Mono- vs. di-fluorous-tagged glucosamines for iterative oligosaccharide synthesis

Article abstract of DOI:10.1016/j.jfluchem.2008.05.001

Fluorous-tagged protecting groups are attractive tools for elongating carbohydrate chains in oligosaccharide synthesis. To eliminate the accumulation of failed sequences during automated oligosaccharide synthesis conditions, an additional C₈F₁₇ ester derived protecting group was attached to the glycosyl donor to better retain the desired doubly tagged glycosylation product on fluorous solid-phase extraction (FSPE) cartridges. Initial studies show that the double-fluorous-tagging strategy offers a robust enough separation using a commercial FSPE cartridge using simple gravity filtration to separate the desired product from the singly fluorous-tagged starting materials and their decomposition products. In addition, removal of the fluorous acetate and its by-products after sodium methoxide treatment and neutralization required only dissolution of the desired sugar in toluene and subsequent removal of the toluene layer from the denser fluorous by-products.

Full text of DOI:10.1016/j.jfluchem.2008.05.001

Journal of Fluorine Chemistry 129 (2008) 978–982
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Mono- vs. di-fluorous-tagged glucosamines for iterative oligosaccharide synthesis
*
Gisun Park, Kwang-Seuk Ko, Aleksandra Zakharova, Nicola L. Pohl
Department of Chemistry and the Plant Sciences Institute, 2756 Gilman, Iowa State University, Ames, IA 50011, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
Fluorous-tagged protecting groups are attractive tools for elongating carbohydrate chains in oligosacchar-
ide synthesis. To eliminate the accumulation of failed sequences during automated oligosaccharide
synthesis conditions, an additional C8F17 ester derived protecting group was attached to the glycosyl donor
to better retain the desired doubly tagged glycosylation product on fluorous solid-phase extraction (FSPE)
cartridges. Initial studies show that the double-fluorous-tagging strategy offers a robust enough separation
using a commercial FSPE cartridge using simple gravity filtration to separate the desired product from the
singly fluorous-tagged starting materials and their decomposition products. In addition, removal of the
fluorous acetate and its by-products after sodium methoxide treatment and neutralization required only
dissolution of the desired sugar in toluene and subsequent removal of the toluene layer from the denser
fluorous by-products.
Received 5 April 2008
Received in revised form 30 April 2008
Accepted 1 May 2008
Available online 8 May 2008
Keywords:
Fluorous-assisted separation
Carbohydrates
Fluorous acetate
ß 2008 Elsevier B.V. All rights reserved.
1. Introduction
of compounds with heavy fluorous tags in organic solvents is hard
to predict. A light fluorous (C8F17) tag, on the other hand, has been
The isolation of pure, structurally well-defined oligosaccharides
from nature is generally a tedious and inefficient process, because
these biomolecules are often present in low concentrations as
microheterogeneous mixtures. A better understanding of the
growing numbers of biological processes that carbohydrates
mediate [1] demands efficient ways to access these structures.
Studies of proteins and nucleic acids have thrived since automated
solid-phase chemistry has been discovered [2]. The same principle
was applied to automated oligosaccharide synthesis as well to
produce various oligosaccharide compounds [3]. However, the
production of these compounds required a large excess of donor
molecules to achieve reasonable coupling yields on a solid support
and reaction monitoring is more difficult than in solution. To
circumvent some of the inherent limitations of automated solid-
phase synthesis, we have pursued a solution-phase approach. A
lipid introduced to a monosaccharide building block [4] while
maintaining solubility in organic solvents offers a handle to easily
purify the desired compound; however, this tag complicates
reaction monitoring by proton NMR. Due to its facile purification
from non-fluorous compounds and silence in proton NMR spectra,
fluorous tags have become an attractive tool for many synthetic
processes [5]. Highly fluorinated versions of silyl, ether, and ester
protecting groups [6] have been applied to oligosaccharides
synthesis using liquid-phase extractions. Unfortunately, solubility
shown to cap failed sequences in solid-phase oligosaccharide
synthesis [7] and more recently has been shown [8] to be stable to
all the reaction conditions required for the requisite glycosylation
and deprotection conditions with no problems with solubility or
purification of intermediates using fluorous solid-phase extraction
(FSPE) [9]. The fast and robust separation of the fluorinated
compounds also makes the method amenable to automation.
