Synthesis of fluorinated ketoheptoses as specific diagnostic agents

Article abstract of DOI:10.1002/ejoc.201101238

The straightforward syntheses of six regioisomeric mono-and difluorinated D-manno-heptulose and Kamusol analogues, which use electrophilic or nucleophilic fluorinaton, are reported. D-manno-Heptulose shows attractive pharmacological properties in vivo, su

Full text of DOI:10.1002/ejoc.201101238

FULL PAPER
DOI: 10.1002/ejoc.201101238
Synthesis of Fluorinated Ketoheptoses as Specific Diagnostic Agents
Daniel Waschke,[a] Yevgeniy Leshch,[a] Julian Thimm,[a] Uwe Himmelreich,[b] and
Joachim Thiem*[a]
Keywords: Carbohydrates / Medicinal chemistry / Synthesis design / Fluorine
The straightforward syntheses of six regioisomeric mono-
and difluorinated
logues, which use electrophilic or nucleophilic fluorinaton,
are reported. -manno-Heptulose shows attractive pharma-
cological properties in vivo, such as antitumour activity, as
well as binding to and accumulating in pancreatic beta cells
to induce hyperglycemia. The synthesised analogues repre-
D
-manno-heptulose and Kamusol ana- sent promising probes for the detection and quantification of
beta cells in vivo by 19F MRI techniques, which could help
to investigate disease progression. In addition, they are po-
tential candidates for the inhibition of tumour growth.
D
raises the need for better diagnostic tools. Compound 1 en-
ters the beta cells through the GLUT2 receptor, which is
almost exclusively expressed by beta cells.[5,9,11a,11b] Experi-
ments with radiolabelled derivatives of 1 showed a much
higher uptake of 1 in islet cells than in acinar pancreatic
cells.[5] Additionally, 1 acts as a potent competitive inhibitor
of glucokinase, which leads to increased blood glucose
levels and decreased insulin secretion.[1a,1b,2a,2b] Further-
more, 1 is slowly phosphorylated by glucokinase[5] and ac-
cumulates inside beta cells, which makes the detection of
suitable analogues of 1 possible. The syntheses of a series
of fluorinated analogues of 1 is reported and their possible
use in the in vivo, noninvasive imaging of pancreatic beta
cells in combination with 19F magnetic resonance imaging
(MRI) is discussed. 19F MRI has been successfully used
to track 19F-labelled compounds in vivo.[12a–12d] After the
proton, 19F is the second most sensitive nucleus for MRI
experiments. Its complete absence in the human body and
the associated absence of unspecific background signals
makes the 19F signal extremely suitable for tracing drugs
Introduction
In 1936, it was observed that the injection of d-manno-
heptulose (1) led to a serious increase of a fermentable com-
ponent in blood sugar, which was later shown to be d-glu-
cose.[1a,1b] This increase is caused by the inhibition of glu-
cose metabolism and insulin secretion in vivo and in vi-
tro.[2a,2b] Due to their diabetogenic properties, heptuloses
are of particular pharmacological interest as potential
therapeutics for hypoglycemia or cancer.[3–5]
These diabetogenic properties are the result of an inhibi-
tion of hexokinase isoenzymes.[6a–6d] Thus, a potential use
of suitable analogues as agents in noninvasive imaging of
pancreatic beta cells has been postulated.[5,7] A dramatic
loss of beta-cell mass is associated with the development of
diabetes mellitus. Although there is only a relative de-
ficiency of beta-cell mass in type 2 diabetes, beta-cell mass
is almost entirely lost during the development of type 1 dia-
betes.[8a–8d] Even today, quantification of beta-cell mass is
still achieved by indirect estimation, and as the function-
ality of individual beta cells is not considered constant,[8c,8d]
estimation techniques are often inaccurate. Over the last 20
years, considerable scientific effort has been put into the
development of in vivo noninvasive imaging techniques of
pancreatic beta cells but there has been no clinical applica-
tion to date.[5,8a,8c,9] The enormous progression of diabetes
(426 million diabetes cases are predicted in 2030)[10a,10b]
1
inside the body.[13a,13b] In contrast to many H MRI meth-
ods, 19F spin density MRI methods provide a means for
absolute quantification.[12d,13c]
Furthermore, the introduction of fluorine into monosac-
charides can modify their biological activity. It has been
shown that deoxygenated derivatives of d-glucose and d-
mannose act as substrates for hexokinase isoenzymes, but
no further metabolism was observed.[14] Thus the phos-
phorylated monosaccharides accumulated inside the cells,
which was followed by labelling with either 14C or 18F.[15,16]
Among all fluorinated hexose analogues, 2-deoxy-2-fluoro-
d-glucose is probably clinically used the most. In particular,
its short lived and unspecific targeting 18F-derivative (2FG)
is widely applied in positron emission tomography for non-
invasive imaging of many types of cancer.[17a–17c] Addition-
ally, fluorinated monosaccharides possess antitumour ac-
[a] University of Hamburg, Faculty of Science, Department of
Chemistry,
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Fax: +49-40-42838-4325
E-mail: thiem@chemie.uni-hamburg.de
[b] Biomedical NMR Unit/MoSAIC, Katholieke Universiteit
Leuven,
Herestraat 49, 3000 Leuven, Belgium
E-mail: uwe.himmelreich@med.kuleuven.be
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101238.
948
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 948–959

Fluorinated Ketoheptoses as Specific Diagnostic Agents
tivity[18a,18b] and can act as substrates or inhibitors for glu-
cosidases and phosphorylases.[19a,19b]
Access to these analogues is complicated. Hence, no fluo-
rination at the 4- or 5-positions of 1 was performed. In
Previously described studies with fluorinated monosac- combination with the antitumour[4] and inhibitory[1a,1b,2a,2b]
charides focussed on hexose-based modifications. Here the activity of unmodified 1, the new fluorinated analogues of
preparation of a variety of new fluorinated d-manno-hept- 1 might enhance this potential. In addition to 18F 2FG, the
ulose analogues as potential agents of high specificity for 19F analogue was traced in vivo using 19F MRI tech-
in vivo, noninvasive imaging of pancreatic beta cells and niques.[12a–12d]
inhibition of tumour growth is reported. An initial evalu-
ation of their usability in 19F MRI by measuring their MR
properties has also been performed.
Synthesis of 1-Deoxy-1-fluoro-D-manno-heptulose
The fluorinated analogue of 1 was prepared starting
from the exocyclic enol ether 3 in a two-step synthesis
(Scheme 2). First 3 was fluorinated using Selectfluor[23a–23c]
(5, Figure 1) as an electrophilic fluorine source, which intro-
duced fluorine selectively at the 1-position.[23a–23c] After flu-
orination with 5, 3,4,5,7-tetra-O-benzyl-1-deoxy-1-fluoro-α-
d-glycero-d-lyxo-hept-2-ulopyranose (6) was isolated in
75% yield. Only the α-anomer was formed during the reac-
tion, which was confirmed by NOESY experiments,
whereby signal intensity increased due to specific cross-cou-
pling between the anomeric hydroxyl proton with axial H-
4 and H-6. 1-Deoxy-1-fluoro-d-glycero-α-d-lyxo-hept-2-
ulopyranose (7) was obtained from 6 in 97% yield by hydro-
genation.
Results and Discussion
Starting from d-mannose, ketoheptose 1 (Scheme 1) was
prepared in high yield by a seven-step synthesis.[20a,20b] The
key step is the preparation of the exocyclic enol ether 3
from the lactone 2 using the Petasis reagent (4, Fig-
ure 1).[21a,21b] The use of 4 compared to other common
methylenating agents, such as Tebbe’s reagent and Grubb’s
titanacyclobutanes, has a number of advantages, and yields
are usually much higher.[21a,21b,22]
Scheme 1. Synthesis of 1.[20]
Scheme 2. Synthesis of 7.
Synthesis of 3-Deoxy-3-fluoro-D-manno-heptulose
Starting with 3,4,6-tri-O-benzyl-d-glucal (8), which in
turn was easily prepared from d-glucose, 14 was obtained
in a five-step synthesis (Scheme 3). First 8[37] was fluori-
Figure 1. Reagents.
By modification of this method, a series of fluorinated
analogues of 1 was synthesised. Based on previous studies
that used fluorinated monosaccharides as potential hexo-
kinase inhibitors and antitumour agents,[18a,18b] hydroxyl
groups in the 1-, 3- and 7-positions with the potential to be
phosphorylated were chosen for replacement with fluorine.
Substitution of the 2-hydroxyl group with fluorine in d-glu-
cose and d-mannose led to a significant decrease of tumour
cells in vivo.[18b] This was also observed after substitution
of the 6-hydroxyl group in both monosaccharides.[18b] Inter-
estingly, modification of d-glucose and d-mannose at the
3- or 4-positions showed neither an inhibitory effect nor
antitumour activity.[18b]
Scheme 3. Synthesis of 14.
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D. Waschke, Y. Leshch, J. Thimm, U. Himmelreich, J. Thiem
To prevent ring inversion and the formation of a 2,6-
FULL PAPER
nated with 5 to give a mixture of 3,4,6-tri-O-benzyl-2-de-
oxy-2-fluoro-α-d-mannopyranose (9, 33%) and 3,4,6-tri-O- anhydro sugar, the oxidation to the lactone was performed
benzyl-2-deoxy-2-fluoro-d-glucopyranose (10, 44%) in an before introduction of fluorine (Scheme 5). Beginning with
overall yield of 77%. The separation of 9 and 10 was 15, the thioglycoside was first cleaved to give 2,3,4-tri-O-
achieved by column chromatography. Only the α-anomer of benzyl-6-O-tert-butyldiphenylsilyl-α-d-mannopyranose (20,
9 was isolated.
91%). Subsequent oxidation yielded the desired 2,3,4-tri-O-
This was confirmed by the relatively small vicinal cis- benzyl-6-O-tert-butyldiphenylsilyl-d-mannono-1,5-lactone
coupling between the anomeric proton and the adjacent flu- (21) in 99% yield. Removal of the silyl ether was performed
orine. The hemiacetal 9 was then oxidised to 3,4,6-tri-O- in 90% yield to obtain 2,3,4-tri-O-benzyl-d-mannono-1,5-
benzyl-2-deoxy-2-fluoro-d-mannono-1,5-lactone (11, 99%) lactone (22). Fluorination of 22 again led to the formation
with acetic anhydride in dimethyl sulfoxide (DMSO).[24]
of an anhydro sugar. 2,6-Anhydro-3,4-di-O-benzyl-d-man-
Methylenation of 11 with 4 gave 4,5,7-tri-O-benzyl-2,6- nono-1,5-lactone (24) was isolated as the major product,
anhydro-1,3-dideoxy-3-fluoro-d-mannohept-1-enitol (12) in which was formed by the elimination of a benzyl cation.
1
75% yield. A subsequent Sharpless dihydroxylation[25a–25c] The conformation of 24 was confirmed by H NMR spec-
led to 4,5,7-tri-O-benzyl-3-deoxy-3-fluoro-α-d-glycero-d- troscopic spin-coupling constants. As fluorination by nucle-
lyxo-hept-2-ulopyranose (13) in 97% yield. Again, only the ophilic substitution in the presence of benzyl ethers had
α-anomer of 13 was isolated, which was indicated by been unsuccessful, a different approach using an acetylated
NOESY cross-coupling. In the final step, 13 was subjected substrate for fluorination was accomplished.
to hydrogenolysis to afford 3-deoxy-3-fluoro-d-glycero-α-d-
lyxo-hept-2-ulopyranose (14) in 96% yield.
Synthesis of 7-Deoxy-7-fluoro-D-manno-heptulose
The first attempts to fluorinate the 7-position began with
d-mannose (Scheme 4) and preparation of the known deriv-
ative 15.[26] Compound 15 was desilylated[27] to give phenyl-
2,3,4-tri-O-benzyl-1-thio-α-d-mannopyranoside (16) in
95% yield. To replace the free hydroxyl group, the estab-
lished fluorinating agent Deoxo-Fluor™ (17, Figure 1) was
used.[28a,28b] The substitution was achieved by the in situ
conversion of the hydroxyl group into a suitable leaving
group following nucleophilic attack by a fluoride anion.
However, the expected substitution and resulting formation
of the fluorinated compound 18 was not observed
(Scheme 4).
Scheme 5. Attempted fluorination of 22 with 17 and unexpected
formation of 24.
d-Mannose (Scheme 6) was peracetylated and directly
glycosylated to give phenyl 2,3,4,6-tetra-O-acetyl-1-thio-α-
d-mannopyranoside (25,[38] 80%). Regioselective cleavage
of the primary acetyl group with the previously report-
ed[30a,30b] organotin catalyst 26 (Figure 1) was performed.
The catalyst was easily accessible from tert-butyl chloride
and tin(IV) chloride.[31a–31d] Thus, phenyl 2,3,4-tri-O-acetyl-
1-thio-α-d-mannopyranoside (27) was isolated in 91%
yield.
To replace the free hydroxyl group, the established fluori-
nating agent diethylaminosulfur trifluoride[32a,32b] (DAST,
28, Figure 1) was used instead of 17 to give phenyl 2,3,4-
Scheme 4. Attempted fluorination of 16 using 17 and the unexpec-
ted formation of 19.
Instead, a ring inversion and the elimination of a benzyl tri-O-acetyl-6-deoxy-6-fluoro-1-thio-α-d-mannopyranoside
1
cation[29] occurred to give the C4-configured 3,6-anhydro (29) in 30% yield. The successful introduction of fluorine
1
compound 19 as the main product in 43% yield. The C4- and the absolute anomeric configuration of 29 were con-
conformation was confirmed by 1H NMR spectroscopy, firmed by crystal structure analysis (Figure 2).
which showed trans-coupling J1,2 = 8.9 Hz. The other con-
stants were small, which accounts for cis-coupling between gave phenyl 6-deoxy-6-fluoro-1-thio-α-d-mannopyranoside
the equatorial protons H-3, H-4 and H-5. (30) in nearly quantitative yield. Subsequent benzylation of
Deacetylation of 29 under Zemplén conditions[33a,33b]
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Fluorinated Ketoheptoses as Specific Diagnostic Agents
Scheme 6. Synthesis of 34.
