The synthesis of mono- and difluorinated 2,3-dideoxy-d-glucopyranoses

Article abstract of DOI:10.1016/j.jfluchem.2014.08.023

The synthesis of 2,3-dideoxy-2,3-difluoro-d-glucose and 2,3-dideoxy-3-fluoro-d-glucose is reported in, respectively, 5 and 6 steps from d-glucal, using a fluorination strategy.

Full text of DOI:10.1016/j.jfluchem.2014.08.023

Journal of Fluorine Chemistry 171 (2015) 92–96
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
The synthesis of mono- and difluorinated
2,3-dideoxy- -glucopyranoses
D
*
Lewis Mtashobya, Lucas Quiquempoix, Bruno Linclau
Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
A R T I C L E I N F O
A B S T R A C T
Article history:
The synthesis of 2,3-dideoxy-2,3-difluoro-
respectively, 5 and 6 steps from -glucal, using a fluorination strategy.
ß 2014 Elsevier B.V. All rights reserved.
D-glucose and 2,3-dideoxy-3-fluoro-D-glucose is reported in,
Received 2 August 2014
D
Received in revised form 26 August 2014
Accepted 28 August 2014
Available online 16 September 2014
Keywords:
Fluorine
Carbohydrate
Deoxofluorination
1,6-Anhydrosugar
Carbohydrate mimetic
1. Introduction
transporter-mediated, and the result was interpreted as due to a
better binding of the ligand to the protein. Interestingly, the
Carbohydrates are central to many fundamental processes [1],
and the glycosylation of proteins and natural products can have a
significant impact on their biological activity [2]. Yet, the affinity of
carbohydrates to proteins is typically rather low, which mainly
originates from their highly hydrophilic character. The design of
carbohydrate-based analogues with greater affinity to carbohy-
drate-processing proteins is of interest for use as probes or
therapeutics [3].
corresponding 2,3,4-trideoxy-2,3,4-trifluoro-
shown to have a slightly lower transport rate than
Our group has been involved in the synthesis of heavily
fluorinated sugars, such as tetrafluorinated -glucose 3 [8], that
still contain a non-anomeric chiral alcohol group within the ring,
believed to be important for the selectivity aspect of binding events
involving carbohydrates [9]. The difference in membrane transport
D
-glucose
2
was
D
-glucose [7].
D
rates between
1 and 2 clearly illustrates the fundamental
An appealing strategy to increase protein–carbohydrate affinity
consists of replacing multiple CHOH groups in the sugar ring with
CF2 groups [4], thus creating a hydrophobic environment without
significantly altering the shape of the sugar. Hydrophobic
desolvation is known to increase affinity, and perfluoroalkyl
desolvation energy is higher compared to that of hydrocarbons,
due to their larger surface [5]. In addition, the highly polarised C–F
bond is able to engage in stabilising electrostatic interactions with
various cationic or polar protein residues [6]. These are weak
interactions, but negligible in aqueous medium (when the ligand is
in the unbound state). The combination of these two effects has
been coined ‘polar hydrophobicity’ [4]. It has been demonstrated
that a hexafluorinated pyranose 1 (Fig. 1) crosses the erythrocyte
difference between the two fluorination motifs of these sugars.
Key parameters include a difference in molecular lipophilicity,
hydrogen bond accepting/donating properties of the adjacent
alcohol groups [10], and the electron density of the fluorine atoms
involved (as illustrated by their different chemical shift values)
impacting on their capacity for intermolecular interactions with
proteins [11].
Hence, we became interested to extend our studies involving 3
to D-glucose analogues with a hydrophobic moiety at C2–C3 (or
C3–C4) having a lighter fluorination pattern. Here we describe the
synthesis and characterisation of the novel sugars 2,3-dideoxy-2,3-
difluoro-D-glucose 4 (Fig. 2) and 2,3-dideoxy-3-fluoro-D-glucose 5
from a common precursor [12].
membrane 10 times as fast as
D-glucose [4]. This process is
2. Results and discussion
The common intermediate, 1,6:2,3-anhydro-4-O-benzyl-
b-
*
Corresponding author. +Tel.: +44 2380593816.
E-mail address: bruno.linclau@soton.ac.uk (B. Linclau).
