Facile Synthesis of Sugar Lactols via Bromine-Mediated Oxidation of Thioglycosides

Abstract

Synthesis of a variety of sugar lactols (hemiacetals) has been accomplished in moderate to excellent yields by using bromine-mediated oxidation of thioglycosides. It was found that acetonitrile is the optimal solvent for this oxidation reaction. This approach involving bromine as oxidant is superior to that using N-bromosuccimide (NBS) which produces byproduct succinimide often difficult to separate from the lactol products.

Introduction

Glycosyl hydroxides, i.e. sugar lactols or hemiacetals, serve as important glycosyl donors (1-hydroxy glycosyl donors) and synthetic intermediates for chemical synthesis of complex biologically significant carbohydrate molecules.^[1–5] Back in 1890s, sugars lactols were first used as glycosyl donors in the well-known Fischer glycosylation.^[6–7] Recently, Gin^[8–14] and Bennett^[15–16] reported dehydrative glycosylations using 1-hydroxy glycosyl donors. In addition, in 1970s Schmidt pioneered the studies of stereoselective synthesis of oligosaccharides and glycoconjugates via anomeric O-alkylation of sugar lactols.^[17–22] Based on Schmidt’s work, recently our group^[23–27] and others^[28–33] resurrected the use of anomeric O-alkylation for stereoselective construction of challenging glycosidic linkages. Specifically, our group disclosed stereoselective synthesis of several classes of challenging glycosides via anomeric O-alkylation of the corresponding sugar hemiacetals, e.g. 2-deoxy-β-glycosdies,^[23–24] 2-deoxy-α-glycosdies,^[25] as well as β-mannosides.^[26–27] Furthermore, sugar hemiacetals are used as precursors for the preparation of commonly used glycosyl donors, e.g. trichloroacetimidates,^[34] N-(phenyl)trifluoroacetimidates,^[35] phosphites and phosphates,^[36–37] or ortho-alkynylbenzoates,^[38] carbonates,^[39–42] sulfonates,^[43–44] and glycosyl esters.^[45–46]

Typically, lactols (2) are obtained by methanolysis of glycosyl esters (1, X = OCOR),^[47–48] hydrolysis of glycosyl halides (1, X = halides)^[49–50] or methyl glycosides (1, X = OMe),^[51] or oxidation of thioglycosides (3)^[52–53] (a and b, Scheme 1). Among those methods, oxidation of readily available and stable thioglycosides (3) to lactols is one of the most popular strategies for preparation of sugar hemiacetals and N-bromosuccimide (NBS) is usually employed as the oxidant (b, Scheme 1). Despite its mild nature, the reaction employing NBS generates the byproduct succinimide which oftentimes is difficult to separate from the desired lactol products, especially when the lactols become quite polar. Therefore, our group has been searching for alternative oxidant to facilitate the purification process.

Scheme 1.

Representative strategies for preparation of sugar lactols.

Bromine is often used to oxidize thioglycosides to the corresponding glycosyl bromide donors for the synthesis of various oligosaccharides and glycoconjugates.^[54–57] In addition, there was limited report that sugar hemiacetals can be prepared by bromine-mediated oxidation of thioglycosides via a two-step sequence: 1) bromine-mediated oxidation of thioglycosides in dry dichloromethane to the corresponding glycosyl bromide; 2) hydrolysis of isolated glycosyl bromide.^[58] Use of bromine as oxidant is advantageous as it can avoid the production of difficultly separable byproducts. However, this two-step procedure may not be suitable for carbohydrate substrates containing acid-sensitive protecting groups or free hydroxyl groups. We wondered if it is possible to develop a one-pot oxidation/hydrolysis under suitable conditions for the preparation of sugar hemiacetals from thioglycosides using bromine as the oxidant. In this Communication, we wish to report the facile synthesis of sugar lactols via bromine-mediated oxidation of thioglycosides in a mixture of acetonitrile and water (c, Scheme 1).