Fluorination of the exocyclic enol ether 12 with 5 gave
4,5,7-tri-O-benzyl-1,3-dideoxy-1,3-difluoro-α-d-glycero-d-
lyxo-hept-2-ulopyranose (35) in 74% yield (Scheme 7). The
anomeric configuration was determined by NOESY cross-
coupling as described for 6. After the subsequent hydrogen-
ation of 35, the nonmutarotating 1,3-dideoxy-1,3-difluoro-
α-d-glycero-d-lyxo-hept-2-ulopyranose (36) was isolated as
the pure α-anomer in 94% yield, which was confirmed by
NOESY.
Figure 2. X-ray structure of 29.
30 to phenyl 2,3,4-tri-O-benzyl-6-deoxy-6-fluoro-1-thio-α-
d-mannopyranoside (18) was performed in 89% yield.
Thioglycoside 18 was hydrolysed using N-bromosuccin-
imide (NBS) in water/acetone to give the hemiacetal 2,3,4-
tri-O-benzyl-6-deoxy-6-fluoro-α-d-mannopyranose (31) in
89% yield. Only α-configured 31 was isolated, which was
proven by NOESY experiments. Then hemiacetal 31 was
oxidised to 2,3,4-tri-O-benzyl-6-deoxy-6-fluoro-d-man-
nono-1,5-lactone (23) in 95% yield. Methylenation of 23
with 4 gave the exocyclic enol ether 3,4,5-tri-O-benzyl-2,6-
anhydro-1,7-dideoxy-7-fluoro-d-mannohept-1-enitol (32).
Subsequent Sharpless dihydroxylation gave 3,4,5-tri-O-
benzyl-7-deoxy-7-fluoro-α-d-glycero-d-lyxo-hept-2-ulo-
pyranose (33, 96%), again only α-configured 33 was iso-
lated. Finally, 33 was hydrogenated to yield 7-deoxy-7-
fluoro-d-glycero-α-d-lyxo-hept-2-ulopyranose (34, 96%).
Scheme 7. Synthesis of 36.
Synthesis of 1,7-Dideoxy-1,7-difluoro-D-manno-heptulose
For fluorination of the 1- and 7-positions, the exocyclic
enol ether 32 was treated with 5, and 3,4,5-tri-O-benzyl-1,7-
dideoxy-1,7-difluoro-α-d-glycero-d-lyxo-hept-2-ulopyr-
anose (37) was isolated in 78 % yield (Scheme 8). Subse-
quent hydrogenation gave 1,7-dideoxy-1,7-difluoro-α-d-gly-
cero-d-lyxo-hept-2-ulopyranose (38) in 97% yield.
Synthesis of 1,3-Dideoxy-1,3-difluoro-D-manno-heptulose
In addition to the monofluorination in 7, 14 and 34, the
substitution of two hydroxy groups was performed to pre-
pare doubly fluorinated analogues of 1. In the first case, the
hydroxy groups in the 1- and 3-positions were replaced with
fluorine.
Scheme 8. Synthesis of 38.
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951

D. Waschke, Y. Leshch, J. Thimm, U. Himmelreich, J. Thiem
Table 2. Longitudinal relaxation times of final products.
FULL PAPER
Synthesis of a Fluorinated Kamusol Analogue
Compound
T1 time[a] [ms]
T2 time[a] [ms]
In addition to the derivatives of 1 described above, a flu-
orinated analogue of the natural product Kamusol was pre- 2-deoxy-2-fluoro-d-glucose[b] 1600Ϯ100[c]
–
7
1400Ϯ200
1700Ϯ300
1700Ϯ200
1500Ϯ100
2000Ϯ200
1500Ϯ200
1600Ϯ200
1500Ϯ100
400Ϯ40
120Ϯ20
330Ϯ50
410Ϯ40
140Ϯ30
420Ϯ40
400Ϯ40
350Ϯ30
pared. Kamusol was first isolated as one of several metabo-
lites from Aspergillus sulphureus.[34a,34b] A feasible and high
yielding synthetic access to this natural product has recently
been reported.[20] From the exocyclic enol ether 39[20] as a
starting compound, the fluorinated Kamusol analogue 41
was prepared as follows. First 39 was fluorinated with 5
to give 4,5,7-tri-O-benzyl-1,3-dideoxy-1-fluoro-α-d-glycero-
d-xylo-hept-2-ulopyranose (40) in 83% yield. Hydrogena-
tion of 40 gave 1,3-dideoxy-1-fluoro-α-d-glycero-d-xylo-
hept-2-ulopyranose (41) in 95% yield (Scheme 9).
14
34
36, C1–F
36, C3–F
38, C1–F
38, C7–F
41
[a] In H2O/D2O (4:1), pH 7.1, room temp. Sample concentration
was 10 mm, determination at 376 MHz. [b] Taken as reference sub-
stance. [c] Taken from ref.[36]
Compared to the reference 2-deoxy-2-fluoro-d-glucose,
all fluorinated analogues of 1 have similar relaxation times.
Only the primary fluorides show slightly lower T1 times.
The measured relaxation times of the prepared compounds
are comparable with those of compounds used for in vivo
MRI and are therefore highly promising for future in vivo
detection and quantification of pancreatic beta cells by
using 19F MRI techniques.[12c,36]
Scheme 9. Synthesis of 41.
Conclusions
NMR Properties
To evaluate the MRI properties and specificity for in vivo
beta cell detection, a series of fluorinated analogues of d-
manno-heptulose (1) were prepared by modification of the
previously reported versatile ketoheptose synthesis. As fluo-
rinating agents, Selectfluor and DAST were employed to
give moderate to good yields. Three monofluorinated ana-
logues (7, 14 and 34) and two difluorinated analogues (36
and 38) of 1 and a fluorinated analogue (41) of Kamusol
were prepared. By determination of relaxation times, an
estimation of their usability in MRI studies was performed,
which proved them to be well suited for 19F MRI and com-
parable to compounds already in use for 19F MRI. The spe-
cific transport of 1 by GLUT2 and its fluorinated deriva-
tives would allow for cell specific targeting. An assumed
intracellular phosphorylation of the mannoheptuloses
should enable prolonged half-life in vivo, which would re-
sult in potent contrast agents for in vivo diagnostic. Our
initial in vitro assays did not show any cytotoxicity. Results
involving cell uptake using beta cells and the influence of
the new fluorinated analogues of 1 on insulin secretion are
ongoing and will be reported in due course.
Spin-coupling constants between 19F and 1H are con-
1
siderably larger than H–1H spin coupling constants and
1
can be used for conformational analysis. H NMR spectra
that contain 19F couplings show very distinct splitting pat-
terns. A summary of the specific signals can be found in
Table 1. As expected, the fluorine signals of the primary
fluorides are shifted further upfield than those of the sec-
ondary fluorides.
Table 1. 19F Chemical shifts, multiplicity, 19F–1H and 19F–13C spin
coupling constants of final products.
[b]
[c]
δ[a]
JF,H
JF,C
Multiplicity[b]
[ppm]
[Hz]
[Hz]
7
14
34
–240.1
–213.7
–237.2
46.8
20.6, 168.9
t
dd
dt
t
dd
t
30.7, 50.0 3.5, 17.5, 24.3, 175.5
26.0, 48.0 7.0, 17.5, 167.6
36, C1–F –239.7
36, C3–F –213.4
38, C1–F –240.9
38, C7–F –238.1
46.3
30.6, 50.3 1.6, 4.6, 17.5, 20.9, 176.3
46.8 20.6, 176.6
28.1, 48.0 7.0, 17.4, 175.7
46.7 19.1, 173.7
1.7, 23.6, 169.8
dt
t
41
–233.4
[a] In H2O/D2O (4:1), pH 7.1, 311 K. Sample concentration was
10 mm. [b] Determined from 1H-coupled 19F NMR spectra. [c] De-
termined from 13C NMR spectra.
Experimental Section
To estimate the suitability of the synthesised fluorinated
analogues of 1 for future MRI experiments, their longitudi-
nal and transversal relaxation times were determined
(Table 2). For quantification, spin-density 19F MRI meth-
ods are commonly used, which require not too short T2
values and, for rapid acquisition, relatively short T1 val-
ues.[35a,35b]
General Remarks: TLC was performed with aluminium sheets
coated with silica gel 60 (Merck) and detection was by UV and
heating with H2SO4. Column chromatography was carried out with
silica gel 60 (40–63 μm; Merck) and silica gel 60 RP18 (40–63 μm;
Merck). NMR spectra were recorded with a Bruker AMX 400, AC
400, AV 2400 (400 MHz for 1H, 100.67 MHz for 13C and 376 MHz
for 19F NMR measurements), a Bruker DRX 500 (500 MHz for 1H
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Fluorinated Ketoheptoses as Specific Diagnostic Agents
1
and 125.84 MHz for 13C NMR measurements) or a Varian Gemini-
2000BB (200 MHz for 19F NMR measurements). Chemical shifts
are in ppm and relate to the corresponding solvent peaks.[39] Deter-
mination of 19F chemical shifts was carried out at 311 K with 5-
fluorocytosine (–172.4 ppm) as a standard. T1 relaxation times
+25.3 (c = 0.97, H2O). H NMR (400 MHz, D2O): δ = 4.65 (dd,
J1a,1b = 9.7, J1a,F = 46.8 Hz, 1 H, 1a-H), 4.41 (dd, J1a,1b = 9.7, J1b,F
= 46.8 Hz, 1 H, 1b-H), 3.99 (dd, J3,4 = 3.5, J4,5 = 9.5 Hz, 1 H, 4-
H), 3.98 (d, J3,4 = 3.5 Hz, 1 H, 3-H), 3.92 (dd, J6,7a = 2.0, J7a,7b
11.7 Hz, 1 H, 7a-H), 3.87 (ddd, J5,6 = 9.8, J6,7a = 2.0, J6,7b = 5.5 Hz,
1 H, 6-H), 3.81 (dd, J6,7b = 5.5, J7a,7b = 11.7 Hz, 1 H, 7b-H), 3.69
(dd, J4,5 = 9.5, J5,6 = 9.8 Hz, 1 H, 5-H) ppm. 13C NMR
=
were determined by using an inversion recovery sequence (T1
=
0.01–30 s). T2 relaxation times were determined by using a Carr–
Purcell–Meiboom–Gill sequence (TEeff = 0.001–2 s). Mass spectra
were recorded with Bruker Biflex II (MALDI-TOF, positive reflec-
tion mode, matrix: 2,5-dihydroxybenzoic acid), Thermo Finnigan
MAT 95 XL or Agilent-6224-TOF ESI/MS (ESI mass spectra) in-
struments. Melting points were determined with an Apotec melting
point apparatus. The optical rotations were measured with a
Kruess P8000 polarimeter (589 nm, Na). Compounds 8[37] and
25[38] were synthesised according to literature methods.
(100.6 MHz, D2O): δ = 96.6 (JC,F = 20.6 Hz, C-2), 84.2 (JC,F
=
168.9 Hz, C-1), 73.3 (C-6), 70.7 (C-3), 69.7 (C-4), 66.8 (C-5), 60.9
(C-7) ppm. 19F NMR (376 MHz, D2O/H2O, 4:1): δ = –240.1 (t,
J1,F
= 46.8 Hz) ppm. HRMS (ESI): calcd. for C7H13FO6
[M + Na]+ 235.0588; found 235.0589.
3,4,6-Tri-O-benzyl-2-deoxy-2-fluoro-α-
3,4,6-Tri-O-benzyl-2-deoxy-2-fluoro-
D
-mannopyranose (9) and
D-glucopyranose (10): 3,4,6-
Tri-O-benzyl-d-glucal (8, 10.0 g, 24.0 mmol) and 5 (17.0 g,
48.0 mmol) in DMF/H2O (340 mL) were used according to GP1.
After stirring overnight and work up, the crude residue was purified
by column chromatography (PE/Et2O, 3:1) to obtain pure α-an-
omer 9 (3.57 g, 7.90 mmol, 33%) as a colourless oil and 10 as an
anomeric mixture (α/β, 2:1, 4.76 g, 10.5 mmol, 44%) as a colourless
solid. 9: [α]2D5 = +12.4 (c = 1.0, CHCl3), 9: Rf = 0.36 (PE/Et2O, 1:1),
10: Rf = 0.45 (PE/Et2O, 1:1). 9: 1H NMR (400 MHz, [D6]DMSO):
δ = 7.37–7.27 (m, 13 H, CH, arom.), 7.22–7.19 (m, 2 H, CH,
arom.), 7.00 (dd, JOH,F = 1.9, J1,OH = 4.7 Hz, 1 H, C1OH), 5.16
(ddd, J1,2 = 1.4, J1,OH = 4.7, J1,F = 7.0 Hz, 1 H, 1-H), 4.83 (ddd,
J1,2 = 1.4, J2,3 = 2.2, J2,F = 50.2 Hz, 1 H, 2-H), 4.77 (d, J = 11.4 Hz,
1 H, CH2Ph), 4.73 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.62 (d, J =
11.9 Hz, 1 H, CH2Ph), 4.53 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.51 (d,
J = 11.9 Hz, 1 H, CH2Ph), 4.46 (d, J = 12.0 Hz, 1 H, CH2Ph), 3.84
(ddd, J4,5 = 9.6, J5,6a = 4.8, J5,6b = 1.5 Hz, 1 H, 5-H), 3.80 (ddd,
General Procedure 1 (GP1). Fluorination using Selectfluor: The
sugar enol ether (1.0 mmol) was dissolved in N,N-dimethylform-
amide (DMF, 4 mL) and water (4 mL) was added. Selectfluor (5,
1.5–10 mmol) was added, and the reaction mixture was stirred at
room temperature until completion. Then the reaction mixture was
diluted with ethyl acetate and washed with water. The organic layer
was dried with sodium sulfate, concentrated under vacuum and
purified by column chromatography.
General Procedure 2 (GP2). Hydrogenation: The monosaccharide
(1.0 mmol) was dissolved in anhydrous methanol (15 mL). A cata-
lytic amount of 10% Pd/C was added, and the reaction mixture
was stirred under a hydrogen atmosphere for the given time. After
completion, it was filtered, concentrated in vacuo and, if necessary,
purified by column chromatography.
