Article pubs.acs.org/JAFC
Stereospecific, High-Yielding, and Green Synthesis of β‑Glycosyl Esters Suliu Feng and Chunbao Li* Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, China S Supporting Information *
ABSTRACT: A new method of synthesizing β-glycosyl esters stereospecifically has been developed by treating O-benzylprotected glycosyl chlorides with Cs2CO3, tetrabutylammomium bromide (TBAB), a carboxylic acid, water, and granular polytetrafluoroethylene (PTFE) at 80 °C under mechanical agitation. D-Glucosyl, D-xylosyl, and D-galactosyl chlorides and 20 carboxylic acids were used to demonstrate the scope of the reaction. Control experiments showed that the water and granular PTFE had indispensable roles. Water-soluble TBAB has been found to be as efficient as N-methyl-N,N,N-trioctyloctan-1ammonium chloride (Aliquat 336) in the reactions. After scaling up to 5−12 g, all of the products were obtained quantitatively via simple filtration and no organic solvents or chromatography was needed for the entire process. KEYWORDS: glycosylation, green chemistry, bioactive molecules, organic synthesis, natural products
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INTRODUCTION Glycosylation is an important tool in modifying the properties of bioactive molecules, including the transformation of carboxylic acids such as ursolic acid into glycosyl esters.1−3 Glycosyl esters are important biocompounds, which occur in tea,4 fruits,5,6 and vegetables.6 They function as antioxidants,5,6 enzyme inhibitors,6 anticancer agents,5,7 and sweeteners such as the well-known food additive stevioside.8 The following methods are used in the preparation of glycosyl esters all of which start from aldosyl hemiacetals: Schmidt glycosylation,9,10 Mitsunobu reaction,11−13 and Steglich esterification.14−16 The methods start from aldosyl hemiacetals using benzoyl chlorides,17 anhydrides,18 or carboxylic acids; amine-promoted reactions;5,6 and heavy metal-catalyzed (Ag2CO3,19 Ag2O,20 CdCO3,5 and SnCl25) reactions starting from carboxylic acids19,20 and glycosyl halide.5,19,20 All of these methods have problems associated with them. First, in most cases either the yields or the stereoselectivities on the anomeric positions are not good. For example, the Schmidt glycosylation has yields of 12−92% with glycoside isomer ratios of α:β = 1:0.24−4;9,10 the amine-promoted reactions give yields of 45−78%;5,6 the heavy metal-catalyzed reactions have yields of 41−91% with glycoside isomer ratios of α:β = 1.5−1.9:1;19,20 the Mitsunobu reactions have yields of 25−95% with glycoside isomer ratios of α:β = 1:2.5−4.5;11−13 and the Steglich esterifications have yields of 67−100% with glycoside isomer ratios of α:β = 1−5:1.14−16 Therefore, tedious chromatography or even high-performance liquid chromatography (HPLC) is required to separate the α- and β-glycosides, consuming large amounts of volatile organic solvents. Second, heavy metal catalysts are toxic and expensive. Third, organic solvents or anhydrous organic solvents are required for all of these reactions. In our group, several synthetic methods have been developed using water, N-methyl-N,N,N-trioctyloctan-1-ammonium chloride (Aliquat 336), and granular polytetrafluoroethylene (PTFE). Granular PTFE is used as a costirrer to realize the © XXXX American Chemical Society
aqueous reactions by dispersing the water-insoluble and highmelting-point starting materials.21−25 Aliquat 336 is a lipophilic liquid, which functions as both solvent and PTC. Therefore, the combination of granular PTFE and Aliquat 336 is beneficial to aqueous reactions using water-insoluble starting materials. To improve the yields and stereoselectivities of the glycosylation reactions, water, PTC, and granular PTFE were used to replace organic solvents in this work. Herein we report our research results in these aspects.
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MATERIALS AND METHODS
General Information. All of the chemicals were obtained from commercial sources (Tianjin Guangfu Fine Chemical Research Institute, Tianjin, China) or prepared according to standard methods. The 1H and 13C NMR spectra were recorded on a Bruker AM-400 spectrometer (400 and 100 MHz, respectively) or a Bruker Avance III spectrometer (600 and 150 MHz, respectively), using tetramethylsilane (TMS) as the internal standard (δ = 0). Multiplicities are reported as follows: singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m). IR spectra were obtained using a Bio-Rad FTS 3000 spectrometer, using potassium bromide disks, and the spectra were scanned from 400 to 4000 cm−1. Melting points were recorded on an X-4 Micromelting Point Apparatus. High-resolution mass spectra (ESI) were obtained on a Bruker microTOF-QII. Analytical data for representative products are listed below. All of the aqueous reactions were conducted in 100 mL flasks and agitated by the modified stirring rod.22,23 The size of the granular PTFE was 70 pieces/g. Typical 300 mg Scale Glycosylation Procedure Using Glucosylation of Benzoic Acid as an Example. A mixture of 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride (300 mg, 0.54 mmol), benzoic acid (1.05 equiv, 69 mg, 0.56 mmol), Cs2CO3 (0.51 equiv, 89 mg, 0.27 mmol), tetrabutylammonium bromide (TBAB) (0.05 equiv, 9 mg, 0.03 mmol), and granular PTFE (5 g) was Received: March 25, 2015 Revised: June 3, 2015 Accepted: June 4, 2015
A
DOI: 10.1021/acs.jafc.5b02534 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
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Journal of Agricultural and Food Chemistry Table 1. Optimization of the Glucosylation of Benzoic Acidsa
entry
base
H2O (equiv)
T (°C)
PTC (equiv)
t (h)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23c 24
Li2CO3 Li2CO3 Li2CO3 Li2CO3 Na2CO3 K2CO3 TBAOH Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Li2CO3 Na2CO3 K2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3
310 20 15 10 10 10 30 10 10 10 10 10 10 10 10 10 310 20 15 5 10 10 10 10
40 40 40 40 40 40 40 40 25 60 80 80 80 80 80 80 80 80 80 80 80 80 80 80
Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.05) TBAB (0.05) TBAB (0.05) TBAB (0.05) TBAB (0.05) TBAB (0.05) TBAB (0.05) TBAB (0.05) TBAB (0.05) TBAB (0.01) TBAB (0.1) TBAB (1.05) SDS (0.05)
2 6 12 12 12 9 1 6 12 2 0.33 0.67 0.67 0.67 0.67 0.67 6.6 0.83 0.75 1.5 2 0.58 0.67 2
Cs2CO3
.yieldb (%) (1:β-2:3) 0:18:82 74:17:9 62:23:15 37:34:29 49:36:15 41:49:10 43:38:19 0:67:33 42:36:22 0:84:16 >99 only >99 only 23:22:55 31:51:18 27:63:10 >99 only 0:29:71 0:74:26 >99 only >99 only >99 only >99 only 32:0:68 NRd
(β-2) (β-2)
(β-2)
(β-2) (β-2) (β-2) (β-2)
a
