D-Gluco-hept-2-ulose and novel deoxyfluoro derivatives as seven-carbon analogues of F-deoxy-d-glucose (FDG)

Article abstract of DOI:10.1055/s-0031-1289598

Ketoheptoses, seven-carbon sugars, were recognized to display pharmacological properties that are potentially suitable for in vivo diagnostic of diabetes and cancers using ¹⁹F-MRI. The present paper describes efficient syntheses towards ketoheptoses and exemplary a series of regioisomeric fluoro derivatives of d-gluco-hept-2-ulose. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1289598

PAPER
3871
D-Gluco-hept-2-ulose and Novel Deoxyfluoro Derivatives as Seven-Carbon
Analogues of F-Deoxy-D-glucose (FDG)
Yevgeniy Leshch, Daniel Waschke, Julian Thimm, Joachim Thiem*
University of Hamburg, Faculty of Science, Department of Chemistry, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Fax +49(40)428384325; E-mail: thiem@chemie.uni-hamburg.de
Received 24 August 2011; revised 26 September 2011
tient. However, there are a number of false positives due
to infection and inflammation or undetected and early
stage tumors – not showing a significant higher metabolic
rate.8 Realization of current limitations of contrast agents
Abstract: Ketoheptoses, seven-carbon sugars, were recognized to
display pharmacological properties that are potentially suitable for
in vivo diagnostic of diabetes and cancers using 19F-MRI. The
present paper describes efficient syntheses towards ketoheptoses
and exemplary a series of regioisomeric fluoro derivatives of D-glu- leads to the search for ‘smarter’ highly specific, nontoxic
co-hept-2-ulose.
MRI contrast agents.
Key words: ketoheptose, fluoro D-glucoheptulose, Petasis reagent,
Selectfluor, C1 chain elongation
Rare naturally occurring ketoheptoses were isolated from
plants early on and their physiological properties studied.9
In 1970 and 1972, Nelkin showed the potential diabetoge-
nic properties of D-manno- or D-gluco-hept-2-ulose in rats
after injection-induced hyperglycemia.10 Other groups
proposed their use in anticancer treatment.11 The mecha-
nism is considered to be caused via their uptake by a sugar
transporter (GLUT2 receptor) leading to an inhibition of
glucose metabolism and insulin secretion, which in turn is
likely due to an inhibition of hexokinase isoenzymes. Re-
gioisomeric fluorinated ketoheptoses do not only allow
for 19F MRI detection, but the study of mechanistic as-
pects and metabolic fate in vivo. This approach enables
organ and tissue specific contrast agent fine tuning.10–12
Synthetic access to ketoheptoses and their derivatives has
been largely disregarded due to the complexity of a C1 ex-
tended anomeric position of hexoses. However, due to
their structural resemblance to hexoses the synthesis of
heptoses represents a promising target. The present work
describes the synthesis of five regioisomeric fluorinated
D-gluco-hept-2-ulose starting from D-glucose. Key step in
the synthesis of ketoheptoses is the C1 chain elongation of
hexoses followed by their bishydroxylation. The exocy-
clic enol ether is a key intermediate for further derivatiza-
tion controlled by suitable protecting group schemes
(Scheme 1).
Understanding the course of diseases is commonly ap-
proached by monitoring the progression of changes in the
system. Most problematic hereby is the choice of an effec-
tive diagnostic marker. Therefore, in vivo diagnostic in
humans remains a challenging task that has to be tailored
for each disease and in future potentially for every pa-
tient.1,2 A number of invasive (e.g., surgery, biopsy) and
noninvasive techniques (PET, MRI, CT) are in clinical
use to date. However, access to nontoxic smart markers
showing high sensitivity as contrast agents and the ability
to specifically target at molecular level are scarce.3
Since carbohydrates play an integral role in animals and
plants, even slightest dysfunctions in the machinery re-
sponsible for sugar transport and metabolism are involved
in a number of major diseases such as diabetes and can-
cer.4 Others involve the presence or absence of carbohy-
drates moieties indicating tumor as well as pathogen
activity.5
Hence it is no surprise that functionalized carbohydrates
are used and are promising markers for quantitative and
qualitative monitoring of modulated or distorted carbohy-
drate uptake and metabolism activity. With respect to car-
bohydrate based contrast agents, tracers like 2-18F-deoxy-
D-glucose as well as other 18F-deoxy-D-glucoses are fre-
quently used, and [18F]fluoroazomycin-arabinofuranoside
(FAZA) is fairly new in positron emission tomography
(PET) scanning.6 Due to undesired toxicity and short half-
life, a shift from 18F-PET to NMR based 19F-MRI or com-
bination techniques are currently under evaluation.7 Since
glucose is ubiquitously present FDG (F-deoxy-D-glucose)
application is based on the rationale that, for example, in
some cancer types, tumorous cells show a spatially cen-
tered relatively higher glucose metabolism in a fasting pa-
O
O
O
(F)n
R
X
R
(OH)m
OH
key intermediate
X = OH, F
m = 3, 4; n = 4–m .
Scheme 1 Generalized pathway towards ketoheptoses and fluoro-
ketoheptoses via the exocyclic enol ether key intermediate allowing
for functionalization
As an example, the synthesis of regioisomer fluoro-D-
gluco-hept-2-ulose is presented. Using the exocyclic enol
ether 1, our group13 reported recently on bishydroxylation
reaction that leads to D-gluco-hept-2-ulose (2). For the
synthesis of 1-deoxy-1-fluoro-D-gluco-hept-2-ulose (4),
SYNTHESIS 2011, No. 23, pp 3871–3877
x
x.
x
x
.
2
0
1
1
Advanced online publication: 09.11.2011
DOI: 10.1055/s-0031-1289598; Art ID: T83811SS
© Georg Thieme Verlag Stuttgart · New York

3872
Y. Leshch et al.
PAPER
the exocyclic enol ether 1 was first fluorinated using Se-
lectfluor.13,14 The regioselective introduction of fluorine
occurred via electrophilic addition of a cationic fluorine to
the double bond of the exocyclic ether 1 and afforded 3 in
65% yield. Exclusively the a-anomer was formed, as con-
firmed by NOESY experiments. Debenzylation of 3 with
palladium(II) hydroxide in MeOH and EtOAc gave 1-
deoxy-1-fluoro-a-D-gluco-hept-2-ulopyranose (4) in
quantitative yield (Scheme 2).
BnO
O
BnO
BnO
5
i
BnO
BnO
BnO
BnO
BnO
BnO
F
O
O
F
+
OH
OH
6
7
ii
HO
O
HO
HO
BnO
BnO
BnO
BnO
BnO
BnO
iii
O
O
OH
HO
OH
2
O
F
F
8
9
iii
i
Scheme 3 Reagents and conditions: (i) Selectfluor, DMF, H2O, r.t.,
12 h, 6: 44%, 7: 33% (ii) Ac2O, DMSO, 30 °C, 24 h, 85%; (iii) Petasis
reagent, toluene, 75 °C, 24 h, 70%.
BnO
BnO
BnO
O
BnO
ii
1
HO
HO
HO
BnO
BnO
BnO
iii
O
F
O
F
BnO
BnO
BnO
HO
HO
HO
O
O
iii
OH
OH
OH
OH
10
11
F
F
BnO
HO
OH
OH
3
4
BnO
BnO
i
O
Scheme 2 Reagents and conditions: (i) K2CO3, K3[Fe(CN)6],
K2OsO2(OH)4, t-BuOH, H2O, r.t., 24 h (ii) Selectfluor, DMF, H2O,
r.t., 12 h, 65%; (iii) H2, Pd(OH)2/C, MeOH, EtOAc, 24 h, ~100%.
BnO
ii
F
9
HO
BnO
BnO
BnO
iii
F
O
3,4,6-Tri-O-benzyl-D-glucal (5) was prepared by the well-
known five-step procedure from D-glucose and served as
precursor for the preparation of 2-deoxysugars.15 Select-
fluor reacted with glucal 5 in the presence of water to give
the D-gluco-configured compound 6 (44%) as a ~2:1 ano-
O
HO
HO
F
F
F
OH
OH
12
13
Scheme 4 Reagents and conditions: (i) K2CO3, K3[Fe(CN)6],
meric mixture (determined by NMR spectroscopy) and K2OsO2(OH)4, t-BuOH, H2O, r.t., 24 h, 87%; (ii) Selectfluor, DMF,
H2O, r.t., 12 h, 75%; (iii) H2, Pd(OH)2/C, MeOH, EtOAc, r.t., 24 h,
the D-manno-configured compound 7 (33%), which could
be easily separated by column chromatography.13 Subse-
11: 92%, 13: 86%.
quently, 6 was oxidized to the related lactone 8 using
DMSO and acetic anhydride at room temperature accord-
of 17 using NBS in acetone and water afforded the desired
hemiacetal 18.21 Oxidation of 18 to the related lactone 19
using DMSO/acetic anhydride at room temperature was
conducted according to the Albright–Goldman proce-
dure.16 Finally, methylenation of 19 led to 2,6-anhydro-
3,4,5-tri-O-benzyl-1,7-dideoxy-7-fluoro-D-gluco-hept-1-
enitol (20) (Scheme 5).
ing to the Albright–Goldman procedure.16 Petasis reagent
(Me2TiCp2) was used17 for methylenation of the lactone 8
and gave the C1 elongated 9 in 70% yield (Scheme 3). In
a likewise manner the manno-configured precursor 7
leads to the 3-deoxy-3-fluoro-D-manno-hept-2-ulose se-
ries (not shown).