Results and Discussion

Phenyl 3,4,6-tri-O-benzyl-1-thio-α-D-mannopyranoside (4, Table 1) was chosen as the substrate for preparing 3,4,6-tri-O-benzyl-D-mannose 5 under bromine-mediated oxidation. It is worth noting that a stock solution of bromine in dichloromethane (5.0 M) was prepared for use instead of pure bromine due to easy handling and safety concerns.^[59] Initially, we used a mixture of acetone and water (10/1, v/v), the solvent system for NBS-mediated oxidation of thioglycosides, for bromine-mediated oxidation. This reaction was sluggish at 0 °C and took 24 hours to complete and 3,4,6-tri-O-benzyl-D-mannose 5 was isolated in 83% yield (α/β=3/1, entry 1, Table 1). The slow reaction rate may be due to that Br₂ is also able to α–brominate acetone, which competes with the oxidation of thioglycosides. Addition of bromine solution at lower temperature followed by warming up to 0 °C did not help (entry 2). Switching to dichloromethane, the solvent used for preparation of glycosyl bromide by bromine oxidation of thioglycosides, did not work well and complex mixtures were obtained (entries 3 and 4). Use of THF as solvent gave similar results as acetone, albeit the reaction was found to be a little faster (entry 5). Finally, we found acetonitrile was the optimal solvent for this reaction which was complete in two hours and gave almost quantitative yield of the corresponding lactol 5 (entry 6). The method was also applied to 0.2 mmol and 1 gram scale of thioglycoside 4 which furnished the desired lactol 5 in 98% and 91% yield, respectively (entry 6). Application of previously reported two-step procedure for this oxidation–hydrolysis only gave 34% yield of the lactol 5 (entry 7). In comparison, use of NBS as the oxidant instead of bromine afforded lactol 5 in 82% yield (entry 8).

Table 1.

Synthesis of 3,4,6-tri-O-benzyl-D-mannose by bromine-mediated oxidation of corresponding thioglycoside.^a

Entry	Solvent/Temp/Timeb	Yield,c α/β ratiod
1	acetone/H2O (10/1, v/v), 0 °C, 24 h	83%, 3/1
2	acetone/H2O (10/1, v/v), −30 to 0 °C, 26 h	79%, 4/1
3	CH2Cl2/H2O (10/1, v/v), −30 to 0 °C, 3.5 h	trace
4	CH2Cl2/H2O (10/1, v/v), 0 °C, 3 h	trace
5	THF/H2O (10/1, v/v), 0 °C, 12 h	81%, 4/1
6	CH3CN/H2O (10/1, v/v), 0 °C, 2 h	97% (98%,e 91%f), 4/1
7	Br2, CH2Cl2, 0 °C, 0.5 h; then acetone/H2O (4/1, v/v), RT, 2 hg	34%
8	NBS (3.0 eq.), acetone/H2O (10/1, v/v), 0 °C, 2 h	82%

^aAll reactions were performed using 0.1 mmol of phenyl 3,4,6-tri-O-benzyl-1-thio-D-mannopyranoside 4 (1.0 eq.) and 60 μL of 5.0 M Br₂ in CH₂Cl₂ (3.0 eq.) in 0.5 mL organic solvent and 50 μL H₂O unless otherwise noted;

^bWhen TLC showed the substrate was completely consumed;

^cIsolated yield;

^dDetermined by ¹H NMR;

^eIsolated yield obtained on 0.2 mmol scale.

^fIsolated yield on a 1 gram scale.

^gsee reference 58.

With the optimal condition established, the bromine-mediated oxidation of thioglycosides was applied to the synthesis of a variety of sugar hemiacetals (Table 2). In general, sugar hemiacetals were obtained in good to excellent yields. It was also found that both aryl (e.g. phenyl) and alkyl (e.g. ethyl) thioglycosides can be oxidized smoothly to afford the corresponding lactols in good yields (entry 1). Various functional groups, such as carbamate, amide, imide, azide, and carboxylic ester, are tolerated. For thioglycosides containing acid-sensitive protecting groups, such as silyl ethers (entry 2), benzylidene acetals (entries 10–12), and 1,2-diketals (entry 13), solid sodium bicarbonate needs to be added to buffer the acidity of the reaction in order to achieve good yields. Interestingly, methoxyethoxymethyl (MEM) ether was found to be stable in this type of reaction and no sodium bicarbonate was added necessarily (entry 9). Obviously, deoxy sugars, such as 6-deoxy and 2,6-dideoxy sugars, are very reactive substrates towards bromine oxidation (entries 2–4). Sugar substrates with acyl protecting groups, i.e. “disarmed donors”, including thioglycoside of peracetylated N-acetyl neuraminic acid (18), D-mannose-derived thioglycoside (30) and phenyl 2,3,4,6-tetra-O-acetyl-1-thio-β-glucopyranoside (32), were found to be relatively unreactive and produced corresponding hemiacetals in moderate yields, probably due to the inductive effect. Allowing the reaction to proceed for an additional period of time or adding more Br₂ did not help, probably due to the decomposition of the starting materials or lactols over time (entries 7, 13 and 14).

