Novel amphiphilic fluoroalkylated derivatives of xylitol, D-glucose and D-galactose for medical applications: Hemocompatibility and co-emulsifying properties

Article abstract of DOI:10.1016/S0008-6215(02)00287-2

1-O-(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononyl)xylitol 6 was synthesized as a novel standard compound for the assessment of hemocompatibility and co-emulsifying properties in microemulsions for biomedical uses. 3-O-(1,1,2,4,4,5,7,7,8,8,9,9,9-Tridecafluoro-5-trifluoro-methyl-3,6- dioxanonyl)-D-glucose 9 and 6-O-(1,1,2,4,4,5,7,7,8,8,9,9,9-tridecafluoro-5-trifluoromethyl-3,6- dioxanonyl)-D-galactose 12 were synthesized by nucleophilic addition of protected carbohydrates to perfluorinated vinyl oligoether. Biological tests revealed very good hemocompatibility and co-emulsifying properties for the amphiphiles 6, 9 and 12.

Full text of DOI:10.1016/S0008-6215(02)00287-2

Carbohydrate Research 337 (2002) 2411–2418
www.elsevier.com/locate/carres
Novel amphiphilic fluoroalkylated derivatives of xylitol,
and -galactose for medical applications: hemocompatibility and
co-emulsifying propertiesꢀ
D-glucose
D
Oldrˇich Paleta,a,* Ivona Dlouha´,a Robert Kapla´nek,a Karel Kefurt,b Milan Kod´ıcˇekc
aDepartment of Organic Chemistry, Prague Institute of Chemical Technology, Technicka´ 5, 16628 Prague 6, Czech Republic
bDepartment of Natural Compounds Chemistry, Prague Institute of Chemical Technology, Technicka´ 5, 16628 Prague 6, Czech Republic
cDepartment of Biochemistry and Microbiology, Prague Institute of Chemical Technology, Technicka´ 5, 16628 Prague 6, Czech Republic
Received 18 February 2002; received in revised form 22 July 2002; accepted 13 August 2002
Abstract
1-O-(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononyl)xylitol 6 was synthesized as a novel standard compound for the assessment of
hemocompatibility and co-emulsifying properties in microemulsions for biomedical uses. 3-O-(1,1,2,4,4,5,7,7,8,8,9,9,9-Tride-
cafluoro-5-trifluoro-methyl-3,6-dioxanonyl)-D-glucose 9 and 6-O-(1,1,2,4,4,5,7,7,8,8,9,9,9-tridecafluoro-5-trifluoromethyl-3,6-diox-
anonyl)- -galactose 12 were synthesized by nucleophilic addition of protected carbohydrates to perfluorinated vinyl oligoether.
D
Biological tests revealed very good hemocompatibility and co-emulsifying properties for the amphiphiles 6, 9 and 12. © 2002
Elsevier Science Ltd. All rights reserved.
Keywords: Radical addition; Reduction of C-I bond; Perfluoroalkyl iodides; Perfluoro(alkyl vinyl oligoether); O-(Fluoroalkyl)xylitol; O-Fluo-
roalkyl-D-glucose; O-Fluoroalkyl-D-galactose; Hemocompatibility; Microemulsion stability
1. Introduction
of xylitol for testing hemocompatibility and co-emulsi-
fying properties; second, to prepare new fluoroalkylated
derivatives of -glucose and -galactose using the per-
Amphiphilic compounds possessing a hydrophilic
sugar moiety and perfluorinated hydrophobic moiety
have been proposed as biocompatible surfactants for a
series of medicinal applications. They display unique
properties for the formulation of multi-phase and
multi-component colloidal systems including perfluoro-
carbon emulsions for oxygen carriers, oxygen trans-
porting gels and drug delivery systems.1–4 A series of
perfluoroalkylated sugar amphiphiles have displayed
stabilisation effects on perfluorocarbon emulsions.1–4
For this purpose, perfluoroalkylated derivatives of xyli-
D
D
fluorinated vinyl ether 1 as a building block.
Recently, perfluoroalkylated derivatives of xylitol
possessing an unsaturated spacer between the hy-
drophilic saccharide and hydrophobic perfluoroalkyls
have been reported.5 However, unsaturation could
cause chemical and biochemical instability of such
molecules in potential medical applications. To avoid
the instability, we have developed here the synthesis of
an analogous O-alkylated xylitol derivative 6 having a
saturated spacer with three carbon atoms. Amphiphilic
sugar derivatives of perfluorinated ethers have not yet
been reported. As perfluorinated vinyl oligoethers have
become industrially available, we applied perfluorinated
vinyl diether in a two-step synthesis of the new sugar
derived surfactants 9 and 12. For an assessment of the
hemocompatibility of the new amphiphiles we have
developed methodology similar to that previously re-
ported.5 Co-emulsifying properties have been assessed
using our methodology.8
tol,5
D D
-glucose6,7 and -galactose6 were prepared and
tested.5–7 The aim of this paper has been, first, synthesis
of a chemically stable standard compound on the basis
ꢀ Presented at the 13th European Symposium on Fluorine
Chemistry, Bordeaux, France, 15–20th July 2001 (Poster
1-P51).
* Corresponding author. Fax: +4202-2431-1082
E-mail address: oldrich.paleta@vscht.cz (O. Paleta).