A potential problem with a single-fluorous-tag strategy occurs
when a reaction does not go to completion. Addition of a fluorous
tag to both rather than just one of the coupling partners offers a
chance to eliminate by-product build up during the synthesis
without addition of a capping [7] step (Fig. 1). The structure/
retention trends in fluorous chromatography have been studied
previously [10] where the larger the tag size, the stronger its
retention on fluorinated silica gel. However, these comparison
studies were performed on a FluoroFlashTM HPLC column. Success
needs to be demonstrated using a simple gravity elution strategy
for ready incorporation into an automation scheme. In addition,
the benefit of removing singly tagged starting materials and their
decomposition products from the doubly tagged desired products
after a glycosylation cycle might be lost if the two single-fluorous-
tagged products generated during the deprotection cycle are not
easily separated by means other than FSPE. Herein we report the
introduction of a light fluorous acetate protecting group for
oligosaccharide synthesis and the viability of separating mono-
from di-tagged saccharides using only simple FSPE cartridges to
remove any excess/unreacted reagents in the context of build-
ing 1–4-linked glucosamine oligomers. We also report a simple
* Corresponding author. Tel.: +1 515 294 2339; fax: +1 515 294 0105.
E-mail address: npohl@iastate.edu (N.L. Pohl).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.05.001

G. Park et al. / Journal of Fluorine Chemistry 129 (2008) 978–982
979
Fig. 1. Comparison of a single- vs. double-fluorous-tag strategy for iterative oligosaccharide synthesis.
method to remove the fluorous acetate by-product from the
desired fluorous-tagged sugar in the deprotection cycle.
served as a good starting point. The 4-position hydroxyl 1 was
treated with 2H,2H,3H,3H-perfluoro undecanoic acid to provide
compound 2. This fluorous-tagged intermediate was then further
elaborated to the trichloroacetimidate [13] donor 4 ready for
glycosylation.
2. Results and discussion
With the fluorous-tagged monosaccharide donor 4 in hand, we
next tested the use of the di-tagging strategy by addition of the
donor to a fluorous allyl [11d] group (Scheme 2). After the 0.5 h
reaction time, the quenched crude mixture was concentrated and
then loaded onto a 2 g fluorous solid-phase extraction cartridge
(Fig. 2). The cartridge was first eluted with 80% methanol/20%
water for five column volumes. All the non-fluorinated compounds
were thereby eluted. The elution solvent was then changed to 90%
methanol/10% water for five column volumes to investigate any
elution of fluorinated compounds. Fortunately, the excess donor
that was now decomposed to hydroxyl 3 started to elute out of the
cartridge along with a trace amount of the unreacted fluorous allyl
tag (Fig. 2). The desired di-fluorous-tagged compound was readily
retained in the FSPE cartridge while all the unreacted/excess
reagents were removed. Finally, the desired di-tagged compound 5
In order to investigate the ease of purification of di-tagged
saccharide products, the synthesis of a fluorous-tagged donor and
fluorous-tagged acceptor was necessary. In our previous studies
using fluorinated tags for oligosaccharide synthesis [11], fluorous
allyl groups are attached at the anomeric position of the reducing
end of the oligosaccharide for chain extension at the nonreducing
end. This fluorous allyl group would again serve as a good acceptor.
