Organofluorine compounds and fluorinating agents; 29: Stereoselective synthesis and reactivity of 2-chlorodifluoromethyl-substituted monosaccharides

Article abstract of DOI:10.1055/s-2003-38076

Chlorodifluoromethyl groups were introduced into the 2-position of the glycals 1, 5, 8, and 11 by dithionite-mediated addition of CF₂ClBr. The reaction proceeded stereoselectively, i.e. the CF₂Cl-group is always found trans to the neighbouring substituent at C-3 in the products. Because the primarily formed glycosyl bromides hydrolyse easily, the corresponding 2-chlorodifluoromethyl-2-deoxypyranoses 3, 6, 9, and 12 were isolated, Only 3,4,6-tri-O-acetyl-2-chlorodifluoromethyl-2-deoxy-D-glucopyranosyl bromide (2) was stable enough for chromatographic separation. The unprotected anomeric pyranoses 3, 6, 9, and 12 were acetylated by acetic anhydride/pyridine yielding the 1-O-acetyl derivatives 4, 7, 10, and 13. These compounds are suitable glycosyl donors, just as the anomeric phenyl thioglycosides 16 and 17 generated from 1,3,4-tri-O-acetyl-2-chlorodifluoromethyl-2-deoxy-D-arabinopyranside (7) and thiophenol (BF₃-catalysis). Furthermore, the reactivity of glucosyl bromide 2, 6-deoxy-L-glucose derivative 13 and thioglycosides 16, 17 was investigated. On treatment of glucosyl bromide 2 with pyridine, the 2-chlorodifluoromethyl substituted glycal 14 is formed as the result of HBr elimination. Furthermore, the chlorodifluoromethyl group of compounds 14 and 16 was converted into a methoxycarbonyl group by refluxing in methanolic sodium methoxide (products 15 and 19, respectively). Finally, the thioglycosides 16 and 17 were subsequently deacetylated by CsF on alumina (yielding the dihydroxy derivatives 18 and 20) and acetalized with chloral/DCC (18 forming acetal 21 and carbonate 22) and acetone (20 forming acetal 23), respectively. X-ray analyses are given for the 1-O-acetate 4 and the thioglycosides 21 and 24.

Full text of DOI:10.1055/s-2003-38076

PAPER
707
Organofluorine Compounds and Fluorinating Agents; 29:1
Stereoselective Synthesis and Reactivity of 2-Chlorodifluoromethyl-
Substituted Monosaccharides
Synthesis of
2
t
e
difluorome
f
thyl-Sub
a
stitute
d
Mo
n
nosaccharides Tews, Ralf Miethchen,* Helmut Reinke
Universität Rostock, Fachbereich Chemie, Albert-Einstein-Strasse 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: ralf.miethchen@chemie.uni-rostock.de
Received 27 November 2002; revised 27 January 2003
diated addition of halogeno-fluoroalkanes to unsaturated
precursors.14–19 The method first reported by Huang is a
very simple procedure working under mild reaction con-
ditions. Best results are obtained in dithionite-mediated
Abstract: Chlorodifluoromethyl groups were introduced into the 2-
position of the glycals 1, 5, 8, and 11 by dithionite-mediated addi-
tion of CF2ClBr. The reaction proceeded stereoselectively, i.e. the
CF2Cl-group is always found trans to the neighbouring substituent
at C-3 in the products. Because the primarily formed glycosyl bro- reactions when approximately equimolar amounts of
mides hydrolyse easily, the corresponding 2-chlorodifluoromethyl-
Na2S2O4 and NaHCO3 in 1:1 acetonitrile–water mixtures
are used. Recently, Dmowski et al.19 pointed out that
2-deoxypyranoses 3, 6, 9, and 12 were isolated. Only 3,4,6-tri-O-
acetyl-2-chlorodifluoromethyl-2-deoxy-D-glucopyranosyl
bro-
dithionite-mediated halothane additions to enol ethers
gave the best results on pre-cooling the aqueous dithionite
solution to 10 °C. We can confirm that this pre-cooling to
about 10 °C is generally important to achieve high yields
in dithionite-mediated reactions. First applications of the
Huang method are also published in carbohydrate chem-
istry,15,20,21 since fluorinated building blocks linked to car-
bohydrates can be used as very useful tools, e.g. in 19F in
vivo NMR spectroscopy or for other biomedical purposes.
Recently, an excellent review was published about C-di-
fluoromethyl- and C-trifluoromethyl-substituted carbohy-
drates by Plantier-Royon and Portella.22
mide (2) was stable enough for chromatographic separation. The
unprotected anomeric pyranoses 3, 6, 9, and 12 were acetylated by
acetic anhydride/pyridine yielding the 1-O-acetyl derivatives 4, 7,
10, and 13. These compounds are suitable glycosyl donors, just as
the anomeric phenyl thioglycosides 16 and 17 generated from 1,3,4-
tri-O-acetyl-2-chlorodifluoromethyl-2-deoxy-D-arabinopyranside
(7) and thiophenol (BF3-catalysis). Furthermore, the reactivity of
glucosyl bromide 2, 6-deoxy-L-glucose derivative 13 and thiogly-
cosides 16, 17 was investigated. On treatment of glucosyl bromide
2 with pyridine, the 2-chlorodifluoromethyl substituted glycal 14 is
formed as the result of HBr elimination. Furthermore, the chlorodi-
fluoromethyl group of compounds 14 and 16 was converted into a
methoxycarbonyl group by refluxing in methanolic sodium meth-
oxide (products 15 and 19, respectively). Finally, the thioglycosides
16 and 17 were subsequently deacetylated by CsF on alumina
(yielding the dihydroxy derivatives 18 and 20) and acetalized with
chloral/DCC (18 forming acetal 21 and carbonate 22) and acetone
(20 forming acetal 23), respectively. X-ray analyses are given for
the 1-O-acetate 4 and the thioglycosides 21 and 24.
Glycals, unsaturated carbohydrates with a double bond
between C-1 and C-2, behave like vinyl ethers. Such com-
pounds often show high regio- and stereoselectivity in ad-
dition reactions. As part of our ongoing efforts in the
synthesis of new fluorinated analogues of natural sub-
stances, we investigated dithionite-mediated chlorodiflu-
oromethylations of D-glucal (1), D-ribal (5), D-xylal (8),
and L-rhamnal (11) with bromochlorodifluoromethane in
acetonitrile–water as shown in Scheme 1. The reactions
were both regio- and stereoselective relative to the chlo-
rodifluoromethyl group, i.e. this group is already intro-
duced trans to the acetyl group at C-3. Thus, 3,4,6-tri-O-
acetyl-2-chlorodifluoromethyl-2-deoxy-α-D-glucopyran-
osyl bromide (2) formed from glucal 1 was isolated by
column chromatography and characterized by NMR and
mass spectrometric data. However, it was contaminated
with small amounts of the hydroxy derivative 3. Treat-
ment with an aqueous methanolic suspension of silver car-
bonate accelerates the hydrolysis of 2 to 3,4,6-tri-O-
acetyl-2-chlorodifluoromethyl-2-deoxy-α-D-glucopyran-
ose (3). The glycosyl bromides generated from the glycals
5, 8, 11 were particularly sensitive towards water and
were predominantly hydrolysed under the reaction condi-
tions. Therefore, the crude mixtures were completely hy-
drolysed before chromatographic separation giving D-
arabinopyranose derivative 6, D-xylopyranose derivative
Key words: carbohydrates, glycals, difluoromethylation, radical
addition reactions, eliminations, acetals
The interest for fluorinated analogues of natural products
is increasing continuously because the introduction of flu-
orine or fluoroalkyl groups may significantly modify their
chemical, physical and biological properties.2–8 In view of
the potential biological properties new gem-difluorinated
compounds find special attention.9,10
Radical additions of halogeno-fluoroalkanes to unsaturat-
ed precursors rank among the well suitable methods for
the introduction of fluoroalkyl groups into organic com-
pounds. Recently, Chen11 and Wang et al.12 reported cor-
responding reactions initiated by UV-irradiation. Electron
rich precursors like enamines even allow such additions
without irradiation or initiation.13 However, one of the
most convenient methods in this field is the dithionite-me-
Synthesis 2003, No. 5, Print: 01 04 2003.
Art Id.1437-210X,E;2003,0,05,0707,0716,ftx,en;T12302SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

708
S. Tews et al.
PAPER
Figure 1 X-ray structure of 1,3,4,6-tetra-O-acetyl-2-chlorodifluo-
romethyl-2-deoxy-α-D-glucopyranose (4)
purification and the acetyl derivative 15 was isolated in
63% overall yield.
Scheme 1 Reagents and conditions: i. CF2ClBr, Na2S2O4, MeCN–
H2O, 5–15 °C; ii. H2O, Ag2CO3; iii. Ac2O, pyridine, 20 °C, 15 h
The relatively easy replacement of the halogen atoms in
14, because of their ‘allylic’-analogous location, is not un-
expected. In a recent review of Burkholder et al.10 on the
synthesis and reactivity of halogeno-difluoromethyl aro-
matics and heterocycles, the selective replacement of the
bromine atom of 2-(bromodifluoromethyl)benzoxazole
by an aryloxy(arylthio) group was reported. This bromine
is likewise located in a relatively reactive position (‘ben-
zylic’-analogous position). The starting material was
treated with phenols (or arylthiols) and sodium hydride in
DMF.
9, and 6-deoxy-L-glucopyranose derivative 12 in 54–86%
yields (Scheme 1).