0008-6215/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(02)00287-2

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O. Paleta et al. / Carbohydrate Research 337 (2002) 2411–2418
on alkyl allyl ether,9 can also be initiated with sodium
2. Results and discussion
dithionite.10,11 Azo-bis(isobutyronitrile) was applied as
an intiator, which afforded the adduct 4 in a higher
yield than reported.5 For the reduction of a C–I bond
in perfluoroalkylated compounds, several methods heve
been reported, viz. catalytic reduction with hydro-
gen,9,11 reduction with zinc in the presence of
hydrochloric12 or acetic acids,13 reduction with sodium
For the synthesis of O-fluoroalkylated xylitol 6
(Scheme 1), we applied a modified previously reported
strategy in the initial two steps, namely the peparation
of protected O-allyl ether of xylitol5 3 and the radical
addition of perfluorohexyl iodide5,6 to the allyl part of
3. The addition, which had been originally performed
Scheme 1. (a) 1. NaH, toluene, 100 °C, 3 h; 2. CH2=CH-CH2Br, toluene, reflux, 18 h; (b) C6F13I, AIBN, 100 °C, 3 h; (c)
Zn–NiCl2·6H2O, THF–H2O, r.t., 24 h; (d) HClconc., methanol, r.t., 1 h; (e) 1.BuLi, THF, −78 °C; 2. 1, THF, −78 °C 2 h+r.t.
96 h; (f) CF3COOH–H2O (9:1), 30 min; (g)=(e); (h)=(f).

O. Paleta et al. / Carbohydrate Research 337 (2002) 2411–2418
2413
Table 1
Hemocompatibility of new amphiphilic compounds
Emulsifier
Substitution of Pluronic F-68 by tested
emulsifiers (% w/v PF-68)
20%
40% 60% 80% 100%
Range of hemolysis (%)
6
9
12
[Xylitol-1-O-yl]-CH2-CH2-CH2-CF2CF2CF2CF2CF2CF3
0a
0
0
0
0
0
0
0
nt
0
0
nt
nt
[D
-Glucose-3-O-yl]-CF2CHF-O-CF2CF(CF3)-O-(CF2)2CF3
-Galactose-6-O-yl]-CF2CHF-O-CF2CF(CF3)-O-(CF2)5CF3
ntb
nt
[D
a Zero value means hemolysis below 0.5%.
b nt, not tested.
borohydride14, tributyltin hydride15 or using zinc-nickel
chloride16 mixture. In the present paper, the reduction
with zinc-nickel chloride16 was applied giving complete
conversion of the iodo compound 4 and afforded the
reduced product 5 in a moderate isolated yield.
sis of multiplet signals in 13C NMR and 19F NMR
spectra.
The sugar amphiphiles 6, 9, 12 were tested as co-sur-
factants for potential oxygen carriers. Their hemolytic
activity on human erythrocytes was tested using a
reference microemulsion of Pluronic F-68 with per-
fluorodecalin mixed with erythrocytes. In this heteroge-
neous mixture, Pluronic was gradually substituted with
the amphiphile tested and the amount of extracellular
hemoglobin was determined spectrophotometrically as
per cent degree of hemolysis. This is a modified method
to that previously reported.5 Compound 6 was synthe-
sized as a reference amphiphile compared to the
reported5 xylitol derivative having unsaturation at the
spacer part that could cause biochemical instability.
Co-emulsifiers for microemulsions are usually used1–5
in amounts up to10% relatively to the main emulsifier,
e.g. Pluronic F-68. The xylitol amphiphile 6 appeared
to be completely non-hemolytic in the whole concentra-
tion range up to 100% substitution of the Pluronic and
it can be used as a non-hemolytic standard. Similarly,
amphiphiles 9 and 12 with 2H-perfluorinated polyether
chain showed no apparent hemolysis up to 60% (9) and
40% (12) substitution of the emulsifier Pluronic. Thus,
their hemocompatibility has appeared to be very good
(Table 1).
Preliminary testing of co-emulsifying properties was
based on visual evaluation of the state of an emulsion
(the methods are described in Section 3). The first test
was 6 h standing of the emulsion with co-emulsifier
(Table 2). The xylitol amphiphile 6 caused no apparent
(visual) colaps of the emulsion even at 100% substitu-
tion of the Pluronic. Glucose derivative 9 caused colaps
of the emulsion at 60% substitution of the Pluronic,
while at 40% content of 9 was the emulsion stable.
Similarly, substitution of Pluronic with 40% of the
galactose amphiphile 12 did not affect the emulsion
stability.
The O-fluoroalkylated
galactopyranose 12 were prepared by nucleophilic addi-
tions of the protected glucofuranose and
D-glucopyranose 9 and
D-
7
galactopyranose 10 to the perfluorinated vinyl diether 1
(Scheme 1). Nucleophilic additions of aliphatic or ali-
cyclic hydroxy compounds to perfluorinated vinyl alkyl
ethers and vinyl oligoethers have rarely been reported
in the literature, e.g. Refs 17–19. Our addition
procedure20–22 was applied in this work to afford the
corresponding adducts 8 or 11 in moderate isolated
yields. The additions of sugar alkoxides were com-
pletely regioselective, no regioisomeric products were
1
observed in H, 19F and 13C NMR spectra. The sodium
alkoxide of the protected glucofuranose 7 afforded the
adduct 8 in a three times lower yield than the corre-
sponding lithium salt (yield 33%). Therefore, the
lithium salt of 10 was also used in the fluoroalkylation
with the perfluorinated vinyl oligoether 1 to afford the
product 11 in a 52% yield. Deprotection of the
fluoroalkylated intermediate 8 using a classical hydroly-
sis with sulfuric acid was completely unsuccessful, while
the deprotection with trifluoroacetic acid afforded the
final amphiphilic sugar derivatives 9 and 12 in ca. 50%
isolated yields.
