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. Author manuscript; available in PMC: 2013 Aug 1.
Published in final edited form as: Carbohydr Res. 2012 May 24;357:47–52. doi: 10.1016/j.carres.2012.05.012

Benzoylated ethyl 1-thioglycosides: direct preparation from per-O-benzoylated sugars

Deepak Sail 1, Pavol Kováč 1,*
PMCID: PMC3568975  NIHMSID: NIHMS380376  PMID: 22739243

Abstract

D-Glucose, lactose, maltose, and melibiose were benzoylated with Bz2O–Et3N reagent to give fully benzoylated β products. Under the same conditions, D-mannose produced a mixture where the β-benzoate predominated. Treatment of the foregoing compounds with EtSH at slightly elevated temperature (50– 60 °C) in the presence of BF3·Et2O as a promoter gave the corresponding ethyl 1-thio glycosides in high yields. The α-products predominated in all cases in the anomeric mixtures formed. Individual products of all reactions were isolated by chromatography, they were obtained in analytically pure state, and were fully characterized by 1H and 13C NMR data and physical constants.

Keywords: β-Selective 1-O-benzoylation, Thioglycosylation, Thioglycosidation

1. Introduction

Because of their long shelf-life, 1-thioglycosides are very popular glycosyl donors.1,2 While synthesis of per-O-acetylated 1-thioglycosides is fairly simple,3–6 their benzoylated counterparts are normally prepared indirectly from acetylated thioglycosides, by sequential deacetylation and benzoylation.7–12 Alternatively, fully benzoylated thioglycosides were prepared from the corresponding glycosyl thiocyanates13 or iodides.14 Cao et al.15 prepared ethyl 2,3,4,6-tetra-O-benzoyl-1-thio-β-D-galactopyranoside (13) from the corresponding penta-O-benzoate by treatment with EtSH in presence of SnCl4.

Following reports on the use of 1-O-β-acetates of common sugars as glycosyl donors in trifluoromethanesulfonate (TMSOTf)-catalyzed glycosylation,16,17 we have extended the method to the use of the corresponding 1-O-β-benzoyl derivatives.18 More than a decade later, Gallo-Rodriguez et al. reported similar approach in their oligosaccharide synthesis.19 Here, we describe a similar approach, but to glycosylation of EtSH, which allows direct preparation of 1-thioglycosides from fully-O-benzoylated saccharides using BF3·Et2O as a promoter (Scheme 1). To our knowledge, such conversion has not been described in accessible literature.

Scheme 1.

Scheme 1

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Benzoylation of D-glucose, D-mannose, D-galactose, lactose, maltose, and melibiose, and thioglycosidation of their per-O-benzoyl derivatives.

2. Results and discussion

Transfer of the acetyl group during glycosylation reactions from 2-O-acetylated glycosyl donors to the free hydroxyl group of glycosyl acceptors is a well established undesirable side reaction, which often occurs during Lewis acid mediated glycosylations. 16,17,20 For example, formation of as much as ~30% of methyl 6-O-acetyl-2,3,4-tri-O-benzoyl-β-D-galactopyranoside was observed when methyl 2,3,4-tri-O-benzoyl-β-D-galactopyranoside was glycosylated with 1,2,3,4,6-penta-O-acetyl-β-D-galactopyranose in the presence of TMSOTf.18 The significance of 2-O-benzoylated glycosyl donors in glycoside or oligosaccharide synthesis lies in the fact that the aforementioned transesterification does not take place when such donors are used.18,21 Also, benzoylated glycosyl donors are often stable at base-deficient conditions, which are required for isomerization of the intermediate orthoesters into glycosides. 21 In view of the above, developing a more straightforward protocol for making benzoylated 1-thio-glycosides than through the corresponding acetates is desirable.

Knowing that 1,2-trans-O-acetates are normally more reactive than their 1,2-cis counterparts,1,2 we searched for a simple preparation of this class of benzoyl derivatives, and have found it in the work by Luo22 et al. who showed one example of using benzoic anhydride–triethylamine (Bz2O–Et3N) reagent in stereoselective 1-O-benzoylation. When treated in this way, D-glucose (1), lactose (14), maltose (18), and melibiose (22) produced virtually only β-anomers. The product formed from mannose (5) was an anomeric mixture of per-O-benzoates where the β-compound predominated (Table 1). There was no advantage to using the Bz2O–Et3N reagent for benzoylation of D-galactose (10). Several products were formed, one major of which co-chromatographed with the authentic sample22,23 of 1,2,3,4,6-penta-O-benzoyl-α-D-galactopyranose (11).23,24 It has been reported that high proportion of furanoses is formed during benzoylation of D-galactose at both elevated19 and sub-ambient25 temperatures. The products were difficult to separate; hence accurate yield of individual compounds formed could not be determined. As we later discovered during this work, when thioglycosidation was conducted at elevated temperature 1,2-cis-O-benzoates served our purpose equally well, which agreed with Xu et al.’s26 similar observation concerning the corresponding penta-O-acetyl derivatives. Thus, α-D-galactopyranose 1122,23 was used in the conversion into the corresponding 1-thio-glycosides 12 and 13.

Table 1.

Benzoylation of saccharides with benzoic anhydride: product composition and yields

Starting material Product(s) formed Combined yield % α/β ratioa
D-Glucose (1) 2 91 β Only
D-Mannose (5) 6, 7 83 1/1.5
Lactose (14) 15 82 β Only
Maltose (18) 19 74 β Only
Melibiose (22) 23 75 β Only
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a

Determined after separation by chromatography.

Reactions of O-benzoyl derivatives with EtSH in the presence of BF3·Et2O as a promoter were examined next. The reactions at room temperature were impractically slow. At moderately elevated temperature, mixtures of anomers were formed in all cases here examined (Table 2), with ethyl 1-thio-α-glycosides predominating. Anomerization of initially formed kinetic products in the presence of Lewis acid cannot be excluded. Ethyl 1-thio-β-glycosides of D-galactose and melibiose, (13) and (25), respectively, were found to co-chromatograph with the starting benzoates. This precluded monitoring of the progress of the reaction by thin-layer chromatography. In these situations small-scale experiments were conducted in NMR tubes using dichloroethane-d4 as solvent, and the reaction times required for complete conversion (see Section 3) of benzoates 11 and 23 were determined by 1H NMR spectroscopy, by monitoring the disappearance of the low-field signals for H-1 of the starting materials. All products were fully characterized and produced NMR spectra consistent with the expected structures.

