Noncovalent fluorous interactions for the synthesis of carbohydrate microarrays

Article abstract of DOI:10.1016/j.jfluchem.2006.01.001

A surface patterning method based on noncovalent immobilization of fluorous-tagged sugars on fluorous-derivatized glass slides allows the facile fabrication of carbohydrate microarrays. To expand the scope of these arrays, the first syntheses are reported

Full text of DOI:10.1016/j.jfluchem.2006.01.001

Journal of Fluorine Chemistry 127 (2006) 571–579
www.elsevier.com/locate/fluor
Noncovalent fluorous interactions for the synthesis
of carbohydrate microarrays
Sreeman K. Mamidyala, Kwang-Seuk Ko, Firoz A. Jaipuri,
*
Gisun Park, Nicola L. Pohl
2756 Gilman, Department of Chemistry and the Plant Sciences Institute, Iowa State University, Ames, IA 50011, USA
Received 4 January 2006; accepted 8 January 2006
Available online 17 February 2006
Abstract
A surface patterning method based on noncovalent immobilization of fluorous-tagged sugars on fluorous-derivatized glass slides allows the
facile fabrication of carbohydrate microarrays. To expand the scope of these arrays, the first syntheses are reported of arabinose, rhamnose, lactose,
maltose, and glucosamine tagged with a single C8F17-tail for ease of purification as well as array formation. Screening of these carbohydrate
microarrays against lectins from Triticum vulgaris (WGA) and Arachis hypogaea (PNA) demonstrate that the noncovalent fluorous–fluorous
interaction is sufficient to retain not only mono- but also disaccharides under the biological assay conditions.
# 2006 Elsevier B.V. All rights reserved.
Keywords: Microarrays; Fluorous-assisted synthesis; Carbohydrates; Noncovalent interactions
1. Introduction
react with thiol- or epoxide-derivatized glass slides [7];
cyclopentadiene-containing carbohydrates can be immobilized
on a benzoquinone-coated gold surface by Diels–Alder
reactions [8]. Unfortunately, such covalent attachment strate-
gies require the tedious optimization of immobilization
conditions such as pH, time, and temperature. The noncovalent
immobilization of carbohydrates has been carried out using
nitrocellulose-coated glass slides, but this method requires
larger oligosaccharides and allows no control over sugar
orientation on the surface [9].
Carbohydrates interact specifically with proteins to promote
a range of biological processes including inflammatory
responses, pathogen invasion, cell–cell communication, cell
adhesion, fertilization, cell differentiation, development, and
tumor cell metastasis [1]. Unfortunately, little is known about
the molecular basis for many of these sugar–protein interac-
tions. Information about these interactions would not only help
illuminate the role of carbohydrates in the life cycles of
organisms but also aid in the development of carbohydrate-
based therapeutics such as vaccines that intervene in these
carbohydrate–protein interactions [2].
Recently, carbohydrate microarrays have been fabricated
based on another type of noncovalent interaction (Fig. 1) [10].
These experiments were the first demonstration that non-
covalent fluorous–fluorous interactions could be used not only
for simplified purification [11–14] but also for surface
patterning of compounds. In fact, a single C8F17 fluorous tail
is sufficient to pattern carbohydrates in arrays on a fluorinated
solid support and to retain the compounds during routine
screening against carbohydrate-binding proteins such as plant
lectins. These initial experiments, however, used only simple
monosaccharides. Ideally, the method would be applicable to a
range of synthetic carbohydrates. To expand the scope of these
arrays, we report here the first syntheses of arabinose,
rhamnose, lactose, maltose, and glucosamine tagged with a
The success of DNA [3] and protein microarrays [4] in
biological screening with a minimal amount of material has led
to related chip-based approaches to probe carbohydrate–protein
interactions [5]. Generally, carbohydrate microarrays are
prepared by the site-specific covalent attachment of chemically
modified sugars to an appropriately derivatized surface [6]. For
example, maleimide- or hydrazide-linked carbohydrates can
* 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 # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.01.001

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Fig. 1. Fluorous-tagged sugars (4–11) included in a microarray for screening with carbohydrate-binding proteins.
single C8F17-tail; their incorporation into expanded carbohy-
drate microarrays; and screening of this microarray against two
lectins to test the scope of a fluorous-based microarray method.
carbohydrate-binding specificity profiles by lectins for use as
glycobiology tools [15]. Of particular interest are the two
disaccharides (10, 11) and the charged amino-sugar (4) to test if
such compounds are viable for inclusion in microarrays based
on noncovalent fluorous–fluorous interactions.
2. Results and discussion
To obtain a flexible glucosamine building block, we selected
the N-p-nitrobenzyloxycarbonyl-protected glucosamine donor
12 [16]. This donor can be readily obtained, can be easily
deprotected by hydrogenolysis to provide a free amine, and also
can be transformed directly to the desired N-acetamido
modified analog in one pot by addition of acetic anhydride
during the hydrogenolysis reaction. Thus, the glycosylation
reaction of 3,4,6-tri-O-acetyl-2-deoxy-2-( p-nitrobenzyloxy-
In order to anchor carbohydrates onto an array surface, a
suitable fluorous tag is needed. This tag needs to survive the
necessary sequential reaction conditions and also be removed if
desired. Our previous work demonstrated that an allyl group
works well with standard tricholoroacetimidate coupling
conditions and other deprotection conditions [10]. Reaction
of cis-1,4-butenediol with 1H,1H,2H,2H-perfluorodecyl iodide
produces an alcohol with the requisite alkene spacer for use in
glycosylations. The reliable synthesis of this tag on a larger
scale proved difficult, however, as iodide elimination can
compete with nucleophilic substitution. Therefore, a slightly
modified tag was developed. An additional methylene spacer
between the leaving group and the electron-withdrawing
fluoroalkane was added to reduce the acidity of the hydrogen
beta to the leaving group. To this end, commercially available
3-(perfluorooctyl)propanol (1) was mixed with methanesulfo-
nyl chloride to provide mesylate derivative 2 quantitatively.