3,4,5,7-Tetra-O-benzyl-1-deoxy-1-fluoro-α-D-glycero-D-lyxo-hept-
J2,3 = 2.2, J3,4 = 9.4, J3,F = 29.6 Hz, 1 H, 3-H), 3.67 (dd, J3,4
=
2-ulopyranose (6): For fluorination of 3 (1.78 g, 3.31 mmol), Se-
lectfluor (5, 11.7 g, 33.1 mmol) in DMF/H2O (27 mL) was used
according to GP1. After stirring overnight and work up, the crude
residue was purified by column chromatography [petroleum ether
(PE)/Et2O, 2:1] to obtain pure 6 (1.42 g, 2.49 mmol) as a colourless
oil in 75% yield. [α]2D3 = +15.1 (c = 2.7, CHCl3), Rf = 0.30 (PE/
9.4, J4,5 = 9.6 Hz, 1 H, 4-H), 3.65 (dd, J5,6a = 4.8, J6a,6b = 10.6 Hz,
1 H, 6a-H), 3.60 (dd, J5,6b = 1.5, J6a,6b = 10.6 Hz, 1 H, 6b-H) ppm.
10α: 1H NMR (400 MHz, [D6]DMSO): δ = 7.36–7.26 (m, 13 H,
CH, arom.), 7.21–7.16 (m, 2 H, CH, arom.), 6.99 (d, J1,OH
=
4.7 Hz, 1 H, C1OH), 5.22 (dd, J1,2 = 3.3, J1,OH = 4.7 Hz, 1 H, 1-
H), 4.77 (d, J = 10.6 Hz, 1 H, CH2Ph), 4.74 (d, J = 11.3 Hz, 1 H,
CH2Ph), 4.71 (d, J = 10.6 Hz, 1 H, CH2Ph), 4.52 (d, J = 11.3 Hz,
1 H, CH2Ph), 4.51 (d, J = 12.1 Hz, 1 H, CH2Ph), 4.45 (d, J =
1
Et2O, 2:1). H NMR (400 MHz, [D6]DMSO): δ = 7.40–7.37 (m, 2
H, CH, arom.), 7.34–7.24 (m, 16 H, CH, arom.), 7.20–7.18 (m, 2
H, CH, arom.), 6.62 (s, 1 H, C2OH), 4.84 (d, J = 11.4 Hz, 1 H,
CH2Ph), 4.80 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.79 (d, J = 11.3 Hz,
1 H, CH2Ph), 4.65 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.60 (d, J =
11.3 Hz, 1 H, CH2Ph), 4.52 (d, J = 11.8 Hz, 1 H, CH2Ph), 4.50 (d,
J = 11.3 Hz, 1 H, CH2Ph), 4.49 (dd, J1a,1b = 9.0, J1a,F = 47.1 Hz,
12.1 Hz, 1 H, CH2Ph), 4.42 (dd, J1,2 = 3.3, J2,3 = 9.2, J2,F
=
50.0 Hz, 1 H, 2-H), 3.92 (ddd, J2,3 = 9.2, J3,4 = 9.5, J3,F = 11.9 Hz,
1 H, 3-H), 3.89 (ddd, J4,5 = 9.7, J5,6a = 4.8, J5,6b = 2.0 Hz, 1 H, 5-
H), 3.63 (dd, J5,6a = 4.8, J6a,6b = 10.6 Hz, 1 H, 6a-H), 3.58 (dd,
J5,6b = 2.0, J6a,6b = 10.6 Hz, 1 H, 6b-H), 3.47 (dd, J3,4 = 9.5, J4,5
= 9.7 Hz, 1 H, 4-H) ppm. 9: 13C NMR: (100.6 MHz, [D6]DMSO):
δ = 138.4, 138.3, 138.3 (Cq, arom.), 128.2, 128.2, 127.7, 127.6,
127.5, 127.5, 127.4 (CH, arom.), 90.8 (JC,F = 28.1 Hz, C-1), 87.1
(JC,F = 174.5 Hz, C-2), 77.4 (JC,F = 16.9 Hz, C-3), 74.4 (C-4), 74.2,
72.3, 70.4 (CH2Ph), 70.3 (C-5), 69.0 (C-6) ppm. 10α: 138.5, 138.2,
138.1 (Cq-arom), 128.2, 128.2, 127.7, 127.6, 127.6, 127.5, 127.5,
1 H, 1a-H), 4.43 (d, J = 11.8 Hz, 1 H, CH2Ph), 4.19 (dd, J1a,1b
=
9.0, J1b,F = 47.1 Hz, 1 H, 1b-H), 3.98 (dd, J3,4 = 2.9, J4,5 = 9.0 Hz,
1 H, 4-H), 3.97 (d, J3,4 = 2.9 Hz, 1 H, 3-H), 3.84 (ddd, J5,6 = 10.0,
J6,7a = 4.4, J6,7b = 1.9 Hz, 1 H, 6-H), 3.79 (dd, J4,5 = 9.0, J5,6
=
10.0 Hz, 1 H, 5-H), 3.63 (dd, J6,7a = 4.4, 1 H, J7a,7b = 10.9 Hz, 7a-
H), 3.58 (dd, J6,7b = 1.9, J7a,7b = 10.9 Hz, 1 H, 7b-H) ppm. 13C
NMR (100.6 MHz, [D6]DMSO): δ = 138.7, 138.6, 138.5, 138.3,
(Cq, arom.), 128.2, 128.2, 128.1, 127.7, 127.6, 127.5, 127.4, (CH,
arom.), 96.3 (JC,F = 22.8 Hz, C-2), 83.6 (JC,F = 169.6 Hz, C-1),
80.3 (C-4), 74.8 (C-3), 74.6 (C-5), 74.1 (2·CH2Ph), 72.2 (CH2Ph),
71.7 (C-6), 71.0 (CH2Ph), 69.0 (C-7) ppm. 19F NMR (200 MHz,
[D6]DMSO): δ = –225.9 (t, J1,F = 47.1 Hz) ppm. HRMS (ESI):
calcd. for C35H37FO6 [M + Na]+ 595.2466; found 595.2475; [M +
K]+ 611.2206; found 611.2214.
127.5, 127.4 (CH, arom.), 91.6 (JC,F = 193.7 Hz, C-2), 89.2 (JC,F
=
21.7 Hz, C-1), 79.4 (JC,F = 15.7 Hz, C-3), 77.3 (C-4), 74.0, 73.8,
72.3 (CH2Ph), 69.0 (C-5), 68.7 (C-6) ppm. 9: 19F NMR: (200 MHz,
[D6]DMSO): δ = –196.4 [dddd (pseudo-ddd), J1,F = 7.0, J2,F = 50.2,
J3,F = 29.6 Hz] ppm. 10α: 19F NMR (376 MHz, [D6]DMSO): δ =
–195.7 (ddd, J1,F = 4.7, J2,F = 50.0, J3,F = 11.9 Hz) ppm. 9: HRMS
(ESI): calcd. for C27H29FO5 [M + Na]+ 475.1891; found 475.1909.
10α: HRMS (ESI): calcd. for C27H29FO5 [M + Na]+ 475.1981;
found 475.1899.
1-Deoxy-1-fluoro-D-glycero-α-D-lyxo-hept-2-ulopyranose (7): Com-
pound 6 (850 mg, 1.49 mmol) and methanol (10 mL) were used ac-
cording to GP2. The reaction time was 24 h, and the residue was
subjected to column chromatography (RP18, H2O) to obtain pure
3,4,6-Tri-O-benzyl-2-deoxy-2-fluoro-D-mannono-1,5-lactone (11):
Compound 9 (2.10 g, 4.64 mmol) was dissolved in anhydrous
DMSO (12 mL) and heated to 30 °C. Acetic anhydride (9.6 mL,
102 mmol) was added, and the reaction mixture was stirred over-
7 (308 mg, 1.45 mmol) as a colourless resin in 97% yield. [α]2D8
=
Eur. J. Org. Chem. 2012, 948–959
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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953

D. Waschke, Y. Leshch, J. Thimm, U. Himmelreich, J. Thiem
FULL PAPER
night at 30 °C. After completion the reaction mixture was diluted
with water, extracted with diethyl ether several times, and the com-
bined organic phases dried with sodium sulfate, concentrated in
vacuo and purified by column chromatography (PE/Et2O, 1:1) to
obtain pure 11 (2.05 g, 4.55 mmol) as a colourless solid in 98%
yield. [α]3D0 = +31.5 (c = 1.0, CHCl3), m.p. 56–58 °C, Rf = 0.50 (PE/
Et2O, 1:1). 1H NMR (500 MHz, [D6]DMSO): δ = 7.37–7.26 (m, 15
H, CH, arom.), 5.78 (dd, J2,3 = 3.2, J2,F = 45.4 Hz, 1 H, 2-H), 4.65
(s, 2 H, CH2Ph), 4.61 (d, J = 11.0 Hz, 1 H, CH2Ph), 4.51 (d, J =
CH2Ph), 4.72 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.61 (d, J = 11.9 Hz, 1
H, CH2Ph), 4.52 (d, J = 12.1 Hz, 1 H, CH2Ph), 4.49 (d, J =
11.0 Hz, 1 H, CH2Ph), 4.45 (d, J = 12.1 Hz, 1 H, CH2Ph), 3.92–
3.81 (m, 2 H, 4-H, 6-H), 3.68 (dd, J4,5 = 9.7, J5,6 = 10.2 Hz, 1 H,
5-H), 3.64 (dd, J6,7a = 4.6, J7a,7b = 10.7 Hz, 1 H, 7a-H), 3.58 (dd,
J6,7b = 1.6, J7a,7b = 10.7 Hz, 1 H, 7b-H), 3.52 (ddd, J1a,1b = 11.1,
J1a,OH = 5.9,J1a,F = 1.9 Hz, 1 H, 1a-H), 3.34–3.30 (m, 1 H, 1b-H)
ppm. 13C NMR: (125.8 MHz, [D6]DMSO): δ = 138.4, 138.3, 138.2
(Cq, arom.), 128.2, 128.2, 127.8, 127.7, 127.6, 127.5, 127.5 (CH,
11.8 Hz, 1 H, CH2Ph), 4.47 (ddd, J4,5 = 8.5, J5,6a = 1.9, J5,6b
=
arom.), 96.5 (C-2), 85.5 (JC,F = 176.0 Hz, C-3), 78.2 (JC,F =
5.4 Hz, 1 H, 5-H), 4.44 (d, J = 11.8 Hz, 1 H, CH2Ph), 4.42–4.37
17.1 Hz, C-4), 74.4 (C-5), 74.1, 72.2 (CH2Ph), 71.1 (C-6), 70.4
(CH2Ph), 68.9 (C-7), 63.1 (JC,F = 2.8 Hz, C-1) ppm. 19F NMR
(200 MHz, [D6]DMSO): δ = –206.2 [ddd (pseudo-dd), J3,F = 50.8,
J4,F = 28.5 Hz] ppm. HRMS (ESI): calcd. for C28H31FO6
(m, 2 H, 3-H, CH2Ph), 3.87–3.82 (m, 1 H, 4-H), 3.65 (dd, J5,6a
1.9, J6a,6b = 11.5 Hz, 1 H, 6a-H), 3.59 (dd, J5,6b = 5.4, J6a,6b
=
=
11.5 Hz, 1 H, 6b-H) ppm. 13C NMR (125.8 MHz, [D6]DMSO): δ
= 166.9 (JC,F = 21.8 Hz, C-1), 137.8, 137.5, 137.1 (Cq, arom.), [M + H]+ 483.2177; found 483.2189; [M + Na]+ 505.1997; found
128.3, 128.3, 128.1, 127.9, 127.8, 127.7, 127.6, 127.6 (CH, arom.),
86.6 (JC,F = 192.7 Hz, C-2), 76.7 (C-5), 76.2 (JC,F = 15.3 Hz, C-3),
74.5 (JC,F = 7.5 Hz, C-4), 72.1, 71.7, 70.9 (CH2Ph), 68.3 (C-6) ppm.
19F NMR (200 MHz, [D6]DMSO): δ = –202.1 (dt, J2,F = 45.4, J3,F
= 6.7 Hz) ppm. HRMS (ESI): calcd. for C27H27FO5 [M + H]+
451.1915; found 451.1920; [M + Na]+ 473.1753; found 473.1755.
505.2031; [M + K]+ 521.1736; found 521.1735.
3-Deoxy-3-fluoro- -glycero-α- -lyxo-hept-2-ulopyranose (14): Com-
D
D
pound 13 (300 mg, 622 μmol) and methanol (10 mL) were used ac-
cording to GP2. The reaction time was 72 h, and the residue was
subjected to column chromatography (RP18, H2O) to obtain pure
14 (127 mg, 599 μmol) as a colourless resin in 96% yield. [α]2D8
+36.7 (c = 0.39, H2O). H NMR (400 MHz, D2O): δ = 4.78 (dd,
=
1
4,5,7-Tri-O-benzyl-2,6-anhydro-1,3-dideoxy-3-fluoro-D-mannohept-
1-enitol (12): The reaction was carried out under an argon atmo-
sphere in the dark. The lactone 11 (1.75 g, 3.89 mmol) and dicy-
clopentadienyldimethyltitanocene (4, 1.78 g, 8.56 mmol) were dis-
solved in anhydrous toluene (20 mL), heated to 60 °C and stirred
for 48 h. After completion, the solvent was removed in vacuo, and
the residue was purified by column chromatography (PE/Et2O, 4:1
+ 0.5% Et3N) to obtain pure 12 (1.30 g, 2.90 mmol) as a yellowish
oil in 75% yield. [α]3D0 = +76.1 (c = 0.85, CHCl3), Rf = 0.50 (PE/
Et2O, 5:1). 1H NMR (400 MHz, [D6]DMSO): δ = 7.39–7.27 (m, 13
J3,4 = 2.6, J3,F = 50.0 Hz, 1 H, 3-H), 4.02 (ddd, J3,4 = 2.6, J4,5
=
9.7, J4,F = 30.7 Hz, 1 H, 4-H), 3.92–3.84 (m, 2 H, 6-H, 7a-H), 3.83–
3.7 (m, 2 H, 1a-H, 7b-H), 3.73 (dd, J4,5 = 9.7, J5,6 = 9.8 Hz, 1 H,
5-H), 3.60 (dd, J1a,1b = 12.0, J1b,F = 3.4 Hz, 1 H, 1b-H) ppm. 13C
NMR (100.6 MHz, D2O): δ = 96.4 (JC,F = 24.3 Hz, C-2), 89.4 (JC,F
= 175.5 Hz, C-3), 73.1 (C-6), 70.1 (JC,F = 17.5 Hz, C-4), 66.8 (C-
5), 63.4 (JC,F = 3.5 Hz, C-1), 60.7 (C-7) ppm. 19F NMR (376 MHz,
D2O/H2O, 4:1): δ = –213.7 (dd, J3,F = 50.0, J4,F = 30.7 Hz) ppm.