Table 2.

Glycosidation of per-O-benzoates with EtSH: combined yields and product composition

Starting material Products formed Combined yield % α/β ratio
2 3, 4 91 2a
6 8, 9 93 8.7a
7 8, 9 89 7.9a
11 12, 13 80 2.7b
15 16, 17 76 1.6b
19 20, 21 90 2.8b
23 24, 25 87 3.8b
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a

Ratio determined after separation by chromatography.

b

Ratio in the crude product determined by NMR.

3. Experimental

3.1. General methods

Optical rotations were measured at ambient temperature for solution in CHCl3 with a digital Jasco automatic polarimeter, Model P-2000. Melting points were measured on a Kofler hot stage. All reactions were monitored by thin-layer chromatography (TLC) on Silica Gel 60 coated glass slides. Column chromatography was performed by elution from prepacked columns of silica gel (Varian, Inc.) with the Isolera Flash Chromatograph (Biotage). Nuclear Magnetic Resonance (NMR) spectra were measured at 400 MHz (1H) and 100 MHz (13C) or at 600 MHz (1H) and 150 MHz (13C) with Bruker Avance spectrometers. Assignments of NMR signals were made by homonuclear and heteronuclear 2-dimensional correlation spectroscopy, run with the software supplied with the spectrometers. When reporting assignments of NMR signals of disaccharides, sugar residues are serially numbered, beginning with the one bearing the aglycon, and are identified by a Roman numeral superscript in listings of signal assignments. Liquid Chromatography– Electron Spray-Ionization Mass Spectrometry (ESI-MS) was performed with a Waters LCT Premier spectrometer. Reactions were carried out in closed flasks. Rubber septa used to close reaction flasks containing organic solvents were protected with a thin Teflon™ sheet (Laboratory Supplies Co., Inc., Hicksville, NY), to avoid leaching. Solutions in organic solvents were dried with anhydrous Na2SO4, and concentrated at 40 °C/2 kPa.

3.2. General procedures for benzoylation

The free sugar (2–5 mmol) was dissolved in DMF (10 mL/mmol), Et3N (4 equiv/OH) was added followed by addition of Bz2O (2 equiv/OH), and the mixture was stirred at conditions specified below. When the conversion was complete (TLC), excess of MeOH was added and the mixture was stirred overnight at room temperature. After concentration, a solution of the residue in CH2Cl2 was washed with saturated solution of sodium bicarbonate. The organic phase was dried, concentrated, and the crude mixture was chromatographed, to give pure substances and, occasionally, mixed fractions. For combined yields, see Table 1.

3.3. General procedure for thioglycosidation

BF3·Et2O was added to a solution of EtSH and sugar per-O-benzoate in 1,2-dichloroethane, and the mixture was stirred until all starting material was consumed (TLC). For amounts of solvent, reagents, and reaction conditions, see individual preparations (below). Et3N (excess of over the molar amount of BF3·Et2O) was added, the mixture was concentrated, and a solution of the residue in CH2Cl2 was washed with saturated solution of sodium bicarbonate. After concentration of the organic phase, chromatography of the material in the residue gave pure substances or mixtures of anomers. For combined yields, see Table 2.

3.3.1. 1,2,3,4,6-Penta-O-benzoyl-β-D-glucopyranose (2)

Reaction conditions: 16 h, rt; flash chromatography, 4:1 hexane– acetone; yield, starting from 1 (0.9 g, 5.0 mmol), 3.2 g (91%); Rf = 0.3 (4:1 hexane–acetone); Mp 182–185 °C (MeOH); [α]D +24.4 (c 1.0, CHCl3); lit.27 Mp 189–192 °C (AcOH); [α]D +24.2 (c 2.6, CHCl3); 1H NMR (600 MHz, CDCl3): δ 6.30 (d, 1H, J1,2 = 8.1 Hz, H-1), 6.05 (t, 1H, J = 9.5 Hz, H-3), 5.90–5.81 (m, 2H, H-2, H-4), 4.66 (dd, 1H, J6a,6b = 12.3, J5,6a = 3.0 Hz, H-6a), 4.52 (dd, 1H, J5,6b = 4.8 Hz, H-6b), 4.41 (ddd, 1H, J4,5 = 9.9 Hz, H-5); 13C NMR (150 MHz, CDCl3) δ 92.65 (C-1), 73.12 (C-5), 72.76 (C-3), 70.78 (C-2), 68.99 (C-4), 62.62 (C-6); ESI-HRMS calc. for C41H36NO11 [M+NH4]+: 718.2288; Found: 718.2292. Anal. Calcd For C41H32O11: C, 70.28; H, 4.60. Found: C, 70.46; H, 4.65.

3.3.2. Ethyl 2,3,4,6-tetra-O-benzoyl-1-thio-α-(3) and β-D-glucopyranoside (4)

Reaction conditions: EtSH (0.45 mL, 6.0mmol), BF3·Et2O (0.554 mL, 4.4mmol), 1 h, 50 °C; flash chromatography, 30:1→;20:1 toluene–EtOAc; yield, starting from 2 (2.80 g, 4.0mmol), 1.53 g (60%) of 3 and 0.80 g (31%) of 4.

