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Methyl 2,3-di-O-methyl-α-d -glucopyranoside 4,6-carbonate
Carbohycfrate Ekcvier Printed
301
Research
Publishing in Belgium
Company.
Amsterdam
Note
Methyl 2,3-di-0-methyl-a-D-glucopyranoside D. TRIMMLL, W. M. DOANE,C.R.RUSSELL,AND
4,6-carbonate
C.E.Rsr
Northern Utilization Research and Development DiGsion, Agricultural Research Service, U.S. Department of Agriculture, Peoria, Illinois 61604 (U.S. A.)
(Received August llth, !969; in revised form, September 26th, 1969)
Reactive, five-membered, ham cyclic carbonates of sugars have been prepared by treating pyranoid sugars having vicinal diequatorial hydroxyl groups with ethyl chloroformate and triethylamine I. These compounds undergo facile ring-opening reactions at the carbonate center with such nucleopbiles as alcohols, thiols, and amines to give acyclic carbonates, monothiolcarbonates, and carbamates, respectively2. In continuing studies on the preparation and properties of carbohydrate carbonates, it was desirable to prepare a six-membered cyclic carbonate of a pyranose. Such a derivative should be highly reactive since it is known3 that simple six-membered cyclic esters are less stable and more susceptible to ring-opening reactions than the corresponding five-membered ring compounds. In 1938 a sugar was reported that contained a six-membered carbonate fused to a furanose ring4. D-Xylose was treated with acetone and phosgene to give 1,2-0isopropylidene-cr-D-xylofuranose 3,Scarbonate. Ring opening of the carbonate took place readily in the presence of methanol. We chose methyl 2,3-di-O-methyl-a-D-glucopyranoside (1) for an attempt to form a cyclic carbonate at C-4 and C-6 since hydroxyl groups here react readily to form six-membered cyclic acetals. When 1 was treated with ethyl chloroformate and triethylamine in the molar proportions of 1:23:8, t.1.c. showed a major component, which was recovered by crystallization from chloroform-hexane. This component
Curbohyd. Res., 13 (1970) 301-305
NOTE
302
was characterized as methyl 2,3-di-0-methyl-sc-D-glucopyranoside 4,6-carbonate (2) by i-r. and n.m.r_ data, microanalyses, and its molecular weight. For comparison of i.r.5 and n._m.r. spectral data, the 4-O- and 6-0-(ethoxycarbonyl) derivatives (3 and 4) of 1 were prepared. Compound 3 was isolated in quantitative yield on detritylation of methyl 4-O-(ethoxycarbonyl)-2,3-di-O-methyl-6-O-trityl-cw-~-glucopyranoside (5) with silica ge16. When detritylation of 5 was performed with hydrochloric acid in methanol’~’ followed by neutralization with ammonium hydroxide, a different compound was formed which was shown to be 4. Compound 4 was also prepared by the direct reaction of 1 with ethyl chloroformate and pyridine and by reaction of 2 with ethanol containing 10% of triethylamine. Although no 3 was detected in either of these reaction products, it is probable that 3 was initially present and transformed into 4 in the presence of base. When lower concentrations of triethylamine were used in the ring-opening of 2, nearly equal amounts of 3 and 4 were formed initially. Subsequently, the amount of 4 increased while that of 3 decreased. Pure 3 was converted into a mixture of 3 and 4 under these reaction conditions. Comparison of the reactivity of 2 with that of methyl 4,6-O-benzylidene-a-Dglucopyranoside 2,3-carbonate in ring-opening reactions revealed that the 4,6carbonate was converted into the acyclic carbonate at a rate more than twice that for the 2,3-carbonate. EXPERIMENTti 1.r. spectra for films cast onto plates of silver chloride were recorded with a
