Synthesis of 3-deoxy-3,3-difluoro-d-ribohexose from gem-difluorohomoallyl alcohol

Article abstract of DOI:10.1016/j.jfluchem.2007.01.007

A novel synthetic route to 3-deoxy-3,3-difluoro-d-ribohexose 1 has been developed. Dihydroxidation of gem-difluorohomoallyl alcohol followed by several steps of protection and deprotection gave key intermediate 9. Oxidation of 1,5-diol 9 with 2 equiv. tri

Full text of DOI:10.1016/j.jfluchem.2007.01.007

Journal of Fluorine Chemistry 128 (2007) 535–539
www.elsevier.com/locate/fluor
Synthesis of 3-deoxy-3,3-difluoro-D-ribohexose from
gem-difluorohomoallyl alcohol
Xiu-Hua Xu a, Zheng-Wei You a, Xingang Zhang a, Feng-Ling Qing a,b,
*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science,
354 Fenglin Lu, Shanghai 200032, China
b College of Chemistry and Chemistry Engineering, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China
Received 10 January 2007; accepted 18 January 2007
Available online 23 January 2007
Abstract
A novel synthetic route to 3-deoxy-3,3-difluoro-D-ribohexose 1 has been developed. Dihydroxidation of gem-difluorohomoallyl alcohol
followed by several steps of protection and deprotection gave key intermediate 9. Oxidation of 1,5-diol 9 with 2 equiv. trichloroisocyanuric acid
and catalytic TEMPO gave lactone 10. Reduction of 10 with DIBAL-H followed by deprotections afforded the target molecule 1.
# 2007 Elsevier B.V. All rights reserved.
Keywords: Fluorosugars; Gem-Difluoromethylenated compounds; Building block
1. Introduction
4-deoxy-4,4-difluorinated [7] and 3-deoxy-4,4-difluorinated [8]
sugars have been described. The difluorinations of keto groups of
carbohydrateshavebeenwell-documentedcomplicationsarising
from neighbouring group participation, group migration and
elimination reactions[9]. Therefore, thedevelopment of efficient
and practical route to gem-difluorinated sugars was anticipated.
Percy and co-workers have reported the synthesis of 4-deoxy-
4,4-difluoroglycosides from gem-difluoromethylene-containing
building block using ring-closing metathesis as the key step
[10]. Recently, our group has developed a practical route
to gem-difluorinated homoallyl alcohol 2. Staring from gem-
difluoromethylene-containing building block 2, several
gem-difluorinated sugars such as 3-deoxy-3,3-difluoro-D-arabi-
nofuranose A [11], 3-deoxy-3,3-difluoro-L-ribofuranose B [12],
gem-difluorinated thiofuranose C [13] and gem-difluorinated
azasugars D–F [14] were synthesized (Scheme 1). Herein, we
wish to describe preparation of 3-deoxy-3,3-difluoro-D-ribohex-
ose 1 from gem-difluorohomoallyl alcohol 2.
The interest of fluorinated analogues of natural substances is
increasing continuously, because the incorporation of fluorine
atom(s) or fluoroalkyl groups may greatly modify the chemical
properties and biological activities of those molecules [1].
Among these fluorinated analogues of natural products,
fluorinated carbohydrates (fluorosugars) have recently attracted
more and more attentions from organic chemists and pharma-
ceutists [2]. Fluorosugars can retain much of the reactivity of
natural saccharides while lacking the ability to enter into critical
hydrogen bonding interactions with nucleic acids or proteins.
Although monofluorinated [3] and trifluoromethylated sugars [4]
have been well studied, only a few gem-difluoromethylenated
sugars have been reported, which is probably due to the
shortcomings of existing synthetic methods. 2-Deoxy-2,2-
difluorinated sugars were obtained either by electrophilic
fluorination of 2-fluoroglycals [5] and by reaction of carbonyl
groups with DAST [6]. The difluorination at the 4-keto- and 3-
keto-groups with DAST for synthesis of the corresponding
2. Results and discussion
The building block gem-difluorohomoallyl alcohol 2 was
prepared by the coupling of gem-difluoroallylindium, in situ
generated from 3-bromo-3,3-difluoropropene 4 and indium in
DMF, with 1-(R)-glyceraldehyde acetonide 3 [11] (Scheme 2).