Compound 3: Rf = 0.7 (15:1 toluene–EtOAc); Mp 137–138 °C (CH2Cl2–MeOH); [α]D +104.2 (c 1.0, CHCl3); lit.7 Mp 135 °C (toluene– pet. ether); [α]D +104 (c 2.0, CHCl3); 1H NMR (600 MHz, CDCl3) δ 6.08 (t, 1H, J = 9.9 Hz, H-3), 5.95 (d, 1H, J1,2 = 5.8 Hz, H-1), 5.68 (t, 1H, J = 9.8 Hz, H-4), 5.51 (dd, 1H, J 2,3 = 10.2 Hz, H-2), 4.88 (ddd, 1H, J4,5 = 10.1, J5,6b = 5.4, J5,6a = 2.8 Hz, H-5), 4.60 (dd, 1H, J6a,6b = 12.2 Hz, H-6a), 4.52 (dd, 1H, J5,6b = 5.5 Hz, H-6b), 2.70–2.55 (m, 2H, CH2), 1.25 (t, 3H, J = 7.4 Hz, CH3); 13C NMR (150 MHz, CDCl3) δ 81.98 (C-1), 71.63 (C-2), 70.87 (C-3), 69.49 (C-4), 68.08 (C-5), 63.02 (C-6), 24.24 (CH2), 14.61 (CH3); ESI-HRMS calcd for C36H36NO9S [M+NH4]+: 658.2111; found: 658.2123; Anal. Calcd for C36H32O9S: C, 67.49; H, 5.03. Found: C, 67.71; H, 5.03.

Compound 4: The solid obtained after freeze-drying of a solution in benzene could not be crystallized. Rf = 0.6 (15:1 toluene–EtOAc); [α]D +29.1 (c 1.0, CHCl3); lit.7 Mp 108–109 °C (ether–petroleum ether); [α]D +27 (c 1.8, CHCl3); 1H NMR (600 MHz, CDCl3): δ 5.93 (t, 1H, J = 9.5 Hz, H-3), 5.67 (t, 1H, J = 9.8 Hz, H-4), 5.57 (t, 1H, J = 9.7 Hz, H-2), 4.87 (d, 1H, J1,2 = 10.0 Hz, H-1), 4.63 (dd, 1H, J6a,6b = 12.2, J5,6a = 3.1 Hz, H-6a), 4.50 (dd, 1H, J5,6b = 5.5 Hz, H-6b), 4.18 (ddd, 1H, J4,5 = 10.0 Hz, H-5), 2.84–2.69 (m, 2H, SCH2CH3), 1.26 (t, 3H, J = 7.4 Hz, SCH2CH3); 13C NMR (150 MHz, CDCl3): δ 83.90 (C-1), 76.25 (C-5), 74.05 (C-3), 70.54 (C-2), 69.57 (C-4), 63.30 (C-6), 24.38 (SCH2CH3), 14.90 (SCH2CH3); ESI-HRMS calcd for C36H36NO9S [M+NH4]+: 658.2111; found: 658.2114. Anal. Calcd for C36H32O9S: C, 67.49; H, 5.03. Found: C, 67.56; H, 5.01.

3.3.3. 1,2,3,4,6-Penta-O-benzoyl-α-(6) and β-D-mannopyranose (7)

Compound 5: Reaction conditions: 40 h, rt; flash chromatography, 50:1→30:1 toluene–EtOAc; yield, starting from 5 (0.180 g, 1.0 mmol), 0.234 g (33%) of 6 and 0.342 g (50%) of 7.

Compound 6: Rf = 0.5 (19:1 toluene–EtOAc); Mp 150.5–152 °C (MeOH); [α]D −20.2 (c 1.0, CHCl3); lit.27 Mp 152–153 °C; [α]D −18.6 (c 1.6, CHCl3); 1H NMR (400 MHz, CDCl3): δ 6.63 (d, 1H, J1,2 = 2.0 Hz, H-1), 6.28 (t, 1H, J = 10.2 Hz, H-4), 6.07 (dd, 1H, J3,4 = 10.2, J2,3 = 3.3 Hz, H-3), 5.91 (dd, 1H, H-2), 4.70 (dd, 1H, J6a,6b = 12.2, J5,6a = 2.5 Hz, H-6a), 4.57 (dt, 1H, J4,5 = 10.0 Hz, H-5), 4.50 (dd, 1H, J5,6b = 3.7 Hz, H-6b); 13C NMR (100 MHz, CDCl3) δ 91.37 (C-1, JC-1,H-1 = 178.8 Hz), 71.18 (C-5), 69.99 (C-3), 69.43 (C-2), 66.18 (C-4), 62.34 (C-6); ESI-HRMS calcd for C41H36NO11 [M+NH4]+: 718.2288; found: 718.2274. Anal. Calcd for C41H32O11: C, 70.28; H, 4.60. Found: C, 70.56; H, 4.80.

Compound 7: Rf = 0.4 (19:1 toluene–EtOAc); Mp 160–161.5 °C (MeOH); [α]D −84.2 (c 1.0, CHCl3); lit.28 Mp 161–161.5 °C (EtOH); [α]D −80.7 (CHCl3); 1H NMR (600 MHz, CDCl3) δ 6.44 (d, 1H, J1,2 = 1.2 Hz, H-1), 6.18 (t, 1H, J = 9.8 Hz, H-4), 6.11 (dd, 1H, J2,3 = 3.2 Hz, H-2), 5.81 (dd, 1H, J3,4 = 9.9 Hz, H-3), 4.76 (dd, 1H, J6a,6b = 12.3, J5,6a = 2.8 Hz, H-6a), 4.56 (dd, 1H, J5,6b = 4.3 Hz, H-6b), 4.38 (ddd, 1H, J4.5 = 9.7 Hz, H-5); 13C NMR (150 MHz, CDCl3) δ 91.19 (C-1, JC-1,H-1 = 163.3 Hz), 73.28 (C-5), 71.51 (C-3), 69.36 (C-2), 69.32 (C-4), 62.61 (C-6); ESI-HRMS calcd for C41H36NO11 [M+NH4]+: 718.2288; found: 718.2292. Anal. Calcd for C41H32O11: C, 70.28; H, 4.60. Found: C, 70.49; H, 4.69.

3.3.4. Ethyl 2,3,4,6-tetra-O-benzoyl-1-thio-α-(8) and β-D-mannopyranoside (9)

Reaction conditions: EtSH (1.5mL, 2.0mmol), BF3·Et2O (0.23 mL, 1.8mmol), 3 h (starting from 6), 5 h (starting from 7), 50 °C; flash chromatography, 50:1→25:1 toluene–EtOAc.