HRMS (ESI): calcd. for C7H13FO6 [M + Na]+ 235.0588; found
235.0589.
H, CH, arom.), 7.21–7.18 (m, 2 H, CH, arom.), 5.44 (dd, J3,4
=
2.5, J3,F = 50.4 Hz, 1 H, 3-H), 4.78 (d, J = 11.9 Hz, 1 H, CH2Ph),
4.76 (d, J = 11.4 Hz, 1 H, CH2Ph), 4.73 (s, 2 H, 1-H), 4.65 (d, J =
11.9 Hz, 1 H, CH2Ph), 4.55 (d, J = 12.2 Hz, 1 H, CH2Ph), 4.52 (d,
J = 11.4 Hz, 1 H, CH2Ph), 4.49 (d, J = 12.2 Hz, 1 H, CH2Ph), 3.88
(ddd, J4,5 = 9.0, J5,6 = 9.1, J5,F = 4.6 Hz, 1 H, 5-H), 3.77 (ddd, J3,4
= 2.5, J4,5 = 9.0, J4,F = 26.4 Hz, 1 H, 4-H), 3.71–3.66 (m, 2 H, 7-
H), 3.63 (ddd, J5,6 = 9.1, J6,7a = 3.1, J6,7b = 6.3 Hz, 1 H, 6-H) ppm.
13C NMR (100.6 MHz, [D6]DMSO): δ = 154.0 (JC,F = 15.3 Hz, C-
2), 138.1, 138.0, 138.0 (Cq, arom.), 128.2, 128.1, 127.8, 127.6,
Phenyl 2,3,4-Tri-O-benzyl-1-thio-α-D-mannopyranoside (16): Com-
pound 15 (2.38 g, 3.05 mmol) was dissolved in methanol (10 mL)
and dichloromethane (10 mL) at room temperature. A catalytic
amount of acetyl chloride (40 μL, 561 μmol) was added, and the
reaction mixture was stirred overnight. After completion, the reac-
tion mixture was diluted with dichloromethane and washed with
saturated saturated sodium hydrogen carbonate solution. The or-
ganic layer was dried with sodium sulfate, concentrated in vacuo
and purified by column chromatography (PE/Et2O, 1:1) to obtain
pure 16 (1.57 g, 2.90 mmol) as a colourless oil in 95% yield. [α]2D5
= +96.9 (c = 1.0, CHCl3), Rf = 0.53 (PE/Et2O, 1:1). 1H NMR:
(400 MHz, [D6]DMSO): δ = 7.50–7.47 (m, 2 H, CH, arom.), 7.39–
7.26 (m, 18 H, CH, arom.), 5.67 (d, J1,2 = 1.5 Hz, 1 H, 1-H), 4.81
127.5, 127.4 (CH, arom.), 100.0 (JC,F = 7.7 Hz, C-1), 86.4 (JC,F
=
174.3 Hz, C-3), 79.5 (JC,F = 19.0 Hz, C-4), 79.0 (C-6), 73.9
(CH2Ph), 73.2 (JC,F = 2.3 Hz, C-5), 72.3, 70.5 (CH2Ph), 68.6 (C-7)
ppm. 19F NMR (200 MHz, [D6]DMSO): δ = –183.4 (ddd, J3,F
=
50.4, J4,F = 26.4, J5,F = 4.6 Hz) ppm. HRMS (ESI): calcd. for
C28H29FO4 [M + H]+ 449.2123; found 449.2126.
(d, J = 11.1 Hz, 1 H, CH2Ph), 4.76 (dd, J6a,OH = 5.3, J6b,OH
=
5.6 Hz, 1 H, C6OH), 4.72 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.64 (d,
J = 11.9 Hz, 1 H, CH2Ph), 4.63 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.60
(d, J = 11.1 Hz, 1 H, CH2Ph), 4.56 (d, J = 11.9 Hz, 1 H, CH2Ph),
4.11 (dd, J1,2 = 1.5, J2,3 = 3.0 Hz, 1 H, 2-H), 3.89 (dt, J5,6 = 3.3,
J4,5 = 9.3 Hz, 1 H, 5-H), 3.81 (dd, J3,4 = 9.0, J4,5 = 9.3 Hz, 1 H, 4-
H), 3.74 (dd, J2,3 = 3.0, J3,4 = 9.0 Hz, 1 H, 3-H), 3.62–3.58 (m, 2
H, 6-H) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 138.6,
138.3, 138.3, 133.9 (Cq, arom.), 131.3, 129.0, 128.2, 128.1, 128.1,
127.8, 127.6, 127.6, 127.5, 127.5, 127.4, 127.4, 127.3 (CH, arom.),
85.0 (C-1), 79.2 (C-3), 75.9 (C-2), 74.4 (C-4), 74.0 (CH2Ph), 73.9
(C-5), 71.3, 70.5 (CH2Ph), 60.3 (C-6) ppm. HRMS (ESI): calcd.
for C33H34O5S [M + H]+ 543.2200; found 543.2199; [M + Na]+
565.2019; found 565.2028; [M + K]+ 581.1759; found 581.1768.
4,5,7-Tri-O-benzyl-3-deoxy-3-fluoro-α-D-glycero-D-lyxo-hept-2-
ulopyranose (13): The exocyclic enol ether 12 (259 mg, 578 μmol)
was dissolved in a mixture of tert-butyl alcohol/water (1:1 v/v,
8 mL) and potassium carbonate (260 mg, 1.88 mmol) was added.
Then potassium hexacyanoferrate(III) (600 mg, 1.82 mmol) and a
catalytic amount of potassium osmate dihydrate were added. The
reaction mixture was stirred at room temperature for 24 h. After
completion the reaction mixture was diluted with ethyl acetate and
washed with water. The organic layer was dried with sodium sul-
fate, concentrated in vacuo and purified by column chromatog-
raphy (Et2O) to obtain pure 13 (270 mg, 560 μmol) as a colourless
oil in 97% yield. [α]3D0 = +44.2 (c = 0.48, CHCl3), Rf = 0.47 (Et2O).
1H NMR: (500 MHz, [D6]DMSO): δ = 7.38–7.25 (m, 13 H, CH,
arom.), 7.21–7.18 (m, 2 H, CH, arom.), 6.34 (d, JOH,F = 3.5 Hz,
C2OH), 4.93 (dd, J1a,OH = 5.9, J1b,OH = 5.6 Hz, 1 H, C1OH), 4.85
Phenyl 3,6-Anhydro-2,4-di-O-benzyl-α-
D-altropyranoside (19): The
reaction was carried out under an argon atmosphere. Compound
(dd, J3,4 = 1.5, J3,F = 50.8 Hz, 1 H, 3-H), 4.78 (d, J = 11.0 Hz, 1 H, 16 (1.25 g, 2.31 mmol) was dissolved in anhydrous dichloromethane
954
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 948–959

Fluorinated Ketoheptoses as Specific Diagnostic Agents
(5 mL) and cooled to 0 °C. Deoxo-Fluor™ (17, 1.09 mL 50% in
THF, 2.54 mmol) was added, and the reaction mixture was stirred
for 1 h at 0 °C. Afterwards the reaction mixture was warmed to
room temperature and stirred for another 6.5 h. After completion,
the reaction was quenched by addition of saturated sodium hydro-
gen carbonate solution, and the phases were separated. The organic
layer was washed with water, dried with sodium sulfate, concen-
trated in vacuo and purified by column chromatography (PE/Et2O,
2:1) to obtain pure 19 (430 mg, 991 μmol) as a colourless oil in
43% yield. [α]2D4 = +14.8 (c = 2.4, CHCl3), Rf = 0.18 (PE/Et2O,
1:1). 1H NMR (400 MHz, [D6]DMSO): δ = 7.51–7.18 (m, 15 H,
CH, arom.), 5.06 (d, J1,2 = 8.8 Hz, 1 H, 1-H), 4.60 (d, J = 11.8 Hz,
in 95% yield. [α]2D5 = –0.4 (c = 0.50, CHCl3), Rf = 0.47 (PE/Et2O,
3:1). 1H NMR (400 MHz, [D6]DMSO): δ = 7.64–7.59 (m, 4 H, CH,
arom.), 7.49–7.27 (m, 19 H, CH, arom.), 7.19–7.15 (m, 2 H, CH,
arom.), 4.88 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.72 (d, J2,3 = 2.3 Hz,
1 H, 2-H), 4.71 (d, J = 12.2 Hz, 1 H, CH2Ph), 4.66 (d, J = 12.2 Hz,
1 H, CH2Ph), 4.62 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.55 (d, J =
11.6 Hz, 1 H, CH2Ph), 4.38 (ddd, J4,5 = 8.2, J5,6a = 2.1, J5,6b
=
4.5 Hz, 1 H, 5-H), 4.33 (d, J = 11.6 Hz, 1 H, CH2Ph), 4.22 (d, J2,3
= 2.3 Hz, 1 H, 3-H), 3.91 (d, J4,5 = 8.2 Hz, 1 H, 4-H), 3.84 (dd,
J5,6a = 2.1, J6a,6b = 11.7 Hz, 1 H, 6a-H), 3.79 (dd, J5,6b = 4.5, J6a,6b
= 11.7 Hz, 1 H, 6b-H), 0.97 (s, 9 H, CH3) ppm. 13C NMR
(100.6 MHz, [D6]DMSO): δ = 169.6 (C-1), 138.0, 138.0, 137.2 (Cq,
1 H, CH2Ph), 4.52 (dd, J4,5 = 2.4, J5,6b = 2.6 Hz, 1 H, 5-H), 4.50– arom.), 135.1, 135.0 (CH, arom.), 132.6, 132.5 (Cq, arom.), 128.2,
4.47 (m, 2 H, CH2Ph), 4.44 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.36 (d,
J3,4 = 6.0 Hz, 1 H, 3-H), 4.10 (d, J6a,6b = 10.7 Hz, 1 H, 6a-H), 4.04
(dd, J4,5 = 2.4, J3,4 = 6.0 Hz, 1 H, 4-H), 3.89 (dd, J5,6b = 2.6, J6a,6b
= 10.7 Hz, 1 H, 6b-H), 3.60 (d, J1,2 = 8.8 Hz, 1 H, 2-H) ppm. 13C
128.1, 127.8, 127.8, 127.5, 127.4, (CH, arom.), 78.0 (C-5), 77.0 (C-
3), 75.6 (C-2), 74.8 (C-4), 71.7, 71.6, 70.7 (CH2Ph), 62.8 (C-6), 26.5
(CH3), 18.8 [C(CH3)3] ppm. HRMS (ESI): calcd. for C43H46O6Si
[M + H]+ 687.3136; found 687.3139; [M + Na]+ 709.2956; found
NMR (100.6 MHz, [D6]DMSO): δ = 138.0, 137.7, 135.6 (Cq, 709.2957; [M + K]+ 725.2696; found 725.2702.
arom.), 130.5, 128.3, 128.2, 128.2, 128.2, 128.1, 127.9, 127.8, 127.6,
2,3,4-Tri-O-benzyl-D-mannono-1,5-lactone (22): Compound 21
127.5, (CH, arom.), 82.0 (C-1), 77.3 (C-4), 73.9 (C-2), 73.7 (C-5),
73.5 (C-3), 71.0, 70.9 (CH2Ph), 68.3 (C-6) ppm. HRMS (ESI):
calcd. for C26H26O4S [M + H]+ 435.1625; found 435.1629; [M +
Na]+ 457.1444; found 457.1445.
(343 mg, 502 μmol) was dissolved in methanol (2 mL) and dichlo-
romethane (2 mL) at room temperature. A catalytic amount of
acetyl chloride (8 μL, 112 μmol) was added and the reaction mix-
ture stirred overnight. After completion, the reaction mixture was
2,3,4-Tri-O-benzyl-6-O-tert-butyldiphenylsilyl-α-D-mannopyranose diluted with dichloromethane and washed with saturated sodium
(20): The thioglycoside 15 (2.50 g, 3.21 mmol) was dissolved in a
mixture of acetone/water (9:1 v/v, 50 mL). NBS (1.14 g, 6.40 mmol)
was added at room temperature and the reaction mixture was
stirred for 20 min. After completion, the reaction mixture was di-
luted with water, extracted with diethyl ether several times and the
combined organic phases washed with saturated sodium hydrogen
carbonate solution and dried with sodium sulfate. After removal of
the solvent, the crude product was purified by column chromatog-
raphy (PE/Et2O, 3:1) to obtain pure 20 (2.01 g, 2.93 mmol) as a
colourless oil in 91% yield. [α]2D5 = +12.6 (c = 0.50, CHCl3), Rf =
hydrogen carbonate solution. The organic layer was dried with so-
dium sulfate, concentrated in vacuo and purified by column
chromatography (PE/EE, 2:1) to obtain pure 22 (202 mg, 451 μmol)
as a colourless solid in 90% yield. [α]2D5 = +9.1 (c = 1.0, CHCl3),
m.p. 114–115 °C, Rf = 0.34 (PE/EE, 2:1). 1H NMR (400 MHz,
[D6]DMSO): δ = 7.42–7.26 (m, 15 H, CH, arom.), 5.13 (dd, J6a,OH
= 5.7, J6b,OH = 5.2 Hz, 1 H, C6OH), 4.86 (d, J = 11.9 Hz, 1 H,
CH2Ph), 4.70 (d, J = 11.8 Hz, 1 H, CH2Ph), 4.69 (d, J2,3 = 2.7 Hz,
1 H, 2-H), 4.65 (d, J = 11.8 Hz, 1 H, CH2Ph), 4.59 (d, J = 11.9 Hz,
1 H, CH2Ph), 4.56 (d, J = 11.5 Hz, 1 H, CH2Ph), 4.47 (d, J =
1
0.25 (PE/Et2O, 4:1). H NMR (400 MHz, [D6]DMSO): δ = 7.71–
11.5 Hz, 1 H, CH2Ph), 4.22 (ddd, J4,5 = 8.3, J5,6a = 2.5, J5,6b
5.3 Hz, 1 H, 5-H), 4.17 (d, J2,3 = 2.7 Hz, 1 H, 3-H), 3.77 (d, J4,5
8.3 Hz, 1 H, 4-H), 3.64 (ddd, J5,6a = 2.5, J6a,OH = 5.7, J6a,6b
=
=
=
7.68 (m, 2 H, CH, arom.), 7.64–7.61 (m, 2 H, CH, arom.), 7.46–
7.25 (m, 20 H, CH, arom.), 7.19–7.16 (m, 1 H, CH, arom.), 6.58
(d, J1,OH = 4.2 Hz, 1 H, C1OH), 5.21 (dd, J1,2 = 1.9, J1,OH = 4.2 Hz,
1 H, 1-H), 4.88 (d, J = 11.2 Hz, 1 H, CH2Ph), 4.74 (d, J = 12.2 Hz,
1 H, CH2Ph), 4.70 (d, J = 12.2 Hz, 1 H, CH2Ph), 4.69 (d, J =
12.4 Hz, 1 H, 6a-H), 3.58–3.50 (m, 1 H, 6b-H) ppm. 13C NMR
(101 MHz, [D6]DMSO): δ = 169.8 (C-1), 138.0, 138.0, 137.5 (Cq,
arom.), 128.2, 128.2, 128.1, 127.9, 127.7, 127.7, 127.5, 127.5, 127.4
12.0 Hz, 1 H, CH2Ph), 4.59 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.58 (d, (CH, arom.), 78.7 (C-5), 77.2 (C-3), 75.7 (C-2), 75.5 (C-4), 71.7,
J = 11.2 Hz, 1 H, CH2Ph), 4.08 (dd, J3,4 = 9.4, J4,5 = 9.6 Hz, 1 H,
4-H), 3.97 (dd, J5,6a = 3.5, J6a,6b = 11.0 Hz, 1 H, 6a-H), 3.89 (dd,
71.6, 70.9 (CH2Ph), 60.6 (C-6) ppm. HRMS (ESI): calcd. for
C27H28O6 [M + H]+ 449.1959; found 449.1976; [M + Na]+
471.1778; found 471.1780; [M + K]+ 487.1517; found 487.1532.