Sharpless dihydroxylation18 and/or fluorination of 9 gave
either the 3-fluoro compound 10 and 1,3-difluoro com-
pound 12 as a-anomers as judged by NOESY experi-
ments. Finally, 10 and 12 were hydrogenated to furnish 3-
deoxy-3-fluoro-a-D-gluco-hept-2-ulopyranose (11) in
92% yield and 1,3-dideoxy-1,3-difluoro-a-D-gluco-hept-
2-ulopyranose (13) in 86% yield (Scheme 4).
Starting from 6-fluoro derivative 1419 the corresponding
thioglycoside 15 was obtained after glycosylation with
thiophenol in 80% yield. Deacetylation under Zemplén
conditions20a,b provided thiolglycoside 16 in 96% yield.
Perbenzylation gave 17 in 91% yield. Finally, hydrolysis
By following dihydroxylation and fluorination of 20,
3,4,5,-tri-O-benzyl-7-deoxy-7-fluoro-a-D-gluco-hept-2-
ulopyranose (21) and 3,4,5-tri-O-benzyl-1,7-deoxy-1,7-
difluoro-a-D-gluco-hept-2-ulopyranose (23) were ob-
tained as a-anomers in good yield (91% for 21, 74% for
23). The configuration of compound 21 and 23 were de-
duced from NOESY experiments. After hydrogenation of
21 and 23, 7-deoxy-7-fluoro-a-D-gluco-hept-2-ulopyra-
nose (22) and 1,7-deoxy-1,7-difluoro-a-D-gluco-hept-2-
ulopyranose (24) were obtained in 94% and 95% yield, re-
spectively (Scheme 6).
Synthesis 2011, No. 23, 3871–3877 © Thieme Stuttgart · New York

PAPER
Fluoro Derivatives of D-Gluco-hept-2-ulose
3873
points were measured on an Apotec capillary melting point appara-
tus and are uncorrected. Optical rotations were determined at 20 °C
using a Kruess P8000 polarimeter (589 nm, Na). HRMS-ESI was
performed on Agilent-6224-TOF ESI/MS and a Thermo Finnigan
MAT 95 XL.
for 17
F
F
iv
O
O
BnO
BnO
RO
X
RO
OH
BnO
OR
14 R = Ac, X = OAc
15 R = Ac, X = SPh
16 R = H, X = SPh
17 R = Bn, X = SPh
18
i
ii
iii
v
Fluorination; General Procedure 1 (GP 1)
F
The enol compound (1 equiv) was dissolved in DMF–H2O (1:1),
Selectfluor (1.5–10 equiv) was added, and the mixture was stirred
at r.t. for 12 h. After completion of the reaction, EtOAc (50 mL) was
added and the organic layer was washed with H2O (3 × 50 mL),
dried (Na2SO4) and the solvent removed in vacuo. The product was
isolated by column chromatography under the indicated conditions.
O
BnO
vi
BnO
Y
BnO
19 Y = O
20 Y = CH2
Scheme 5 Reagents and conditions: (i) BF3·OEt2, thiophenol,
CH2Cl2, 0 °C to r.t., 12 h, 80%; (ii) NaOMe, MeOH, r.t., 8 h, 96%;
(iii) NaH, Bu4NI, BnBr, DMF, r.t., 12 h, 91%; (iv) NBS, acetone,
H2O, r.t., 2 h, 83%; (v) Ac2O, DMSO, 30 °C, 24 h, 86%; (vi) Petasis
reagent, toluene, 75 °C, 24 h, 80%.
Hydrogenation; General Procedure 2 (GP 2)
The protected monosaccharide (1 equiv) was dissolved in MeOH–
EtOAc (1:1), a catalytic amount of 20% Pd(OH)2/C was added, and
the reaction mixture was stirred under a H2 for 24 h. The solution
was filtered and the solvent was removed in vacuo. The product was
isolated by column chromatography (RP-18, H2O).
F
F
O
O
iii
BnO
BnO
HO
HO
Dihydroxylation; General Procedure 3 (GP 3)
OH
OH
BnO
HO
OH
OH
The enol compound (1 equiv) was dissolved in t-BuOH-H2O (1:1),
and K2CO3 (3 equiv) and K3[Fe(CN)6] (3 equiv), and catalytic
amount of K2OsO2(OH)4 were added. The reaction mixture was
stirred at r.t. for 24 h. After completion, EtOAc (30 mL) and H2O
(30 mL) were added, the organic layer washed with H2O (3 × 30
mL), and dried (Na2SO4).The product was isolated by column chro-
matography (Et2O).
21
22
F
i
O
BnO
BnO
BnO
20
ii
3,4,5,7-Tetra-O-benzyl-1-deoxy-1-fluoro-a-D-gluco-hept-2-ulo-
pyranose (3)
F
F
O
O
iii
BnO
BnO
HO
HO
The synthesis was carried out according to GP 1 with 1 (500 mg,
0.93 mmol), DMF–H2O (15 mL), and Selectfluor (3.36 g, 9.3
mmol). After workup, the crude residue was purified by column
chromatography (PE–EtOAc, 2:1) to give 3 as a colorless oil; yield:
F
F
BnO
HO
OH
OH
23
24
25
343 mg (65%); [a]D +29.5 (c 0.55, CHCl3); Rf = 0.19 (PE–Et2O,
Scheme 6 Reagents and conditions: (i) K2CO3, K3[Fe(CN)6],
K2OsO2(OH)4, t-BuOH, H2O, r.t., 24 h, 91%; (ii) Selectfluor, DMF,
H2O, r.t., 12 h, 74%; (iii) H2, Pd(OH)2/C, MeOH, EtOAc, r.t., 24 h,
22: 94%, 24: 95%.
1:1).
1H NMR (400 MHz, DMSO-d6): d = 7.42–7.15 (m, 20 H, H-Ar),
6.50 (br s, 1 H, OH), 4.83–4.77 (m, 3 H, CH2Ph), 4.75 (d, J = 11.1
Hz, 1 H, CH2Ph), 4.59 (d, J = 11.1 Hz, 1 H, CH2Ph), 4.55 (d,
J = 12.0 Hz, 1 H, CH2Ph), 4.54 (d, J = 11.0 Hz, 1 H, CH2Ph), 4.48
(d, J = 12.0 Hz, 1 H, CH2Ph), 4.35 (dd, J1a,1b = 9.5 Hz, J1a,F = 47.5
Hz, 1 H, H-1a), 4.22 (dd, J1b,1a = 9.5 Hz, J1b,F = 47.5 Hz, 1 H, H-1b),
3.95 (dd, J4,3 = 9.3 Hz, J4,5 = 9.3 Hz, 1 H, H-4), 3.89 (ddd, J6,7b = 2.6
Hz, J6,7a = 4.5 Hz, J6,5 = 10.0 Hz, 1 H, H-6), 3.67 (dd, J7a,6 = 4.5 Hz,
J7a,7b = 10.9 Hz, 1 H, H-7a), 3.58 (dd, J7b,6 = 2.6 Hz, J7b,7a = 10.9 Hz,
1 H, H-7b), 3.55–3.46 (m, 2 H, H-3, H-5).
13C NMR (101 MHz, DMSO-d6): d = 138.6, 138.3, 138.2 (Cq-Ar),
128.2, 128.1, 127.8, 127.7, 127.6, 127.5, 127.4 (CH-Ar), 95.7
(JC,F = 18.5 Hz, C-2), 82.5 (JC,F = 178.3 Hz, C-1), 82.2 (C-4), 78.7
(C-3), 78.2 (C-5), 74.5, 74.4, 73.9, 72.3 (CH2Ph), 70.8 (C-6), 68.7
(C-7).