Compound 2 can be made on a 50 g scale in our group. The ratio
* Corresponding author at: Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 354
Fenglin Lu, Shanghai 200032, China. Tel.: +86 21 54925187;
fax: +86 21 64166128.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.01.007

536
X.-H. Xu et al. / Journal of Fluorine Chemistry 128 (2007) 535–539
Scheme 3.
of catalytic TEMPO [16]. We were interested in extending
Giacomelli’s reaction condition to compound 9. It was
expected that the primary hydroxyl group of 9 was oxidized
to aldehyde followed by the subsequent cyclization to give the
desired lactol. Initially, when compound 9 was oxidized with
1.0 equiv. of trichloroisocyanuric acid in the presence of
catalytic TEMPO in CH2Cl2, the byproduct lactone 10 was
formed even the oxidation was carried out at À5 8C. This result
showed that compound 9 was overoxidized under Giacomelli’s
reaction condition. To obtain the single lactone 10, the
oxidation of 9 with 2.0 equiv. of trichloroisocyanuric acid and
catalytic TEMPO was carried out. We were pleased to find that
the single product 10 was isolated in 72% yield. Treatment of
lactone 10 with DIBAL-H allowed efficient reduction of the
lactone as well as removal of the benzoyl group to give 4-O-
benzyl-2-O-(tert-butyldimethylsilyl)-3-deoxy-3,3-difluoro-D-
ribohexose 11 in 73% yield as a 4:1 mixture of anomers
determined by 19F NMR. Finally, compound 11 was
deprotected by treatment with 4 M HCl and followed by
hydrogenation in the presence of Pd/C to furnish the target
molecule 3-deoxy-3,3-difluoro-D-ribohexose 1 in 83% yield as
a 4:1 mixture of anomers.
Scheme 1.
of anti/syn compound 2 is 7.7:1 determined by 19F NMR. The
difluoromethylene group of anti-2 appeared at a higher field
than that of syn-2. Notably, the anti-2 isomer is our desired
compound.
With gem-difluorohomoallyl alcohol 2 in hand, 3-deoxy-
3,3-difluoro-D-ribohexose 1 was synthesized in a straightfor-
ward fashion (Scheme 3). Utilizing the kinetic resolution
method and optimized reaction condition, benzylation of the
gem-difluorohomoallyl alcohol 2 was easily accomplished by
treatment with sodium hydride (0.8 equiv.) and catalytic TBAI,
followed by benzyl bromide. The desired single anti-isomer
was afforded in 78% yield. Then, the Os-catalyzed dihydrox-
ylation of the resulting benzyl ether gave the mixture of diol
compounds 5 and 6 in 95% yield and in 1:1 ratio, which could
be easily separated by column chromatography. The two
hydroxyl groups of diol 6 were protected to the tert-
butyldimethylsilyl ether form and the desired compound 7
was provided in 94% yield. Deprotection of the acetonide
moiety was achieved in a chemoselective manner by using
SnCl2 as the promoter to give diol 8 in 87% yield [15]. The
beneficial effect of SnCl2 was cleavage of the acetonide moiety
without interference with the TBDMS and benzyl groups,
which were easily cleaved under Lewis acids such as BCl3.
Selective benzoylation of the primary hydroxyl group of diol 8
followed by selective removal of the primary TBS group gave
1,5-diol 9 in 76% yield.
In summary, a novel gem-difluorinated sugar 3-deoxy-3,3-
difluoro-D-ribohexose 1 has been synthesized from gem-
difluoromethylene-containing building block 2. The method
was divergent and stereocontrolled and could be easily
expanded to synthesize other similar gem-difluorinated
sugars.
Recently, Giacomelli and co-workers described the
chemoselective oxidation of primary alcohol to aldehyde
without no overoxidation to carboxylic acids at room
temperature using trichloroisocyanuric acid in the presence
3. Experimental
3.1. General
All reagents were used as received from commercial
sources, unless specified otherwise, or prepared as described
in the literature. Reactions requiring anhydrous conditions
were performed in vacuum flame-dried glassware under
nitrogen atmosphere. NMR spectra were recorded on either
300 MHz (1H NMR), 75 MHz (13C NMR) or 282 MHz (19F
NMR, FCCl3 as outside standard and low field is positive).
Chemical shifts (d) are reported in ppm, and coupling
constants (J) are in Hz.
Scheme 2.

