2-Dichloromethyl-1,3-dioxolan-2-yl orthoesters. A potential protecting group for sugar derivatives

Article abstract of DOI:10.1081/CAR-120016854

Reactions of 2-dichloromethylene-1,3-dioxolane (2) with acetal protected sugar derivatives in neutral media gave 2-dichloromethyl-1,3-dioxolan-2-yl orthoesters. These orthoesters are readily hydrolysed under mild acidic conditions offering a new method for the preparation of readily removable protecting groups. This strategy was realised in the preparation of 6-O-acetyl-3,5-di-O-methyl-1,2-O-isopropylidene-α-D-glucofuranose.

Full text of DOI:10.1081/CAR-120016854

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2-DICHLOROMETHYL-1,3-DIOXOLAN-2-YL
ORTHOESTERS. A POTENTIAL PROTECTING GROUP FOR
SUGAR DERIVATIVES
a
b
H. Özgener & L. Yüceer
a
Department of Chemistry, Faculty of Science, Ege University, Bornova, Izmir, Turkey
Department of Chemistry, Faculty of Science, Ege University, Bornova, Izmir, Turkey
b
Published online: 16 Aug 2006.
To cite this article: H. Özgener & L. Yüceer (2002) 2-DICHLOROMETHYL-1,3-DIOXOLAN-2-YL ORTHOESTERS. A POTENTIAL
PROTECTING GROUP FOR SUGAR DERIVATIVES, Journal of Carbohydrate Chemistry, 21:6, 559-567
To link to this article: http://dx.doi.org/10.1081/CAR-120016854
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 21, No. 6, pp. 559–567, 2002
2
-DICHLOROMETHYL-1,3-DIOXOLAN-2-YL
ORTHOESTERS. A POTENTIAL PROTECTING
GROUP FOR SUGAR DERIVATIVES
¨
H. Ozgener and L. Y u¨ ceer
*
Department of Chemistry, Faculty of Science, Ege University,
Bornova, Izmir, Turkey
ABSTRACT
Reactions of 2-dichloromethylene-1,3-dioxolane (2) with acetal protected
sugar derivatives in neutral media gave 2-dichloromethyl-1,3-dioxolan-2-yl
orthoesters. These orthoesters are readily hydrolysed under mild acidic con-
ditions offering a new method for the preparation of readily removable pro-
tecting groups. This strategy was realised in the preparation of 6-O-acetyl-
3,5-di-O-methyl-1,2-O-isopropylidene-a-D-glucofuranose.
Key Words: Sugar derivatives; Protecting groups; Orthoesters; Ketene
acetals
INTRODUCTION
The importance of protecting groups in carbohydrate chemistry is well known
[1]
and many such groups are widely used. However, a wider choice of protecting
groups would be useful and might help to solve some specific problems. Protection
of a single hydroxyl group without using an acidic or basic medium, and its re-
moval under very mild acidic conditions may be beneficial in some cases. Or-
*
Corresponding author. E-mail: yuceer@sci.ege.edu.tr
5
59
DOI: 10.1081/CAR-120016854
0732-8303 (Print); 1532-2327 (Online)
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Copyright D 2002 by Marcel Dekker, Inc.

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¨
OZGENER AND YUCEER
¨
560
[
2]
thoester
groups are base stable and can be removed like cyclic acetals under
acidic conditions. 2-Dichloromethyl-1,3-dioxolan-2-yl orthoesters reported here are
comparable to the isopropylidene acetals in terms of acid stability, but unlike cyclic
acetals, they can be prepared without any acid catalyst and used for the protection
of a single hydroxyl group. Related to this work, reactions of sugars with the ketene
acetal 1,1-dimethoxyethene under kinetic control to give cyclic orthoesters have been
[
3,4]
described.
RESULTS AND DISCUSSION
[5]
The ketene acetal 2-dichloromethylene-1,3-dioxolane
5]
dehydrochlorination of 2-trichloromethyl-1,3-dioxolane
(2) was prepared by
(1) with potassium t-
[
butoxide in t-butyl alcohol at room temperature and was purified by crystallization
from petroleum ether. The ketene acetal 2 was prepared freshly prior to the
orthoester reaction since it was sensitive to atmospheric moisture. In most cases, the
solvent was evaporated under reduced pressure, the product was extracted with
petroleum ether, and 2 was obtained as a solid after removal of the solvent and used
À 1
6]
as such. The IR spectrum of pure 2 contained a sharp peak at 1702 cm
[
due to
When the product was partially hydrolyzed, a
carbonyl (1753 cm ) and a hydroxyl peak (3380 cm ) appeared. This method
was used as a test to monitor the purity of 2. Alternatively 2 can be purified by
distillation under reduced pressure according to the method of McElvaine and
the ketene acetal double bond.