D-mannopyranose 6 (Scheme 1) was obtained in two steps from
http://dx.doi.org/10.1016/j.jfluchem.2014.08.023
0022-1139/ß 2014 Elsevier B.V. All rights reserved.

L. Mtashobya et al. / Journal of Fluorine Chemistry 171 (2015) 92–96
93
reaction with DAST then gave 10. Interestingly, this deoxyfluorination
proceeded again with overall retention of configuration, despite no
axial C–F bond is now present at C2. This was again clear from the
3
2
small JH3–H2/4 coupling values (<5 Hz), the JC4–F value of 26.2 Hz,
and the very small (in this case unobserved) 3JC5–F value (indicating a
gauche dihedral angle between C3–F and C4–C5). The 1,6-anhydro
derivative 10 was hydrolysed in excellent yield to give the 4-O-benzyl
pyranose 11, which was easily purified. The resulting chair inversion
going from 10 to 11 was again clear from 13C NMR analysis, in that the
Fig. 1. Fluorinated D-glucose derivatives.
3
2JC4–F value reduced to a value of 16.1 Hz, and the JC5–F value
increased to 8.1–9.5 Hz, all indicative of an equatorial C–F bond. Final
hydrogenolysis then resulted in colourless 5 in almost quantitative
yield.
3. Conclusion
Fig. 2. Target D-glucose derivatives.
The novel sugars 2,3-dideoxy-2,3-difluoro-
lighter fluorinated analogue, 2,3-dideoxy-3-fluoro-
been synthesised from -glucal. A sugar fluorination approach has
D
-glucose, and its
D-glucose, have
D
D
-glucal as described, using well-established methodology
been employed, with the fluorine at the 2-position introduced by
fluoride mediated epoxide opening, and the fluorine at the
3-position by a deoxofluorination reaction. Interestingly, the latter
reaction proceeded with retention of configuration, even when the
2-position is unsubstituted. All steps proceeded in excellent yield.
These sugar analogues having a hydrophobic domain within the ring
will be used as probes to study the physical and biological properties
of this class of compounds. This work is in progress in our group.
[13–15]. From 6, the synthesis of 4 started by a regioselective
epoxide opening with potassium hydrogen bifluoride in refluxing
ethylene glycol [16–17], in a reasonable 65% yield (74% on small
scale). Jensen recently reported a 40% yield under these conditions,
which they could improve to 69% when conducted in a sealed
vessel under microwave conditions at 220 8C [18]. However, in our
hands this procedure gave lower yields. DAST-mediated deoxo-
fluorination of the 3-OH, already described by Sarda et al. [19],
gave the difluoride 8 in excellent yield. As noted by Sarda et al. [19],
the retention of configuration was clearly proven by the small
3JH3–H2/4 values (<5 Hz). In addition, given the axial position of the
4. Experimental
4.1. 1,6-Anhydro-4-O-benzyl-2-deoxy-2-fluoro-
b-D-
2
OBn substituent, the JC4–F value of 26.3 Hz clearly indicates an
axial C–F bond, and the small (2.3 Hz) JC5–F value indicates a
glucopyranoside (7)
3
gauche dihedral angle between C3–F and C4–C5 [20]. This
stereochemical outcome may be due to anchimeric assistance
by the axial benzyloxy group [21], given the steric hindrance
exerted by the axial OBn and F groups at C4 and C2. Benzyl
deprotection and concomitant anomeric hydrolysis was achieved
in one pot by treatment of 8 with BCl3 followed by quenching with
water, leading to pure 4 in 79% yield.
The resulting chair inversion in comparison with the levoglu-
cosan 8 was clearly observed from 13C NMR analysis in that the
abovementioned 26.3 Hz 2JC4–F value reduced to 17.6 Hz, (equato-
rial F gauche to C4–OH) [22]. The 3JC5–F3 value increased to 8.0 Hz in
4, indicating the equatorial C3–F is antiperiplanar to C4–C5.
The synthesis of 5 is shown in Scheme 2. Regioselective epoxide
reduction [22] of 6 led to the 2-deoxyderivative 9 in excellent yield.
On larger scale (ꢀ4 g), a workup involving dilution with Et2O and
addition of MgSO4 after quenching with water/aq. NaOH was found
important to ensure consistent high yields. Deoxofluorination
The epoxide 6 (0.515 g, 2.20 mmol) was boiled with potassium
hydrogen difluoride (10.280 g, 131.57 mmol) in ethylene glycol
(40 mL) for 2.5 h under nitrogen. After completion of the reaction,
the mixture was cooled and then poured into 5% K2CO3 (20 mL).