This electrophile was then reacted with cis-1,4-butenediol to
produce fluorous-tagged alcohol 3 in 70% yield for use in
subsequent glycosylation reactions (Scheme 1).
carbonylamino)-a/b-D-glucopyranosyl
trichloroacetimidate
(12) [16] with fluorous alcohol with trimethylsilyl triflate as
an activator gave the desired fluorous-tagged compound (13) in
84% yield. Compound 13 was deacetylated under basic
conditions to give compound 14, which upon hydrogenolysis
in methanol provided the 3-(perfluorooctyl)propanyloxybuta-
nyl-2-deoxy-2-amino-b-D-glucopyranoside (4) in 94% yield
(Scheme 2). Alternately, the hydrogenolysis of 14 when
performed using acetic anhydride in methanol resulted in the
formation of 3-(perfluorooctyl)propanyloxybutanyl-2-deoxy-
2-acylamino-b-D-glucopyranoside (5) in 82% (Scheme 2).
Similarly, the glycosylation reactions of fluorous alcohol 3
were performed with the known tricholoroacetimidate donors
of D-mannose 15 [19], D-galactose 16 [20], L-arabinose 17 [21],
L-rhamnose 18 [22], D-lactose 19 [23], and D-maltose 20 [24] to
provide fluorous-tagged glycosides 21–26 (Table 1). Alkene
Sugars 4–11 were chosen as targets for glycosylation
reactions with alcohol 3 (Fig. 1). Screening of microarrays
containing these sugars could lead to the discovery of new

S.K. Mamidyala et al. / Journal of Fluorine Chemistry 127 (2006) 571–579
573
Scheme 1.
Scheme 2.
hydrogenation of all the intermediates followed by global
deacylation resulted in the formation of the desired compounds
6–11 (Scheme 3) for formation of microarrays.
With the fluorous-tagged carbohydrates in hand, we next
probed the ability of the single C8F17-tail to anchor these mono-
and disaccharides to a glass slide surface even after repeated
washes. The fluorous-tagged carbohydrates 4–11 were dis-
solved in 80% methanol/water and were spotted onto
fluoroalkylsilane-derivatized glass slides [10] employing a
standard robot used for DNA arraying. The slides then were
incubated for 30 min with the commercially available FITC
(fluorescein isothiocyanate)-labeled lectins from Triticum
vulgaris (wheat germ, FITC-WGA) [25] in phosphate buffered
saline (PBS buffer) (0.25 M) and Arachis hypogaea (peanut,
FITC-PNA) in PBS buffer (0.5 M) and rinsed repeatedly with
the assay buffer followed by distilled water. After drying, the
slide was scanned with a standard fluorescent slide scanner at
488 nm to reveal the carbohydrate-binding specificities of these
Scheme 3.

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S.K. Mamidyala et al. / Journal of Fluorine Chemistry 127 (2006) 571–579
Fig. 2. A scan at 488 nm of glass slides arrayed with fluorous-tagged carbohydrates after incubation with fluorescently-labeled lectins.
Table 1
sufficient to retain not only mono- but also disaccharides under
Glycosylation reactions of fluorous alcohol 3 with various glycosyl donors and
the corresponding deprotection products
biological assay conditions. As the fluorous tag also facilitates
purification during synthesis, this microarray approach should
be particularly valuable for screening of synthetic carbohydrate
libraries. Future work will test the scope of using noncovalent
fluorous interactions for the production of microarrays that
contain additional charged compounds such as glycosamino-
glycan fragments [17,18] and larger saccharides as well as other
classes of biomolecules such as peptides and nucleic acids.
Entry
Donors
Glycosylated products (%)
Deprotection products (%)
1
2
3
4
5
6
15
16
17
18
19
20
21 (92%)
22 (80%)
23 (89%)
24 (76%)
25 (52%)
26 (54%)
6 (100%)
7 (98%)
8 (80%)
9 (82%)
10 (99%)
11 (98%)
4. Experimental
two lectins. As expected [25] the wheat germ lectin WGA
bound only to the fluorous-tagged N-acetylglucosamine (5)
(Fig. 2). In contrast, the peanut lectin PNA bound to both
galactose (7) and lactose (10) in the array experiment. This
lectin is known to bind to galactose both alone and in the
context of the lactose disaccharide [25,26]. This experiment
vividly demonstrates that the disaccharide is retained on the
fluorous-derivatized glass slides under the conditions required
for screening of proteins for their carbohydrate-binding
specificities.
4.1. General experimental procedures
Dichloromethane was distilled from calcium hydride before
use. Amberlyst 15 ion-exchange resin was washed repeatedly
with methanol before use. All other commercial reagents and
solvents were used as received without further purification.
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. Flash chromatography was
performed with Selecto Scientific silica gel, 32–63 mm particle
size. Fluorous phase chromatography was performed [12] using
fluorous solid-phase extraction cartridges containing silica gel
bonded with perfluorooctylethylsilyl chains (Fluorous Tech-
nologies, 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 a nitrogen atmosphere. Bath temperatures
3. Conclusion
In conclusion, our new method for the facile fabrication of
carbohydrate microarrays by using the noncovalent immobi-
lization of carbohydrates on fluorous derivatized glass slides
clearly can be extended beyond monosaccharides. Screening of
these carbohydrate microarrays against two lectins demon-
strates that the noncovalent fluorous–fluorous interaction is

S.K. Mamidyala et al. / Journal of Fluorine Chemistry 127 (2006) 571–579
575
were used to record the reaction temperature. All reactions were
stirred magnetically at ambient temperature unless otherwise
indicated.
and tetrabutylammonium bromide (0.27 g, 0.83 mmol) in DMF
(20 mL) was added powdered KOH (0.47 g, 8.32 mmol). The
reaction mixture was heated at 70 8C for 1 h and then poured
into water (20 mL). The aqueous layer was extracted with ethyl
acetate (2 mL Â 60 mL) and the organic layer was washed with
water (30 mL) and brine (30 mL), and dried over MgSO4. The
solvent was removed under reduced pressure. The crude
product was purified by flash column chromatography on silica
gel using 27% EtOAc/hexane as eluent to provide 3 (1.57 g,
70%) as a yellow oil.