X.-H. Xu et al. / Journal of Fluorine Chemistry 128 (2007) 535–539
537
3.2. (2R,4R,5R)-4-O-Benzyl-3,3-difluoro-5,6-O-
isopylidenehexane-1,2,4,5,6-pentol (5) and (2S,4R,5R)-4-
O-benzyl-3,3-difluoro-5,6-O-isopylidenehexane-1,2,4,5,6-
pentol (6)
13C NMR (75.5 MHz, CDCl3) d 137.08, 128.54, 128.20,
121.79 (dd, JC–F = 252.9 Hz, 248.9 Hz), 109.36, 77.52 (dd,
J
C–F = 47.8 Hz, 23.6 Hz), 75.68, 74.26, 71.36 (dd, JC–
F = 28.8 Hz, 24.0 Hz), 65.73, 60.76, 26.23, 24.92; MS m/z
317 (1), 101 (41), 91 (100); IR (thin film) ymax 3423, 1499,
1456 cmÀ1; Anal. Calcd for C16H22O5F2: C, 57.82; H, 6.67.
Found: C, 57.71; H, 6.57.
To a suspension of NaH (60% in oil, 0.277 g, 6.94 mmol)
and Bu4NI (0.325 g, 0.85 mmol) in anhydrous THF (36 mL)
was added a solution of compound 2 (1.803 g, 8.55 mmol) in
anhydrous THF (18 mL) slowly at 0 8C. After the mixture was
stirred for 20 min at 0 8C. The reaction mixture was stirred at
room temperature for 30 min. Then the reaction mixture was
cooled to 0 8C and treated with BnBr (1.08 mL, 9.10 mmol) in
anhydrous THF (11 mL) and stirred at room temperature
overnight. Water was added and the aqueous layer was
extracted with ether. The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered,
and the solvent was removed in vacuo. The residue was
purified by silica gel column chromatography (petroleum
ether:ethyl acetate = 10:1) to give 2.002 g (78.5% yield) of
benzyl protected product (anti/syn = 21.8/1) as a clear oil and
0.353 g of recovered compounds 2 (anti/syn = 1.8/1, 19.6%
recovery). Then to a solution of the benzyl ether (2.002 g,
6.71 mmol) in acetone (40 mL) was added NMNO (1.723 g,
12.75 mmol), followed by addition of water (8 mL) at room
temperature with stirring. Then a catalytic amount of OsO4
(5–10 mol%) solution in water (4% solution) was added.
After the reaction mixture was stirred at room temperature for
48 h. The reaction was quenched with saturated NaHSO3
solution. The layers were separated and the aqueous layer was
extracted with ethyl acetate. The combined organic layers
were washed with 1N HCl, then saturated NaHCO3 solution
and brine, dried over anhydrous Na2SO4, filtered, and the
solvent was removed in vacuo. The residue was purified by
silica gel column chromatography (petroleum ether:ethyl
acetate = 1:1) to give 1.052 g (37.5% yield from compound 2)
of compound 5 as a white solid and 1.048 g (37.5% yield from
compound 2) of compound 6 as a white solid. Compound 5:
solid, mp 82–83 8C; [a]D20 = +12.48 (c 0.35, CHCl3); 1H
NMR (300 MHz, CDCl3) d 7.38–7.35 (m, 5H), 4.93 (d,
J = 10.8 Hz, 1H), 4.80 (d, J = 10.8 Hz, 1H), 4.49–4.45 (m,
1H), 4.28 (ddd, J = 22.6 Hz, 5.7 Hz, 2.5 Hz, 1H), 4.10–3.99
(m, 3H), 3.81 (s, 2H), 1.46 (s, 3H), 1.32 (s, 3H); 19F NMR
(282 MHz, CDCl3) d À119.4 (dd, J = 265.6 Hz, 25.9 Hz),
À121.3 (dd, J = 265.6 Hz, 21.0 Hz, 19.7 Hz); 13C NMR
(75.5 MHz, CDCl3) d 137.37, 128.57, 128.15, 128.08, 122.04,
108.49, 75.78 (dd, JC–F = 28.6 Hz, 23.1 Hz), 75.66, 74.47,
69.53 (dd, JC–F = 31.3 Hz, 23.6 Hz), 64.62 (d, JC–F = 6.0 Hz),
60.27 (t, JC–F = 3.6 Hz), 26.20, 24.99; MS m/z 317 (1), 101
(46), 91 (100); IR (thin film) ymax 3341, 1500, 1455,
1230 cmÀ1; Anal. Calcd for C16H22O5F2: C, 57.82; H, 6.67.