In conclusion, exocyclic enol ethers were obtained from
hexoses using a C1 chain elongation by Petasis reagent.
These key precursors could be employed for facile synthe-
sis of regioisomerically fluorinated compounds by Select-
fluor. Employing methods, which should be as well
applicable to other configurations, D-gluco-hept-2-ulose
and five novel mono- and difluorinated derivatives of D-
gluco-heptoses were synthesized in good yields. Their
ability to be selectively taken up via sugar transporters
and their use for 19F-MRI are under current investigation.
19F NMR (188 MHz, DMSO-d6): d = –226.2 (t, JF,1 = 47.5 Hz).
Commercially available starting materials were used without fur-
ther purification. All solvents used for the syntheses were purified
according to conventional procedures. Petroleum ether (PE) refers
to a hydrocarbon mixture with a boiling range of 50–70 °C. TLC
was carried out on aluminum sheets coated with silica gel 60
(Merck). For detection, TLC plates were treated with an alcoholic
solution of H2SO4, followed by heating. Flash column chromatog-
raphy was performed on silica gel 60 (40–63 mm; Merck) and silica
gel 60 RP-18 (40–63 mm; Merck). 1H and 13C NMR spectra were re-
corded on Bruker AMX 400, AC 400, DRX 500 spectrometers and
19F NMR spectra were recorded on a Varian Gemini-2000BB spec-
trometer with the residual solvent as the internal standard. Melting
HRMS-ESI: m/z [M + Na]+ calcd for C35H37FO6 + Na: 595.2466;
found: 595.2483; [M + K]+ 611.2206; found: 611.2216.
1-Deoxy-1-fluoro-a-D-gluco-hept-2-ulopyranose (4)
The synthesis was carried out according to GP 2 with 3 (300 mg,
0.52 mmol), MeOH–EtOAc (10 mL), and a catalytic amount of
20% Pd(OH)2/C. The crude residue was purified by column chro-
matography to give 4 as a colorless syrup; yield: 110 mg (~100%);
[a]D25 +58.9 (c 0.50, H2O).
1H NMR (400 MHz, D2O): d = 4.54 (dd, J1a,1b = 9.8 Hz, J1a,F = 46.6
Hz, 1 H, H-1a), 4.40 (dd, J1b,1a = 9.8 Hz, J1b,F = 46.6 Hz, 1 H, H-1b),
Synthesis 2011, No. 23, 3871–3877 © Thieme Stuttgart · New York

3874
Y. Leshch et al.
PAPER
3.92–3.83 (m, 2 H, H-6, H-7a), 3.82–3.75 (m, 2 H, H-4, H-7b), 3.54
(d, J3,4 = 9.5 Hz, 1 H, H-3), 3.45 (dd, J5,4 = 9.6 Hz, J5,6 = 9.6 Hz, 1
H, H-5).
13C NMR (100 MHz, D2O): d = 96.2 (JC,F = 17.5 Hz, C-2), 83.3
(JC,F = 175.2 Hz, C-1), 73.5 (C-4), 72.7 (C-6), 70.3 (C-3), 69.6 (C-
5), 60.7 (C-7).
19F NMR (188 MHz, D2O): d = –231.2 (t, JF,1 = 46.6 Hz).
HRMS-ESI: m/z [M + Na]+ calcd for C7H13FO6 + Na: 235.0588;
4,5,7-Tri-O-benzyl-3-deoxy-3-fluoro-a-D-gluco-hept-2-ulopyra-
nose (10)
The synthesis was carried out according to GP 3 with 9 (267 mg,
595 mmol), t-BuOH–H2O (10 mL), K2CO3 (247 mg, 1.79 mmol),
K3[Fe(CN)6] (589 mg, 1.79 mmol), and a catalytic amount of
K2OsO2(OH)4. The reaction mixture was stirred at r.t. for 24 h. After
workup, the crude product was purified by column chromatography
to give 10 as a colorless oil; yield: 251 (87%); [a]D25 +42.8 (c 0.26,
CHCl3); Rf = 0.43 (Et2O).
1H NMR (400 MHz, DMSO-d6): d = 7.42–7.14 (m, 15 H, H-Ar),
6.28 (s, 1 H, OH), 4.99 (dd, JOH,1 = 6.0 Hz, JOH,1 = 6.2 Hz, 1 H, OH),
4.78 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.75 (d, J = 10.8 Hz, 1 H,
CH2Ph), 4.72 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.53 (d, J = 12.0 Hz, 1
H, CH2Ph), 4.52 (d, J = 10.8 Hz, 1 H, CH2Ph), 4.48 (dd, J3,4 = 9.7
Hz, J3,F = 50.2 Hz, 1 H, H-3), 4.46 (d, J = 12.0 Hz, 1 H, CH2Ph),
4.03–3.94 (m, 1 H, H-4), 3.90 (ddd, J6,7b = 2.2 Hz, J6,7a = 4.6 Hz,
J6,5 = 10.0 Hz, 1 H, H-6), 3.65 (dd, J7a,6 = 4.6 Hz, J7a,7b = 11.0 Hz, 1
H, H-7a), 3.58 (dd, J7b,6 = 2.2 Hz, J7b,7a = 11.0 Hz, 1 H, H-7b), 3.50–
3.35 (m, 3 H, H-1, H-5).
13C NMR (100 MHz, DMSO-d6): d = 138.6, 138.2, 138.1 (Cq-Ar),
128.2, 128.1, 127.8, 127.7, 127.6, 127.5, 127.4, 127.4 (CH-Ar),
95.7 (JC,F = 18.9 Hz, C-2), 89.8 (JC,F = 188.6 Hz, C-3), 80.7
(JC,F = 16.5 Hz, C-4), 77.5 (JC,F = 7.8 Hz, C-5), 73.9, 73.8, 73.3
(CH2Ph), 70.4 (C-6), 68.8 (C-7), 62.9 (C-1).
found: 235.0595.
3,4,6-Tri-O-benzyl-2-deoxy-2-fluoro-D-glucono-1,5-lactone (8)
To a solution of 6 (1.96 g, 4.33 mmol) in anhyd DMSO (11.0 mL)
was added Ac2O (8.9 mL) at 30 °C. The reaction mixture was
stirred for 24 h at 30 °C and then diluted with H2O (100 mL). The
aqueous layer was extracted with Et2O (3 × 100 mL) and the com-
bined organic layers were dried (Na2SO4). The solvent was removed
under reduced pressure, and the crude residue was isolated by col-
umn chromatography (PE–Et2O, 1:2) to give 8 as a colorless solid;
25
yield: 1.66 g (85%); mp 58–59 °C; [a]D +44.5 (c 1.02, CHCl3);
Rf = 0.53 (PE–Et2O, 1:2).
1H NMR (400 MHz, DMSO-d6): d = 7.40–7.18 (m, 15 H, H-Ar),
5.38 (dd, J2,3 = 8.6 Hz, J2,F = 47.0 Hz, 1 H, H-2), 4.73–4.67 (m, 3 H,
CH2Ph), 4.57–4.50 (m, 3 H, H-5, CH2Ph), 4.48 (d, J = 12.0 Hz, 1 H,
CH2Ph), 4.22 (ddd, J3,4 = 7.7 Hz, J3,2 = 8.6 Hz, J3,F = 15.3 Hz, 1 H,
H-3), 3.96 (dd, J4,5 = 7.7 Hz, J4,3 = 7.7 Hz, 1 H, H-4), 3.71–3.55 (m,
2 H, H-6a, H-6b).
13C NMR (100 MHz, DMSO-d6): d = 166.4 (JC,F = 21.8 Hz, C-1),
137.8, 137.7, 137.5 (Cq-Ar), 128.3, 128.3, 128.2, 127.9, 127.8,
127.7, 127.7, 127.6 (CH-Ar), 88.2 (JC,F = 189.5 Hz, C-2), 79.8
(JC,F = 18.3 Hz, C-3), 78.3 (C-5), 74.4 (JC,F = 9.5 Hz, C-4), 73.2,
73.0, 72.3 (CH2Ph), 68.0 (C-6).
19F NMR (188 MHz, DMSO-d6): d = –197.4 (dd, JF,4 = 12.7 Hz,
JF,3 = 50.2 Hz).
HRMS-ESI: m/z [M + Na]+ calcd for C28H31FO6 + Na: 505.1997;
found: 505.1999.
3-Deoxy-3-fluoro-a-D-gluco-hept-2-ulopyranose (11)
The synthesis was carried out according to GP 2 with 10 (238 mg,
493 mmol), MeOH–EtOAc (10 mL), and a catalytic amount of 20%
Pd(OH)2/C. The crude residue was purified by column chromatog-
19F NMR (188 MHz, DMSO-d6): d = –195.2 (dd, JF,3 = 15.3 Hz,
JF,2 = 47.0 Hz).