Finally, the pyranoses 3, 6, 9, and 12 were acetylated by
acetic acid anhydride/pyridine at room temperature to
give the 1-O-acetyl derivatives 4, 7, 10, and 13 in high
yields (Scheme 1). These fluoro-marked monosaccha-
rides are interesting glycosyl donors. Crystals of 1,3,4,6-
tetra-O-acetyl-2-chlorodifluoromethyl-2-deoxy-α-D-glu-
copyranose (4) were suitable for an X-ray analysis
(Figure 1). The pyranose ring adopts a distorted 4C1-con-
formation.
The thioglycosides 16, 17, 24, and 25 were prepared in
high yields by S-glycosidation of thiophenol with 1,3,4-
tri-O-acetyl-2-chlorodifluoromethyl-2-deoxy-β-D-arabi-
nopyranose (7) and 1,3,4-tri-O-acetyl-2-chlorodifluoro-
methyl-2,6-dideoxy-β-L-glucopyranose (13), respective-
ly, catalysed by boron trifluoride. Thiophenol was used in
excess (1.2 equiv). Because the chlorodifluoromethyl
group at C-2 is not influenced by the neighbouring group,
the ratio of α- and β-anomeric thioglycosides was almost
1:1 (Scheme 2).
Glycals, which contain substituents at C-2 are interesting
synthetic building blocks in carbohydrate chemistry. They
are traditionally prepared from acylglycosyl halides by
elimination of hydrogen halide with bases in aprotic polar
solvents.23–25 We prepared the glycal derivative 14 by re-
fluxing 3,4,6-tri-O-acetyl-2-chlorodifluoromethyl-2-de-
oxy-α-D-glucopyranosyl bromide (2) in pyridine–methyl
ethyl ketone. The dehydrobromination was over after 30
minutes and glycal 14 was isolated in 79% yield
(Scheme 2).
A selective deacetylation of phenyl 3,4-di-O-acetyl-2-
chlorodifluoromethyl-2-deoxy-1-thio-β-D-arabinopyran-
oside (16) and phenyl 3,4-di-O-acetyl-2-chlorodifluoro-
methyl-2-deoxy-1-thio-α-D-arabinopyranoside (17) to the
dihydroxy derivatives 18 and 20, respectively, was suc-
cessful by using alumina-supported caesium fluoride in
methanolic suspension.27 On the contrary, refluxing 16 in
1% methanolic sodium methoxide solution caused simul-
taneously deacetylation, elimination of thiophenol and
conversion of the chlorodifluoromethyl group into a
methoxycarbonyl moiety. Thus, 1,5-anhydro-1,2-
Deacetylation of 14 by boiling in a 1% methanolic sodium
methoxide solution (Zemplén reagent26) gave an interest-
ing result, because a nucleophilic attack on the chlorodi-
fluoromethyl group was observed in addition to the
deacetylation reaction (Scheme 2). The product, 1,5-an-
hydro-1,2-dideoxy-2-methoxycarbonyl-D-arabino-hex-
1-enitol, was acetylated before column chromatographic
Synthesis 2003, No. 5, 707–716 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthesis of 2-Chlorodifluoromethyl-Substituted Monosaccharides
709
hemiacetals (like intermediate A). The latter causes acid-
ification of neighboured OH-groups. However, only ade-
quately
acidified
OH-groups
can
add
to
dicyclohexylcarbodiimide generating an isourea interme-
diate like B. The hypothesis is that only such OH-groups
are adequately acidified which are surrounded by two
strongly electron-withdrawing substituents. The model
experiments with compound 18 confirm this hypothesis.
Thus, refluxing of 18 and DCC for 30 hours in 1,2-
dichloroethane gave only a complex mixture of products
and unreacted starting material, i.e., the chlorodifluorom-
ethyl group alone causes only very slow formation of
isourea intermediates. On the contrary, the starting mate-
rial 18 already disappeared after 8 hours, when DCC and
0.5 equivalent of chloral were added to the reaction mix-
ture. In this case, the OH-group in 3-position can be ade-
quately acidified by an additional electron withdrawing
hemiacetal function in 4-position (Scheme 3).
Scheme 2 Reagents and conditions: i. pyridine, EtCOMe, reflux, 30
min; ii. MeOH, NaOMe, reflux, 6 h; iii. pyridine, Ac2O, r.t.; iv. PhSH,
BF3 OEt2, CH2Cl2; v. CsF, Al2O3, MeOH, 20 °C; vi. chloral, DCC,
ClCH2CH2Cl, reflux, 3 h; vii. acetone, H2SO4, CuSO4, 20 °C
Scheme 3
dideoxy-2-methoxycarbonyl-D-threo-pent-1-enitol (19)
was produced in good yield28 (Scheme 2). The chlorodi-
fluoromethyl group in compound 16 increases probably
the C-H-acidity of H-2, which facilitates the elimination
of thiophenol. The latter is subsequently deprotonated by
sodium methoxide and thus removed from the prior equi-
librium. The relatively high reactivity of the chlorodifluo-
romethyl moiety indicates that the conversion of this
group probably follows the elimination of thiophenol. The
halogens are, like those in compound 14, after the elimi-
nation in an ‘allylic’ location. The increased acidity of H-
2, caused by the chlorodifluoromethyl electron-withdraw-
ing group, facilitates the elimination of thiophenol sup-
ported by sodium methoxide.
It is noteworthy that the reaction of such an isourea pro-
ceeds via a cyclic imido carbonic ester (intermediate C) to
the final chloral acetal provided the isourea group is
neighboured to a cis-arranged vicinal OH-group. The for-
mation of an imido carbonic ester is confirmed by isola-
tion of the cyclic carbonic ester 22 generated by
hydrolysis of the imido ester intermediate during the
workup procedure (Scheme 3).29–31
The configuration of acetal 21 (Figure 2) indicates a di-
vergent pathway of the acetal formation from intermedi-
ate B. The hypothesis is that, after protonation of the
isourea moiety by the cis-arranged hemiacetal, dicyclo-
hexylurea leaves the molecule in an SN1-type reaction.
Consequently, this reaction step competes with the forma-
tion of an imidocarbonic ester, which is likewise formed
via intermediate B. The final ring-closure step proceeds
with retention, because a cis-arrangement of the acetal is
favoured. Comparative experiments of 1,2-O-isopropy-
lidene-3-O-(N,N′-dicyclohexylisoureido)-β-D-fructopy-
ranose and 1,2-O-isopropylidene-4-O-(N,N′-dicyclo-
hexylisoureido)-β-D-fructopyranose with chloral allowed
the conclusion that direct replacement of the isoureido
Finally, the anomeric 1-thioarabinosides 18 and 20 were
acetalized generating the trichloroethylidene 21 and the
isopropylidene derivative 23, respectively (Scheme 2).
The inclusion of the chloral/DCC procedure in our inves-
tigations can help to support the proposed mechanism of
this non-conventional acetalisation method for carbohy-
drates.29 The acetalisation starts with formation of chloral
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710
S. Tews et al.
PAPER
group by intramolecular attack of a trans neighbouring
hemiacetal are not favoured in competition with the for-
mation of imidocarbonic ester intermediates.30
The prochiral reagent chloral produces always two dia-
stereomeric acetals, endo-H form and exo-H form. In all
previously investigated non-conventional acetalisations
with chloral/DCC, the endo-H form was predominant (5:1
to 30:1). It is noteworthy, that we found for the first time
an exo-H acetal as a major product (Figure 2). The corre-
sponding endo-H diastereomer could only be detected as
byproduct by GC-MS measurements. This atypical con-
figuration of acetal 21 could also be a pointer for a diver-
gent mechanistic way (see above).
Figure 3 X-ray structure of phenyl 3,4-di-O-acetyl-2-chlorodi-
fluoromethyl-2,6-dideoxy-1-thio-α-L-glucoside (24)
with geminal F,F-couplings of JF,F = 168–176 Hz and C,F-
1
couplings of JF,C = 288–299 Hz. Larger F,F-coupling
constants were only found for the two bicyclic derivatives
21 (2JF,F = 231 Hz) and 22 (2JF,F = 229 Hz). The glycals
14, 15, and 19 show characteristic downfield shifts for H-
1 (14: δ = 7.18; 15: δ = 7.69; 19: δ = 7.55) and for C-1 and
C-2 (14: δC-1 = 148.3, δC-2 = 107.2; 15: δC-1 = 156.4,
δ
C-2 = 103.7; 19: δC-1 = 157.5, δC-2 = 106.9). Because of
the C,F- and H,F-couplings, the corresponding signals of
compound 14 give a doublet (H-1; one coupling of H-1
with the two F atoms is zero) and triplets C-1 and C-2, re-
spectively. By coupling of H-2 with the two vicinal fluo-
rine atoms, a large multiplet is observed in their 1H NMR
spectra.
In the mass spectra the molecular peak region shows the
typical chlorine isotope pattern (30% of M at M + 2). The
X-ray analysis of phenyl 1-thio-β-D-arabinopyranoside 21
1
shows that the compound adopts a distorted C4-confor-
mation (Figure 2). The singlet of the acetal proton (exo-H)
is found at δ = 5.34.
Figure 2 X-ray structure of phenyl 2-chlorodifluoromethyl-2-de- Crystal Structure Determination Data32
oxy-3,4-O-[(1R)-2,2,2-trichloroethylidene]-1-thio-β-D-arabinopyra-
noside (21)
For the X-ray structure determination on a Bruker P4
four-circle diffractometer (Mo-Kα,λ = 0.71073 Å, graph-
ite monochromator) crystals of the compounds 4, 21 and
24 were checked by rotational photographs and suitable
reduced cells were found by the automatic cell determina-
tion routine of the Bruker SHELXTL software (Table 2).
