Straightforward S-S Bond Formation via the Oxidation of S-Acetyl by

containing glycosides in which the S-acetyl group is located in non-anomeric positions. In this study, we. Page 2 of 33. ACS Paragon Plus Environment...
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Straightforward S−S Bond Formation via the Oxidation of S‑Acetyl by Iodine in the Presence of N‑Iodosuccinimide Jian-Tao Ge, Lang Zhou, Fu-Long Zhao, and Hai Dong* Key Laboratory of Material Chemistry for Energy Conversion and Storage, Ministry of Education, School of Chemistry & Chemical Engineering, Huazhong University of Science & Technology, Luoyu Road 1037, Wuhan 430074, PR China S Supporting Information *

ABSTRACT: Straightforward S−S bond formation via the oxidation of S-acetyl group by iodine was reported here. The reaction was further applied in the synthesis of per-Oacetylated glycosyl disulfides. These studies demonstrated great improvement in reaction rate, yield, and general convenience in the presence of N-iodosuccinimide. Furthermore, selectively deacetylated glycosyl thiols were obtained in high yields when these per-O-acetylated glycosyl disulfides were reduced with tris(2-carboxyethyl)-phosphine (TCEP). Our method supplied an efficient way to obtain both per-O-acetylated glycosyl disulfides and per-O-acetylated glycosyl thiols in which the sulfur group was located at any position.

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INTRODUCTION Disulfides are frequently the key constituents of proteins, peptides, and many other biologically active natural products, and S−S bond formation is therefore the key step in the synthesis of these products.1 Over recent years, glycosyl disulfides have been attracting an increasing interest as useful tools in the study of glycobiology.2 For example, as O-glycoside mimics, glycosyl disulfides have been studied in lectin binding2c−f and dynamic library,2f,g as potential anticancer agents2e,f and for the carbohydrate structure researches.2h,i Glycosyl disulfides have been reported to be formed via the oxidation of the corresponding glycosyl thiols by iodine (I2),3 H2O2,2f diethyl azodicarboxylate (DEAD),4 and m-chloroperoxybenzoic acid (m-CPBA)5 (Figure 1a). However, acquiring glycosyl thiols from glycosyl precursors commonly requires extra steps and special means, especially for per-O-acetylated thio-containing glycosides in which the S-acetyl group is located in nonanomeric positions. In this study, we demonstrate straightforward S−S bond formation via the oxidation of Sacetyl by I2. We found great improvement in reaction rate, yield and general convenience with the presence of N-iodosuccinimide (NIS). To our best knowledge, this type of reaction has never been reported. In the application of the reaction to synthesize per-O-acetylated glycosyl disulfides, almost quantitative yields were directly obtained starting with per-Oacetylated glycosyl precursors in which the S-acetyl group was located at any position (Figure 1b). In addition, per-Oacetylated glycosyl thiols were obtained in high yields when these disulfides were reduced with tris(2-carboxyethyl)phosphine (TCEP). It is known that glycosyl thiols can be used for the preparation of active glycosyl donors6 in glycosylation reaction and drugs7 (such as auranofin) due to the good affinity of glycosyl thiols toward gold. Just recently, it was found by us that deoxyglycosides could be highly efficiently synthesized through desulfurization of glycosyl thiols.8 Therefore, methods for the obtaining of per-O-acetylated glycosyl © 2017 American Chemical Society

thiols are urgently required. However, the per-O-acetylated glycosyl thiols in which the SH group was located at anomeric position were usually obtained in all reported methods.9 Herein, our method supplied an efficient way to obtain per-Oacetylated glycosyl thiols in which the SH group was located at any position (Figure 1b).

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RESULTS AND DISCUSSION We have been making an efforts to synthesize S-glycosides in which the thio-group can be located at any position on the carbohydrate ring.10 It was observed that the deacylation of acetylated S-glycosides required more than a stoichiometric amount of base for each thioacetate group, as the preferential formation of sulfhydryl group neutralized the base.10b Inspired by a recent report on the straightforward synthesis of glycosyl disulfides from their corresponding isothiouronium derivatives,11 we wondered whether we could achieve straightforward S−S bond formation from a thioacetate group via a sequential approach using a base and oxidant together. Our initial idea was to use a catalytic amount of base, such as NaOH, Na2CO3 or K2CO3, and a large amount of H2O2 in the methanol solvent of per-O-acetylated thio-containing glycosides. It was hypothesized that the S−S bond would form immediately via the oxidation of the sulfhydryl group by H2O2 once the sulfhydryl group formed via the deacylation of the S-acetyl group catalyzed by the base. Thus, the base would not be consumed by the sulfhydryl group and would catalyze deacylation until completion. However, the experiments (Figure 2) indicated that the method was inefficient for the per-O-acetylated glycoside 3 in which the thio-group was located in a nonanomeric position. Straightforward S−S Bond Formation. We then noticed a report12 on disulfide formation via the oxidation of SReceived: September 19, 2017 Published: October 30, 2017 12613

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Figure 1. Comparison of our method versus reported methods.