The structures of the sugar parts in the products 6, 9
and 12 were elucidated on the basis of reported NMR
data.5,6,23–25 The NMR spectra are consistent with the
pyranose structure for 9; it forms a mixture of
anomers23,24 in the approximate ratio a:b=60:40 (13C
NMR). For 12, the approximate anomer ratio a:b=
35:65 (13C NMR) was found.23,24 The polyether fluori-
nated chains in structures 8–9 and 11–12 possess two
stereogenic carbon atoms thus giving the possibility of
the formation of four stereoisomers. However, no
defined stereoisomers could be recognized by the analy-
Centrifugation is a very efficient test of the emulsion
stability that was first used in this study. The results of

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O. Paleta et al. / Carbohydrate Research 337 (2002) 2411–2418
testing for amphiphiles 6, 9 and 12 are summarised in
Table 3. The xylitol derivative 6 caused unstability of
the emulsion when more than 60% of Pluronic was
substituted with 6. Co-emulsifiers 9 and 12 did not
affect the emulsion stability when their portion of
Pluronic substitution was not higher than 40%. It can
be summarised that all three new amphiphiles 6, 9 and
12 let the Pluronic emulsion stable in much higher
concentrations than that usually applied1–5 (up to 10%)
for co-emulsifiers.
gen) instruments. NMR spectra were recorded on a
Varian Gemini 300 HC (1H at 300 MHz, 13C at 75.46
MHz) and a Bruker WP 80 SY (19F at 75.4 MHz)
instruments: TMS and CFCl3 as the internal standards,
chemical shifts in ppm (s singlet, d doublet, t triplet,
qua quadruplet, qui quintet, sex sextet, m multiplet, bs
broad singlet, q quasi), coupling constants J in Hz,
solvent CDCl3 and DMSO-d6. For the assignment of
1
signals in NMR spectra of compounds 9, 11 and 12, H
and 13C HETCOR technique was applied. MS spectra
were scanned on a Hewlett-Packard MSD 5971A in-
strument (1989, EI 70 eV). UV-VIS spectra were mea-
sured on a UV-160A apparatus (Shimadzu). Infrared
spectra were scanned on a NICOLET 740 USA
apparatus.
3. Experimental
General.—The temperature data were not corrected.
Distillations of high boiling compounds were carried
out on a Vacuubrand RC5 high vacuum oil pump.
Column chromatography: silica gel, aluminum oxide;
weight ratio compound/sorbent 1/30. GC analyses were
performed on a Micromat HRGC 412 (GCa, Nordion
Analytical; 25 m glass capilary column, SE-30) and
Chrom 5 (GCb, Laboratorn´ı pr´ıstroje, Prague; FID,
380×0.3 cm packed column, silicone elastomer E-301
on Chromaton N-AW-DMCS (Lachema, Brno), nitro-
Chemicals used were as follows: Silica gel (60–100
mm, Merck), hexafluoropropene-1,2-oxide (Aldrich), per-
fluorohexyl iodide (gift of Elf Atochem S.A.); xylitol,
1,2:5,6-di-O-isopropylidene-a-D-glucofuranose and D-
galactose (all Aldrich) were dried before use; allyl bro-
mide (Lachema), trifluoroacetic acid (Reachim). Zinc
chloride (anhydrous, Lachema), nickel chloride hydrate
(Lachema), sodium hydride (60% suspension in oil,
Aldrich), butyllithium (2.5 M in hexane, Aldrich), azo-
Table 2
Stability after mixing at 37°C for 6 hrs
Emulsifier
Substitution of Pluronic F-68 by tested
emulsifiers (% w/v PF-68)
20%
40% 60% 80% 100%
Emulsion stability
a
6
9
12
[Xylitol-1-O-yl]-CH2-CH2-CH2-CF2CF2CF2CF2CF2CF3
+
+
+
+
+
−
nt
+
−
nt
+
ntb
nt
[D
-Glucose-3-O-yl]-CF2CHF-O-CF2CF(CF3)-O-(CF2)2CF3
-Galactose-6-O-yl]-CF2CHF-O-CF2CF(CF3)-O-(CF2)5CF3
+
+
[D
a Plus value means no apparent change of emulsion; minus value means colapse of the emulsion.
b nt, not tested.
Table 3
Stability after centrifugation
Emulsifier
Substitution of Pluronic F-68 by tested
emulsifiers (% w/v PF-68)
20%
40% 60% 80% 100%
Emulsion stability
a
6
9
12
[Xylitol-1-O-yl]-CH2-CH2-CH2-CF2CF2CF2CF2CF2CF3
+
+
+
+
+
−
nt
−
−
nt
−
ntb
nt
[D
-Glucose-3-O-yl]-CF2CHF-O-CF2CF(CF3)-O-(CF2)2CF3
-Galactose-6-O-yl]-CF2CHF-O-CF2CF(CF3)-O-(CF2)5CF3
+
+
[D
a Plus value means no apparent change of emulsion; minus value means colaps of the emulsion.
b nt, not tested.

O. Paleta et al. / Carbohydrate Research 337 (2002) 2411–2418
2415
bis(isobutyronitril) (AIBN, crystallised before use,
Fluka). Diethyl ether (distilled over Na), dichloro-
methane (distilled, b.p. 42 °C), methanol (distilled over
Na, stored over molecular sieves); other solvents used
were purified and dried according to standard proce-
dures.