The data collections were performed in routine ω-scan,
the structures were solved by direct methods. In the cases
of 4 and 24, the solutions were done with the Bruker
SHELXTL software (Bruker Analytical X-ray Inst. Inc.,
1990) and for 21 with SHELXS-86.33 The refinement cal-
culations were performed by the full matrix least-squares
method of Bruker SHELXTL, Vers.5.10, Copyright 1997,
Bruker Analytical X-ray Systems. All nonhydrogen atoms
The structures of all new compounds are supported by
their 1H, 13C and 19F NMR spectra. The relative small H-
1/H-2-coupling constants of glycosyl bromide 2 (J = 3.2
Hz), 1-O-acetates 4, 7, 10 (J = 3.2–3.4 Hz) and thioglyco-
sides 17, 20, 23 (J = 1.4–3.1 Hz) indicate that an α-con-
figuration prevails. The 1-thio-β-glycosides 16, 18, 21, 22
show H-1/H-2 couplings at J = 4.7–5.1 Hz. The two ano-
meric thioglycosides 24 and 25 couple with 5.0 and 9.4
Hz, respectively. Additionally, the β-configuration of
compound 21 and the α-configuration of compound 24 is
confirmed by X-ray analyses (Figures 2 and 3).
For all CF2Cl-substituted monosaccharides (except for 14, were refined anisotropically. The hydrogens were put into
15, and 19), a triplet of ring C-atom 2 is characteristic. The theoretical positions and refined using the riding model.
latter is found in the range of δ = 48.0–56.1 (2JC-2,F = 20–
27 Hz). In the case of glycal derivative 14, this triplet is
The molecular structures are shown in Figures 1– 3 with
30% level for the thermal ellipsoids. In Figure 2 only one
of the two independent molecules in the asymmetric unit
downfield shifted to δ = 107.2. The CF2Cl group itself
produces 19F-signals in the range of δ = –47.1 to –52.7
Synthesis 2003, No. 5, 707–716 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthesis of 2-Chlorodifluoromethyl-Substituted Monosaccharides
711
Table 1 Analytical Data for Compounds 2–4, 6, 7, 9, 10, 12–25
Product
2
Precursor
Yield (%)
57
Mp (°C) (solvent)
colourless syrup
colourless syrup
99 (CHCl3)
[α]D22 (c, CHCl3)
+139.19 (1.45)
+ 47.23 (0.97)
+121.26 (1.05)
–134.45 (1.00)
–139.87 (1.30)
+ 71.46 (1.05)
+ 97.33 (1.02)
–115.31 (1.03)
–139.21 (1.01)
+ 15.38 (1.10)
– 10.82 (1.10)
–207.17 (1.17)
+175.51 (1.02)
–234.37 (1.08)
+ 58.58 (0.99)
+184.76 (1.06)
–124.75 (1.07)
–192.60 (1.10)
+209.21 (1.32)
–251.15 (1.11)
–124.24 (1.35)
Rf (eluent)
1
1
0.63 (toluene– EtOAc, 3:1)
0.24 (toluene– EtOAc, 3:1)
0.39 (heptane– EtOAc, 1:1)
0.38 (toluene– EtOAc, 2:1)
0.41 (toluene– EtOAc, 5:1)
0.39 (toluene– EtOAc, 3:1)
0.40 (toluene– EtOAc, 5:1)
0.16 (toluene– EtOAc, 5:1)
0.52 (toluene– EtOAc, 5:1)
0.13 (toluene– EtOAc, 8:1)
0.17 (toluene– EtOAc, 8:1)
0.27 (heptane– EtOAc, 3:1)
0.32 (heptane– EtOAc, 3:1)
0.24 (toluene– EtOAc, 2:1)
0.18 (toluene– EtOAc, 1:1)
0.44 (toluene–EtOAc, 1:1)
0.58 (heptane– EtOAc, 2:1)
0.39 (heptane– EtOAc, 2:1)
0.43 (heptane– EtOAc, 6:1)
0.32 (heptane– EtOAc, 3 :1)
0.29 (heptane– EtOAc, 3:1)
3
64
4
3
92
6
5
86
colourless syrup
colourless syrup
114 (Et2O–pentane)
93 (Et2O–pentane)
135 (Et2O–pentane)
95 (Et2O–pentane)
colourless syrup
colourless syrup
colourless syrup
colourless syrup
127–129 (Et2O–pentane)
colourless syrup
85–86 (Et2O–pentane)
153 (CHCl3)
7
6
84
9
8
54
10
12
13
14
15
16
17
18
19
20
21
22
23
24
25
9
89
11
12
2
83
96
79
14
7
63
49
7
45
16
16
17
18
18
20
13
13
86
73
88
27
33
85–93a
92
colourless syrup
113–114 (Et2O–pentane)
colourless syrup
39
49
a Crystallised from the syrupy liquid only after several weeks.
ter 1 h, the addition of Na2S2O4 (700 mg) was repeated and stirring
was continued for further 3 h. Finally, Et2O (20 mL) and H2O (20
mL) were added. The organic phase was separated, washed with
brine (2 × 20 mL), dried (Na2SO4), and concentrated under reduced
pressure. The residue was purified by column chromatography. For
analytical data of the syrupy product 2, see Table 1.
is shown. The differences can be seen from the puckering
parameters34 (Table 3).
Melting points were obtained using a Leitz polarizing microscope
(Laborlux 12 Pol) equipped with a hot stage (Mettler FP 90) and are
uncorrected. 1H, 13C and 19F NMR spectra were recorded on Bruker
instruments: AC 250 and ARX 300, internal standard TMS for 1H
and 13C NMR spectra, and CFCl3 for 19F NMR spectra. Optical ro-
tations were measured on a polar LµP (IBZ Meßtechnik) instru-
ment. Column chromatography was carried out with Merck silica
gel 60 (63–200 µm) and TLC on Merck silica gel 60 F254 sheets.
1H NMR (250 MHz, CDCl3): δ = 6.54 (d, 1 H, 3J1,2 = 3.4 Hz, H-1),
5.73 (dd, 1 H, 3J3,4 = 9.2, 3J2,3 = 11.0 Hz, H-3), 5.12 (dd, 1 H, 3J3,4
=
9.2, 3J4,5 = 10.0 Hz, H-4), 4.31 (m, 2 H, 3J4,5 = 10.0, 2J6a,6b = 13.7 Hz,
H-5, H-6a), 4.09 (dd, 1 H, 3J5,6b = 3.0, 2J6a,6b = 13.7 Hz, H-6b), 3.21
(m, 1 H, 3J1,2 = 3.4, 3J2,3 = 11.0 Hz, H-2), 2.07, 2.04, 2.02 (3 s, 9 H,
3 × CH3).
13C NMR (62 MHz, CDCl3): δ = 170.8, 170.0, 169.6 (3 × C=O),
127.5 (t, 1JC,F = 299 Hz, CF2Cl), 82.3 (t, 3JC,F = 4 Hz, C-1), 73.0 (C-
3), 68.6 (C-4), 68.2 (C-6), 61.4 (C-5), 55.4 (t, 2JC,F = 23 Hz, C-2),
21.1, 21.0, 20.9 (3 × CH3).
3,4,6-Tri-O-acetyl-2-chlorodifluoromethyl-2-deoxy- -D-gluco-
pyranosyl Bromide (2); Typical Procedure
To a vigorously stirred solution of 3,4,6-tri-O-acetyl-D-glucal (1;
1.09 g, 4.0 mmol) in MeCN (20 mL) and H2O (10 mL) was added
NaHCO3 (2.0 g) and the resulting suspension was cooled to –10 °C
under argon. Subsequently, Na2S2O4 (700 mg, 4.0 mmol) was added
and CF2ClBr (excess) was condensed into this mixture using an
acetone–dry ice cold trap. Then the mixture was allowed to warm
up to about 10 °C to achieve continuous refluxing of the Freon. Af-
19F NMR (235 MHz, CDCl3): δ = –48.3 [d, 2J (Fa,Fb) = 168 Hz, Fa),
–51.5 [d, 2J (Fa,Fb) = 168 Hz, Fb].
Anal. Calcd for C13H16BrClF2O7 (437.61): C, 35.68; H, 3.69.
Found: C, 36.18; H, 3.74.