J2,3 = 2.9, J3,4 = 9.4 Hz, 1 H, 3-H), 3.86 (dd, J1,2 = 1.9, J2,3
=
2.9 Hz, 1 H, 2-H), 3.79 (dd, J5,6b = 1.4, J6a,6b = 11.0 Hz, 1 H, 6b-
H), 3.75 (ddd, J4,5 = 9.6, J5,6a = 3.5, J5,6b = 1.4 Hz, 1 H, 5-H), 0.98
(s, 9 H, CH3) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 139.0,
138.7, 138.7 (Cq, arom.), 135.3, 135.0 (CH, arom.), 133.3, 132.9
(Cq, arom.), 128.1, 128.1, 128.0, 127.7, 127.5, 127.5, 127.3, 127.2,
127.2, 127.1 (CH, arom.), 91.3 (C-1), 79.1 (C-3), 75.9 (C-2), 74.2
(C-4), 74.0, 71.7 (CH2Ph), 71.6 (C-5), 70.5 (CH2Ph), 63.1 (C-6),
26.5 (CH3), 18.8 [C(CH3)3] ppm. HRMS (ESI): calcd. for
C43H48O6Si [M + Na]+ 711.3112; found 711.3123; [M + K]+
727.2852; found 727.2854.
2,6-Anhydro-3,4-di-O-benzyl-D-mannono-1,5-lactone (24): The reac-
tion was carried out under an argon atmosphere. Compound 22
(80.0 mg, 179 μmol) was dissolved in anhydrous dichloromethane
(2 mL) and cooled to 0 °C. Deoxo-Fluor™ (17, 101 μL 50 % in
THF, 235 μmol) was added, and the reaction mixture was stirred
for 5 h at room temperature. After completion, the reaction was
quenched by addition of saturated sodium hydrogen carbonate
solution, and the phases were separated. The organic layer was
washed with water, dried with sodium sulfate, concentrated in
vacuo and purified by column chromatography (PE/EE, 1:1) to ob-
2,3,4-Tri-O-benzyl-6-O-tert-butyldiphenylsilyl-
D
-mannono-1,5-
tain pure 24 (35.2 mg, 103 μmol) as a colourless oil in 58% yield.
lactone (21): Compound 20 (1.90 g, 2.76 mmol) was dissolved in [α]2D4 = –120.9 (c = 1.8, CHCl3), Rf = 0.51 (PE/EE, 1:1). H NMR
1
anhydrous DMSO (25 mL) and heated to 30 °C. Acetic anhydride
(5.70 mL, 60.6 mmol) was added, and the reaction mixture was
stirred overnight at 30 °C. After completion, the reaction mixture
was diluted with water, extracted with diethyl ether several times
and the combined organic phases dried with sodium sulfate, con-
centrated in vacuo and purified by column chromatography (PE/
(400 MHz, [D6]DMSO): δ = 7.39–7.29 (m, 10 H, CH, arom.), 5.05
(dd, J4,5 = 4.7, J5,6a = 2.5 Hz, 1 H, 5-H), 4.89 (d, J = 11.7 Hz, 1 H,
CH2Ph), 4.71 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.68 (d, J = 11.7 Hz, 1
H, CH2Ph), 4.60 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.58–4.45 (m, 2 H,
3-H, 4-H), 4.17 (d, J2,3 = 1.5 Hz, 1 H, 2-H), 4.06 (dd, J5,6a = 2.5,
J6a,6b = 10.8 Hz, 1 H, 6a-H), 3.96 (d, J6a,6b = 10.8 Hz, 1 H, 6b-H)
Et2O, 3:1) to obtain pure 21 (1.88 g, 2.74 mmol) as a colourless oil ppm. 13C NMR (101 MHz, [D6]DMSO): δ = 170.1 (C-1), 137.7,
Eur. J. Org. Chem. 2012, 948–959
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
955

D. Waschke, Y. Leshch, J. Thimm, U. Himmelreich, J. Thiem
FULL PAPER
137.1 (Cq, arom.), 128.3, 128.2, 127.8, 127.8, 127.7, 127.6 (CH,
arom.), 77.0 (C-5), 76.9 (C-3), 74.6 (C-2), 73.0 (C-4), 72.4, 71.5
(CH2Ph), 71.2 (C-6) ppm. HRMS (ESI): calcd. for C20H20O5 [M
+ H]+ 341.1384; found 341.1392; [M + Na]+ 363.1203; found
363.1206.
tralisation. The ion-exchange resin was removed by filtration, and
the solvent was removed in vacuo to give pure 30 (200 mg,
730 μmol) as a colourless oil in 99% yield. [α]2D3 = +224.3 (c = 0.37,
1
CHCl3). H NMR (400 MHz, [D4]MeOH): δ = 7.56–7.52 (m, 2 H,
CH, arom.), 7.38–7.30 (m, 3 H, CH, arom.), 5.47 (d, J1,2 = 1.5 Hz,
1 H, 1-H), 4.69 (ddd, J5,6a = 5.0, J6a,6b = 10.2, J6a,F = 48.0 Hz, 1
H, 6a-H), 4.63 (ddd, J5,6b = 1.3, J6a,6b = 10.2, J6b,F = 48.0 Hz, 1
Phenyl 2,3,4-Tri-O-acetyl-1-thio-α-D-mannopyranoside (27): The re-
action was carried out under an argon atmosphere. Compound 25
(2.40 g, 5.44 mmol) was dissolved in anhydrous methanol (27 mL)
and heated to 30 °C. Compound 26 (156 mg, 272 μmol) was added
and the reaction mixture was stirred for 4 h at 30 °C. After comple-
tion, the solvent was removed in vacuo, and the residue was puri-
fied by column chromatography (PE/EE, 1:1) to obtain pure 27
(1.97 g, 4.95 mmol) as a colourless oil in 91% yield. [α]2D5 = +99.4
(c = 0.75, CHCl3), Rf = 0.20 (PE/EE, 2:1). 1H NMR (400 MHz,
[D6]DMSO): δ = 7.57–7.53 (m, 2 H, CH, arom.), 7.40–7.34 (m, 3
H, 6b-H), 4.23 (dddd, J4,5 = 9.4, J5,6a = 5.0, J5,6b = 1.3, J5,F
=
25.2 Hz, 1 H, 5-H), 4.14 (dd, J1,2 = 1.5, J2,3 = 3.0 Hz, 1 H, 2-H),
3.79 (dd, J3,4 = 9.5, J4,5 = 9.4 Hz, 1 H, 4-H), 3.73 (dd, J2,3 = 3.0,
J3,4 = 9.5 Hz, 1 H, 3-H) ppm. 13C NMR (100.6 MHz, [D4]MeOH):
δ = 135.8 (Cq, arom.), 133.0, 130.5, 128.8 (CH, arom.), 90.6 (C-1),
83.6 (JC,F = 171.7 Hz, C-6), 74.5 (JC,F = 18.1 Hz, C-5), 73.7 (C-2),
73.3 (C-3), 67.8 (JC,F = 7.2 Hz, C-4) ppm. 19F NMR (200 MHz,
[D4]MeOH): δ = –233.6 (td, J5,F = 25.2, J6,F = 48.0 Hz) ppm.
HRMS (ESI): calcd. for C12H15FO4S [M + Na]+ 297.0567; found
297.0567.
H, CH, arom.), 5.64 (d, J1,2 = 1.3 Hz, 1 H, 1-H), 5.36 (dd, J1,2
=
1.3, J2,3 = 3.3 Hz, 1 H, 2-H), 5.19 (dd, J3,4 = 10.5, J4,5 = 9.6 Hz, 1
H, 4-H), 5.11 (dd, J2,3 = 3.3, J3,4 = 10.5 Hz, 1 H, 3-H), 4.85 (t,
J6,OH = 5.7 Hz, 1 H, C6OH), 4.21–4.16 (m, 1 H, 5-H), 3.50–3.45
(m, 2 H, 6-H), 2.09 [s, 3 H, C(O)CH3], 2.04 [s, 3 H, C(O)CH3], 1.96
[s, 3 H, C(O)CH3] ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ =
169.7, 169.6, 169.2 [C(O)CH3], 132.4 (Cq, arom.), 131.2, 129.2,
127.9 (CH, arom.), 84.7 (C-1), 72.3 (C-5), 70.1 (C-2), 69.3 (C-3),
65.8 (C-4), 59.9 (C-6), 20.6, 20.4, 20.3 [C(O)CH3] ppm. HRMS
(ESI): calcd. for C18H22O8S [M + Na]+ 421.0928; found 421.0927;
[M + K]+ 437.0667; found 437.0664.
Phenyl 2,3,4-Tri-O-benzyl-6-deoxy-6-fluoro-1-thio-α-D-manno-
pyranoside (18): The reaction was carried out under an argon atmo-
sphere. The partially unprotected glycoside 30 (170 mg, 619 μmol)
was added to a suspension of sodium hydride (67.0 mg, 2.79 mmol)
in anhydrous DMF (5 mL) at 0 °C. The reaction mixture was
stirred for 2 h at room temperature and a catalytic amount of tetra-
butylammonium iodide (22.9 mg, 61.9 μmol) was added. Benzyl
bromide (242 μL, 2.04 mmol) was added dropwise and the reaction
mixture was stirred overnight at room temperature. After comple-
tion, ethanol was added until gas evolution ceased. The reaction
mixture was diluted with water and ether, the phases separated,
and the aqueous phase extracted with diethyl ether several times.
The combined organic phases were dried with sodium sulfate, con-
centrated in vacuo and purified by column chromatography (PE/
Et2O, 4:1) to obtain pure 18 (299 mg, 550 μmol) as a colourless oil
in 89% yield. [α]2D5 = +74.4 (c = 0.25, CHCl3), ref.[40] [α]2D4 = +69.6
Phenyl 2,3,4-Tri-O-acetyl-6-deoxy-6-fluoro-1-thio-α-D-mannopyr-
anoside (29): The reaction was carried out under an argon atmo-
sphere. Compound 27 (1.50 g, 3.77 mmol) was dissolved in anhy-
drous dichloromethane (4 mL) and cooled to 0 °C. DAST (28,
768 μL, 5.66 mmol) was added, and the mixture was stirred for
30 min at 0 °C. The reaction mixture was allowed to warm to room
temperature and stirring was continued for another 30 min. After-
wards the reaction was quenched by the addition of saturated so-
dium hydrogen carbonate solution and extracted with ethyl ether
several times. The organic layer was dried with sodium sulfate, con-
centrated in vacuo and purified by column chromatography (PE/
Et2O, 2:1) to obtain pure 28 (448 mg, 1.12 mmol) as a colourless
1
(c = 0.46, CHCl3), Rf = 0.65 (PE/Et2O, 4:1). H NMR (500 MHz,
[D6]DMSO): δ = 7.48–7.45 (m, 2 H, CH, arom.), 7.39–7.27 (m, 18
H, CH, arom.), 5.75 (d, J1,2 = 1.9 Hz, 1 H, 1-H), 4.84 (d, J =
11.1 Hz, 1 H, CH2Ph), 4.75 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.65 (d,
J = 11.7 Hz, 1 H, CH2Ph), 4.64 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.61
(ddd, J5,6a = 4.2, J6a,6b = 10.2, J6a,F = 45.5 Hz, 1 H, 6a-H), 4.59
(d, J = 11.1 Hz, 1 H, CH2Ph), 4.57 (d, J = 11.7 Hz, 1 H, CH2Ph),
4.51 (ddd, J5,6b = 1.5, J6a,6b = 10.2, J6b,F = 45.5 Hz, 1 H, 6b-H),
4.15 (dd, J1,2 = 1.9, J2,3 = 2.8 Hz, 1 H, 2-H), 4.10 (dddd, J4,5 = 9.5,
solid in 30% yield. [α]2D6 = +118.2 (c = 1.0, CHCl3), ref.[40] [α]2D3
=
+112.2 (c = 0.19, CHCl3), m.p. 116–117 °C, ref.[40] 105–109 °C, Rf
= 0.51 (PE/Et2O, 1:1). 1H NMR (400 MHz, [D6]DMSO): δ = 7.56–
7.51 (m, 2 H, CH, arom.), 7.41–7.35 (m, 3 H, CH, arom.), 5.73 (d,
J1,2 = 1.5 Hz, 1 H, 1-H), 5.39 (dd, J1,2 = 1.5, J2,3 = 3.2 Hz, 1 H, 2-
H), 5.23 (dd, J3,4 = 10.2, J4,5 = 10.0 Hz, 1 H, 4-H), 5.13 (dd, J2,3
J5,6a = 4.2, J5,6b = 1.5, J5,F = 27.8 Hz, 1 H, 5-H), 3.83 (dd, J3,4
=
9.3, J4,5 = 9.5 Hz, 1 H, 4-H), 3.77 (dd, J2,3 = 2.8, J3,4 = 9.3 Hz, 1
H, 3-H) ppm. 13C NMR (125.8 MHz, [D6]DMSO): δ = 138.2,
138.2, 138.1, 133.4 (Cq, arom.), 131.3, 129.2, 128.3, 128.2, 127.8,
= 3.2, J3,4 = 10.2 Hz, 1 H, 3-H), 4.53 (ddd, J5,6a = 3.8, J6a,6b
10.9, J6a,F = 47.3 Hz, 1 H, 6a-H), 4.47 (ddd, J5,6b = 1.4, J6a,6b
10.9, J6b,F = 47.3 Hz, 1 H, 6b-H), 4.41 (dddd, J4,5 = 10.0, J5,6a
=
=
=
127.8, 127.7, 127.6, 127.5 (CH, arom.), 84.7 (C-1), 82.2 (JC,F
170.9 Hz, C-6), 79.0 (C-3), 75.5 (C-2), 74.2 (CH2Ph), 73.2 (JC,F
=
=
3.8, J5,6b = 1.4, J5,F = 26.2 Hz, 1 H, 5-H), 2.10 [s, 3 H, C(O)CH3],
2.08 [s, 3 H, C(O)CH3], 1.97 [s, 3 H, C(O)CH3] ppm. 13C NMR
(101 MHz, [D6]DMSO): δ = 169.7, 169.6, 169.3 [C(O)CH3], 131.9
(Cq, arom.), 131.7, 129.3, 128.1 (CH, arom.), 84.6 (C-1), 80.9 (JC,F
= 171.7 Hz, C-6), 70.0 (JC,F = 18.2 Hz, C-5), 69.8 (C-2), 69.1 (C-
3), 64.3 (JC,F = 7.0 Hz, C-4), 20.6, 20.5, 20.4 [C(O)CH3] ppm. 19F
NMR (376 MHz, [D6]DMSO): δ = –231.6 (dt, J5,F = 26.2, J6,F
= 47.3 Hz) ppm. HRMS (ESI): calcd. for C18H21FO7S [M + H]+
401.1065; found 401.1065; [M + Na]+ 423.0884; found 423.0883;
[M + K]+ 439.0624; found 439.0619.