25
raphy to give 11 as a colorless syrup; yield: 96 mg (92%); [a]D
+56.9 (c 1.70, H2O).
HRMS-ESI: m/z [M + H]+ calcd for C27H27FO5: 451.1915; found:
451.1950; [M + Na]+ 473.1735; found: 473.1770.
1H NMR (400 MHz, D2O): d = 4.43 (dd, J3,4 = 9.4 Hz, J3,F = 49.7
Hz, 1 H, H-3), 4.02 (ddd, J4,3 = 9.4 Hz, J4,5 = 9.4 Hz, J4,F = 13.9 Hz,
1 H, H-4), 3.90–3.77 (m, 3 H, H-6, H-7), 3.73 (dd, J1a,F = 1.5 Hz,
J1a,1b = 12.0 Hz, 1 H, H-1a), 3.61 (dd, J1b,F = 1.5 Hz, J1b,1a = 12.0
Hz, 1 H, H-1b), 3.51 (dd, J5,4 = 9.4 Hz, J5,6 = 9.5 Hz, 1 H, H-5).
13C NMR (100 MHz, D2O): d = 96.4 (JC,F = 18.9 Hz, C-2), 89.4
(JC,F = 186.8 Hz, C-3), 72.5 (C-6), 71.9 (JC,F = 17.5 Hz, C-4), 66.8
(JC,F = 7.6 Hz, C-1), 63.4 (C-5), 60.7 (C-7).
19F NMR (188 MHz, D2O): d = –201.2 (dd, JF,4 = 13.9 Hz,
JF,3 = 49.7 Hz).
HRMS-ESI: m/z [M + Na]+ calcd for C7H13FO6 + Na: 235.0588;
2,6-Anhydro-4,5,7-tri-O-benzyl-1,3-dideoxy-3-fluoro-D-gluco-
hept-1-enitol (9)
The lactone 8 (1.09 g, 2.41 mmol) and Me2TiCp2 (1.04 g, 4.86
mmol) were dissolved in anhyd toluene (20 mL) under an argon at-
mosphere and heated to 75 °C. The reaction mixture was stirred for
48 h at 75 °C and the solvent was removed under reduced pressure.
The crude residue was purified by column chromatography (PE–
Et2O + 0.5% Et3N, 5:1) to give 8 as a yellowish solid; yield: 753 mg
(70%), mp 49–50 °C; [a]D25 +58.8 (c 0.33, CHCl3); Rf = 0.43 (PE–
Et2O, 5:1).
1H NMR (400 MHz, DMSO-d6): d = 7.40–7.13 (m, 15 H, H-Ar),
5.10 (dd, J3,4 = 7.0 Hz, J3,F = 49.1 Hz, 1 H, H-3), 4.77 (d, J = 11.5
Hz, 1 H, CH2Ph), 4.71 (d, J = 11.5 Hz, 1 H, CH2Ph), 4.69 (d,
J = 11.1 Hz, 1 H, CH2Ph), 4.67 (s, 1 H, H-1a), 4.58 (s, 1 H, H-1b),
4.54 (d, J = 12.1 Hz, 1 H, CH2Ph), 4.50 (d, J = 11.1 Hz, 1 H,
CH2Ph), 4.48 (d, J = 12.1 Hz, 1 H, CH2Ph), 3.81 (ddd, J4,3 = 7.0 Hz,
J4,5 = 7.0 Hz, J4,F = 13.3 Hz, 1 H, H-4), 3.76–3.63 (m, 4 H, H-5, H-
6, H-7).
13C NMR (100 MHz, DMSO-d6): d = 154.1 (JC,F = 18.7 Hz, C-2),
138.0, 137.9, 137.8 (Cq-Ar), 128.2, 128.1, 127.8, 127.7, 127.6,
127.5, 124.3 (CH-Ar), 94.1 (JC,F = 6.1 Hz, C-1), 89.2 (JC,F = 182.1
Hz, C-3), 81.6 (JC,F = 19.8 Hz, C-4), 77.5 (C-6), 76.1 (JC,F = 6.2 Hz,
C-5), 73.3, 72.9, 72.3 (CH2Ph), 68.4 (C-7).
found: 235.0589.
4,5,7-Tri-O-benzyl-1,3-dideoxy-1,3-difluoro-a-D-gluco-hept-2-
ulopyranose (12)
The synthesis was carried out according to GP 1 with 9 (90 mg, 200
mmol), DMF–H2O (5 mL), and Selectfluor (710 mg, 2.0 mmol). Af-
ter workup, the crude residue was purified by column chromatogra-
phy (PE–Et2O, 2:1) to give 12 as a colorless oil; yield: 73 (75%);
[a]D25 +47.9 (c 0.21, CHCl3); Rf = 0.34 (PE–Et2O, 1:1).
1H NMR (500 MHz, DMSO-d6): d = 7.40–7.23 (m, 13 H, H-Ar),
7.22–7.14 (m, 2 H, H-Ar), 6.98 (br s, 1 H, -OH), 4.82–4.69 (m, 3 H,
CH2Ph), 4.56–4.46 (m, 3 H, CH2Ph), 4.40 (dd, J3,4 = 9.2 Hz,
J3,F = 50.6 Hz, 1 H, H-3), 4.38 (dd, J1a,1b = 9.7 Hz, J1a,F = 47.1 Hz, 1
H, H-1a), 4.30 (dd, J1b,1a = 9.7 Hz, J1b,F = 47.1 Hz, 1 H, H-1b), 4.02
(ddd, J4,3 = 9.2 Hz, J4,5 = 9.4 Hz, J4,F = 12.4 Hz, 1 H, H-4), 3.91
(ddd, J6,7b = 1.1 Hz, J6,7a = 4.4 Hz, J6,5 = 9.5 Hz, 1 H, H-6), 3.66 (dd,
J7a,6 = 4.4 Hz, J7a,7b = 10.9 Hz, 1 H, H-7a), 3.58 (dd, J7b,6 = 1.1 Hz,
19F NMR (188 MHz, DMSO-d6): d = –185.6 (dd, JF,4 = 13.3 Hz,
JF,3 = 49.1 Hz).
HRMS-ESI: m/z [M + H]+ calcd for C28H29FO4: 449.2123; found:
449.2152; [M + Na]+ 471.1942; found: 471.1978.
Synthesis 2011, No. 23, 3871–3877 © Thieme Stuttgart · New York

PAPER
Fluoro Derivatives of D-Gluco-hept-2-ulose
3875
J7b,7a = 10.9 Hz, 1 H, H-7b), 3.52 (dd, J5,4 = 9.4 Hz, J5,6 = 9.5 Hz, 1
H, H-5).
Phenyl 6-Deoxy-6-fluoro-1-thio-b-D–glucopyranoside (16)
Compound 15 (1.75 g, 4.37 mmol) was dissolved in anhyd MeOH
(20 mL) and a catalytic amount of a 0.5 M NaOMe in MeOH was
added. The reaction mixture was stirred at r.t. After completion of
the reaction, Amberlite IR-120 H+ was added until the mixture was
neutralized. The ion exchange resin was filtered off and the solvent
removed in vacuo. The crude product was purified by column chro-
matography (EtOAc) to give 16 as a colorless solid, yield: 1.15 g
13C NMR (125 MHz, DMSO-d6): d = 138.4, 138.1, 138.0 (Cq-Ar),
128.2, 128.2, 127.9, 127.7, 127.6, 127.6, 127.5 (CH-Ar), 93.9
(JC,F = 18.1, JC,F = 18.4 Hz, C-2), 89.8 (JC,F = 190.7 Hz, C-3), 82.1
(JC,F = 178.6 Hz, C-1), 80.2 (JC,F = 15.8 Hz, C-4), 77.1 (JC,F = 7.7
Hz, C-5), 74.0, 73.9, 72.3 (CH2Ph), 70.6 (C-6), 68.4 (C-7).
19F NMR (188 MHz, DMSO-d6): d = –197.1 (dd, JF,4 = 12.4 Hz,
JF,3 = 50.6 Hz), –227.8 (t, JF,1 = 47.1 Hz).
25
(96%); mp 128–129 °C; [a]D –47.1 (c 0.51, MeOH); Rf = 0.27
(EtOAc).