The mixture was then extracted with chloroform (5 ꢁ 30 mL). After
drying over MgSO4 and evaporation of solvent, the obtained syrup
was chromatographed on silica gel (chloroform/acetone 95:05)
and afforded 7 as a colourless oil (0.412 g, 1.62 mmol, 74%). Mw
254.25 (C13H15FO4); Rf 0.32 (chloroform/acetone 95:05); 1H NMR
(400 MHz, CDCl3)
d
7.40 ꢂ 7.30 (5H, m, HAr), 5.56 (1H, d, J 5.4 Hz,
0
H1), 4.73 (1H, d, J 12.2 Hz, H7), 4.67 (1H, d, J 12.2 Hz, H7 ), 4.63 (1H,
br. d, J 4.6 Hz, H5), 4.27 (1H, br. dd, J 47.4, 3.2 Hz, H2), 4.01 (1H, m, J
19.6 Hz can be observed, H3), 3.89 (1H, br. dd, J 7.6, 0.5 Hz, H6), 3.70
(1H, br. dd, J 7.3, 5.4 Hz, H6 ), 3.35 (1H, br. d, J 3.2 Hz, H4) ppm; 13C
0
NMR (101 MHz, CDCl3) d 137.5 (CAr), 128.6 (CAr), 128.1 (CAr), 127.9
(CAr), 99.7 (d, J 30.1 Hz,C1), 89.9 (d, J 183.4 Hz,C2), 78.4 (d, J
6.6 Hz,C4), 75.1 (C5), 71.8 (C7), 70.2 (d, J 26.4 Hz,C3), 66.3 (C6) ppm;
Scheme 1. Synthesis of 4.
Scheme 2. Synthesis of 5.

94
L. Mtashobya et al. / Journal of Fluorine Chemistry 171 (2015) 92–96
19F NMR (376 MHz, CDCl3)
NMR data correspond to literature data [18].
d
ꢂ 187.8 (1F, ddd, J 47.8, 20.0, 5.2 Hz).
19F NMR (471 MHz, acetone-d6)
d
ꢂ 195.4 (dq, J 53.2, 14.6 Hz,
simplifies to d, J 14.0 Hz upon H-decoupling, F ), ꢂ199.5 (dddd, J
b
52.3, 16.1, 13.8, 2.5 Hz, simplifies to d, J 14.0 Hz upon H-
4.2. 1,6-Anhydro-4-O-benzyl-2,3-dideoxy-2,3-difluoro-
glucopyranoside (8)
b
-
D
-
decoupling, F ), ꢂ200.9 (dt, 50.9, 13.6 Hz, simplifies to d, J
b
14.0 Hz upon H-decoupling, F ), ꢂ201.1 (ddtdd, J 55.3, 15.1, 13.4,
a
3.6, 1.7 Hz, simplifies to d, J 12.9 Hz upon H-decoupling, F ) ppm;
a
To a solution of 7 (4.3 g, 16.91 mmol) in dry toluene (80.0 mL)
DAST was added slowly (11.17 mL, 84.56 mmol) at rt. The mixture
was refluxed under nitrogen atmosphere for 24 h when TLC
indicated completion of the reaction. Quenching of excess reagent
was carried out by adding dry MeOH (10 mL) very slowly at
ꢂ20 8C. The solvent was evaporated and the sample dried under
high vacuum. Column chromatography (EtOAc/PE 20:80) with
addition of 0.5% TEA afforded 8 as a colourless oil (3.67 g, 86%). Mw
ESIS-MS: m/z 183 [M–H]– (35%).