Compound 8: yield, starting from 6 (0.700 g, 1 mmol), 0.536 g (84%), starting from 7 (0.700 g, 1 mmol), 0.504 g (79%); Rf = 0.7 (15:1 toluene–EtOAc); Mp 120–121.5 °C (EtOH); [α]D −14.0 (c 1.0, CHCl3); lit.29: Mp 124–125 °C (EtOH); [α]D −15.8 (c 0.8, CHCl3). 1H NMR (600 MHz, CDCl3) δ 6.17 (t, 1H, J = 10.0 Hz, H-4), 5.89 (dd, 1H, J3,4 = 9.9, J2,3 = 3.2 Hz, H-3), 5.87 (dd, 1H, J1,2 = 1.3 Hz, H-2), 5.59 (br d, 1H, H-1), 4.85 (ddd, 1H, J4,5 = 10.1, J5,6b = 4.5, J5,6a = 2.6 Hz, H-5), 4.69 (dd, 1H, J6a,6b = 12.2 Hz, H-6a), 4.54 (dd, 1H, H-6b), 2.95– 2.58 (m, 2H, SCH2CH3), 1.35 (t, 3H, SCH2CH3); 13C NMR (150 MHz, CDCl3) δ 82.29 (C-1, JC-1,H-1 = 168.3 Hz), 72.08 (C-2), 70.48 (C-3), 69.19 (C-5), 66.99 (C-4), 62.82 (C-6), 25.57 (SCH2CH3), 14.81 (SCH2CH3); ESI-HRMS calcd for C36H36NO9S [M+NH4]+: 658.2111; found: 658.2126. Anal. Calcd for C36H32O9S: C, 67.49; H, 5.03. Found: C, 67.70; H, 5.09.

Compound 9: Amorphous solid after freeze-drying of a solution in benzene; yield, starting from 6 (0.700 g, 1 mmol), 0.062 g (10%); yield, starting from 7 (0.700 g, 1 mmol), 0.061 g (10%); Rf = 0.5 (15:1 toluene–EtOAc); [α]D −150.4 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3) δ 6.02 (dd, 1H, J2,3 = 3.3, J1,2 = 0.9 Hz, H-2), 6.00 (t, 1H, J = 10.0 Hz, H-4), 5.67 (dd, 1H, J3,4= 10.1 Hz, H-3), 5.11 (br d, 1H, H-1), 4.71 (dd, 1H, J6a,6b = 12.1, J5,6a = 2.9 Hz, H-6a), 4.54 (dd, 1H, J5,6b = 5.4 Hz, H-6b), 4.20–4.18 (m, 1H, H-5), 2.83–2.74 (m, 2H, SCH2CH3), 1.31 (t, 3H, J = 7.4 Hz, SCH2CH3); 13C NMR (150 MHz, CDCl3) δ 82.84 (C-1, JC-1,H-1 = 152.2 Hz), 76.53 (C-5), 72.77 (C-3), 71.35 (C-2), 66.85 (C-4), 63.43 (C-6), 25.86 (SCH2CH3), 14.97 (SCH2CH3); ESI-HRMS calcd for C36H36NO9S [M+NH4]+: 658.2111; found: 658.2119; Anal. Calcd for C36H32O9S: C, 67.49; H, 5.03. Found: C, 67.19; H, 4.99.

3.3.5. 1,2,3,4,6-Penta-O-benzoyl-α-D-galactopyranose (11)

This compound was prepared as described.24 Mp 161.5–162.5 °C (EtOH); [α]D +193.9 (c 1.0, CHCl3); lit.24 Mp 158–159 °C (MeOH); [α]D +187.0 (c 4.0, CHCl3); 1H NMR (600MHz, CDCl3) δ: 6.96 (d, 1H, J1,2 = 3.7 Hz, H-1), 6.20 (br d, 1H, H-4), 6.13 (dd, 1H, J2,3 = 10.7, J3,4 = 3.4 Hz, H-3), 6.03 (dd, 1H, H-2), 4.84 (t, 1H, J = 6.8 Hz, H-5), 4.64 (dd, 1H, J6a,6b = 11.4, J5,6a = 6.4 Hz, H-6a), 4.43 (dd, 1H, J5,6b = 6.9 Hz, H-6b); 13C NMR (150 MHz, CDCl3): δ 90.65 (C-1), 69.41 (C-5), 68.50 (C-3), 68.43 (C-4), 67.66 (C-2), 61.80 (C-6). ESI-HRMS calcd for C41H36NO11 [M+NH4]+: 718.2288; found: 718.2258; Anal. Calcd for C41H32O11: C, 70.28; H, 4.60. Found: 70.14; H, 4.70.

3.3.6. Ethyl 2,3,4,6-tetra-O-benzoyl-1-thio-α-(12) and β-D-galactopyranoside (13)

Reaction conditions: EtSH (0.375 mL, 5.0 mmol), BF3·Et2O (0.504 mL, 4.0 mmol), 16 h (optimum time determined by NMR spectroscopy), 60 °C; flash chromatography, 5:1 hexane–acetone; yield, starting from 11 (1.40 g, 2.0 mmol), 0.422 g of pure 12 (33%), 0.317 g of pure 13 (25%). Unresolved mixture of 12 and 13 (0.282 g, 22%) was also obtained.

Compound 12: Amorphous solid after freeze-drying of a solution in benzene; Rf = 0.4 (3:1 hexane–acetone); [α]D +166.6 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3) δ 6.09–5.99 (m, 2H, H-1, H-4), 5.92–5.82 (m, 2H, H-2, H-3), 5.03 (dd, 1H, J5,6a = 7.0, J5,6b = 5.6 Hz, H-5), 4.62 (dd, 1H, J6a,6b = 11.5 Hz, H-6a), 4.44 (dd, 1H, H-6b), 2.74–2.49 (m, 2H, SCH2CH3), 1.25 (m, 3H, SCH2CH3); 13C NMR (150 MHz, CDCl3) δ 81.22 (JC-1,H-1 = 168.5 Hz, C-1), 68.05, 67.96, 67.90 (C-2, C-3, C-4), 66.22 (C-5), 61.60 (C-6), 23.03 (SCH2CH3), 13.57 (SCH2CH3); ESI-HRMS calcd for C36H36NO9S [M+NH4]+: 658.2111; found: 658.2111; Anal. Calcd for C36H32O9S: C, 67.49; H, 5.03. Found: C, 67.39; H, 5.00.