Reaction conditions: 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride (300 mg, 0.54 mmol), benzoic acid (1.05 equiv), base, water, PTC, granular PTFE (5 g), mechanical stirring (400 rpm). bDetermined by 1H NMR. cReaction conditions: 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride (300 mg, 0.54 mmol), TBAB (182 mg, 0.56 mmol), water (97 mg, 5.38 mmol), granular PTFE (5 g), mechanical stirring (400 rpm). dNo reaction. mechanically stirred (400 rpm) at 80 °C for 2 min followed by the addition of water (10 equiv, 97 mg, 5.38 mmol). Initially, the reaction media appeared as thick milk, and it gradually turned to a semisolid, which adhered to the glass. After thin-layer chromatography (TLC) indicated completion of the reaction, ethyl acetate (2 × 10 mL) was added to extract the crude product, which was washed with 5% aqueous Na2CO3 (1 × 10 mL) and water (1 × 10 mL) and dried over Na2SO4. Concentration under reduced pressure gave benzoic acid 1O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester: (351 mg, >99%). Typical 5−12 g Scale Glycosylation Procedure Using Glucosylation of Benzoic Acid at an 11.7 g Scale as an Example. A mixture of 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride (10 g, 17.89 mmol), benzoic acid (1.05 equiv, 2.29 g, 18.75 mmol), Cs2CO3 (0.51 equiv, 2.97 g, 9.12 mmol), TBAB (0.05 equiv, 288 mg, 0.89 mmol), and granular PTFE (5 g) was mechanically stirred (400 rpm) at 80 °C for 2 min, followed by the addition of water (10 equiv, 3.22 g, 178.69 mmol). Initially, the reaction mixture appeared as thick milk and had good fluidity. After completion of the reactions as detected by TLC and removing the oil bath, the products started to solidify and eventually became fine granules. The product was filtered after the addition of water (3 × 15 mL) to wash the reaction flask, and the filtrates were washed with 5% aqueous Na2CO3 (3 × 10 mL) and water (3 × 10 mL) and air-dried to give benzoic acid 1-O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester (11.7 g, > 99%). Benzoic acid 1-O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester,9 p-nitrobenzoic acid 1-O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester,9 2-acetyloxybenzoic acid 1-O-[2,3,4,6-tetra-O-benzyl-β26 D-glucopyranosyl] ester, palmitic acid 1-O-[2,3,4,6-tetra-O-benzyl-β27 D-glucopyranosyl] ester, bile acid 24-O-[2,3,4,6-tetra-O-benzyl-β-D28 glucopyranosyl] ester, benzoic acid 1-O-[2,3,4,6-tetra-O-benzyl-β-Dgalactopyranosyl] ester,29 p-nitrobenzoic acid 1-O-[2,3,4,6-tetra-O-
benzyl-β-D-galactopyranosyl] ester,30 and p-nitrobenzoic acid 1-O[2,3,4-tri-O-benzyl-β-D-xylopyranosyl] ester31 are known compounds. 2-(Benzyloxycarbonylamino)-3-phenylpropanoic acid 1-O-[2,3,4,6tetra-O-benzyl-β-D-glucopyranosyl] ester: 410 mg, 93% yield; white solid, mp 108−109 °C; 1H NMR (600 MHz, CDCl3) δ 7.35−7.14 (m, 30H) 5.65 (d, J = 8.1 Hz, 1H, H-1), 5.13 (d, J = 8.3 Hz, 1H), 5.09 (q, J = 12.3 Hz, 1H), 4.90 (d, J = 11.0 Hz, 1H), 4.84 (m, 2H), 4.71 (s, 1H), 4.58 (m, 3H), 4.53 (d, J = 12.0 Hz, 1H), 3.75 (dt, J = 17.8, 9.1 Hz, 5H), 3.60 (dd, J = 18.4, 9.7 Hz, 3H), 3.12 (dd, J = 20.7, 5.5 Hz, 2H); 13 C NMR (151 MHz, CDCl3) δ 170.20, 137.86, 135.23, 129.74, 128.58, 128.48, 128.26, 128.17, 127.98, 127.95, 127.89, 127.80, 127.14, 94.85 (C-1), 84.79, 80.40, 75.74, 75.58, 75.09, 74.98, 73.68, 67.02, 54.57, 37.54; IR (KBr) v 3327, 3030, 3897, 1765, 1695, 1537, 1453, 1265, 1157, 1079, 751, 696; HRMS calcd for C51H51NO9Na [M + Na]+, 844.3456, found, 844.3454. 4-{[(1,1-Dimethylethyl)dimethylsilyl]oxy}-1-[(4-methylphenyl)sulfonyl]-L-proline 6-O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester: 480 mg, 97% yield; white solid; mp 117−118 °C; 1H NMR (600 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.40−7.28 (m, 18H), 7.22 (d, J = 6.6 Hz, 2H), 5.78 (d, J = 8.0 Hz, 1H, H-1), 5.01 (d, J = 11.0 Hz, 1H), 4.96 (d, J = 10.9 Hz, 1H), 4.88 (t, J = 10.4 Hz, 2H), 4.80 (d, J = 11.0 Hz, 1H), 4.67 (d, J = 12.1 Hz, 1H), 4.62 (d, J = 10.7 Hz, 1H), 4.56 (d, J = 12.1 Hz, 1H), 4.49 (t, J = 7.7 Hz, 1H), 4.41 (s, 1H), 3.85−3.75 (m, 4H), 3.71 (t, J = 8.2 Hz, 1H), 3.67−3.60 (m, 2H), 3.31 (d, J = 10.3 Hz, 1H), 2.44 (s, 3H), 2.25−2.04 (m, 2H), 0.81 (s, 9H), −0.00 (d, J = 2.6 Hz, 6H); 13C NMR (151 MHz, CDCl3) δ 171.09, 143.60, 143.55, 138.45, 138.07, 129.69, 128.48, 128.42, 127.97, 127.95, 127.86, 127.76, 95.05 (C-1), 84.70, 80.59, 75.68, 75.05, 74.86, 73.51, 70.57, 59.63, 56.43, 40.12, 25.67, 21.58, 17.94, −4.88, −5.01; IR (KBr) v 3060, 2931, 2860, 1769, B
DOI: 10.1021/acs.jafc.5b02534 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
Article
Journal of Agricultural and Food Chemistry 1596, 1453, 1348, 1411, 1170, 1090, 777, 698; HRMS calcd for C52H63NO10SSiNa [M + Na]+, 944.3834, found, 944.3834. 4-Pentenoic acid 1-O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester: 338 mg, >99% yield; white solid; mp 74−75 °C; 1H NMR (600 MHz, CDCl3) δ 7.40−7.25 (m, 18H), 7.14 (d, J = 5.5 Hz, 2H), 5.80 (dd, J = 13.9, 7.4 Hz, 1H), 5.63 (d, J = 8.0 Hz, 1H, H-1), 5.05 (d, J = 17.1 Hz, 1H), 4.99 (d, J = 10.1 Hz, 1H), 4.89 (d, J = 10.8 Hz, 1H), 4.86−4.80 (m, 2H), 4.76 (q, J = 11.4 Hz, 2H), 4.63 (d, J = 12.1 Hz, 1H), 4.53 (d, J = 10.6 Hz, 1H), 4.48 (d, J = 12.1 Hz, 1H), 3.82−3.67 (m, 4H), 3.59 (dd, J = 18.8, 9.6 Hz, 2H), 2.45 (dd, J = 18.3, 9.5 Hz, 1H), 2.36 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 171.47, 138.43, 138.16, 138.08, 137.98, 136.37, 128.49, 128.45, 128.03, 127.97, 127.94, 127.85, 127.78, 115.85, 94.11 (C-1), 84.88, 81.10, 77.28, 75.80, 75.57, 75.08, 73.57, 68.10, 33.50, 28.44; IR (KBr) v 3063, 3030, 2917, 2864, 1751, 1495, 1453, 1359, 1155, 1081,916, 748, 698; HRMS calcd for C39H42O7Na [M + Na]+, 645.2823, found, 645.2828. Ursolic acid 28-O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester: 483 mg, 92% yield; white solid; mp 79−80 °C; 1H NMR (600 MHz, CDCl3) δ 7.39−7.21 (m, 18H), 7.17 (s, 2H), 5.49 (d, J = 8.1 Hz, 1H, H-1), 5.26 (s, 1H), 4.84 (d, J = 33.2 Hz, 5H), 4.61 (dd, J = 20.3, 10.7 Hz, 2H), 4.50 (d, J = 10.2 Hz, 1H), 3.81−3.65 (m, 4H), 3.64−3.48 (m, 2H), 3.20 (s, 1H), 2.24 (s, 1H), 2.03 (s, 1H), 1.87 (s, 3H), 1.71 (d, J = 8.9 Hz, 2H), 1.55 (d, J = 59.8 Hz, 4H), 1.45−1.14 (m, 10H), 1.03 (d, J = 9.4 Hz, 3H), 0.97 (dd, J = 19.9, 9.6 Hz, 9H), 0.86 (d, J = 8.8 Hz, 6H), 0.77 (d, J = 9.4 Hz, 3H), 0.69 (t, J = 14.