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Table 2 Crystal Data and Structure Refinement for Compounds 4, 21 and 24
Parameter
4
21
24
Empirical formula
Formula weight
Crystal system
Space group
C15H19ClF2O9
416.75
trigonal
P32
C14H12Cl4F2O3S
440.10
C17H19ClF2O5S
408.83
monoclinic
P21
monoclinic
P21
Unit cell dimensions
a/Å
b/Å
c/Å
/°
10.478(2)
10.478(2)
15.832(3)
90
9.959(3)
12.352(3)
14.664(4)
90
9.838(4)
5.510(2)
18.462(7)
90
/°
/°
90
120
92.640(10)
90
95.940(10)
90
Volume/Å3
1505.3(5)
1802.0(9)
995.4(7)
Z
3
4
2
Density (calculated)/Mg/m3
Absorption coefficient/mm–1
F(000)
1.379
1.622
1.364
0.251
0.802
0.338
648
888
424
Crystal size/mm3
0.68 × 0.5 × 0.54
0.40 × 0.30 × 0.24
2.05 to 22.00
0.36 × 0.42 × 0.74
2.08 to 21.98
Θ range for data collection/°
Index ranges
2.24 to 21.99
–9≤h≤9, –11≤k≤11, –16≤l≤16
–10≤h≤10, –13≤k≤13, –15≤l≤15 –10≤h≤10, –5≤k≤5, –19≤l≤19
Reflections collected
Independent reflections
R(int)
4028
4951
2895
2446
4408
2435
0.0292
99.8
0.0348
99.9
0.0327
99.6
Completeness to Θ = 21.99°/%
Data/restraints/parameters
Goodness-of-fit on F2
2446/1/245
1.096
4408/1/433
1.068
2435/1/236
1.074
Final R indices [I>2σ(I)]
wR2
0.0426
0.1130
0.0528
0.1245
0.0586
0.1602
R indices (all data)
wR2
0.0488
0.1189
0.0735
0.1388
0.0670
0.1695
Absolute structure parameter
Extinction coefficient
–0.08(10)
0.06(10)
–0.08(15)
0.005(3)
–
0.016(7)
Larg. diff. peak and hole/eÅ–3
0.147 and –0.184
0.338 and –0.421
0.314 and –0.363
Table 3 Puckering Parameters for Compounds 4, 21 and 24 with
Deviation in Brackets
3,4,6-Tri-O-acetyl-2-chlorodifluoromethyl-2-deoxy-D-glucopy-
ranose (3)
To a solution of 2 (1.0 g, 2.3 mmol) in MeOH (20 mL) and H2O (2
mL) was added freshly prepared Ag2CO3 (0.5 g) in portions. After
stirring the suspension for 2 h at r.t., filtration over Kieselguhr and
evaporation of the solvents, the crude product 3 was purified by col-
umn chromatography. For analytical data of the syrupy product 3,
see Table 1.
Compound
Amplitude Q/Å
0.545(4)
Θ/°
3.1(4)
Φ/°
62(7)
4
21
0.537(8)
0.524(7)
158.4(9)
155.7(9)
234(2)
237(2)
1H NMR (250 MHz, CDCl3): δ = 5.75 (dd, 1 H, 3J2,3 = 11.2, 3J3,4
=
=
24
0.566(6)
175.7(6)
243(7)
9.3 Hz, H-3), 5.61 (d, 1 H, 3J1,2 = 3.3 Hz, H-1), 5.04 (t, 1 H, 3J3,4
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Synthesis of 2-Chlorodifluoromethyl-Substituted Monosaccharides
713
9.3 Hz, H-4), 4.26 (m, 2 H, 3J5,6 = 9.7, 3J5,6 = 4.0 Hz, H-6a, H-6b),
4.09 (dd, 1 H, 3J5,6 = 4.0, 3J5,6 = 9.7 Hz, H-5), 3.76 (s, 1 H, OH, OH-
1), 2.93 (m, 1 H, 3J1,2 = 3.3, 3J2,3 = 11.2 Hz, H-2), 2.08, 2.03, 2.01 (3
s, 9 H, 3 × CH3).
13C NMR (62 MHz, CDCl3): δ = 170.9, 170.0, 169.7 (3 × C=O),
128.1 (t, 1JC,F = 296 Hz, CF2Cl), 90.9 (t, 3JC,F = 4 Hz, C-1), 69.1 (C-
3), 68.5 (C-4), 67.3 (C-6), 62.6 (C-5), 53.6 (t, 2JC,F = 21 Hz, C-2),
20.8, 20.7, 20.6 (3 × CH3).
1H NMR (250 MHz, CDCl3): δ = 6.50 (d, 1 H, 3J1,2 = 3.2 Hz, H-1),
5.62 (dd, 1 H, 3J3,4 = 3.2, 3J2,3 = 11.6 Hz, H-3), 5.33 (m, 1 H, H-4),
3
2
4.01 (dd, 1 H, J4,5a = 1.2, J5a,5b = 13.3 Hz, H-5a), 3.83 (dd, 1 H,
3J4,5b = 2.0, 2J5a,5b = 13.3 Hz, H-5a), 3.12 (m, 1 H, 3J1,2 = 3.2, 3J2,3
11.3 Hz, H-2), 2.15, 2.13, 2.04 (3 s, 9 H, 3 × CH3).
=
13C NMR (62 MHz, CDCl3): δ = 170.1, 169.5, 168.4 (3 × C=O),
127.5 (t, 1JC,F = 296 Hz, CF2Cl), 89.2 (t, 3JC,F = 6 Hz, C-1), 66.8 (C-
2
3), 65.6 (C-4), 62.6 (C-5), 48.0 (t, JC,F = 21 Hz, C-2), 20.9, 20.7,
20.6 (3 × CH3).
19F NMR (235 MHz, CDCl3): δ = –47.1 [d, 2J (Fa,Fb) = 174 Hz, Fa],
–49.1 [d, 2J (Fa,Fb) = 174 Hz, Fb].
19F NMR (235 MHz, CDCl3): δ = –48.4 [d, 2J (Fa,Fb) = 176 Hz, Fa],
–49.3 [d, 2J (Fa,Fb) = 176 Hz, Fb].
Anal. Calcd for C13H17ClF2O8 (374.72): C, 41.67; H, 4.57. Found:
C, 41.66; H, 4.72.
Anal. Calcd for C12H15ClF2O7 (344.70): C, 41.81; H, 4.39. Found:
C, 42.20; H, 4.27.
1,3,4,6-Tetra-O-acetyl-2-chlorodifluoromethyl-2-deoxy- -D-
glucopyranose (4); Typical Procedure
3,4-Di-O-acetyl-2-chlorodifluoromethyl-2-deoxy-D-xylopyra-
nose (9)
Compound 3 (1.12 g, 3.0 mmol) was dissolved in Ac2O (10 mL) at
r.t., followed by dropwise addition of pyridine (10 mL) with stir-
ring. The stirring was continued overnight. Then, the solvents were
evaporated under reduced pressure and the syrupy residue was
purified by column chromatography. For analytical data of the crys-
talline product 4, see Table 1.
3,4-Di-O-acetyl-D-xylal (8; 2.0 g, 10.0 mmol) dissolved in MeCN
(50 mL) and H2O (25 mL) was fluoroalkylated with CF2ClBr (ex-
cess) in the presence of NaHCO3 (5.0 g) and Na2S2O4 (3.48 g, 20
mmol, added in two portions). The procedure was analogous to that
of 2. For analytical data of the crystalline product 9, see Table 1.
1H NMR (300 MHz, CDCl3): δ = 5.75 (dd, 1 H, 3J2,3 = 11.2, 3J3,4
=
=
1H NMR (300 MHz, CDCl3): δ = 5.75 (dd, 1 H, 3J2,3 = 11.1, 3J3,4
=
3
9.3 Hz, H-3), 5.61 (d, 1 H, 3J1,2 = 3.3 Hz, H-1), 5.04 (t, 1 H, 3J3,4
9.4 Hz, H-3), 5.56 (d, 1 H, J1,2 = 3.1 Hz, H-1), 4.94 (m, 1 H,
9.3 Hz, H-4), 4.26 (m, 2 H, 3J5,6 = 9.7, 3J5,6 = 4.0 Hz, H-6a, H-6b),
4.09 (dd, 1 H, 3J5,6 = 4.0, 3J5,6 = 9.7 Hz, H-5), 3.76 (s, 1 H, OH, OH-
1), 2.93 (m, 1 H, 3J1,2 = 3.3, 3J2,3 = 11.2 Hz, H-2), 2.08, 2.03, 2.01 (3
s, 9 H, 3 × CH3).
3J4,5b = 6.2, 3J3,4 = 9.4, 3J4,5a = 10.7 Hz, H-4), 3.91 (dd, 1 H, 3J4,5a
=
10.7, 2J5a,5b = 11.0 Hz, H-5a), 3.79 (dd, 1 H, 3J4,5a = 6.2, 2J5a,5b = 11.0
Hz, H-5b), 3.35 (s, 1 H, OH), 2.85 (m, 1 H, 3J1,2 = 3.1, 3J2,3 = 11.1
Hz, H-2), 2.03, 2.02 (2 s, 6 H, 2 × CH3).
13C NMR (75 MHz, CDCl3): δ = 170.5, 169.5, 169.4, 167.9 (4 ×
C=O), 127,0 (t, 1JC,F = 296 Hz, CF2Cl), 88.4 (t, 3JC,F = 5 Hz, C-1),
69.5 (C-3), 68.3 (C-4), 67.5 (C-5), 61.4 (C-6), 52.4 (t, 2JC,F = 22 Hz,
C-2), 20.6, 20.55, 20.5, 20.4 (4 × CH3).
13C NMR (75 MHz, CDCl3): δ = 170.7, 170.0 (2 × C=O), 127.2 (t,
1JC,F = 297 Hz, CF2Cl), 91.8 (s, C-1), 70.3 (C-3), 67.5 (C-4), 58.9
(C-5), 54.1 (t, 2JC-2,F = 23 Hz, C-2), 21.2, 21.1 (2 × CH3).
19F NMR (235 MHz, CDCl3): δ = –48.8 [d, 2J (Fa,Fb) = 171 Hz, Fa],
19F NMR (235 MHz, CDCl3): δ = –49.1 [d, 2J (Fa,Fb) = 176 Hz, Fa],
–50.1 [d, 2J (Fa,Fb) = 171 Hz, Fb].
–50.4 [d, 2J (Fa,Fb) = 176 Hz, Fb].
Anal. Calcd for C10H13ClF2O6 (302.65): C, 39.68; H, 4.33. Found:
C, 40.14; H, 4.51.