Compound 13; Amorphous solid after freeze-drying of a solution in benzene; Rf = 0.3 (3:1 hexane–acetone); [α]D +98.4 (c 1.0, CHCl3); lit.30 [α]D +106 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3) δ: 6.04 (br d, 1H, H-4), 5.84 (t, 1H, J = 9.9 Hz, H-2), 5.65 (dd, 1H, J2,3 = 9.9, J3,4 = 3.5 Hz, H-3), 4.88 (d, 1H, J1,2 = 10.0 Hz, H-1), 4.67 (dd, 1H, J6a,6b = 11.2, J5,6a = 6.5 Hz, H-6a), 4.41 (dd, 1H, J5,6b = 6.5 Hz, H-6b), 4.36 (t, 1H, J = 6.6 Hz, H-5), 2.95–2.72 (m, 2H, SCH2CH3), 1.32 (t, 3H, SCH2SCH3); 13C NMR (150 MHz, CDCl3) δ: 84.31 (JC-1,H-1 = 152.5 Hz, C-1), 75.03 (C-5), 72.70 (C-3), 68.36 (C-4), 68.19 (C-2), 62.60 (C-6), 24.53 (SCH2CH3), 14.98 (SCH2CH3); ESI-HRMS calcd for C36H36NO9S [M+NH4]+: 658.2111; found: 658.2111; Anal. Calcd for C36H32O9S: C, 67.49; H, 5.03. Found: C, 67.73; H, 5.02.

3.3.7. 1,2,3,6-Tetra-O-benzoyl-4-O-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyl)-β-D-glucopyranose (Octa-O-benzoyl-β-lactose, 15)

Reaction conditions: 40 h, 50 °C; flash chromatography, 30:1→20:1 toluene–EtOAc; yield, starting from lactose monohydrate (1.44 g, 4.0mmol), 3.85 g (82%); Rf = 0.5 (10:1 toluene–EtOAc); [α]D +45.7 (c 1.0, CHCl3); lit.31 Mp 140–142 °C (acetone–MeOH); [α]D +38.1 (c 0.9, CHCl3); 1H NMR (600 MHz, CDCl3) δ 6.15 (d, 1H, J1,2 = 8.1 Hz, H-1′), 5.96 (t, 1H, J = 9.3 Hz, H-3), 5.80 (dd, 1H, J2,3 = 9.6 Hz, H-2), 5.78–5.72 (m, 2H, H-2′,4′), 5.39 (dd, 1H, J2′,3′ = 10.4, J3′,4′ = 3.4 Hz, H-3′), 4.90 (d, 1H, J1′,2′ = 7.9Hz, H-1′), 4.60 (dd, 1H, J6a,6b = 12.4, J5,6a = 1.9 Hz, H-6a), 4.54 (dd, 1H, J5,6b = 3.9 Hz, H-6b), 4.41 (t, 1H, J = 9.4 Hz, H-4), 4.08 (ddd, 1H, J4,5 = 9.9 Hz, H-5), 3.90 (t, 1H, J = 6.8Hz, H-5′), 3.78 (dd, 1H, J6a′,6b′ = 11.3, J5′,6a′ = 6.4 Hz, H-6a′), 3.71 (dd, 1H, J5′,6b′ = 7.1Hz, H-6b′); 13C NMR (150 MHz, CDCl3) δ 101.00 (C-1′), 92.53 (C-1), 75.48 (C-4), 73.75 (C-5), 72.76 (C-3), 71.69 (C-3′), 71.32 (C-5′), 70.61 (C-2), 69.73, 67.39 (C-2′,4′), 62.04 (C-6), 60.92 (C-6′); ESI-HRMS calcd for C68H58NO19 [M+NH4]+: 1192.3603; found: 1192.3623; Anal. Calcd for C68H54O19: C, 69.50; H, 4.63. Found: C, 69.53; H, 4.61.

3.3.8. Ethyl 2,3,6-tri-O-benzoyl-4-O-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyl)-1-thio-α-(16) and β-D-glucopyranoside (17) (Hepta-O-benzoyl-1-thio-α- and β-lactoside)

Reaction conditions: EtSH (0.15 mL, 2.0 mmol), BF3·Et2O (0.23 mL, 1.8 mmol), 2 h, 50 °C; chromatography, 50:1→25:1 toluene– EtOAc; yield, starting from 15 (1.175 g, 1.0 mmol), 1.024 g (76%) of mixture of 16 and 17. Compound 16 crystallized from DCM–MeOH.

Compound 16: Rf = 0.5 (19:1 toluene–EtOAc); Mp 221–222.5 °C (CH2Cl2–MeOH); [α]D +91.3 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3) δ 5.95 (t, 1H, J = 9.6 Hz, H-3), 5.82 (d, 1H, J1,2 = 5.9 Hz, H-1), 5.75 (br d, partially overlapped, H-4′), 5.73 (dd, partially overlapped, J2′,3′ = 10.2, J1′,2′ = 8.0 Hz), 5.43 (dd, 1H, J2,3 = 10.2 Hz, H-2), 5.38 (dd, 1H, J3′,4′ = 3.4 Hz, H-3′), 4.92 (d, 1H, H-1′), 4.61– 4.52 (m, 3H, H-5, H-6a′, H-6b′), 4.21 (t, 1H, J = 9.5 Hz, H-4), 3.91 (t, 1H, J = 6.7 Hz, H-5′), 3.85 (d, 1H, J6a′,6b′ = 11.3, J5′,6a′ = 6.4 Hz, H-6a′), 3.76 (dd, 1H, J5′,6b′ = 7.1 Hz, H-6b′), 2.61–2.45 (m, 2H, SCH2CH3), 1.18 (t, J = 7.4 Hz, 3H, SCH2CH3); 13C NMR (150 MHz, CDCl3) δ 101.13 (JC-1′,H-1′ = 160.1 Hz, C-1′), 81.91 (JC-1,H-1 = 168.2 Hz, C-1), 76.35 (C-4), 71.95 (C-3′), 71.49 (C-2), 71.30 (C-5′), 70.87 (C-3), 69.88 (C-2′), 68.78 (C-5), 67.45 (C-4′), 62.53 (C-6), 61.05 (C-6′), 24.23 (SCH2CH3), 14.55 (SCH2CH3); ESI-HRMS calcd for C63H58 NO17S [M+NH4]+: 1132.3425; found: 1132.3457; Anal. Calcd for C63H54O17S: C, 67.85; H, 4.88. Found: C, 67.94; H, 4.90.

