Modified Julia olefination on sugar-derived lactones: Synthesis of difluoro exo-glycals

Article abstract of DOI:10.1002/ejoc.201403175

We report the preparation of difluoro-exo-glycals by gem-difluoroolefination of benzylated sugar-derived lactones using a modified Julia reaction. The addition is highly stereo-selective, and the Smiles-rearrangement-elimination sequence can be carried out under microwave irradiation.

Full text of DOI:10.1002/ejoc.201403175

Job/Unit: O43175
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Date: 18-12-14 12:38:27
Pages: 6
FULL PAPER
DOI: 10.1002/ejoc.201403175
Modified Julia Olefination on Sugar-Derived Lactones: Synthesis of Difluoro-
exo-glycals
Samuel Habib[a] and David Gueyrard*[a]
Keywords: Fluorine / Carbohydrates / Glycals / Lactones / Olefination
We report the preparation of difluoro-exo-glycals by gem-
selective, and the Smiles-rearrangement–elimination se-
difluoroolefination of benzylated sugar-derived lactones quence can be carried out under microwave irradiation.
using a modified Julia reaction. The addition is highly stereo-
in 1993 by the same group.[5] An indirect method involving
Introduction
an addition–elimination sequence was described in 2006 by
C-Glycosylidenes or exo-glycals are C-glycosyl com-
Bonnet-Delpon.[6] These compounds are useful synthetic
pounds having a carbon–carbon double bond at the anom-
intermediates, and they have been used by Sinaÿ for the
eric center.[1] Over the last decade, we have been involved
preparation of fluorinated analogs of UDP-C-d-galactofur-
in the synthesis of diversely functionalized exo-glycals by
anose,[7] and for the synthesis of 5a-gem-difluorocarba-α-d-
the modified Julia olefination of sugar-derived lactones.[2]
glucopyranose.[8]
We now report the synthesis of difluoro-exo-glycals using
difluoromethyl-2-pyridyl sulfone (Scheme 1).[3]
Results and Discussion
We started with difluoromethyl-2-benzothiazolyl sulfone
and 2,3,4,6-tetra-O-benzyl-d-gluconolactone as typical sub-
strates. The sulfone was prepared by two different methods
Scheme 1. Julia olefination of sugar-derived lactones.
developed by Hu[9] and Lequeux,[10] which gave similar
The synthesis of difluoro-exo-glycals was first reported in yields (Scheme 2).
1989 by Motherwell[4] using dibromodifluoromethane and
The results of this initial study are given in Table 1. Un-
HMPA (hexamethylphosphoramide), and it was improved der our standard, two-step reaction conditions (Table 1, en-
Scheme 2. Synthesis of difluorinated benzothiazolyl sulfone; Btz = benzothiazolyl, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, TMG =
1,1,3,3-tetramethylguanidine, NFSI = N-fluorobenzenesulfonimide.
[a] Université de Lyon, ICBMS, UMR 5246 – CNRS, Bat. 308 –
try 1),[2] the difluorinated exo-glycal was obtained in low
Curien (CPE Lyon), Université Claude Bernard Lyon 1,
yield (15%). We therefore investigated the nature of the
base [LiHMDS (lithium hexamethyldisilazide) or tBuOK]
and the Lewis acid (BF3 or TiCl4), and the sulfone/lactone
ratio. Changing the nature of the base and/or the Lewis acid
43 Bd du 11 Novembre 1918, 69622 Villeurbanne, France
E-mail: gueyrard@univ-lyon1.fr
http://www.icbms.fr/co2glyco/goekjian/cv-david-gueyrard
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403175.
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S. Habib, D. Gueyrard
FULL PAPER
did not improve the yield significantly (Table 1, entries 1–4). resulting intermediate was unreactive, since the Smiles re-
When we used an excess (1.5 equiv.) of the sulfone, the yield arrangement did not occur in the presence of DBU at room
increased to 25%. The best results were obtained when the temperature.
reaction was carried out with a slight excess (1.2 equiv.) of
the lactone (32% yield). Further increasing the amount of
lactone to 1.5 equiv. did not improve the yield (21%).