Anal. Calcd for C15H19ClF2O9 (416.76): C, 43.23; H, 4.60. Found:
C, 43.25; H, 4.60.
1,3,4-Tri-O-acetyl-2-chlorodifluoromethyl-2-deoxy- -D-xy-
lopyranoside (10)
Compound 9 (210 mg, 0.69 mmol) was acetylated as described for
4 and the crude product was purified by column chromatography.
For analytical data of the crystalline product 10, see Table 1.
3,4-Di-O-acetyl-2-chlorodifluoromethyl-2-deoxy-D-arabinopy-
ranose (6)
3,4-Di-O-acetyl-D-ribal (5; 2.0 g, 10 mmol) was fluoroalkylated
with CF2ClBr as described for compound 2. However, unlike gluc-
osyl bromide 2 the generated pentosyl bromide was so sensitive to-
wards H2O that it was completely hydrolysed to 6 during workup.
The latter was isolated by column chromatography. For analytical
data of the syrupy product 6, see Table 1.
1H NMR (300 MHz, CDCl3): δ = 5.63 (br s, 1 H, H-1), 5.62 (dd, 1
H, 3J3,4 = 3.3, 3J2,3 = 11.5 Hz, H-3), 5.29 (m, 1 H, 3J4,5a = 1.5 Hz, H-
4), 4.22 (dd, 1 H, 3J4,5a = 1.5, 2J5a,5b = 13.2 Hz, H-5a), 3.72 (dd, 1 H,
3J4,5b = 2.1, 2J5a,5b = 13.2 Hz, H-5a), 3.26 (br s, 1 H, OH), 3.12 (m, 1
H, 3J1,2 = 3.1, 3J2,3 = 11.5 Hz, H-2), 2.14, 2.01 (2 s, 6 H, 2 × CH3).
1H NMR (250 MHz, CDCl3): δ = 6.43 (d, 1 H, 3J1,2 = 3.4 Hz, H-1),
5.73 (dd, 1 H, 3J2,3 = 11.1 Hz, 3J3,4 = 9.4 Hz, H-3), 5.01 (m, 1 H,
3
3
3J3,4 = 9,4 Hz, J4,5 = 6.0 Hz, H-4), 3.91 (dd, 1 H, J4,5a = 6.0 Hz,
2J5a,5b = 11.2 Hz, H-5a), 3.68 (t, 1 H, 2J5a,5b = 11.2 Hz, H-5b), 3.01
(m, 1 H, 3J1,2 = 3.4 Hz, 3J2,3 = 11.1 Hz, H-2), 2.14, 2.05, 2.03 (3 s, 9
H, 3 × CH3).
13C NMR (62 MHz, CDCl3): δ = 169.9, 169.5, 168.3 (3 × C=O),
126.8 (t, 1JC,F = 296 Hz CF2Cl), 88.6 (t, 3JC-1,F = 4.2 Hz, C-1), 69.2
2
(C-3), 67.1 (C-4), 60.4 (C-5), 52.6 (t, JC-2,F = 22 Hz, C-2), 20.8,
13C NMR (75 MHz, CDCl3): δ = 170.4, 169.7 (2 × C=O), 128.5 (t,
1JC,F = 297 Hz, CF2Cl), 91.2 (t, 3JC,F = 6 Hz, C-1), 67.6 (C-3), 65.5
(C-4), 60.7 (C-5), 49.2 (t, 2JC,F = 22 Hz, C-2), 20.9, 20.7 (2 × CH3).
20.7, 20.6 (3 × CH3).
19F NMR (235 MHz, CDCl3): δ = –49.1 [d, 2J (Fa,Fb) = 168 Hz, Fa],
–49.9 [d, 2J (Fa,Fb) = 168 Hz, Fb].
19F NMR (235 MHz, CDCl3): δ = –48.5 [d, 2J (Fa,Fb) = 168 Hz, Fa],
Anal. Calcd for C12H15ClF2O7 (344.69): C, 41.81; H, 4.39. Found:
C, 42.20; H, 4.59.
–49.3 [d, 2J (Fa,Fb) = 168 Hz, Fb].
Anal. Calcd for C10H13ClF2O6 (302.65): C, 39.68; H, 4.33. Found:
C, 39.90; H, 4.51.
3,4-Di-O-acetyl-2-chlorodifluoromethyl-2,6-dideoxy-L-glu-
copyranose (12)
1,3,4-Tri-O-acetyl-2-chlorodifluoromethyl-2-deoxy- -D-ara-
binopyranoside (7)
Compound 6 (1.54 g, 5.09 mmol) was acetylated as described for 4
and the syrupy crude product was purified by column chromatogra-
phy. For analytical data, see Table 1.
Compound 1135 (2.0 g, 9.34 mmol) dissolved in MeCN (50 mL) and
H2O (25 mL) was fluoroalkylated with CF2ClBr (excess) in the
presence of NaHCO3 (5.0 g) and Na2S2O4 (3.48 g, 20 mmol, added
in two portions). The procedure was analogous to the preparation of
2. For analytical data of the crystalline product 12, see Table 1.
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3
1H NMR (300 MHz, CDCl3): δ = 5.71 (dd, 1 H, J2,3 = 11.1 Hz,
3J3,4 = 9.4 Hz, H-3), 5.55 (d, 1 H, 3J1,2 = 3.3 Hz, H-1), 4.76 (t, 1 H,
3J3,4 = 9.4 Hz, H-4), 4.18 (dd, 1 H, 3J5,6 = 6.3 Hz, 3J4,5 = 10.0 Hz, H-
5), 3.24 (s, 1 H, OH, OH-1), 2.89 (m, 1 H, 3J1,2 = 3.3 Hz, 3J2,3 = 11.1
Hz, H-2), 2.03, 2.01 (2 s, 6 H, 2 × CH3), 1.17 (d, 3 H, 3J5,6 = 6.3 Hz,
CH3-6).
were evaporated under reduced pressure. The crude product was pu-
rified by column chromatography. For analytical data of the syrupy
ester 15, see Table 1.
1H NMR (300 MHz, CDCl3): δ = 7.69 (s, 1 H, H-1), 5.64 (dd, 1 H,
4J1,3 = 1.6 Hz, 3J3,4 = 3.0 Hz, H-3), 5.14 (t, 1 H, 3J3,4 = 3.0 Hz, H-4),
4.54 (m, 1 H, H-5), 4.42 (dd, 1 H, 3J6a,5 = 7.9 Hz, 2J6a,6b = 11.9 Hz,
H-6a), 4.14 (dd, 1 H, 3J6b,5 = 4.3 Hz, 2J6a,6b = 11.9 Hz, H-6b), 3.72
(s, 3 H, OCH3), 2.04, 2.06, 2.08 (3 s, 9 H, 3 × CH3).
13C NMR (75 MHz, CDCl3): δ = 170.3 (CO2CH3), 169.4, 169.3,
166.1 (3 × C=O), 156.4 (C-1), 103.7 (C-2), 74.6 (C-5), 65.9 (C-4),
62.2 (C-3), 60.9 (C-6), 51.6 (OCH3), 20.79, 20.76, 20.67
(3 × COCH3).
13C NMR (75 MHz, CDCl3): δ = 170.3, 169.7 (2 × C=O), 127.3 (t,
1JC,F = 296, CF2Cl), 90.4 (C-1), 74.6 (C-3), 67.6 (C-4), 65.3 (C-5),
53.9 (t, 2JC,F = 22 Hz, C-2), 20.8, 20.7 (2 × CH3), 17.4 (C-6).
19F NMR (235 MHz, CDCl3): δ = –48.9 [d, 2J (Fa,Fb) = 164 Hz, Fa),
–50.3 [d, 2J (Fa,Fb) = 164 Hz, Fb].
Anal. Calcd for C11H15ClF2O6 (316.69): C, 41.72; H, 4.77. Found:
C, 41.91; H, 4.98.
Anal. Calcd for C14H18O9 (330.29): C, 50.91; H, 5.49. Found: C,
50.77; H, 5.66.
1,3,4-Tri-O-acetyl-2-chlorodifluoromethyl-2,6-dideoxy- -L-
glucopyranoside (13)
Compound 12 (1.10 g, 3.47 mmol) was acetylated as described for
4 and the crude product was purified by column chromatography.
For analytical data of the crystalline product 13, see Table 1.
Phenyl 3,4-Di-O-acetyl-2-chlorodifluoromethyl-2-deoxy-1-thio-
-D-arabinopyranoside (16) and Phenyl 3,4-Di-O-acetyl-2-chlo-
rodifluoromethyl-2-deoxy-1-thio- -D-arabinopyranoside (17)
To a solution of 7 (850 mg, 2.47 mmol) in anhyd CH2Cl2 (10 mL)
was added thiophenol (0.31 mL, 3.2 mmol) at 0 °C with stirring un-
der argon followed by dropwise addition of BF3 OEt2 (0.93 mL, 7.4
mmol). The mixture was allowed to warm up to r.t., and the stirring
was continued overnight. Subsequently, the solution was washed
with H2O (10 mL), sat. aq NaHCO3 (10 mL), and H2O (10 mL).
Then, the organic phase was separated, dried (Na2SO4), and the sol-
vent was evaporated. The products 16 and 17 were isolated from the
residue by column chromatography. For analytical data, see
Table 1.