À 1
À 1
[
5]
Curry.
Nitromethane was the most suitable solvent for reactions of 2 with sugar de-
rivatives. When the solubility of the substrate in this solvent was satisfactory, the
reaction was completed at a relatively low temperature. In one case, an N,N-dime-
thylformamide-nitromethane mixture was used. However N,N-dimethylformamide was
not preferred due to the difficulties in drying of this solvent completely. Excess of 2
was usually necessary to complete the reaction.
2-Dichloromethyl-1,3-dioxolan-2-yl orthoesters reported here were difficult to
crystallise but they could be purified by chromatography on silica gel. These ortho-
esters were sensitive to acidic conditions, hence the solvents must be free of traces of
acid. Although the total yields of the orthoester derivatives were reasonable, the
yields of the individual compounds were low due to the low regioselectivity which is
somewhat less than that of the tosyl esters. This low regioselectivity reduces the
efficiency of this method as a protecting group for polyhydroxy compounds. Never-
theless, we think that the method may be useful in some applications especially
where acidic and basic media are not preferred.
The reactivity of ketene acetal 2 towards a primary hydroxyl group was de-
[7]
monstrated by its reaction with 1,2:3,4-di-O-isopropylidene-a-D-galactopyranose (3)
which yielded 6-O-(2-dichloromethyl-1,3-dioxolan-2-yl)-1,2:3,4-di-O-isopropylidene-a-
D-galactopyranose (4) (63%). Furthermore 1,2:5,6-di-O-isopropylidene-a-D-glucofura-
[
7]
nose (5) gave 3-O-(2-dichloromethyl-1,3-dioxolan-2-yl)-1,2:5,6-di-O-isopropylidene-
a-D-glucofuranose (6) in 31% yield, indicating that appreciable reaction on a secondary
hydroxyl group is also possible.

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PROTECTING GROUP FOR SUGAR DERIVATIVES
561
Further reactions of 2 were carried out with 1,2-O-alkylidene protected furanose
derivatives 7, 10 and 13. The absolute configuration of the acetal carbon of 1,2-O-(S)-
[
8]
[9]
trichloroethylidene-a-D-galactofuranose (7) was determined by us recently, relative
[10]
to the diastereoisomer of 10 (b-chloralose).
Reaction of 2 with 7 gave crystalline 6-
O-(2-dichloromethyl-1,3-dioxolan-2-yl)-1,2-O-(S)-trichloroethylidene-a-D-galactofura-
nose (8) in 50% yield and was characterised as its diacetate 9. The reaction mixture
contained three other products as judged from TLC, but these were not isolated.
[10]
1,2-O-(R)-Trichloroethylidene-a-D-glucofuranose
(10) is a commercially avail-
able compound also known as a-chloralose, which is used as an anesthetic for ani-
[
11]
mals.
relative chemical shift values of this compound and its diastereoisomer.
The acetal carbon configuration of 10 was first assigned, on the basis of the
[10]
The
Reaction
[12]
structure of 10 is also supported by published x-ray crystallographic data.
of 2 with 10 was completed (TLC) in 20 minutes at 40°C, but the yields of the isolated
pure compounds were low, due to separation problems. Chromatography on silica gel,
eluting with dichloromethane–ethyl acetate (4:1), afforded as the first product 3,6-di-O-
(2-dichloromethyl-1,3-dioxolan-2-yl)-1,2-O-(R)-trichloroethylidene-a-D-glucofuranose
in low yield, which was characterised as its monoacetate 11. The second fraction gave
a mixture which could not be purified, even after acetylation. The final product eluted

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¨
OZGENER AND YUCEER
562
from the column contained 6-O-(2-dichloromethyl-1,3-dioxolan-2-yl)-1,2-O-(R)-tri-
chloroethylidene-a-D-glucofuranose which was acetylated to give the diacetate 12.
[7]
The reaction of 2 with 1,2-O-isopropylidene-a-D-glucofuranose (13) also gave a
mixture of products. Column chromatography on silica gel yielded a mixture of two
minor products as a first fraction. Crystallization of this mixture from toluene afforded
5
(
,6-di-O-(2-dichloromethyl-1,3-dioxolan-2-yl)-1,2-O-isopropylidene-a-D-glucofuranose
14) in a low yield and was characterised as its monoacetate 15. Further fractions gave
a syrupy product which mainly contained 6-O-(2-dichloromethyl-1,3-dioxolan-2-yl)-
,2-isopropylidene-a-D-glucofuranose. This product was also obtained by removing the
1
minor components from the main mixture, with boiling petroleum ether extraction.