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 175.93, 138.47, 138.28, 138.19, 137.50, 128.39, 128.34, 128.31, 127.93, 127.81, 127.63, 127.58, 127.46, 127.13, 125.95, 94.21 (C-1), 85.10, 80.70, 79.05, 77.53, 75.61, 74.96, 74.66, 73.46, 68.29, 55.27, 52.83, 48.12, 47.63, 42.10, 39.50, 39.18, 38.92, 38.75, 36.97, 36.20, 32.73, 30.72, 29.73, 28.32, 28.21, 27.28, 24.43, 23.29, 21.21, 18.31, 17.08, 16.94, 15.68, 15.53; IR (KBr) v 2923, 2866, 1747, 1496, 1454, 1360, 1308, 1072, 739, 696; HRMS calcd for C64H82O8Na [M + Na]+, 1001.5902, found, 1001.5901. Stearic acid 1-O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester: 435 mg, >99% yield; syrup; 1H NMR (600 MHz, CDCl3) δ 7.30 (m, 18H), 7.13 (m, 2H), 5.62 (d, J = 8.2 Hz, 1H, H-1), 4.89 (d, J = 10.9 Hz, 1H), 4.82 (dd, J = 10.5, 8.7 Hz, 2H), 4.77 (s, 2H), 4.63 (d, J = 12.1 Hz, 1H), 4.50 (dd, J = 23.6, 11.4 Hz, 2H), 3.74 (m, 4H), 3.59 (m, 2H), 2.34 (dd, J = 15.6, 7.8 Hz, 1H), 2.28 (t, J = 7.7 Hz, 1H), 1.61 (m, 2H), 1.27 (dd, J = 27.3, 9.0 Hz, 28H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 172.26, 138.46, 138.18, 138.09, 137.98, 128.52, 128.50, 128.46, 128.08, 128.00, 127.98, 127.86, 127.80, 94.04 (C-1), 84.88, 81.13, 77.30, 75.84, 75.56, 75.11, 75.09, 73.58, 68.08, 34.36, 32.05, 29.83, 29.81, 29.79, 29.74, 29.56, 29.50, 29.39, 29.23, 29.18, 24.91, 24.65, 22.83, 14.29; IR (KBr) v 2924, 2853, 1756, 1458, 1359, 1081, 910, 737, 698; HRMS calcd for C52H70O7Na [M + Na]+, 829.5014, found, 829.5015. 4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3-methoxybenzoic acid 1-O-[2,3,4-tri-O-benzyl-β-D-xylopyranosyl] ester: 433 mg, 92% yield; syrup; 1H NMR (600 MHz, CDCl3) δ 7.39 (dd, J = 8.3, 1.8 Hz, 1H), 7.35 (d, J = 1.7 Hz, 1H), 7.18−7.14 (m, 10H), 7.08 (s, 1H), 7.04 (s, 4H), 6.68 (d, J = 8.3 Hz, 1H), 5.65 (d, J = 7.6 Hz, 1H, H-1), 4.70 (dd, J = 21.6, 10.9 Hz, 2H), 4.61 (t, J = 6.5 Hz, 1H), 4.57 (d, J = 11.7 Hz, 1H), 4.48 (d, J = 11.6 Hz, 1H), 3.81 (dt, J = 14.1, 7.1 Hz, 1H), 3.68 (s, 1H), 3.64 (s, 2H), 3.52 (ddd, J = 19.5, 16.3, 8.5 Hz, 4H), 3.30−3.25 (m, 1H), 0.82 (d, J = 7.6 Hz, 9H), 0.01 (d, J = 8.0 Hz, 6H); 13C NMR (151 MHz, CDCl3) δ 164.79, 150.81, 150.33, 138.44, 137.98, 137.86, 128.58, 128.48, 128.43, 128.06, 127.95, 127.85, 127.81, 123.92, 122.50, 120.61, 113.20, 95.03 (C-1), 83.45, 80.19, 77.33, 77.12, 76.91, 75.63, 75.05, 73.35, 64.54, 55.52, 25.67, 18.57, −4.52; IR (KBr) v 2931, 2859, 1729, 1596, 1511, 1460, 1287, 1215, 1079, 890, 698; HRMS calcd for C40H48O8SiNa [M + Na]+, 707.3011, found, 707.3013.
were used; the PTC was Aliquat 336 or TBAB, the amount of water was varied from 10 to 310 equiv, and the reaction temperature ranged from 25 to 80 °C. For all reaction combinations, the desired product, β-glucosyl ester, was contaminated with a substantial amount of the partially hydrolyzed products. Therefore, 2,3,4,6-tetra-O-benzyl-α-Dglucopyranosyl chloride (1, Table 1) was used as the starting material. When Li2CO3, Na2CO3, K2CO3, or tetrabutylammonium hydroxide (TBAOH·30H2O) was used as the base and Aliquat 336 (0.15 equiv) as the catalyst, the amount of undesired hydrolysis product, 2,3,4,6-tetra-O-benzyl-D-glucose (3) varied from 29 to 19% (Table 1, entries 4−7). However, the amount of 3 was affected by the amount of water, and 10 equiv of water was found to be optimal in reducing the amount of side product 3 (Table 1, entries 1−6 and 8). When Li2CO3 was replaced with Cs2CO3 and the reactions were performed at 40 and 25 °C, the yields of the desired product β-2 were 67 and 36% (Table 1, entries 8 and 9), respectively. Thus, raising the reaction temperature could improve the reaction yield. When the temperature was increased to 60 °C, the yield of β-2 increased to 84% and only 16% of 3 was formed (Table 1, entry 10). Further raising the temperature to 80 °C completely avoided the side reaction (the hydrolysis of 1 to 3) and gave β-2 in quantitative yield (Table 1, entry 11). When the amount of Aliquat 336 was reduced to 0.05 equiv, the yields were similar, but the reaction time increased from 0.33 to 0.67 h (Table 1, entries 11 and 12). The only problem associated with this new synthesis is that Aliquat 336 is water-insoluble and contaminates the product. Replacing 0.05 equiv of Aliquat 336 with 0.05 equiv of TBAB led to the quantitative and stereospecific synthesis of β-2 (Table 1, entry 16). Increasing the amount of water to 20 or 310 equiv yielded a mixture of β-2:3 in ratios of 74:26 and 29:71 (Table 1, entries 18 and 17), respectively. Decreasing the amount of water to 5 equiv increased the reaction time (1.5 h) (Table 1, entry 20). The reaction rates were altered by variation of the amounts of TBAB (0.01 equiv, 2 h; 0.05 equiv, 0.67 h; and 0.1 equiv, 0.58 h) (Table 1, entries 21, 16, and 22). The reaction rates and yields became worse after using Li2CO3, Na2CO3, and K2CO3 to replace Cs2CO3 (Table 1, entries 13− 15). The fact that Cs2CO3 is much better than the other bases for this glucosylation (Table 1, entries 1−6 vs 8 and 13−15 vs 16) is probably due to the cesium effect.26,32 It has been reported by Lemieux et al.33−35 that the anomerizations of tetra-O-acetyl-β-D-glucopyranosyl chloride took place in the presence of tetraethylammonium chloride, TBAB, or tetrabutylammonium iodide in organic solvents. However, no anomerization was observed when 1 was treated with 1.05 equiv of TBAB (Table 1, entry 23) in this aqueous reaction. The only detected products were 3 and 1 (68:32). This indicated that the reaction rates of 1 with carboxylates were fast enough to avoid the possible hydrolysis of 1 in these aqueous conditions. Using sodium dodecyl sulfate (SDS) (0.05 equiv) instead of TBAB did not produce β-2 (Table 1, entry 24). On the basis of all these results, the optimized conditions are 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride (1.0 equiv), benzoic acid (1.05 equiv), TBAB (0.05 equiv), Cs2CO3 (0.51 equiv), water (10 equiv), and granular PTFE (5 g) at 80 °C with mechanical agitation at 400 rpm (Table 1, entry 16). We believe that this reaction system is probably micellecatalyzed,36,37 which is based on the following observations. First, the reaction mixture was milky at the beginning of the reaction and then turned to a semisolid, which adhered to the
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RESULTS AND DISCUSSION Initially, a mixture of benzoic acid with acetobromoglucose or acetochloroglucose in the presence of a carbonate, a PTC, water, and granular PTFE was stirred mechanically at various temperatures using the modified stirring rod.22,23 Various carbonates including lithium, sodium, potassium, and cesium C
DOI: 10.1021/acs.jafc.5b02534 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
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Journal of Agricultural and Food Chemistry Table 2. β-Glycosylation of a Series of Carboxylic Acidsa
a
Reaction conditions: glycosyl chloride (300 mg, 0.54 mmol), acid (1.05 equiv), water (10 equiv), Cs2CO3 (0.51 equiv), TBAB (0.05 equiv), granular PTFE (5 g), mechanical stirring (400 rpm) at 80 °C. bAll conversions were 100%, and all yields are isolated yields.