1H NMR (300 MHz, CDCl3): δ = 6.43 (d, 1 H, 3J1,2 = 3.4 Hz, H-1),
3
3
5.69 (dd, 1 H, J3,4 = 9.8 Hz, J2,3 = 11.2 Hz, H-3), 4.81 (t, 1 H,
3J3,4 = 9.8 Hz, H-4), 3.96 (ddd, 1 H, J5,6 = 6.2 Hz, 3J4,5 = 10.0 Hz,
3
H-5), 3.08 (m, 1 H, 3J1,2 = 3.4 Hz, 3J2,3 = 11.2 Hz, H-2), 2.13, 2.04,
2.02 (3 s, 9 H, 3 × CH3), 1.17 (d, 3 H, 3J5,6 = 6.2 Hz, CH3-6).
13C NMR (75 MHz, CDCl3): δ = 169.9, 169.6, 168.3 (3 × C=O),
126.7 (t, 1JC,F = 296, CF2Cl), 88.4 (C-1), 73.8 (C-3), 67.6 (C-4), 67.5
(C-5), 52.8 (t, 2JC,F = 23 Hz, C-2), 20.8, 20.7, 20.6 (3 × CH3), 17.4
(C-6).
19F NMR (235 MHz, CDCl3): δ = –48.9 [d, 2J (Fa,Fb) =171 Hz, Fa],
16
1H NMR (300 MHz, CDCl3): δ = 7.27–7.52 (2 m, 5 H, SC6H5), 5.73
–50.3 [d, 2J (Fa,Fb) = 171 Hz, Fb].
3
3
(d, 1 H, 3J1,2 = 4.7 Hz, H-1), 5.45 (dd, 1 H, J3,4 = 3.3, J2,3 = 11.7
Anal. Calcd for C13H17ClF2O7 (358.72): C, 43.53; H, 4.78. Found:
C, 43.78; H, 4.91.
Hz, H-3), 5.34 (m, 1 H, 3J4,5a = 1.4, 3J3,4 = 3.3 Hz, H-4), 4.57 (dd, 1
H, J4,5a = 1.4, J5a,5b = 13.4 Hz, H-5a), 3.79 (dd, 1 H, J4,5b = 1.9,
2J5a,5b = 13.4 Hz, H-5b), 3.55 (m, 1 H, 3J1,2 = 4.7, 3J2,3 = 11.7 Hz, H-
2), 2.15, 2.03 (2 s, 6 H, 2 × CH3).
3
3
3
1,5-Anhydro-3,4,6-tri-O-acetyl-2-chlorodifluoromethyl-1,2-
dideoxy-D-arabino-hex-1-enitol (14)
13C NMR (75 MHz, CDCl3): δ = 169.8, 169.4 (2 × C=O), 132.3,
To a solution of 2 (1.6 g, 3.66 mmol) in methyl ethyl ketone (80 mL)
was added pyridine (5 mL) under stirring and the mixture was re-
fluxed for 2 h. After cooling to r.t., toluene (20 mL) was added and
the solution was concentrated under reduced pressure. Column
chromatographic purification gave the syrupy product 14, an unsta-
ble compound. For analytical data, see Table 1.
1
129.2, 128.1 (SC6H5), 128.0 (t, JF,C = 294 Hz, CF2Cl), 85.6 (t,
3JF,C1 = 4 Hz, C-1), 67.5 (C-3), 66.3 (C-4), 61.8 (C-5), 50.0 (t,
2JF,C2 = 23 Hz, C-2) 20.9, 20.7 (2 × CH3).
19F NMR (235 MHz, CDCl3): δ = –47.2 [d, 2J (Fa,Fb) = 169 Hz, Fa]),
–49.8 [d, 2J (Fa,Fb) = 169 Hz, Fb].
1H NMR (300 MHz, CDCl3): δ = 7.18 (d, 1 H, 4J1,F = 2.0 Hz, H-1),
5.64 (d, 1 H, 3J3,4 = 3.2 Hz, H-3), 5.15 (t, 1 H, 3J3,4 = 3.2 Hz, H-4),
4.52 (m, 1 H, H-5), 4.43 (dd, 1 H, 3J6a,5 = 7.5 Hz, 2J6a,6b = 11.7 Hz,
H-6a), 4.14 (dd, 1 H, 3J6b,5 = 4.1 Hz, 2J6a,6b = 11.7 Hz, H-6b), 2.06–
2.08 (3 s, 9 H, 3 × CH3).
13C NMR (75 MHz, CDCl3): δ = 170.7, 169.62, 169.59 (3 × C=O),
148.3 (t, C-1), 125.7 (t, 1JF,C = 288 Hz, CF2Cl), 107.2 (t, 2JF,C2 = 26
Hz, C-2), 74.3 (C-5), 65.6 (C-4), 62.6 (C-3), 60.8 (C-6), 20.66–
20.72 (3 × COCH3).
Anal. Calcd for C16H17ClF2O5S (394.81): C, 48.67; H, 4.34. Found:
C, 49.17; H, 4.45.
17
1H NMR (300 MHz, CDCl3): δ = 7.29–7.53 (2 m, 5 H, SC6H5), 5.63
(m, 2 H, H-1, H-3), 5.21 (m, 1 H, 3J4,5a = 8.6 Hz, H-4), 4.41 (dd, 1
3
3
3
H, J4,5a = 8.6, J5a,5b = 11.5 Hz, H-5a), 3.81 (dd, 1 H, J4,5b = 5.5,
2J5a,5b = 11.5 Hz, H-5b), 3.11 (m, 1 H, 3J2,1 = 2.2, 3J2,3 = 12.1 Hz, H-
2), 2.19, 2.08 (2 s, 6 H, 2 × CH3).
13C NMR (75 MHz, CDCl3):δ = 169.9, 169.6 (2 × C=O), 131.8,
19F NMR (235 MHz, CDCl3): δ = –44.9 [d, 2J (Fa,Fb) = 174 Hz, Fa],
1
–51.6 [d, 2J (Fa,Fb) = 174 Hz, Fb].
129.2, 128.0 (SC6H5), 128.4 (t, JF,C = 297 Hz, CF2Cl), 82.2 (t,
3JF,C1 = 3 Hz, C-1), 65.5 (C-3), 65.3 (C-4), 58.7 (C-5), 54.2 (t,
2JF,C2 = 22 Hz, C-2) 20.9, 20.8 (2 × CH3).
Anal. Calcd for C13H15ClF2O7 (356.70): C, 43.77; H, 4.24. Found:
C, 43.15; H, 4.37.
19F NMR (235 MHz, CDCl3): δ = –51.0 [d, 2J (Fa,Fb) = 170 Hz, Fa],
–51.9 [d, 2J (Fa,Fb) = 170 Hz, Fb].
1,5-Anhydro-3,4,6-tri-O-acetyl-1,2-dideoxy-2-methoxycarbon-
yl-D-arabino-hex-1-enitol (15)
Anal. Calcd for C16H17ClF2O5S (394.81): C, 48.67; H, 4.34. Found:
C, 48.49; H, 4.46.
A solution of 14 (600 mg, 1.68 mmol) in 1% methanolic NaOMe
(25 mL) was refluxed for 6 h. After cooling to r.t., neutralisation
with Amberlite IR 120, and filtration, the solvent was evaporated
under reduced pressure. The resulting residue was dissolved in
Ac2O (20 mL) and pyridine (20 mL) and the mixture was stirred
overnight at r.t. Then, toluene (20 mL) was added and the solvents
Phenyl 2-Chlorodifluoromethyl-2-deoxy-1-thio- -D-arabinopy-
ranoside (18)
To a solution of 16 (600 mg, 1.52 mmol) in anhyd MeOH (25 mL)
was added CsF/Al2O3 (70 mg, 0.11 mmol fluoride, 1.53 mmol CsF/
Synthesis 2003, No. 5, 707–716 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Chlorodifluoromethyl-Substituted Monosaccharides
715
g solid27) and the mixture was stirred overnight at r.t. Then, a solu-
tion of CaCl2 6H2O (100 mg) in H2O (0.5 mL) was added and the
stirring was continued for 30 min. After filtration over Kieselguhr
and evaporation of the solvents under reduced pressure, the crude
product 18 was extracted with EtOAc. The solution was washed
with H2O (20 mL), dried (Na2SO4), and concentrated. The residue
was purified by column chromatography. For analytical data of the
crystalline product 18, see Table 1.
and CH2Cl2 (20 mL) were added and the mixture was shaken for 30
min. The organic layer was separated, washed with H2O (2 × 20
mL), dried (Na2SO4), and concentrated. The crystalline product 21
and the syrupy compound 22 were separated by column chromato-
graphy. For analytical data, see Table 1.
21
1H NMR (300 MHz, CDCl3): δ = 7.28–7.51 (m, 5 H, SC6H5), 5.76
3
(d, 1 H, J1,2 = 4.8 Hz, H-1), 5.34 (s, 1 H, Hacetal), 4.79 (dd, 1 H,
1H NMR (250 MHz, CDCl3): δ = 7.28–7.52 (m, 5 H, SC6H5), 5.68
(d, 1 H, 3J1,2 = 4.7 Hz, H-1), 4.49 (dd, 1 H, 3J4,5a = 1.5, 2J5a,5b = 12.9
Hz, H-5a), 4.23 (dd, 1 H, 3J3,4 = 3.2, 3J2,3 = 10.9 Hz, H-5a), 3.99 (m,
3J2,3 = 9.9, 3J3,4 = 5.9 Hz, H-3), 4.65 (dd, 1 H, 3J4,5 = 3.2, 2J5,5 = 14.1
3
Hz, H-5a), 4.40 (dd, 1 H, J4,5 = 3.2, 3J3,4 = 5.9 Hz, H-4), 4.30 (d,
1H, 2J5,5 = 14.1 Hz, H-5b), 3.61 (m, 1 H, 3J1,2 = 4.8, 3J2,3 = 9.9 Hz,
3
1 H, 3J4,5a = 1.5 Hz, H-4), 3.85 (dd, 1 H, J4,5b = 1.8, 3J5a,5b = 12.9
H-2).