The mother liquor contained predominantly ethyl 2,3,6-tri-O-benzoyl-4-O-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyl)-1-t hio-β-D-glucopyranoside 17, and a solvent suitable for separation by chromatography could not be found; Rf = 0.5 (19:1 toluene–EtOAc); amorphous solid; lit.30 amorphous solid; 1HNMR(600 MHz,CDCl3) δ 5.82 (t, 1H, J = 9.3 Hz, H-3), 5.73 (m, partially overlapped, H-4′), 5.72 (dd, partially overlapped, J2′,3′ = 10.3, J1′2′ = 7.9 Hz, H-2′), 5.50 (t, 1H, J = 9.7 Hz, H-2), 5.37 (dd, 1H, J3′,4′ = 3.4 Hz, H-3′), 4.87 (d, 1H, H-1′), 4.73 (d, 1H, J1,2 = 10.0 Hz, H-1), 4.60 (dd, 1H, J6a,6b = 12.2, J5,6a = 1.8 Hz, H-6a), 4.49 (dd, 1H, J5,6b = 4.7 Hz, H-6b), 4.24 (t, 1H, J = 9.5 Hz, H-4), 3.90 (t, 1H, J = 6.8 Hz, H-5′), 3.86 (ddd, 1H, J4,5 = 10.0 Hz, H-5), 3.72 (m, 2H, H-6a′, H-6b′), 2.75–2.61 (m, 2H, SCH2CH3), 1.20 (t, J = 7.5 Hz, 3H, SCH2CH3); 13C NMR (150 MHz, CDCl3) δ 100.92 (JC-1′,H-1′ = 161.4 Hz, C-1′), 83.74 (JC-1,H-1 = 153.5 Hz, C-1), 77.00 (C-5), 75.92 (C-4), 73.97 (C-3), 71.75 (C-3′), 71.31 (C-5′), 70.48 (C-2), 69.82 (C-2′), 67.44 (C-4′), 62.65 (C-6), 60.98 (C-6′), 24.43 (SCH2CH3), 14.85 (SCH2CH3); ESI-HRMS calcd for C63H58NO17S [M+NH4]+: 1132.3425; found: 1132.3441; Anal. Calcd for C63H54 O17S: C, 67.85; H, 4.88. Found: C, 67.82; H, 4.80.

3.3.9. 1,2,3,6-tetra-O-benzoyl-4-O-(2,3,4,6-tetra-O-benzoyl-α-D-glucopyranosyl)-β-D-glucopyranose (Octa-O-benzoyl-β-maltose, 19)

Reaction conditions: 40 h, 50 °C; flash chromatography, 50:1→25:1 toluene–EtOAc; yield, starting from 18 (1.71 g, 5.0 mmol), 4.32 g (74%); Rf = 0.5 (15:1 toluene–EtOAc); Mp 193– 195 °C (MeOH); [α]D +62.0 (c 1.0, CHCl3); lit.32 Mp 190–192 °C (acetone–MeOH); [α]D +68.2 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3) δ 6.27 (d, 1H, J1,2 = 7.4 Hz, H-1), 6.11 (t, 1H, J = 10.0 Hz, H-3′), 5.85 (t, 1H, J = 8.6 Hz, H-3), 5.79 (d, 1H, J1′2′ = 3.9 Hz, H-1′), 5.68 (t, 1H, J = 9.8 Hz, H-4′), 5.64 (dd, 1H, J2,3 = 8.7 Hz, H-2), 5.26 (dd, 1H, J2′,3′ = 10.5 Hz, H-2′), 4.90 (dd, 1H, J6a,6b = 12.3, J5,6a = 2.5 Hz, H-6a), 4.78 (dd, 1H, J5,6b = 3.8 Hz, H-6b), 4.67 (t, 1H, J = 9.0 Hz, H-4), 4.44 (dt, 1H, J4′,5′ = 10.1 Hz, H-5′), 4.41 – 4.35 (m, 2H, H-6a′, H-5), 4.21 (dd, 1H, J6a′,6b′ = 12.3, J5′,6b′ = 3.5 Hz, H-6b′); 13C NMR (150 MHz, CDCl3) δ 96.37 (C-1′), 92.13 (C-1), 74.81 (C-3), 73.47 (C-5), 72.60 (C-4), 71.09 (C-2), 70.91 (C-2′), 69.80 (C-3′), 69.14 (C-5′), 68.94 (C-4′), 63.09 (C-6), 62.34 (C-6′); ESI-HRMS calcd for C68H58NO19 [M+NH4]+: 1192.3603; found: 1192.3596; Anal. Calcd for C68H54O19: C, 69.50; H, 4.63. Found: C, 69.39; H, 4.80.

3.3.10. Ethyl 2,3,6-tri-O-benzoyl-4-O-(2,3,4,6-tetra-O-benzoyl-α-D-glucopyranosyl)-1-thio-α-(20) and β-D-glucopyranoside (21) (Ethyl hepta-O-benzoyl-1-thio-α- and β-maltoside)

Reaction conditions: EtSH (0.34 mL, 4.5 mmol), BF3·Et2O (0.42 mL, 3.3 mmol), 3 h, 50 °C; chromatography, 50:1 toluene– EtOAc; yield, starting from 19 (3.525 g, 3.0 mmol), 3.02 g (90%) of mixture of 20 and 21. Only small amounts of pure 20 and 21 could be isolated by flash chromatography.