4.4. 1,6-Anhydro-4-O-benzyl-2-deoxy-
D-glucopyranoside (9)
To refluxed solution of LiAlH4 (1 M in THF, 18.4 mL,
a
18.40 mmol) in THF (40 mL) was added drop wise a solution of
6 (4.102 g, 17.51 mmol) in THF (20 mL). Reflux was continued for
additional 2 h. The reaction mixture was cooled to ambient
temperature and quenched by successive addition of water (4 mL)
and 15% aq. NaOH (22 mL). Ether (80 mL) was then added to ensure
even stirring, followed by MgSO4 (30 g), and the mixture was left
stirring overnight. The solid was filtered and rinsed with ether
(6 ꢁ 40 mL), then the filtrate was evaporated under vacuum. The
crude product was then purified by column chromatography (7:3
PE/acetone) to yield 9 as a colourless oil (3.899 g, 16.50 mmol,
94%). Mw 236.26; Rf 0.23 (acetone/PE 30:70); IR (neat) 3451 (br,
256.25 (C13H14F2O3); Rf 0.38 (EtOAc/PE 20:80); [
a
]
D ꢂ 33.4 (c 1.00,
acetone, 24 8C); 1H NMR (500 MHz, CDCl3)
d
7.45 ꢂ 7.29 (5H, m,
HAr), 5.58 (1H, br. d., J 3.0 Hz, simplifies to s upon F-decoupling, H1),
4.77 (1H, m, J 44.3, 16.1 Hz can be observed, which disappear upon
F-decoupling, H3), 4.78 (1H, d, J 12.2 Hz, H7), 4.68 (1H, d, J 12.4 Hz,
0
H7 ), 4.66 (br. dd, J 5.7, 1.0 Hz, simplifies to d, J 1.0 Hz upon
F-decoupling, H5), 4.42 (1H, br. dd, J 45.6, 15.6 Hz, simplifies to bs
upon F-decoupling, H2), 3.87 (1H, d, J 7.3 Hz, changes to dd, J 7.7,
0.7 Hz upon F-decoupling, H6), 3.76 (1H, app t, changes to dd, J 7.6,
5.9 Hz upon F-decoupling, H6), 3.49 (1H, br. d, J 16.9 Hz, simplifies
m), 1126 (s), 1070 (s) cm1; 1H NMR (500 MHz, CDCl3)
d 7.28–7.42
(5H, m, HAr), 5.66 (1H, br. d, J 1.2 Hz, H1), 4.71 (1H, d, J 12.2 Hz, H7),
to br. S upon F-decoupling, H4) ppm; 13C NMR (125.7 MHz, CDCl3)
d
4.66 (1H, d, J 12.3 Hz, H7 ), 4.60 (1H, m, J 5.4 Hz can be observed,
0
137.1 (CAr), 128.7 (CAr), 128.2 (CAr), 127.92 (CAr), 98.7 (dd, J 29.3,
2.9 Hz,C1), 88.6 (dd, J 179.6, 30.4 Hz,C3), 85.9 (dd, J 183.0,
27.5 Hz,C2), 74.8 (dd, J 26.4, 4.6 Hz,C4), 74.3 (d, J 2.3 Hz,C5), 71.7
(C7), 65.5 (d, J 2.3 Hz,C6)ppm; 19F NMR (470.6 MHz, CDCl3)
H5), 4.19 (1H, dd, J 7.5, 0.7 Hz, H6), 3.93 (1H, m, H3), 3.72 (1H, dd, J
0
7.6, 5.4 Hz, H6 ), 3.46 (1H, br d (app q), J 1.1 Hz, H4), 2.69 (1H, d, J
8.0 Hz, OH3), 2.22 (1H, ddd, J 15.0, 5.3, 1.6 Hz, H2), 1.84 (1H, br m, J
15.0 Hz can be observed, H2 ) ppm; 13C NMR (101 MHz, CDCl3)
d
0
d
ꢂ 186.9 (1F, ddt, J 44.9, 16.1, 13.3 Hz, F3), ꢂ192.32 (1F, dddd
app as m, J 45.6, 15.8, 12.8, 3.1 Hz, F2); ppm; 19F{1H} NMR
(282 MHz, CDCl3)
137.8 (CAr), 128.6 (2C,CAr), 127.9 (CAr), 127.8 (2C,CAr), 101.0 (C1),
77.8 (C4), 74.5 (C5), 71.6 (C7), 66.6 (C3), 65.2 (C6), 35.9 (C2) ppm;
ESI+-MS: m/z 275.2 [+K]ꢂ (53%). This is a known compound, [23]
but no NMR data had been reported.
d
ꢂ 187.2 (d, J 12.9 Hz, F3), ꢂ192.4 (d, J 12.9 Hz,
F2) ppm; ESI+MS: m/z 320.1 [M + MeCN + Na]+ (83%). 13C NMR
spectra details corresponded to those reported by Sarda et al.