HRMS-ESI: m/z [M + Na]+ calcd for C28H30F2O5 + Na: 507.1954;
1H NMR (500 MHz, CD3OD): d = 7.60–7.53 (m, 2 H, H-Ar), 7.37–
7.25 (m, 3 H, H-Ar), 4.65 (ddd, J6a,5 = 1.8 Hz, J6a,6b = 10.3 Hz,
J6a,F = 47.6 Hz, 1 H, H-6a), 4.62 (d, J1,2 = 9.8 Hz, 1 H, H-1), 4.60
(ddd, J6b,5 = 4.7 Hz, J6b,6a = 10.6 Hz, J6b,F = 47.6 Hz, 1 H, H-6b),
3.49 (dddd, J5,6a = 1.8 Hz, J5,6b = 4.7 Hz, J5,4 = 9.8 Hz, J5,F = 23.8
Hz, 1 H, H-5), 3.42 (dd, J3,2 = 9.3 Hz, J3,4 = 9.3 Hz, 1 H, H-3), 3.36–
3.32 (m, 1 H, H-4), 3.22 (dd, J2,3 = 9.3 Hz, J2,1 = 9.8 Hz, 1 H, H-2).
13C NMR (125 MHz, CD3OD): d = 134.9 (Cq-Ar), 133.1, 129.9,
128.6 (CH-Ar), 89.3 (C-1), 83.4 (JC,F = 171.9 Hz, C-6), 80.2
(JC,F = 17.9 Hz, C-5), 79.6 (C-3), 73.6 (C-2), 67.9 (JC,F = 7.1 Hz, C-
4).
found: 507.1953; [M + K]+ 523.1693; found: 523.1691.
1,3-Dideoxy-1,3-difluoro-a-D-gluco-hept-2-ulopyranose (13)
The synthesis was carried out according to GP 2 with 12 (65 mg,
134 mmol), MeOH–EtOAc (3 mL), and a catalytic amount of 20%
Pd(OH)2/C. The crude residue was purified by column chromatog-
25
raphy to give 13 as a colorless syrup; yield: 24 mg (86%); [a]D
+48.9 (c 1.65, H2O).
1H NMR (500 MHz, D2O): d = 4.55 (dd, J1a,1b = 10.0 Hz,
J1a,F = 47.2 Hz, 1 H, H-1a), 4.45 (dd, J3,4 = 9.3 Hz, J3,F = 50.3 Hz, 1
H, H-3), 4.40 (dd, J1b,1a = 10.0 Hz, J1b,F = 47.2 Hz, 1 H, H-1b), 4.12
(ddd, J4,3 = 9.3 Hz, J4,5 = 9.5 Hz, J4,F = 12.6 Hz, 1 H, H-4), 3.93–
3.84 (m, 2 H, H-6, H-7a), 3.68 (dd, J7b,6 = 5.3 Hz, J7b,7a = 12.4 Hz,
1 H, H-7b), 3.52 (dd, J5,4 = 9.5 Hz, J5,6 = 9.7 Hz, 1 H, H-5).
19F NMR (188 MHz, CD3OD): d = –236.9 (td, JF,5 = 23.8 Hz,
JF,6 = 47.6 Hz).
HRMS-ESI: m/z [M + Na]+ calcd for C12H15FO4S + Na: 297.0567;
found: 297.0568.
13C NMR (100 MHz, D2O): d = 89.3 (JC,F = 188.5 Hz, C-3), 82.8
(JC,F = 176.2 Hz, C-1), 72.7 (C-6), 71.7 (JC,F = 17.4 Hz, C-4), 69.0
(JC,F = 7.8 Hz, C-5), 60.3 (C-7).
19F NMR (188 MHz, DMSO-d6): d = –201.0 (dd, JF,4 = 12.6 Hz,
JF,3 = 50.3 Hz), –231.6 (t, JF,1 = 47.2 Hz).
HRMS-ESI: m/z [M + Na]+ calcd for C7H12F2O5 + Na: 237.0545;
found: 237.0529.
Phenyl 2,3,4-Tri-O-benzyl-6-deoxy-6-fluoro-1-thio-b-D-glu-
copyranoside (17)
Thioglycoside 16 (1.07 g, 3.90 mmol) was added to a suspension of
NaH (0.7 g, 18.3 mmol) in anhyd DMF (25 mL) at 0 °C. The reac-
tion mixture was allowed to warm to r.t. and stirred for 2 h. Then a
catalytic amount of Bu4NI (15 mg, 39 mmol) was added and the mix-
ture was treated dropwise with benzyl bromide (1.6 mL, 13 mmol).
The mixture was stirred overnight and the remaining NaH was de-
stroyed with EtOH. The reaction mixture was diluted with H2O (100
mL) and Et2O (100 mL) and the aqueous layer was extracted with
Et2O (3 × 100 mL). The combined organic layers were dried
(Na2SO4) and the solvent was removed in vacuo. The crude residue
was purified by column chromatography (PE–Et2O, 3:1) to give 17
Phenyl 2,3,4-Tri-O-acetyl-6-deoxy-6-fluoro-1-thio-b-D-glucopy-
ranoside (15)
Under an argon atmosphere, compound 1413b (1.97 g, 5.63 mmol)
was dissolved in anhyd CH2Cl2 (20 mL), and thiophenol (1.72 mL,
16.9 mmol) was added. Then BF3·OEt2 (3.56 mL, 28.2 mmol) was
added dropwise at 0 °C and he mixture stirred for 1 h. The mixture
was warmed up to r.t. and stirred overnight. After completion of the
reaction, sat. aq NaHCO3 (20 mL) was added and the organic layer
was washed with H2O (20 mL), sat. aq NaHCO3 (20 mL), and dried
(Na2SO4). The solvent was removed in vacuo. The crude product
25
as a colorless solid; yield: 1.93 (91%); mp 111–112 °C; [a]D
+2.11(c 0.53, CHCl3); Rf = 0.32 (PE–Et2O, 3:1).
1H NMR (400 MHz, DMSO-d6): d = 7.50–7.45 (m, 2 H, H-Ar),
7.38–7.22 (m, 18 H, H-Ar), 5.04 (d, J1,2 = 9.8 Hz, 1 H, H-1), 4.84–
4.77 (m, 3 H, CH2Ph), 4.75 (d, J = 11.3 Hz, 1 H, CH2Ph), 4.69 (d,
J = 10.7 Hz, 1 H, CH2Ph), 4.66–4.62 (m, 1 H, H-6a, H-6b), 4.59 (d,
J = 11.1 Hz, 1 H, CH2Ph), 4.55-4.48 (m, 1 H, H-6a, H-6b), 3.82 (dd,
J3,2 = 9.4 Hz, J3,4 = 9.5 Hz, 1 H, H-3), 3.75 (dddd, J5,6a = 2.2 Hz,
J5,6b = 4.7 Hz, J5,4 = 9.9 Hz, J5,F = 26.6 Hz, 1 H, H-5), 3.49 (dd,
J4,3 = 9.5 Hz, J4,5 = 9.9 Hz, 1 H, H-4), 3.44 (dd, J2,3 = 9.4 Hz,
J2,1 = 9.8 Hz, 1 H, H-2).
13C NMR (100 MHz, DMSO-d6): d = 138.4, 138.0, 137.9, 133.9
(Cq-Ar), 130.1, 129.1, 128.2, 128.2, 128.1, 127.8, 127.7, 127.7,
127.6, 127.5, 127.5, 127.4, 127.0 (CH-Ar), 85.5 (C-1), 85.2 (C-3),
82.1 (JC,F = 170.2 Hz, C-6), 80.3 (C-2), 76.6 (JC,F = 18.7 Hz, C-5),
76.5 (JC,F = 6.9 Hz, C-4), 74.6, 74.2, 74.0 (CH2Ph).
was purified by column chromatography (PE–EtOAc, 2:1) to give
25
15 as a colorless solid; yield: 1.8 g (80%); mp 126–127 °C; [a]D
10.1 (c 0.51, CHCl3); Rf = 0.28 (PE–EtOAc, 2:1).
–
1H NMR (400 MHz, CDCl3): d = 7.45–7.40 (m, 2 H, H-Ar), 7.30–
7.23 (m, 3 H, H-Ar), 5.18 (dd, J3,2 = 9.3 Hz, J3,4 = 9.3 Hz, 1 H, H-
3), 4.94 (dd, J4,3 = 9.3 Hz, J4,5 = 9.9 Hz, 1 H, H-4), 4.89 (dd,
J2,3 = 9.3 Hz, J2,1 = 10.0 Hz, 1 H, H-2), 4.66 (d, J1,2 = 10.0 Hz, 1 H,
H-1), 4.50–4.44 (m, 1 H, H-6a, H-6b), 4.38–4.32 (m, 1 H, H-6a, H-
6b), 3.68 (dddd, J5,6a = 2.1 Hz, J5,6b = 4.4 Hz, J5,4 = 9.9 Hz,
J5,F = 24.2 Hz, 1 H, H-5), 2.02 (s, 3 H, OCOCH3), 1.96 (s, 3 H,
OCOCH3), 1.92 (s, 3 H, OCOCH3).