Table 2.

Synthesis of various sugar lactols by bromine-mediated oxidation of thioglycosides.^a

Entry	Thioglycosides	Lactols	Yield,b α/β ratio,c Reaction Condition, Time
1			84%, 2/1 from 6a, A, 2 h; 86%, 2/1 from 6b, A, 2 h
2			95%, 1.4/1, B, 1 h
3			90%, 1/1, A, 2 h
4			93%, 2/1, A, 2 h
5			94%, α only, A, 2 h
6			84%, 2.5/1, A, 2 h
7			66%,d 1/10, A, 12 h; 63%,e 1/10, A, 12 h
8			75%, 10/1, A, 4 h
9			81%, 2.5/1, A, 3 h
10			15%, 2/1, A, 2 h; 72%, 2/1, B, 3 h
11			64%, β only, B, 5 h
12			61%, 1.4/1, B, 5 h
13			60%,f >20/1, B, 18 h; 55%,g, >20/1, B, 36 h; 59%h
14			20%,i 4/1, 2 h; 38%,j 4/1, 12 h
15			86%, 2/1, 3 h

^aAll reactions were performed using 0.2 mmol of thioglycosides (1.0 eq.) and 120 μL of 5.0 M Br₂ in CH₂Cl₂ (3.0 eq.) in 1 mL acetonitrile and 0.1 mL H₂O at 0 °C;

^bIsolated yield;

^cDetermined by ¹H NMR;

^d29% of starting material was recovered;

^e4.5 eq. of bromine was used. Trace amount of starting material was recovered;

^f31% of starting material was recovered;

^gThe reaction was stirred for 36 hours and 24% of starting material was recovered;

^hNBS (3.0 eq.) was used and the reaction was stirred for 18 hours and 29% of starting material was recovered;

ⁱ64% of starting material was recovered;

^j24% of starting material was recovered.

In conclusion, an approach for the synthesis of sugar hemiacetals has been developed via bromine-mediated oxidation of thioglycosides in a mixture of acetonitrile/water. Various functional groups and protecting groups are tolerated and a wide range of sugar lactols were obtained in moderate to excellent yields. This method is advantageous as it avoids the production of byproducts difficult to separate.

Experimental

Materials and Methods

Proton and carbon nuclear magnetic resonance spectra (¹H NMR and ¹³C NMR) were recorded on either Bruker 600 (¹H NMR-600 MHz; ¹³C NMR 150) or INOVA 600 (¹H NMR-600 MHz; ¹³C NMR-150 MHz) at ambient temperature with CDCl₃ as the solvent unless otherwise stated. Chemical shifts are reported in parts per million relative to residual protic solvent internal standard CDCl3: ¹H NMR at δ 7.26, ¹³C NMR at δ 77.36. Data for ¹H NMR are reported as follows: chemical shift, integration, multiplicity (app = apparent, par obsc = partially obscure, ovrlp = overlapping, s = singlet, d = doublet, dd = doublet of doublet, t = triplet, q = quartet, m = multiplet) and coupling constants in Hertz. All ¹³C NMR spectra were recorded with complete proton decoupling. High resolution mass spectra (HRMS) were acquired on a Waters Acuity Premiere XE TOF LC-MS by electrospray ionization. Optical rotations were measured with Autopol-IV digital polarimeter; concentrations are expressed as g/100 mL.

All reagents and chemicals were purchased from Acros Organics, Sigma Aldrich, Fisher Scientific, Alfa Aesar, and Strem Chemicals and used without further purification. THF, methylene chloride, toluene, and diethyl ether were purified by passing through two packed columns of neutral alumina (Innovative Technology). Anhydrous DMF and benzene were purchased from Acros Organics and Sigma-Aldrich and used without further drying. All reactions were carried out in oven-dried glassware under an argon atmosphere unless otherwise noted. Analytical thin layer chromatography was performed using 0.25 mm silica gel 60-F plates. Flash column chromatography was performed using 200–400 mesh silica gel (Scientific Absorbents, Inc.). Yields refer to chromatographically and spectroscopically pure materials, unless otherwise stated.

General procedure for synthesis of sugar lactols by bromine-mediated oxidation of thioglycosides.