[19]. The 1H NMR and 19F NMR data were not reported.
4.5. 1,6-Anhydro-4-benzyl-2,3-dideoxy-3-fluoro-D-glucopyranose
(10)
4.3. 2,3-Dideoxy-2,3-difluoro-D-glucopyranose (4)
To a solution of 9 (2.6 g, 11.0 mmol) in dry toluene (40.0 mL)
DAST was slowly added (7.3 mL, 55.0 mmol) at rt. The mixture was
refluxed under argon for 24 h. Decomposition of excess reagent was
carried out by adding dry MeOH (10 mL) very slowly at ꢂ20 8C. The
solvent was evaporated and the sample dried under vacuum.
Column chromatography (EtOAc/PE 20:80) afforded 10 as a brown
oil (1.9 g, 73%). Mw 238.25 (C13H15FO3); Rf 0.3 (EtOAc/PE 20:80);
To a stirred solution of 8 (0.444 g, 1.73 mmol) in DCM at 0 8C
was added a solution of BCl3 in DCM (1 M, 2.3 mL, 2.30 mmol).
After 30 min at 0 8C the solution was allowed to reach room
temperature and the solution was stirred for 2 h. The reaction
mixture was quenched with H2O (16 mL), then the solvents were
removed under vacuum. The crude product was then purified by
column chromatography (PE/acetone 70:30) to yield 4 as a
colourless oil (0.253 g, 1.38 mmol, 79%). Mw 184.14; Rf 0.30
[a]
D ꢂ 55.6 (c 0.25, CHCl3, 19 8C);IR (neat) 2952 (m), 1493 (w), 1452
(w), 1039 (s) cmꢂ1; 1H NMR (500 MHz, CDCl3)
7.40 ꢂ 7.28 (5H, m,
Ar), 5.58(1H,br.s, H1), 4.74(1H, m,J45.9 Hzcanbeobserved, which
d
(MeOH/CH2Cl2 10:90); Rf 0.12 (PE/acetone 60:40); [
0.08, acetone, 19 8C); IR (neat) 3315 (br, m), 1024 (s, CO) cmꢂ1; 1H
NMR (500 MHz, acetone-d6) 6.30 (1H, d, J 6.5 Hz, OH1 ), 6.07 (1H,
a
]D + 50.6 (c
H
disappears upon F-decoupling, H3), 4.72 (1H, d, J, 12.2 Hz, H7), 4.69
0
d
(1H, d, J 12.2 Hz, H7 ), 4.61 (1H, br. d, J 5.9 Hz, H5), 4.06 (1H, br. dt, J
b
d, J 4.3 Hz, OH1 ), 5.38 (1H, app q, J 3.9 Hz, simplifies to app t, J
7.5 Hz, J 1.0 Hz, simplifies to 1H, dd, J 7.5 Hz, 1.0 Hz upon
a
3.9 Hz upon F-decoupling, H1 ), 4.92 (1H, d, J 5.3 Hz, OH ),
F-decoupling, H6), 3.76 (1H, ddd, J 7.4, 6.0, 3.6 Hz, simplifies to
a
b
0
4.87 ꢂ 4.77 (2H, m, H1 + OH), 4.76 (1H, ddt, J 55.4, 13.7, 8.7 Hz,
dd, J 7.3 6.0 Hz upon F-decoupling, H6 ), 3.53 (1H, br. dd, J 13.9,
b
simplifies to t, J 8.7 Hz upon F-decoupling, H3 ), 4.57 (1H, ddt, J
1.2 Hz, simplifies to br. d, J 1.0 Hz upon F-decoupling, H4), 2.15 (1H,
dddd, J 40.2, 15.6, 4.9, 2.0 Hz, simplifies to ddd, J 15.6, 4.9, 2.0 Hz
upon F-decoupling, H2ax), 2.03 (1H, br. dd, J 22.6, 15.5 Hz, simplifies
to br. d, J 15.4 Hz upon F-decoupling, H2eq) ppm. 13C NMR
a
53.6, 16.0, 8.6 Hz, simplifies to t, J 8.7 Hz upon F-decoupling, H3 ),
b
4.45 (1H, dddd, J 51.1, 12.9, 9.1, 3.7 Hz, simplifies to dd, J 9.0, 3.8 Hz