Preparation of chemicals.—Perfluoro-[2,5-dimethyl-
(3,6-dioxa)nonanoyl] fluoride was prepared according
to our previously reported procedure.26,27 1,2:3,4-Di-O-
isopropylidenexylitol was prepared according to Refs
5,28.
filtration fractionally distilled (Vigreux column, 15 cm
heated jacket) to afford pure 1, b.p. 101–102 °C, yield
10.9 g (62%), purity 98% (check by 19F NMR and GC).
When the sodium salt was not completely dry,
1,1,1,2,4,4,5,7,7,8,8,9,9,9 - tetradecafluoro - 5 - trifluoro-
methyl-3,6-dioxanonane was formed up to 25% rel.
19F NMR (CDCl3): l −80.4 (qs, 3F, F-e), −81.9
(qs, 3F, F-a), −82.2 (qs, 2F, F-c), −85.2 (qs, 2F, F-f),
−113.5 (dd, 1F, JF,F 83.0 Hz, JF,Fcis 65.9 Hz, F-hcis),
−122.0 (tdd, 1F, JF,Ftrans 112.0 Hz, JF,F 5.5 Hz, F-
htrans), −130.1 (qs, 2F, F-b), −136.0 (tdd, 1F, JF,F 5.8
Preparation of emulsions.—Perfluorodecalin (0.125
mL) was mixed with isotonic Tris–HCl buffer of pH
7.4 and Pluronic F-68 (block co-polymer of poly-
oxypropylene and polyoxyethylene, 5% w/v) as a stan-
dard emulsifier and the mixture was sonicated for 15 s
to afford 0.5 mL of an emulsion. (For a more detailed
description of the testing procedures see Ref. 29).
Hemocompatibility testing5,29.—Human erythrocytes
(from a healthy donor, stored in a refrigerator not
longer than 1 week) were washed by isotonic Tris-HCl
buffer. Packed erythrocytes (0.5 mL) were added to the
emulsion of perfluorodecalin (see above), the mixture
was then gently stirred at 37 °C for 6 h and after that
shortly centrifuged. The amount of the extracellular
hemoglobin in the water phase was determined spec-
trophotometrically and used as a measure of hemolytic
activity of the co-emulsifier tested. (For a more detailed
description of the procedure see Ref. 29).
Testing of co-emulsifying properties: in the prepara-
tion of an emulsion (see above), Pluronic F-68 was
partly or completely substituted by the tested co-
emulsifier; if any apparent phase separation of water
and perfluorodecalin phases did not appear immedi-
ately after finishing the test, the emulsion was consid-
ered to be stable (indicated as ‘+’ in Tables 2 and 3).
Unstable emulsion is marked by the sign ‘−‘ in Tables
2 and 3. Stabilities of the mixtures were tested under
two different conditions: (1) Stability at 37 °C: the
emulsion was gently stirred (magnetic spibar) at 37 °C
for 6 h (see hemolytic test above). (2) Stability during
centrifugation: the emulsion was centrifuged for 5 min.
at 400×g.
Hz, F-g), −145.4 (m, 1F, F-d).
1-O-Allyl-2,3:4,5-di-O-isopropylidenexylitol5 3.—To
a suspension of NaH (0.36 g, 15 mmol) in toluene (15
mL) a solution of diacetonexylitol 2 (2.32 g, 10 mmol)
in toluene (3 mL) was added dropwise. The mixture
was stirred at 100 °C for 3 h, then cooled to r.t. and
allyl bromide (2.42 g, 20 mmol) in toluene (3 mL) was
added portionwise. The mixture was refluxed for 18 h
while stirring, then cooled to r.t. and water was added
dropwise under reflux condenser. The resulting mixture
was extracted with diethyl ether (2×15 mL), the ethe-
real extract was washed with NaHCO3 water solution
to neutral pH, dried over MgSO4 and the solvent was
removed on rotary evaporator at 40 °C. Distillation of
the residue—a raw product 3 on a Hickmann-type
short-way distillation apparatus in vacuum of the oil
pump afforded product 3 as a colourless liquid, yield
1.78 g (69%), b.p. 95 °C/0.4 mmHg (lit.:5 b.p. 90–
100 °C/0.3 mm Hg).
1H NMR (CDCl3): l 1.33 and 1.38 (2x s (1:3), 12H,
4x CH3), 3.52 (m, 2H, H-1%, H-1% ), 3.70-4.24 (m, 7H,
a
b
xylitol protons), 5.06 (dd, 1H, J 1.65 Hz, J 10.4 Hz,
H-3%trans), 5.30 (dd, 1H, J 1.65 Hz, J 17.6 Hz, H-3c%is),
5.80 (ddt, 1H, J 5.5 Hz, J 10.4 Hz, J 17.5 Hz, H-2%).
13C NMR (CDCl3): l 25.3 and 26.1 and 26.9 (3x s,
4C, 4x CH3), 65.5, 70.5, 72.3 (3x s, 3C, C-1, C-1%, C-5),
75.5, 76.3, 78.3 (3x s, 3C, C-2, C-3, C-4), 109.4 (s, 1C,
kvart. C), 109.5 (s, 1C, kvart. C), 107.1 (s, 1C, C-3%),
134.2 (s, 1C, C-2%).
IR (CHCl3); w 1060 (s), 1080 (s), 1157 (m), 1372 (s),
2897 (m), 2937 (m), 2991 (s), 3017 (s).
Anal. Calcd for C14H24O5: C, 61.74; H, 8.88. Found:
C, 61.72; H, 9.02.