The synthesis of an activated glucosamine donor was then
undertaken in which a fluorous acetate was installed at the chain
extension position. Among the different functionalities of fluori-
nated-protecting groups that could be applied, an ester derived
fluorous protecting group was selected for its simple and readily
automated deprotection conditions. The known partially protected
glucosamine building block 1 (Scheme 1) [12] with an easily
removable tert-butyl dimethyl silyl group on the anomeric position
Scheme 1.
Scheme 2.

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G. Park et al. / Journal of Fluorine Chemistry 129 (2008) 978–982
Fig. 2. (a) Selective elution of the multiple fluorous-tagged compounds using a FSPE cartridge and various elution conditions. (b) HPLC traces of the compounds eluted off the
FSPE cartridge with 90% or 100% methanol elution. (HPLC conditions: 15% ethyl acetate/85% hexane, 1 ml/min flow rate, injection peak appeared at 1.5 min on a standard
silica gel column.)
Scheme 3.
was eluted from the cartridge using 100% methanol as eluent. HPLC
traces (Fig. 2) of the eluents confirmed the complete separation of
the desired di-fluorous-tagged compound from the crude glyco-
sylation mixture.
drate synthesis. Use of a fluorous tag on not just the glycosyl
acceptor, but also the glycosyl donor proved useful in the
separation of the desired glycosylation product from the unreacted
or decomposed starting materials with only simple gravity
filtration over a commercially available FSPE cartridge. The doubly
tagged carbohydrate compound was retained in the cartridge
sufficiently well to allow facile separation with a discrete increase
of methanol concentrations in the aqueous eluent. The problem of
thereby generating two singly fluorous-tagged components in the
deprotection cycle was avoided by exploiting the difference in
solubility between the tagged sugar and the fluorous acetate
protecting group by-products. Work is now in progress to test the
feasibility of this double-fluorous-tagging approach in the iterative
synthesis of oligosaccharides using FSPE separations on a solution-
based automation platform.
The di-tagged monosaccharide 5 was then deprotected at the 4-
position to allow further chain elongation (Scheme 3). Removal of
the 2H,2H,3H,3H-perfluoro undecanoyl group was performed under
standard sodium methoxide conditions to provide compound 6.
Now, of course, the desired product and the by-product both contain
just one C8F17 tag and therefore FSPE is no longer a simple strategy
for separation. However, alcohol 6, containing a large organic
portion in addition to the fluorous tag, readily dissolved in toluene
whereas the fluorous acetate by-products formed a separate denser
layer for easy separation. Hence, the physical property differences
could be exploited for facile separation. Because growing saccharide
chains with the fluorous allyl tag have good solubility in toluene as a
rule, this method of fluorous acetate removal from the desired
compound after the deprotection reaction should be a general
strategy. In addition to fluorous acetate, other fluorous protecting
groups have the potential to be used after testing of their solubility
and volatility properties.
4. Experimental
4.1. General experimental procedures
Commercial reagents and solvents were used as received
without further purification unless otherwise stated. The reactions
were monitored and the Rf values determined using analytical thin
layer chromatography (tlc) with 0.25 mm EM Science silica gel
plates (60F-254). The developed tlc plates were visualized by
immersion in p-anisaldehyde solution followed by heating on a hot
plate. Silica gel flash chromatography was performed with Selecto
3. Conclusion
In conclusion, we have introduced a fluorous acetate group as a
second protecting group to use in conjunction with our previously
reported fluorous allyl group for light-fluorous-based carbohy-

G. Park et al. / Journal of Fluorine Chemistry 129 (2008) 978–982
981
Scientific silica gel, 32–63 mm particle size. Fluorous-phase
chromatography was performed using fluorous solid-phase extrac-
tion cartridges containing silica gel bonded with perfluoroocty-
lethylsilyl chains (Fluorous Technologies, Inc., Pittsburgh, PA). All
other fluorous reagents were also obtained from Fluorous
Technologies, Inc. All moisture sensitive reactions were performed
in flame- or oven-dried glassware under nitrogen atmosphere.
Bath temperatures were used to record the reaction temperature.