General procedure A:

Thioglycosides (0.2 mmol) were dissolved by 1.0 mL acetonitrile in a 10 mL flask, followed by the addition of 0.1 mL water. The mixture was stirred at 0 °C for 30 min. 120 μL of Br₂ (3.0 eq.) solution in CH₂Cl₂ (5.0 M) was added dropwise and then the yellow mixture was stirred at this temperature until the TLC showed that the substrate was completely consumed. Then the mixture was diluted by 5 mL saturated NaHCO₃ aqueous solution and evaporated under reduced pressure to remove acetonitrile. The residue was extracted by CH₂Cl₂ (10 mL × 3, for lactol 11 10% n-butanol was used together). The organic layers were combined and dried over anhydrous Na₂SO₄. The filtrate was concentrated and purified by flash column chromatography to give the desired lactols.

General procedure B:

Thioglycosides (0.2 mmol) were dissolved by 1.0 mL acetonitrile in a 10 mL flask, followed by the addition of 0.1 mL water and 168 mg of NaHCO₃ (10.0 eq.). The mixture was stirred at 0 °C for 30 min. 120 μL of Br₂ (3.0 eq.) solution in CH₂Cl₂ (5.0 M) was added dropwise and then the yellow mixture was stirred at this temperature until the TLC showed that the substrate was completely consumed. Then the mixture was diluted by 5 mL saturated NaHCO₃ aqueous solution and evaporated under reduced pressure to remove acetonitrile. The residue was extracted by CH₂Cl₂ (10 mL × 3). The organic layers were combined and dried over anhydrous Na₂SO₄. The filtrate was concentrated and purified by flash column chromatography to give the desired lactol.

3,4,6-Tri-O-benzyl-α/β-D-mannopyranose (5).

Lactol 5 was prepared from thioglycoside 4^[60] (109 mg, 0.201 mmol) following the general procedure A. The crude reaction mixture was purified by flash column chromatography (Hexanes/EtOAc = 2/1 to CH₂Cl₂/MeOH = 15/1) to give 88.8 mg (0.197 mmol, 98%) of lactol 5 (α/β = 4/1) as colorless syrup. ¹H and ¹³C NMR data of 5 were in agreement with reported ones.^[61]

2,3,4,6-Tetra-O-benzyl-α/β-D-glucopyranose (7).

Lactol 7 was prepared from thioglycoside 6^[62] (127 mg, 0.201 mmol) following the general procedure A. The crude reaction mixture was purified by flash column chromatography (Hexanes/EtOAc = 5/1 to CH₂Cl₂/MeOH = 20/1) to give 90.8 mg (0.168 mmol, 84%) of lactol 7 (α/β = 2/1) as white solids. ¹H and ¹³C NMR data of 7 were in agreement with reported ones.^[63]

3,4-Di-O-tert-butyldimethylsilyl-2,6-dideoxy-α/β-D-glucopyranose (9).

Lactol 9 was prepared from thioglycoside 8^[64] (93.7 mg, 0.2 mmol) following the general procedure B. The crude reaction mixture was purified by flash column chromatography (Hexanes/EtOAc = 35/1) to give 71.5 mg (0.19 mmol, 95%) of lactol 9 (α/β = 1.4/1) as colorless syrup. $[{\alpha ]}_{\mathrm{D}}^{23}$= +61.5 (c 0.1, CHCl₃). ¹H NMR (600 MHz, CDCl₃) δ 5.28 (d, J = 2.9 Hz, 1H), 4.85 (ddd, J = 8.8, 6.1, 2.2 Hz, 0.6H), 4.01 (ddd, J = 10.5, 7.6, 4.4 Hz, 1H), 3.89 (dq, J = 8.5, 6.5 Hz, 1H), 3.69 (dddd, J = 10.8, 7.8, 4.6, 1.0 Hz, 0.6H), 3.41 (d, J = 6.7 Hz, 0.6H), 3.37 – 3.28 (m, 0.6H), 3.26 – 3.11 (m, 1.6H), 2.81 – 2.60 (m, 1H), 2.24 (ddd, J = 12.8, 4.7, 2.2 Hz, 0.6H), 2.16 – 2.01 (m, 1H), 1.68 (ddd, J = 13.6, 10.2, 3.6 Hz, 1H), 1.62 – 1.52 (m, 0.6H), 1.31 (d, J = 6.4 Hz, 1.8H), 1.26 (d, J = 6.5 Hz, 3H), 0.97 – 0.86 (m, 29H), 0.17 – 0.02 (m, 19H). ¹³C NMR (150 MHz, CDCl₃) δ 93.66, 91.60, 77.90, 77.44, 73.06, 72.86, 70.44, 69.90, 41.82, 39.27, 26.40, 26.37, 26.22, 19.10, 18.78, 18.44, 18.42, 18.22, 18.19, −2.69, −2.79, −2.97, −3.15, −3.81, −3.93, −4.12, −4.26. ESIHRMS calculated for C₁₈H₄₀O₄Si₂Na [M+Na]⁺ 399.2363, found 399.2363.