1,1,2,4,4,5,7,7,8,8,9,9,9 - Tridecafluoro - 5 - trifluoro-
methyl-(3,6-dioxa)non-1-ene27,30 1.—A mixture of per-
fluoro-(2,5-dimethyl-3,6-dioxanonanoyl) fluoride (20.75
g, 41.7 mmol), distilled water (20 mL) and ethanolic
solution of phenolphthaleine (6 drops) in a flask
equipped with a dropping funnel was titrated with a
water solution of NaOH (10%) while stirring (magnetic
spinbar). The mixture was evaporated to dryness and
then dried on an oil pump (0.3 mmHg, 150 °C, 6 h).
1,2:3,4-Di-O-isopropylidene-h-D
-galactopyranose31
10.—Anhydrous ZnCl2 (21.6 g, 158.5 mmol) was dis-
solved in acetone (225 mL) by stirring under inert
atmosphere. Small amount of Zn(OH)2 present was
dissolved by dropwise addition of H2SO4 through sep-
tum. Finely ground anhydrous galactose (18 g, 0.1 mol)
was added to the solution and stirred (magnetic spin-
bar) for 4 h at r.t. A suspension of Na2CO3 (36 g) in
water (63 mL) was then added portionwise to the
mixture, which was stirred until the liquid layer con-
tained zinc ions, and filtrated. The solid was washed on
Dry
sodium
perfluoro-(2,5-dimethyl-3,6-diox-
anonanoate) was then heated to 260–340 °C in a distil-
lation apparatus to afford raw product 1 (fraction
95-140 °C). This distillate was dried (MgSO4) and after

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O. Paleta et al. / Carbohydrate Research 337 (2002) 2411–2418
the filter with acetone (3×15 mL) and combined
filtrates were evaporated under reduced pressure (30 °C,
200 mmHg, rotary evaporator). The residue was ex-
tracted with diethyl ether (3×50 mL) and the ethereal
extract was dried over MgSO4. After distilling off the
solvent, the residue was dried in vacuum (0.05 mmHg,
100 °C) to afford a sirup-like raw product (23.4 g). Its
distillation on a Hickmann-type short-way distillation
apparatus in vacuum of the oil pump afforded product
10 as a colourless viscous liquid, yield 21.9 g (84.1%)
b.p. 131–135 °C/0.3 mmHg.
water in a flask under inert atmosphere for 30 min at
r.t. 1-O-(4,4,5,5,6,6,7,7,-8,8,9,9,9-Tridecafluoro-2-iodo-
nonyl)-2,3:4,5-di-O-isopropylidenexylitol (4) (0.25 g,
0.36 mmol) was then added to the agent and the
mixture was stirred for 24 h at r.t. Volatile components
were then removed on a rotary evaporator (40 °C, 60
mmHg) and the residue was chromatographed (silica
gel, 20 g, diethyl ether) to afford product 5 as slightly
yellowish viscous liquid, yield 95 mg (46%).
1H NMR (CDCl3): l 1.38 and 1.43 (2x s, 12 H, 4x
CH3), 1.80-1.98 (m, 2H, H-2%), 2.05-2.44 (m, 2H, H-3%),
3.40–4.30 (m, 9H, H-1%and 7x xylitol protons).
13C NMR (CDCl3): l 20.7 (s, 1C, C-2%), 28.9 (s, 1C,
C-3%), 65.6, 70.0, 71.4 (3x s, 3C, C-1, C-5, C-1%), 75.4,
76.4, 78.0 (3x s, 3C, C-2, C-3, C-4), 109.6 (s, 1C, kvart.
C), 109.7 (s, 1C, kvart. C), 105.0-125.0 (m, 6C, 5x CF2
and CF3).
4. Products 4-12
Radical addition of perfluorohexyl iodide to protected
1-O-allylxylitol (3). 2,3:4,5-Di-O-isopropylidene-1-
O - (4,4,5,5,6,6,7,7,8,8,9,9,9 - tridecafluoro - 2 - iodononyl)-
xylitol (4).—The reaction was carried out in a double-
neck round-bottomed flask equipped with a Dimroth
condenser that was connected with atmosphere by a
hydraulic seal. Nitrogen was slowly introduced in the
mixture of 1-O-allyl-2,3:4,5-di-O-isopropylidenexylitol
(3, 0.5 g, 1.94 mmol), perfluorohexyl iodide (1.34 g, 3
mmol) and AIBN (20 mg) for 20 min while stirring
(magnetic spinbar) and the mixture was then heated on
a oil bath at 100–110 °C for 3 h.
19F NMR (CDCl3): l −81.3 (t, 3F, JF,F 9.8 Hz,
CF3), −114.8 (m, 2F, CF2–CH2), −122.4 (m, 2F,
CF2), −123.4 (qs, 2F, CF2), −124.0 (m, 2F, CF2),
−126.6 (m, 2F, CF2).
Anal. Calcd for C20H25F13O5: C, 40.05; H, 4.25.
Found: C, 39,74; H, 4.73.
1 - O - (4,4,5,5,6,6,7,7,8,8,9,9,9 - Tridecafluorononyl)-
xylitol (6).—To a solution of 2,3:4,5-di-O-isopropyli-
dene-1-O-(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyl)-
xylitol (5) (0.50 g, 0.9 mmol) in methanol (25 mL)
concentrated HCl (36%, 5 mL) was added dropwise by
a syringe and the mixture was stirred (magnetic spin-
bar) at r.t. After 24 h reaction, no starting compound
was detected in the mixture (TLC, CHCl3/CH3OH 5:1).
Volatile components were then removed on a rotary
evaporator (40 °C, 35 mmHg) and the residue was
chromatographed (silica gel, 50 g, CHCl3/CH3OH 5:1)
to afford product 6 as a slightly yellow waxy com-
pound, yield 240 mg (55%).