1H NMR (300 MHz, CDCl3): d 1.78–1.88 (m, 2H), 2.04–
2.19 (m, 2H), 2.99 (s, 1H), 3.45 (t, J = 6.0 Hz, 2H), 4.0 (d,
J = 6.3 Hz, 2H), 4.13 (d, J = 6.3 Hz, 2H), 5.57–5.65 (m, 1H),
5.70–5.78 (m, 1H). 13C NMR (75 MHz, CDCl3): d 20.8, 28.0,
58.4, 66.4, 68.9, 127.9, 132.3.
1H NMR, and 13C NMR spectra were obtained with a Bruker
1
DRX400 at 400, 100, and 162 MHz, respectively. H NMR
spectra were reported in parts per million (d) relative to CDCl3
(7.27 ppm) andCD3OD (4.80) asaninternalreference. 13C NMR
spectra were reported in parts per million (d) relative to CDCl3
(77.23 ppm) or CD3OD (49.15 ppm). A Shimadzu LCMS 2010
quadrupole mass spectrometer (Shimadzu Scientific Instru-
ments, Columbia, MD) equipped with an electrospray ionization
(ESI) source was used in positive ion mode.
4.2. Microarray preparation and screening
Fluorous-tagged carbohydrate compounds were dissolved in
80% methanol/water (2 mM) and spotted on clean fluorinated
glass slides [10] using a robotic spotter (Cartesian PixSys 5500
Arrayer, Cartesian Technologies, Inc., Irvine, CA) at 30%
humidity. The glass slide was dried in a humidifying chamber at
30% humidity for 2 h.
4.5. Synthesis of 3-(perfluorooctyl)propanyloxybutenyl-
3,4,6-tri-O-acetyl-2-deoxy-2( p-
nitrobenzyloxycarbonylamino)-b-D-glucopyranoside (13)
To a solution of 3,4,6-tri-O-acetyl-2-deoxy-2-( p-nitro-
trichloro-
and 3-
FITC-labeled PNA or WGA (EY Laboratories, San Mateo,
CA) [25] in PBS buffer (pH = 7.3–7.4, 2.35 mM CaCl2,
0.85 mM MgCl2, 114 mM NaCl, 4 mM KCl, 1 mM Na2HPO4,
15 mM NaHCO3, 11.1 mM glucose; 0.5 M for PNA and 0.25 M
for WGA assay) were used for the detection of protein–
carbohydrate interactions. The arrays were incubated with the
protein solution (0.1 mL) by using a PC500 CoverWell
incubation chamber (Grace Biolabs, Bend, OR) and gently
shaken every 5 min for 30 min. The slides were then washed
three times with the incubation buffer followed by three washes
with distilled water. The slides were subsequently dried for
30 min in a dark humidity chamber. The glass slides were
scanned using a General Scanning ScanArray 5000 set at
488 nm.
benzyloxycarbonylamino)-a/b-D-glucopyranosyl
acetimidate (12) (1.68 g, 2.7 mmol)
(perfluorooctyl)propanyloxybutenyl alcohol (3) (1.0 g,
1.8 mmol) in dichloromethane (20 mL) was added TMSOTf
(0.16 mL, 0.9 mmol) at À15 8C. The reaction mixture was
stirred at À15 8C for 30 min. The reaction mixture was
quenched with triethylamine (0.5 mL) and then concentrated
under reduced pressure. The crude product was purified by
solid-phase extraction using a fluorous solid-phase extraction
cartridge. Nonfluorous compounds were eluted with 80%
MeOH/water and the desired product was eluted by 100%
MeOH. The solvent was removed under reduced pressure to
provide 13 (1.53 g, 84%) as a solid.
1H NMR (300 MHz, CDCl3): d 1.50–2.40 (m, 4H), 1.98, 2.02,
2.08 (3s, 9H), 3.50 (t, J = 6.0 Hz, 2H), 3.54–3.75 (m, 2H), 4.00
(d, 1H, J = 5.0 Hz, 2H), 4.04–4.40 (m, 4H), 4.66 (s, 1H), 4.94 (s,
1H), 5.06 (t, J = 9.4 Hz, 1H), 5.14–5.30 (m, 3H), 5.50–5.70 (m,
2H), 7.48 (d, J = 8.3 Hz, 2H), 8.20 (d, J = 8.8 Hz, 2H). 13C NMR
(75 MHz, CDCl3): d 20.6, 20.7, 20.8, 20.9, 28.0, 56.3, 62.3, 65.4,
66.5, 68.9, 69.0, 71.9, 72.3, 99.7, 123.8, 128.0, 130.5, 144.1,
147.7, 155.6, 169.6, 170.8. MS (ESI) m/z 1037 (M + Na)+.
4.3. Synthesis of 3-(perfluorooctyl)propanyl methyl
sulfonate (2)
To a solution of 3-(perfluorooctyl)propanol 1 (2.0 g,
4.2 mmol) in dichloromethane (20 mL) was added triethyla-
mine (1.20 mL, 8.36 mmol) and the mixture was cooled to
0 8C. Mesyl chloride (0.64 mL, 8.4 mmol) was added drop wise
over 5 min and the reaction mixture was allowed to warm to
ambient temperature over 2 h. The reaction mixture was diluted
with dichloromethane (100 mL) and the organic layer was
washed with water (40 mL), HCl (2N, 40 mL), and brine
(30 mL), and dried over MgSO4. The solvent was removed
under reduced pressure to provide 2 (2.32 g, 100%) as a solid.