6.7 Hz, C-4), 71.5 (JC,F = 18.1 Hz, C-5), 70.4, 71.3 (CH2Ph) ppm.
19F NMR (200 MHz, [D6]DMSO): δ = –229.7 (td, J5,F = 27.8, J6,F
= 45.5 Hz) ppm. HRMS (ESI): calcd. for C33H33FO4S [M + Na]+
567.1976; found 567.1972.
2,3,4-Tri-O-benzyl-6-deoxy-6-fluoro-α-D-mannopyranose (31): The
thioglycoside 18 (250 mg, 460 μmol) was dissolved in a mixture of
acetone/water (9:1 v/v, 10 mL). NBS (258 mg, 1.45 mmol) was
added at room temperature, and the reaction mixture was stirred
for 30 min. After completion, the reaction mixture was diluted with
water, extracted with diethyl ether several times, and the combined
organic phases were washed with saturated sodium hydrogen car-
bonate solution and dried with sodium sulfate. After removal of
the solvent, the crude product was purified by column chromatog-
raphy (PE/Et2O, 1:1) to obtain pure 31 (183 mg, 406 μmol) as a
colourless solid in 89% yield. [α]3D0 = +22.2 (c = 0.45, CHCl3), m.p.
Phenyl 6-Deoxy-6-fluoro-1-thio-α-D-mannopyranoside (30): Com-
pound 29 (296 mg, 739 μmol) was dissolved in anhydrous methanol
(10 mL) and treated with a catalytic amount of sodium methoxide
solution (0.5 m). The reaction mixture was stirred at room tempera-
ture until completion. Amberlite® IR-120 H+ was added for neu-
956
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 948–959

Fluorinated Ketoheptoses as Specific Diagnostic Agents
121–123 °C, Rf = 0.42 (PE/Et2O, 1:1). 1H NMR (500 MHz,
3,4,5-Tri-O-benzyl-7-deoxy-7-fluoro-α-
ulopyranose (33): Compound 32 (80.0 mg, 178 μmol) was dissolved
4.0 Hz, 1 H, C1OH), 5.13 (dd, J1,2 = 1.8, J1,OH = 4.0 Hz, 1 H, 1- in a mixture of tert-butyl alcohol/water (1:1 v/v, 5 mL), and potas-
D-glycero-D-lyxo-hept-2-
[D6]DMSO): δ = 7.39–7.26 (m, 15 H, CH, arom.), 6.72 (d, J1,OH
=
H), 4.83 (d, J = 11.1 Hz, 1 H, CH2Ph), 4.67 (b, 2 H, CH2Ph), 4.65
(d, J = 11.9 Hz, 1 H, CH2Ph), 4.63–4.44 (m, 4 H, CH2Ph, 6-H),
3.86 (dd, J2,3 = 3.0, J3,4 = 9.1 Hz, 1 H, 3-H), 3.82 (dd, J1,2 = 1.8,
sium carbonate (80.0 mg, 564 μmol) was added. Potassium hexacy-
anoferrate(III) (180 mg, 546 μmol) and a catalytic amount of po-
tassium osmate dihydrate were added. The reaction mixture was
stirred at room temperature for 24 h. After completion, the reaction
mixture was diluted with ethyl acetate and washed with water. The
J2,3 = 2.4 Hz, 1 H, 2-H), 3.81 (dddd, J4,5 = 9.9, J5,6a = 1.5, J5,6b
=
3.5, J5,F = 24.7 Hz, 1 H, 5-H), 3.72 (dd, J3,4 = 9.1, J4,5 = 9.6 Hz,
4-H) ppm. 13C NMR (125.8 MHz, [D6]DMSO): δ = 138.7, 138.5, organic layer was dried with sodium sulfate, concentrated in vacuo
138.7 (Cq, arom.), 128.2, 128.2, 127.7, 127.6, 127.5, 127.4, 127.4 and purified by column chromatography (Et2O) to obtain pure 33
(CH, arom.), 91.4 (C-1), 82.8 (JC,F = 169.5 Hz, C-6), 78.9 (C-3), (82.0 mg, 170 μmol) as a colourless oil in 96% yield. [α]2D4 = –39.1
75.3 (C-2), 74.1 (CH2Ph), 73.6 (JC,F = 6.9 Hz, C-4), 71.8, 70.5 (c = 0.57, CHCl3), Rf = 0.59 (Et2O). 1H NMR (400 MHz, [D6]-
(CH2Ph), 70.0 (JC,F = 17.9 Hz, C-5) ppm. 19F NMR (200 MHz,
[D6]DMSO): δ = –229.7 (dt, J5,F = 24.7, J6,F = 48.6 Hz) ppm.
HRMS (ESI): calcd. for C27H29FO5 [M + Na]+ 475.1891; found
475.1915; [M + K]+ 491.1631; found 491.1637.
DMSO): δ = 7.40–7.24 (m, 15 H, CH, arom.), 6.02 (s, 1 H, C2OH),
4.84 (dd, J1a,OH = 6.7, J1b,OH = 4.2 Hz, 1 H, C1OH), 4.83 (d, J =
11.1 Hz, 1 H, CH2Ph), 4.79 (d, J = 11.5 Hz, 1 H, CH2Ph), 4.76 (d,
J = 12.3 Hz, 1 H, CH2Ph), 4.67 (d, J = 11.5 Hz, 1 H, CH2Ph), 4.63
(d, J = 12.3 Hz, 1 H, CH2Ph), 4.56 (d, J = 11.1 Hz, 1 H, CH2Ph),
4.54 (ddd, J6,7a = 4.3, J7a,7b = 10.1, J7a,F = 48.2 Hz, 1 H, 7a-H),
4.46 (ddd, J6,7b = 1.3, J7a,7b = 10.1, J7b,F = 48.2 Hz, 1 H, 7b-H),
4.02–3.97 (m, 2 H, 3-H, 4-H), 3.81 (dddd, J5,6 = 9.6, J6,7a = 4.3,
2,3,4-Tri-O-benzyl-6-deoxy-6-fluoro-D-mannono-1,5-lactone (23):
Compound 31 (155 mg, 343 μmol) was dissolved in anhydrous
DMSO (2 mL) and heated to 30 °C. Acetic anhydride (715 μL,
7.60 mmol) was added and the reaction mixture was stirred over-
night at 30 °C. After completion, the reaction mixture was diluted
with water, extracted with diethyl ether several times, and the com-
bined organic phases were dried with sodium sulfate, concentrated
in vacuo and purified by column chromatography (PE/Et2O, 1:1)
to obtain pure 23 (147 mg, 327 μmol) as a colourless solid in 95%
yield. [α]3D0 = –3.9 (c = 0.67, CHCl3), m.p. 85–86 °C Rf = 0.46 (PE/
Et2O, 1:1). 1H NMR (400 MHz, [D6]DMSO): δ = 7.27–7.43 (m, 15
J6,7b = 1.3, J6,F = 28.3 Hz, 1 H, 6-H), 3.72 (dd, J4,5 = 9.4, J5,6
=
9.6 Hz, 1 H, 5-H), 3.58 (dd, J1a,1b = 10.7, J1a,OH = 6.7 Hz, 1 H, 1a-
H), 3.32 (dd, J1a,1b = 10.7, J1b,OH = 4.2 Hz, 1 H, 1b-H) ppm. 13C
NMR (100.6 MHz, [D6]DMSO): δ = 139.1, 138.6, 138.4 (Cq,
arom.), 128.1, 128.1, 128.0, 127.6, 127.5, 127.4, 127.4, 127.3, 127.2
(CH, arom.), 98.3 (C-2), 80.7 (JC,F = 170.3 Hz, C-7), 80.5 (C-4),
75.1 (C-3), 73.9 (2·CH2Ph), 73.7 (JC,F = 6.7 Hz, C-5), 70.8
(CH2Ph), 70.7 (JC,F = 18.9 Hz, C-6), 63.7 (C-1) ppm. 19F NMR
(200 MHz, [D6]DMSO): δ = –229.9 (dt, J6,F = 28.3, J7,F = 48.2 Hz)
ppm. HRMS (ESI): calcd. for C28H31FO6 [M + Na]+ 505.1997;
found 505.2012; [M + K]+ 521.1736; found 521.1745.
H, CH, arom.), 4.86 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.74 (d, J2,3
=
2.3 Hz, 1 H, 3-H), 4.71–4.51 (m, 7 H, 5-H, 6-H, CH2Ph), 4.48 (d,
J = 11.7 Hz, 1 H, CH2Ph), 4.22 (d, J2,3 = 2.3 Hz, 1 H, 2-H), 3.76
(d, J4,5 = 8.1 Hz, 1 H, 4-H) ppm. 13C NMR (100.6 MHz, [D6]-
DMSO): δ = 169.1 (C-1), 137.9, 137.8, 137.2 (Cq, arom.), 128.3,
128.2, 128.2, 128.0, 127.9, 127.7, 127.6, 127.5, 127.4, (CH, arom.),
81.6 (JC,F = 172.6 Hz, C-6), 76.8 (C-2), 76.0 (JC,F = 17.8 Hz, C-5),
75.6 (C-3), 74.5 (JC,F = 6.8 Hz, C-4), 70.9, 70.7, 70.7 (CH2Ph) ppm.
19F NMR (200 MHz, [D6]DMSO): δ = –228.3 (dt, J5,F = 23.6, J6,F
= 50.2 Hz) ppm. HRMS (ESI): calcd. for C27H27FO5 [M + H]+
451.1915; found 451.1920; [M + Na]+ 473.1735; found 473.1752;
[M + K]+ 489.1474; found 489.1471.
7-Deoxy-7-fluoro-D-glycero-α-D-lyxo-hept-2-ulopyranose (34): Com-
pound 33 (66.8 mg, 139 μmol) and methanol (10 mL) were used
according to GP2. The reaction time was 48 h, and the residue was
subjected to column chromatography (RP18, H2O) to obtain pure
34 (28.5 mg, 134 μmol) as a colourless resin in 96% yield. [α]2D8
=
1
+20.8 (c = 0.13, H2O). H NMR (500 MHz, D2O): δ = 4.74 (ddd,
J6,7a = 3.8, J7a,7b = 10.5, J7a,F = 48.0 Hz, 1 H, 7a-H), 4.68 (ddd,
J6,7b = 1.5, J7a,7b = 10.5, J7b,F = 48.0 Hz, 1 H, 7b-H), 3.96 (dd, J3,4
= 2.9, J4,5 = 9.6 Hz, 1 H, 4-H), 3.93 (d, J3,4 = 2.9 Hz, 1 H, 3-H),
3.93 (dddd, J5,6 = 9.8, J6,7a = 3.8, J6,7b = 1.5, J6,F = 26.0 Hz, 1 H,
6-H), 3.76 (d, J1a,1b = 11.8 Hz, 1 H, 1a-H), 3.75 (dd, J4,5 = 9.6, J5,6
3,4,5-Tri-O-benzyl-2,6-anhydro-1,7-dideoxy-7-fluoro-D-mannohept-
1-enitol (32): The reaction was carried out under an argon atmo-
sphere in the dark. Lactone 23 (115 mg, 255 μmol) and 4 (117 mg,
561 μmol) were dissolved in anhydrous toluene (3 mL), and the
mixture was heated to 60 °C and stirred for 24 h. After completion,
the solvent was removed in vacuo, and the residue was purified by
column chromatography (PE/Et2O, 5:1 + 0.5% Et3N) to obtain
pure 32 (88.0 mg, 196 μmol) as a yellowish oil in 77% yield. [α]2D3
= +8.8 (c = 0.25, CHCl3), Rf = 0.51 (PE/Et2O, 5:1). 1H NMR
(400 MHz, [D6]DMSO): δ = 7.38–7.27 (m, 15 H, CH, arom.), 4.81
(d, J = 11.1 Hz, 1 H, CH2Ph), 4.72 (s, 1 H, 1a-H), 4.68–4.53 (m, 7
= 9.8 Hz, 1 H, 5-H), 3.56 (d, J1a,1b = 11.8 Hz, 1 H, 1b-H) ppm. 13
NMR (125.8 MHz, D2O): δ = 98.2 (C-2), 82.4 (JC,F = 167.6 Hz, C-
C
7), 71.8 (JC,F = 17.5 Hz, C-6), 70.8 (C-4), 69.7 (C-3), 65.6 (JC,F
=
7.0 Hz, C-5), 63.8 (C-1) ppm. 19F NMR (376 MHz, D2O/H2O, 4:1):
δ = –237.2 (dt, J6,F = 26.0, J7,F = 48.0 Hz) ppm. HRMS (ESI):
calcd. for C7H13FO6 [M + Na]+ 235.0588; found 235.0590.