flask walls and the stirrer after the completion of the reaction. Second, in our previous research in which Aliquat 336 was used as both a solvent and a catalyst,21−25 the amount of water used was not important. In contrast, the amount of water was critical for this reaction (Table 1, entries 20, 18, and 17 vs entry 16). Third, the reaction temperature had to be raised to 80 °C to reduce the amount of side product 3. This can be attributed to the efficient formation of micelles at this temperature. All of these facts support the reaction being micelle-catalyzed. One of the reasons for the stereospecificity of the βglycosylation is the closer contact between the carboxylates and the glucosyl chlorides in the micelles than in conventional organic solvents. Although it is commonly believed that the
negatively charged head of the carboxylates is oriented toward the aqueous phase, it is possible that certain amounts of the carboxylates are oriented toward the glycosyl chlorides because of the geometry or charge demands in the micelles. Water-soluble TBAB can form ionic pairs with carboxylic acids under basic conditions, which are lipophilic enough to replace Aliquat 336 to form micelles with glycosyl chloride. In the literature, surfactants containing 8−18 carbon atoms in straight alkyl chains are often used in micelle-catalyzed reactions, but there have been no reports of using TBAB in these types of reactions.38 Next a series of β-glycosyl esters were synthesized under the optimized conditions. Most of the reaction yields were >90%, D
DOI: 10.1021/acs.jafc.5b02534 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
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Journal of Agricultural and Food Chemistry with some being quantitative, and all of the reaction times were short (0.67−2.5 h) (Table 2). In all cases, only the β-glycosyl esters were obtained. The reactions were compatible with a series of functional groups including alkenes (Table 2, entries 1, 12, 14, and 18), nitro groups (Table 2, entries 2, 20, and 24), ethers (Table 2, entries 3 and 25), halide (Table 2, entry 5), aliphatic esters (Table 2, entry 10), phenolic esters (Table 2, entries 6, 9, and 23), benzyloxycarbonylamino group (Table 2, entry 7), ketone (Table 2, entry 8), silyl ethers (Table 2, entries 11 and 25), and hydroxyl groups (Table 2, entries 17 and 18). The 1H NMR and 13C NMR data for the β-glycosyl esters are 5.49−5.92 ppm (1H, J = 7.1−8.2 Hz, H-1) and 94.01−95.48 ppm (C-1), respectively, which are in agreement with the data from the literature.9,26−31 It has been reported that glycosylation can improve the properties of peptide biopharmaceuticals.2,39,40 Therefore, three amino acid derivatives were subjected to the glucosylation conditions, and the yields were excellent (Table 2, entries 7, 10, and 11). However, the yields for carbohydrate−peptide conjugations are around 30% in the literature.39 Bile acid glycoside, which has been identified in biological materials, has been synthesized as a mixture of α- and β-anomers (ratio of α:β = 1:3) in 99 (only β-2) 60 (38:22)
46
t = 1.10 h >99 (only β-2) 17 (9:8)
43
t = 0.85 h >99 (only β-2) 34 (only β-2)
yieldb (β-2:α-2) (%)
3 (%)
3 (%)
t = 1.50 h 19 (only β-2)
31
81
t = 3.30 h 37
45 (26:19)
55
t = 2.5 h 64 (only β-2)
23
36
a
Reaction conditions: 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride (300 mg, 0.54 mmol), benzoic acid (1.05 equiv), Cs2CO3 (0.51 equiv), water (10 equiv), TBAB (0.05 equiv), granular PTFE, mechanical stirring (400 rpm) at 80 °C. bDetermined by 1H NMR.
Table 4. Control Experiments in Water and in Organic Solvents
t = 40 min entry b
1 2c 3c 4c 5c 6c
solvent H2O DMF AcOEt THF toluene CHCl3
recovered 1 (%) 12 15
t=6h
a
yield (β-2:α-2) (%)
3 (%)
>99 (only β-2) 69 (54:15) 21(12:9) NRd NRd NRd
19 64
recovered 1 (%)
yielda (β-2:α-2) (%)
3 (%)
3 66 28
59 (only β-2) 27 (19:8) 21 (only β-2) 55 (42:13) NRd
41 70 13 17
a Determined by 1H NMR, bReaction conditions: 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride (300 mg, 0.54 mmol), benzoic acid (1.05 equiv), Cs2CO3 (0.51 equiv), water (10 equiv), TBAB (0.05 equiv), granular PTFE (5 g), mechanical stirring (400 rpm) at 80 °C. cReaction conditions: 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride (100 mg, 0.18 mmol), benzoic acid (1.05 equiv), Cs2CO3 (0.51 equiv) in DMF or toluene (1 mL) at 80 °C or AcOEt, THF or CHCl3 (1 mL) at refluxing temperatures. dNo reaction.
Table 4. In DMF and AcOEt, a mixture of α-2 and β-2 (β-2:α2 = 54:15 and 12:9, respectively) and byproduct 3 (19 and 64%, respectively) was obtained in 40 min (Table 4, entries 2 and 3). When the reaction time was prolonged to 6 h, the product distributions were 59% (β-2 only) and 41% (3) in DMF and 27% (β-2:α-2 = 19:8) and 70% (3) in AcOEt (Table 4, entries 2 and 3). No reactions occurred in THF and toluene after 40 min, and after 6 h, yields of only 21% of β-2 and 55% of β-2/α-2 (42:13) were obtained, respectively (Table 4, entries 4 and 5). The reaction did not take place in CHCl3 after 6 h (Table 4, entry 6). Only in water could the β-glycosyl esters be synthesized with excellent yields and high stereoselectivities. In conclusion, a simple, efficient, and green method for synthesizing β-glycosyl esters has been developed. The glycosylation is stereospecific and produces excellent yields. The micelle-catalyzed reactions used water-soluble TBAB as the surfactant and water as the medium. Therefore, the workup was simple with no need for chromatography. Five β-glucosyl esters were scaled up to 5−12 g, and all of the yields were quantitative. No organic solvents were used in the entire processes. The indispensable roles of granular PTFE and the correct amount of water in these reactions have also been demonstrated. This procedure should be assumed to be
particularly useful in synthesizing food additives and modifying the properties of bioactive molecules through glycosylation.
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ASSOCIATED CONTENT
S Supporting Information *
Pictures of glucosylations at different scales, general information, typical glycosylation procedures for different scales, analytic data of the products, procedure for the debenzylation of benzoic acid 1-O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester, 1H NMR and 13C NMR spectra for all compounds, mass spectra for new compounds, and references. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jafc.5b02534.
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AUTHOR INFORMATION
Corresponding Author
*(C.L.) Phone: +86-022-27892351. Fax: +86-022-27403475. Email: [email protected]. Notes
The authors declare no competing financial interest. F
DOI: 10.1021/acs.jafc.5b02534 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
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Journal of Agricultural and Food Chemistry
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(21) Cui, X.; Li, B.; Liu, T.; Li, C. A practical solution for aqueous reactions of water-insoluble high-melting-point organic substrates. Green Chem. 2012, 14, 668−672. (22) Li, B.; Li, C. Neighboring heteroatom effect unique to aqueous aldol reactions of water-insoluble substrates. J. Org. Chem. 2014, 79, 2242−2254. (23) Li, B.; Li, C. Darzens reaction rate enhancement using aqueous media leading to a high level of kinetically controlled diastereoselective synthesis of steroidal epoxyketones. J. Org. Chem. 2014, 79, 8271− 8277. (24) Li, T.; Cui, X.; Sun, L.; Li, C. Economical and efficient aqueous reductions of high-melting-point imines and nitroarenes to amines: promotion effects of granular PTFE. RSC Adv. 2014, 4, 33599−33606. (25) He, G.; Li, B.; Li, C. Quantitative “on water” ring-opening of steroidal epoxides accelerated by sand: a green procedure. J. Agric. Food Chem. 2013, 61, 2913−2918. (26) Kunz, H.; Kullmann, R.; Wernig, P.; Zimmer, J. Stereoselective synthesis of β-1-O-acyl derivatives of carbohydrates: an application of the cesium effect. Tetrahedron Lett. 1992, 33, 1969−1972. (27) Pfeffer, P. E., Moore, G. G. Preparation of 1-α- and 1-β-glucose esters by stereoselective acylation of metalated 2,3,4,6-tetra-O-benzylD-glucopyranose. US4107425, Aug 15, 1978. (28) Iida, T.; Nakamori, R.; Yabuta, R.; Yada, S.; Takagi, Y.; Mano, N.; Ikegawa, S.; Goto, J.; Nambara, T. Potential bile acid metabolites. 24. An efficient synthesis of carboxyl-linked glucosides and their chemical properties. Lipids 2002, 37, 101−110. (29) Mao, J.; Chen, H.; Zhang, J.; Cai, M. Studies on glycosides XIV. stereoselectivity and reactivity of new C1 leaving group trichloroacetoxyl in glycosylation reaction. Synth. Commun. 1995, 25, 1563− 1565. (30) Ané, A.; Josse, S.; Naud, S.; Lacône, V.; Vidot, S.; Fournial, A.; Kar, A.; Pipelier, M.; Dubreuil, D. Unusual anomeric rearrangement of p-nitrobenzoylxanthate D-glycosides: a new direct stereoselective access to α-thioglycosides from pyranose sugars. Tetrahedron 2006, 62, 4784−4794. (31) Bar-Guilloux, É.; Defaye, J.; Driguez, H.; Robic, D. Synthèse, conformation et affinité tréhalasique des α-D-glucopyranosyl-α-Dxylopyranoside, α-D-glucopyranosyl-α-D-mannopyranoside et α-Dallopyranosyl-α-D-glucopyranoside. Carbohydr. Res. 1975, 45, 217− 236. (32) Gisin, B. F. The preparation of Merrifield-resins through total esterification with cesium salts. Helv. Chim. Acta 1973, 56, 1476−1482. (33) Lemieux, R. U.; Levine, S. Synthesis of alkyl 2-deoxy-α-Dglycopyranoside and their 2-deuterio derivative. Can. J. Chem. 1964, 42, 1473−1480. (34) Lemieux, R. U.; Hayami, J. The mechanism of the anomerization of the tetra-O-acetyl-D-glucopyranosyl chlorides. Can. J. Chem. 1965, 43, 2161−2173. (35) Lemieux, R. U.; Lineback, D. R. The mechanism of the dehydrobromination of tetra-O-acetyl-α-D-glucopyranosyl bromide. Can. J. Chem. 1965, 43, 94−105. (36) Gawande, M. B.; Bonifacio, V. D.; Luque, R.; Branco, P. S.; Varma, R. S. Benign by design: catalyst-free in-water, on-water green chemical methodologies in organic synthesis. Chem. Soc. Rev. 2013, 42, 5522−5551. (37) La Sorella, G.; Strukul, G.; Scarso, A. Recent advances in catalysis in micellar media. Green Chem. 2015, 17, 644−683. (38) Tehrani-Bagha, A.; Holmberg, K. Solubilization of hydrophobic dyes in surfactant solutions. Materials 2013, 6, 580−608. (39) Jerić, I.; Horvat, Š. Novel ester-linked carbohydrate−peptide adducts: effect of the peptide substituent on the pathways of intramolecular reactions. Eur. J. Org. Chem. 2001, 2001, 1533−1539. (40) Brimble, M. A.; Edwards, P. J.; Harris, P. W. R.; Norris, G. E.; Patchett, M. L.; Wright, T. H.; Yang, S.-H.; Carley, S. E. Synthesis of the antimicrobial S-linked glycopeptide, glycocin F. Chem.−Eur. J. 2015, 21, 3556−3561. (41) Choi, T. J.; Baek, J. Y.; Jeon, H. B.; Kim, K. S. A new efficient glycosylation method employing glycosyl pentenoates and PhSeOTf. Tetrahedron Lett. 2006, 47, 9191−9194.