conversion) under the optimized condition in which 3 was treated with 2.5 equiv of I2 in the presence of 0.5 equiv of NIS in acetonitrile at room temperature for 1 h (Entry 1, Table 1). During the optimization process, we first compared disulfide bond formation in the presence of 2.0 equiv of I2 in various solvents (Entries 2−9). The best isolated yield of disulfide 4 (76% or 74%) was obtained using acetonitrile or ethyl acetate as the solvent. Then disulfide bond formation was compared using various amounts of I2 in acetonitrile (Entries 2, 10−12, 16−17). The 79% yield of disulfide 4 was isolated using 2.5 equiv of I2. The increase (by 5.0 equiv) in the amount of I2 used and the prolonged reaction time did not lead to more disulfide 4 than 79% yield. Interestingly, disulfide formation in acetonitrile largely improved in terms of reaction rate, yield and general convenience by adding NIS (Entries 1, 13−19). The yield of disulfide 4 increased to 86% with the use of 2.5 equiv of I2 and 0.3 equiv of NIS (Entry 13), and with the use of 2 equiv of I2 and 0.5 equiv of NIS (Entry 15), whereas no or trace reactions occurred with the use of NIS alone for 1 h (Entry 18). The 83% yield of disulfide 4 was isolated using 2 equiv of I2 and 0.5 equiv of NIS for 1 h and prolonging the reaction time by 2− 3 h only increased the yield of disulfide 4 by 86% (Entries 14− 16). With the reaction time further prolonged (more than 3 h), deacylation side products started to generate, leading to steady decrease in disulfide yields. The yield of 4 decreased by 61% with the reduced amount of I2 by 1 equiv (Entry 17). The addition of NIS was of no use for disulfide formation in ethyl acetate (Entry 19), which was probably due to the poor solubility of NIS. The method was further tested with 6-S-acetyl per-Oacetylated glycosides 5, 7, 9 and 11. The isolated yields of glycosyl disulfides 6, 8, 10 and 12 were 93%, 90%, 86% and 90% (Figure 3), respectively. For 1-S-acetyl per-O-acetylated glycosides 1, 13, 15, 17 and 19, disulfide formation completed in 40 min using this method. Glycosyl disulfides 2, 14, 16, 18 and 20 were obtained in 85%, 91%, 92%, 93% and 90% yields, respectively. However, formation of disulfide 22 require 7 h reaction without any deacylation side products. This method is also valid for the per-O-acetylated glycosides in which the Sacetyl group is in a secondary position. However, more NIS is required in these cases. Glycosyl disulfide 24 was isolated in 72% yield with 0.5 equiv of NIS, but the yield increased to 92% when 1.3 equiv of NIS were used instead. Disulfide 26 was obtained in 94% yield under the same conditions. It was failed to obtain disulfide 28 where the thio-group was in axial 3position due to complex side products. To oxidize S-acetyl group in 4-position, 2.5 equiv of NIS were required. Glycosyl disulfides 30 and 32 were obtained in 78% and 79% yields, respectively. We hypothesized that side-reactions in the method

Figure 2. Per-O-acetylated glycosyl disulfide formation via a sequential approach using a base and oxidant together.

(acetyl)aminomethyl (Acm) by I2 in peptide synthesis. We wondered whether a disulfide bond could form via the direct oxidation of S-acetyl by I2. Therefore, we started investigating this type of disulfide bond formation reaction using 6-S-acetyl glycoside 3 as a model (Table 1). Fortunately, glycosyl disulfide 4 was isolated in 92% yield (TLC plate indicating full Table 1. Comparison of Results by Variation from the Optimized Conditiona

entry

reaction conditions

yields (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

I2 (2.5 equiv), CH3CN, NIS (0.5 equiv) 1 h I2 (2 equiv), CH3CN, 1.5 h I2 (2 equiv), EtOAc, 1.5 h I2 (2 equiv), CH2Cl2, 1.5 h I2 (2 equiv), toluene (CHCl3, DMSO, or AcOH), 1.5 h I2 (2 equiv), THF, 1.5 h I2 (2 equiv), Et2O, 1.5 h I2 (2 equiv), Acetone, 1.5 h I2 (2 equiv), CH3OH, 1.5 h I2 (1.2 equiv), CH3CN, 4 h I2 (2.5 equiv), CH3CN, 1.5−4 h I2 (5 equiv), CH3CN, 1.5 h I2 (2.5 equiv), CH3CN, NIS (0.3 equiv) 1 h I2 (2 equiv), CH3CN, NIS (0.5 equiv) 1 h I2 (2 equiv), CH3CN, NIS (0.5 equiv) 2 h I2 (2 equiv), CH3CN, NIS (0.5 equiv) 3 h I2 (1 equiv), CH3CN, NIS (0.5 equiv) 3 h NIS (0.5 equiv), CH3CN, 1 h I2 (2.5 equiv), EtOAc, NIS (0.5 equiv) 1 h

92 76 74 35 −b 39 48 20 47 55 79 79 86 83 86 85 61 −b 76

a Optimized condition: substrate 3 (100 mg), I2 (2.5 equiv), NIS (0.5 equiv), acetonitrile (2 mL), room temperature, 1 h. bNo or trace reactions.

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Figure 4. A proposed mechanism for how NIS improves the oxidation of S-acetyl by I2.

may have led to complex side products in this disulfide formation process. Obtaining of Per-O-acetylated Glycosyl Thiols. The method to obtain per-O-acetylated glycosyl thiols in which the SH group is located in nonanomeric positions is rarely reported.9 Apparently, they can be obtained via the reduction of per-O-acetylated disulfides obtained above. Therefore, we started investigating kinds of reductants to explore the most efficient reduction method using disulfide 2 as a model compound (Table 2). We first used 3 equiv of 1,4-dithiothreitol (DTT) as the reductant (Entry 1). After the reduction reaction have been proceeding in metanol at room temperature for 8 h, glycosyl thiol 37 was isolated in 80% yield. There was no reduction occurred with NaHSO3 as the reductant (Entry 2). The use of 20 equiv of Zn (powder) in acetic acid led to 76%

Figure 3. Synthesis of per-O-acetylated glycosyl disulfides via the oxidation of S-acetyl: (a) substrates (100 mg), I2 (2.5 equiv), NIS (0.5 equiv), acetonitrile (2 mL), r.t.; (b) substrates (100 mg), I2 (2.5 equiv), NIS (1.3 equiv), acetonitrile (2 mL), r.t.; (c) substrates (100 mg), I2 (2.5 equiv), NIS (2.5 equiv), acetonitrile (2 mL), r.t.