Methylation of the crude 6-O-orthoester fraction was carried out without further pu-
rification to give 3,5-di-O-methyl-6-O-(2-dichloromethyl-1,3-dioxolan-2-yl)-1,2-O-iso-
propylidene-a-D-glucofuranose (16). Hydrolysis of 16 in aqueous methanol using
+
Amberlite IR-120 (H ) as acid catalyst and subsequent acetylation and purification
gave 6-O-acetyl-3,5-di-O-methyl-1,2-O-isopropylidene-a-D-glucofuranose (17).
EXPERIMENTAL
1
13
General methods. H (400 MHz) and C NMR (100.6 MHz) spectra were
recorded with a Bruker DPX-400 High Performance FT NMR spectrometer in CDCl3.
IR spectra (KBr) were obtained on a Mattson 1000 FTIR spectrophotometer. Mass
spectra were recorded with a Micromass UK Platform-II spectrometer. Optical rotations
were measured with a Schmidt–Haensch Polartronic-E polarimeter. Column chroma-
tography and TLC were performed on Merck G-60 silica gel (7734) and on precoated
silica gel plates (Merck 5553), respectively. Chlorinated solvents were shaken with a
sodium carbonate solution (5%) and dried with anhydrous sodium sulfate before use.
Petroleum ether refers to the fraction having bp 40–60°C.
2
-Trichloromethyl-1,3-dioxolane (1). A mixture of chloral (108 g, 0.73 mol),
ethylene glycol (46 g, 0.74 mol) and concentrated sulfuric acid (25 mL) was heated at
0°C for 2 h. The mixture was poured over crushed ice and extracted with chloroform
9
(
5 Â 50 mL) after adjusting to pH =5.5 with sodium hydroxide solution (10%). The
combined chloroform extracts were washed with water and dried with anhydrous
sodium sulfate. The solvent was removed and the residue was dissolved in petroleum
ether (250 mL) and decolorised with activated carbon. The compound 1 (80 g, 56%)
was crystallised by concentrating the petroleum ether solution; mp 41–42°C, lit. mp
[
5]
4
1–42°C.
2-Dichloromethylene-1,3-dioxolane (2). A solution of compound 1 (3.0 g,
5.67 mmol) in t-butyl alcohol (50 mL) was stirred under dry nitrogen with potassium
1
t-butoxide (2.0 g, 17.84 mmol) at 20–25°C for 16 h. The solvent was removed
completely under vacuum at 60°C, and the residue was extracted with petroleum ether
(
3 Â 25 mL), filtered and concentrated under reduced pressure to give a product which
solidified. The concentrated solution of this product in petroleum ether gave crystals of
2
[5]
(2.0 g, 82%); mp 54–55°C, lit mp 55–57°C.

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PROTECTING GROUP FOR SUGAR DERIVATIVES
563
6
-O-(2-Dichloromethyl-1,3-dioxolan-2-yl)-1,2:3,4-di-O-isopropylidene-a-D-
galactopyranose (4). A solution of the ketene acetal 2 (1.2 g, 7.74 mmol) and
,2:3,4-di-O-isopropylidene-a-D-galactopyranose (3) (1.9 g, 7.30 mmol) in nitro-
1
methane (25 mL) was stirred for 16 h under dry nitrogen at room temperature. The
solvent was removed, and the residue was purified on a silica gel column, eluting with
dichloromethane-petroleum ether (19:1). Compound 4 was obtained as a syrup (1.9 g,
2
4
6
9
3%), [a]D À 51° (c 0.07, dichloromethane). IR: 3004, 2927, 1395, 1242, 1089, 1012,
À 1
2 1,2
1
10, 808, 782 cm . H NMR: d 5.78 (s, 1H, HCCl ), 5.50 (d, J = 5.0 Hz, H-1), 4.60
(
dd, 1H, J2,3 = 7.8, J3.4 = 2.0 Hz, H-3), 4.35–4.29 (m, 6H, H-2, H-4 and dioxolane ring
H), 4.00 (td, 1H, J4,5 = ꢀ 1.5 Hz, H-5), 3.82 (dd, 1H, J = ꢀ 6.5, J =9.8 Hz, H-
5,6a
6a,6b
6a), 3.73 (dd, 1H, J5,6b = ꢀ 6.5 Hz, H-6 ), 1.53 (s, 3H, CH ), 1.44 (s, 3H, CH ), 1.34
b
3
3
1
3
and 1.32 (2 Â s, 6H, 2 Â CH ). C NMR: d 121.27 (orthoester C), 109.63 and 109.06
3
(
2 Â ketal C), 96.70 (C-1), 73.12, 71.23, 71.15, 70.97, 67.86, 67.72, 67.04, 62.05 (C-2
to C-6, HCCl and dioxolane ring C), 26.43, 26.36, 25, 37, 24.77 (4 Â isopropylidene
2
+
+
CH ). MS (EI): m/z 415, 417 (9/6; 2 Â Cl; M +1), 413 (M À 1), 399, 401, 403 (9/6/
3
+
+
1
2
; 2 Â Cl; M –CH ), 243 [M -(O-dichloromethyl-dioxolane)], 155, 157, 159 (9/6/1;
3
 Cl; dichloromethyldioxolanyl).