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DOI: 10.1021/acs.jafc.5b02534 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
Stereospecific, High-Yielding, and Green Synthesis of β‑Glycosyl Esters Suliu Feng and Chunbao Li* Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, China S Supporting Information *
ABSTRACT: A new method of synthesizing β-glycosyl esters stereospecifically has been developed by treating O-benzylprotected glycosyl chlorides with Cs2CO3, tetrabutylammomium bromide (TBAB), a carboxylic acid, water, and granular polytetrafluoroethylene (PTFE) at 80 °C under mechanical agitation. D-Glucosyl, D-xylosyl, and D-galactosyl chlorides and 20 carboxylic acids were used to demonstrate the scope of the reaction. Control experiments showed that the water and granular PTFE had indispensable roles. Water-soluble TBAB has been found to be as efficient as N-methyl-N,N,N-trioctyloctan-1ammonium chloride (Aliquat 336) in the reactions. After scaling up to 5−12 g, all of the products were obtained quantitatively via simple filtration and no organic solvents or chromatography was needed for the entire process. KEYWORDS: glycosylation, green chemistry, bioactive molecules, organic synthesis, natural products
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INTRODUCTION Glycosylation is an important tool in modifying the properties of bioactive molecules, including the transformation of carboxylic acids such as ursolic acid into glycosyl esters.1−3 Glycosyl esters are important biocompounds, which occur in tea,4 fruits,5,6 and vegetables.6 They function as antioxidants,5,6 enzyme inhibitors,6 anticancer agents,5,7 and sweeteners such as the well-known food additive stevioside.8 The following methods are used in the preparation of glycosyl esters all of which start from aldosyl hemiacetals: Schmidt glycosylation,9,10 Mitsunobu reaction,11−13 and Steglich esterification.14−16 The methods start from aldosyl hemiacetals using benzoyl chlorides,17 anhydrides,18 or carboxylic acids; amine-promoted reactions;5,6 and heavy metal-catalyzed (Ag2CO3,19 Ag2O,20 CdCO3,5 and SnCl25) reactions starting from carboxylic acids19,20 and glycosyl halide.5,19,20 All of these methods have problems associated with them. First, in most cases either the yields or the stereoselectivities on the anomeric positions are not good. For example, the Schmidt glycosylation has yields of 12−92% with glycoside isomer ratios of α:β = 1:0.24−4;9,10 the amine-promoted reactions give yields of 45−78%;5,6 the heavy metal-catalyzed reactions have yields of 41−91% with glycoside isomer ratios of α:β = 1.5−1.9:1;19,20 the Mitsunobu reactions have yields of 25−95% with glycoside isomer ratios of α:β = 1:2.5−4.5;11−13 and the Steglich esterifications have yields of 67−100% with glycoside isomer ratios of α:β = 1−5:1.14−16 Therefore, tedious chromatography or even high-performance liquid chromatography (HPLC) is required to separate the α- and β-glycosides, consuming large amounts of volatile organic solvents. Second, heavy metal catalysts are toxic and expensive. Third, organic solvents or anhydrous organic solvents are required for all of these reactions. In our group, several synthetic methods have been developed using water, N-methyl-N,N,N-trioctyloctan-1-ammonium chloride (Aliquat 336), and granular polytetrafluoroethylene (PTFE). Granular PTFE is used as a costirrer to realize the © XXXX American Chemical Society
aqueous reactions by dispersing the water-insoluble and highmelting-point starting materials.21−25 Aliquat 336 is a lipophilic liquid, which functions as both solvent and PTC. Therefore, the combination of granular PTFE and Aliquat 336 is beneficial to aqueous reactions using water-insoluble starting materials. To improve the yields and stereoselectivities of the glycosylation reactions, water, PTC, and granular PTFE were used to replace organic solvents in this work. Herein we report our research results in these aspects.