After a brief optimization of the addition step, the inter-
mediate was obtained in 69% yield by using 1.0 equiv. of
difluoromethyl-2-pyridyl sulfone 11, 2.0 equiv. of lactone,
2.0 equiv. of LiHMDS, and 2.0 equiv. of boron trifluoride–
diethyl ether in THF at low temperature (Scheme 5). A de-
scribed by Shen et al.,[3] we observed that the addition was
highly stereoselective, and that the compound with the
hydroxy group in the axial position was formed exclusively.
We then turned our attention to the elimination step,
starting from the intermediate. We decided to investigate
this transformation under basic, acidic, and thermal condi-
tions.
Under base-catalyzed conditions, we observed that the
Smiles rearrangement did not occur in the presence of
NaHMDS. The use of sodium hydride in THF provided the
difluoro-exo-glycal in poor yield (27%). The use of sodium
hydride in other solvents or the use of cesium carbonate led
to retroaddition. We then explored the possibility of carry-
ing out the Smiles rearrangement under acidic condi-
tions.[9b] We found that triflic acid in dichloromethane at
Table 1. Julia olefination of a sugar-derived lactone.
Entry Sulfone
(equiv.)
Lactone Base
(equiv.)
Lewis acid
Yield
[%]
1
2
3
4
5
6
7
1.2
1.2
1.2
1.2
1.5
1
1
1
1
1
1
1.2
1.5
LiHMDS BF3·Et2O
tBuOK BF3·Et2O
LiHMDS TiCl4
tBuOK TiCl4
LiHMDS BF3·Et2O
LiHMDS BF3·Et2O
LiHMDS BF3·Et2O
15
14
18
15
25
32
21
1
Inspired by the work of Hu[9] using difluoromethyl-2- room temperature was not effective for this transformation,
pyridyl sulfone in a modified Julia olefination with alde- and led instead to decomposition. We ran the reaction using
hydes and ketones,[11] we decided to modify the nature of trifluoroacetic acid (TFA) in dichloromethane at 50 °C, and
the heterocyclic moiety. Thus, the pyridyl sulfone was pre- obtained the desired compound in moderate yield (64%).
pared following a similar approach to that used for the With the same acid, the use of toluene at 70 °C allowed us
benzothiazolyl sulfone (Scheme 3).
to increase the yield to 85%. Finally, we decided to investi-
Under our standard conditions using DBU in the second gate the reaction under thermal conditions (toluene at re-
step, we were surprised to observe that the reaction pro- flux), and we observed that by heating in refluxing toluene
duced mainly the hemiketal intermediate in good yield for 4 h, the transformation occurred in a satisfactory yield
(62%; Scheme 4). This result showed that the pyridyl sulf- (81%). In order to reduce the reaction time, the reaction
one was suitable for the nucleophilic addition of the lithi- was carried out in a microwave oven at 140 °C for 1 h in
ated sulfone onto the sugar-derived lactone, and that the toluene, and the desired compound was obtained in 93%
Scheme 3. Synthesis of difluorinated pyridyl sulfone.
Scheme 4. Use of difluorinated pyridyl sulfone.
2
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Synthesis of Difluoro-exo-glycals
Scheme 5. Optimization of the addition step.
yield (Table 2). We also showed that, similarly to our pre-
The reaction gave the difluoromethylene-exo-glycals in
vious work, we could perform the sequence under our opti- good yields (58–69%) with benzyl-protected sugar-derived
mized conditions without purification of the hemiketal in- lactones. The reaction was shown to proceed efficiently in
termediate without loss of yield.
both pyranose (d-gluco, d-galacto, d-manno, 2-deoxy-d-
gluco) and furanose (d-arabino) sugar series. However, the
reaction did not provide the desired product with silyl-pro-
tected sugar lactones. This could be due to the presence of
boron trifluoride in the first step. In addition, the presence
of a 2,3-diisopropylidene protecting group in furanose-de-
rived lactones significantly decreased the overall yield of the
sequence (to 7 and 19%).