Volatile components were then removed on a rotary
evaporator (45 °C, 30 mm Hg) and lastly by oil pump
(45 °C, 30 mm Hg) to get the raw product 4. Pure
product 4 was obtained as a slightly pinky liquid by
purification on column chromatography (silica gel, 40
g, dichloromethane), yield 1.19 g (88%).
1H NMR (CDCl3): l 1.30 and 1.35 (2x s (1:3), 12H,
4x CH3), 2.44-2.80 and 2.83-3.16 (2x m, 2H, H-3%),
3.46-4.44 (m, 10H, 7x xylitol protons and H-2% and
H-1%).
1H NMR (CDCl3): l 1.78–2.00 (m, 2H, H-2%), 2.14–
2.50 (m, 2H, H-3%), 3.40–4.00 (m, 9H, H-1% and 7x
xylitol protons), 4.86 (s, 4H, 4x OH).
13C NMR (CDCl3): l 13.9 and 14.0 (2x s, 1C, C-2%),
25.2 (s, 1C, CH3), 26.0 (s, 1C, CH3), 26.7 (s, 1C, CH3),
26.8 (s, 1C, CH3), 37.5 and 37.6 (2x t, 1C, JC,F 20 Hz,
C-3%), 65.5, 70.5, 71,1, 71.2, 76.3 (4x s, 3C, C-1, C-1%,
C-5), 75.1, 75.2, 76.2, 77.7, 77.8 (5x s, 3C, C-2, C-3,
C-4), 109.6 (s, 1C, kvart. C), 109.7 (s, 1C, kvart. C),
103.8-123.6 (m, 6C, 5x CF2 and CF3).
13C NMR (CDCl3): l 21.9 (s, 1C, C-2%), 29.3 (s, 1C,
C-3%), 64.3, 70.8, 73.4 (3x s, 3C, C-1, C-5, C-1%), 72.2,
72.3, 73.9 (3x s, 3C, C-2, C-3, C-4), 106.0–126.0 (m,
6C, 5x CF2 and CF3).
19F NMR (CD3OD) l −81.0 (t, 3F, JF,F 9.8 Hz,
CF3), −112.4 (m, 2F, CF2–CH2), -121.5 (qs, 2F, CF2),
−122.6 (qs, 2F, CF2), −123.3 (qs, 2F, CF2), −126.0
(m, 2F, CF2).
19F NMR (CDCl3): d −81.4 (t, 3F, JF,F 10.2 Hz,
CF3), −113.9 (m, 2F, CF2-CH2), -122.2 (qs, 2F, CF2),
−123.3 (qs, 2F, CF2), −124.0 (qs, 2F, CF2), −126.6
(m, 2F, CF2).
Addition of 1,2:5,6-di-O-isopropylidene-h-D-gluco-
Anal. Calcd for C20H24F13IO5: C, 33.44; H, 3.37.
Found: C, 33.69; H, 3.73.
furanose (7) to perfluoro6inyl ether (1); 1,2:5,6-di-O-iso-
propylidene-3-O-(1,1,2,4,4,5,7,7,8,8,9,9,9-tridecafluoro-
Reduction of C–I bond in adduct 4. 2,3:4,5-Di-O-iso-
propylidene-1-O-(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoro-
nonyl)xylitol (5).—Reducing agent was prepared by
stirring (magnetic spinbar) a mixture of powdered zinc
(0.34 g, 4.80 mmol), nickel(II) chloride hexahydrate
(0.10 g, 0.42 mmol), THF (3 mL) and a droplet of
5 - trifluoromethyl - 3,6 - dioxanonyl) - h -
(8).—Procedure A (reaction of lithium salt): To a
solution of 1,2:5,6-di-O-isopropylidene-a- -glucofura-
nose (7, 112 mg, 0.43 mmol) in dry THF (2 mL) under
nitrogen atmosphere in a flask with septum, which was
immersed in dry-ice bath (ethanol), a solution of butyl-
D - glucofuranose
D

O. Paleta et al. / Carbohydrate Research 337 (2002) 2411–2418
2417
identified in the reaction mixture (TLC check, hep-
tane:ethyl acetate 10:1).
lithium (0.1 mL, 0.12 mmol, 2.47 mol/L in hexane) was
added dropwise. The solution of lithium salt of 7 was
transferred under nitrogen in 5 min by syringe to a
mixture of perfluoro-5-methyl-3,6-dioxanon-1-ene (1,
193 mg, 0.45 mmol) immersed to a dry-ice bath (etha-
nol). The reaction mixture, which formed two layers,
was stirred at −70 °C for 2 h and then 40 h at r.t., but
the mixture still contained unreacted perfluoro vinyl
ether 1. The reaction was stopped by the addition of
trifluoroacetic acid (pH$5.5), volatile components
were removed on a rotary evaporator (40 °C, 30
mmHg) and the residue was chromatographed (alu-
minum oxide, 30 g, heptane:acetone 4:1) to afford
syrup-like pure product 8 (TLC check, heptane:ethyl
acetate 10:1) yield 101 mg (33%).
Procedure B (reaction of sodium salt): Using the
methodology as above, sodium salt of 7 was prepared
by its reaction with NaH in DMF at r.t. and reacted
with perfluorinated vinyl ether 1 at r.t. After 2 d
reaction at r.t., the mixture did not contained any
product and 93% of the starting 7 was recovered.