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MATERIALS AND METHODS
General Information. All of the chemicals were obtained from commercial sources (Tianjin Guangfu Fine Chemical Research Institute, Tianjin, China) or prepared according to standard methods. The 1H and 13C NMR spectra were recorded on a Bruker AM-400 spectrometer (400 and 100 MHz, respectively) or a Bruker Avance III spectrometer (600 and 150 MHz, respectively), using tetramethylsilane (TMS) as the internal standard (δ = 0). Multiplicities are reported as follows: singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m). IR spectra were obtained using a Bio-Rad FTS 3000 spectrometer, using potassium bromide disks, and the spectra were scanned from 400 to 4000 cm−1. Melting points were recorded on an X-4 Micromelting Point Apparatus. High-resolution mass spectra (ESI) were obtained on a Bruker microTOF-QII. Analytical data for representative products are listed below. All of the aqueous reactions were conducted in 100 mL flasks and agitated by the modified stirring rod.22,23 The size of the granular PTFE was 70 pieces/g. Typical 300 mg Scale Glycosylation Procedure Using Glucosylation of Benzoic Acid as an Example. A mixture of 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride (300 mg, 0.54 mmol), benzoic acid (1.05 equiv, 69 mg, 0.56 mmol), Cs2CO3 (0.51 equiv, 89 mg, 0.27 mmol), tetrabutylammonium bromide (TBAB) (0.05 equiv, 9 mg, 0.03 mmol), and granular PTFE (5 g) was Received: March 25, 2015 Revised: June 3, 2015 Accepted: June 4, 2015
A
DOI: 10.1021/acs.jafc.5b02534 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
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Journal of Agricultural and Food Chemistry Table 1. Optimization of the Glucosylation of Benzoic Acidsa
entry
base
H2O (equiv)
T (°C)
PTC (equiv)
t (h)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23c 24
Li2CO3 Li2CO3 Li2CO3 Li2CO3 Na2CO3 K2CO3 TBAOH Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Li2CO3 Na2CO3 K2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3
310 20 15 10 10 10 30 10 10 10 10 10 10 10 10 10 310 20 15 5 10 10 10 10
40 40 40 40 40 40 40 40 25 60 80 80 80 80 80 80 80 80 80 80 80 80 80 80
Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.05) TBAB (0.05) TBAB (0.05) TBAB (0.05) TBAB (0.05) TBAB (0.05) TBAB (0.05) TBAB (0.05) TBAB (0.05) TBAB (0.01) TBAB (0.1) TBAB (1.05) SDS (0.05)
2 6 12 12 12 9 1 6 12 2 0.33 0.67 0.67 0.67 0.67 0.67 6.6 0.83 0.75 1.5 2 0.58 0.67 2
Cs2CO3
.yieldb (%) (1:β-2:3) 0:18:82 74:17:9 62:23:15 37:34:29 49:36:15 41:49:10 43:38:19 0:67:33 42:36:22 0:84:16 >99 only >99 only 23:22:55 31:51:18 27:63:10 >99 only 0:29:71 0:74:26 >99 only >99 only >99 only >99 only 32:0:68 NRd
(β-2) (β-2)
(β-2)
(β-2) (β-2) (β-2) (β-2)
a
Reaction conditions: 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride (300 mg, 0.54 mmol), benzoic acid (1.05 equiv), base, water, PTC, granular PTFE (5 g), mechanical stirring (400 rpm). bDetermined by 1H NMR. cReaction conditions: 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride (300 mg, 0.54 mmol), TBAB (182 mg, 0.56 mmol), water (97 mg, 5.38 mmol), granular PTFE (5 g), mechanical stirring (400 rpm). dNo reaction. mechanically stirred (400 rpm) at 80 °C for 2 min followed by the addition of water (10 equiv, 97 mg, 5.38 mmol). Initially, the reaction media appeared as thick milk, and it gradually turned to a semisolid, which adhered to the glass. After thin-layer chromatography (TLC) indicated completion of the reaction, ethyl acetate (2 × 10 mL) was added to extract the crude product, which was washed with 5% aqueous Na2CO3 (1 × 10 mL) and water (1 × 10 mL) and dried over Na2SO4. Concentration under reduced pressure gave benzoic acid 1O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester: (351 mg, >99%). Typical 5−12 g Scale Glycosylation Procedure Using Glucosylation of Benzoic Acid at an 11.7 g Scale as an Example. A mixture of 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride (10 g, 17.89 mmol), benzoic acid (1.05 equiv, 2.29 g, 18.75 mmol), Cs2CO3 (0.51 equiv, 2.97 g, 9.12 mmol), TBAB (0.05 equiv, 288 mg, 0.89 mmol), and granular PTFE (5 g) was mechanically stirred (400 rpm) at 80 °C for 2 min, followed by the addition of water (10 equiv, 3.22 g, 178.69 mmol). Initially, the reaction mixture appeared as thick milk and had good fluidity. After completion of the reactions as detected by TLC and removing the oil bath, the products started to solidify and eventually became fine granules. The product was filtered after the addition of water (3 × 15 mL) to wash the reaction flask, and the filtrates were washed with 5% aqueous Na2CO3 (3 × 10 mL) and water (3 × 10 mL) and air-dried to give benzoic acid 1-O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester (11.7 g, > 99%). Benzoic acid 1-O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester,9 p-nitrobenzoic acid 1-O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester,9 2-acetyloxybenzoic acid 1-O-[2,3,4,6-tetra-O-benzyl-β26 D-glucopyranosyl] ester, palmitic acid 1-O-[2,3,4,6-tetra-O-benzyl-β27 D-glucopyranosyl] ester, bile acid 24-O-[2,3,4,6-tetra-O-benzyl-β-D28 glucopyranosyl] ester, benzoic acid 1-O-[2,3,4,6-tetra-O-benzyl-β-Dgalactopyranosyl] ester,29 p-nitrobenzoic acid 1-O-[2,3,4,6-tetra-O-
benzyl-β-D-galactopyranosyl] ester,30 and p-nitrobenzoic acid 1-O[2,3,4-tri-O-benzyl-β-D-xylopyranosyl] ester31 are known compounds. 2-(Benzyloxycarbonylamino)-3-phenylpropanoic acid 1-O-[2,3,4,6tetra-O-benzyl-β-D-glucopyranosyl] ester: 410 mg, 93% yield; white solid, mp 108−109 °C; 1H NMR (600 MHz, CDCl3) δ 7.35−7.14 (m, 30H) 5.65 (d, J = 8.1 Hz, 1H, H-1), 5.13 (d, J = 8.3 Hz, 1H), 5.09 (q, J = 12.3 Hz, 1H), 4.90 (d, J = 11.0 Hz, 1H), 4.84 (m, 2H), 4.71 (s, 1H), 4.58 (m, 3H), 4.53 (d, J = 12.0 Hz, 1H), 3.75 (dt, J = 17.8, 9.1 Hz, 5H), 3.60 (dd, J = 18.4, 9.7 Hz, 3H), 3.12 (dd, J = 20.7, 5.5 Hz, 2H); 13 C NMR (151 MHz, CDCl3) δ 170.20, 137.86, 135.23, 129.74, 128.58, 128.48, 128.26, 128.17, 127.98, 127.95, 127.89, 127.80, 127.14, 94.85 (C-1), 84.79, 80.40, 75.74, 75.58, 75.09, 74.98, 73.68, 67.02, 54.57, 37.54; IR (KBr) v 3327, 3030, 3897, 1765, 1695, 1537, 1453, 1265, 1157, 1079, 751, 696; HRMS calcd for C51H51NO9Na [M + Na]+, 844.3456, found, 844.3454. 4-{[(1,1-Dimethylethyl)dimethylsilyl]oxy}-1-[(4-methylphenyl)sulfonyl]-L-proline 6-O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester: 480 mg, 97% yield; white solid; mp 117−118 °C; 1H NMR (600 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.40−7.28 (m, 18H), 7.22 (d, J = 6.6 Hz, 2H), 5.78 (d, J = 8.0 Hz, 1H, H-1), 5.01 (d, J = 11.0 Hz, 1H), 4.96 (d, J = 10.9 Hz, 1H), 4.88 (t, J = 10.4 Hz, 2H), 4.80 (d, J = 11.0 Hz, 1H), 4.67 (d, J = 12.1 Hz, 1H), 4.62 (d, J = 10.7 Hz, 1H), 4.56 (d, J = 12.1 Hz, 1H), 4.49 (t, J = 7.7 Hz, 1H), 4.41 (s, 1H), 3.85−3.75 (m, 4H), 3.71 (t, J = 8.2 Hz, 1H), 3.67−3.60 (m, 2H), 3.31 (d, J = 10.3 Hz, 1H), 2.44 (s, 3H), 2.25−2.04 (m, 2H), 0.81 (s, 9H), −0.00 (d, J = 2.6 Hz, 6H); 13C NMR (151 MHz, CDCl3) δ 171.09, 143.60, 143.55, 138.45, 138.07, 129.69, 128.48, 128.42, 127.97, 127.95, 127.86, 127.76, 95.05 (C-1), 84.70, 80.59, 75.68, 75.05, 74.86, 73.51, 70.57, 59.63, 56.43, 40.12, 25.67, 21.58, 17.94, −4.88, −5.01; IR (KBr) v 3060, 2931, 2860, 1769, B
DOI: 10.1021/acs.jafc.5b02534 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