2 8
Anal. Calcd for C H Cl O : C, 46.27; H, 5.82. Found: C, 46.35; H, 5.92%.
6
1
24
3-O-(2-Dichloromethyl-1,3-dioxolan-2-yl)-1,2:5,6-di-O-isopropylidene-a-D-glu-
cofuranose (6). A solution of the ketene acetal 2 (1.3 g, 8.39 mmol) and 1,2:5,6-di-
O-isopropylidene-a-D-glucofuranose (5) (1.6 g, 6.15 mmol) in nitromethane (15 L) was
stirred for 72 h under dry nitrogen at room temperature. The solvent was removed
under reduced pressure and the residue was purified on a silica gel column, eluting with
2
8
chloroform-ethyl acetate (1:4) to give 6 as a syrup (0.8 g, 31%), [a]D À 1.5° (c 0.06,
1
dichloromethane). H NMR: d 5.87 (d, 1H, J =3.7 Hz, H-1), 5.69 (s, 1H, HCCl ),
1
,2
2
4
(
3
.66 (d, 1H, J2,3 = 0 Hz, H-2), 4.40–4.28 (m, 6H, H-3, H-5 and dioxolane ring H), 4.21
dd, 1H, J3,4 = 3.1, J4,5 =6.3 Hz, H-4), 4.06 (dd, 1H, J5,6a =6.4, J6a,6b =8.4 Hz, H-6a),
.98 (dd, 1H, J5,6b =6.0 Hz, H-6 ), 1.48 (s, 3H, CH ), 1.41 (s, 3H, CH ) 1.32, 1.30
b
3
3
1
3
(
(
(
2 Â s, 6H, 2Â CH ). C NMR: d 121.51 (orthoester C), 112.26, 109.24 and 105.45
3
C-1 and 2Â ketal C), 84.32, 80.74, 76.32, 73.00 (2 Â C), 72.90, 68.09, 67.68, 67.02
C-2 to C-6, CHCl and dioxolane ring C), 27.17, 27.08, 26.71, 25.69 (4 Â CH ).
2
3
+
+
MS (EI): m/z 415, 417 (9/6; 2Â Cl; M + 1), 399, 401, 403 (9/6/1; 2 Â Cl; M –CH ),
3
+
2
43 [M -(O-dichloromethyl-dioxolane)], 155, 157, 159 (9/6/1; 2 Â Cl; dichlorome-
thyldioxolanyl), 185 (243-acetone), 101 (2,2-dimethyl-1,3-dioxolane, from C-5, C-6
bond fission).
Anal. Calcd for C H Cl O : C, 46.27; H, 5.82. Found: C, 46.38; H, 5.92%.
1
6
24
2 8
6
-O-(2-Dichloromethyl-1,3-dioxolan-2-yl)-1,2-O-(S)-trichloroethylidene-a-D-
galactofuranose (8). Reagent 2 (1.6 g, 10.32 mmol) and 1,2-O-(S)-trichloroethyli-
dene-a-D-galactofuranose (7) (1.6 g, 5.17 mmol) were dissolved in a mixture of N,N-
dimethylformamide (25 mL) and nitromethane (25 mL). The solution was stirred for
8
h at 75–80°C. TLC (dichloromethane-methanol, 9:1) indicated four spots. The sol-
vent was removed under reduced pressure, and the residue was extracted with dichlo-
romethane, which contained a main product and a trace of 7 (TLC). The solvent was
removed, and the residue was extracted with boiling water to remove unreacted 7. The

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OZGENER AND YUCEER
564
remaining part was crystallized from ethyl acetate to give 8 (1.2 g, 50%); mp 176–
2
4
1
1
77°C, [a]D À 30° (c 0.01, methanol). IR: 3565, 3489, 3004, 2927, 1319, 1217, 1165,
À 1
114, 1112, 1089, 961, 808, 627 cm
Anal. Calcd for C H O Cl : C, 31.03; H, 3.25. Found C, 30.90; H, 3.48%.
.