1H NMR (300 MHz, CDCl3): d 2.05–2.13 (m, 2H), 2.20–
2.36 (m, 2H), 3.04 (s, 3H), 4.31 (t, J = 6 Hz, 2H).
4.6. Synthesis of 3-(perfluorooctyl)propanyloxybutenyl-2-
deoxy-2( p-nitrobenzyloxycarbonylamino)-b-D-
glucopyranoside (14)
To a solution of 3-(perfluorooctyl)propanyloxybutenyl-
3,4,6-tri-O-acetyl-2-deoxy-2( p-nitrobenzyloxycarbonyla-
mino)-b-D-glucopyranoside (13) (1.4 g, 1.4 mmol) in methanol
(15 mL) was added NaOMe (70 mg); the reaction mixture was
stirred at ambient temperature for 3 h. The reaction mixture was
neutralized with Amberlyst-15 ion-exchange resin and filtered.
The solvent was removed under reduced pressure to provide 14
(1.2 g, 98%) as a solid.
4.4. Synthesis of 4-[3-(perfluorooctyl)propyloxy]-cis-2-
butenyl alcohol (3)
To a solution of cis-1,4-butenediol (0.48 g, 5.4 mmol), 3-
(perfluorooctyl)propanyl methyl sulfonate (2.3 g, 4.16 mmol),
1H NMR (300 MHz, CD3OD): d 1.70–1.90 (m, 2H), 2.10–
2.40 (m, 2H), 3.10–3.50 (m, 7H), 3.54–3.66 (m, 1H), 3.90 (d,

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J = 10.4 Hz, 1H), 4.06 (d, J = 5.0 Hz, 1H), 4.20–4.50 (m, 3H),
5.10–5.40 (m, 2H) 5.50–5.80 (m, 2H), 7.60 (d, J = 8.2 Hz, 2H),
8.20 (d, J = 8.5 Hz, 2H). 13C NMR (75 MHz, CDCl3): d 21.0,
28.0, 58.1, 61.9, 64.7, 65.1, 66.7, 68.8, 71.3, 75.1, 77.2, 101.0,
123.6, 128.1, 128.6, 130.0, 145.4, 147.9, 157.7, 169.5. MS
(ESI) m/z 911 (M + Na)+.
solvent was removed under reduced pressure to provide 21
(0.36 g, 92%) as a viscous yellow oil.
1H NMR (300 MHz, CDCl3): d 1.80–1.88 (m, 2H), 2.11–
2.27 (m, 2H) (s, 3H), 3.43 (t, J = 6.0 Hz, 2H), 3.75–3.92 (m,
4H), 4.01–4.04 (m, 3H), 4.07–4.15 (m, 1H), 4.19–4.26 (m, 1H),
4.45–4.58 (m, 3H), 4.70 (dd, J = 12.0 Hz, 2H), 4.88 (dd,
J = 6.6 Hz, 8.4 Hz, 2H), 5.35–5.41 (m, 1H), 5.64–5.77 (m, 2H),
7.15–7.36 (m, 15H). 13C NMR (75 MHz, CDCl3): d 20.1, 61.7,
65.4, 67.6, 67.7, 67.9, 70.5, 70.7, 72.4, 73.3, 74.2, 77.2, 95.8,
126.6, 126.7, 126.8, 126.8, 126.9, 126.9, 127.0, 127.3, 127.4,
129.3, 136.9, 137.1, 137.2, 169.4.
4.7. Synthesis of 4-[3-(perfluorooctyl)propyloxy]butyl-2-
deoxy-2-amino-b-D-glucopyranoside (4)
To a solution of 3-(perfluorooctyl)propanyloxybutenyl-2-
deoxy-2( p-nitrobenzyloxycarbonylamino)-b-D-glucopyrano-
side (14) (60 mg, 0.07 mmol) in methanol (2 mL) was added
5% Pd/C (7 mg). The reaction mixture was stirred at ambient
temperature under hydrogen atmosphere for 2 h. The reaction
mixture was then filtered over Celite and the solvent was
removed under reduced pressure to provide 4 (45 mg, 94%) as a
solid.
1H NMR (300 MHz, CD3OD): d 1.60–1.90 (m, 6H), 2.10–
2.40 (m, 2H), 2.50–2.80 (m, 2H), 3.30–3.70 (m, 12H), 3.86 (d,
J = 11.4 Hz, 1H), 3.92–4.08 (m, 1H), 4.34 (d, J = 8.2 Hz, 1H).
13C NMR (100 MHz, CD3OD): d 20.7, 26.2, 26.3, 27.7, 57.2,
61.5, 68.8, 69.3, 70.5, 70.6, 76.5, 76.9, 103.5. MS (ESI) m/z 734
(M + Na)+.
4.10. Synthesis of 3-(perfluorooctyl)propanyloxybutenyl-
3,4,6-O-benzyl-a-D-mannopyranoside (27)
To a solution of 3-(perfluorooctyl)propanyloxybutenyl-2-O-
acetyl-3,4,6-O-benzyl-a-D-mannopyranoside (21) (0.36 g,
0.352 mmol) in methanol (4 mL) was added NaOMe
(40 mg) and the reaction mixture was stirred at ambient
temperature for 1 h. The reaction mixture was neutralized with
Amberlyst-15 ion-exchange resin and filtered. The solvent was
removed under reduced pressure to provide 27 (0.35 g, 100%)
as a yellow oil.