Table 2. Optimization of the elimination step.
Entry Acid Base
Solvent
T [°C]
Yield [%]
Conclusions
1
2
3
4
5
6
7
8
9
9
–
–
–
–
NaHMDS THF
NaH
NaH
NaH
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
50
no reaction
27
In summary, we have demonstrated that the gem-di-
fluoroolefination of benzylated sugar-derived lactones by a
modified Julia olefination can be achieved in good yields.
This reaction is competitive in term of yield and number of
steps compared to the Motherwell[4] and Bonnet-Delpon[5]
methods, respectively. This transformation extends the field
of applications of modified Julia olefinations of lactones.[2]
THF
DMF
toluene
THF
CH2Cl2
CH2Cl2
toluene
toluene
toluene
retroaddition
retroaddition
retroaddition
degradation
64
–
CsCO3
TfOH
TFA
TFA
–
–
–
–
–
–
70
110
85
81
–
140 (microwave) 93
To evaluate the scope and limitations of this method, we
Experimental Section
carried out the modified Julia olefination with a variety of
sugar-derived lactones under the optimized reaction condi-
tions for the two-step process (Scheme 6).
General Methods: All reactions were carried out under an argon
atmosphere. Solvents were distilled and dried by standard methods.
NMR spectra were recorded at 293 K, unless otherwise stated,
using a 300, 400, or 500 MHz spectrometer. Chemical shifts are
referenced relative to residual solvent peaks. The following abbrevi-
ations are used to explain the observed multiplicities: s, singlet; d,
doublet; dd, doublet of doublets; ddd, doublet of doublet of dou-
blets; t, triplet; td, triplet of doublets; m, multiplet; br. s, broad
singlet. 13C NMR multiplicities were assigned on the basis of
DEPT experiments. Low- and high-resolution mass spectra were
recorded with a Bruker MicrOTOF-Q II XL spectrometer. Thin-
layer chromatography (TLC) was carried out on aluminium sheets
coated with silica gel 60 F254 (Merck). TLC plates were inspected
using UV light (λ = 254 nm), and developed by treatment with
H2SO4 (10% solution in EtOH/H2O, 1:1, v/v) followed by heating.
Silica gel column chromatography was carried out with silica gel Si
60 (40–63 μm).
Ethyl 2-(Pyridin-2-ylsulfonyl)acetate (13): Ethyl 2-(pyridin-2-yl-
thio)acetate (2.566 g, 12.96 mmol, 1.0 equiv.) was dissolved in eth-
anol (43 mL) in a round-bottomed flask (100 mL) under argon.
This solution was cooled to 0 °C, and ammonium molybdate
(801 mg, 0.05 equiv.) and hydrogen peroxide solution (35% aq.;
10 mL, 8.0 equiv.) were added. The reaction mixture was stirred at
room temperature overnight, then it was quenched by the addition
of water, and the mixture was extracted twice with ethyl acetate.
Scheme 6. Synthesis of difluoromethylene-exo-glycals in various
sugar series. TES = triethylsilyl; TBDPS = tert-butyldiphenylsilyl.
Eur. J. Org. Chem. 0000, 0–0
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S. Habib, D. Gueyrard
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The combined organic layers were washed with an aqueous solu-
tion of Na2S2O3, and with brine, dried with sodium sulfate, and
the solvents were evaporated. The residue was purified by flash
chromatography (petroleum ether/EtOAc, 6:4) to give compound
1 H), 4.17 (t, J = 3.8 Hz, 1 H), 3.99 (ddd, J = 9.4, 6.4, 2.9 Hz, 1
H), 3.79 (ddd, J = 6.2, 4.1, 1.1 Hz, 1 H), 3.71–3.61 (m, 3 H) ppm.