1
2
15
8
5
3
,5-Di-O-acetyl-6-O-(2-dichloromethyl-1,3-dioxolan-2-yl)-1,2-O-(S)-trichlo-
roethylidene-a-D-galactofuranose (9). A solution of 8 (0.16 g, 0.34 mmol) in
pyridine (5 mL) was acetylated with acetic anhydride (0.5 mL, 5.3 mmol) for 16 h at
room temperature. The solvent was removed under reduced pressure, and the residue
was extracted with dichloromethane. Removal of the solvent and crystallization of
the residue from petroleum ether-ethanol gave 9 (0.16 g, 85%); mp 101–102°C,
2
4
[
a]D À 22° (c 0.01, dichloromethane). IR: 3037, 2987, 2975, 2925, 2900, 1753,
À 1
1
1
J1,2 =3.8 Hz, H-1) 5.80 (s, 1H, CHCl ), 5.75 (s, 1H, HC–CCl ), 5.29 (dt, 1H,
228, 1160, 1114, 1040, 1012, 978, 808, 649 cm
. H NMR: d 6.26 (d, 1H,
2
3
J4,5 = ꢀ 12 Hz, H-5), 5.24 (d, 1H, J = 0, J3.4 = 1.3 Hz, H-3), 4.96 (d, 1H, H-2),
2.3
4
Hz, H-6 ), 3.81 (dd, 1H, J =5.5 Hz, H-6 ), 2.16 (s, 3H, OAc), 2.11 (s, 3H, OAc).
.38–4.29 (m, 5H, dioxolane ring H and H-4), 3.87 (dd, 1H, J = 5.5, J6a,6b =10.7
5,6a
a
5,6b
b
1
3
C NMR: d 170.47 and 169.95 (2 Â OCOCH ), 121.26 (orthoester C), 109.97 and
3
1
07.75 (C-1 and acetal C), 99.59 (CCl ), 86.94, 85.21, 77.02, 73.03, 70.88, 67.98
3
(
2 Â C), 61.53 (C-2 to C-6, HCCl and dioxolane ring C), 21.15, 21.02 (2 Â
2
OCOCH ).
3
Anal. Calcd for C H Cl O : C, 35.03; H, 3.49. Found: C, 35.12; H, 3.78%.
19
1
6
5 10
5
-O-Acetyl-3,6-di-O-(2-dichloromethyl-1,3-dioxolan-2-yl)-1,2-O-(R)-trichlo-
roethylidene-a-D-glucofuranose (11). A solution of the reagent 2 (1.0 g, 6.45 mmol)
and 1,2-O-(R)-trichloroethylidene-a-D-glucofuranose (10) (1.8 g, 5.81 mmol) in
nitromethane (25 mL) was stirred at 40°C for 20 min. TLC indicated three spots
(dichloromethane-ethyl acetate, 4:1) and no remaining 10. The mixture was poured
into ice–water containing Na CO . The resultant solution was slightly alkaline (pH
2
3
8
anhydrous Na SO , and the solvent was removed under reduced pressure to give a
). The mixture was extracted with dichloromethane (4 Â 25 mL), dried with
2
4
syrupy mixture (2.7 g). This mixture was applied to a silica gel column which was
eluted with dichloromethane-ethyl acetate (4:1). The first fraction collected (0.39 g)
gave a single spot on TLC (the fastest moving). The IR spectrum of this product
showed a carbonyl peak, indicating contamination due to the decomposition products of
the ketene acetal 2. A solution of this syrupy mixture in dichloromethane was extracted
with alkaline water (pH 8) several times. The purified syrup was crystallized from
carbon tetrachloride-petroleum ether at 0°C to give a crude product (0.39 g, 11%; mp
2
2
1
9
(
40–143°C, [a]D À 11° (c 0.02, methanol). IR: 3489, 3004, 2928, 1217, 1114, 1063,
À 1
61, 808 cm ) an aliquot of which (0.09 g, 0.145 mmol) was acetylated in pyridine
5 mL) with acetic anhydride (0.5 mL, 5.3 mmol) as described for 9, and 11 was
2
0
obtained (0.08 g, 83%); mp 188–190°C (from ethyl acetate), [a]D À 7° (c 0.01,
À 1
1
dichloromethane). IR: 3004, 2927, 1753, 1268, 1414, 1040, 1012, 961, 808 cm . H
NMR: d 6.10 (d, 1H, J1,2 =3.8 Hz, H-1), 5.70, 5.69 (2 Â s, 2H, 2Â HCCl ), 5.33 (s, 1H,
2
HC–CCl ), 5.08 (ddd ꢀ dt, 1H, J = 9.9 Hz, H-5), 4.95 (dd, 1H, H-4), 4.94 (d, 1H,
3
4,5
J
=0 Hz, H-2), 4.48 (d, 1H, J = 3.5 Hz, H-3), 4.44–4.25 (m, 8H, dioxolane ring H),
3,4
2
,3

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PROTECTING GROUP FOR SUGAR DERIVATIVES
565
4
.00 (dd, 1H, J5,6a =2.3, J6a,6b =11.1 Hz, H-6 ), 3.81 (dd, 1H, J =3.4 Hz, H-6 ), 2.07
a
5,6b
b
(
s, 3H, OAc).