Perkin-Elmer* Model 137 spectrophotometer. A Perkin-Elmer Model 621 spectrophotometer was used to record the spectrum of 2 in bromoform. Wavelengths were calibrated with polystyrene film. N.m.r. spectra were recorded for solutions in chloroform-d by means of a Varian HA-100 spectrometer with tetramethylsilane (r 10.00) as the internal reference standard. Melting points were determined in sealed capillaries in an oil bath and are uncorrected. Optical rotations were measured with a Rudolph polarimeter. Molecular weights were measured with a Mechrolab Model 301A vapor-pressure osmometer. T.1.c. was performed on Silica Gel G (E_ Merck, Germany) with ether or 4:l (v/v) ether-amyl acetate, and detection was with either 19:l (v/v) methanol-sulfuric acid for charring or Rhodamine 6-G (1 mg per liter of water) as a fluorescent indicator. Methyl 2,3-di-O-methyl-a-D-glucopyranoside 4,&carbonate (2). - A solution of methyl 2,3-di-0-methyl-ar-D-g1ucopyranoside6 (1,500 mg, 2.25 mmoles) in tetrahydrofuran (5 ml) was cooled to 5” and mixed with ethyl chloroformate (5 ml, 52 mmoles). Triethylamine (2.5 ml, 18 mmoles) in tetrahydrofuran (20ml) was added dropwise during 30 min. The mixture was kept for 18 h at - 15Oand filtered, and the *The mention of firmnames or trade products does not imply that they are endorsed or recommended by the Department of Agriculture over other firms or similar products not mentioned. Carbohyd. Res., 13 (1970) 301-305
NO-E
304 the amine.
The
chloroform
phase
was separated,
dried with sodium
evaporated to a syrup, 46 mg (78%), which showed Crystallization from hexane gave m.p. 56-57”, [ali LIXS 1740 (C = 0), (2-proton multiplet, triplet, respectively,
sulfate,
and
a single component by t-1-c. +99.7” (c 1.52, chloroform);
1260 (O-C-O), and 793 cm-’ [O(C = O)O]; n.m.r. data: r 5.62 H-6 and H-6’), T 5.82 and z 8.70 (2-proton quartet and S-proton OEt). The appearance of the characteristic resonances for H-6
and H-6’ at z 5.62 represented a downfield compounds unsubstituted by ethoxycarbonyl
displacement at C-6, and
of 0.73 confirmed
p.p.m. from substitution
at this position. Anal. Calc. for C,,H,,Os: C, 49.0; H, 7.54. Found: C, 49.0; H, 7.67. (b) Direct ethoxycarbonylation of 1. To a solution of 1 (500 mg, 2.25 ran-roles) in pyridine (5 ml) at 5” was added ethyl chloroformate (0.4 ml, 4.2 mmoles). After being kept for 18 h at 25”, the mixture was diluted with chloroform (100 ml) and the solution was successively washed with dilute hydrochloric acid and sodium hydrogen carbonate solution, dried (sodium sulfate), and evaporated under diminished pressure at 40” to a syrup. This syrup was resolved into monoethoxycarbonyl and diethoxycarbonyl fractions by preparative t.1.c. The zone of lower R, (monoethoxycarbonyl fraction) was separated by sectioning and eluted with ethyl acetate, and the eluate was evaporated. The syrupy residue (89 mg, 13%) crystallized when kept for 18 h at 25”. After recrystallization from hexane it had m.p. 56-58”. The mixed m.p. of this product with that from part (a) showed no depression; the i.r. spectra of (a) and (b) were identical. (c) Detritylation of 5. Compound 5 (340 mg, 0.635 mmole) was mixed with 0.03~ hydrochloric acid in methanol (20 ml) and stirred for 2.5 h at 50” to remove the trityl group. The mixture was made neutral with ammonium hydroxide, mixed with ice-water (100 ml), and extracted with four 20-ml portions of hexane to remove methyl triphenylmethyl ether. The aqueous-alcoholic solution was then extracted with four 20-ml portions of chloroform and the chloroform solution was dried and evaporated to a syrup that crystallized from hexane to give 90 mg (48%), m-p. 55-57”. The n.m.r_ and i-r. spectra were identical with those of authentic 4 and the mixed m.p. with authentic
4 showed no depression.