2-O-Methyl-4-O-benzyl-6-deoxy-α/β-D-allopyranose (11).

Lactol 11 was prepared from thioglycoside 10^[64] (69.7 mg, 0.194 mmol) following the general procedure A. The crude reaction mixture was purified by flash column chromatography (CH₂Cl₂/MeOH = 10/1) to give 46.9 mg (0.175 mmol, 90%) of lactol 11 (α/β = 1/1) as colorless syrup. $[{\alpha ]}_{\mathrm{D}}^{23}$= +128.5 (c 0.1, CHCl₃). ¹H NMR (600 MHz, CDCl₃) δ 7.38 – 7.27 (m, 10H), 5.18 (s, 2H), 4.96 (dd, J = 7.9, 3.6 Hz, 1H), 4.68 – 4.64 (m, 2H), 4.55 – 4.51 (m, 2H), 4.45 (m, 1H), 4.39 (t, J = 2.9 Hz, 1H), 4.19 (s, 1H), 4.08 (m, 1H), 3.89 (m, 1H), 3.51 (s, 3H), 3.47 (s, 3H), 3.27 (s, 1H), 3.18 (m, 1H), 3.10 – 3.06 (m, 2H), 2.95 (dd, J = 7.8, 2.9 Hz, 1H), 2.58 (s, 1H), 1.28 (d, J = 6.2 Hz, 3H), 1.26 (d, J = 6.2 Hz, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 137.48, 137.23, 128.70, 128.60, 128.33, 128.14, 128.08, 128.02, 93.68, 91.61, 81.15, 79.87, 79.43, 76.27, 71.52, 71.46, 68.27, 67.53, 65.44, 61.28, 58.16, 56.72, 17.91, 17.76. ESIHRMS calculated for C₁₄H₂₀O₅Na [M+Na]⁺ 291.1208, found 291.1213.

2,3,4-Tri-O-benzyl-6-deoxy-α/β-L-galactopyranose (13).

Lactol 13 was prepared from thioglycoside 12^[65] (108.9 mg, 0.201 mmol) following the general procedure A. The crude reaction mixture was purified by flash column chromatography (Hexanes/EtOAc = 2/1) to give 78.7 mg (0.181 mmol, 90%) of lactol 13 (α/β = 2/1) as colorless syrup. ¹H and ¹³C NMR data of 13 were in agreement with reported ones.^[66]

2-N-(Benzyloxy)carbonyl-3,4,6-tri-O-benzyl-2-deoxy-2-amino-α-D-mannopyranose (15).

Lactol 15 was prepared from thioglycoside 14 (134.4 mg, 0.199 mmol) following the general procedure A. The crude reaction mixture was purified by flash column chromatography (Hexanes/EtOAc = 3/1 to 1/1) to give 109.4 mg (0.187 mmol, 94%) of lactol 15 (α only) as white solids. $[{\alpha ]}_{\mathrm{D}}^{23}$= +89.0 (c 0.1, CHCl₃). ¹H NMR (600 MHz, CDCl₃) δ 7.40 – 7.28 (m, 18H), 7.16 (dd, J = 7.0, 2.3 Hz, 2H), 5.34 – 5.28 (m, 1H), 5.26 (d, J = 8.8 Hz, 1H), 5.15 (s, 2H), 4.87 (d, J = 10.8 Hz, 1H), 4.79 (d, J = 11.0 Hz, 1H), 4.59 (d, J = 12.2 Hz, 1H), 4.52 (d, J = 11.1 Hz, 1H), 4.47 (d, J = 12.2 Hz, 1H), 4.45 – 4.38 (m, 2H), 4.18 (d, J = 3.9 Hz, 1H), 4.14 (dd, J = 9.4, 4.5 Hz, 1H), 4.06 (ddd, J = 9.9, 4.8, 2.1 Hz, 1H), 3.66 (dd, J = 10.5, 4.8 Hz, 1H), 3.62 (dd, J = 10.4, 2.3 Hz, 1H), 3.56 (t, J = 9.6 Hz, 1H). ¹³C NMR (150 MHz, CDCl₃) δ 156.55, 138.24, 138.04, 137.63, 136.29, 128.63, 128.50, 128.44, 128.40, 128.29, 128.26, 128.24, 128.19, 128.02, 127.90, 127.76, 93.83, 77.47, 75.15, 74.29, 73.44, 71.20, 70.31, 68.85, 67.12, 51.54. ESIHRMS calculated for C₃₅H₃₇NO₇Na [M+Na]⁺ 606.2468, found 606.2469.