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Journal of Agricultural and Food Chemistry 1596, 1453, 1348, 1411, 1170, 1090, 777, 698; HRMS calcd for C52H63NO10SSiNa [M + Na]+, 944.3834, found, 944.3834. 4-Pentenoic acid 1-O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester: 338 mg, >99% yield; white solid; mp 74−75 °C; 1H NMR (600 MHz, CDCl3) δ 7.40−7.25 (m, 18H), 7.14 (d, J = 5.5 Hz, 2H), 5.80 (dd, J = 13.9, 7.4 Hz, 1H), 5.63 (d, J = 8.0 Hz, 1H, H-1), 5.05 (d, J = 17.1 Hz, 1H), 4.99 (d, J = 10.1 Hz, 1H), 4.89 (d, J = 10.8 Hz, 1H), 4.86−4.80 (m, 2H), 4.76 (q, J = 11.4 Hz, 2H), 4.63 (d, J = 12.1 Hz, 1H), 4.53 (d, J = 10.6 Hz, 1H), 4.48 (d, J = 12.1 Hz, 1H), 3.82−3.67 (m, 4H), 3.59 (dd, J = 18.8, 9.6 Hz, 2H), 2.45 (dd, J = 18.3, 9.5 Hz, 1H), 2.36 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 171.47, 138.43, 138.16, 138.08, 137.98, 136.37, 128.49, 128.45, 128.03, 127.97, 127.94, 127.85, 127.78, 115.85, 94.11 (C-1), 84.88, 81.10, 77.28, 75.80, 75.57, 75.08, 73.57, 68.10, 33.50, 28.44; IR (KBr) v 3063, 3030, 2917, 2864, 1751, 1495, 1453, 1359, 1155, 1081,916, 748, 698; HRMS calcd for C39H42O7Na [M + Na]+, 645.2823, found, 645.2828. Ursolic acid 28-O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester: 483 mg, 92% yield; white solid; mp 79−80 °C; 1H NMR (600 MHz, CDCl3) δ 7.39−7.21 (m, 18H), 7.17 (s, 2H), 5.49 (d, J = 8.1 Hz, 1H, H-1), 5.26 (s, 1H), 4.84 (d, J = 33.2 Hz, 5H), 4.61 (dd, J = 20.3, 10.7 Hz, 2H), 4.50 (d, J = 10.2 Hz, 1H), 3.81−3.65 (m, 4H), 3.64−3.48 (m, 2H), 3.20 (s, 1H), 2.24 (s, 1H), 2.03 (s, 1H), 1.87 (s, 3H), 1.71 (d, J = 8.9 Hz, 2H), 1.55 (d, J = 59.8 Hz, 4H), 1.45−1.14 (m, 10H), 1.03 (d, J = 9.4 Hz, 3H), 0.97 (dd, J = 19.9, 9.6 Hz, 9H), 0.86 (d, J = 8.8 Hz, 6H), 0.77 (d, J = 9.4 Hz, 3H), 0.69 (t, J = 14.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 175.93, 138.47, 138.28, 138.19, 137.50, 128.39, 128.34, 128.31, 127.93, 127.81, 127.63, 127.58, 127.46, 127.13, 125.95, 94.21 (C-1), 85.10, 80.70, 79.05, 77.53, 75.61, 74.96, 74.66, 73.46, 68.29, 55.27, 52.83, 48.12, 47.63, 42.10, 39.50, 39.18, 38.92, 38.75, 36.97, 36.20, 32.73, 30.72, 29.73, 28.32, 28.21, 27.28, 24.43, 23.29, 21.21, 18.31, 17.08, 16.94, 15.68, 15.53; IR (KBr) v 2923, 2866, 1747, 1496, 1454, 1360, 1308, 1072, 739, 696; HRMS calcd for C64H82O8Na [M + Na]+, 1001.5902, found, 1001.5901. Stearic acid 1-O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester: 435 mg, >99% yield; syrup; 1H NMR (600 MHz, CDCl3) δ 7.30 (m, 18H), 7.13 (m, 2H), 5.62 (d, J = 8.2 Hz, 1H, H-1), 4.89 (d, J = 10.9 Hz, 1H), 4.82 (dd, J = 10.5, 8.7 Hz, 2H), 4.77 (s, 2H), 4.63 (d, J = 12.1 Hz, 1H), 4.50 (dd, J = 23.6, 11.4 Hz, 2H), 3.74 (m, 4H), 3.59 (m, 2H), 2.34 (dd, J = 15.6, 7.8 Hz, 1H), 2.28 (t, J = 7.7 Hz, 1H), 1.61 (m, 2H), 1.27 (dd, J = 27.3, 9.0 Hz, 28H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 172.26, 138.46, 138.18, 138.09, 137.98, 128.52, 128.50, 128.46, 128.08, 128.00, 127.98, 127.86, 127.80, 94.04 (C-1), 84.88, 81.13, 77.30, 75.84, 75.56, 75.11, 75.09, 73.58, 68.08, 34.36, 32.05, 29.83, 29.81, 29.79, 29.74, 29.56, 29.50, 29.39, 29.23, 29.18, 24.91, 24.65, 22.83, 14.29; IR (KBr) v 2924, 2853, 1756, 1458, 1359, 1081, 910, 737, 698; HRMS calcd for C52H70O7Na [M + Na]+, 829.5014, found, 829.5015. 4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3-methoxybenzoic acid 1-O-[2,3,4-tri-O-benzyl-β-D-xylopyranosyl] ester: 433 mg, 92% yield; syrup; 1H NMR (600 MHz, CDCl3) δ 7.39 (dd, J = 8.3, 1.8 Hz, 1H), 7.35 (d, J = 1.7 Hz, 1H), 7.18−7.14 (m, 10H), 7.08 (s, 1H), 7.04 (s, 4H), 6.68 (d, J = 8.3 Hz, 1H), 5.65 (d, J = 7.6 Hz, 1H, H-1), 4.70 (dd, J = 21.6, 10.9 Hz, 2H), 4.61 (t, J = 6.5 Hz, 1H), 4.57 (d, J = 11.7 Hz, 1H), 4.48 (d, J = 11.6 Hz, 1H), 3.81 (dt, J = 14.1, 7.1 Hz, 1H), 3.68 (s, 1H), 3.64 (s, 2H), 3.52 (ddd, J = 19.5, 16.3, 8.5 Hz, 4H), 3.30−3.25 (m, 1H), 0.82 (d, J = 7.6 Hz, 9H), 0.01 (d, J = 8.0 Hz, 6H); 13C NMR (151 MHz, CDCl3) δ 164.79, 150.81, 150.33, 138.44, 137.98, 137.86, 128.58, 128.48, 128.43, 128.06, 127.95, 127.85, 127.81, 123.92, 122.50, 120.61, 113.20, 95.03 (C-1), 83.45, 80.19, 77.33, 77.12, 76.91, 75.63, 75.05, 73.35, 64.54, 55.52, 25.67, 18.57, −4.52; IR (KBr) v 2931, 2859, 1729, 1596, 1511, 1460, 1287, 1215, 1079, 890, 698; HRMS calcd for C40H48O8SiNa [M + Na]+, 707.3011, found, 707.3013.
were used; the PTC was Aliquat 336 or TBAB, the amount of water was varied from 10 to 310 equiv, and the reaction temperature ranged from 25 to 80 °C. For all reaction combinations, the desired product, β-glucosyl ester, was contaminated with a substantial amount of the partially hydrolyzed products. Therefore, 2,3,4,6-tetra-O-benzyl-α-Dglucopyranosyl chloride (1, Table 1) was used as the starting material. When Li2CO3, Na2CO3, K2CO3, or tetrabutylammonium hydroxide (TBAOH·30H2O) was used as the base and Aliquat 336 (0.15 equiv) as the catalyst, the amount of undesired hydrolysis product, 2,3,4,6-tetra-O-benzyl-D-glucose (3) varied from 29 to 19% (Table 1, entries 4−7). However, the amount of 3 was affected by the amount of water, and 10 equiv of water was found to be optimal in reducing the amount of side product 3 (Table 1, entries 1−6 and 8). When Li2CO3 was replaced with Cs2CO3 and the reactions were performed at 40 and 25 °C, the yields of the desired product β-2 were 67 and 36% (Table 1, entries 8 and 9), respectively. Thus, raising the reaction temperature could improve the reaction yield. When the temperature was increased to 60 °C, the yield of β-2 increased to 84% and only 16% of 3 was formed (Table 1, entry 10). Further raising the temperature to 80 °C completely avoided the side reaction (the hydrolysis of 1 to 3) and gave β-2 in quantitative yield (Table 1, entry 11). When the amount of Aliquat 336 was reduced to 0.05 equiv, the yields were similar, but the reaction time increased from 0.33 to 0.67 h (Table 1, entries 11 and 12). The only problem associated with this new synthesis is that Aliquat 336 is water-insoluble and contaminates the product. Replacing 0.05 equiv of Aliquat 336 with 0.05 equiv of TBAB led to the quantitative and stereospecific synthesis of β-2 (Table 1, entry 16). Increasing the amount of water to 20 or 310 equiv yielded a mixture of β-2:3 in ratios of 74:26 and 29:71 (Table 1, entries 18 and 17), respectively. Decreasing the amount of water to 5 equiv increased the reaction time (1.5 h) (Table 1, entry 20). The reaction rates were altered by variation of the amounts of TBAB (0.01 equiv, 2 h; 0.05 equiv, 0.67 h; and 0.1 equiv, 0.58 h) (Table 1, entries 21, 16, and 22). The reaction rates and yields became worse after using Li2CO3, Na2CO3, and K2CO3 to replace Cs2CO3 (Table 1, entries 13− 15). The fact that Cs2CO3 is much better than the other bases for this glucosylation (Table 1, entries 1−6 vs 8 and 13−15 vs 16) is probably due to the cesium effect.26,32 It has been reported by Lemieux et al.33−35 that the anomerizations of tetra-O-acetyl-β-D-glucopyranosyl chloride took place in the presence of tetraethylammonium chloride, TBAB, or tetrabutylammonium iodide in organic solvents. However, no anomerization was observed when 1 was treated with 1.05 equiv of TBAB (Table 1, entry 23) in this aqueous reaction. The only detected products were 3 and 1 (68:32). This indicated that the reaction rates of 1 with carboxylates were fast enough to avoid the possible hydrolysis of 1 in these aqueous conditions. Using sodium dodecyl sulfate (SDS) (0.05 equiv) instead of TBAB did not produce β-2 (Table 1, entry 24). On the basis of all these results, the optimized conditions are 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride (1.0 equiv), benzoic acid (1.05 equiv), TBAB (0.05 equiv), Cs2CO3 (0.51 equiv), water (10 equiv), and granular PTFE (5 g) at 80 °C with mechanical agitation at 400 rpm (Table 1, entry 16). We believe that this reaction system is probably micellecatalyzed,36,37 which is based on the following observations. First, the reaction mixture was milky at the beginning of the reaction and then turned to a semisolid, which adhered to the
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RESULTS AND DISCUSSION Initially, a mixture of benzoic acid with acetobromoglucose or acetochloroglucose in the presence of a carbonate, a PTC, water, and granular PTFE was stirred mechanically at various temperatures using the modified stirring rod.22,23 Various carbonates including lithium, sodium, potassium, and cesium C
DOI: 10.1021/acs.jafc.5b02534 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
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Journal of Agricultural and Food Chemistry Table 2. β-Glycosylation of a Series of Carboxylic Acidsa
a
Reaction conditions: glycosyl chloride (300 mg, 0.54 mmol), acid (1.05 equiv), water (10 equiv), Cs2CO3 (0.51 equiv), TBAB (0.05 equiv), granular PTFE (5 g), mechanical stirring (400 rpm) at 80 °C. bAll conversions were 100%, and all yields are isolated yields.