All reactions were stirred magnetically at ambient temperature
unless otherwise indicated. 1H NMR and 13C NMR spectra were
obtained with a Bruker DRX400 at 400 MHz and 162 MHz. 1H NMR
was stirred at room temperature for 0.5 h and then filtered over a
pad of Celite. The filtered solution was concentrated under reduced
pressure and the crude product was purified by flash column
chromatography on silica gel using 10% EtOAc/hexane as eluent to
obtain compound 4 (83 mg, 0.08 mmol, 93%) as a colorless oil.
1H NMR (400 MHz, CDCl3):
d 2.22-2.54 (4H, m, CH2CH2), 3.50–
3.67(2H,m,H-3, H-5),4.01–4.09(2H,m,H-6), 4.37(1H, t,J = 10.0 Hz,
H-2), 4.43–4.70 (4H, m), 5.40 (1H, t, J = 9.9 Hz, H-4), 6.47 (1H, d,
J = 3.6 Hz, H-1), 6.67(1H, d, J = 8.8 Hz, NH), 7.25–7.39 (10H, m, C6H5),
8.80 (1H, s, NH); 13C NMR (162 MHz, CDCl3):
d 61.2, 68.3, 69.8, 69.9,
70.0, 72.1, 73.2, 73.6, 76.0, 90.7, 92.1, 94.3, 127.7, 128.2, 128.3, 128.4,
128.4, 128.7, 137.0, 137.8, 158.9, 161.8, 170.0; MS (ESI) m/z = calcd.
for C35H27Cl6F17N2NaO7: 1142.9576; found: 1142.9590 [M+Na]+.
spectra were reported in parts per million (
(7.27 ppm) as an internal reference. 13C NMR spectra were
reported in parts per million ( ) relative to CDCl3 (77.23 ppm).
HPLC traces were obtained using a Varian Inc. HPLC with a Waters
Nova-pak 4
d) relative to CDCl3
d
4.4. Synthesis of cis-4-(1H,1H,2H,2H,3H,3H-perfluoroundecyloxy)-2-
butenyl-3,6-di-O-benzyl-2-deoxy-2-trichloroacetimido-4-
m
l 3.9 mm  150 mm silica column. High resolution
mass spectrometry was obtained with an Applied Biosystems
QSTAR XL Hybrid System.
(2H,2H,3H,3H-perfluoroundecanoyl)-b-D-glucopyranoside (5)
To a solution of the imidate (83 mg, 0.07 mmol) in anhydrous
toluene (2 ml) at 0 8C was added fluorous allyl alcohol [11d]
(25.5 mg, 0.05 mmol) in anhydrous toluene (2 ml) followed by
4.2. Synthesis of tert-butyldimethylsilyl 3,6-di-O-benzyl-2-deoxy-2-
trichloroacetimido-4-2H,2H,3H,3H-perfluoroundecanoatyl-b-D-
glucopyranoside (2)
trimethylsilyl trifluoromethanesulfonate (0.9 ml, 5.0 mmol). The
reaction mixture was stirred for 0.5 h and then quenched with
three drops of triethylamine. The reaction mixture was concen-
trated under reduced pressure and dissolved with DMF (0.4 ml) to
load onto a 2 g FSPE cartridge. The loaded cartridge was first
washed with 3 ml (one column volume) 80% methanol/20% water
mixture five times and then was washed with 3 ml 90% methanol/
10% water mixture five times. After TLC confirmed that no other
compounds were eluting from the cartridge, the solvent was
changed into 100% methanol (10 ml) to elute out the desired
compound. The eluent was concentrated under reduced pressure
to provide 5 as a colorless oil (65 mg, 0.044 mmol, 87%).