4,5,7-Tri-O-benzyl-1,3-dideoxy-1,3-difluoro-α-D-glycero-D-lyxo-
hept-2-ulopyranose (35): For fluorination of 12 (300 mg, 669 μmol),
5 (2.37 g, 6.69 mmol) in DMF/H2O (10 mL) was used according to
H, 1b-H, 7-H, CH2Ph), 4.40 (d, J = 12.2 Hz, 1 H, CH2Ph), 4.32 GP1. After stirring overnight and work up, the crude residue was
(d, J3,4 = 3.1 Hz, 1 H, 3-H), 3.93 (dd, J4,5 = 8.6, J5,6 = 9.0 Hz, 1
H, 5-H), 3.76 (dd, J3,4 = 3.1, J4,5 = 8.6 Hz, 1 H, 4-H), 3.69 (dddd,
J5,6 = 9.0, J6,7a = 2.5, J6,7b = 5.0, J6,F = 26.7 Hz, 1 H, 6-H) ppm.
13C NMR (100.6 MHz, [D6]DMSO): δ = 154.6 (C-2), 138.3, 138.2,
purified by column chromatography (PE/Et2O, 1:1) to obtain pure
35 (238 mg, 492 μmol) as a colourless oil in 74% yield. [α]3D0 = +37.0
1
(c = 0.71, CHCl3), Rf = 0.24 (PE/Et2O, 2:1). H NMR (500 MHz,
[D6]DMSO): δ = 7.39–7.26 (m, 13 H, CH, arom.), 7.21–7.18 (m, 2
138.1 (Cq, arom.), 128.2, 127.8, 127.5, 127.4, 127.4 (CH, arom.), H, CH, arom.), 7.06 (d, JOH,F = 3.9 Hz, 1 H, C2OH), 4.85 (dd, J3,4
98.3 (C-1), 82.2 (JC,F = 170.5 Hz, C-7), 80.0 (C-4), 78.1 (JC,F
=
= 1.5, J3,F = 51.5 Hz, 1 H, 3-H), 4.78 (d, J = 11.5 Hz, 1 H, CH2Ph),
4.76 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.63 (d, J = 11.9 Hz, 1 H,
18.0 Hz, C-6), 73.9 (C-3), 73.8 (CH2Ph), 72.6 (JC,F = 7.1 Hz, C-5),
70.2, 69.3 (CH2Ph) ppm. 19F NMR (200 MHz, [D6]DMSO): δ = CH2Ph), 4.52 (d, J = 11.8 Hz, 1 H, CH2Ph), 4.50 (d, J = 11.5 Hz,
–229.7 (dt, J6,F = 26.7, J7,F = 47.6 Hz) ppm. HRMS (ESI): calcd.
for C28H29FO4 [M + H]+ 449.2123; found 449.2115; [M + Na]+
471.1942; found 471.1939; [M + K]+ 487.1681; found 487.1676.
1 H, CH2Ph), 4.46 (d, J = 11.8 Hz, 1 H, CH2Ph), 4.45 (ddd, J1a,1b
= 9.6, J1a,F = 1.3, J1a,F = 46.7 Hz, 1 H, 1a-H), 4.26 (ddd, J1a,1b
9.6, J1b,F = 2.6, J1b,F = 46.7 Hz, 1 H, 1b-H), 3.89 (ddd, J3,4 = 1.5,
=
Eur. J. Org. Chem. 2012, 948–959
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
957

D. Waschke, Y. Leshch, J. Thimm, U. Himmelreich, J. Thiem
FULL PAPER
J4,5 = 9.7, J4,F = 28.9 Hz, 1 H, 4-H), 3.87 (ddd, J5,6 = 9.8, J6,7a
4.8, J6,7b = 1.6 Hz, 1 H, 6-H), 3.69 (dd, J4,5 = 9.7, J5,6 = 9.8 Hz, 1
=
[α]2D3 = +22.2 (c = 0.23, H2O). 1H NMR (400 MHz, D2O): δ = 4.76
(ddd, J6,7a = 4.1, J7a,7b = 10.7, J7a,F = 48.0 Hz, 1 H, 7a-H), 4.67
H, 5-H), 3.65 (dd, J6,7a = 4.8, J7a,7b = 11.0 Hz, 1 H, 7a-H), 3.60 (ddd, J6,7b = 1.5, J7a,7b = 10.7, J7b,F = 48.0 Hz, 1 H, 7b-H), 4.61
(dd, J6,7b = 1.6, J7a,7b = 11.0 Hz, 1 H, 7b-H) ppm. 13C NMR (dd, J1a,1b = 9.7, J1a,F = 46.8 Hz, 1 H, 1a-H), 4.39 (dd, J1a,1b = 9.7,
(125.8 MHz, [D6]DMSO): δ = 138.3, 138.2, 138.1 (Cq, arom.),
J1b,F = 46.8 Hz, 1 H, 1b-H), 3.98 (dd, J3,4 = 3.3, J4,5 = 9.4 Hz, 1
H, 4-H), 3.97 (dddd, J5,6 = 9.8, J6,7a = 4.1, J6,7b = 1.5, J6,F
28.1 Hz, 1 H, 6-H), 3.96 (d, J3,4 = 3.3 Hz, 1 H, 3-H), 3.78 (dd, J4,5
128.2, 128.2, 127.8, 127.7, 127.5, 127.5 (CH, arom.), 94.7 (JC,F
25.1, 47.8 Hz, C-2), 85.4 (JC,F = 178.1 Hz, C-3), 82.7 (JC,F
=
=
=
170.1 Hz, C-1), 77.8 (JC,F = 17.1 Hz, C-4), 74.2 (CH2Ph), 74.0 (C- = 9.4, J5,6 = 9.8 Hz, 1 H, 5-H) ppm. 13C NMR (100.6 MHz, D2O):
5), 72.2 (CH2Ph), 71.2 (C-6), 70.5 (CH2Ph), 68.7 (C-7) ppm. 19F
δ = 97.0 (JC,F = 20.6 Hz, C-2), 84.1 (JC,F = 176.6, C-1), 82.4 (JC,F
= 175.7 Hz, C-7), 72.1 (JC,F = 17.4 Hz, C-6), 70.5 (C-4), 69.6 (C-
3), 65.5 (JC,F = 7.0 Hz, C-5) ppm. 19F NMR (376 MHz, D2O/H2O,
4:1): δ = –238.1 (dt, J6,F = 28.1, J7,F = 48.0 Hz, C7-F), –240.9 (t,
J1,F = 46.8 Hz, C1-F) ppm. HRMS (ESI): calcd. for C7H12F2O5 [M
+ H]+ 215.0726; found 215.0720.
NMR (200 MHz, [D6]DMSO): δ = –206.5 (ddd, J3,F = 51.5, J4,F
=
28.9, J5,F = 6.7 Hz, C3-F), –232.4 (t, J1,F = 46.7 Hz, C1-F) ppm.
HRMS (ESI): calcd. for C28H30F2O5 [M + H]+ 485.2134; found
485.2149; [M + Na]+ 507.1954; found 507.1983.
1,3-Dideoxy-1,3-difluoro-α-D-glycero-D-lyxo-hept-2-ulopyranose
(36): Compound 35 (220 mg, 454 μmol) and methanol (10 mL)
were used according to GP2. The reaction time was 7 d, and the
residue was subjected to column chromatography (RP18, H2O) to
obtain pure 36 (91.7 mg, 428 μmol) as a colourless solid in 94%
yield. [α]2D8 = +43.3 (c = 0.27, H2O), m.p. 156–157 °C. 1H NMR
(500 MHz, D2O): δ = 4.80 (dd, J3,4 = 2.4, J3,F = 50.3 Hz, 1 H, 3-
H), 4.62 (ddd, J1a,1b = 9.9, J1a,F = 1.6, J1a,F = 46.3 Hz, 1 H, 1a-
H), 4.40 (ddd, J1a,1b = 9.9, J1b,F = 3.2, J1b,F = 46.3 Hz, 1 H, 1b-
H), 4.03 (ddd, J3,4 = 2.4, J4,5 = 9.7, J4,F = 30.6 Hz, 1 H, 4-H), 3.90–
3.85 (m, 2 H, 6-H, 7a-H), 3.82 (dd, J6,7b = 5.7, J7a,7b = 12.8 Hz, 1
H, 7b-H), 3.75 (dd, J4,5 = 9.7, J5,6 = 9.4 Hz, 1 H, 5-H) ppm. 13C
NMR (100.6 MHz, D2O): δ = 89.2 (JC,F = 176.3, 1.7 Hz, C-3), 83.4
(JC,F = 169.8, 4.6 Hz, C-1), 73.3 (C-6), 69.9 (JC,F = 17.5 Hz, C-4),
66.6 (JC,F = 1.6 Hz, C-5), 60.5 (C-7) ppm. 19F NMR (376 MHz,
D2O/H2O, 4:1): δ = –213.4 (dd, J3,F = 50.3, J4,F = 30.6 Hz, C3-
F), –239.7 (t, J1,F = 46.3 Hz, C1-F) ppm. HRMS (ESI): calcd. for
C7H12F2O5 [M + Na]+ 237.0545; found 237.0545.
4,5,7-Tri-O-benzyl-1,3-dideoxy-1-fluoro-α-D-glycero-D-xylo-hept-2-
ulopyranose (40): For fluorination of 39 (150 mg, 349 μmol), 5
(1.24 g, 3.49 mmol) in DMF/H2O (6 mL) was used according to
GP1. After stirring overnight and work up, the crude residue was
purified by column chromatography (PE/Et2O, 2:1) to obtain pure
40 (123 mg, 264 μmol) as a colourless oil in 76% yield. [α]2D4 = +34.7
1
(c = 0.32, CHCl3), Rf = 0.15 (PE/Et2O, 2:1). H NMR (400 MHz,
[D6]DMSO): δ = 7.38–7.24 (m, 13 H, CH, arom.), 7.23–7.17 (m, 2
H, CH, arom.), 6.24 (d, JOH,F = 1.2 Hz, 1 H, C2OH), 4.81 (d, J =
11.1 Hz, 1 H, CH2Ph), 4.65 (d, J = 11.6 Hz, 1 H, CH2Ph), 4.54 (d,
J = 11.6 Hz, 1 H, CH2Ph), 4.53–4.50 (m, 2 H, CH2Ph), 4.46 (d, J
= 12.1 Hz, 1 H, CH2Ph), 4.22 (dd, J1a,1b = 9.0, J1a,F = 47.8 Hz, 1
H, 1a-H), 4.18 (dd, J1a,1b = 9.0, J1b,F = 47.8 Hz, 1 H, 1b-H), 3.90
(ddd, J3ax,4 = 4.9, J3eq,4 = 11.3, J4,5 = 8.9 Hz, 1 H, 4-H), 3.84 (ddd,
J5,6 = 9.8, J6,7a = 4.6, J6,7b = 1.7 Hz, 1 H, 6-H), 3.65 (dd, J6,7a
4.6, J7a,7b = 10.7 Hz, 1 H, 7a-H), 3.59 (dd, J6,7b = 1.7, J7a,7b
10.7 Hz, 1 H, 7b-H), 3.41–3.35 (m, 1 H, 5-H), 2.24 (dd, J3ax,3eq
12.6, J3ax,4 = 4.9 Hz, 1 H, 3ax-H), 1.49 (dd, J3ax,3eq = 12.6, J3eq,4
=
=
=
=
3,4,5-Tri-O-benzyl-1,7-dideoxy-1,7-difluoro-α-D-glycero-D-lyxo-
11.3 Hz, 1 H, 3eq-H) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ
= 138.8, 138.5, 138.2 (Cq, arom.), 128.2, 128.2, 128.1, 127.8, 127.6,
127.5, 127.4, 127.4, 127.3 (CH, arom.), 94.9 (JC,F = 20.0 Hz, C-2),
86.2 (JC,F = 175.1 Hz, C-1), 78.0 (C-5), 77.0 (C-4), 73.9, 72.2
(CH2Ph), 71.2 (C-6), 70.2 (CH2Ph), 69.1 (C-7), 35.4 (JC,F = 7.1 Hz,
hept-2-ulopyranose (37): For fluorination of 32 (160 mg, 357 μmol),
5 (1.10 g, 3.11 mmol) in DMF/H2O (3 mL) was used according to
GP1. After stirring overnight and work up, the crude residue was
purified by column chromatography (PE/Et2O, 2:1) to obtain pure
37 (135 mg, 279 μmol) as a colourless oil in 78% yield. [α]2D4 = +21.1
C-3) ppm. 19F NMR (200 MHz, [D6]DMSO): δ = –225.9 (t, J1,F
=
1
(c = 0.55, CHCl3), Rf = 0.47 (PE/Et2O, 1:1). H NMR (500 MHz,
47.8 Hz) ppm.
[D6]DMSO): δ = 7.42–7.25 (m, 15 H, CH, arom.), 6.75 (s, 1 H,
C2OH), 4.85–4.79 (m, 3 H, CH2Ph), 4.66 (d, J = 11.9 Hz, 1 H,
CH2Ph), 4.60 (d, J = 11.2 Hz, 1 H, CH2Ph), 4.58 (d, J = 10.9 Hz,
1 H, CH2Ph), 4.55 (ddd, J6,7a = 4.1, J7a,7b = 10.7, J7a,F = 47.9 Hz,
1 H, 7a-H), 4.49 (ddd, J6,7b = 1.3, J7a,7b = 10.7, J7b,F = 47.9 Hz, 1
H, 7b-H), 4.48 (dd, J1a,1b = 9.1, J1a,F = 47.0 Hz, 1 H, 1a-H), 4.20
(dd, J1a,1b = 9.1, J1b,F = 47.0 Hz, 1 H, 1b-H), 4.01 (dd, J3,4 = 2.3,
J4,5 = 9.5 Hz, 1 H, 4-H), 4.00 (d, J3,4 = 2.3 Hz, 1 H, 3-H), 3.85
(dddd, J5,6 = 9.5, J6,7a = 4.1, J6,7b = 1.3, J6,F = 28.2 Hz, 1 H, 6-
H), 3.75 (dd, J4,5 = 9.5, J5,6 = 9.5 Hz, 1 H, 5-H) ppm. 13C NMR
(125.8 MHz, [D6]DMSO): δ = 138.5, 138.5, 138.3 (Cq, arom.),
128.3, 128.2, 128.2, 127.7, 127.7, 127.6, 127.5, 127.5, 127.5 (CH,
arom.), 96.5 (JC,F = 22.7 Hz, C-2), 83.4 (JC,F = 169.4, C-1), 82.5
(JC,F = 169.9 Hz, C-7), 80.1 (C-4), 74.8 (C-3), 74.2, 74.1 (CH2Ph),
73.4 (JC,F = 6.8 Hz, C-5), 71.0 (CH2Ph), 70.9 (JC,F = 17.7 Hz, C-
1,3-Dideoxy-1-fluoro-α-D-glycero-D-xylo-hept-2-ulopyranose (41):
Compound 40 (90.0 mg, 193 μmol) and methanol (10 mL) were
used according to GP2. The reaction time was 24 h, and the residue
was subjected to column chromatography (RP18, H2O) to obtain
pure 41 (36.0 mg, 184 μmol) as a colourless solid in 95% yield.