Compound 20: Amorphous solid after freeze-drying of a solution in benzene; Rf = 0.5 (19:1 toluene–EtOAc); [α]D +112.2 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3) δ 6.11 (dd, 1H, J2′,3′ = 10.5, J3′,4′ = 9.6 Hz, H-3′), 5.96 (dd, 1H, J2,3 = 10.0, J3,4= 8.9 Hz, H-3), 5.82 (d, 1H, J1,2 = 5.6 Hz, H-1), 5.77 (d, 1H, J1′,2′ = 3.9 Hz, H-1′), 5.68 (t, 1H, J = 9.8 Hz, H-4′), 5.29 (dd, partially overlapped, H-2′), 5.28 (dd, partially overlapped, H-2), 4.87 (dd, 1H, J6a,6b = 11.9, J5,6a = 2.1 Hz, H-6a), 4.83–4.80 (m, 1H, H-5), 4.78 (dd, 1H, J5,6b = 4.5 Hz, H-6b), 4.50 (dt, 1H, J4′,5′ = 10.1, J5′,6a′,b′ = 3.4 Hz, H-5′), 4.45 (dd, 1H, J6a′,6b′ = 12.3, J5′,6a′ = 3.1 Hz, H-6a′), 4.42 (t, J = 9.3 Hz, H-4), 4.31 (dd, 1H, J5′,6b′ = 3.7 Hz, H-6b′), 2.65–2.55 (m, 2H, SCH2CH3), 1.25 (t, 3H, J = 7.4 Hz, SCH2CH3); 13C NMR (150 MHz, CDCl3) δ 96.72 (JC-1′,H-1′ = 176.2 Hz, C-1′), 81.78 (JC-1,H-1 = 168.3 Hz, C-1), 73.90 (C-4), 72.74 (C-3), 72.03 (C-2), 70.83 (C-2′), 69.84 (C-3′), 69.17 (C-5′), 69.08 (C-4′), 68.62 (C-5), 63.54 (C-6), 62.44 (C-6′), 24.33 (SCH2CH3), 14.69 (SCH2CH3); ESI-HRMS calcd for C63H58NO17S [M+NH4]+: 1132.3425; found: 1132.3400; Anal. Calcd for C63H54O17S: C, 67.85; H, 4.88. Found: C, 67.87; H, 4.80.

Compound 21: Rf = 0.5 (19:1 toluene–EtOAc); Mp 146–148 °C (MeOH); [α]D +69.6 (c 1.0, CHCl3); lit.33, mode of preparation and characterization data were not disclosed; 1H NMR (600 MHz, CDCl3) δ 6.08 (dd, 1H, J2′,3′ = 10.5, J3′,4′ = 9.6 Hz, H-3′), 5.80 (t, 1H, J = 9.2 Hz, H-3), 5.74 (d, 1H, J1′,2′ = 3.9 Hz, H-1′), 5.65 (t, 1H, J = 9.8 Hz, H-4′), 5.36 (t, 1H, J = 9.6 Hz, H-2), 5.24 (dd, 1H, H-2′), 4.93 (dd, 1H, J6a,6b = 12.1, J5,6a = 2.4 Hz, H-6a), 4.81 (d, 1H, J1,2 = 9.8 Hz, H-1), 4.74 (dd, 1H, J5,6b = 4.4 Hz, H-6b), 4.49 (t, 1H, J = 9.3 Hz, H-4), 4.45 (dt, partially overlapped, J4′,5′ = 10.1, J5′,6a′,b′ = 3.5 Hz, H-5′), 4.40 (dd, 1H, J6a′,6b′ = 12.2 Hz, J5′,6a′ = 3.1 Hz, H-6a′), 4.26 (dd, 1H, J5′,6b′ = 3.8 Hz, H-6b′), 4.10 (ddd, 1H, J4,5 = 9.6 Hz, H-5), 2.86–2.58 (m, 2H, SCH2CH3), 1.22 (t, 3H, J = 7.5 Hz, SCH2CH3); 13C NMR (150 MHz, CDCl3) δ 96.3 (JC-1′,H-1′ = 175.7 Hz, C-1′), 83.5 (JC-1,H-1 = 154.7 Hz, C-1), 76.76 (C-5), 76.11 (C-3), 73.03 (C-4), 70.98 (C-2), 70.87 (C-2′), 69.81 (C-3′), 69.12 (C-5′), 69.04 (C-4′), 63.62 (C-6), 62.48 (C-6′), 24.3 (SCH2CH3), 14.9 (SCH2CH3); ESI-HRMS calcd for C63H58NO17S [M+NH4]+: 1132.3425; found: 1132.3401; Anal. Calcd for C63H54O17S: C, 67.85; H, 4.88. Found: C, 67.93; H, 4.76.

3.3.11. 1,2,3,4-tetra-O-benzoyl-6-O-(2,3,4,6-tetra-O-benzoyl-α-D-galactopyranosyl)-β-D-glucopyranose (Octa-O-benzoyl-β-melibiose, 23)

Reaction conditions: 16 h, 50 °C; flash chromatography, 50:1→20:1 toluene–EtOAc; yield, starting from melibiose monohydrate (1.08 g, 3.0 mmol), 2.53 g (75%); Rf = 0.5 (15:1 toluene– EtOAc); Mp 165–168 °C (MeOH); [α]D +141.3 (c 1.0, CHCl3); lit.34 (anomeric configuration not specified; in the absence of NMR data, judging by physical constants, the compound reported previously is likely the α anomer): Mp 111–112 °C (EtOH), [α]D +174 (c 4.55, CHCl3); 1H NMR (600 MHz, CDCl3) δ 6.15 (d, 1H, J1,2 = 8.2 Hz, H-1), 6.12 (dd, 1H, J2′,3′ = 10.7, J3′,4′ = 3.5 Hz, H-3′), 6.02–5.99 (m, partially overlapped, H-4′), 5.98 (t, partially overlapped, J 9.7 Hz, H-3), 5.71 (dd, 1H, J1′,2′ = 3.7 Hz, H-2′), 5.70 (t, 1 H, J = 9.8 Hz, H-4), 5.61 (dd, 1H, J2,3 = 9.8 Hz, H-2), 5.43 (d, 1H, H-1′), 4.65 (br t, 1H, H-5′), 4.36 (dd, 1H, J6a′,6b′ = 11.5, J5′,6a′ = 7.7 Hz, H-6′a′), 4.23 (ddd, 1H, J4,5 = 10.1, J5,6a = 5.1, J5,6b = 1.8 Hz, H-5), 4.09 (dd, 1H, J5′,6b′ = 4.9 Hz, H-6b′), 4.02 (dd, 1H, J6a,6b = 11.4 Hz, H-6a), 3.83 (dd, 1H, H-6b); 13C NMR (150 MHz, CDCl3) δ 96.57 (C-1′), 92.92 (C-1), 74.20 (C-5), 72.87 (C-3), 70.85 (C-2), 69.35 (C-4′), 68.89 (C-2′), 68.59 (C-4), 68.55 (C-3′), 67.14 (C-5′), 65.68 (C-6), 62.86 (C-6′); ESI-HRMS calcd for C68H58NO19 [M+NH4]+: 1192.3603; found: 1192.3628; Anal. Calcd for C68H54O19: C, 69.50; H, 4.63. Found: C, 69.23; H, 4.89.

