Improved Synthesis of 1-O-Acyl-β-d-Glucopyranose Tetraacetates

An improved synthesis of 1-O-acyl glucosyl esters that avoids the use of expensive Ag reagents as well as the hydrolysis of unstable glucosyl bromides is reported. Notably, β-configuration products were obtained exclusively in good yields.


Introduction
Numerous glycosyl esters have been investigated because of their biologically activity. Compounds such as tuliposide-A and tuliposide-B show bacteriotoxic and fungitoxic effects [1,2]. Some saturated fatty acid glycosyl esters were examined for antitumor activity [3]. In addition, glycosyl esters have also been used in cosmetics, detergents, oral-care products and medical supplies as flavor precursors.
The fact that few 1-O-acyl glycosyl esters have been found in Nature, has led to the development of various synthetic methods to access these compounds. The Koenigs-Knorr reaction using glycosyl bromide and an acid is the most attractive. Several publications have disclosed the glycosylation of carboxylic acids promoted by Ag catalysts through Koenigs-Knorr reaction (1a) [4][5][6]. However, the need for expensive Ag catalysts (at least one equivalent) has limited its application (Scheme 1).

Introduction
Numerous glycosyl esters have been investigated because of their biologically activity. Compounds such as tuliposide-A and tuliposide-B show bacteriotoxic and fungitoxic effects [1,2]. Some saturated fatty acid glycosyl esters were examined for antitumor activity [3]. In addition, glycosyl esters have also been used in cosmetics, detergents, oral-care products and medical supplies as flavor precursors.
The fact that few 1-O-acyl glycosyl esters have been found in Nature, has led to the development of various synthetic methods to access these compounds. The Koenigs-Knorr reaction using glycosyl bromide and an acid is the most attractive. Several publications have disclosed the glycosylation of carboxylic acids promoted by Ag catalysts through Koenigs-Knorr reaction (1a) [4][5][6]. However, the need for expensive Ag catalysts (at least one equivalent) has limited its application (Scheme 1).
in contrast with the known data [9][10][11]23,24] the β-configuration product was exclusively obtained through SN 2 substitution,. and in contrast with the known data [9][10][11]23,24] the β-configuration product was exclusively obtained through SN2 substitution,. Next, the PTC and the solvent were varied. From Table 2, it seems that the reaction did not happen without a PTC. Only 10% mol of a PTC such as tetrabutylammonium bromide (TBAB), tetraethylammonium bromide (TEAB), benzyltriethylammonium chloride (BTEAC), hexadecyltrimethylammonium bromide (CTMAB) led the reaction to give the product in high yield ( Table 2, entries 1-4). In the comparison of the solvents, DCM proved to be the best solvent (Table 2, entries 6-8). The role of the PTC is unclear, but it seems to increase the solubility of carboxylate formed at the beginning of the reaction, due to the quite low solubility of the latter.
Next, various acids were chosen to verify the scope of this reaction (Tables 3 and 4). Aromatic acids with different kind of substituent groups at different positions on benzene ring, gave the desired product in 80-99% yield. For example, electron-donating groups, such as methoxy, benzyloxy or Next, the PTC and the solvent were varied. From Table 2, it seems that the reaction did not happen without a PTC. Only 10% mol of a PTC such as tetrabutylammonium bromide (TBAB), tetraethylammonium bromide (TEAB), benzyltriethylammonium chloride (BTEAC), hexadecyltrimethylammonium bromide (CTMAB) led the reaction to give the product in high yield ( Table 2, entries 1-4). and in contrast with the known data [9][10][11]23,24] the β-configuration product was exclusively obtained through SN2 substitution,. Next, the PTC and the solvent were varied. From Table 2, it seems that the reaction did not happen without a PTC. Only 10% mol of a PTC such as tetrabutylammonium bromide (TBAB), tetraethylammonium bromide (TEAB), benzyltriethylammonium chloride (BTEAC), hexadecyltrimethylammonium bromide (CTMAB) led the reaction to give the product in high yield ( Table 2, entries 1-4). In the comparison of the solvents, DCM proved to be the best solvent (Table 2, entries 6-8). The role of the PTC is unclear, but it seems to increase the solubility of carboxylate formed at the beginning of the reaction, due to the quite low solubility of the latter.
Next, various acids were chosen to verify the scope of this reaction (Tables 3 and 4). Aromatic acids with different kind of substituent groups at different positions on benzene ring, gave the desired product in 80-99% yield. For example, electron-donating groups, such as methoxy, benzyloxy or In the comparison of the solvents, DCM proved to be the best solvent (Table 2, entries 6-8). The role of the PTC is unclear, but it seems to increase the solubility of carboxylate formed at the beginning of the reaction, due to the quite low solubility of the latter.