2-N-Acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-amino-α/β-D-mannopyranose (17).

Lactol 17 was prepared from thioglycoside 16^[67] (116.6 mg, 0.2 mmol) following the general procedure A. The crude reaction mixture was purified by flash column chromatography (CH₂Cl₂/MeOH=100/1) to give 84.4 mg (0.167 mmol, 84%) of lactol 17 (α/β = 2.5/1) as white solid. ¹H and ¹³C NMR data of 17 were in agreement with reported ones.^[68]

Methyl 4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-acetamido-α/β-D-glycero-D-galacto-2-nonulopyranosonate (19).

Lactol 19 was prepared from thioglycoside 18^[69] (118.0 mg, 0.202 mmol) following the general procedure A. The crude reaction mixture was purified by flash column chromatography (Hexanes/Acetone = 3/2) to give 65.0 mg (0.132 mmol, 65%) of lactol 19 (α/β = 1/10) as white solids with 34.2 mg (29%) of thioglycoside 18 recovered. ¹H and ¹³C NMR data of 19 were in agreement with reported ones.^[70]

Benzyl (3,4-di-O-benzyl-α/β-D-mannopyranose) uronate (21).

Lactol 21 was prepared from thioglycoside 20 (106.3 mg, 0.191 mmol) following the general procedure A. The crude reaction mixture was purified by flash column chromatography (Hexanes/EtOAc = 2/1 to CH₂Cl₂/MeOH = 15/1) to give 66.5 mg (0.143 mmol, 75%) of lactol 21 (α/β = 10/1) as white solids. $[{\alpha ]}_{\mathrm{D}}^{23}$= +35.3 (c 0.1, CHCl₃). ¹H NMR (600 MHz, CDCl₃) δ 7.34 – 7.25 (m, 15H), 7.23 – 7.20 (m, 2H), 5.38 (t, J = 4.1 Hz, 1H), 5.17 (d, J = 12.1 Hz, 0.1H), 5.12 (d, J = 12.1 Hz, 1H), 5.04 (d, J = 12.2 Hz, 1H), 4.83 (d, J = 9.8 Hz, 0.1H), 4.71 (d, J = 11.0 Hz, 0.1H), 4.68 (d, J = 11.2 Hz, 1H), 4.66 – 4.61 (m, 0.2H), 4.58 – 4.55 (m, 3H), 4.52 (d, J = 6.8 Hz, 1H), 4.44 (t, J = 10.5 Hz, 0.1H), 4.15 (t, J = 7.0 Hz, 1H), 4.10 (t, J = 8.1 Hz, 0.1H), 4.05 (d, J = 8.0 Hz, 0.1H), 4.00 (s, 0.1H), 3.95 (t, J = 3.7 Hz, 1H), 3.92 (dd, J = 7.1, 3.2 Hz, 1H), 3.65 (d, J = 4.7 Hz, 1H), 2.63 (d, J = 5.4 Hz, 1H). ¹³C NMR (150 MHz, CDCl₃) δ 169.60, 169.43, 137.82, 137.74, 137.62, 137.39, 135.19, 135.03, 128.74, 128.72, 128.70, 128.67, 128.64, 128.54, 128.49, 128.25, 128.11, 127.99, 127.97, 127.91, 127.89, 94.43, 93.82, 79.86, 78.21, 75.42, 75.30, 74.57, 74.33, 74.03, 72.50, 72.42, 72.11, 68.94, 67.93, 67.64, 67.37. ESIHRMS calculated for C₂₇H₂₈O₇Na [M+Na]⁺ 487.1733, found 487.1732.

3,4-Di-O-benzyl-6-O-(methoxyethoxy)methyl-α/β-D-mannopyranose (23).