13C NMR (100 MHz, CDCl3): d = 170.2, 169.4, 169.2 (C=O), 133.2
(CH-Ar), 131.5 (Cq-Ar), 129.1, 128.5 (CH-Ar), 85.8 (C-1), 81.4
(JC,F = 175.8 Hz, C-6), 75.5 (JC,F = 19.7 Hz, C-5), 73.9 (C-3), 69.9
(C-2), 67.9 (JC,F = 6.9 Hz, C-4), 20.7, 20.6, 20.5 (OCOCH3).
19F NMR (188 MHz, DMSO-d6): d = –230.9 (td, JF,5 = 26.6 Hz,
JF,6 = 47.7 Hz).
HRMS-ESI: m/z [M + Na]+ calcd for C33H33FO4S + Na: 567.1976;
19F NMR (188 MHz, DMSO-d6): d = –232.1 (td, JF,5 = 24.2 Hz,
JF,6 = 47.2 Hz).
found: 567.1989.
HRMS-ESI: m/z [M + Na]+ calcd for C18H21FO7S + Na: 423.0884;
found: 423.0883.
2,3,4-Tri-O-benzyl-6-deoxy-6-fluoro-D-glucopyranose (18)
Compound 17 (1.39 g, 2.55 mmol) was dissolved in a mixture of ac-
etone–H2O (9:1, 50 mL) and treated with NBS (1.43 g, 8.03 mmol).
The reaction mixture was stirred at r.t. for 2 h. After completion of
Synthesis 2011, No. 23, 3871–3877 © Thieme Stuttgart · New York

3876
Y. Leshch et al.
PAPER
the reaction, H2O (150 mL) was added and the aqueous layer was
extracted with Et2O (3 × 150 mL). The combined organic layers
were washed with sat. aq NaHCO3 (150 mL) and dried (Na2SO4).
The solvent was removed in vacuo and the crude residue was puri-
fied by column chromatography (PE–Et2O, 1:1) to give an anomeric
mixture (a/b = 1.4:1) 18 as a colorless solid; yield: 0.96 g (83%);
Rf = 0.23 (PE–Et2O, 1:1).
CH2Ph), 4.67 (d, J = 11.4 Hz, 1 H, CH2Ph), 4.67–4.54 (m, 4 H, H-
1a, H-7, CH2Ph), 4.57 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.53 (d,
J = 11.4 Hz, 1 H, CH2Ph), 4.47 (s, 1 H, H-1b), 4.11 (d, J3,4 = 4.9 Hz,
1 H, H-3), 4.03 (dddd, J6,7a = 2.1 Hz, J6,7b = 4.7 Hz, J6,5 = 10.2 Hz,
J6,F = 27.4 Hz, 1 H, H-6), 3.78 (dd, J4,3 = 4.9 Hz, J4,5 = 6.0 Hz, 1 H,
H-4), 3.59 (dd, J5,4 = 6.0 Hz, J5,6 = 10.2 Hz, 1 H, H-5).
13C NMR (125 MHz, DMSO-d6): d = 154.5 (C-2), 137.9, 137.8,
137.7 (Cq-Ar), 128.3, 128.2, 128.2, 127.9, 127.8, 127.7, 127.6 (CH-
Ar), 93.8 (C-1), 82.0 (JC,F = 170.9 Hz, C-7), 81.9 (C-4), 77.0 (C-3),
76.2 (JC,F = 6.5 Hz, C-5), 75.0 (JC,F = 17.6 Hz, C-6), 72.5, 72.0, 70.8
(CH2Ph).
18a
1H NMR (500 MHz, DMSO-d6): d = 7.40–7.21 (m, 15 H, H-Ar),
6.74 (d, JOH,1 = 4.8 Hz, 1 H, OH), 5.24 (dd, J1,2 = 3.7 Hz, J1,OH = 4.8
Hz, 1 H, H-1), 4.87 (d, J = 11.2 Hz, 1 H, CH2Ph), 4.78 (d, J = 11.4
Hz, 1 H, CH2Ph), 4.77–4.72 (m, 1 H, CH2Ph), 4.69 (d, J = 12.0 Hz,
1 H, CH2Ph), 4.63 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.63–4.60 (m, 1 H,
H-6a, H-6b), 4.58 (d, J = 11.4 Hz, 1 H, CH2Ph), 4.54–4.50 (m, 1 H,
H-6a, H-6b), 3.89 (dddd, J5,6a = 2.2 Hz, J5,6a = 4.7 Hz, J5,4 = 9.9 Hz,
J5,F = 26.4 Hz, 1 H, H-5), 3.87 (dd, J3,2 = 9.1 Hz, J3,4 = 9.2 Hz, 1 H,
H-3), 3.46–3.35 (m, 2.7 H, H-2, H-4).
19F NMR (188 MHz, DMSO-d6): d = –232.4 (dd, JF,6 = 27.4 Hz,
JF,7 = 47.9 Hz).
HRMS-ESI: m/z [M + Na]+ calcd for C28H29FO4 + Na: 471.1942;
found: 471.1449.
3,4,5-Tri-O-benzyl-7-deoxy-7-fluoro-a-D-gluco-hept-2-ulopyra-
nose (21)
13C NMR (125 MHz, DMSO-d6): d = 138.7, 138.6, 138.5 (Cq-Ar),
128.2, 128.2, 128.1, 127.7, 127.7, 127.6, 127.4, 127.3 (CH-Ar),
89.6 (C-1), 82.2 (JC,F = 170.2 Hz, C-6), 80.8 (C-3), 79.9 (C-2), 76.7
(JC,F = 6.9 Hz, C-4), 74.4, 74.0, 73.5 (CH2Ph), 71.6 (CH2Ph), 68.7
(JC,F = 17.9 Hz, C-5).
19F NMR (188 MHz, DMSO-d6): d = –231.2 (td, JF,5 = 26.4 Hz,
JF,6 = 47.5 Hz).
The synthesis was carried out according to GP 3 with 20 (80 mg,
178 mmol), t-BuOH–H2O (5 mL), K2CO3 (80 mg, 579 mmol),
K3[Fe(CN)6] (180 mg, 546 mmol), and catalytic amount of
K2OsO2(OH)4. The reaction mixture was stirred at r.t. for 24 h. After
workup, the crude product was purified by column chromatography
to give 21 as a colorless solid; yield: 78 mg (91%); mp 110–111 °C;
[a]D25 –5.2 (c 0.25, CHCl3); Rf = 0.48 (Et2O).
1H NMR (500 MHz, DMSO-d6): d = 7.42–7.22 (m, 15 H, H-Ar),
5.97 (s, 1 H, OH), 4.96 (dd, JOH,1b = 5.3 Hz, JOH,1a = 6.7 Hz, 1 H,
OH), 4.83 (d, J = 11.3 Hz, 1 H, CH2Ph), 4.81–4.77 (m, 2 H, CH2Ph),
4.75 (d, J = 11.1 Hz, 1 H, CH2Ph), 4.68 (d, J = 11.1 Hz, 1 H,
CH2Ph), 4.57 (d, J = 11.2 Hz, 1 H, CH2Ph), 4.60 (ddd, J7a,6 = 4.1
Hz, J7a,7b = 10.4 Hz, J7a,F = 47.3 Hz, 1 H, H-7a), 4.51 (ddd,
J7b,6 = 1.1 Hz, J7b,7a = 10.4 Hz, J7b,F = 47.3 Hz, 1 H, H-7b), 3.93 (dd,
J4,5 = 9.3 Hz, J4,3 = 9.6 Hz, 1 H, H-4), 3.89 (dddd, J6,7b = 1.1 Hz,
J6,7a = 4.1 Hz, J6,5 = 10.0 Hz, J6,F = 28.7 Hz, 1 H, H-6), 3.59 (d,
J3,4 = 9.6 Hz, 1 H, H-3), 3.51 (dd, J1a,OH = 6.7 Hz, J1a,1b = 11.3 Hz, 1
H, H-1a), 3.42 (dd, J5,4 = 9.3 Hz, J5,6 = 10.0 Hz, 1 H, H-5), 3.39 (dd,
J1b,OH = 5.3 Hz, J1b,1a = 11.3 Hz, 1 H, H-1b).
HRMS-ESI: m/z [M + Na]+ calcd for C27H29FO5 + Na: 475.1891;
found: 475.1899.