13C NMR (75.46 MHz, CDCl3): δ = 153.7 (dd, J = 290.3, 278.4 Hz,
CIV), 138.2 (CIV), 138.1 (CIV), 137.8 (CIV), 137.5 (CIV), 128.6 (CH),
128.6 (CH), 128.5 (CH), 128.1 (CH), 128.1 (CH), 128.02 (CH),
1
13 (2.715 g, 95%). H NMR (300 MHz, CDCl3): δ = 8.72 (d, J =
4.8 Hz, 1 H), 8.07 (d, J = 7.8 Hz, 1 H), 7.97 (td, J = 7.8, 1.8 Hz, 1 127.9 (CH), 127.7 (CH), 112.4 (dd, J = 38.5, 13.2 Hz, CIV), 82.4
H), 7.57 (ddd, J = 7.5, 4.5, 1.2 Hz, 1 H), 4.45 (s, 2 H), 4.08 (q, J =
(CH), 77.3 (CH), 76.9 (CH), 73.8 (CH2), 73.6 (CH2), 73.1 (t, J =
7.2 Hz, 2 H), 1.11 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (75.46 MHz, 2 Hz, CH), 73.0 (CH) ppm. 19F NMR (282 MHz, CDCl3): δ =
CDCl3): δ = 162.8, 157.0, 150.6, 138.6, 128.1, 122.8, 62.7, 56.5,
–99.76 (d, J = 74.3 Hz), –116.71 (dd, J = 74.2, 3.3 Hz) ppm. HRMS
14.2 ppm. HRMS (ESI+): calcd. for [M + Na]+ 252.0301; found (ESI+): calcd. for [M + Na]+ 595.2267; found 595.2252.
252.0304.
2,6-Anhydro-1-deoxy-1,1-difluoro-3,4,5,7-tetra-O-benzyl-
D
-
1
2-[(Difluoromethyl)sulfonyl]pyridine (11): Ethyl 2-(pyridin-2-yl-
sulfonyl)acetate (53 mg, 0.23 mmol, 1.0 equiv.) and NFSI (167 mg,
2.2 equiv.) were dissolved in THF (500 μL) in a round-bottomed
flask (10 mL) under argon at room temperature. DBU (90 μL,
3 equiv.) and water (2 drops, approximately 100 μL) were added,
and the reaction mixture was stirred overnight at 50 °C. The reac-
tion was quenched by the addition of water, and the mixture was
extracted twice with ethyl acetate. The combined organic layers
were washed with brine, and dried with sodium sulfate, and the
solvents were evaporated. The mixture was purified by flash
chromatography (petroleum ether/EtOAc, 6:4) to give compound
11 (14 mg, 30%). Data were identical to those described in the
literature.[9]
galacto-hept-1-enitol (15): H NMR (300 MHz, CDCl3): δ = 7.42–
7.23 (m, 20 H), 4.69–4.50 (m, 8 H), 4.36 (d, J = 11.7 Hz, 1 H), 4.21
(dd, J = 5.7, 3.0 Hz, 1 H), 4.00–3.93 (m, 2 H), 3.85 (dd, J = 12.0,
2.4 Hz, 3 H) ppm. 13C NMR (75.46 MHz, CDCl3): δ = 155.5 (dd,
J = 290.3, 278.4 Hz, CIV), 138.4 (CIV), 138.1 (CIV), 138.0 (CIV),
137.5 (CIV), 128.5 (CH), 128.4 (CH), 128.3 (CH), 127.9 (CH), 127.8
(CH), 127.7 (CH), 127.6 (CH), 127.5 (CH), 108.7 (dd, J = 53.1,
17.6 Hz, CIV), 78.5 (CH), 75.6 (CH), 73.4 (CH), 73.2 (CH2), 73.1
(CH2), 71.1 (t, J = 4.2 Hz, CH), 70.5 (CH), 67.4 (CH) ppm. 19F
NMR (282 MHz, CDCl3): δ = –97.48 (d, J = 63.7 Hz), –112.03
(dd, J = 63.7, 2.8 Hz) ppm. HRMS (ESI+): calcd. for [M + Na]+
595.2267; found 595.2248.