Found: C, 57.74; H, 6.66. Compound 6: solid, mp 46–48 8C;
[a]D20 = +22.98 (c 0.66, CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.36 (s, 5H), 4.82 (d, J = 11.1 Hz, 1H), 4.78 (d, J = 11.1 Hz,
1H), 4.38 (q, J = 6.0 Hz, 1H), 4.12–4.09 (m, 2H), 4.04–3.96
(m, 2H), 3.80 (d, J = 5.4 Hz, 2H), 2.97 (br, 2H), 1.45 (s, 3H),
1.37 (s, 3H); 19F NMR (282 MHz, CDCl3) d À116.7 (dt,
J = 268.3 Hz, 8.7 Hz), À120.6 (dt, J = 268.3 Hz, 16.3 Hz);
3.3. (2S,4R,5R)-4-O-Benzyl-1,2-O-bis-(tert-
butyldimethylsilyl)-3,3-difluoro-5,6-O-isopylidenehexane-
1,2,4,5,6-pentol (7)
To a solution of 6 (853 mg, 2.70 mmol) and DMAP (660 mg,
5.40 mmol) in DMF (1.4 mL) at 0 8C was added imidazole
(919 mg, 13.50 mmol), followed by TBDMSCl (2034 mg,
13.50 mmol). Then, the mixture was warmed to room
temperature and stirred over night. EtOAc (100 mL) was
added and the resulting mixture was washed with brine (3Â
30 mL). The combined organic phases were dried over
anhydrous Na2SO4. After filtration and removal of the solvent,
the residue was purified by flash chromatography (petroleum
ether:ethyl acetate = 50:1) to afford 7 (1423 mg, 94%) as a
1
clear oil: [a]D25 = +5.3 (c 0.75, CHCl3); H NMR (300 MHz,
CDCl3) d 7.35–7.30 (m, 5H), 4.97 (d, J = 10.5 Hz, 1H), 4.72 (d,
J = 11.1 Hz, 1H), 4.53–4.48 (m, 1H), 4.33 (ddd, J = 22.5 Hz,
6.3 Hz, 2.1 Hz, 1H), 4.12 (t, J = 8.1 Hz, 1H), 4.06–3.95 (m,
2H), 3.76 (dt, J = 11.4 Hz, 2.4 Hz, 1H), 3.63–3.57 (m, 1H),
1.43, 1.39 (2s, 6H), 0.94, 0.84 (2s, 18H), 0.14, 0.12, À0.03,
À0.04 (4s, 12H); 19F NMR (282 MHz, CDCl3) d À108.6 (dt,
J = 264.8, 15.2 Hz, 1F), À118.8 (dd, J = 263.7, 23.1 Hz, 1F);
MS (ESI) m/z 561.2 (M + H+), 578.2 (M + NH4 ); IR (thin film)
+
ymax 2957, 2860, 1473, 1381, 1257, 1137, 1058, 836 cmÀ1
;
Anal. Calcd for C28H50F2O5Si2: C, 60.02; H, 8.99. Found: C,
60.02; H, 8.98.
3.4. (2S,4R,5R)-4-O-Benzyl-1,2-O-bis-(tert-
butyldimethylsilyl)-3,3-difluorohexane-1,2,4,5,6-pentol (8)
A mixture of compound 7 (1380 mg, 2.46 mmol) and tin(II)
chloride (1242 mg, 4.92 mmol) were in anhydrous CH2Cl2 was
stirred at room temperature for 0.5 h. The reaction was
monitored by TLC with hexanes/EtOAc (4/1). The undissolved
tin chloride was removed by filtration, and the filtrate was
neutralized with saturated NaHCO3 solution. The organic layer
was dried over anhydrous Na2SO4. After the solvent was
removed, the residue was purified by silica gel column
chromatography (petroleum ether:ethyl acetate = 3:1) to give 7
(1114 mg, 87%) as a clear oil: [a]D25 = +10.5 (c 0.55, CHCl3);
1H NMR (300 MHz, CDCl3) d 7.35–7.30 (m, 5H), 4.82 (d,
J = 10.5 Hz, 1H), 4.72 (d, J = 10.8 Hz, 1H), 4.01–3.93 (m, 3H),
3.82–3.71 (m, 4H), 2.87 (br, 2H), 0.93, 0.90 (2s, 18H), 0.16,
0.15 (2s, 6H), 0.06 (s, 6H); 19F NMR (282 MHz, CDCl3) d
À112.5 (dt, J = 268.2, 9.3 Hz, 1F), À114.3 (dt, J = 265.6,
14.4 Hz, 1F); MS (ESI) m/z 521.1 (M + H+), 543.0 (M + Na+);
IR (thin film) ymax 3301, 2931, 2859, 1473, 1256, 1139, 1051,
838 cmÀ1; Anal. Calcd for C28H50F2O5Si2: C, 57.71; H, 8.91.
