were
2-(allyloxy)phenyl-acetyl, levulinoyl, and acetyl.5 Recently, other
sets of protecting groups were tested,6 but there are still numerous
combinations left to be examined.
Glucose is a monosaccharide that can be obtained and
hydrolysis of sucrose (cane sugar) or polysaccharides such as
starch and starch which are mostly found in sweet potatoes, corn,
rice, potatoes and others. Glucose contains primary alcohol
groups and secondary alcohols that can undergo oxidation.
Generally primary alcohols are more easily oxidized and
secondary alcohols. Glucose oxidation can occur in several places
depending on the reaction conditions and the type of oxidizer
used and produces various types of acids temperature (Scheme 1).
which was very difficult to purify due to migration and/or loss of
the chloroacetyl functional group during column chromatography.
To avoid this problem we decided to first protect the remaining
free hydroxyl functional group (2-OH) of derivative 2 as the
Fmoc carbonate using Fmoc-chloride significant chloroacetate
in a mixture of CH2Cl2/pyridine, affording the fully protected
derivative 3.
Opening of the napthylidene acetal with borane-THF and
TMSOTf7 as a catalyst gave compound 4 (Scheme 1) in high yield
with no observed loss or migration of the chloroacetyl functional
group during work-up or purification. Protection of the 6-OH resi-
due using levulinic acid and DCC gave the fully protected target
compound 5 as white crystals.
With fully protected D-galactose containing five different pro-
tecting groups in hand, the orthogonality of the protecting group
pattern was tested by the selective removal each protecting group
(Scheme 2). Removal of the levulinoyl ester from 5 with hydrazine
acetate9 in a mixture of CH2Cl2/MeOH afforded the 6-OH derivative
4 in excellent yield with no decomposition of the other protecting
groups. Chloroacetate ester cleavage using thiourea10 in a mixture
of toluene/methanol at reflux gave compound 6, having a free
hydroxyl in the 3-position, in almost quantitative yield (Scheme 2).
For the removal of the Fmoc group from compound 5 different
conditions were tested. Hünig’s base in CH2Cl2 resulted in only
trace cleavage of the carbamate, even after 24 h. Treatment with
triethylamine in CH2Cl2 resulted in almost complete cleavage of
the Fmoc-group after 24 h. However, this also resulted in

NAPO OLev
O
SPh
OLev ClAcO
NAPO OLev
OH HO
O 7
SPh
c O
HO SPh
ClAcO
OFmoc OFmoc
6 b OLev d
NAPO 8
O
SPh
ClAcO
NAPO OH
OFmoc
a 5 e OLev
O NAPO
SPh
ClAcO O
f OH
OFmoc
4 ClAcO
OBn
NAPO OLev OFmoc
9
O
O
O
ClAcO BnO
OBn
OFmoc
10 OMe

Scheme 2. Reagents and conditions: (a) H2NNH2/AcOH, DCM, MeOH, rt, 30 min, 85%; (b) Thiourea, Toluene, MeOH, 80 C, 45 min, 94%; (c) DBU, DCM, rt, 2 min, 65%; (d) CAN,
MeCN, H2O, rt, 2 h, 71%; (e) NBS, Acetone, H2O, 0 C, 10 min, 68%; (f) NIS, TfOH, methyl 2,3,6-tri-O-benzyl-a-D-glucopyranoside, MeCN, DCM, 30 C, 10 min, 72%.
5012 K. Ágoston et al. / Tetrahedron Letters 56 (2015) 5010–5012
significant chloroacetate ester migration to the 2-position. Finally,
catalytic DBU in DCM was found to cleave the Fmoc group with a
very short reaction time to give compound 7. Short reaction times
were found to be necessary as stopping the reaction after 10 min
resulted in partial chloroacetate ester migration to the 2-position.
Reducing the reaction time to 2 min suppressed ester migration,
while still permitting complete cleavage of the carbonate protect-
ing group.
The cleavage of the 1-naphthylmethyl ether from 5 was per-
formed using 3 equiv of CAN in wet acetonitrile to give product
8. This was isolated by crystallization since column chromatogra-
phy resulted in partial chloroacetyl group migration onto the 4-po-
sition. Gratifyingly, when the C18 stationary phase was used, no
migration of the chloroacetyl group was observed, however no
purification was achieved on a preparative scale.
The thiophenyl group was removed using NBS in acetone/water
to obtain hemiacetal 9. Finally, we examined the fully protected
galactose 5 as a glycosyl donor. Methyl 2,3,6-tri-O-benzyl-a-D-glu-
copyranoside was selected as an acceptor for glycosylation and the
thiophenyl functional group was activated with NIS/TfOH at 30 C
to give disaccharide 10. Analysis of the NMR spectrum indicated
selective formation of the b anomer.
In conclusion, a monosaccharide residue with 4 temporary pro-
tecting groups (chloroacetyl and levulinoyl esters, Fmoc carbonate,
and 1-naphthylmethyl ether) has been synthesized. The orthogo-
nality of these groups and the anomeric thiophenyl moiety has
been demonstrated. The prepared crystalline monosaccharide
derivative provides the possibility of selective modification of
any of its positions. The above mentioned protecting groups form
a new orthogonal set of which the use in oligosaccharide synthesis
is currently being investigated.
Acknowledgment
We are grateful to RCNS-HAS for their generous support of this
study.
Supplementary data
Supplementary data (detailed experimental procedures and
NMR data of the compounds) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2015.07.015.
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