2,6-Anhydro-1-deoxy-1,1-difluoro-3,4,5,7-tetra-O-benzyl-D-manno-
1
Typical Experimental Procedure for the Synthesis of Difluorinated
hept-1-enitol (16): H NMR (400 MHz, CDCl3): δ = 7.38–7.27 (m,
13 H), 7.24–7.18 (m, 2 H), 4.89 (d, J = 10.9 Hz, 1 H), 4.72 (d, J =
11.6 Hz, 1 H), 4.69–4.62 (m, 2 H), 4.58 (d, J = 10.9 Hz, 1 H), 4.54
(d, J = 12.1 Hz, 1 H), 3.84–3.76 (m, 2 H), 3.75 (d, J = 8.9 Hz, 1
H), 3.67 (m, 1 H), 3.58 (dt, J = 9.1, 2.9 Hz, 1 H), 2.83 (dt, J =
13.8, 3.7 Hz, 1 H), 2.24–2.11 (m, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 153.1 (dd, J = 287.2, 276.7 Hz, CIV), 138.4 (CIV), 138.3
(CIV), 138.2 (CIV), 128.7 (CH), 128.6 (CH), 128.2 (CH), 128.1
(CH), 128.0 (CH), 128.0 (CH), 127.9 (CH), 127.9 (CH), 112.5 (dd,
J = 43.9, 15.7 Hz, CIV), 81.0 (CH), 79.2 (dd, J = 3.0, 1.8 Hz, CH),
77.4 (CH), 75.2 (CH2), 73.8 (CH2), 72.0 (CH2), 68.7 (CH2), 27.6
(d, J = 2.3 Hz, CH2) ppm. 19F NMR (376 MHz, CDCl3): δ =
–103.20 (dd, J = 74.8, 6.4 Hz), –117.41 (dt, J = 74.7, 3.7 Hz) ppm.
HRMS (ESI+): calcd. for [M + Na]+ 489.1848; found 489.1838.
exo-Glycals:
Tetra-O-benzyl-d-gluconolactone
7
(402 mg,
0.878 mmol, 2.0 equiv.), 2-difluoromethylsulfonylpyridine (85 mg,
1.0 equiv.), and boron trifluoride–diethyl ether (108 μL, 2.0 equiv.)
were dissolved in freshly distilled THF (1.7 mL) in a round-bot-
tomed flask (10 mL) at –78 °C under argon. LiHMDS (1 m solu-
tion in THF; 880 μL, 2.0 equiv.) was added dropwise over 10 min.
The mixture was stirred for a further 30 min, and then the reaction
was quenched by the addition of water. The mixture was extracted
twice with ethyl acetate. The combined organic layers were washed
with brine, and dried with sodium sulfate, and the solvents were
evaporated.
The residue was dissolved in dry toluene (3 mL), and the solution
was heated to 140 °C in a microwave oven for 1 h. The mixture
was concentrated in vacuo, and the residue was purified by flash
chromatography (petroleum ether/EtOAc, 9:1) to give compound 8
(161 mg, 64%).