1H NMR23 (CDCl3): l 1.33 and 1.39 (2x s, 6H, 2x
CH3), 1.51 (s, 6H, 2x CH3), 3.99 (m, 1H, H-6a), 4.06
(m, 1H, J 7.7 Hz, H-6b), 4.17 (m, 2H, H-4 and H-5),
4.62 (m, 1H, H-2), 4.82 (m, 1H, H-3), 5.88 (d, 1H, J1,2
3.3 Hz, H-1), 6.10 (d, 1H, JH,F 53.3 Hz, H-g).
Procedure B6: A mixture of fluoroalkylated derivative
8 (363 mg, 0.10 mmol), water solution of trifluoroacetic
acid (1.5 mL, 1:9) was stirred (magnetic spinbar) for 30
min at r.t. when the conversion was complete (TLC as
in Procedure A.). Reaction mixture was evaporated to
dryness (rotary evaporator), then, petroleum ether (2.5
mL) was added to the wet residue, evaporated and the
operation was twice repeated. The crude product 9 was
chromatographed (aluminum oxide, 50 g, methanol) to
afford pure waxy product 9, yield 158 mg (49%). For
analytical purposes, the product 9 was dried for 42 h
(35 °C, 0.02 mm Hg).
1H NMR24 (CDCl3 and MeOD): l 3.7 and 3.8 (m,
H-6), 4.57 (d, J1,2 7.6 Hz, H-1-b) and 5.21 (bs, H-1-a),
6.22 (d, JH,F 53.1 Hz, H-g).
13C NMR24 (CDCl3 and MeOD): anomer ratio a:b
ca. 60:40: l 61.0 and 61.2 (2x s, 1C, a- and b-C-6), 70.0
and 70.1 (2x s, 1C, a- and b-C-4), 72.6 and 75.6 (2x s,
1C, a- and b-C-5), 92.2 and 96.2 (2x s, 1C, a,b-C-1),
98.3 (td, 1C, JC,F 241.7 Hz, JC,F 39.9 Hz, C-g), 102.5
(sex d, 1C, JC,F 259.4 Hz, JC,F 35.4 Hz, C-d), 106.2 (sex
t, 1C, JC,F 268.0 Hz, JC,F 37.5 Hz, C-b), 115.1 (tt, 1C,
JC,F 290.1 Hz, JC,F 27.9 Hz, C-c), 115.2 (dt, 1C, JC,F
288.1 Hz, JC,F 28.9 Hz, C-f), 117.2 (tq, 1C, JC,F 279.4
Hz, JC,F 39.0 Hz, C-a), 116.8 (dt, 1C, JC,F 286.9 Hz,
JC,F 28.6 Hz, C-h), 117.5 (dq, 1C, JC,F 280.8 Hz, JC,F
29.0 Hz, C-e).
13C NMR23 (CDCl3): l 25.6 and 26.8 and 27.3 and
27.5 (4x s, 4C, 4x CH3), 67.9 (s, 1C, C-6), 72.6 (s, 1C,
C- 5), 77.9 (s, 1C, C-4), 80.5 (s, 1C, C-2), 84.0 (s, 1C,
C-3), 105.6 (s, 1C, C-1), 98.5 (ttd,, JC,F 244.9 Hz, JC,F
41.8 Hz, JC,F 4.5 Hz, C-g), 103.0 (sex d, 1C, JC,F 268.4
Hz, JC,F 37.2 Hz, C-d), 107.7 (sex t, 1C, JC,F 268.4 Hz,
JC,F 36.1 Hz, C-b), 110.1 and 113.3 (2x s, 2C, kvart. C),
115.8 (dt, 1C, JC,F 287.3 Hz, JC,F 32.8 Hz, C-c), 117.0
(dt, 1C, JC,F 282.1 Hz, JC,F 29.2 Hz, C-f), 117.7 (tq, 1C,
JC,F 287.7 Hz, JC,F 32.9 Hz, C-a), 118.2 (dt, 1C, JC,F
268.9 Hz, JC,F 29.2 Hz, C-h), 118.3 (dq, 1C, JC,F 288.1
Hz, JC,F 31.2 Hz, C-e).
19F NMR (CDCl3 and MeOD): l −80.5 (m, 3F,
F-e), −81.8 (q, 3F, F-a), −82.0 (m, 2F, F-c), −84 to
−88 (m, 4F, F-h and F-f), −130.1 (s, 2F, F-b),
−145.3 (m, 1F, F-d), −144.6 to −145.8 (m, 1F, F-g).
Anal. Calcd for C14H12O8F16: C, 27.46; H, 2.01.
Found: C, 26,83; H, 2.55.
Addition
of
1,2:3,4-di-O-isopropylidene-h-D-
galactopyranose (10) to perfluoro6inyl ether 1. 1,2:3,4-di-
O-isopropylidene-6-O-(1,1,2,4,4,5,7,7,8,8,9,9,9-trideca-
fluoro-5-trifluoromethyl-3,6-dioxanonyl)-h-
pyranose (11).—To a solution of 1,2:3,4-di-O-isopropy-
lidene-a- -galactopyranose (10, 390 mg, 1.50 mmol) in
D-galacto-
19F NMR (CDCl3): l −80.5 (m, 3F, F-e), −81.8 (q,
3F, F-a), −81.9 and −82.3 (m, 2F, JF,F 147.4 Hz,
F-c), −85.7 and −87.0 (d, 2F, JF,F 146.1 Hz, F-h),
−84.1 and −86.1 and −83.9 and −85.7 (2x d, 2F,
JF,F 5.6 Hz, JF,F 141.5, JF,F 144.2 Hz, F-f), −130.1 (s,
2F, F-b), −143.9 and −144.7 and −144.1 and
−144.8 (2x d, 1F, JF,F 8.3 Hz, F-g), −145.4 (t, 1F,
JFd,Ff 21.0 Hz, F-d).