Anal. Calcd for C H Cl O : C, 32.68; H, 3.20. Found: C, 32.90; H, 3.38%.
1
8
21
7 11
3
,5-Di-O-acetyl-6-O-(2-dichloromethyl-1,3-dioxolan-2-yl)-1,2-O-(R)-trichlo-
roethylidene-a-D-glucofuranose (12). A part (0.13 g, 0.280 mmol) of the third
2
2
fraction from the previous column separation (0.6 g, 22.2%, [a]D À 21° (c 0.03,
À 1
methanol). IR: 3490, 3004, 2953, 2927, 1319, 1217, 1114, 1063, 961, 808 cm ) was
acetylated in pyridine (5 mL) with acetic anhydride (0.5 mL, 5.3 mmol) as described
2
0
for 9 to give syrupy 12 (0.10 g, 65%). [a]D À 14.5° (c 0.01, dichloromethane), IR:
À 1
1
2
6
3
4
928, 2876, 1753, 1302, 1248, 1174, 1100, 1010, 965, 817 cm
. H NMR: d
.10 (d, 1H, J1,2 = 3.7 Hz, H-1), 5.70 (s, 1H, HCCl ), 5.57 (d, 1H, J =2.9 Hz, H-
2
3,4
), 5.35 (s, 1H, HC–CCl ), 5.14 (dt, 1H, H-5), 4.94 (dd, 1H, J =9.6 Hz, H-4),
3
4,5
.67 (d, 1H, J2,3 =0 Hz, H-2), 4.30–4.28 (m, 4H, dioxolane ring H), 3.94 (dd, 1H,
J5,6a = 2.0 Hz, H-6 ), 3.80 (dd, 1H, J =4.6, J6a,6b =10.9 Hz, H-6 ), 2.08 (s, 3H, OAc),
a
5,6b
b
2.03 (s, 3H, OAc).
Anal. Calcd for C H Cl O : C, 35.15; H, 3.50. Found: C, 35.32; H, 3.72%.
5 10
1
6
19
5,6-Di-O-(2-dichloromethyl-1,3-dioxolan-2-yl)-1,2-O-isopropylidene-a-D-gluco-
furanose (14). A solution of the reagent 2 (2.2 g, 14.2 mmol) and 1,2-O-iso-
propylidene-a-D-glucofuranose (13) (3.0 g, 13.6 mmol) in nitromethane (25 mL) was
stirred at 75°C for 16 h. The solvent was removed under reduced pressure, and the
syrupy residue was dissolved in dichloromethane. The unreacted starting material
crystallized on standing and was filtered off. The TLC of the remaining solution
indicated a major and two minor faster moving spots (chloroform-ethyl acetate; 1:4).
Evaporation of the solvent gave a syrup (2.9 g), which was applied to a silica gel
column eluting with (chloroform-ethyl acetate; 4:1) to give two fractions. The first
fraction eluted as a mixture and was obtained as a syrup (0.4 g) after removal of the
solvent. The toluene solution of this mixture gave crystalline 14 at 0°C (0.2 g, 2.7%);
2
6
mp 149–150°C, [a]D À 39° (c 0.01, dichloromethane). IR: 3489, 3004, 2935, 2927,
À 1
1
1
390, 1370, 1252, 1212, 1123, 1093, 1014, 954, 806, 766 cm . H NMR: d 5.92 (d,
J1,2 = 3.3 Hz, H-1), 5.79 (s, 1H, HCCl ), 5.77 (s, 1H, HCCl ), 4.53 (d, 1H, J =0 Hz,
H-2), 4.44–4.25 (m, 9H, H-4 and dioxolane ring H), 4.15 (bm, 1H, H-5), 4.00 (dd, 1H,
J5,6a = 2.2, J6a,6b =10.6 Hz, H-6 ), 3.82 (dd, 1H, J = 4.2 Hz, H-6 ), 3.39 (bs, 1H,
2
2
2,3
a
5,6b
3
b
1
H-3), 1.49 (s, 3H, CH ), 1.32 (s, 3H, CH ). C NMR: d 121.68 and 121.15
3
3
(
7
2 Â orthoester C), 112.25 and 105.51 (C-1 and acetal C), 85.12, 79.14, 74.92, 73.20,
3.02, 71.01, 68.09, 67.80, 67.64 (2 Â C), 64.06 (C-2 to C-6, HCCl and dioxolane ring
2
C), 27.22, 26.69 (2 Â CH ).