2,6-Anhydro-1-deoxy-1,1-difluoro-3,4,5,7-tetra-O-benzyl-D-manno-
1
hept-1-enitol (17): H NMR (400 MHz, CDCl3): δ = 7.39–7.21 (m,
18 H), 7.14 (dd, J = 7.2, 1.9 Hz, 2 H), 4.91 (d, J = 10.8 Hz, 1 H),
4.69 (d, J = 12.4 Hz, 1 H), 4.63 (d, J = 12.0 Hz, 1 H), 4.57–4.44
(m, 4 H), 4.35–4.29 (m, 2 H), 4.17 (t, J = 9.6 Hz, 1 H), 3.78 (d, J
= 3.1 Hz, 2 H), 3.56 (dd, J = 9.5, 3.5 Hz, 2 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 154.2 (dd, J = 294.7, 281.2 Hz, CIV), 138.5
(CIV), 138.4 (CIV), 138.1 (CIV), 137.7 (CIV), 128.6 (CH), 128.6
(CH), 128.5 (CH), 128.2 (CH), 128.1 (CH), 128.0 (CH), 128.0
(CH), 127.9 (CH), 127.8 (CH), 112.5 (dd, J = 41.0, 12.2 Hz, CIV),
82.0 (CH), 81.7 (dd, J = 3.1, 1.3 Hz, CH), 75.7 (CH2), 74.1 (CH),
73.7 (CH2), 71.6 (CH2), 70.2 (CH2), 69.1 (CH2), 67.9 (t, J = 3.0 Hz,
CH) ppm. 19F NMR (376 MHz, CDCl3): δ = –98.09 (dd, J = 63.7,
2.7 Hz), –113.60 (dd, J = 63.7, 3.0 Hz) ppm. HRMS (ESI+): calcd.
for [M + Na]+ 595.2267; found 595.2252.
1-C-(Pyridine-2-yl-sulfonyldifluoromethyl)-2,3,4,6-tetra-O-benzyl-
D
-glucopyranoside (14): 1H NMR (500 MHz, CDCl3): δ = 8.82
(ddd, J = 4.7, 1.6, 0.7 Hz, 1 H), 8.20 (d, J = 7.9 Hz, 1 H), 7.90 (td,
J = 7.8, 1.7 Hz, 1 H), 7.57 (ddd, J = 7.7, 4.7, 1.0 Hz, 1 H), 7.41–
7.24 (m, 18 H), 7.24–7.20 (m, 2 H), 4.93–4.88 (m, 2 H), 4.86–4.83
(m, 2 H), 4.76 (d, J = 10.3 Hz, 1 H), 4.65 (d, J = 10.9 Hz, 1 H),
4.61 (d, J = 12.1 Hz, 1 H), 4.53 (d, J = 12.1 Hz, 1 H), 4.09–4.01
(m, 3 H), 3.79–3.73 (m, 2 H), 3.62 (dd, J = 11.6, 1.6 Hz, 1 H) ppm.
13C NMR (126 MHz, CDCl3): δ = 154.0 (CIV), 150.6 (CH), 138.5
(CIV), 138.4 (CIV), 138.3 (CH), 138.05 (CIV), 137.4 (CIV), 128.6
(CH), 128.5 (CH), 128.5 (CH), 128.5 (CH), 128.4 (CH), 128.3
(CH), 128.0 (CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 127.6
(CH), 126.2 (CH), 119.5 (dd, J = 303.0, 301.0 Hz, CIV), 97.8 (dd,
J = 25.2, 23.8 Hz, CIV), 83.2 (CH), 78.9 (CH), 77.3 (CH), 76.0
(CH2), 75.5 (CH2), 75.2 (CH2), 73.6 (CH2), 73.1 (CH), 68.1 (CH2)
ppm. 19F NMR (471 MHz, CDCl3): δ = –107.55 (dd, J = 331.7,
237.8 Hz) ppm. HRMS (ESI+): calcd. for [M + H]+ 732.2437;
found 732.2463.