Hz, H-5b), 3.35 (m, 1 H, 3J1,2 = 4.7, 3J1,2 = 10.9 Hz, H-2), 2.55 (s, 2
H, 2 × OH).
13C NMR (75 MHz, CDCl3): δ = 131.6, 129.3, 128.0 (3 s, SC6H5),
127.8 (t, 1JC,F = 293 Hz, CF2Cl), 106.7 (Cacetal), 96.2 (CCl3), 82.6 (C-
1), 74.8 (C-3), 70.4 (C-4), 59.2 (C-5), 53.2 (t, 2JC2,F = 27 Hz, C-2).
13C NMR (62 MHz, CDCl3): δ = 133.4, 132.2, 129.2, 127.9
(SC6H5), 129.1 (t, 1JC,F = 296 Hz, CF2Cl), 85.5 (t, 3JC,F = 3 Hz, C-1),
68.3 (C-5), 66.7 (C-3), 63.6 (C-4), 52.0 (t, 2JC,F = 21 Hz, C-2).
19F NMR (235 MHz, CDCl3): δ = –48.6 [d, 2J (Fa,Fb) = 231 Hz, Fa],
–53.3 [d, 2J (Fa,Fb) = 231 Hz, Fb].
19F NMR (235 MHz, CDCl3): δ= –45.0 [d, 2J (Fa,Fb) = 169 Hz, Fa],
–49.8 [d, 2J (Fa,Fb) = 169 Hz, Fb].
MS (30 eV): m/z = 438, 440, 442, 444 (M+, 4 chlorine atoms), 329,
331, 333, 335 (M – SPh, 4 chlorine atoms), 110 (HSPh).
Anal. Calcd for C12H13ClF2O3S (310.74): C, 46.38; H, 4.22. Found:
C, 46.56; H, 4.27.
Anal. Calcd for C14H12Cl4F2O3S (440.11): C, 38.21; H, 2.75. Found:
C, 38.48; H, 2.81.
1,5-Anhydro-1,2-dideoxy-2-methoxycarbonyl-D-threo-pent-1-
enitol (19)
22
A solution of 16 (1.05 g, 2.66 mmol) in 1% methanolic MeONa (50
mL) was refluxed for 6 h. After cooling to r.t., neutralisation with
Amberlite IR 120 and filtration, the solvent was evaporated under
reduced pressure. The crude product was purified by column chro-
matography. For analytical data of the syrupy ester 19, see Table 1.
1H NMR (300 MHz, CDCl3): δ = 7.23–7.52 (m, 5 H, SC6H5), 5.78
(d, 1 H, 3J1,2 = 5.1 Hz, H-1), 5.12 (dd, 1 H, J2,3 = 10.0, 3J3,4 = 6.6
3
Hz, H-3), 4.81 (dd, 1 H, 3J4,5 = 2.9, 3J3,4 = 6.6 Hz, H-4), 4.62 (dd, 1
H, 3J4,5 = 2.9, 2J5,5 = 14.5 Hz, H-5a), 4.22 (d, 1 H, 2J5,5 = 14.5 Hz, H-
5b), 3.25 (m, 1 H, 3J1,2 = 5.1, 3J2,3 = 10.0 Hz, H-2).
1H NMR (250 MHz, CDCl3): δ = 7.55 (s, 1 H, H-1), 4.56 (d, 1 H,
3J3,4 = 2.3 Hz, H-3), 3.89–4.07 (m, 4 H, H-4, H-5a, H-5b, OH-3),
3.71 (s, 3 H, OCH3), 3.27 (s, 1 H, OH-4).
13C NMR (75 MHz, CDCl3): δ = 132.0, 129.5, 128.5 (3 s, SC6H5),
126.8 (t, 1JC,F = 296 Hz, CF2Cl), 81.9 (C-1), 73.1 (C-3), 70.5 (C-4),
58.3 (C-5), 52.9 (t, 2JC2,F = 26 Hz, C-2).
13C NMR (62 MHz, CDCl3): δ = 168.0 (CO2Me), 157.5 (C-1),
106.9 (C-2), 65.7 (C-5), 64.6 (C-3), 61.3 (C-4), 51.6 (OCH3).
19F NMR (235 MHz, CDCl3): δ = –48.7 [d, 2J (Fa,Fb) = 229 Hz, Fa],
–54.4 [d, 2J (Fa,Fb) = 229 Hz, Fb].
Anal. Calcd for C7H10O5 (174.15): C, 48.28; H, 5.79. Found: C,
48.30; H, 5.94.
MS (30 eV): m/z = 336, 338 (M+, 1 chlorine atom), 227, 229 (M –
SPh, 1 chlorine atom), 191 (m – HSPh – Cl), 110 (HSPh).
Anal. Calcd for C13H11ClF2O4S (336.73): C, 46.37; H, 3.29. Found:
C, 46.71; H, 3.42.
Phenyl 2-Chlorodifluoromethyl-2-deoxy-1-thio- -D-arabinopy-
ranoside (20)
Compound 17 (900 mg, 2.28 mmol) was deacetylated as described
for 18 and the crude product was purified by column chromatogra-
phy. For analytical data of the crystalline product 20, see Table 1.
1H NMR (250 MHz, CDCl3): δ = 7.21–7.54 (m, 5 H, SC6H5), 5.67
(d, 1 H, 3J1,2 = 1.4 Hz, H-1), 4.42 (t, 1 H, 3J2,3 = 3.2 Hz, H-3), 4.27
(t, 1 H, 3J5a,5b = 11.2 Hz, H-5a), 4.02–4.11 (m, 1 H, H-4), 3.67 (dd,
1 H, 3J4,5b = 5.3 Hz, 3J5a,5b = 11.2 Hz, H-5b), 3.10 (m, 1 H, 3J2,3 = 3.2
Hz, 3J1,2 = 1.4 Hz, H-2), 2.3–2.6 (br s, 2 H, 2 × OH).
Phenyl 2-Chlorodifluoromethyl-2-deoxy-3,4-O-isopropylidene-
1-thio- -D-arabinopyranoside (23)
To a solution of 20 (250 mg, 0.80 mmol) in anhyd acetone (20 mL)
were added conc. H2SO4 (1 drop) and anhyd CuSO4 (200 mg). The
mixture was stirred for 2.5 h at r.t. After completion of the reaction
(TLC control), solid NaHCO3 (0.6 g) was added and the stirring was
continued for 15 min. Then, the suspension was filtered over Kie-
selguhr and the filtrate was concentrated under reduced pressure.
The residue was purified by column chromatography. For analytical
data of the syrupy compound 23, see Table 1.
13C NMR (62 MHz, CDCl3): δ = 134.8, 131.6, 129.1, 127.8
(SC6H5), 128.3 (t, 1JC,F = 295 Hz, CF2Cl), 81.1 (t, 3JC,F = 3 Hz, C-1),
66.36 (C-5), 64.6 (C-4), 59.6 (C-3), 56.1 (t, 2JC,F = 21 Hz, C-2).
1H NMR (250 MHz, CDCl3): δ = 7.29–7.52 (2 m, 5 H, SPh), 5.57
(d, 1 H, 3J1,2 = 3.1 Hz, H-1), 4.49 (dd, 1 H, 3J2,3 = 2.8, 3J3,4 = 5.5 Hz,
H-3), 4.36 (m, 1 H, 3J3,4 = 5.5, 3J4,5b = 6.2 Hz, H-4), 4.22 (dd, 1 H,
19F NMR (235 MHz, CDCl3): δ = –50.3 [d, 2J (Fa,Fb) = 172 Hz, Fa],
–51.3 [d, 2J (Fa,Fb) = 172 Hz, Fb].
3
3
3J4,5a = 8.5, J5a,5b = 11.7 Hz, H-5a), 3.78 (dd, 1 H, J4,5b = 6.2,
2J5a,5b = 11.7 Hz, H-5b), 3.08 (m, 1 H, 3J1.2 = 3.1 Hz, H-2), 1.60, 1.40
(2 s, 6 H, 2 × CH3).
Anal. Calcd for C12H13ClF2O3S (310.74): C, 46.38; H, 4.22; S,
10.32. Found: C, 46.27; H, 4.16; S, 10.79.
13C NMR (75 MHz, CDCl3): δ = 131.6, 129.1, 127.7 (SPh), 128.7
(t, 1JF,C = 294 Hz, CF2Cl), 81.3 (C-1), 70.5 (C-3), 69.2 (C-4), 60.5
(C-5), 52.9 (t, 2JF,C2 = 23 Hz, C-2) 27.9, 26.2 (2 × CH3).
Phenyl 2-Chlorodifluoromethyl-2-deoxy-3,4-O-(2,2,2-trichloro-
ethylidene)-1-thio- -D-arabinopyranoside (21) and Phenyl 3,4-
O-Carbonato-2-chlorodifluoromethyl-2-deoxy-1-thio- -D-ara-
binopyranoside (22)
To a solution of 18 (400 mg, 1.3 mmol) in anhyd 1,2-dichloroethane
(20 mL) were added chloral (0.9 mL, 9.2 mmol) and dicyclohexyl-
carbodiimide (0.6 g, 2.91 mmol) under argon. The mixture was re-
fluxed for about 5 h (TLC control). Then, 10% aq AcOH (20 mL)
19F NMR (235 MHz, CDCl3): δ = –51.6 [d, 2J (Fa,Fb) = 167 Hz, Fa],
–52.7 [d, 2J (Fa,Fb) = 167 Hz, Fb].