upon F-decoupling, H2 ), 4.17 (1H, dddd, J 52.2, 14.5, 8.5, 7.7 Hz,
a
simplifies to app t, J 7.9 Hz upon F-decoupling, H2 ), 3.83 (2H, m, J
(125.7 MHz, CDCl3) d 128.66 (CAr), 128.17 (CAr), 127.87 (CAr),
b
0
9.9, 4.4, 2.7 Hz, H5 + H6 ), 3.80 ꢂ 3.66 (6H, m, H4 , H6 , H6
,
,
a b
99.42 (d, J 1.2, C1), 86.52 (d, J 175.3 Hz,C3), 75.16 (d, J 26.2 Hz,C4),
73.38 (C5), 71.77 (C7), 64.48 (C6), 33.87 (d, J 20.0 Hz,C2) ppm; 19F
,
a b
a
a
b
OH), 3.61 (2H, app t, J 6.1 Hz, OH ), 3.38 (1H, dddd, J 9.6, 4.7, 2.7,
a
1.3 Hz, simplifies to ddd, J 9.8, 4.7, 2.7 Hz upon F-decoupling, H5 )
NMR (470.5 MHz, CDCl3)
d
ꢂ 176.28 ppm (1F, ddddd, J 46.0, 40.1,
b
ppm; 13C NMR (101 MHz, acetone-d6)
d
95.5 (dd, J 183.4,
22.7, 13.9, 3.5 Hz)ppm; EI-MS: m/z 91 (100), 238 (M+ꢃ, 0.3).
17.6 Hz,C3 ), 93.9 (dd, J 22.0, 11.0 Hz,C1 ), 93.6 (dd, J 179.7,
b
b
15.4 Hz,C3 ), 91.9 (dd, J 187.1, 17.6 Hz,C2 ) 90.3 (dd, J 20.5,
4.6. 4-O-Benzyl-2,3-dideoxy-3-fluoro-D-glucopyranose (11)
a
b
10.3 Hz,C1 ), 88.7 (dd, J 191.5, 17.6 Hz,C2 ), 75.3 (dd, J 7.3,
a
a
1.5 Hz,C5 ), 71.3 (dd, J 7.3, 1.5 Hz,C5 ), 68.74 (dd, J 17.6, 6.6 Hz,
To a stirred solution of 10 (515 mg, 2.16 mmol) in dioxane
b
a
C4 ), 68.71 (dd, J 17.6, 6.6 Hz, C4 ), 61.13 (C6 ), 61.08 (C6 ) ppm;
(10 mL) was added an aqueous solution of H2SO4 (1 M, 32.5 mL,
b
a
b
a

L. Mtashobya et al. / Journal of Fluorine Chemistry 171 (2015) 92–96
95
32.5 mmol), followed by heating at 75 8C for 3 h. The reaction
mixture was cooled to ambient temperature and quenched by
addition of sat NaHCO3 (80 mL). The mixture was extracted with
ethyl acetate (4 ꢁ 150 mL), the combined organic layers were dried
over MgSO4 and solvent was removed under vacuum. The crude
product was then purified by HPLC (petroleum hexane/acetone
65:35) to yield 11 as a slight yellow oil (445 mg, 1.74 mmol, 80%).
F-decoupling, H2eq, ), 1.69 (1H, m, H2ax, ), 1.58 (1H, qd, J 11.5,
a a
9.7 Hz, simplifies to td, J 11.9, 9.6 Hz upon F-decoupling, H2ax, );
b
13C NMR (101 MHz, acetone-d6)
177.5 Hz,C3 ), 91.5 (d, J 14.7 Hz,C1 ), 91.4 (d, J 175.3 Hz,C3 ), 75.3
d 93.2 (d, J 16.9 Hz,C1 ), 92.8 (d, J
b
b
a
a
(d, J 8.1 Hz,C5 ), 71.8 (d, J 6.6 Hz,C5 ), 70.5 (d, J 16.9 Hz,C4 ), 70.0
b
a
a
(d, J 17.6 Hz,C4 ), 61.7 (m, C6 + C6 ), 38.7 (d, J 17.6 Hz,C2 ), 36.3
b
a
b
b
(d, J 16.9 Hz,C2 ) ppm; 19F NMR (282 MHz, acetone-d6)
d
ꢂ 184.5
a
a
Mw 256.27 (C13H17FO4); Rf 0.22 (PE/acetone 70:30); [
a
]
D + 59.0 (c
(br. app dt, J 51.6, 12.9 Hz, F ), ꢂ188.9 (1F, br. d, J 52.4 Hz, F ) ppm;
b
1.02, acetone, 21 8C); 1H NMR (500 MHz, acetone-d6)
d
7.39 ꢂ 7.26
EI-MS: m/z 166, (M+ꢃ, 0.1).