Found: C, 57.87; H, 8.75.

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X.-H. Xu et al. / Journal of Fluorine Chemistry 128 (2007) 535–539
3.5. (2S,4R,5R)-4-O-Benzyl-6-O-benzoyl-2-O-(tert-
butyldimethylsilyl)-3,3-difluorohexane-1,2,4,5,6-pentol (9)
(d, J = 7.8 Hz, 2H), 7.15–6.97 (m, 5H), 4.78 (d, J = 11.1 Hz,
1H), 4.49–4.38 (m, 3H), 4.31 (dd, J = 12.3 Hz, 3.3 Hz, 1H),
4.16 (dd, J = 17.4 Hz, 4.8 Hz, 1H), 3.88–3.78 (m, 3H), 0.77 (s,
9H), 0.03, 0.00 (2s, 6H); 19F NMR (282 MHz, CDCl3) d À107.5
(dt, J = 246.5 Hz, 5.9 Hz, 1F), À118.7 (dd, J = 246.2 Hz,
13.5 Hz, 1F); 13C NMR (75.5 MHz, CDCl3) d 166.4 (dd, JC–
F = 8.1 Hz, 2.4 Hz), 165.6, 135.8, 133.4, 129.7, 129.2, 128.6,
128.4, 117.9 (dd, JC–F = 257.2 Hz, 249.8 Hz), 75.3 (dd, JC–
F = 6.0 Hz, 1.9 Hz), 75.0 (d, JC–F = 3.1 Hz), 71.8 (dd, JC–
F = 23.5 Hz, 19.3 Hz), 71.4 (dd, JC–F = 21.1 Hz, 16.5 Hz), 61.8,
25.4, 18.3, À4.9, À5.6; MS (ESI) m/z 507.2 (M + H+), 524.3
To a solution of compound 8 (1040 mg, 2.00 mmol) in
anhydrous CH2Cl2 (10 mL) and pyridine (5 mL) was slowly
added a solution of BzCl (0.22 mL, 2 mmol) in CH2Cl2 (1.5 mL)
at À78 8C. After the mixture was stirred at the same temperature
for 2 h, MeOH (2 mL) was added and the mixture was stirred for
30 min. Then water was added to quench the reaction. The layers
were separated and the aqueous layer was extracted with ether.
The combined organic layers were washed with 1N HCl,
saturated aqueous NaHCO3 and brine. After the resultant
solution was dried over anhydrous Na2SO4 and filtered, the
solvent was removed in vacuo. The residue was purified by silica
gel column chromatography (petroleum ether:ethyl acet-
ate = 12:1) to give 1.142 g product with the primary hydroxyl
protected by benzoyl group. This compound then was dissolved
in MeOH (30 mL), cooled to 0 8C and p-TsOH (348 mg,
1.83 mmol) was added. The reaction was stirred at 0 8C for 2 h
and then partitioned between EtOAc (60 mL) and saturated
aqueous NaHCO3 and saturated aqueous NaCl (15 mL each).
The aqueous layer was separated and washed with EtOAc
(30 mL each). The organic layers were combined and washed
with saturated aqueous NaCl (30 mL). The organic extracts were
then dried over MgSO4, filtered, and concentrated in vacuo.