Next, various acids were chosen to verify the scope of this reaction (Tables 3 and 4). Aromatic acids with different kind of substituent groups at different positions on benzene ring, gave the desired product in 80-99% yield. For example, electron-donating groups, such as methoxy, benzyloxy or methyl could all make the reaction happen smoothly (Table 3, entries 1-5). Electron-withdrawing group also produced the corresponding products in 85-99% yield (Table 3, entries 6-8). Similarly, β-naphtoic acid gave product 22 quantitatively (Table 3, entry 9). In the comparison experiments, the yield decreased evidently because compound 1 is sensitive to hydrolysis as described before when the reaction was conducted in the presence of water (Table 3, entry 1, 3, 7 and 9). The β-configuration of the products was confirmed by 2D-NMR data of compound 8 [25]  methyl could all make the reaction happen smoothly (Table 3, entries 1-5). Electron-withdrawing group also produced the corresponding products in 85-99% yield ( Table 3, entries [6][7][8]. Similarly, β-naphtoic acid gave product 22 quantitatively (Table 3, entry 9). In the comparison experiments, the yield decreased evidently because compound 1 is sensitive to hydrolysis as described before when the reaction was conducted in the presence of water (Table 3, entry 1, 3, 7 and 9). The β-configuration of the products was confirmed by 2D-NMR data of compound 8 [25]    methyl could all make the reaction happen smoothly (Table 3, entries 1-5). Electron-withdrawing group also produced the corresponding products in 85-99% yield ( Table 3, entries [6][7][8]. Similarly, β-naphtoic acid gave product 22 quantitatively (Table 3, entry 9). In the comparison experiments, the yield decreased evidently because compound 1 is sensitive to hydrolysis as described before when the reaction was conducted in the presence of water (Table 3, entry 1, 3, 7 and 9). The β-configuration of the products was confirmed by 2D-NMR data of compound 8 [25]    methyl could all make the reaction happen smoothly (Table 3, entries 1-5). Electron-withdrawing group also produced the corresponding products in 85-99% yield ( Table 3, entries [6][7][8]. Similarly, β-naphtoic acid gave product 22 quantitatively (Table 3, entry 9). In the comparison experiments, the yield decreased evidently because compound 1 is sensitive to hydrolysis as described before when the reaction was conducted in the presence of water (Table 3, entry 1, 3, 7 and 9). The β-configuration of the products was confirmed by 2D-NMR data of compound 8 [25]    methyl could all make the reaction happen smoothly (Table 3, entries 1-5). Electron-withdrawing group also produced the corresponding products in 85-99% yield ( Table 3, entries [6][7][8]. Similarly, β-naphtoic acid gave product 22 quantitatively (Table 3, entry 9). In the comparison experiments, the yield decreased evidently because compound 1 is sensitive to hydrolysis as described before when the reaction was conducted in the presence of water (Table 3, entry 1, 3, 7 and 9). The β-configuration of the products was confirmed by 2D-NMR data of compound 8 [25]    methyl could all make the reaction happen smoothly ( Table 3, entries 1-5). Electron-withdrawing group also produced the corresponding products in 85-99% yield ( Table 3, entries [6][7][8]. Similarly, β-naphtoic acid gave product 22 quantitatively (Table 3, entry 9). In the comparison experiments, the yield decreased evidently because compound 1 is sensitive to hydrolysis as described before when the reaction was conducted in the presence of water (Table 3, entry 1, 3, 7 and 9). The β-configuration of the products was confirmed by 2D-NMR data of compound 8 [25]   methyl could all make the reaction happen smoothly (Table 3, entries 1-5). Electron-withdrawing group also produced the corresponding products in 85-99% yield ( Table 3, entries [6][7][8]. Similarly, β-naphtoic acid gave product 22 quantitatively (Table 3, entry 9). In the comparison experiments, the yield decreased evidently because compound 1 is sensitive to hydrolysis as described before when the reaction was conducted in the presence of water (Table 3, entry 1, 3, 7 and 9). The β-configuration of the products was confirmed by 2D-NMR data of compound 8 [25]    methyl could all make the reaction happen smoothly (Table 3, entries 1-5). Electron-withdrawing group also produced the corresponding products in 85-99% yield ( Table 3, entries [6][7][8]. Similarly, β-naphtoic acid gave product 22 quantitatively (Table 3, entry 9). In the comparison experiments, the yield decreased evidently because compound 1 is sensitive to hydrolysis as described before when the reaction was conducted in the presence of water (Table 3, entry 1, 3, 7 and 9). The β-configuration of the products was confirmed by 2D-NMR data of compound 8 [25]    methyl