1H NMR (400 MHz, CDCl3): d 1.78–1.87 (m, 2H), 2.08–
2.23 (m, 2H), 2.53 (s, 1H), 3.40 (t, J = 6.0 Hz, 2H), 3.68–3.92
(m, 5H), 4.0–4.12 (m, 4H), 4.18–4.24 (m, 1H), 4.50 (d,
J = 10.8 Hz, 1H), 4.53–4.65 (m, 2H), 4.68 (d, J = 2.4 Hz, 2 H),
4.82 (d, J = 10.8 Hz, 1H), 4.92 (d, J = 1.6 Hz, 1H), 5.60–5.75
(m, 2H), 7.15–7.34 (m, 15H). 13C NMR (100 MHz, CDCl3): d
20.8, 28.0, 62.5, 66.4, 68.3, 68.7, 69.0, 71.2, 72.0, 73.5, 74.3,
75.2, 80.2, 98.3, 127.6, 127.7, 127.8, 128.0, 128.1, 128.3, 128.4,
128.6, 130.2, 137.9, 138.2.
4.8. Synthesis of 4-[3-(perfluorooctyl)propyloxy]butyl-2-
deoxy-2-acetylamino-b-D-glucopyranoside (5)
To a solution of 3-(perfluorooctyl)propanyloxybutenyl-2-
deoxy-2( p-nitrobenzyloxycarbonylamino)-b-D-glucopyrano-
side (14) (40 mg, 0.04 mmol) in methanol (0.5 mL) and acetic
anhydride (1.0 mL) was added 5% Pd/C (4 mg). The reaction
mixture was stirred at ambient temperature under hydrogen
atmosphere for 13 h. The reaction mixture was then filtered
over Celite and the solvent was removed under reduced
pressure to provide 5 (28 mg, 82%) as a solid.
4.11. Synthesis of 3-(perfluorooctyl)propanyloxybutanyl-a-
D-mannopyranoside (6)
1H NMR (300 MHz, CD3OD): d 1.40–1.74 (m, 4H), 1.80–
1.90 (m, 2H), 1.98 (s, 3H), 2.10–2.40 (m, 4H), 3.20–3.80 (m,
14H), 3.80–4.10 (m, 2H), 4.38 (d, J = 8.4 Hz, 1H). 13C NMR
(100 MHz, CD3OD): d 20.7, 21.8, 26.0, 26.1, 26.2, 27.7, 29.2,
56.2, 61.6, 61.7, 68.8, 68.9, 69.1, 70.5, 70.6, 70.9, 74.9, 76.8,
101.5, 172.8.
To a solution of 3-(perfluorooctyl)propanyloxybutenyl-3,4,6-
O-benzyl-a-D-mannopyranoside (27) (60 mg, 0.061 mmol) in
methanol (3 mL) was added 10% Pd/C (20 mg). The reaction
mixture was stirred at ambient temperature under hydrogen
atmosphere for 12 h. The reaction mixture was then filtered over
Celite and the solvent was removed under reduced pressure to
provide 6 (44 mg, 100%) as a solid.
4.9. Synthesis of 3-(perfluorooctyl)propanyloxybutenyl-2-
O-acetyl-3,4,6-O-benzyl-a-D-mannopyranoside (21)
1H NMR (400 MHz, CD3OD): d 1.60–1.69 (m, 4H), 1.80–
1.89 (m, 2H), 2.18–2.33 (m, 2H), 3.40–3.88 (m, 12H), 4.74 (m,
1H). 13C NMR (100 MHz, CD3OD): d 20.8, 26.2, 26.4, 27.6,
61.6, 67.1, 67.4, 68.8, 70.5, 71.1, 71.4, 73.5, 101.2.
To a solution of 2-O-acetyl-3,4,6-O-benzyl-a/b-D-manno-
pyranosyl trichloroacetimidate (15) (0.37 g, 0.58 mmol) and 3-
(perfluorooctyl)propanyloxybutenyl
alcohol
(3)(0.21 g,
4.12. Synthesis of 3-(perfluorooctyl)propanyloxybutenyl-
2,3,4,6-tetra-O-acetyl-b-D-galactopyranoside (22)
0.38 mmol) in dichloromethane (4 mL) was added TMSOTf
(14 mL, 0.077 mmol) at 5 8C. The reaction mixture was stirred
at 5 8C for 30 min. The reaction mixture was quenched with
triethylamine (0.5 mL) and then concentrated under reduced
pressure. The crude product was purified by solid-phase
extraction using a fluorous solid-phase extraction cartridge.
Nonfluorous compounds were eluted with 80% MeOH/water
and the desired product was eluted by 100% MeOH. The
To a solution of 2,3,4,6-tetra-O-acetyl-a/b-D-galactopyra-
nosyl trichloroacetimidate (16) (100 mg, 0.20 mmol) and 3-
(perfluorooctyl)propanyloxybutenyl alcohol (3) (75 mg,
0.14 mmol) in dichloromethane (3 mL) was added TMSOTf
(5 mL, 0.027 mmol) at À15 8C. The reaction mixture was
stirred at À15 8C for 30 min. The reaction mixture was

S.K. Mamidyala et al. / Journal of Fluorine Chemistry 127 (2006) 571–579
577
quenched with triethylamine (0.5 mL) and then concentrated
under reduced pressure. The crude product was purified by
solid-phase extraction using a fluorous solid-phase extraction
cartridge. Nonfluorous compounds were eluted with 80%
MeOH/water and the desired product was eluted by 100%
MeOH. The solvent was removed under reduced pressure to
provide 22 (97 mg, 80%) as a syrup.
MeOH. The solvent was removed under reduced pressure to
provide 23 (0.2 g, 89%) as a solid.
1H NMR (300 MHz, CDCl3): d 1.80–1.95 (m, 2H), 2.0–2.3
(m, 2H), 2.00, 2.02, 2.11 (3s, 9H), 3.46 (t, J = 6.0 Hz, 2H), 3.61
(d, J = 1.9 Hz, 1H), 3.97–4.03 (m, 3H), 4.20 (dd, J = 6.3,
12.6 Hz 1H), 4.36 (dd, J = 5.7, 12.6 Hz, 1H), 4.41 (d,
J = 6.9 Hz, 1H), 5.02 (dd, J = 3.6, 9.3 Hz, 1H), 5.13 (dd,
J = 4.2, 6.6 Hz, 1H), 5.23 (m, 1H), 5.60–5.75 (m, 2H). 13C
NMR (75 MHz, CDCl3): d 20.9, 21.0, 21.1, 19.9, 61.6, 64.7,
66.7, 67.8, 69.0, 69.3, 70.3, 91, 92, 100.0, 128.2, 130.1, 169.7,
170.4, 170.6.