Purification of the residue by silica gel column chromatography
(petroleum ether:ethyl acetate = 3:1) afforded 9 (541 mg) as a
clear oil: [a]D27 = +36.7 (c 0.50, CHCl3); 1H NMR (300 MHz,
CDCl3) d 7.87 (d, J = 7.5 Hz, 2H), 7.40 (t, J = 7.2 Hz, 1H), 7.28
(d, J = 7.5 Hz, 2H), 7.18–7.12(m, 5H), 4.68(d, J = 11.1 Hz, 1H),
4.60 (d, J = 11.1 Hz, 1H), 4.50–3.35 (m, 2H), 4.20–4.15 (m, 1H),
4.05–3.91 (m, 2H), 3.67 (dd, J = 12.0 Hz, 3.6 Hz, 1H), 3.59 (dd,
J = 11.7 Hz, 5.4 Hz, 1H), 2.44 (br, 2H), 0.77 (s, 9H), 0.00, À0.01
(2s, 6H); 19F NMR (282 MHz, CDCl3) d À113.0 (dd, J = 27.3,
13.8 Hz, 2F); 13C NMR (75.5 MHz, CDCl3) d 166.9, 136.9,
133.1, 129.7, 128.5, 128.4, 128.2, 128.1, 122.0 (t, JC–
F = 251.1 Hz), 78.5 (t, JC–F = 23.5 Hz), 75.6, 74.5 (t, JC–
F = 27.2 Hz), 69.5 (t, JC–F = 2.7 Hz), 66.3 (t, JC–F = 2.6 Hz),
62.5 (t, JC–F = 4.3 Hz), 25.7, 18.1, À4.8, À5.0; MS (ESI) m/z
511.2(M + H+), 533.2(M + Na+);IR(thinfilm)ymax 3462, 2935,
2859, 1723, 1457, 1278, 1126, 838 cmÀ1; HRMS (ESI) calcd for
C26H36F2O6SiNa 533.2141, found 533.2145.
+
(M + NH4 ); IR (thin film) ymax 2931, 2860, 1778, 1727, 1454,
1267, 1168, 841 cmÀ1; HRMS (ESI) calcd for C26H32F2O6-
SiNa 529.1828, found 529.1831.
3.7. 4-O-Benzyl-2-O-(tert-butyldimethylsilyl)-3-deoxy-3,3-
difluoro-D-ribohexose (11)
To a solution of 10 (360 mg, 0.71 mmol) in anhydrous
CH2Cl2 (15 mL) was added a 1 M solution of DIBALH in
cyclohexane (3.0 mL, 3.0 mmol) dropwise at À78 8C. The
reaction mixture was stirred at this temperature for 1 h. MeOH
(10 mL) was added dropwise, and the mixture was allowed to
warm to rt. The resultant suspension was filtered through Celite,
and the filter was washed with MeOH (3Â 20 mL). The filtrate
was concentrated in vacuo and the residue was purified by flash
chromatography (petroleum ether:ethyl acetate = 2:1) to afford
11 (210 mg, 73%) as a clear oil: [a]D26 = +47.9 (c 1.00,
1
CHCl3); H NMR (300 MHz, CDCl3) d, major 7.35–7.30 (m,
5H), 4.92 (d, J = 12.0 Hz, 1H), 4.75 (d, J = 7.5 Hz, 1H), 4.64 (d,
J = 11.7 Hz, 1H), 3.87–3.49 (m, 6H), 1.77 (s, 2H), 0.93 (s, 9H),
0.15 (s, 6H), minor 7.35–7.30 (m, 5H), 5.14 (s, 1H), 4.75–4.64
(m, 2H), 3.87–3.49 (m, 6H), 1.77 (s, 2H), 0.93 (s, 9H), 0.15 (s,
6H); 19F NMR (282 MHz, CDCl3) d, major À111.8 (d,
J = 243.9 Hz, 1F), À132.3 (dt, J = 243.1 Hz, 18.6 Hz, 1F),
minor À108.9 (d, J = 245.9 Hz, 1F), À127.1 (dt, J = 247.0 Hz,
19.5 Hz, 1F); 13C NMR (75.5 MHz, CDCl3) d, major 136.9,
128.5, 128.3, 128.2, 120.1 (t, JC–F = 251.3 Hz), 95.7 (d, JC–
F = 9.8 Hz), 74.8 (t, JC–F = 3.2 Hz), 74.4 (t, JC–F = 18.5 Hz),
74.1 (t, JC–F = 18.5 Hz), 73.5 (d, JC–F = 7.5 Hz), 61.4, 25.6,
18.3, À4.6, À5.1 (d, JC–F = 1.7 Hz), minor 137.0, 128.5, 128.3,
128.2, 120.1 (t, JC–F = 251.3 Hz), 92.6 (d, JC–F = 8.0 Hz), 74.9
(t, JC–F = 3.9 Hz), 73.5 (t, JC–F = 18.4 Hz), 74.4 (dd, JC–
F = 19.1 Hz, 17.7 Hz), 69.1 (d, JC–F = 6.8 Hz), 61.1, 25.5, 18.1,
3.6. (2S,4R,5R)-4-Benzyloxy-6-benzoyloxy-2-(tert-
butyldimethylsilyloxy)-3,3-difluorotetrahydropyran-2-one
(10)
À5.0 (d,
J
C–F = 2.0 Hz), À5.2; MS (ESI) m/z 422.2
+
(M + NH4 ), 427.2 (M + Na+); IR (thin film) ymax 3400,
2931, 1706, 1473, 1362, 1249, 1099, 840 cmÀ1; HRMS (ESI)
calcd for C19H30F2O5SiNa 427.1723, found 427.1723.