be caused by acyl group migration which is easily occurred with an activated OH (or SH) group.10c,13 The use of pivaloyl instead of acetyl should restrain acyl group migration, thus increasing the yields of glycosyl disulfides where the thiogroups were in 3- or 4-position. The hypothesis was supported by further experiments. Disulfides 34 and 36 were obtained in 89% yield. Upon analysis of the reaction rates, the reactivity order for the oxidation of S-acetyl at different positions can be arranged as 1 > 6 > 2 > 3, 4. Disulfide formation via the oxidation of thiol (RSH) by I2 involving the formation of intermediate sulfenyl iodide (RSI) is a well-known reaction.14 Disulfide formation via the oxidation of S-acetyl (RSAc) by I2 should have an analogous mechanism, as shown in eqs 1−3. RSAc + I 2 → RSI + AcI

(1)

RSI + RSAc → RSSR + AcI

(2)

2RSI → RSSR + I 2

(3)

Table 2. Comparison of Reductants to Explore the Optimized Conditiona

A proposed mechanism for how NIS improves the oxidation of S-acetyl by I2 is shown in Figure 4. I2 can both accept electrons from sulfur and supply electrons to carbonyl, which therefore leads to the formation of RSI and AcI (Figure 4a). NIS has a stronger ability than I2 to accept electrons from sulfur, which therefore improves the formation of RSI (Figure 4b). However, the formation of RSI with NIS alone is difficult due to a lack of carbonyl group activation by I2 (Figure 4c). An acyl migration mechanism was proposed in Figure 4d, which

entry

reaction conditions

yields (%)

1 2 3 4 5 6 7 8 9

DTT (3 equiv), MeOH, r.t., 8 h NaHSO3 (2 equiv), MeOH, 50 °C, 18 h Zn (20 equiv), AcOH, 50 °C, 4 h P(Et)3 (1.1 equiv), MeCN, r.t., 15 min P(Bu)3 (1.1 equiv), MeCN, r.t., 15 min TCEP (2.5 equiv), MeCN/MeOH (2/1), r.t., 4 h TCEP (1.5 equiv), MeCN/H2O (2/1), r.t., 1 h TCEP (2.3 equiv), MeCN/H2O (2/1), r.t., 0.5 h TCEP (1.5 equiv), DMF, r.t., 1 h

80 No react. 76 55 55 45 67 Quant. Quant.

a

Optimized condition: substrate 2 (100 mg), TCEP (1.5 equiv), DMF (1 mL), r.t., 1 h.

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Figure 5. Synthesis of per-O-acetylated glycosyl thiols via the reduction of disulfides: (a) substrates (100 mg), TCEP (2.3 equiv), MeCN/H2O (1 mL, 2/1), r.t.; (b) substrates (100 mg), TCEP (1.5 equiv), DMF (1 mL), r.t.; (c) substrates (100 mg), TCEP (2.5 equiv), DMF (1 mL), r.t.; (d) substrates (100 mg), TCEP (4.0 equiv), DMF/H2O (1 mL, 2/1), 50 °C.

yield of 37 (Entry 3). With P(Et)3 or P(Bu)3 as the reductant, though high reactivity was observed (reduction completed in 15 min.), 55% yield of 37 was only obtained due to the formation of unknown side-products (Entries 4 and 5). With tris(2-carboxyethyl)-phosphine (TCEP) as the reductant, though low reactivity was observed (45% yield of 37 was only obtained after 4 h reduction), there was no any sideproducts that were observed (Entry 6). During the optimization of the conditions that TCEP was used as the reductant (Entries 7−9), it was found that glycosyl thiol 37 could be obtained in very high yields when MeCN/MeOH (2/ 1) or DMF was used as the solvent. Glycosyl thiol 37 was easily separated from the reaction solvents by the extraction with using dicholoromethane. All the obtained glycosyl disulfides were then reduced with TCEP (Figure 5). It can be seen that glycosyl thiols 37−51 were isolated in very high yields (>95%) after the reduction reactions. The reduction of disulfides 34 and 36 to obtain thiols 50 and 51 required 2.5 equiv of TCEP in DMF and longer reaction time (6 h), which might be due to the large pivaloyl group. The reduction of disulfides 24 and 26 is much more difficult likely due to the steric effects. Thiols 52 and 53 were isolated respectively in moderate yields (75% and 76%) after the reduction proceeded with 4 equiv of TCEP at 50 °C for 6− 12 h. The addition of water to DMF is to increase the solubility of TCEP.

using dicholoromethan. Our method supplied an efficient way to obtain both per-O-acetylated glycosyl disulfides and per-Oacetylated glycosyl thiols in which the sulfur group can be located at any position.

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EXPERIMENTAL SECTION

General Methods. All commercially available starting materials and solvents were of reagent grade and used without further purification. Chemical reactions were monitored with thin-layer chromatography using precoated silica gel 60 (0.25 mm thickness) plates. Flash column chromatography was performed on silica gel 60 (SDS 0.040−0.063 mm). 1H NMR spectra were recorded at 298 K in CDCl3, using the residual signals from CHCl3 (1H = 7.26 ppm) as internal standard. 1H peak assignments were made by first order analysis of the spectra, supported by standard 1H−1H correlation spectroscopy (COSY). General S−S Bond Formation via the Oxidation of S-Acetyl by I2 and NIS. To a solution of substrates containing thioacetate group (100 mg), in CH3CN (1−2 mL) was added I2 (2.5 equiv) and NIS (0.5−2.5 equiv). The reaction mixture was stirred at room temperature for 40−120 min. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were washed with 5% Na2S2O3, brine, dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography afforded the disulfide products. General Synthesis of Glycosyl Thiols by the Reduction of S− S Bond with TCEP. To a solution of glycosyl disulfides (100 mg) synthesized above, in DMF (1.0 mL) was added TCEP·HCl (1.5−2.5 equiv). The reaction mixture was stirred at room temperature for 30− 120 min. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography afforded the thiol products. Bis(2,3,4,6-tetra-O-acetyl-1-thio-1-deoxy-α-D-mannopyranosyl)-1,1′-disulfide (2).15 To a solution of 2,3,4,6-tetra-O-acetyl-1-Sacetyl-α-D-mannopyranose 19a (107 mg, 0.26 mmol), in CH3CN (1.5 mL) was added I2 (168 mg, 0.65 mmol) and NIS (30 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 40 min. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were washed with 5% Na2S2O3, brine,