2,3,4-Tri-O-benzyl-6-deoxy-6-fluoro-D-glucono-1,5-lactone (19)
To a solution of 18 (300 mg, 663 mmoL) in anhyd DMSO (4 mL)
was added Ac2O (1.4 mL) at 30 °C. The reaction mixture was
stirred for 24 h at 30 °C and then diluted with H2O (50 mL). The
aqueous layer was extracted with Et2O (3 × 50 mL) and the com-
bined organic layers were dried (Na2SO4). The solvent was removed
under reduced pressure, and the crude residue was purified by col-
umn chromatography (PE–Et2O, 1:1) to give 19 as a colorless solid;
25
yield: 254 mg (86%); mp 71–72 °C; [a]D +72.1 (c 1.00, CHCl3);
Rf = 0.38 (PE–Et2O, 1:1).
13C NMR (125 MHz, DMSO-d6): d = 138.1, 138.7, 138.2 (Cq-Ar),
128.3, 128.2, 128.1, 127.8, 127.7, 127.6, 127.4 (CH-Ar), 98.0 (C-
2), 82.5 (JC,F = 170.7 Hz, C-7), 82.4 (C-4), 78.7 (C-3), 77.3
(JC,F = 6.4 Hz, C-5), 74.4, 74.2, 73.9 (CH2Ph), 69.9 (JC,F = 17.4 Hz,
C-6), 63.4 (C-1).
19F NMR (188 MHz, DMSO-d6): d = –230.0 (td, JF,6 = 28.7 Hz,
JF,7 = 47.3 Hz).
1H NMR (500 MHz, DMSO-d6): d = 7.42–7.26 (m, 15 H, H-Ar),
4.87 (d, J = 11.4 Hz, 1 H, CH2Ph), 4.75–4.62 (m, 7 H, H-5, H-6,
CH2Ph), 4.59 (d, J = 11.4 Hz, 1 H, CH2Ph), 4.41 (d, J2,3 = 5.7 Hz, 1
H, H-2), 4.09 (dd, J3,2 = 5.7 Hz, J3,4 = 6.3 Hz, 1 H, H-3), 3.86 (dd,
J4,3 = 6.3 Hz, J4,5 = 8.6 Hz, 1 H, H-4).
13C NMR (125 MHz, DMSO-d6): d = 168.6 (C-1), 137.1, 137.5,
137.4 (Cq-Ar), 128.3, 128.3, 127.9, 127.8, 127.8, 127.7 (CH-Ar),
81.4 (JC,F = 171.0 Hz, C-6), 79.3 (C-3), 77.4 (C-2), 76.7 (JC,F = 18.3
Hz, C-5), 76.6 (JC,F = 6.1 Hz, C-4), 72.8, 72.5, 72.4 (CH2Ph).
HRMS-ESI: m/z [M + Na]+ calcd for C28H31FO6 + Na: 505.1997;
found: 505.2009.
19F NMR (188 MHz, DMSO-d6): d = –230.2 (td, JF,5 = 26.4 Hz,
JF,6 = 47.7 Hz).
7-Deoxy-7-fluoro-a-D-gluco-hept-2-ulopyranose (22)
The synthesis was carried out according to GP 2 with 21 (60 mg,
124 mmol), MeOH–EtOAc (4 mL), and a catalytic amount of 20%
Pd(OH)2/C. The crude residue was purified by column chromatog-
HRMS-ESI: m/z [M + H]+ calcd for C27H27FO5: 451.1915; found:
451.1928; [M + Na]+ 473.1735; found: 473.1750.
25
raphy to give 22 as a colorless syrup; yield: 24 mg (94%); [a]D
+39.5 (c 0.80, H2O).
2,6-Anhydro-3,4,5-tri-O-benzyl-1,7-dideoxy-7-fluoro-D-gluco-
hept-1-enitol (20)
1H NMR (400 MHz, D2O): d = 4.75 (ddd, J7a,6 = 3.7 Hz,
J7a,7b = 10.7 Hz, J7a,F = 47.4 Hz, 1 H, H-7a), 4.68 (ddd, J7b,6 = 1.7
Hz, J7b,7a = 10.6 Hz, J7b,F = 47.4 Hz, 1 H, H-7b), 3.93 (dddd,
J6,7a = 1.7 Hz, J6,7b = 3.7 Hz, J6,5 = 10.0 Hz, J6,F = 28.8 Hz, 1 H, H-
6), 3.77 (dd, J4,5 = 9.6 Hz, J4,3 = 9.6 Hz, 1 H, H-4), 3.72 (d,
J1a,1b = 11.8 Hz, 1 H, H-1a), 3.57 (d, J1b,1a = 11.8 Hz, 1 H, H-1b),
3.53 (d, J3,4 = 9.6 Hz, 1 H, H-3), 3.52 (dd, J5,4 = 9.6 Hz, J5,6 = 10.0
Hz, 1 H, H-5).
The lactone 19 (214 mg, 472 mmol) and Me2TiCp2 (220 mg, 1.06
mmol) were dissolved in anhyd toluene (20 mL) under an argon at-
mosphere and heated to 75 °C. The reaction mixture was stirred for
24 h at 75 °C and the solvent was removed under reduced pressure.
The crude residue was purified by column chromatography (PE–
Et2O + 0.5% Et3N, 5:1) to give 20 as a colorless solid; yield: 169 mg
(80%), mp 76–78 °C; [a]D25 +44.07 (c 0.26, CHCl3); Rf = 0.36 (PE–
Et2O 5:1).
13C NMR (100 MHz, D2O): d = 97.8 (C-2), 82.7 (JC,F = 166.9 Hz,
C-7), 73.5 (C-4), 71.3 (JC,F = 17.4 Hz, C-6), 70.6 (C-3), 68.7
(JC,F = 6.9 Hz, C-5), 63.8 (C-1).
1H NMR (500 MHz, DMSO-d6): d = 7.40–7.23 (m, 15 H, H-Ar),
4.73 (d, J = 11.5 Hz, 1 H, CH2Ph), 4.68 (d, J = 11.7 Hz, 1 H,
Synthesis 2011, No. 23, 3871–3877 © Thieme Stuttgart · New York

PAPER
Fluoro Derivatives of D-Gluco-hept-2-ulose
3877
19F NMR (188 MHz, D2O): d = –234.8 (td, JF,6 = 28.8 Hz,
JF,7 = 47.4 Hz).
HRMS-ESI: m/z [M + Na]+ calcd for C7H13FO6 + Na: 235.0588;
References
(1) Chin, L.; Andersen, J. N.; Futreal, J. N.; Andrew, P. Nat.
Med. 2011, 17, 297.
found: 235.0597.
(2) Nicholson, J. K. Mol. Syst. Biol. 2006, 2, 52.
(3) Chen, K.; Chen, X. Curr. Top. Med. Chem. 2010, 1227.
(4) (a) Varki, A.; Lowe, J. B. In Essentials of Glycobiology, 2nd
ed.; Varki, A.; Cummings, R. D.; Esko, J. D.; Freeze, H. H.;
Stanley, P.; Bertozzi, C. R.; Hart, G. W.; Etzler, M. E., Eds.;
Cold Spring Harbor Laboratory Press: New York, 2009,
Chap. 6. (b) Cummings, R. D. Mol. BioSyst. 2009, 5, 1087.
(c) Galan, M. C.; Benito-Alifonso, D.; Watt, G. M. Org.
Biomol. Chem. 2011, 9, 3598.
(5) Hakamori, S. In The Molecular Immunology of Complex
Carbohydrates-2; Wu, A. M., Ed.; Kluwer Academic/
Plenum Publishing: New York, 2001, 369.
(6) (a) Busk, M.; Horsman, M. R.; Jakobsen, S.; Bussink, J.;
Kogel, A.; Overgaard, J. Eur. J. Nucl. Med. Mol. Imaging
2008, 35, 2294. (b) Basu, S.; Torigian, D.; Alavi, A.
Gastroenterology 2008, 135, 1055. (c) Hustinx, R.; Alavi,
A. Tumor Imaging, In Handbook of Radiopharmaceuticals:
Radiochemistry and Applications; Welch, M. J.; Redvanly,
C. S., Eds.; Wiley: New York, 2003, 629–642.
(7) (a) Ruiz-Cabello, J.; Barnett, B. P.; Bottomley, P. A.; Bulte,
J. W. M. NMR in Biomedicine 2011, 24, 114.
(b) Himmelreich, U.; Dresselaers, T. Methods 2009, 48, 112.
(8) Strauss, L. G. Eur. J. Nucl. Med. 1996, 23, 1409.