2,2,6,6-Tetramethyl-1-piperidinyloxy (TEMPO) (0.4 mg,
0.025 mmol) was added at 0 8C to a solution of compound 9
(615 mg, 1.21 mmol) and trichloroisocyanuric acid (TCCA)
(562 mg, 2.42 mmol) in methylene chloride (20 mL). The
reaction mixture was stirred for 15 min at room temperature
and then filtered. The solvent was removed in vacuo and the
residue was purified by flash chromatography (petroleum
ether:ethyl acetate = 6:1) to afford 10 (440 mg, 72%) as a clear
oil: [a]D25 = +100.0 (c 0.75, CHCl3); 1H NMR (300 MHz,
CDCl3) d 7.72 (d, J = 8.4 Hz, 2H), 7.40 (t, J = 7.8 Hz, 1H), 7.25
3.8. 3-Deoxy-3,3-difluoro-D-ribohexose (1)
To a solution of 11 (96 mg, 0.24 mmol) in THF (6 mL) was
added 4 M HCl (4 mL). The reaction mixture was stirred at
room temperature for 4 h. Then the reaction mixture was
concentrated in vacuo and the residue was purified by flash
chromatography (ethyl acetate:MeOH = 10:1) to afford 62 mg
product. A suspension of Pd/C (62 mg) and the above product

X.-H. Xu et al. / Journal of Fluorine Chemistry 128 (2007) 535–539
539
[3] (a) For review of monofluoro sugars, see: K. Dax, M. Albert, J. Ortner,
B.J. Paul, Carbohydr. Res. 327 (2000) 47–86;
in MeOH (10 mL) was stirred under a hydrogen atmosphere
over night. Filtration and removal of the solvent gave the crude
product, which was purified by column chromatography on
silica gel (CH2Cl2/MeOH = 5:1) to give 1 (54 mg, 83%) as an
oil: [a]D22 = +28.2 (c 0.50, CH3OH); 1H NMR (300 MHz,
CDCl3) d, major 4.62 (dd, J = 7.8 Hz, 1.8 Hz, 1H), 3.85 (dt,
J = 12.0 Hz, 1.8 Hz, 1H), 3.78–3.62 (m, 3H), 3.47–3.36 (m,
1H), minor 5.20 (t, J = 4.8 Hz, 1H), 3.94 (dt, J = 10.2 Hz,
3.3 Hz, 1H), 3.78–3.62 (m, 1H), 3.47–3.36 (m, 3H); 19F NMR
(282 MHz, CDCl3) d, major À118.2 (dt, J = 242.2 Hz, 4.5 Hz,
1F), À137.3 (dd, J = 242.5 Hz, 20.9 Hz, 1F), minor À115.0
(ddd, J = 239.7 Hz, 10.2 Hz, 4.8 Hz, 1F), À132.3 (dt,
J = 240.8 Hz, 19.2 Hz, 1F); 13C NMR (75.5 MHz, CDCl3) d,
major 121.0 (dd, JC–F = 250.7 Hz, 243.5 Hz), 96.8 (d, JC–
F = 9.7 Hz), 76.1 (d, JC–F = 7.0 Hz), 74.1 (t, JC–F = 19.3 Hz),
69.1 (t, JC–F = 20.2 Hz), 62.1 (d, JC–F = 1.7 Hz), minor 120.9
(dd, JC–F = 249.0 Hz, 247.6 Hz), 93.3 (dd, JC–F = 9.2 Hz,
2.0 Hz), 71.1 (d, JC–F = 6.8 Hz), 70.5 (t, JC–F = 19.6 Hz),
68.7 (t, JC–F = 19.9 Hz), 61.9 (d, JC–F = 1.1 Hz); MS (ESI) m/z
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Acknowledgements
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6743.
We thank the National Natural Science Foundation of China,
Ministry of Education of China and Shanghai Municipal
Scientific Committee for funding this work.
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