2,5-Anhydro-1-deoxy-1,1-difluoro-3,4,6-tri-O-benzyl-D-arabino-
1
hept-1-enitol (19): H NMR (300 MHz, CDCl3): δ = 7.39–7.23 (m,
15 H), 4.62 (d, J = 3.3 Hz, 1 H), 4.53 (m, 6 H, 5 H), 4.38 (d, J =
11.7 Hz, 1 H), 4.11 (br. s, 1 H), 3.64 (ddd, J = 27.4, 10.0, 6.7 Hz,
2 H) ppm. 13C NMR (75.46 MHz, CDCl3): δ = 151.4 (dd, J =
282.7, 264.0 Hz, CIV), 138.1 (CIV), 137.5 (CIV), 137.3 (CIV), 128.8
(CH), 128.7 (CH), 128.7 (CH), 128.3 (CH), 128.2 (CH), 128.1
(CH), 128.0 (CH), 119.1 (dd, J = 49.3, 13.1 Hz), 85.9 (CH), 83.4
2,6-Anhydro-1,3-dideoxy-1,1-difluoro-4,5,7-tri-O-benzyl-
hept-1-enitol (8): H NMR (300 MHz, CDCl3): δ = 7.34–7.01 (m,
D
-gluco-
1
20 H), 4.65–4.54 (m, 3 H), 4.54–4.40 (m, 4 H), 4.35 (d, J = 11.7 Hz, (CH), 79.1 (t, J = 4.0 Hz, CH), 73.6 (CH2), 71.9 (CH2), 71.2 (CH2),
4
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Synthesis of Difluoro-exo-glycals
69.5 (CH2) ppm. 19F NMR (282 MHz, CDCl3): δ = –103.40 (dd, J
= 89.4, 2.0 Hz), –118.13 (dd, J = 89.4, 2.1 Hz) ppm. HRMS (ESI+):
calcd. for [M + Na]+ 475.1691; found 475.1691.
Fontaine, P. G. Goekjian, D. Gueyrard, Tetrahedron Lett. 2008,
49, 747–749; c) B. Bourdon, M. Corbet, D. Gueyrard, P. G.
Goekjian, Tetrahedron Lett. 2008, 49, 750–754; d) L. Tomas,
D. Gueyrard, P. G. Goekjian, Tetrahedron Lett. 2010, 51, 4599–
4601; e) L. Tomas, G. Boije af Gennäs, M. A. Hiebel, P. Hamp-
son, D. Gueyrard, B. Pelotier, J. Yli-Kauhaluoma, O. Piva,
J. M. Lord, P. G. Goekjian, Chem. Eur. J. 2012, 18, 7452–7466.
For the synthesis of monofluorinated exo-glycals, see: f) S.
Habib, F. Larnaud, E. Pfund, T. Mena Barragan, T. Lequeux,
C. Ortiz-Mellet, P. G. Goekjian, D. Gueyrard, Eur. J. Org.
Chem. 2013, 10, 1872–1875; g) S. Habib, F. Larnaud, E. Pfund,
T. Lequeux, B. Fenet, P. G. Goekjian, D. Gueyrard, Org. Bio-
mol. Chem. 2014, 12, 690–699.
2,5-Anhydro-1-deoxy-1,1-difluoro-3,4-diisopropylidene-6-O-tert-
1
butyldimethylsilyl-
D
-ribo-hept-1-enitol (20): H NMR (300 MHz,
CDCl3): δ = 7.58–7.54 (m, 4 H), 7.38–7.30 (m, 6 H), 5.34 (dd, J =
6.0, 3.0 Hz, 1 H), 4.82 (br. d, J = 5.4 Hz, 1 H), 4.40 (br. s, 1 H),
3.75 (dd, J = 11.4, 3.0 Hz, 1 H), 3.64 (dd, J = 11.4, 2.7 Hz, 1 H),
1.44 (s, 3 H), 1.34 (s, 3 H), 0.96 (s, 9 H) ppm. 19F NMR (282 MHz,
CDCl3): δ = –105.01 (d, J = 92.2 Hz), –120.82 (d, J = 92.2 Hz)
ppm. HRMS (ESI+): calcd. for [M + Na]+ 483.1774; found
483.1765.
[3] During the preparation of this manuscript, a paper was pub-
lished that reports the preparation of difluorinated 2-ketoses
by a similar strategy. The authors describe a single example of
a Smiles rearrangement to produce difluorinated exo-glycals.
X. Liu, Q. Yin, J. Yin, G. Chen, X. Wang, Q. D. You, Y. L.
Chen, B. Xiong, J. Shen, Eur. J. Org. Chem. 2014, 6150–6154.
[4] W. B. Motherwell, M. J. Tozer, B. C. Ross, J. Chem. Soc., Chem.