To a solution of tert-butyldimethylsilyl 3,6-di-O-benzyl-2-
deoxy-2-trichloroacetimido- -glucopyranoside 1 [9] (100 mg,
b
-D
0.16 mmol) in dichloromethane (10 ml) cooled to 0 8C, was added
DCC (66.5 mg, 0.32 mmol), DMAP (19.5 mg, 0.16 mmol) and
2H,2H,3H,3H-perfluoroundecanoic acid (157 mg, 0.32 mmol).
The reaction mixture was allowed to warm to room temperature
over 2 h. The reaction was diluted with dichloromethane (20 ml),
washed with water (20 ml), HCl (2N, 20 ml), and brine (20 ml), and
dried over MgSO4. After the solvent was removed under reduced
pressure, crude product was purified by flash column chromato-
graphy on silica gel using 15% EtOAc/hexane as eluent to obtain the
title compound (160 mg, 0.14 mmol, 92%) as colorless oil.
1H NMR (400 MHz, CDCl3):
OCH2CH2CH2C8F17), 2.01–2.43 (6H, m, C(O)CH2CH2C8F17
d
1.87–1.88 (2H, m,
–
–
,
1H NMR (400 MHz, CDCl3):
d
0.23 (6H, 2CH3), 0.9 (9H, s, t-Bu-),
OCH2CH2CH2C8F17), 3.46 (3H, m, CH2O–, H-3), 3.56 (2H, d,
J = 4.8 Hz, H-6), 3.66 (1H, m, H-5), 4.04 (2H, t, J = 5.2 Hz, CH2CH ),
), 4.26–4.38 (3H, m, H-2, CH2CH ), 4.46–4.73 (4H, m, 2CH2), 5.07
(1H, d, J = 8.0 Hz, H-1), 5.12 (1H, t, J = 9.6 Hz, H-4), 5.64–5.76 (2H,
2.11–2.29 (4H, m, CH2CH2), 3.45 (1H, m, H-3), 3.56 (2H, m, H-6),
3.74 (1H, m, H-5), 4.35 (1H, dd, J = 9.2 Hz, 10.4 Hz, H-2), 4.46–4.74
(4H, m, 2CH2), 5.12 (1H, t, J = 9.2 Hz, H-4), 5.23 (1H, d, J = 7.8 Hz, H-
1), 7.06 (1H, d, J = 7.6 Hz, NH), 7.22–7.40 (10H, m, –2 C6H5); 13C
m, –CH CH–), 7.01 (1H, d, J = 6.8 Hz, NH), 7.27-7.35 (m, 10H); 13
NMR (162 MHz, CDCl3): 25.4, 26.3, 64.9, 66.6, 69.0, 69.7, 72.5,
C
NMR (162 MHz, CDCl3):
d
À5.2, À4.2, 17.9, 25.7, 61.1, 69.8, 72.5,
d
72.8, 73.6, 74.2, 76.8, 77.1, 77.3, 92.4, 94.0, 127.7, 127.7, 127.8,
128.0, 128.4, 128.5, 137.6, 137.7, 161.8, 170.0; MS (ESI) m/z = calcd.
for C39H41Cl3F17NNaO7Si: 1014.1344; found: 1014.1367 [M+Na]+.
72.7, 73.1, 73.2, 73.8, 74.8, 77.4, 77.5, 97.6, 98.5, 127.7, 128.2,
128.3, 128.4, 128.4, 128.7, 130.8, 130.9,137.0, 137.7, 162.0, 170.2;
MS (ESI) m/z = calcd. for C48H38Cl3F34NNaO8: 1530.1018; found:
1530.1198 [M+Na]+.