1H NMR (400 MHz, CDCl3,): d 1.82–1.89 (m, 2H), 1.95,
2.02, 2.03 (3s, 9H), 2.08–2.24 (m, 2H) (s, 3H), 3.46 (t,
J = 6.0 Hz, 2H), 3.86 (t, J = 5.2 Hz, 1H), 4.01 (t, J = 5.2 Hz,
1H), 4.10–4.23 (m, 4H), 4.34 (dd, J = 5.6, 10.0 Hz, 1H), 4.75
(d, J = 8 Hz, 1H), 4.99 (dd, J = 3.6, 10.4 Hz, 1H), 5.19 (dd,
J = 8.0, 10.4 Hz, 1H), 5.36 (d, J = 3.6 Hz, 1H), 5.60–5.76 (m,
2H). 13C NMR (100 MHz, CDCl3): d 20.5, 20.6, 20.7, 20.8,
20.9, 61.2, 64.7, 66.5, 67.0, 68.7, 68.8, 70.7, 70.9, 76.7, 100.1,
127.8, 130.2, 169.4, 170.1, 170.2, 170.3.
4.15. Synthesis of 3-(perfluorooctyl)propanyloxybutanyl-a-
L-arabinopyranoside (8)
To a solution of 3-(perfluorooctyl)propanyloxybutenyl-
2,3,4-tri-O-acetyl-a-L-arabinopyranoside (23) (0.1 g, 0.12
mmol) in methanol (10 mL) was added 5% Pd/C (0.25 g).
The reaction mixture was stirred at ambient temperature
under hydrogen atmosphere for 2 h. The reaction mixture was
then filtered over Celite and partially concentrated under
reduced pressure. To this solution, K2CO3 (67 mg) was added
and the mixture was stirred at ambient temperature for 3 h. The
reaction mixture was neutralized with Amberlyst-15 ion-
exchange resin and filtered over Celite. The solvent was
removed under reduced pressure to provide 8 (68 mg, 80%) as a
solid.
4.13. Synthesis of 3-(perfluorooctyl)propanyloxybutanyl-b-
D-galactopyranoside (7)
To a solution of 3-(perfluorooctyl)propanyloxybutenyl-
2,3,4,6-tetra-O-acetyl-b-D-galactopyranoside (22) (97 mg,
0.110 mmol) in methanol (3 mL) was added 5% Pd/C
(25 mg). The reaction mixture was stirred at ambient
temperature under hydrogen atmosphere for 2 h. The reaction
mixture was then filtered over Celite and the solvent was
removed under reduced pressure. The product was used directly
in the next step. To a solution of 3-(perfluorooctyl)propanylox-
ybutanyl-2,3,4,6-tetra-O-acetyl-b-D-galactopyranoside (97 mg,
0.110 mmol) in methanol (3 mL) was added NaOMe (15 mg)
and the reaction mixture was stirred at ambient temperature
for 2 h. The reaction mixture was neutralized with A
mberlyst-15 ion-exchange resin and filtered. The solvent was
removed under reduced pressure to provide 7 (75 mg, 98%) as a
solid.
1H NMR (300 MHz, CD3OD): d 1.80–1.95 (m, 2H), 2.1–2.3
(m, 2H), 3.4–3.9 (m, 14H), 4.17(d, J = 4.8 Hz, 1H). 13C NMR
(75 MHz, CD3OD): d 13.2, 19.6, 20.6, 21.5, 48.8, 56.7, 60.3,
66.7, 67.8, 69.0, 69.3, 102.8. MS (ESI) m/z 682 (M + H)+.
4.16. Synthesis of 3-(perfluorooctyl) propanyloxybutenyl-
2,3,4-tri-O-acetyl-a-L-rhamnopyranoside (24)
1H NMR (300 MHz, CD3OD): d 1.62–1.71 (m, 4H), 1.79–
1.87 (m, 2H), 2.11–2.36 (m, 2H), 3.22–3.34 (m, 1H), 3.41–3.63
(m, 6H), 3.70–3.74 (m, 3H), 3.81–3.99 (m, 2H), 4.20 (d,
J = 6.9 Hz, 1H). 13C NMR (75 MHz, CD3OD): d 26.1,
26.2, 26.3, 53.3, 61.9, 69.2, 69.3, 69.4, 71.1, 72.6, 74.1,
76.2, 114.4.
To a solution of 2,3,4-tri-O-acetyl-a/b-L-rhamnopyranosyl
tricholoroacetimidate (18) (0.2 g, 0.46 mmol) and 3-(perfluor-
ooctyl)propanyloxybutenyl alcohol (3) (0.13 g, 0.23 mmol) in
dry dichloromethane (5 mL) was added TMSOTf (0.02 mL,
0.11 mmol) at ambient temperature. The reaction mixture was
stirred for 15 min. The reaction mixture was quenched with
triethylamine (0.5 mL) and then concentrated under reduced
pressure. The crude product was purified by solid-phase
extraction using a fluorous solid-phase extraction cartridge.
Nonfluorous compounds were eluted with 50% MeOH/water
and the desired product was eluted by 100% MeOH. The
solvent was removed under reduced pressure to provide 24
(0.15 g, 76%) as a solid.