(5H, m, HAr), 5.79 (1H, dd, J 6.6, 1.4 Hz, simplifies to d, J 6.4 Hz upon
F-decoupling, OH1 ), 5.40 (1H, dd, J 3.7, 1.9 Hz, OH1 ), 5.36 (1H, m
b
a
5. Supporting information
(bq, simplifies to bt upon F-decoupling), H1 ), 5.00 (1H, dddd, J
a
General information, copies of 1H, 13C, and 19F NMR spectra of
all compounds.
52.4, 11.5, 8.5, 5.6 Hz, simplifies to ddd, J 11.4, 8.5, 5.6 Hz upon F-
0
decoupling, H3 ), 4.89-4.79 (3H, m, H1 , H7 , H7 (and half of H3 ),
a
b
b
b
b
simplifies to the following: 4.86 (1H, ddd, J 9.6, 6.4, 1.9 Hz, H1 ),
b
4.85 (1H, d, J 11.1 Hz, H7 ), and 4.83 (1H, d, J 11.1 Hz, H7 ) upon F-
decoupling, 4.77 (1H, dddd, J 51.1, 11.7, 8.4, 5.6 Hz, simplifies to
a
b
Acknowledgements
ddd, J 11.7, 8.4, 5.6 Hz upon F-decoupling, H3 ), 4.68 (1H, d, J
b
LM sincerely thank Mkwawa University College of Education
(TR 28) for financial support, and LQ thank the European
Community (INTERREG IVa Channel Programme, AI-Chem, project
4494/4196) for financial support.
0
0
11.4 Hz, H7 ), 4.67 (1H, d, J 11.4 Hz, H7 ), 3.83 ꢂ 3.79 (2H, m, H5
,
a
a
b
H6 ), 3.77 ꢂ 3.68 (3H, m, H6 , H6 , OH), 3.71 (ddd, J 11.7, 7.1,
a
a
b
4.7 Hz, H6 ), 3.62 (ddd, J 13.3, 9.7, 8.6 Hz, simplifies to app t, J
b
9.2 Hz upon F-decoupling, H4 ), 3.60 (dd, J 7.1, 6.0 Hz, H6 ), 3.55
a
b
(1H, ddd, J 13.3, 9.3, 8.6 Hz, simplifies to app t, J 9.1 Hz upon F-
Appendix A. Supplementary data
decoupling, H4 ), 3.47 (1H, dd, J 6.6, 5.9 Hz, OH), 3.27 (1H, dddd, J
b
9.5, 4.6, 2.2, 1.5 Hz, simplifies to ddd, J 9.5, 4.6, 2.2 Hz upon F-
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.jfluchem.
2014.08.023.
decoupling, H5 ), 2.36 (1H, dtd, J 12.0, 5.2, 1.7 Hz, simplifies to ddd,
b
J 12.1, 5.7, 1.9 Hz upon F-decoupling, H2eq, ), 2.24 (1H, dtd, J 12.4,
b
5.4, 1.4 Hz, simplifies to ddd, J 12.4, 5.6, 1.3 Hz upon F-decoupling,
H2eq, ), 1.76 (1H, dtdd, J 12.5, 11.3, 3.5, 1.9 Hz, simplifies to dddd J
a
References
12.4, 11.5, 3.4, 1.7 Hz upon F-decoupling, H2ax, ), 1.65 (1H, dq, J
a
11.7, 9.6 Hz, simplifies to dt, J 11.7, 9.6 Hz upon F-decoupling,
H2ax, ) ppm; 13C NMR (100.6 MHz, acetone-d6)
d
139.0 (CAr,
),
or
b
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b
a
138.9 (CAr
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), 127.7 (2CAr,
), 127.6
b
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+
or
a
b
a
a
b
(2CAr
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,
), 93.9 (d, J
a
or
or
or
b
b
a
a
b
126.9 Hz,C3
), 93.2 (d, J 16.4 Hz,C1
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or
b b
or
a
b
a
(c) Z. Tu, Y.-N. Lin, C.-H. Lin, Chem. Soc. Rev. 42 (2013) 4459–4475;
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), 91.4 (d, J 16.1 Hz,C1
), 77.7 (d, J 16.1 Hz,C4
), 77.3 (d, J
or
b
or
or
a
b
a
a
16.1 Hz,C4
), 74.6 (d, J 9.5 Hz,C5
), 73.9 (1d, J 2.2 Hz,C7
or or
b a
or
b
a
a
), 73.8 (1d, J 2.2 Hz,C7
), 71.1 (1 C, d, J 8.1 Hz,C5
), 61.7 (d, J
or
a
or
b
b
a
b
2.2 Hz,C6
36.6 (d, J 17.6 Hz,C2
), 61.6 (d, J 1.4 Hz,C6
), 39.0 (d, J 16.9 Hz,C2
)
or
b
or
or
a
b
b
a
a
) ppm; 19F NMR
d
(470.6 MHz, acetone-d6)