(9) Rendig, V. V.; McComb, E. A. Arch. Biochem. Biophys.
1960, 89, 323.
(10) (a) Paulsen, E. P.; Richenderfer, L.; Winick, P. Nature 1967,
214, 276. (b) Coore, H. G.; Randle, P. J. Biochem. J. 1964,
91, 56. (c) Nelkin, W. Acta Physiol. 1970, 38, 401.
(d) Nelkin, W. Acta Physiol. 1972, 41, 181.
3,4,5-Tri-O-benzyl-1,7-deoxy-1,7-difluoro-a-D-gluco-hept-2-
ulopyranose (23)
The synthesis was carried out according to GP 1 with 20 (80 mg,
178 mmol), DMF–H2O (4 mL), and Selectfluor (630 mg, 1.78
mmol). After workup, the crude residue was purified by column
chromatography (PE–Et2O, 1:1) to give 23 as a colorless oil; yield:
64 mg (74%); mp 85–86 °C; [a]D25 +12.7 (c 0.36, CHCl3); Rf = 0.29
(PE–Et2O, 1:1).
1H NMR (500 MHz, DMSO-d6): d = 7.40–7.23 (m, 15 H, H-Ar),
6.61 (s, 1 H, OH), 4.85–4.76 (m, 4 H, CH2Ph), 4.61 (d, J = 11.1 Hz,
1 H, CH2Ph), 4.60 (ddd, J7a,6 = 3.9 Hz, J7a,7b = 10.5 Hz, J7a,F = 48.2
Hz, 1 H, H-7a), 4.59 (d, J = 11.1 Hz, 1 H, CH2Ph), 4.53 (ddd,
J7b,6 = 1.1 Hz, J7b,7a = 10.5 Hz, J7b,F = 48.2 Hz, 1 H, H-7b), 4.35 (dd,
J1a,1b = 9.5 Hz, J1a,F = 47.7 Hz, 1 H, H-1a), 4.23 (dd, J1b,1a = 9.5 Hz,
J1b,F = 47.7 Hz, 1 H, H-1b), 3.98 (dd, J4,5 = 9.3 Hz, J4,3 = 9.5 Hz, 1
H, H-4), 3.91 (ddd, J6,7a = 3.9 Hz, J6,5 = 9.8 Hz, J6,F = 28.8 Hz, 1 H,
H-6), 3.50 (d, J3,4 = 9.5 Hz, 1 H, H-3), 3.49 (dd, J5,4 = 9.3 Hz,
J5,6 = 9.8 Hz, 1 H, H-5).
13C NMR (125 MHz, DMSO-d6): d = 138.5, 138.1, 138.0 (Cq-Ar),
128.3, 128.2, 128.2, 127.8, 127.7, 127.6, 127.6, 127.5, 127.4 (CH-
Ar), 95.9 (JC,F = 18.4 Hz, C-2), 83.4 (JC,F = 178.2 Hz, C-1), 83.2
(JC,F = 171.2 Hz, C-7), 82.0 (C-4), 78.5 (C-3), 77.1 (JC,F = 6.2 Hz,
C-5), 74.5, 74.4, 73.0 (CH2Ph), 70.1 (JC,F = 17.6 Hz, C-6).
19F NMR (188 MHz, DMSO-d6): d = –226.6 (t, JF,1 = 47.7 Hz),
–230.9 (td, JF,6 = 28.8 Hz, JF,7 = 48.2 Hz).
HRMS-ESI: m/z [M + H]+ calcd for C28H30F2O5: 507.1954; found:
(11) (a) Board, M.; Colquhoun, A.; Newsholme, E. A. Cancer
Res. 1995, 55, 3278. (b) Xu, L. Z.; Weber, I. T.; Harrison, R.
W.; Gidh-Jain, M.; Pilkis, S. J. Biochemistry 1995, 34, 6083.
(12) (a) Coore, H. G.; Randle, P. J. Biochem. J. 1964, 91, 56.
(b) Zelent, D.; Najafi, H.; Odili, S.; Buettger, C.; Weik-
Collins, H.; Li, C.; Doliba, N.; Grimsby, J.; Matschinsky, F.
M. Biochem. Soc. Trans. 2005, 33 , 306. (c) Malaisse, W.
J.; Lea, M. A.; Malaisse-Lagae, F. Metabolism 1968, 17,
126. (d) Malaisse, W. J.; Louchami, K.; Sener, A. Nat. Rev.
Endocrinol. 2009, 5, 394.
(13) (a) Waschke, D.; Thimm, J.; Thiem, J. Org. Lett. 2011, 13,
3628. (b) Waschke, D.; Thimm, J.; Himmelreich U.; Thiem,
J. Eur. J. Org. Chem. 2011, submitted.
(14) (a) Nyffeler, P. T.; Gonzales, D. S.; Burkart, M. D.; Vincent,
S. P.; Wong, C.-H. Angew. Chem. Int. Ed. 2005, 44, 192.
(b) Burkart, M. D.; Zhang, Z.; Hung, S.-C.; Wong, C.-H.
J. Am. Chem. Soc. 1997, 119, 11743.
507.1954.
1,7-Deoxy-1,7-difluoro-a-D-gluco-hept-2-ulopyranose (24)
The synthesis was carried out according to GP 2 with 23 (50 mg,
103 mmol), MeOH–EtOAc (4 mL), and a catalytic amount of 20%
Pd(OH)2/C. The crude residue was purified by column chromatog-
raphy to give 24 as a colorless syrup; yield: 20 mg (95%); [a]D
+37.5 (c 0.55, H2O).
1H NMR (400 MHz, D2O): d = 4.80 (ddd, J7a,6 = 3.7 Hz,
J7a,7b = 10.9 Hz, J7a,F = 47.4 Hz, 1 H, H-7a), 4.71 (ddd, J7b,6 = 1.7
Hz, J7b,7a = 10.9 Hz, J7b,F = 47.4 Hz, 1 H, H-7b), 4.58 (dd,
J1a,1b = 9.9 Hz, J1a,F = 46.6 Hz, 1 H, H-1a), 4.42 (dd, J1b,1a = 9.9 Hz,
J1b,F = 46.6 Hz, 1 H, H-1b), 4.03 (dddd, J6,7b = 1.7 Hz, J6,7a = 3.7 Hz,
J6,5 = 10.3 Hz, J6,F = 28.7 Hz, 1 H, H-6), 3.83 (dd, J4,5 = 9.4 Hz,
J4,3 = 9.6 Hz, 1 H, H-4), 3.59 (d, J3,4 = 9.6 Hz, 1 H, H-3), 3.58 (dd,
J5,4 = 9.4 Hz, J5,6 = 10.3 Hz, 1 H, H-5).
25
13C NMR (100 MHz, D2O): d = 95.9 (JC,F = 17.6 Hz, C-2), 82.8
(JC,F = 175.75 Hz, C-1), 82.2 (JC,F = 168.0 Hz, C-7), 73.2 (C-4),
71.4 (JC,F = 17.6 Hz, C-6), 70.1 (C-3), 68.4 (JC,F = 7.0 Hz, C-5).
(15) Somsák, L.; Németh, I. J. Carbohydr. Chem. 1993, 12, 679.
(16) Albright, J. D.; Goldman, L. J Am. Chem. Soc. 1965, 87,
4214.
(17) (a) Petasis, N. A.; Bzowej, E. I. J. Am Chem. Soc. 1990, 112,
6392. (b) Csuk, R.; Glänzer, B. I. Tetrahedron 1991, 47,
1655.
(18) (a) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroeder,
G.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968.
(b) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483. (c) Minato, M.; Yamamoto, K.;
Tsuji, J. J. Org. Chem. 1990, 55, 766.
19F NMR (188 MHz, D2O): d = –231.6 (t, JF,1 = 46.6 Hz), –235.3
(td, JF,6 = 28.7 Hz, JF,7 = 47.4 Hz).
HRMS-ESI: m/z [M + H]+ calcd for C7H12F2O5: 215.0726; found:
215.1266.
Acknowledgment
(19) Sharma, M.; Korytnyk, W. Tetrahedron Lett. 1977, 6, 573.
(20) (a) Zemplén, G. Ber. Dtsch. Chem. G es. 1926, 59B, 1254.
(b) Zemplén, G.; Pascu, E. Ber. Dtsch. Chem. Ges. 1929,
62B, 1613.
We thank the EU Program FP7-NMP-228933-VIBRANT for finan-
cial support.
(21) Motawia, M. S.; Marcussen, J.; Møller, B. L. J. Carbohydr.
Chem. 1995, 14, 1279.
Synthesis 2011, No. 23, 3871–3877 © Thieme Stuttgart · New York