1H NMR (300 MHz, CDCl3): d 1.24 (d, J = 6.3, 3H), 1.80–
1.95 (m, 2H), 2.0–2.3 (m, 2H), 1.98, 2.04, 2.14 (3s, 9H), 3.46 (t,
J = 6.0 Hz, 2H), 3.9 (m, 1H), 4.05 (d, J = 5.1 Hz, 2H), 4.06 (d,
J = 6.9 Hz, 1H), 4.15 (dd, J = 4.9, 11.7 Hz, 1H), 4.74 (d,
J = 3.0 Hz, 1H), 5.06 (t, J = 9.9 Hz, 1H), 5.21 (m, 1H), 5.28 (dd,
J = 0.2, 3.6 Hz, 0.2 1H), 5.65–5.8 (m, 2H). 13C NMR (75 MHz,
CDCl3): d 17.6, 20.9, 21, 21.01, 21.1, 63.3, 66.6, 66.7, 69.3,
69.5, 70.5, 71.2, 97, 128, 130.5, 170.2, 170.4.
4.14. Synthesis of 3-(perfluorooctyl)propanyloxybutenyl-
2,3,4-tri-O-acetyl-a-L-arabinopyranoside (23)
To a solution of 2,3,4-tri-O-acetyl-a/b-L-arabinosyl tricho-
loroacetimidate (17) (0.27 g, 0.64 mmol) and 3-(perfluorooc-
tyl)propanyloxybutenyl alcohol (3)(0.15 g, 0.28 mmol) in dry
dichloromethane (5 mL) was added TMSOTf (0.025 mL,
0.14 mmol) at ambient temperature. The reaction mixture
was stirred at ambient temperature for 15 min. The reaction
mixture was quenched with triethylamine (0.5 mL) and then
concentrated under reduced pressure. The crude product was
purified by solid-phase extraction using a fluorous solid-phase
extraction cartridge. Nonfluorous compounds were eluted with
50% MeOH/water and the desired product was eluted by 100%

578
S.K. Mamidyala et al. / Journal of Fluorine Chemistry 127 (2006) 571–579
4.17. Synthesis of 3-(perfluorooctyl)propanyloxybutanyl-a-
L-rhamnopyranoside (9)
(5 mL) was added 5% Pd/C (250 mg). The reaction mixture was
stirred at ambient temperature under hydrogen atmosphere for
2 h. The reaction mixture was then filtered over Celite and
partially concentrated under reduced pressure. To this solution,
K2CO3 (66 mg) was added and the mixture was stirred at
ambient temperature for 3 h. The reaction mixture was
neutralized with Amberlyst-15 ion-exchange resin and filtered
over Celite. The solvent was removed under reduced pressure to
provide 10 (75 mg, 99%) as a solid.
To a solution of 3-(perfluorooctyl)propanyloxybutenyl-
2,3,4-tri-O-acetyl-a-L-rhamnopyranoside (24) (0.1 g, 0.12
mmol) in methanol (5 mL) was added 5% Pd/C (250 mg).
The reaction mixture was stirred at ambient temperature under
hydrogen atmosphere for 2 h. It was then filtered over Celite
and partially concentrated. To the solution, K2CO3 (66 mg) was
added and the mixture was stirred at ambient temperature for
3 h. The reaction mixture was neutralized with Amberlyst-15
ion-exchange resin and filtered over Celite. The solvent was
removed under reduced pressure to provide 9 (70 mg, 82%) as a
solid.
1H NMR (400 MHz, CDCl3): d 1.50–1.70 (m, 4H), 1.80–
1.90 (m, 2H), 2.10–2.40 (m, 2H), 3.10–4.00 (m, 20H), 4.26 (d,
J = 8.0 Hz, 1H), 4.33 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d 25.9, 26.1, 27.4, 60.6, 61.1, 68.6, 68.9, 69.2, 70.3,
71.1, 73.4, 73.5, 75.0, 75.1, 75.7, 102.8, 103.7.
1H NMR (300 MHz, CD3OD): d 1.20 (d, J = 6.3 Hz, 3H),
1.80–1.95 (m, 2H), 2.1–2.3 (m, 2H), 2.9 (d, J = 4.8 Hz, 1H), 3.0
(d, J = 7.2, 1H), 3.30–3.70 (m, 11H), 3.75 (m, 1H), 4.65 (m,
1H). 13C NMR (75 MHz, CD3OD): d 16.7, 26.2, 26.4, 67.2,
68.6, 68.9, 70.5, 71.1, 71.2, 72.7, 100.4. MS (ESI) m/z 696
(M + H)+.
4.20. Synthesis of 3-(perfluorooctyl)propanyloxybutenyl-4-
O-(2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl)-2,3,6-tri-O-
acetyl-b-D-glucopyranoside (26)
To a solution of 4-O-(2,3,4,6-tetra-O-acetyl-a-D-gluco-
pyranosyl)-2,3,6-tri-O-acetyl-b-D-glucopyranosyl
trichlor-
3-
4.18. Synthesis of 3-(perfluorooctyl)propanyloxybutenyl-4-
O-(2,3,4,6-tetra-O-acetyl-b-D-galactopyranosyl)-2,3,6-tri-
O-acetyl-b-D-glucopyranoside (25)
oacetimidate
(20)
(0.16 g,
(perfluorooctyl)propanyloxybutenyl
0.18 mmol)
alcohol
and
(3)(1.0 g,
1.8 mmol) in dichloromethane (20 mL) was added TMSOTf
(0.13 mL, 0.15 mmol) at À15 8C. The reaction mixture was
stirred at À15 8C for 30 min. The reaction mixturewas quenched
with triethylamine (0.2 mL) and concentrated under reduced
pressure. The crude product was purified by solid-phase
extraction using a fluorous solid-phase extraction cartridge.
Nonfluorouscompoundswereeluted with80%MeOH/waterand
the desired product was eluted by 100% MeOH. The solvent was
removed under reduced pressure to provide 26 (0.12 g, 54%) as a
solid.