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CONCLUSION A method for straightforward disulfide formation via the oxidation of S-acetyl by I2 was reported in present studies. Great improvement in reaction rate, yield, and general convenience was demonstrated in the presence of NIS. PerO-acetylated glycosyl disulfides were obtained with high efficiency and in very high yields (>90% in most cases) using this method. Furthermore, these per-O-acetylated glycosyl disulfides were efficiently reduced with TCEP in polar solvents, leading to very high yields of per-O-acetylated glycosyl thiols (>90% in most cases). These glycosyl thiols can be easily separated from the reaction solvents by the extraction with 12616

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The Journal of Organic Chemistry

dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:3) afforded the disulfide 10 as colorless oil (50 mg, 86% yield). 1H NMR (400 MHz, CDCl3) δ = 5.43 (d, J = 3.6 Hz, 2H, H-4), 5.19 (dd, J = 8.0 Hz, 10.8 Hz, 2H, H-2), 5.04 (dd, J = 3.6 Hz, 10.8 Hz, 2H, H-3), 4.40 (d, J = 8.0 Hz, 2H, H-1), 3.92 (dd, J = 5.6 Hz, 8.0 Hz, 2H, H-1), 3.53 (s, 6H, OMe), 2.92 (dd, J = 8.0 Hz, 14.0 Hz, 2H, H-6a), 2.76 (dd, J = 5.6 Hz, 14.0 Hz, 2H, H-6a), 2.17 (s, 6H, OAc), 2.06 (s, 6H, OAc), 1.99 (s, 6H, OAc) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.3, 170.1, 169.5, 102.1, 71.7, 71.1, 68.8, 68.7, 57.1, 38.9, 20.8, 20.7, 20.6 ppm. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C26H38O16S2Na 693.1499, found 693.1505. Methyl 2,3,4-tri-O-acetyl-6-S-acetyl-α-D-mannopyranoside (11). To a solution of methyl 6-tosyl-α-D-mannopyranoside2f (980 mg, 2.8 mmol) in dry pyridine (4 mL) was added acetic anhydride (3 mL). After the reaction mixture was stirred at room temperature overnight, it was diluted with water, then extracted with ethyl acetate. The combined organic phases were washed with 2 M HCl, water and then brine, dried with MgSO4, and concentrated. The crude product was dissolved in dry DMF (6 mL). After the afforded solution was stirred at room temperature for 6 h in the presence of potassium thioacetate (479 mg, 4.2 mmol), the resulting mixture was diluted with water, then extracted with ethyl acetate. The combined organic phases were washed with water and then brine, dried with Na2SO4, and concentrated. Purification of the residue by flash column chromatography (hexane/ethyl acetate, 2:1) afforded 762 mg of product 11 (72%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ = 5.28 (dd, J = 3.2 Hz, 10.0 Hz, 1H, H-3), 5.25−5.20 (m, 2H, H-2, H-4), 4.64 (s, 1H, H-1), 3.90−3.79 (m, 1H, H-5), 3.39 (s, 3H, OMe), 3.27 (dd, J = 2.4 Hz, 14.0 Hz, 1H, H-6a), 3.02 (dd, J = 8.0 Hz, 14.0 Hz, 1H, H-6b), 2.35 (s, 3H, SAc), 2.15 (s, 3H, OAc), 2.10 (s, 3H, OAc), 1.98 (s, 3H, OAc) ppm; 13C NMR (100 MHz, CDCl3) δ = 194.6, 170.0, 169.9, 169.8, 98.4, 69.7, 69.5, 68.9, 68.7, 55.2, 30.4, 20.8, 20.7, 20.6 ppm. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H22O9SNa 401.0882, found 401.0887. Bis(methyl 2,3,4-tri-O-acetyl-6-thio-6-deoxy-α-D-mannopyranoside)-6,6′-disulfide (12).20 To a solution of methyl 2,3,4-tri-Oacetyl-6-S-acetyl-α-D-mannopyranoside 113 (135 mg, 0.36 mmol) in CH3CN (1 mL) was added I2 (227 mg, 0.73 mmol) and NIS (40 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 1 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were washed with 5% Na2S2O3, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:3) afforded the disulfide 12 as colorless oil (108 mg, 90% yield). 1H NMR (400 MHz, CDCl3) δ = 5.31 (dd, J = 3.2 Hz, 10.0 Hz, 2H, H-3), 5.23 (dd, J = 1.2 Hz, 3.2 Hz, 2H, H-2), 5.14 (dd, J = 10.0 Hz, 2H, H4), 4.68 (d, J = 1.2 Hz, 2H, H-1), 4.00 (ddd, J = 5.2 Hz, 6.8 Hz, 10.0 Hz, 2H, H-5), 3.43 (s, 6H, OMe), 2.92−2.88 (m, 4H, H-6a, H-6b), 2.14 (s, 6H, OAc), 2.07 (s, 6H, OAc), 1.99 (s, 6H, OAc) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.1, 170.0, 169.8, 98.4, 69.6, 69.2, 68.9, 68.8, 55.3, 41.4, 20.9, 20.8, 20.7 ppm. Bis(2,3,4,6-tetra-O-acetyl-1-thio-1-deoxy-β- D -glucopyranosy-l)-1,1′-disulfide (14).3b To a solution of 2,3,4,6-tetra-O-acetyl1-S-acetyl-β-D-glucopyranose 139f (115 mg, 0.28 mmol) in CH3CN (1.5 mL) was added I2 (180 mg, 0.7 mmol) and NIS (32 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 40 min. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were washed with 5% Na2S2O3, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:2) afforded the disulfide 14 as colorless oil (94 mg, 91% yield). 1H NMR (400 MHz, CDCl3) δ = 5.17−5.31 (m, 4H, H-2, H-3), 5.10 (t, J = 10.0 Hz, 2H, H-4), 4.65 (d, J = 10.0 Hz, 2H, H-1), 4.33 (dd, J = 4.4 Hz, 12.8 Hz, 2H, H-6a), 4.22 (dd, J = 1.6 Hz, 12.8 Hz, 2H, H-6b), 3.79 (ddd, J = 1.6 Hz, 4.4 Hz, 10.0 Hz, 2H, H-5), 2.13 (s, 6H, OAc), 2.10 (s, 6H, OAc), 2.03 (s, 6H, OAc), 2.00 (s, 6H, OAc) ppm; 13C NMR

dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:2) afforded the disulfide 2 as colorless oil (81 mg, 85% yield). 1H NMR (400 MHz, CDCl3) δ = 5.46 (dd, J = 2.8 Hz, 9.6 Hz, 2H, H-3), 5.34−5.23 (m, 6H, H-1, H-2, H-4), 4.32 (dd, J = 4.8 Hz, 12.4 Hz, 2H, H-6a), 4.21 (ddd, J = 2.0 Hz, 4.8 Hz, 12.4 Hz, 2H, H-5), 4.09 (dd, J = 2.0 Hz, 12.4 Hz, 2H, H-6b), 2.17 (s, 6H, OAc), 2.11 (s, 6H, OAc), 2.05 (s, 6H, OAc), 2.01 (s, 6H, OAc) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.6, 169.7, 169.7, 169.6, 87.3, 70.9, 69.6, 68.9, 65.8, 61.9, 20.8, 20.7, 20.6, 20.5 ppm. Bis(methyl 2,3,4-tri-O-acetyl-6-thio-6-deoxy-α-D-glucopyranoside)-6,6′-disulfide (4).16 To a solution of methyl 2,3,4-tri-Oacetyl-6-S-acetyl-α-D-glucopyranoside 316 (105 mg, 0.28 mmol) in CH3CN (1.5 mL) was added I2 (176 mg, 0.7 mmol) and NIS (31.5 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 1 h. When TLC indicated full conversion of the starting material, the reaction mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were washed with 5% Na2S2O3, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:3) afforded the disulfide 4 as colorless oil (87 mg, 92% yield). 1H NMR (400 MHz, CDCl3) δ = 5.46 (t, J = 10.0 Hz, 2H, H-3), 4.94−4.85 (m, 6H, H-1, H-2, H-4), 4.02 (td, J = 2.8 Hz, 9.2 Hz, 2H, H-5), 3.44 (s, 6H, OMe), 2.94−2.81 (m, 4H, H-6a, H-6b), 2.08 (s, 6H, OAc), 2.06 (s, 6H, OAc), 2.01 (s, 6H, OAc) ppm. Bis(methyl 2,3,4-tri-O-acetyl-6-thio-6-deoxy-β-D-glucopyranoside)-6,6′-disulfide (6). To a solution of methyl 2,3,4-tri-Oacetyl-6-S-acetyl-β-D-glucopyranoside 517 (110 mg, 0.29 mmol) in CH3CN (1.5 mL) was added I2 (185 mg, 0.73 mmol) and NIS (33 mg, 0.145 mmol). The reaction mixture was stirred at room temperature for 1 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were washed with 5% Na2S2O3, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:3) afforded the disulfide 6 as colorless oil (90 mg, 93% yield). 1H NMR (400 MHz, CDCl3) δ = 5.20 (t, J = 10.0 Hz, 2H, H-3), 4.98−4.92 (m, 4H, H-2, H-4), 4.43 (d, J = 7.6 Hz, 2H, H-1), 3.72 (ddd, J = 3.6 Hz, 7.6 Hz, 10.0 Hz, 2H, H-5), 3.52 (s, 6H, OMe), 2.95−2.85 (m, 4H, H-6a, H-6b), 2.06 (s, 6H, OAc), 2.05 (s, 6H, OAc), 2.00 (s, 6H, OAc) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.2, 169.8, 169.4, 101.5, 72.7, 72.4, 71.5, 71.4, 57.0, 41.3, 20.8, 20.7, 20.6 ppm. HRMS (ESI-TOF) m/z [M + Na] + calcd for C26H38O16S2Na 693.1499, found 693.1495. Bis(methyl 2,3,4-tri-O-acetyl-6-thio-6-deoxy-α-D-galactopyranoside)-6,6′-disulfide (8). To a solution of methyl 2,3,4-tri-Oacetyl-6-S-acetyl-α-D-galactopyranoside 718 (65 mg, 0.17 mmol) in CH3CN (1 mL) was added I2 (110 mg, 0.73 mmol) and NIS (19 mg, 0.09 mmol). The reaction mixture was stirred at room temperature for 1 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were washed with 5% Na2S2O3, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:3) afforded the disulfide 8 as colorless oil (52 mg, 90% yield). 1H NMR (400 MHz, CDCl3) δ = 5.40−5.34 (m, 4H, H-3, H-4), 5.15 (dd, J = 3.6 Hz, 10.8 Hz, 2H, H-2), 4.99 (d, J = 3.6 Hz, 2H, H-1), 4.20 (dd, J = 3.6 Hz, 9.2 Hz, 2H, H-5), 3.43 (s, 6H, OMe), 2.84−2.71 (m, 4H, H-6a, H-6b), 2.16 (s, 6H, OAc), 2.09 (s, 6H, OAc), 1.98 (s, 6H, OAc) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.4, 170.3, 169.9, 97.1, 70.0, 68.0, 67.8, 66.9, 55.6, 39.7, 20.8, 20.7, 20.6 ppm. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C26H38O16S2Na 693.1499, found 693.1505. Bis(methyl 2,3,4-tri-O-acetyl-6-thio-6-deoxy-β-D-galactopyranoside)-6,6′-disulfide (10). To a solution of methyl 2,3,4-tri-Oacetyl-6-S-acetyl-β-D-galactopyranoside 919 (65 mg, 0.17 mmol) in CH3CN (1 mL) was added I2 (110 mg, 0.73 mmol) and NIS (19 mg, 0.09 mmol). The reaction mixture was stirred at room temperature for 1 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were washed with 5% Na2S2O3, brine, 12617