Comparison between ring-opening reactions of 2 and of methyl 4,6-O-benzylideneEquimolar portions (0.1 mmole) of the title compounds were separately dissolved in 10 ml of a stock solution of chloroform containing ethanol (1 n-mole) and triethylamine (0.1 mmole). The progress of the reaction was monitored by t.1.c. and i.r. spectroscopy. After 18 h, 2 was completely converted into an equimolar mixture of 3 and 4. In the same interval, methyl 4,6-0benzylidene-a-D-glucopyranoside 2,3-carbonate showed only about 50% conversion a-m©rar;oside
2,3-carbonate.
-
into acychc products. The large proportion of chloroform used retards the intramolecular migration of the ethoxycarbonyl group from C-4 to C-6. Within the interval studied, 0.1 mmole of 3 in 10 ml stock solution showed about 10% conversion into 4, and 0.1 mmole
Curbohyd.
Res.,
of 4 under these conditions
13 (1970)
301-305
showed no change.
305
NOTE
ACKNOWLEDGMENTS
The authors thank C. A. Glass and Dr. D. Weisleder for n.m.r. measurements, and C. E. McGrew, l3. R. Heaton, and K. A. Jones for microanaIyses and determination of molecular weights.
1 W. M. DOANE, B. S. SI~ASHA, E. I. STOUT, C. R. RUSSELL, AND C. E. RIST, Curb&d. Res., 4 (1967) 445. 2 E. I. STOUT, W. M. DOANE, B. S. SHASHA, C. R. RUSSELL, AND C. E. R~s-r, Tetrahedron Letr., 45 (1967) 4481. 3 H. C. BROWN, J. H. BREWSTER, AND H. SHECHTER, J. Amer. Chem. Sot., 76 (1954) 467. 4 W. N. HAWORTH, C. R. PORTER, AND A. C. WAINE, Rec. Trav. Chim., 57 (1938) 541. 5 R A. NYQUIST AND W. J. Porn, Spectrochim. Acfu, 17 (1961) 679. 6 J. LEHRFELD, J. Org. Chem., 32 (1967) 2544. 7 D. TRIMNELL, W. M. DOANE, C. R. RUSSELL, AND C. E. RIOT, Carbohyd. Res.. 11 (1969) 497. 8 G. J. ROBERTSON, J. Chem. Sot., (1933) 737.
Curbohyd.
Res., 13 (1970) 301-305
301
Research
Publishing in Belgium
Company.
Amsterdam
Note
Methyl 2,3-di-0-methyl-a-D-glucopyranoside D. TRIMMLL, W. M. DOANE,C.R.RUSSELL,AND
4,6-carbonate
C.E.Rsr
Northern Utilization Research and Development DiGsion, Agricultural Research Service, U.S. Department of Agriculture, Peoria, Illinois 61604 (U.S. A.)
(Received August llth, !969; in revised form, September 26th, 1969)
Reactive, five-membered, ham cyclic carbonates of sugars have been prepared by treating pyranoid sugars having vicinal diequatorial hydroxyl groups with ethyl chloroformate and triethylamine I. These compounds undergo facile ring-opening reactions at the carbonate center with such nucleopbiles as alcohols, thiols, and amines to give acyclic carbonates, monothiolcarbonates, and carbamates, respectively2. In continuing studies on the preparation and properties of carbohydrate carbonates, it was desirable to prepare a six-membered cyclic carbonate of a pyranose. Such a derivative should be highly reactive since it is known3 that simple six-membered cyclic esters are less stable and more susceptible to ring-opening reactions than the corresponding five-membered ring compounds. In 1938 a sugar was reported that contained a six-membered carbonate fused to a furanose ring4. D-Xylose was treated with acetone and phosgene to give 1,2-0isopropylidene-cr-D-xylofuranose 3,Scarbonate. Ring opening of the carbonate took place readily in the presence of methanol. We chose methyl 2,3-di-O-methyl-a-D-glucopyranoside (1) for an attempt to form a cyclic carbonate at C-4 and C-6 since hydroxyl groups here react readily to form six-membered cyclic acetals. When 1 was treated with ethyl chloroformate and triethylamine in the molar proportions of 1:23:8, t.1.c. showed a major component, which was recovered by crystallization from chloroform-hexane. This component