4.3. Synthesis of 3,6-di-O-benzyl-2-deoxy-2-trichloroacetimido-4-
(2H,2H,3H,3H-perfluoroundecanoyl)-
a
-
D-glucopyranosyl
4.5. Synthesis of cis-4-(1H,1H,2H,2H,3H,3H-perfluoroundecyloxy)-2-
trichloroacetimidate (4)
butenyl-3,6-di-O-benzyl-2-deoxy-2-trichloroacetimido-b-D-
glucopyranoside (6)
To a solution of tert-butyldimethylsilyl 3,6-di-O-benzyl-2-
deoxy-2-trichloroacetimido- -glucopyranoside (100 mg,
b
-
D
2
To a solution of the glycosylated compound 5 (50 mg,
0.09 mmol) in anhydrous THF, 1.0 M TBAF solution in THF
(0.18 ml, 0.18 mmol) was added dropwise in a 0 8C ice bath. The
reaction mixture was allowed to warm to room temperature over
1 h. After the solvent was removed under reduced pressure, crude
reaction mixture was dissolved with DMF (0.4 ml) and loaded onto
a 2 g FSPE cartridge. The cartridge was washed with 80% methanol
(10 ml) followed by 100% methanol (10 ml) to elute the fluorinated
desired product. The solvent was removed under reduced pressure
to obtain the product (80 mg, 0.08 mmol, 89%) as colorless oil. The
compound was used directly for the next step without further
purification.
0.03 mmol) in methanol (1 ml) was added 0.5 M NaOMe solution
(0.06 ml, 0.03 mmol). The reaction mixture was stirred for 0.5 h
and then was neutralized with Amberlyst acidic resin. The reaction
mixture was filtered and the solvent was removed under reduced
pressure. The crude product was shaken with toluene (1 ml). The
clear solution was removed with a pipette from a denser yellow oil
and the solvent was removed under reduced pressure to yield 6 as
a colorless oil (31 mg, 0.027 mol, 91%).
1H NMR (400 MHz, CDCl3):
d
1.72–1.80 (2H, m,
–
OCH2CH2CH2C8F17), 2.04–2.17 (2H, m, –OCH2CH2CH2C8F17), 3.01
(1H, d, J = 2.2 Hz, –OH), 3.46 (2H, m, CH2O–), 3.60–3.65 (1H, m, H-
5), 3.75–3.91 (5H, m, H-4, H-6, CH2CH ), 4.05–4.21 (4H, m, H-2, H-
3, CH2CH ), 4.50–4.77 (4H, m, 2CH2), 5.12 (1H, d, J = 8.0 Hz, H-1),
5.64–5.76 (2H, m, –CH CH–), 7.00 (1H, d, J = 6.9 Hz, NH), 7.27–
To a solution of the alcohol (80 mg, 0.08 mmol) in anhydrous
DCM (5 ml) was added Cs2CO3 (66.6 mg, 0.2 mmol) and distilled
trichloroacetonitrile (0.04 ml, 0.4 mmol). The reaction mixture

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G. Park et al. / Journal of Fluorine Chemistry 129 (2008) 978–982
(c) T. Miura, K. Goto, D. Hosaka, T. Inazu, Angew. Chem. Int. Ed. 42 (2003) 2047–
2051;
(d) T. Miura, K. Goto, H. Waragai, H. Matsumoto, Y. Hirose, M. Ohmae, H.-k. Ishida,
A. Satoh, I. Inazu, J. Org. Chem. 69 (2004) 5348–5353;
(e) T. Miuram, A. Satoh, K. Goto, Y. Murakami, N. Imai, T. Inazu, Tetrahedron
Asymmetry 16 (2005) 3–6.
7.35 (10H, m); MS (ESI) m/z = calcd. for C37H35Cl3F17NNaO7:
1056.1105; found: 1056.1177 [M+Na]+.
Acknowledgements
[7] E.R. Palmacci, M.C. Hewitt, P.H. Seeberger, Angew. Chem. Int. Ed. 40 (2001) 4433–
4437.
This material is based in part upon work supported by the
National Institute of General Medical Sciences (1R41M075436-01
and 2R42GM075436-02). N.L.P. is a Cottrell Scholar of Research
Corporation and an Alfred P. Sloan Research Fellow.
[8] F.A. Jaipuri, N.L. Pohl, Org. Biomol. Chem. 6 (2008), doi:10.1039/b803451f.
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