3.3.12. Ethyl 2,3,4-tri-O-benzoyl-6-O-(2,3,4,6-tetra-O-benzoyl-α-D-galactopyranosyl)-1-thio-α-(24) and β-D-glucopyranoside (25) (Ethyl hepta-O-benzoyl-1-thio-α- and β-melibioside)

Reaction conditions: EtSH (0.19 mL, 2.5 mmol), BF3·Et2O (0.25 mL, 2.0 mmol), 16 h, 60 °C (optimum reaction time determined by NMR spectroscopy); chromatography, 50:1→30:1 toluene– EtOAc; yield, starting from 23 (1.175 g, 1.0 mmol), 0.320 g (29%) of 24, 0.159 g (14%) of 25. Unresolved mixture of 24 and 25 (0.495 g, 44%) was also obtained.

Compound 24: Amorphous solid after freeze-drying of a solution in benzene; Rf = 0.6 (12:1 toluene–EtOAc); [α]D +165.0 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3) δ 6.05 (br d, 1H, J3′,4′ = 3.4 Hz, H-4′), 6.01 (dd, J2′,3′ = 10.5, Hz, H-3′), 5.98 (t, 1H, J = 9.9 Hz, H-3), 5.81 (d, 1H, J1,2 = 5.9 Hz, H-1), 5.71 (dd, 1H, J1′,2′ = 3.7 Hz, H-2′), 5.48 (d, 1H, H-1′), 5.35 (t, 1H, J = 9.9 Hz, H-4), 5.05 (dd, 1H, J2,3 = 10.1 Hz, H-2), 4.72 (br dd, 1H, H-5′), 4.69 (ddd, 1H, J4,5 = 10.1, J5,6a = 6.5, J5,6b = 1.9 Hz, H-5), 4.51 (dd, 1H, J6a′,6b′ = 11.5, J5′,6a′ = 4.8 Hz, H-6a′), 4.43 (dd, 1H, J5′,6b′ = 7.7 Hz, H-6b′), 4.04 (dd, 1H, J6a,6b = 11.0 Hz, H-6a), 3.65 (dd, 1H, H-6b), 2.76–2.58 (m, 2H, SCH2CH3), 1.35 (t, 3H, J = 7.4 Hz, SCH2CH3); 13C NMR (150 MHz, CDCl3) δ 96.25 (JC-1′,H-1′ = 173.7 Hz, C-1′), 81.10 (JC-1,H-1 = 170.0 Hz, C-1), 71.57 (C-2), 70.84 (C-3), 69.30 (C-4′), 69.17 (C-4), 69.08 (C-2′), 68.71 (C-5), 68.42 (C-3′), 67.18 (C-5′), 65.98 (C-6), 62.84 (C-6′), 23.93 (SCH2CH3), 14.45 (SCH2CH3); ESI-HRMS calcd for C63H58NO17S [M+NH4]+: 1132.3425; found: 1132.3422; Anal. Calcd for C63H54O17S: C, 67.85; H, 4.88. Found: C, 67.82; H, 5.02.

Compound 25: Rf = 0.5 (19:1 toluene–EtOAc); Mp 157–159 °C; [α]D +128.7 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3) δ 6.06 (dd, 1H, J2′,3′ = 10.6, J3′,4′ = 3.4 Hz, H-3′), 6.03 (dd, 1H, J4,5 = 1.2 Hz, H-4′), 5.85 (t, 1H, J = 9.6 Hz, H-3), 5.73 (dd, 1H, J1′,2′ = 3.7 Hz, H-2′), 5.59 (t, 1H, J = 9.6 Hz, H-4), 5.49 (d, 1H, H-1′), 5.33 (t, 1H, J = 9.7 Hz, H-2), 4.74 (d, 1H, J1,2 = 10.0 Hz, H-1), 4.66 (br t, 1H, H-5′), 4.47 (dd, 1H, J6a′,6b′ = 11.4, J5′,6a′ = 7.2Hz, H-6a′), 4.31 (dd, 1H, 5′,6b′ = 5.6 Hz, H-6b′), 4.06–3.98 (m, 2H, H-5, H-6a), 3.80–3.76 (m, 1H, H-6b), 2.64 (q, 2H, J = 7.4 Hz, SCH2CH3), 1.16 (t, 3H, J = 7.4 Hz, SCH2CH3); 13C NMR (150 MHz, CDCl3) δ 96.57 (JC-1′,H-1′ = 173.7 Hz, C-1′), 83.64 (JC-1,H-1 = 153.0 Hz, C-1), 77.42 (C-5), 74.23 (C-3), 70.41 (C-2), 69.19 (C-4′), 69.02 (C-2′), 68.98 (C-4), 68.40 (C-3′), 67.15 (C-5′), 66.29 (C-6), 62.60 (C-6′), 23.84 (SCH2CH3), 14.69 (SCH2CH3); ESI-HRMS calcd for C63H58NO17S [M+NH4]+: 1132.3425; found: 1132.3397; Anal. Calcd for C63H54O17S: C, 67.85; H, 4.88. Found: C, 67.96; H, 5.15.

Acknowledgments

This research was supported by the Intramural Research Program of the NIH, NIDDK.

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