3
Anal. Calcd for C H Cl O : C, 38.51; H, 4.56. Found: C, 38.61; H, 4.72%.
4 10
1
7
24
3
-O-Acetyl-5,6-di-O-(2-dichloromethyl-1,3-dioxolan-2-yl)-1,2-O-isopropyli-
dene-a-D-glucofuranose (15). Acetylation of 14 (0.13 g, 0.245 mmol) in pyridine (5
mL) with acetic anhydride (0.5 mL, 5.3 mmol) as described for 9 gave crystalline 15 (0.13
2
4
g, 92%), from ethanol–petroleum ether; mp 167–168°C, [a]D À 23° (c 0.013,
dichloromethane). IR: 2992, 2930, 1751, 1741, 1377, 1243, 1221, 1200, 1108, 1073,
À 1 1
1
044, 1023, 959, 796 cm . H NMR: d 5.88 (d, J1,2 = 3.7 Hz, H-1), 5.79 (s, 1H, HCCl2),

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©
2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
¨
¨
OZGENER AND YUCEER
566
5
4
1
.73 (s, 1H, HCCl ), 5.27 (d, 1H, J3.4 = 2.7 Hz, H-3), 4.49 (d, 1H, J2,3 = 0 Hz, H-2), 4.41–
2
.25 (m, 10H, H-4, H-5 and dioxolane ring H), 4.03 (dd, 1H, J5,6a = 2.7 Hz, H-6 ), 3.84 (dd,
a
H, J5 = 4.2, J6a,6b =10.6 Hz, H-6 ), 2.12 (s, 3H, OAc), 1.52 (s, 3H, CH ), 1.31 (s, 3H,
,6b
b
3
1
3
CH3). C NMR: d 170.22 (OCOCH ), 121.48 and 121.08 (2 Â orthoester C), 112.79 and
3
1
6
05.09 (C-1 and acetal C), 83.54, 75.88, 73.37, 72.97, 69.97 (2 Â C), 67.94, 67.78, 67.35,
4.19 (C-2 to C-6, HCCl and dioxolane ring C), 27.04, 26.69, 21.34 (3 Â CH ).
2
3
Anal. Calcd for C H Cl O : C, 39.89; H, 4.58. Found: C, 39.87; H, 4.22%.
1
9
26
4 11
3
,5-Di-O-methyl-6-O-(2-dichloromethyl-1,3-dioxolan-2-yl)-1,2-O-isopropyli-
dene-a-D-glucofuranose (16). The crude syrupy orthoester mixture (3.0 g) from the
reaction of 2 with 13 as described for 14 was boiled with petroleum ether several times,
and the solvent layer was decanted until TLC of the residue indicated no diorthoester
spots. The remaining syrup (1.6 g) contained impure 6-O-(2-dichloromethyl-1,3-dioxo-
lan-2-yl)-1,2-O-isopropylidene-a-D-glucofuranose. An aliquot (0.9 g, max 2.2 mmol) in
N,N-dimethylformamide (20 mL) was stirred with methyl iodide (2.5 mL, 40 mmol) and
BaO (2.5 g) at room temperature for 16 h. The solid material was filtered, and the filtrate
was concentrated under reduced pressure. The residue was dissolved in dichloromethane
which was washed with 5% sodium thiosulfate and then with water several times and
dried with anydrous sodium sulfate. Removal of dichloromethane afforded a crude
product, which was purified on a silica gel column, eluting with dichloromethane-ethyl
2
7
acetate (4:1) to give 16 as a syrup (0.5 g, 16%), [a] À 24° (c 0.02, dichloromethane).
D
1
H NMR: d 5.65 (d, J1,2 =3.8 Hz, H-1), 3.58 (d, 1H, J3.4 =3.0 Hz, H-3), 5.57 (s, 1H,
HCCl ), 4.34 (d, 1H, J = 0 Hz, H-2), 4.13–4.03 (m, ꢀ 4H, dioxolane ring H), 3.85 (dd,
2
2,3
1
3
H, J4,5 = ꢀ 9.0 Hz, H-4), 3.82–3.76 (m, 1H, H-5), 3.52–3.48 (m, 2H, H-6 and H-6 ),
a
b
.29 (s, 3H, OCH ), 3.23 (s, 3H, OCH ), 1.13 (s, 3H, CH ), 1.10 (s, 3H, CH ).