[α]2D3 = +39.0 (c = 0.17, H2O). 1H NMR (500 MHz, D2O): δ = 4.36
(d, J1,F = 46.7 Hz, 2 H, H-1), 4.00 (ddd, J3ax,4 = 11.7 Hz, J3eq,4
5.1 Hz, J4,5 = 9.3 Hz, 1 H, H-4), 3.90–3.80 (m, 3 H, H-6, H-7), 3.41
(dd, J4,5 = 9.3 Hz, J5,6 = 9.8 Hz, 1 H, H-5), 2.17 (dd, J3ax,3eq
=
=
13.2 Hz, J3eq,4 = 5.1 Hz, 1 H, H-3eq), 1.71 (dd, J3ax,3eq = 13.2 Hz,
J3ax,4 = 11.7 Hz, 1 H, H-3ax) ppm. 13C NMR (125.8 MHz, D2O):
δ = 95.6 (JC,F = 19.1 Hz, C-2), 86.3 (JC,F = 173.7 Hz, C-1), 73.2
(C-6), 70.8 (C-5), 68.5 (C-4), 60.6 (C-7), 36.8 (C-3) ppm. 19F NMR
(376 MHz, D2O/H2O, 4:1): δ = –233.4 (t, J1,F = 46.7 Hz) ppm.
HRMS (ESI): calcd. for C7H13FO5 [M + Na]+ 219.0639; found
219.0642; [M + K]+ 235.0379; found 235.0299.
6) ppm. 19F NMR (200 MHz, [D6]DMSO): δ = –230.1 (dt, J6,F
=
28.2, J7,F = 47.9 Hz, C7-F), –231.9 (t, J1,F = 47.0 Hz, C1-F) ppm.
HRMS (ESI): calcd. for C28H30F2O5 [M + Na]+ 507.1954; found
507.1959; [M + K]+ 523.1693; found 523.1699.
CCDC-840082 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
1,7-Dideoxy-1,7-difluoro-α-D-glycero-D-lyxo-hept-2-ulopyranose
(38): Compound 37 (100 mg, 207 μmol) and methanol (10 mL)
were used according to GP2. The reaction time was 48 h, and the
residue was subjected to column chromatography (RP18, H2O) to
obtain pure 38 (43.1 mg, 201 μmol) as a colourless oil in 97% yield.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra of all key compounds.
958
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 948–959

Fluorinated Ketoheptoses as Specific Diagnostic Agents
Res. 2009, 2, 1–10; c) J. E. Mortimer, M. E. Taylor, Breast Can-
cer Res. 2003, 5, 239–331.
Acknowledgments
[18] a) E. M. Bessell, A. B. Foster, J. H. Westwood, Biochem. J.
1972, 128, 199–204; b) E. M. Bessell, V. D. Courtenay, A. B.
Foster, M. Jones, J. H. Westwood, Eur. J. Cancer 1973, 9, 463–
470.
[19] a) J. E. G. Barnett, Biochem. J. 1971, 123, 607–611; b) S. J. Wil-
liams, S. G. Withers, Carbohydr. Res. 2000, 327, 27–46.
[20] a) D. Waschke, J. Thimm, J. Thiem, Org. Lett. 2011, 13, 3628–
3631; b) Y. Leshch, D. Waschke, J. Thimm, J. Thiem, Synthesis
2011, 3871–3877.
[21] a) N. A. Petasis, E. I. Bzowej, J. Am. Chem. Soc. 1990, 112,
6392–6394; b) R. Csuk, B. I. Glänzer, Tetrahedron 1991, 47,
1655–1664.
[22] H. Siebeneicher, S. Doye, J. Prakt. Chem. 2000, 342, 102–106.
[23] a) P. T. Nyffeler, S. Gonzales Durón, M. D. Burkart, S. P. Vin-
cent, C.-H. Wong, Angew. Chem. 2005, 117, 196; Angew. Chem.
Int. Ed. 2005, 44, 192–212; b) M. D. Burkart, Z. Zhang, S.-C.
Hung, C.-H. Wong, J. Am. Chem. Soc. 1997, 119, 11743–11746;
c) M. Albert, K. Dax, J. Ortner, Tetrahedron 1998, 54, 4839–
4848.
We thank the European Union (EU) (grant number FP7-NMP-
228933-VIBRANT) for financial support. Preliminary A549-cell
toxicity tests were performed by C. Schlundt, CAN GmbH, Ham-
burg, Germany.
[1] a) J. H. Roe, C. S. Hudson, J. Biol. Chem. 1936, 112, 443–449;
b) E. Simon, P. F. Kraicer, Arch. Biochem. Biophys. 1957, 69,
592–601.
[2] a) E. P. Paulsen, L. Richenderfer, P. Winick, Nature 1967, 214,
276–277; b) H. G. Coore, P. J. Randle, Biochem. J. 1964, 91,
56–59.
[3] E. P. Paulsen, Ann. N. Y. Acad. Sci. 1968, 150, 455–456.
[4] M. Board, A. Colquhoun, E. A. Newsholme, Cancer Res. 1995,
55, 3278–3285.
[5] W. J. Malaisse, Diabetologia 2001, 44, 393–406.
[6] a) H. G. Coore, P. J. Randle, Biochem. J. 1964, 91, 56–59; b) D.
Zelent, H. Najafi, S. Odili, C. Buettger, H. Weik-Collins, C. Li,
N. Doliba, J. Grimsby, F. M. Matschinsky, Biochem. Soc.
Trans. 2005, 33, 306–310; c) W. J. Malaisse, M. A. Lea, F. Ma-
laisse-Lagae, Metabolism 1968, 17, 126–132; d) L. Z. Xu, I. T.
Weber, R. W. Harrison, M. Gidh-Jain, S. J. Pilkins, Biochemis-
try 1995, 34, 6083–6092.
[24] J. D. Albright, L. Goldman, J. Am. Chem. Soc. 1965, 87, 4214–
4216.
[25] a) E. N. Jacobsen, I. Marko, W. S. Mungall, G. Schroeder,
K. B. Sharpless, J. Am. Chem. Soc. 1988, 110, 1968–1970; b)
H. C. Kolb, M. S. van Nieuwenhze, K. B. Sharpless, Chem.
Rev. 1994, 94, 2483–2547; c) M. Minato, K. Yamamoto, J.
Tsuji, J. Org. Chem. 1990, 55, 766–768.
[7] W. J. Malaisse, P. Courtois, M. M. Kadiata, A. Sener, Diabetes
2000, 49, A418.
[8] a) N. R. Simpson, F. Souza, P. Witkowski, A. Maffei, A. Raffo,
A. Herron, M. Kilbourn, A. Jurewicz, K. Herold, E. Liu,
M. A. Hardy, R. Van Heertum, P. E. Harris, Nucl. Med. Biol.
2006, 33, 855–864; b) B. Wängler, S. Schneider, O. Thews, E.
Schirrmacher, S. Comagica, P. Feilen, C. Schwanstecher, M.
Schwanstecher, C.-Y. Shiue, A. Alavi, S. Höhnemann, M. Piel,
F. Rösch, R. Schirrmacher, Nucl. Med. Biol. 2004, 31, 639–647;
c) C. Kargar, A. Ktorza, Diabetes Obes. Metab. 2008, 10, 43–
53; d) S. E. Kahn, R. L. Hull, K. M. Utzschneider, Nature
2006, 444, 840–846.
[9] W. J. Malaisse, K. Louchami, A. Sener, Nat. Rev. Endocrinol.
2009, 5, 394–400.
[10] a) International Diabetes Federation, IDF Diabetes Atlas, 4th
edition, International Diabetes Federation, Brussels, 2009; b)
S. Wild, G. Roglic, A. Green, R. Sicree, H. King, Diabetes Care
2004, 5, 1047–1053.
[26] M. Martín-Lomas, N. Khiar, S. García, J.-L. Koessler, P. M.
Nieto, T. W. Rademacher, Chem. Eur. J. 2000, 6, 3608–3621.
[27] A. T. Khan, E. Mondal, Synlett 2003, 5, 694–698.
[28] a) G. S. Lal, G. P. Pez, R. J. Pesaresi, F. M. Prozonic, Chem.
Commun. 1999, 215–216; b) G. S. Lal, G. P. Pez, R. J. Pesaresi,
F. M. Prozonic, H. Cheng, J. Org. Chem. 1999, 64, 7048–7054.
[29] S. Juers, J. Thiem, J. Carbohydr. Chem. 2009, 28, 293–297.
[30] a) J. Otera, N. Dan-oh, H. Nozaki, J. Org. Chem. 1991, 56,
5307–5311; b) A. Orita, Y. Hamada, T. Nakano, S. Toyoshima,
J. Otera, Chem. Eur. J. 2001, 7, 3321–3327.
[31] a) K. B. Starowieyski, J. Lewinski, R. Wozniak, J. Lipkowski,
A. Chrost, Organometallics 2003, 22, 2458–2463; b) S. A. Kan-
dil, A. L. Allred, J. Chem. Soc. A 1970, 2987–2992; c) H. Puff,
W. Schuh, R. Sievers, W. Wald, R. Zimmer, J. Organomet.
Chem. 1984, 260, 271–280; d) H. Puff, H. Hevendehl, K. Höfer,
H. Reuter, W. Schuh, J. Organomet. Chem. 1985, 287, 163–178.
[32] a) W. Choong, N. C. Stephenson, J. D. Stevens, Cryst. Struct.
Commun. 1975, 4, 491–496; b) W. J. Middleton, J. Org. Chem.
1975, 40, 574–578.
[11] a) G. W. Gould, G. I. Bell, Trends Biochem. Sci. 1990, 15, 18–
23; b) S. U. Devaskar, M. M. Mueckler, Pediatr. Res. 1992, 31,
1–13.
[12] a) M. Srinivas, P. A. Morel, L. A. Ernst, D. H. Laidlaw, E. T.
Ahrens, Magnet. Reson. Med. 2007, 58, 725–734; b) T. Nakada,
I. L. Kwee, P. J. Card, M. A. Matwiyoff, B. V. Griffey, R. H.
Griffey, Magnet. Reson. Med. 1988, 6, 307–313; c) J. M. Janjic,
M. Srinivas, D. K. K. Kadayakkara, E. T. Ahrens, J. Am.
Chem. Soc. 2008, 130, 2832–2841; d) M. Srinivas, L. J. Cruz,
F. Bonetto, A. Heerschap, C. G. Figdor, I. J. M. de Vries, Bio-
materials 2010, 27, 7070–7077.
[13] a) H. Peng, I. Blakey, B. B. Dargaville, F. Rasoul, S. Rose, A. K.
Whittaker, Biomacromolecules 2009, 10, 374–381; b) Z.-X. Ji-
ang, X. Liu, E.-K. Jeong, B. Y. Yihua, Angew. Chem. 2009,
121, 4849; Angew. Chem. Int. Ed. 2009, 48, 4755–4758; c) U.
Himmelreich, T. Dresselærs, Methods 2009, 48, 112–124.
[14] A. Sols, R. K. Crane, J. Biol. Chem. 1954, 210, 581–595.
[15] L. Sokoloff, M. Reivich, C. Kennedy, M. H. Des Rosiers, C. S.
Patlak, K. D. Pettigrew, O. Sakurada, M. Shinohara, J. Neuro-
chem. 1977, 28, 897–916.
[33] a) G. Zemplén, Ber. Dtsch. Chem. Ges. 1926, 59, 1254–1266; b)
G. Zemplén, E. Pacsu, Ber. Dtsch. Chem. Ges. 1929, 62, 1613–
1614.
[34] a) A. Kamal, Y. Haider, R. Arkhtar, A. A. Qureshi, Pak. J. Sci.
Ind. Res. 1971, 14, 63–67; b) A. Kamal, Y. Haider, A. A. Qure-
shi, Pak. J. Sci. Ind. Res. 1971, 14, 68–70.
[35] a) A. V. Ratner, S. Quay, H. H. Muller, B. B. Simpson, R.
Hurd, S. W. Young, Invest. Radiol. 1989, 24, 227–227; b) H.
Lee, R. R. Price, G. E. Holburn, C. L. Partain, M. D. Adams,
W. P. Cacheris, Magnet. Reson. Imaging 1994, 4, 609–613.
[36] Y. Kanazawa, Y. Monozono, M. Ishikawa, T. Yamada, H. Ya-
mane, T. Haradahira, M. Maeda, M. Kojima, Life Sci. 1986,
39, 737–742.
[37] L. Somsák, I. Németh, J. Carbohydr. Chem. 1993, 12, 679–684.
[38] T. Kametani, K. Kawamura, T. Honda, J. Am. Chem. Soc.
1987, 109, 3010–3017.
[39] H. E. Gottlieb, V. Kotlyar, A. Nudelman, J. Org. Chem. 1997,
62, 7512–7515.
[16] B. M. Gallagher, J. S. Foweler, N. I. Gutterson, R. R. Mac-
Gregor, C.-N. Wan, A. D. Wolf, J. Nucl. Med. 1978, 19, 1154–
1161.
[40] D. Crich, O. Vinogradova, J. Am. Chem. Soc. 2007, 129, 11756–
11765.
[17] a) H. Jadvar, Nat. Rev. Urol. 2009, 6, 317–323; b) Y. Yoshida,
Received: August 24, 2011
Published Online: December 21, 2011
T. Kurokawa, T. Tsujikawa, H. Okazawa, F. Kotsuji, J. Ovonic
Eur. J. Org. Chem. 2012, 948–959
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
959