DOI: 10.1021/acs.joc.7b02367 J. Org. Chem. 2017, 82, 12613−12623

Article

The Journal of Organic Chemistry (100 MHz, CDCl3) δ = 170.7, 170.1, 169.3, 169.2, 87.2, 76.2, 73.8, 69.7, 67.9, 61.5, 20.8, 20.7, 20.6, 20.5 ppm. Bis(2,3,4,6-tetra-O-acetyl-1-thio-1-deoxy-β-D-galactopyranosyl)-1,1′-disulfide (16).4 To a solution of 2,3,4,6-tetra-O-acetyl-1S-acetyl-β-D-galactopyranose 159f (50 mg, 0.12 mmol) in CH3CN (0.65 mL) was added I2 (78 mg, 0.31 mmol) and NIS (14 mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 40 min. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were washed with 5% Na2S2O3, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:2) afforded the disulfide 16 as colorless oil (41 mg, 92% yield). 1H NMR (400 MHz, CDCl3) δ = 5.44 (d, J = 2.8 Hz, 2H, H-4), 5.36 (t, J = 10.0 Hz, 2H, H-2), 5.09 (dd, J = 2.8 Hz, 10.0 Hz, 2H, H-3), 4.57 (d, J = 10.0 Hz, 2H, H-1), 4.24 (dd, J = 6.0 Hz, 10.8 Hz, 2H, H-6a), 4.16− 4.00 (m, 4H, H-6b, H-5), 2.18 (s, 6H, OAc), 2.10 (s, 6H, OAc), 2.05 (s, 6H, OAc), 1.99 (s, 6H, OAc) ppm. Bis(2,3,4,6-tetra-O-acetyl-1-thio-1-deoxy-β-D-mannopyranosyl)-1,1′-disulfide (18). To a solution of 2,3,4,6-tetra-O-acetyl-1-Sacetyl-β-D-mannopyranose 179f (110 mg, 0.27 mmol) in CH3CN (1.5 mL) was added I2 (172 mg, 0.68 mmol) and NIS (31 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 40 min. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were washed with 5% Na2S2O3, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:2) afforded the disulfide 18 as colorless oil (92 mg, 93% yield). 1H NMR (400 MHz, CDCl3) δ = 5.60 (d, J = 3.2 Hz, 2H, H-2), 5.30 (t, J = 10.0 Hz, 2H, H-4), 5.11 (dd, J = 3.2 Hz, 10.0 Hz, 2H, H-3), 4.93 (s, 2H, H-1), 4.30−4.20 (m, 4H, H-6a, H-6b), 3.83−3.73 (m, 2H, H-5), 2.19 (s, 6H, OAc), 2.12 (s, 6H, OAc), 2.05 (s, 6H, OAc), 1.99 (s, 6H, OAc) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.7, 170.1, 170.0, 169.5, 88.2, 76.9, 71.6, 69.3, 65.3, 62.0, 20.8, 20.7, 20.6, 20.5 ppm. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H38O18S2Na 749.1397, found 749.1401. Bis(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl-(1 → 4)2,3,6-tri-O-acetyl-1-thio-1-deoxy-β-D-glucopyranose)-1,1′-disulfide (20). To a solution of 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl-(1 → 4)-2,3,6-tri-O-acetyl-l-S-acetyl-1-thio-β-D-glucopyranose 199f (100 mg, 0.15 mmol) in CH3CN (1.5 mL) was added I2 (95 mg, 0.375 mmol) and NIS (16.8 mg, 0.075 mmol). The reaction mixture was stirred at room temperature for 1 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were washed with 5% Na2S2O3, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:1) afforded the disulfide 20 as colorless oil (85 mg, 90% yield). 1H NMR (400 MHz, CDCl3) δ = 5.35 (d, J = 3.2 Hz, 2H, H-4’), 5.24 (t, J = 9.6 Hz, 2H, H3), 5.15−5.04 (m, 4H, H-2, H-2’), 4.98 (dd, J = 3.2 Hz, 10.4 Hz, 2H, H-3′), 4.85−4.54 (m, 6H, H-1, H-1′,H-6a), 4.19−4.05 (m, 6H, H-6a’, H-6b’, H-6b), 3.93−3.82 (m, 4H, H-5′, H-4), 3.77−3.69 (m, 2H, H-5), 2.18 (s, 6H, OAc), 2.16 (s, 6H, OAc), 2.07 (s, 6H, OAc), 2.06 (s, 6H, OAc), 2.06 (s, 6H, OAc), 2.05 (s, 6H, OAc), 1.97 (s, 6H, OAc) ppm; 13 C NMR (100 MHz, CDCl3) δ = 170.4, 170.2, 170.1, 170.0, 169.7, 169.3, 169.0, 100.8, 88.7, 77.0, 75.7, 73.8, 71.0, 70.6, 70.1, 69.1, 66.6, 61.8, 60.7, 21.0, 20.8, 20.7, 20.6, 20.5 ppm. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C52H70O34S2Na 1325.3088, found 1325.3083. Bis(3,4,6-tri-O-acetyl-2-N-acetyl-1-thio-1-deoxy-β-D-glucosamine)-1,1′-disulfide (22).21 To a solution of 3,4,6-tri-O-acetyl-Nacetyl-S-acetyl-1-thio-β-D-glucosamine 219f (51 mg, 0.13 mmol) in CH3CN (0.65 mL) was added I2 (83 mg, 0.325 mmol) and NIS (14 mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 7 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were washed with 5% Na2S2O3, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl

acetate/petroleum ether = 3:1) afforded the disulfide 22 as colorless oil (42 mg, 89% yield). 1H NMR (400 MHz, CDCl3) δ = 6.17 (d, J = 8.4 Hz, 2H, NH), 5.41 (t, J = 9.6 Hz, 2H, H-3), 5.01 (t, J = 9.6 Hz, 2H, H-4), 4.89 (d, J = 10.0 Hz, 2H, H-1), 4.44 (dd, J = 5.2 Hz, 12.4 Hz, 2H, H-6a), 4.08 (dd, J = 2.4 Hz, 12.4 Hz, 2H, H-6b), 4.00 (dd, J = 10.0 Hz, 9.6 Hz, 2H, H-2), 3.85−3.71 (m, 2H, H-5), 2.14 (s, 6H, OAc), 2.03 (s, 6H, OAc), 2.03 (s, 6H, OAc), 2.02 (s, 6H, OAc) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.9, 170.6, 170.5, 169.5, 88.8, 76.1, 73.0, 68.5, 82.1, 53.4, 23.4, 20.9, 20.7, 20.6 ppm. Bis(methyl 3,4,6-tri-O-acetyl-2-thio-2-deoxy-α-D-mannopyranoside)-2,2′-disulfide (24). To a solution of methyl 3,4,6-tri-Oacetyl-2-S-acetyl-α-D-mannopyranoside 2310a (133 mg, 0.35 mmol) in CH3CN (1.8 mL) was added I2 (223 mg, 0.88 mmol) and NIS (103 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 1 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were washed with 5% Na2S2O3, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:3) afforded the disulfide 24 as colorless oil (110 mg, 92% yield). 1H NMR (400 MHz, CDCl3) δ = 5.41 (dd, J = 4.8 Hz, J = 10.0 Hz, 2H, H-3), 5.28 (t, J = 10.0 Hz, 2H, H-4), 5.03 (d, J = 1.2 Hz, 2H, H-1), 4.18 (dd, J = 4.8 Hz, J = 12.0 Hz, 2H, H-6a), 4.12 (dd, J = 2.4 Hz, J = 12.0 Hz, 2H, H-6b), 3.96−3.88 (m, 2H, H-5), 3.55 (dd, J = 1.2 Hz, J = 4.8 Hz, 2H, H-2), 3.41 (s, 6H, OMe), 2.10 (s, 6H, OAc), 2.08 (s, 6H, OAc), 2.04 (s, 6H, OAc) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.7, 170.2, 169.5, 100.8, 70.3, 68.5, 66.2, 62.3, 56.8, 55.3, 20.8, 20.7, 20.6 ppm. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C26H38O16S2Na 693.1499, found 693.1501. Bis(methyl 3,4,6-tri-O-acetyl-2-thio-2-deoxy-β-D-mannopyranoside)-2,2′-disulfide (26). To a solution of methyl 3,4,6-tri-Oacetyl-2-S-acetyl-β-D-mannopyranoside 2510a (75 mg, 0.2 mmol) in CH3CN (1 mL) was added I2 (126 mg, 0.5 mmol) and NIS (58 mg, 0.26 mmol). The reaction mixture was stirred at room temperature for 1 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases werewashed with 5% Na2S2O3, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:3) afforded the disulfide 26 as colorless oil (63 mg, 94% yield). 1H NMR (400 MHz, CDCl3) δ = 5.27 (t, J = 9.2 Hz, 2H, H-4), 5.14 (dd, J = 4.0 Hz, 9.2 Hz, 2H, H-3), 4.56 (d, J = 1.6 Hz, 2H, H-1), 4.22−4.13 (m, 4H, H-6a, H-6b), 3.65 (dd, J = 1.6 Hz, 4.0 Hz, 2H, H-2), 3.59 (ddd, J = 3.2 Hz, 4.8 Hz, 9.2 Hz, 2H, H-5), 3.50 (s, 6H, OMe), 2.11 (s, 6H, OAc), 2.07 (s, 6H, OAc), 2.05 (s, 6H, OAc) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.7, 170.4, 169.3, 100.6, 72.6, 71.9, 66.4, 62.4, 58.84, 56.8, 20.8, 20.7, 20.6 ppm. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C26H38O16S2Na 693.1499, found 693.1495. Methyl 2,3,6-tri-O-acetyl-4-S-acetyl-α-D-glucopyranoside (29). To a solution of methyl 2,3,6-tri-O-acetyl-α-D-galactopyranoside (1.23 g, 3.85 mmol) in CH2Cl2 was added pyridine (760 mg) at −30 °C. Trifluoromethanesulfonic anhydride (2.73 g) in CH2Cl2 (20 mL) was added dropwise, and the mixture was stirred while allowing to warm from −30 to 10 °C for 2 h. The resulting mixture was subsequently diluted with CH2Cl2 and washed with 1 M HCl, aqueous NaHCO3, water, and brine. The organic phases were dried with MgSO4 and concentrated in vacuo at low temperature. The residue was solved in dry DMF (5.0 mL) which was used directly in the next step. KSAc (1.5 equiv) was added to the solution. After stirring at room temperature for 24 h under nitrogen atmosphere, the mixture was diluted by ethyl acetate, and washed with brine. The organic phases were dried with MgSO4 and concentrated in vacuo. Purification of the residue by flash column chromatography (ethyl acetate/ petroleum ether 1:3) afforded compound 29 (1.06 g, 73%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ = 5.44 (dd, J = 10.0 Hz, 11.2 Hz, 1H, H-3), 4.98 (d, 1H, J = 3.6 Hz, H-1), 4.93 (dd, J = 3.6 Hz, 10.0 Hz, 1H, H-2), 4.37 (dd, J = 5.2 Hz, 12.4 Hz, 1H, H-6a), 4.16 (dd, J = 2.0 Hz, 12.4 Hz, 1H, H-6b), 4.00 (ddd, J = 1.6 Hz, 4.8 Hz, 6.8 Hz, 1H, H5), 3.78 (t, J = 11.2 Hz, 1H, H-4), 3.40 (s, 3H, OMe), 2.33 (s, 3H, SAc), 2.10 (s, 3H, OAc), 2.06 (s, 3H, OAc), 2.00 (s, 3H, OAc) ppm; 12618