Anal. Calcd for C15H17ClF2O3S (350.80): C, 51.36; H, 4.88. Found:
C, 51.46; H, 4.99.
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716
S. Tews et al.
PAPER
(4) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
Phenyl 3,4-Di-O-acetyl-2-chlorodifluoromethyl-2,6-dideoxy-1-
thio- -L-glucopyranoside (24) and Phenyl 3,4-Di-O-acetyl-2-
chlorodifluoromethyl-2,6-dideoxy-1-thio- -L-glucopyranoside
(25)
To a solution of 13 (1.0 g, 2.79 mmol) in anhyd CH2Cl2 (20 mL) was
added thiophenol (0.4 mL, 3.35 mmol) at 0 °C with stirring under
argon, followed by dropwise addition of BF3 OEt2 (1.0 mL, 3
equiv). The mixture was allowed to warm up to r.t., and the stirring
was continued overnight. Workup procedure was analogous to
products 16 and 17. For analytical data of the crystalline thioglyco-
side 24 and its syrupy anomer 25, see Table 1.
Chemistry; Wiley: New York, 1991.
(5) Organofluorine Compounds-Chemistry and Applications;
Yamamoto, H., Ed.; Springer-Verlag: Berlin, 2000.
(6) Organofluorine Compounds. Houben–Weyl, Methods of
Organic Chemistry, E10a-c; Baasner, B.; Hagemann, H.;
Tatlow, J. C., Eds.; Thieme Verlag: Stuttgart, 1999/2000.
(7) Special Issue on Fluorosugars. Carbohydrate Research,
Vol. 327; Miethchen, R.; Defaye, J., Eds.; Elsevier:
Amsterdam, 2000, 1–218.
(8) Brace, N. O. J. Fluorine Chem. 1999, 93, 1.
(9) Tozer, M. J.; Herpin, T. Tetrahedron 1996, 52, 8619; and
references cited therein.
(10) Burkholder, C. R.; Dolbier, W. R.; Medebielle, M. J.
Fluorine Chem. 2001, 109, 39; and references cited therein.
(11) Chen, Q. Y. Israel J. Chem. 1999, 39, 172.
(12) Ding, Z.; Xia, S.; Ji, X.; Yang, H.; Tao, F.; Wang, Q.
Synthesis 2002, 349.
(13) Rico, I.; Cantacuzene, D.; Wakselman, C. Tetrahedron Lett.
1981, 22, 3405.
(14) Huang, W.-Y. J. Fluorine Chem. 1992, 58, 1.
(15) Huang, W.-Y.; Xie, Y. Chinese J. Chem. 1991, 9, 351;
Chem. Abstr. 1992, 116, 106596.
(16) Wu, F. H.; Huang, B. N.; Lu, L.; Huang, W.-Y. J. Fluorine
Chem. 1996, 80, 91.
(17) Huang, W.-Y.; Wu, F.-H. Israel J. Chem. 1999, 39, 167.
(18) Rong, G.; Keese, R. Tetrahedron Lett. 1990, 31, 5615.
(19) Plenkiewicz, H.; Dmowski, W.; Lipinski, M. J. Fluorine
Chem. 2001, 111, 227.
24
1H NMR (300 MHz, CDCl3): δ = 7.28–7.51 (2 m, 5 H, SPh), 5.61
(d, 1 H, 3J1,2 = 5.0 Hz, H-1), 5.56 (dd, 1 H, J3,4 = 9.0, 3J2,3 = 11.5
3
Hz, H-3), 4.80 (dd, 1 H, 3J3,4 = 9.0, 3J4,5 = 9.9 Hz, H-4), 4.53 (dd, 1
H, 3J5,6 = 6.2, 3J4,5 = 9.9 Hz, H-5), 3.29 (m, 1 H, 3J1,2 = 5.0, 3J2,3
=
11.5 Hz, H-2), 2.06, 2.03 (2 s, 6 H, 2 × COCH3), 1.19 (d, 3 H,
3J5,6 = 6.2 Hz, CH3).
13C NMR (75 MHz, CDCl3): δ = 170.1, 169.4 (2 × C=O), 132.4,
129.2, 128.2 (SC6H5), 126.8 (1JF,C = 296 Hz, CF2Cl), 84.2 (C-1),
74.7 (C-3), 68.2 (C-4), 66.7 (C-5), 54.6 (t, JC,F = 22.5 Hz, C-2),
2
20.7, 20.6 (2 s, 2 × COCH3), 17.3 (CH3).
19F NMR (235 MHz, CDCl3): δ = –47.7 [d, 2J (Fa,Fb) = 168 Hz, Fa],
–50.5 [d, 2J (Fa,Fb) = 168 Hz, Fb].
Anal. Calcd for C17H19ClF2O5S (408.84): C, 49.94; H, 4.68. Found:
C, 50.25; H, 4.92.
(20) Zur, C.; Miethchen, R. Eur. J. Org. Chem. 1998, 531.
(21) Miethchen, R.; Hein, M.; Reinke, H. Eur. J. Org. Chem.
1998, 919.
(22) Platier-Royon, R.; Portella, C. Carbohydr. Res. 2000, 327,
119.
(23) Monosaccharides. Their Chemistry and Their Roles in
Natural Products; Collins, P.; Ferrier, R., Eds.; Wiley: New
York, 1995, 317–319.
(24) Lemieux, R. U.; Lineback, D. R. Can. J. Chem. 1965, 43, 94.
(25) Hughes, N. A. Carbohydr. Res. 1972, 25, 242.
(26) Zemplén, G.; Gerecs, A.; Hadácsy, I. Ber. Dtsch. Chem. Ges.
1936, 69, 1827.
25
1H NMR (300 MHz, CDCl3): δ = 7.29–7.58 (2 m, 5 H, SC6H5), 5.46
(dd, 1 H, 4JH,F = 1.2, 3J1,2 = 9.4 Hz, H-1), 4.78 (dd, 1 H, 3J3,4 = 6.3,
3J2,3 = 9.8 Hz, H-3), 4.52 (dd, 1 H, 3J3,4 = 6.3, 3J4,5 = 10.0 Hz, H-4),
3.54 (dd, 1 H, 3J5,6 = 6.2, 3J4,5 = 10.0 Hz, H-5), 2.85 (m, 1 H, 3J1,2
=
9.4, 3J2,3 = 9.8 Hz, H-2), 2.01, 1.98 (2 s, 6 H, 2 × COCH3), 1.22 (d,
3 H, 3J5,6 = 6.2 Hz, CH3).
13C NMR (75 MHz, CDCl3): δ = 169.9, 169.6 (2 × C=O), 133.6,
132.4, 129.0 (SC6H5), 126.8 (1JF,C = 298 Hz, CF2Cl), 83.4 (C-1),
2
73.9 (C-3), 69.9 (C-4), 66.7 (C-5), 53.7 (t, JC,F = 20.0 Hz, C-2),
20.71, 20.68 (2 s, 2 × COCH3), 17.7 (CH3).
19F NMR (235 MHz, CDCl3): δ = –47.6 [d, 2J (Fa,Fb) = 172 Hz, Fa],
(27) Ando, T.; Yamawaki, J.; Kawate, T.; Sumi, S.; Hanafusa, T.
Bull. Chem. Soc. Jpn. 1982, 55, 2504.
–50.4 [d, 2J (Fa,Fb) = 172 Hz, Fb].
(28) Treatment of thioglycoside 16 with Zemplén reagent at r.t.
for 12 h gave a mixture of 18 and 19 (ratio, ca. 3:1).
(29) Miethchen, R.; Sowa, Chr.; Frank, M.; Michalik, M.;
Reinke, H. Carbohydr. Res. 2002, 337, 1; and references
cited therein.
(30) Sowa, Chr.; Miethchen, R.; Reinke, H. J. Carbohydr. Chem.
2002, 21, 293.
(31) Zur, C.; Miller, A. O.; Miethchen, R. J. Fluorine Chem.
1998, 90, 67.
(32) Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC 198524–198526. Copies of the data
can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax
+44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk) or
via www.ccdc.cam.ac.uk/conts/retrieving.html.
(33) Sheldrick, G. M. University of Göttingen: Göttingen, 1986.
(34) Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 97, 1354.
(35) Roth, W.; Pigman, W. Methods Carbohydr. Chem. 1963, 2,
407.
Anal. Calcd for C17H19ClF2O5S (408.84): C, 49.94; H, 4.68. Found:
C, 50.38; H, 4.53.
Acknowledgements
We are grateful to Prof. Dr. Manfred Michalik (IfOK Rostock) for
NMR spectroscopic investigations, to Dr. Wolfgang Ruth (Univer-
sity of Rostock, Department of Technical Chemistry) for GC-MS
measurements and to Mrs. Claudia Vinke for technical assistance.
References
(1) Part 28: Schwäbisch, D.; Miethchen, R. J. Fluorine Chem.
2002, in press.
(2) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M. In
Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Elsevier: Amsterdam, 1993.
(3) Fluoroorganic Chemistry: Synthetic Challenges and
Biomedical Rewards, Tetrahedron Symposia 58, Vol. 52;
Resnati, G.; Soloshnok, V. A., Eds.; Tetrahedron:
Pergamon, 1996, 1–330.
Synthesis 2003, No. 5, 707–716 ISSN 0039-7881 © Thieme Stuttgart · New York