Lactol 23 was prepared from thioglycoside 22 (109.8 mg, 0.203 mmol) following the general procedure A. The crude reaction mixture was purified by flash column chromatography (Hexanes/EtOAc = 1/1 to CH₂Cl₂/MeOH = 15/1) to give 74.1 mg (0.165 mmol, 81%) of lactol 23 (α/β = 2.5/1) as colorless syrup. $[{\alpha ]}_{\mathrm{D}}^{23}$= +91.0 (c 0.1, CHCl₃). ¹H NMR (600 MHz, CDCl₃) δ 7.39 – 7.27 (m, 14H), 5.27 (d, J = 1.7 Hz, 1H), 4.92 (d, J = 10.9 Hz, 0.4H), 4.89 (d, J = 11.0 Hz, 1H), 4.77 – 4.66 (m, 6.4H), 4.63 (d, J = 10.9 Hz, 0.4H), 4.59 (d, J = 11.0 Hz, 1H), 4.11 (ddd, J = 9.3, 6.7, 2.1 Hz, 1H), 4.06 (dd, J = 3.3, 1.8 Hz, 2H), 4.01 (dd, J = 3.3, 1.2 Hz, 0.4H), 3.97 (dd, J = 9.1, 3.2 Hz, 1H), 3.87 – 3.59 (m, 8H), 3.56 – 3.49 (m, 3H), 3.43 (ddd, J = 9.8, 4.7, 2.3 Hz, 0.4H), 3.35 (d, J = 5.7 Hz, 4.2H). ¹³C NMR (150 MHz, CDCl₃) δ 138.34, 138.24, 137.94, 137.72, 128.66, 128.63, 128.53, 128.49, 128.12, 128.03, 127.98, 127.96, 127.92, 127.91, 127.82, 96.32, 96.17, 94.21, 93.88, 81.73, 79.84, 75.19, 75.13, 74.92, 74.46, 73.99, 72.04, 71.93, 71.80, 70.59, 68.97, 68.64, 68.33, 67.16, 67.10, 67.08, 59.07, 59.04. ESIHRMS calculated for C₂₇H₃₂O₈Na [M+Na]⁺ 471.1995, found 471.1978.

3-O-Benzyl-4,6-O-[(R)-phenylmethylene]-α/β-D-mannopyranose (25).

Lactol 25 was prepared from thioglycoside 24^[71] (91.4 mg, 0.203 mmol) following the general procedure B. The crude reaction mixture was purified by flash column chromatography (Hexanes/Acetone = 2/1 to CH₂Cl₂/MeOH = 20/1) to give 52.3 mg (0.146 mmol, 72%) of lactol 25 (α/β = 2/1) as colorless syrup. ¹H and ¹³C NMR data of 25 were in agreement with reported ones.^[26]

3-O-Benzyl-4,6-O-[(R)-phenylmethylene]-2-deoxy-2-phthalimido-β-D-glucopyranose (27).

Lactol 27 was prepared from thioglycoside 26^[72] (113.6 mg, 0.196 mmol) following the general procedure B. The crude reaction mixture was purified by flash column chromatography (Hexanes/Acetone = 4/1 to 1/1) to give 61.2 mg (0.126 mmol, 64%) of lactol 27 (β only) as white solids. ¹H and ¹³C NMR data of 27 were in agreement with reported ones.^[73]

3-O-Benzyl-4,6-O-[(R)-phenylmethylene]-2-deoxy-2-azido-α/β-D-mannopyranose (29).