D
dry THF (3 mL) under nitrogen atmosphere in a flask
with septum, which was immersed in dry-ice bath (etha-
nol), a solution of butyllithium (0.6 mL, 0.48 mmol,
2.47 mol/L in hexane) was added dropwise. The solu-
tion lithium salt of 10 was transferred under nitrogen in
5 min by syringe to a mixture of perfluoro-5-methyl-
3,6-dioxanon-1-ene (1, 647 mg, 1.50 mmol) immersed to
a dry-ice bath (ethanol). The reaction mixture was
stirred at −70 °C for 2 h and then 40 h at r.t. The
reaction was stopped by the addition of trifluoroacetic
acid (pH$5.5), volatile components were removed on
a rotary evaporator (40 °C, 30 mm Hg) and the residue
was chromatographed (aluminum oxide, 50 g, hep-
tane:acetone 4:1) to afford waxy pure product 11 (TLC
check, heptane:ethyl acetate 10:1) yield 537 mg (52%).
Anal. Calcd for C20H20O8F16: C, 34.70; H, 2.91; F,
43.90. Found: C, 34.45; H, 2.85; F, 44.34.
Deprotection of 8. 3-O-(1,1,2,4,4,5,7,7,8,8,9,9,9-
Tridecafluoro-5-trifluoromethyl-3,6-dioxanon-1-yl)-
D-
glucopyranose (9).—Procedure A: mixture of
A
fluoroalkylated glucofuranose 8 (141 mg, 0.20 mmol),
methanol (1 mL), water (1 mL) and H2SO4 (0.1 mL)
was refluxed for 1 h and then neutralized with a warm
solution of BaCO3. No deprotected product 9 was

2418
O. Paleta et al. / Carbohydrate Research 337 (2002) 2411–2418
1H NMR24,25 (CDCl3): l 1.33 (s, 6H, 2x CH3), 1.45
References
(s, 3H, CH3), 1.51 (s, 3H, CH3), 3.99 (m, 1H, H-6a),
4.06 (m, 1H, Ja,b 7.7 Hz, H-6b), 4.17 (m, 2H, H-4 and
H-5), 4.62 (m, 1H, H-2), 4.82 (m, 1H, H-3), 5.88 (d, 1H,
J1,2 3.3 Hz, H-1), 5.89 (d, 1H, JH,F 53.4 Hz, H-g).
19F NMR (CDCl3): l −80.3 (m, 3F, F-e), −81.6 (q,
3F, F-a), −81.6 and −82.0 (d q, 2F, JF,F 150.5 Hz,
F-c), −89.5 and −90.7 (d q, 2F, JF,F 140.0 Hz, F-h),
−83.5 (−86.1) (m, 2F, F-f), −129.8 (s, 2F, F-b),
−145.1 (t, 1F, JF,F 21.0 Hz, F-d), −144.5 (−145.1)
(m, 1F, F-g).
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D
galactopyranose (11, 216 mg, 0.31 mmol), water solu-
tion of trifluoroacetic acid (3 mL, 1:9) was stirred
(magnetic spinbar) for 30 min at r.t. when the conver-
sion was complete (TLC as for 9). Reaction mixture
was evaporated to dryness (rotary evaporator).
Petroleum ether (2.5 mL) was then added to the wet
residue, evaporated and the operation was twice re-
peated. The crude product 12 crystallised (THF/chloro-
form 1:3) to afford pure product 12, yield 103 mg
(51%). For analytical purposes, product 12 was dried
for 42 h (35 °C, 0.02 mmHg).
1H NMR24,25 (DMSO): l 3.5 and 3.6 (m, H-6), 4.2
(m, H-1-b) and 4.9 (s, H-1-a), 6.8 (d, JH,F 52.6 Hz,
H-g).
13C NMR24,25 (DMSO): anomer ratio a:b ca. 35:65: l
60.5 (s, 1C, C-6); 68.2, 68.8, 70.3, 72.1, 73.5, 75.0 (6x s,
C-2, C-3, C-4, C-5) 92.5 and 97.5 (2x s, 1C, a and
b-C-1).
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19F NMR (CDCl3 and MeOD): l −80.0 (m, 3F,
F-e), −81.2 (m, 3F, F-a), −81.3 (m, 2F, F-c), −83 to
−93 (m, 2F, F-h), −83.8 (m, 1F, F-f), −129.4 (s, 2F,
F-b), −144.7 (m, 1F, F-d), −144.3 to −145.5 (m, 1F,
F-g).
22. Dlouha´, I.; Kv´ıcˇala, J.; Paleta, O. J. Fluorine Chem. 2002,
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Anal. Calcd for C14H12O8F16: C, 27.46; H, 2.01.
Found: C, 26,91; H, 2.60.
25. C´ırkva, V. Dissertation. Institute of Chemical Technol-
ogy, Prague, 1997.
Acknowledgements
26. Kv´ıcˇala, J.; Paleta, O.; Deˇdek, V. J. Fluorine Chem. 1990,
47, 441–457.
The authors thank the Atofina S.A. (Elf Atochem
S.A.) for the gift of perfluorohexyl iodide The research
was supported by the Grant Agency of the Czech
Republic (grants No. 203/98/1174 and 203/01/1311)
and the grant of the Ministry of Education of the Czech
Republic (Project MSM 22310002). The authors thank
heartily Mrs. I. Ferjentsikova´ for kind assistance in
measurements of hemocompatibility and co-emulsifying
properties.
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29. Kod´ıcek, M.; Forman, S.; Paleta, O. In preparation.
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