could all make the reaction happen smoothly (Table 3, entries 1-5). Electron-withdrawing group also produced the corresponding products in 85-99% yield ( Table 3, entries [6][7][8]. Similarly, β-naphtoic acid gave product 22 quantitatively (Table 3, entry 9). In the comparison experiments, the yield decreased evidently because compound 1 is sensitive to hydrolysis as described before when the reaction was conducted in the presence of water (Table 3, entry 1, 3, 7 and 9). The β-configuration of the products was confirmed by 2D-NMR data of compound 8 [25]    methyl could all make the reaction happen smoothly (Table 3, entries 1-5). Electron-withdrawing group also produced the corresponding products in 85-99% yield ( Table 3, entries [6][7][8]. Similarly, β-naphtoic acid gave product 22 quantitatively (Table 3, entry 9). In the comparison experiments, the yield decreased evidently because compound 1 is sensitive to hydrolysis as described before when the reaction was conducted in the presence of water (Table 3, entry 1, 3, 7 and 9). The β-configuration of the products was confirmed by 2D-NMR data of compound 8 [25]    methyl could all make the reaction happen smoothly (Table 3, entries 1-5). Electron-withdrawing group also produced the corresponding products in 85-99% yield ( Table 3, entries [6][7][8]. Similarly, β-naphtoic acid gave product 22 quantitatively (Table 3, entry 9). In the comparison experiments, the yield decreased evidently because compound 1 is sensitive to hydrolysis as described before when the reaction was conducted in the presence of water (Table 3, entry 1, 3, 7 and 9). The β-configuration of the products was confirmed by 2D-NMR data of compound 8 [25]    methyl could all make the reaction happen smoothly (Table 3, entries 1-5). Electron-withdrawing group also produced the corresponding products in 85-99% yield ( Table 3, entries [6][7][8]. Similarly, β-naphtoic acid gave product 22 quantitatively (Table 3, entry 9). In the comparison experiments, the yield decreased evidently because compound 1 is sensitive to hydrolysis as described before when the reaction was conducted in the presence of water (Table 3, entry 1, 3, 7 and 9). The β-configuration of the products was confirmed by 2D-NMR data of compound 8 [25]    methyl could all make the reaction happen smoothly (Table 3, entries 1-5). Electron-withdrawing group also produced the corresponding products in 85-99% yield ( Table 3, entries [6][7][8]. Similarly, β-naphtoic acid gave product 22 quantitatively (Table 3, entry 9). In the comparison experiments, the yield decreased evidently because compound 1 is sensitive to hydrolysis as described before when the reaction was conducted in the presence of water (Table 3, entry 1, 3, 7 and 9). The β-configuration of the products was confirmed by 2D-NMR data of compound 8 [25]    methyl could all make the reaction happen smoothly (Table 3, entries 1-5). Electron-withdrawing group also produced the corresponding products in 85-99% yield ( Table 3, entries [6][7][8]. Similarly, β-naphtoic acid gave product 22 quantitatively (Table 3, entry 9). In the comparison experiments, the yield decreased evidently because compound 1 is sensitive to hydrolysis as described before when the reaction was conducted in the presence of water (Table 3, entry 1, 3, 7 and 9). The β-configuration of the products was confirmed by 2D-NMR data of compound 8 [25] Table 4. The reaction of glucosyl bromide 1 with aliphatic acids a .   Table 4. The reaction of glucosyl bromide 1 with aliphatic acids a .  Table 4. The reaction of glucosyl bromide 1 with aliphatic acids a .   Table 4. The reaction of glucosyl bromide 1 with aliphatic acids a .   Table 4. The reaction of glucosyl bromide 1 with aliphatic acids a .   Table 4. The reaction of glucosyl bromide 1 with aliphatic acids a .   Table 4. The reaction of glucosyl bromide 1 with aliphatic acids a .   Table 4. The reaction of glucosyl bromide 1 with aliphatic acids a .  Table 4. The reaction of glucosyl bromide 1 with aliphatic acids a .  Table 4. The reaction of glucosyl bromide 1 with aliphatic acids a .   Table 4. The reaction of glucosyl bromide 1 with aliphatic acids a .   Table 4. The reaction of glucosyl bromide 1 with aliphatic acids a .   Table 4. The reaction of glucosyl bromide 1 with aliphatic acids a .  Table 4. The reaction of glucosyl bromide 1 with aliphatic acids a . Not only aromatic acids, but aliphatic acids could be used in the reaction too. The results are listed in Table 4. Phenylacetic acid (23) and 2,4,5-trifluorophenylacetic acid (25) provided the corresponding product in no less than 95% yield (Table 4, entries 1-2). Good results were also obtained using other aliphatic acids. For example, isobutyric acid (27) and isovaleric acid (29) gave the products in more than 90% yield respectively. Lower yield was obtained for pivalic acid (31), probably due to the steric hindrance (Table 4, entries 3-5).