Lactol 29 was prepared from thioglycoside 28^[74] (95 mg, 0.2 mmol) following the general procedure B. The crude reaction mixture was purified by flash column chromatography (Hexanes/EtOAc = 7/1) to give 47 mg (0.122 mmol, 61%) of lactol 29 (α/β = 1.4/1) as colorless syrup. $[{\alpha ]}_{\mathrm{D}}^{23}$= +34.0 (c 0.1, CHCl₃). ¹H NMR (600 MHz, CDCl₃) δ 7.49 (ddd, J = 7.3, 3.8, 1.8 Hz, 3H), 7.43 – 7.27 (m, 14H), 5.63 (s, 1H), 5.61 (s, 0.7H), 5.17 (dd, J = 3.4, 1.5 Hz, 1H), 4.95 – 4.90 (m, 1.7H), 4.80 – 4.71 (m, 2.4H), 4.32 (dd, J = 10.5, 4.9 Hz, 0.7H), 4.23 (dd, J = 10.3, 4.9 Hz, 1H), 4.19 (dd, J = 9.7, 3.7 Hz, 1H), 4.13 (t, J = 9.5 Hz, 1H), 4.08 – 4.00 (m, 3.5H), 3.87 (dd, J = 9.6, 3.7 Hz, 0.7H), 3.82 (td, J = 10.3, 2.2 Hz, 1.7H), 3.60 (d, J = 11.7 Hz, 0.7H), 3.36 (td, J = 9.7, 4.9 Hz, 0.7H), 2.78 (d, J = 3.5 Hz, 1H). ¹³C NMR (150 MHz, CDCl₃) δ 138.11, 137.76, 137.47, 137.29, 129.19, 129.11, 128.67, 128.56, 128.41, 128.37, 128.13, 127.90, 127.78, 127.66, 126.17, 126.12, 101.75, 101.67, 94.15, 93.28, 79.28, 78.61, 77.57, 75.29, 73.50, 73.45, 68.83, 68.50, 67.13, 65.09, 64.07, 62.99. ESIHRMS calculated for C₂₀H₂₁N₃O₅Na [M+Na]⁺ 406.1379, found 406.1379.

2,6-Di-O-benzoyl-3,4-O-[(1S,2S)-1,2-dimethoxy-1,2-dimethyl-1,2-ethanediyl]-α/β-D-mannopyranose (31).

Lactol 31 was prepared from thioglycoside 30 (119.3 mg, 0.201 mmol) following the general procedure B. The crude reaction mixture was purified by flash column chromatography (Hexanes/EtOAc = 4/1 to 1/1) to give 60.9 mg (0.121 mmol, 60%) of lactol 31 (α/β > 20/1) as colorless syrup with 37.1 mg (31%) of thioglycoside 30 recovered. $[{\alpha ]}_{\mathrm{D}}^{23}$= +123.5 (c 0.1, CHCl₃). ¹H NMR (600 MHz, CDCl₃) δ 8.08 – 8.02 (m, 4H), 7.60 – 7.52 (m, 2H), 7.38 (q, J = 7.7 Hz, 4H), 5.39 (dd, J = 4.0, 1.6 Hz, 1H), 5.34 (dd, J = 3.0, 1.7 Hz, 1H), 4.62 (dd, J = 12.0, 2.2 Hz, 1H), 4.56 (dd, J = 12.0, 3.5 Hz, 1H), 4.48 (t, J = 10.2 Hz, 1H), 4.38 (dd, J = 10.3, 3.0 Hz, 1H), 4.34 (dt, J = 10.0, 2.8 Hz, 1H), 3.69 (dd, J = 4.0, 1.6 Hz, 1H), 3.29 (s, 3H), 3.19 (s, 3H), 1.29 (s, 3H), 1.24 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 166.59, 166.10, 133.23, 133.21, 130.27, 130.06, 129.97, 129.75, 128.51, 128.49, 100.39, 100.10, 92.98, 71.56, 68.99, 65.86, 63.48, 62.67, 48.28, 48.05, 17.86, 17.76. ESIHRMS calculated for C₂₆H₂₀O₁₀Na [M+Na]⁺ 525.1737, found 525.1743.

2,3,4,6-Tetra-O-acetyl-α/β-D-glucopyranose (33).

Lactol 33 was prepared from thioglycoside 32^[75] (88.6 mg, 0.201 mmol) following the general procedure A. The crude reaction mixture was purified by flash column chromatography (Hexanes/Acetone = 2/1) to give 26.9 mg (0.077 mmol, 38%) of lactol 33 (α/β = 4/1) as colorless syrup with 21.3 mg (24%) of thioglycoside 32 recovered. ¹H and ¹³C NMR data of 33 were in agreement with reported ones.^[76]

2,3,6-Tri-O-benzyl-4-O-(2,3,4,6-tetra-O-beznyl-β-D-galactopyranosyl)-α/β-D-glucopyranose (35).

Lactol 35 was prepared from thioglycoside 34^[77] (207.0 mg, 0.194 mmol) following the general procedure A. The crude reaction mixture was purified by flash column chromatography (Hexanes/EtOAc = 3/1) to give 163.0 mg (0.167 mmol, 86%) of lactol 35 (α/β = 2/1) as white solids. ¹H and ¹³C NMR data of 35 were in agreement with reported ones.^[78]