1H NMR (400 MHz, CDCl3): d 1.80–1.90 (m, 2H), 1.96,
1.97, 1.98, 1.99, 2.00, 2.06, 2.10 (7s, 21H), 1.94–2.40 (m, 2H),
3.45 (t, J = 6.0 Hz, 2H), 3.60–3.70 (m, 1H), 3.84–34.08 (m,
5H), 4.10–4.26 (m, 3H), 4.30 (dd, J = 5.6, 12.8 Hz, 1H), 4.46
(dd, J = 2.4, 12.0 Hz, 1H), 4.52 (d, J = 8.0 Hz, 1H), 4.74–4.86
(m, 2H), 5.02 (t, J = 10.0 Hz, 1H), 5.20 (t, J = 9.2 Hz, 1H), 5.38
(d, J = 4.0 Hz, 1H), 5.40–5.80 (m, 2H). 13C NMR (100 MHz,
CDCl3): d 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 27.7,
27.9, 61.5, 62.7, 64.7, 66.5, 68.0, 68.5, 68.8, 69.3, 70.0, 72.0,
72.1, 72.2, 72.6, 75.4,76.7, 95.5, 99.0, 127.6, 130.4, 169.4,
169.6, 169.9, 170.2, 170.4, 170.5.
To a solution of 4-O-(2,3,4,6-tetra-O-acetyl-b-D-galactopyr-
anosyl)-2,3,6-tri-O-acetyl-b-D-glucopyranosyltrichloroacetimi-
date (19) (0.17 g, 0.22 mmol) and 3-(perfluorooctyl)pro-
panyloxybutenyl alcohol (3) (0.1 g, 0.17 mmol) in dichloro-
methane (5 mL) was added TMSOTf (0.16 mL, 0.9 mmol) at
À15 8C. The reaction mixture was stirred at À15 8C for 30 min.
The reaction mixture was quenched with triethylamine (0.2 mL)
andthen concentrated underreduced pressure. Thecrudeproduct
was purified by solid-phase extraction using a fluorous solid-
phase extraction cartridge. Nonfluorous compounds were eluted
with 80% MeOH/water and the desired product was eluted by
100% MeOH. The solvent was removed under reduced pressure
to provide 25 (0.12 g, 52%) as a solid.
1H NMR (400 MHz, CDCl3): d 1.80–1.90 (m, 2H),
1.93,1.98, 2.00, 2.02, 2.08, 2.11 (7s, 21H), 1.90–2.30 (m,
2H), 3.44 (t, J = 6.0 Hz, 2H), 3.52–3.60 (m, 1H), 3.76 (t, 1H,
J = 9.2 Hz, 1H), 3.83 (t, J = 6.8 Hz, 1H), 3.94–4.20 (m, 6H),
4.30 (dd, J = 5.6, 12.8 Hz, 1H), 4.42–4.52 (m, 3H), 4.85, 4.87
(2d, J = 8.0 Hz, 1H), 4.92 (dd, J = 3.2, 10.4 Hz, 1H), 5.06, 5.08
(2d, J = 8.0 Hz, 1H), 5.15 (t, J = 9.2 Hz, 1H), 5.30 (d,
J = 2.8 Hz, 1H), 5.56–5.78 (m, 2H). 13C NMR (100 MHz,
CDCl3): d 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 27.9, 60.8,
61.9, 64.8, 66.5, 66.5, 69.1, 70.6, 71.0, 71.6, 72.7, 72.8, 76.2,
76.7, 99.3, 101.1, 127.8, 130.3, 169.1, 169.6, 169.8, 170.1,
170.18, 170.3, 170.4.
4.21. Synthesis of 3-(perfluorooctyl)propanyloxybutanyl-4-
O-b-D-glucopyranosyl)-b-D-glucopyranoside (11)
To a solution of 3-(perfluorooctyl)propanyloxybutenyl-4-O-
(2,3,4,6-tetra-O-acetyl)-a-D-glucopyranosyl)-2,3,6-tri-O-
acetyl-b-D-glucopyranoside (26) (0.12 g, 0.1 mmol) in metha-
nol (5 mL) was added 5% Pd/C (0.25 g). The reaction mixture
was stirred at ambient temperature under hydrogen atmosphere
for 2 h. The reaction mixture was then filtered over Celite and
partially concentrated under reduced pressure. To this solution,
K2CO3 (66 mg) was added and the mixture was stirred at
ambient temperature for 3 h. The reaction mixture was
4.19. Synthesis of 3-(perfluorooctyl)propanyloxybutanyl-4-
O-b-D-galactopyranosyl)-b-D-glucopyranoside (10)
To a solution of 3-(perfluorooctyl)propanyloxybutenyl-4-O-
(2,3,4,6-tetra-O-acetyl)-b-D-galactopyranosyl)-2,3,6-tri-O-
acetyl-b-D-glucopyranoside (25) (0.1 g, 0.1 mmol) in methanol

S.K. Mamidyala et al. / Journal of Fluorine Chemistry 127 (2006) 571–579
579
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neutralized with Amberlyst-15 ion-exchange resin and filtered
over Celite. The solvent was removed under reduced pressure to
provide 11 (90 mg, 98%) as a solid.
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1H NMR (400 MHz, CDCl3): d 1.52–1.70 (m, 4H), 1.74–
1.90 (m, 2H), 2.10–2.40 (m, 2H), 3.10–3.38 (m, 4H), 3.40–3.70
(m, 12H), 3.72–4.00 (m, 4H), 4.24 (d, J = 8.0 Hz, 1H), 5.12 (d,
J = 3.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 20.4, 25.9,
26.1, 27.4, 27.6, 60.8, 61.3, 68.6, 69.2, 70.1, 70.3, 72.7, 73.3,
73.4, 75.2, 76.4, 79.9, 101.5, 102.9.
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Acknowledgements
This material is based in part upon work supported by the
Institute
(b) S. Fukui, T. Feizi, C. Galustian, A.M. Lawson, W. Chai, Nat.
Biotechnol. 20 (2002) 1011–1017.
National
of
General
Medical
Sciences
(1R41GM075436-01). N.L.P. is a Cottrell Scholar of Research
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