Curbohyd. Res., 13 (1970) 301-305
NOTE
302
was characterized as methyl 2,3-di-0-methyl-sc-D-glucopyranoside 4,6-carbonate (2) by i-r. and n.m.r_ data, microanalyses, and its molecular weight. For comparison of i.r.5 and n._m.r. spectral data, the 4-O- and 6-0-(ethoxycarbonyl) derivatives (3 and 4) of 1 were prepared. Compound 3 was isolated in quantitative yield on detritylation of methyl 4-O-(ethoxycarbonyl)-2,3-di-O-methyl-6-O-trityl-cw-~-glucopyranoside (5) with silica ge16. When detritylation of 5 was performed with hydrochloric acid in methanol’~’ followed by neutralization with ammonium hydroxide, a different compound was formed which was shown to be 4. Compound 4 was also prepared by the direct reaction of 1 with ethyl chloroformate and pyridine and by reaction of 2 with ethanol containing 10% of triethylamine. Although no 3 was detected in either of these reaction products, it is probable that 3 was initially present and transformed into 4 in the presence of base. When lower concentrations of triethylamine were used in the ring-opening of 2, nearly equal amounts of 3 and 4 were formed initially. Subsequently, the amount of 4 increased while that of 3 decreased. Pure 3 was converted into a mixture of 3 and 4 under these reaction conditions. Comparison of the reactivity of 2 with that of methyl 4,6-O-benzylidene-a-Dglucopyranoside 2,3-carbonate in ring-opening reactions revealed that the 4,6carbonate was converted into the acyclic carbonate at a rate more than twice that for the 2,3-carbonate. EXPERIMENTti 1.r. spectra for films cast onto plates of silver chloride were recorded with a
Perkin-Elmer* Model 137 spectrophotometer. A Perkin-Elmer Model 621 spectrophotometer was used to record the spectrum of 2 in bromoform. Wavelengths were calibrated with polystyrene film. N.m.r. spectra were recorded for solutions in chloroform-d by means of a Varian HA-100 spectrometer with tetramethylsilane (r 10.00) as the internal reference standard. Melting points were determined in sealed capillaries in an oil bath and are uncorrected. Optical rotations were measured with a Rudolph polarimeter. Molecular weights were measured with a Mechrolab Model 301A vapor-pressure osmometer. T.1.c. was performed on Silica Gel G (E_ Merck, Germany) with ether or 4:l (v/v) ether-amyl acetate, and detection was with either 19:l (v/v) methanol-sulfuric acid for charring or Rhodamine 6-G (1 mg per liter of water) as a fluorescent indicator. Methyl 2,3-di-O-methyl-a-D-glucopyranoside 4,&carbonate (2). - A solution of methyl 2,3-di-0-methyl-ar-D-g1ucopyranoside6 (1,500 mg, 2.25 mmoles) in tetrahydrofuran (5 ml) was cooled to 5” and mixed with ethyl chloroformate (5 ml, 52 mmoles). Triethylamine (2.5 ml, 18 mmoles) in tetrahydrofuran (20ml) was added dropwise during 30 min. The mixture was kept for 18 h at - 15Oand filtered, and the *The mention of firmnames or trade products does not imply that they are endorsed or recommended by the Department of Agriculture over other firms or similar products not mentioned. Carbohyd. Res., 13 (1970) 301-305
NO-E
304 the amine.