Commun. 1989, 19, 1437–1439.
[5] J. S. Houlton, W. B. Motherwell, B. C. Ross, M. J. Tozer, D. J.
Williams, A. M. Z. Slawin, Tetrahedron 1993, 49, 8087–8106.
[6] G. Magueur, B. Crousse, M. Ourévitch, D. Bonnet-Delpon, J.-
P. Bégué, J. Fluorine Chem. 2006, 127, 637–642.
2,5-Anhydro-1-deoxy-1,1-difluoro-3,4-diisopropylidene-D-erythro-
1
hept-1-enitol (21): H NMR (300 MHz, CDCl3): δ = 5.26 (dd, J =
6.0, 3.0 Hz, 1 H), 4.82 (m, 1 H), 4.23 (br. d, J = 10.5 Hz, 1 H),
3.89 (dd, J = 10.2, 4.2 Hz, 1 H), 1.43 (s, 3 H), 1.32 (s, 3 H) ppm.
19F NMR (282 MHz, CDCl3): δ = –102.66 (d, J = 85.4, 2.3 Hz),
–117.91 (dd, J = 85.2, 2.3 Hz) ppm. HRMS (ESI+): calcd. for [M
+ Na]+ 215.0490; found 215.0497.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H, 13C, and 19F NMR spectra of products.
[7] J. Kovensky, M. McNeil, P. Sinaÿ, Org. Chem. 1999, 64, 6202–
6205.
[8] A. Deleuze, C. Menozzi, M. Sollogoub, P. Sinaÿ, Angew. Chem.
Int. Ed. 2004, 43, 6680–6683; Angew. Chem. 2004, 116, 6848–
6851.
Acknowledgments
The authors would like to thank the Ministère de l’Enseignement
Supérieur et de la Recherche for a scholarship (to S. H.). Dr. T.
Billard is thanked for the generous gift of difluorochloromethane.
[9] a) Y. Zhao, W. Huang, L. Zhu, J. Hu, Org. Lett. 2010, 12,
1444–1447; b) B. Gao, Y. Zhao, M. Hu, C. Ni, J. Hu, Chem.
Eur. J. 2014, 20, 7803–7810.
[10] T. Lequeux, C. Calata, E. Pfund, J.-M. Catel, Tetrahedron 2009,
65, 3967–3973.
[1] a) C. Taillefumier, Y. Chapleur, Chem. Rev. 2004, 104, 263–292;
b) C. H. Lin, H. C. Lin, W. B. Yang, Curr. Top. Med. Chem.
2005, 5, 1431–1457.
[2] For the synthesis of methylene exo-glycals, see: a) D. Gueyrard,
R. Haddoub, A. Salem, N. S. Bacar, P. G. Goekjian, Synlett
2005, 520–522. For the preparation of functionalized tri- and
tetrasubstituted exo-glycals, see: b) B. Bourdon, M. Corbet, P.
[11] Recently, an efficient method for the gem-difluoroolefination
of aldehydes using potassium 2-pyridinesulfonyldifluoroacetate
was described, but this method has not been tried on sugar-
derived lactones: X. P. Wang, J. H. Lin, J. C. Xiao, X. Zheng,
Eur. J. Org. Chem. 2014, 928–932.
Received: September 5, 2014
Published Online: ᭿
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5

Job/Unit: O43175
/KAP1
Date: 18-12-14 12:38:28
Pages: 6
S. Habib, D. Gueyrard
FULL PAPER
Difluorinated Enol Ethers
We report the preparation of difluoro-exo-
glycals by olefination of sugar-derived lac-
tones using a modified Julia reaction.
S. Habib, D. Gueyrard* .................... 1–6
Modified Julia Olefination on Sugar-De-
rived Lactones: Synthesis of Difluoro-exo-
glycals
Keywords: Fluorine / Carbohydrates / Gly-
cals / Lactones / Olefination
6
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Eur. J. Org. Chem. 0000, 0–0