3
3
3
3
Anal. Calcd for C H Cl O : C, 44.68; H, 6.00. Found: C, 44.34; H, 5.84%.
1
5
24
2 8
6
-O-Acetyl-3,5-di-O-methyl-1,2-O-isopropylidene-a-D-glucofuranose
17). The solution of the dimethyl ether 16 (0.25 g, 0.62 mmol) in methanol (15 mL) was
stirred at room temperature for 8 h with 2 mL of ion exchange resin Amberlite IR-120
(
+
(H ) and water (1 mL). TLC indicated the completion of hydrolysis. The solvent mixture
was concentrated under reduced pressure to give a syrup (0.13 g) which was acetylated to
2
8
give 17 (0.12 g, ꢀ 67%), [a]D À 20° (c 0.01, dichloromethane). The product contained a
trace impurity, most probably due to the trace hydrolysis of the 1,2-O-isopropylidene
1
group, as implied by the very small extra methyl (OAc and OMe) signals in the H NMR
1
spectrum. H NMR: d 5.97 (d, 1H, J = 3.7 Hz, H-1), 4.70 (dd, 1H, J5,6a = 2.3, J6a,6b =12.0
1
,2
Hz, H-6 ), 4.68 (d, 1H, H-2), 4.27 (dd, 1H, J = 3.1, J4,5 =9.2 Hz, H-4), 4.19 (dd, 1H,
J5,6b =4.7 Hz, H-6 ), 3.91(d, 1H, J =0 Hz, H-3), 3.79 (ddd, 1H, H-5), 3.56, 3.55 (2 Â s,
a
3,4
b
2,3
6
H, 2Â OMe), 2.19 (s, 3H, OAc), 1.59 (s, 3H, CH ), 1.43 (s, 3H, CH ).
3
3
Anal. Calcd for C H O : C, 53.78; H, 7.64. Found: C, 54.04; H, 7.34%.
1
3
22
7
ACKNOWLEDGMENTS
The authors are grateful for the support of TUBITAK (The Scientific and
Technical Research Council of Turkey) and The Graduate School of Natural and Ap-
plied Sciences, Ege University.

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2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
PROTECTING GROUP FOR SUGAR DERIVATIVES
REFERENCES
567
1.
2.
3.
Green, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 3rd Ed.;
Wiley: New York, 1999.
De Wolfe, R.H. Carboxylic Orthoacid Derivatives; Organic Chemistry, A Series of
Monographs, Academic Press: New York, 1970; Vol. 14.
Bouchra, B.; Calinaud, P.; Gelas, J. A new method of orthoesterification, under
kinetic control, at non-anomeric positions. Application to the D-glucose and
lD-mannose series and selective hydrolysis of the corresponding orthoesters.
Carbohydr. Res. 1995, 267, 227–237.
4.
Bouchra, B.; Gelas, J. Further examples of orthoesterification under kinetically
controlled conditions. Application to the selective acylation of sucrose, maltose and
a,a-trehalose. Carbohydr. Res. 1998, 305, 17–25.
5
.
.
McElvain, S.M.; Curry, M.J. Ketene acetals. XIX. 2-Methylene-1,3-dioxolanes and
1,3-dioxanes. J. Am. Chem. Soc. 1948, 70, 3781–3786.
Salman, Y.G.; Makinabakan, O.; Y u¨ ceer, L. Tricyclic orthoester formation from
¨
6
trichloroethylidene acetals of sugars via ketene acetals. Tetrahedron Lett. 1994, 35,
9233–9236.
7.
Gelas, J.; Calinaud, P. Synthesis of Isopropylidene, Benzylidene and Related
Acetals. In Preparative Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel
Dekker: New York, 1997; 3–33.
8
.
.
Anil, H.; Y u¨ ceer, T.; Y u¨ ceer, L. 1,2-O-trichloroethylidene-a-D-galactofuranose.
Carbohydr. Res. 1983, 123, 153–156.
Yenil, N.; Y u¨ ceer, L., Unpublished Results.
9
1
1
0. Forsen, S.; Lindberg, B.; Silvander, B.G. Trichloroethylidene derivatives of
D-glucose. Acta Chem. Scand. 1965, 19, 359–369.
1. Metz, C.J.S.; Ise, T.; Haberle, D.A. Chloralose/ketamine anesthesia preserves a
form of postprandial sodium chloride balance in wistar rats. Eur. J. Physiol. 1996,
432, 944–947.
12. Taga, T.; Kaji, T.; Osaki, K. Structure of 1,2-O-(2,2,2-trichloroethylidene)-a-D-
glucofuranose (a-D-chloralose). Acta Crystallogr., B 1982, 38, 1874–1876.
Received November 5, 2001
Accepted August 30, 2002