flask walls and the stirrer after the completion of the reaction. Second, in our previous research in which Aliquat 336 was used as both a solvent and a catalyst,21−25 the amount of water used was not important. In contrast, the amount of water was critical for this reaction (Table 1, entries 20, 18, and 17 vs entry 16). Third, the reaction temperature had to be raised to 80 °C to reduce the amount of side product 3. This can be attributed to the efficient formation of micelles at this temperature. All of these facts support the reaction being micelle-catalyzed. One of the reasons for the stereospecificity of the βglycosylation is the closer contact between the carboxylates and the glucosyl chlorides in the micelles than in conventional organic solvents. Although it is commonly believed that the
negatively charged head of the carboxylates is oriented toward the aqueous phase, it is possible that certain amounts of the carboxylates are oriented toward the glycosyl chlorides because of the geometry or charge demands in the micelles. Water-soluble TBAB can form ionic pairs with carboxylic acids under basic conditions, which are lipophilic enough to replace Aliquat 336 to form micelles with glycosyl chloride. In the literature, surfactants containing 8−18 carbon atoms in straight alkyl chains are often used in micelle-catalyzed reactions, but there have been no reports of using TBAB in these types of reactions.38 Next a series of β-glycosyl esters were synthesized under the optimized conditions. Most of the reaction yields were >90%, D
DOI: 10.1021/acs.jafc.5b02534 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
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Journal of Agricultural and Food Chemistry with some being quantitative, and all of the reaction times were short (0.67−2.5 h) (Table 2). In all cases, only the β-glycosyl esters were obtained. The reactions were compatible with a series of functional groups including alkenes (Table 2, entries 1, 12, 14, and 18), nitro groups (Table 2, entries 2, 20, and 24), ethers (Table 2, entries 3 and 25), halide (Table 2, entry 5), aliphatic esters (Table 2, entry 10), phenolic esters (Table 2, entries 6, 9, and 23), benzyloxycarbonylamino group (Table 2, entry 7), ketone (Table 2, entry 8), silyl ethers (Table 2, entries 11 and 25), and hydroxyl groups (Table 2, entries 17 and 18). The 1H NMR and 13C NMR data for the β-glycosyl esters are 5.49−5.92 ppm (1H, J = 7.1−8.2 Hz, H-1) and 94.01−95.48 ppm (C-1), respectively, which are in agreement with the data from the literature.9,26−31 It has been reported that glycosylation can improve the properties of peptide biopharmaceuticals.2,39,40 Therefore, three amino acid derivatives were subjected to the glucosylation conditions, and the yields were excellent (Table 2, entries 7, 10, and 11). However, the yields for carbohydrate−peptide conjugations are around 30% in the literature.39 Bile acid glycoside, which has been identified in biological materials, has been synthesized as a mixture of α- and β-anomers (ratio of α:β = 1:3) in 99 (only β-2) 60 (38:22)
46
t = 1.10 h >99 (only β-2) 17 (9:8)
43
t = 0.85 h >99 (only β-2) 34 (only β-2)
yieldb (β-2:α-2) (%)
3 (%)
3 (%)
t = 1.50 h 19 (only β-2)
31
81
t = 3.30 h 37
45 (26:19)
55
t = 2.5 h 64 (only β-2)
23
36
a
Reaction conditions: 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride (300 mg, 0.54 mmol), benzoic acid (1.05 equiv), Cs2CO3 (0.51 equiv), water (10 equiv), TBAB (0.05 equiv), granular PTFE, mechanical stirring (400 rpm) at 80 °C. bDetermined by 1H NMR.
Table 4. Control Experiments in Water and in Organic Solvents
t = 40 min entry b
1 2c 3c 4c 5c 6c
solvent H2O DMF AcOEt THF toluene CHCl3
recovered 1 (%) 12 15
t=6h
a
yield (β-2:α-2) (%)
3 (%)
>99 (only β-2) 69 (54:15) 21(12:9) NRd NRd NRd
19 64
recovered 1 (%)
yielda (β-2:α-2) (%)
3 (%)
3 66 28
59 (only β-2) 27 (19:8) 21 (only β-2) 55 (42:13) NRd
41 70 13 17
a Determined by 1H NMR, bReaction conditions: 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride (300 mg, 0.54 mmol), benzoic acid (1.05 equiv), Cs2CO3 (0.51 equiv), water (10 equiv), TBAB (0.05 equiv), granular PTFE (5 g), mechanical stirring (400 rpm) at 80 °C. cReaction conditions: 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride (100 mg, 0.18 mmol), benzoic acid (1.05 equiv), Cs2CO3 (0.51 equiv) in DMF or toluene (1 mL) at 80 °C or AcOEt, THF or CHCl3 (1 mL) at refluxing temperatures. dNo reaction.
Table 4. In DMF and AcOEt, a mixture of α-2 and β-2 (β-2:α2 = 54:15 and 12:9, respectively) and byproduct 3 (19 and 64%, respectively) was obtained in 40 min (Table 4, entries 2 and 3). When the reaction time was prolonged to 6 h, the product distributions were 59% (β-2 only) and 41% (3) in DMF and 27% (β-2:α-2 = 19:8) and 70% (3) in AcOEt (Table 4, entries 2 and 3). No reactions occurred in THF and toluene after 40 min, and after 6 h, yields of only 21% of β-2 and 55% of β-2/α-2 (42:13) were obtained, respectively (Table 4, entries 4 and 5). The reaction did not take place in CHCl3 after 6 h (Table 4, entry 6). Only in water could the β-glycosyl esters be synthesized with excellent yields and high stereoselectivities. In conclusion, a simple, efficient, and green method for synthesizing β-glycosyl esters has been developed. The glycosylation is stereospecific and produces excellent yields. The micelle-catalyzed reactions used water-soluble TBAB as the surfactant and water as the medium. Therefore, the workup was simple with no need for chromatography. Five β-glucosyl esters were scaled up to 5−12 g, and all of the yields were quantitative. No organic solvents were used in the entire processes. The indispensable roles of granular PTFE and the correct amount of water in these reactions have also been demonstrated. This procedure should be assumed to be
particularly useful in synthesizing food additives and modifying the properties of bioactive molecules through glycosylation.
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ASSOCIATED CONTENT
S Supporting Information *
Pictures of glucosylations at different scales, general information, typical glycosylation procedures for different scales, analytic data of the products, procedure for the debenzylation of benzoic acid 1-O-[2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl] ester, 1H NMR and 13C NMR spectra for all compounds, mass spectra for new compounds, and references. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jafc.5b02534.
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AUTHOR INFORMATION
Corresponding Author
*(C.L.) Phone: +86-022-27892351. Fax: +86-022-27403475. Email: [email protected]. Notes
The authors declare no competing financial interest. F
DOI: 10.1021/acs.jafc.5b02534 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
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Journal of Agricultural and Food Chemistry
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