´
A. Molinaro, P.V. Murphy, C. Nativi, S. Oscarson, S. Penades, F. Peri, R.J. Pieters, O.
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b
a
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d
ppm ꢂ 180.49 (1F, m, J 50.8, 12.1 Hz is visible, F3 ), ꢂ184.71 (1F,
b
m, J 52.5, 12.2 Hz is visible, F3 ) ppm.
a
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4.7. 2,3-Dideoxy-3-fluoro-D-glucopyranose (5)
To a solution of 11 (0.443 g, 1.73 mmol) in methanol (1.4 mL)
was added 20 wt% Pd(OH)2/C (0.038 g, 0.05 mmol). The solution
was stirred overnight under hydrogen atmosphere. The catalyst
was filtered through celite and the solvent removed under vaccum.
This afforded 6 as a colourless oil (0.2803 g, 1.69 mmol, 97%). Mw
166.15 (C6 H9O3); Rf 0.23 (MeOH/CH2Cl2 20:80); 0.10 (PE/acetone
60:40); [
1058 (s), 968 (s) cmꢂ1; 1H NMR (500 MHz, acetone-d6)
acetone-d6)
ppm 5.76 (1H, b.s, OH1 ), 5.38 ꢂ 5.32 (2H, m, H1
a]D + 68.7 (c 1.00, acetone, 20 8C); IR (neat) 3312 (br,m),
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d
(500 MHz,
d
,
a
b
OH1 ), 4.88 ꢂ 4.79 (1.5H, m-overlap with H3 , which simplifies as
a
a
(b) R.S. Timofte, B. Linclau, Org. Lett. 10 (2008) 3673–3676;
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br. ddd, J 9.6, 6.2, 1.6 Hz upon F-decoupling, H1 ), 4.78 (1H, dddd, J
b
46.4, 11.5, 8.6, 5.5 Hz, simplifies to ddd, J 11.4, 8.5, 5.5 Hz upon F-
decoupling, H3 ), 4.62 ꢂ 4.52 (2.5H, m-overlap with H3 , OH
),
+
a b
a
b
4.52 (1H, dddd, J 51.1, 11.6, 8.5, 5.6 Hz, simplifies to ddd, J 11.6, 8.5,
5.5 Hz, H3 ), 3.84 ꢂ 3.65 (3H, m, H6 + H5 ), 3.63 ꢂ 3.48 (4H, m,
(e) I. N’Go, S. Golten, A. Arda, J. Canada, J. Jimenez-Barbero, B. Linclau, S. Vincent,
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b
a
b
a
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H4
a
+ OH6
, simplifies upon F-decoupling to: 3.58 (2H, app
+
b
+
b
a
dt visible for H4 , J 8.9, 4.5 Hz, overlaps with OH6 ), 3.50 (app dt, J
a
b
[11] (a) C. Dalvit, A. Vulpetti, ChemMedChem 6 (2011) 104–114;
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b
a
br. ddd, J 9.4, 5.0, 3.1 Hz upon F-decoupling, H5 ), 2.88 (2H, m, OH),
2.31 (1H, m, simplifies to ddd, J 12.0, 5.5, 1.9 Hz upon F-decoupling,
b
H2eq, ), 2.19 (1H, m, simplifies to ddd, J 12.4, 5.5, 1.1 Hz upon
b

96
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