The
chloroform
phase
was separated,
dried with sodium
evaporated to a syrup, 46 mg (78%), which showed Crystallization from hexane gave m.p. 56-57”, [ali LIXS 1740 (C = 0), (2-proton multiplet, triplet, respectively,
sulfate,
and
a single component by t-1-c. +99.7” (c 1.52, chloroform);
1260 (O-C-O), and 793 cm-’ [O(C = O)O]; n.m.r. data: r 5.62 H-6 and H-6’), T 5.82 and z 8.70 (2-proton quartet and S-proton OEt). The appearance of the characteristic resonances for H-6
and H-6’ at z 5.62 represented a downfield compounds unsubstituted by ethoxycarbonyl
displacement at C-6, and
of 0.73 confirmed
p.p.m. from substitution
at this position. Anal. Calc. for C,,H,,Os: C, 49.0; H, 7.54. Found: C, 49.0; H, 7.67. (b) Direct ethoxycarbonylation of 1. To a solution of 1 (500 mg, 2.25 ran-roles) in pyridine (5 ml) at 5” was added ethyl chloroformate (0.4 ml, 4.2 mmoles). After being kept for 18 h at 25”, the mixture was diluted with chloroform (100 ml) and the solution was successively washed with dilute hydrochloric acid and sodium hydrogen carbonate solution, dried (sodium sulfate), and evaporated under diminished pressure at 40” to a syrup. This syrup was resolved into monoethoxycarbonyl and diethoxycarbonyl fractions by preparative t.1.c. The zone of lower R, (monoethoxycarbonyl fraction) was separated by sectioning and eluted with ethyl acetate, and the eluate was evaporated. The syrupy residue (89 mg, 13%) crystallized when kept for 18 h at 25”. After recrystallization from hexane it had m.p. 56-58”. The mixed m.p. of this product with that from part (a) showed no depression; the i.r. spectra of (a) and (b) were identical. (c) Detritylation of 5. Compound 5 (340 mg, 0.635 mmole) was mixed with 0.03~ hydrochloric acid in methanol (20 ml) and stirred for 2.5 h at 50” to remove the trityl group. The mixture was made neutral with ammonium hydroxide, mixed with ice-water (100 ml), and extracted with four 20-ml portions of hexane to remove methyl triphenylmethyl ether. The aqueous-alcoholic solution was then extracted with four 20-ml portions of chloroform and the chloroform solution was dried and evaporated to a syrup that crystallized from hexane to give 90 mg (48%), m-p. 55-57”. The n.m.r_ and i-r. spectra were identical with those of authentic 4 and the mixed m.p. with authentic
4 showed no depression.
Comparison between ring-opening reactions of 2 and of methyl 4,6-O-benzylideneEquimolar portions (0.1 mmole) of the title compounds were separately dissolved in 10 ml of a stock solution of chloroform containing ethanol (1 n-mole) and triethylamine (0.1 mmole). The progress of the reaction was monitored by t.1.c. and i.r. spectroscopy. After 18 h, 2 was completely converted into an equimolar mixture of 3 and 4. In the same interval, methyl 4,6-0benzylidene-a-D-glucopyranoside 2,3-carbonate showed only about 50% conversion a-m©rar;oside
2,3-carbonate.
-
into acychc products. The large proportion of chloroform used retards the intramolecular migration of the ethoxycarbonyl group from C-4 to C-6. Within the interval studied, 0.1 mmole of 3 in 10 ml stock solution showed about 10% conversion into 4, and 0.1 mmole
Curbohyd.
Res.,
of 4 under these conditions
13 (1970)
301-305
showed no change.
305
NOTE
ACKNOWLEDGMENTS
The authors thank C. A. Glass and Dr. D. Weisleder for n.m.r. measurements, and C. E. McGrew, l3. R. Heaton, and K. A. Jones for microanaIyses and determination of molecular weights.
1 W. M. DOANE, B. S. SI~ASHA, E. I. STOUT, C. R. RUSSELL, AND C. E. RIST, Curb&d. Res., 4 (1967) 445. 2 E. I. STOUT, W. M. DOANE, B. S. SHASHA, C. R. RUSSELL, AND C. E. R~s-r, Tetrahedron Letr., 45 (1967) 4481. 3 H. C. BROWN, J. H. BREWSTER, AND H. SHECHTER, J. Amer. Chem. Sot., 76 (1954) 467. 4 W. N. HAWORTH, C. R. PORTER, AND A. C. WAINE, Rec. Trav. Chim., 57 (1938) 541. 5 R A. NYQUIST AND W. J. Porn, Spectrochim. Acfu, 17 (1961) 679. 6 J. LEHRFELD, J. Org. Chem., 32 (1967) 2544. 7 D. TRIMNELL, W. M. DOANE, C. R. RUSSELL, AND C. E. RIOT, Carbohyd. Res.. 11 (1969) 497. 8 G. J. ROBERTSON, J. Chem. Sot., (1933) 737.
Curbohyd.
Res., 13 (1970) 301-305