Entry
In addition, a long chain glucosyl ester was prepared in good yield from acid 33 (Table 4, entry 6). Satisfactorily, this reaction could be also be extended to aliphatic acids with olefins and rings (Table 4, entries 7-11). For the same reason as before, the results were not good when water was added in the comparison sample due to the hydrolysis of 1 (Table 4, entry 1, 4, 6 and 10).
It is noteworthy that when we tried to prepare two 1-O-acyl-β-D-glucopyranose tetraacetates on a large scale (3 and 24, more than 100 g), these could be purified without column chromatography. It seems that this method could be applicable in industrial manufacture due to the high yields generally obtained. The scaled-up synthesis of other compounds and the study of other kinds of glycosylation are now underway.

General Methods
All solvents and reagents, except for compound 1, were purchased from the commercial supplier Tansoole (Shanghai, China) and were used without further purification. Compound 1 was prepared according to the known method [26]. 4 Å MS were activated at 600 • C for one-day and kept in a dessicator. The progress of the reactions was assessed by thin-layer chromatography (TLC) with GF 254 silica-gel precoated sheets using EtOAc/hexane as eluent. Column chromatography was performed on silica gel (200-300 mesh) using EtOAc/hexane or EtOAc/petroleum ether as eluent. 1 H (400 MHz) and 13 C (100 MHz) NMR spectra were recorded on an Avance 400 spectrometer (Bruker, Karlsruhe, Germany) in CDCl 3 using tetramethylsilane (TMS) as internal standards. 2D-NMR was recorded on a Bruker Avance 500 spectrometer. J values were given in Hertz. Mass spectra a high resolution mass spectra were recorded on an ESQUIRE-LC mass spectrometer (Agilent, Palo Alto, CA, USA). Elemental analysis was performed on an Elemental Vario-III CHN analyzer (Elementar Analysensysteme GmbH, Hanau, Germany). Optical rotations were measured on a WZZ-2S polarimeter (Suoguang Electric Tech Co., Shanghai, China) in DCM, with concentrations denoted in g/100 mL. Melting points were determined on a SGW-X4 melting point instruments (Shenguang Instrument Co., Ltd., Shanghai, China).

General Procedure for the Synthesis of 1-O-Acyl-β-D-Glucopyranose Tetraacetates
A mixture of glucosyl bromide 1 (1.03 g, 2.5 mmol), acid (5.0 mmol), K 2 CO 3 (0.69 g, 5.0 mmol), TEAB (0.05 g, 0.25 mmol) and 4 Å MS (0.25 g) in 35 mL DCM was stirred 24-48 h at room temperature. Next, the insoluble substances, made up of the slightly soluble potassium carboxylate, 4 Å MS and other salts, were filtered off. The filtrate was washed with water, and the separated organic layer was then washed with 25% aqueous K 2 CO 3 to removed any remaining potassium carboxylate. After drying over MgSO 4 and concentration in vacuo, the residue was purified via silica gel column chromatography using EtOAc/hexane or EtOAc/petroleum ether (1:10 to 1:1) as eluents to yield the desired product.

Scaled-Up Synthesis of Compound 3
A mixture of glucosyl bromide 1 (150.0 g, 0.36 mol), benzoic acid 2 (89.0 g, 0.73 mol), K 2 CO 3 (100.7 g, 0.73 mol), TEAB (7.5 g, 36 mmol) and 4 Å MS (36.0 g) in 5 L DCM was stirred 24 h at room temperature. Next, the insoluble substances, made up of the slightly soluble potassium benzoate, 4 Å MS and other salts, were filtered off. The filtrate was washed by water, and the separated organic layer was then washed with 25% aqueous K 2 CO 3 to remove any remaining potassium benzoate. After drying over MgSO 4 and concentration in vacuo, the crude was purified in refluxing EtOH to give 3 as a white solid in 89% yield after cooling down.

Conclusions
The formation of 1-O-acyl glucosyl esters by condensation of acids with glucosyl bromide was developed on a large scale in DCM without water. A diverse array of 1-O-acyl glucosyl esters were prepared in good yields, which seems to indicate that our reaction conditions could be applied to a broad substrate scope. In addition, scaled-up preparations were also successfully attempted.
Supplementary Materials: Supplementary materials can be accessed online.