DOI: 10.1021/acs.joc.7b02367 J. Org. Chem. 2017, 82, 12613−12623

Article

The Journal of Organic Chemistry C NMR (100 MHz, CDCl3) δ = 192.6, 170.8, 170.2, 169.9, 97.1, 72.1, 68.5, 68.4, 63.1, 55.4, 43.8, 30.7, 20.8, 20.7, 20.6 ppm. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H22O9SNa 401.0882, found 401.0871. Bis(methyl 2,3,6-tri-O-acetyl-4-thio-4-deoxy-α-D-glucopyranoside)-4,4′-disulfide (30). To a solution of methyl 2,3,6-tri-Oacetyl-4-S-acetyl-α-D-glucopyranoside 29 (50 mg, 0.13 mmol) in CH3CN (1 mL) was added I2 (84 mg, 0.33 mmol) and NIS (74 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 2.5 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were washed with 5% Na2S2O3, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:3) afforded the disulfide 30 as colorless oil (35 mg, 78% yield). 1H NMR (400 MHz, CDCl3) δ = 5.48 (t, J = 10.4 Hz, 2H, H-3), 4.90 (d, J = 3.6 Hz, 2H, H-1), 4.56 (dd, J = 3.6 Hz, 10.4 Hz, 2H, H-2), 4.54 (dd, J = 2.0 Hz, 12.0 Hz, 2H, H-6a), 4.37 (dd, J = 4.4 Hz, 12.4 Hz, 2H, H6b), 3.99−3.90 (m, 2H, H-5), 3.39 (s, 6H, OMe), 3.07 (t, J = 10.4 Hz, 2H, H-4), 2.15 (s, 6H, OAc), 2.13 (s, 6H, OAc), 2.05 (s, 6H, OAc) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.8, 170.2, 169.6, 97.1, 72.2, 69.3, 68.2, 63.1, 55.6, 29.6, 20.9, 20.8, 20.7 ppm. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C26H38O16S2Na 693.1499, found 693.1487. Bis(methyl 2,3,6-tri-O-benzoyl-4-thio-4-deoxy-α-D-glucopyranoside-)-4,4′-disulfide (32). To a solution of methyl 2,3,6-tri-Obenzoyl-4-S-acetyl-α-D-glucopyranoside 3122 (65 mg, 0.12 mmol) in CH3CN (1 mL) was added I2 (73 mg, 0.29 mmol) and NIS (65 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 2.5 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were washed with 5% Na2S2O3, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:3) afforded the disulfide 32 as colorless oil (47 mg, 79% yield). 1H NMR (400 MHz, CDCl3) δ = 8.08−7.94 (m, 12H, Ph), 7.58−7.30 (m, 18H, Ph), 5.94 (t, J = 10.0 Hz, 2H, H-3), 5.13−5.07 (m, 4H, H-1, H2), 4.92 (d, J = 11.6 Hz, 2H, H-6a), 4.51 (dd, J = 6.4 Hz, 11.6 Hz, 2H, H-6b), 4.32−4.19 (m, 2H, H-5), 3.32 (s, 6H, OMe), 3.31−3.20 (m, 2H, H-4) ppm; 13C NMR (100 MHz, CDCl3) δ = 166.1, 165.9, 165.5, 133.5, 133.4, 133.1, 129.9, 129.9, 129.8, 129.7, 129.3, 129.0, 128.6, 128.5, 128.4, 96.9, 77.2, 73.0, 69.9, 68.8, 64.2, 55.5 ppm. HRMS (ESITOF) m/z [M + Na]+ calcd for C56H50O16S2Na 1065.2438, found 1065.2440. Methyl 2,3,6-tri-O-pivaloyl-4-S-acetyl-α-D-glucopyranoside (33). To a solution of the methyl 2,3,6-tri-O-pivaloyl-α-D-galactopyranoside (0.5 g, 1.12 mmol) in CH2Cl2 was added pyridine (221 mg) at −30 °C. Trifluoromethanesulfonic anhydride (0.8 g) in CH2Cl2 (10 mL) was added dropwise, and the mixture was stirred while allowing to warm from −30 to 10 °C for 2 h. The resulting mixture was subsequently diluted with CH2Cl2 and washed with 1 M HCl, aqueous NaHCO3, water, and brine. The organic phases were dried with MgSO4 and concentrated in vacuo at low temperature. The residue was solved in dry DMF (5.0 mL) which was used directly in the next step. KSAc (1.5 equiv) was added to the solution. After stirring at room temperature for 24 h under nitrogen atmosphere, the mixture was diluted by ethyl acetate, and washed with brine. The organic phases were dried with MgSO4 and concentrated in vacuo. Purification of the residue by flash column chromatography (ethyl acetate/ petroleum ether, 1:4−1:7) afforded methyl compound 33 (423 mg, 75%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ = 5.46 (t, J = 10.0 Hz, 1H, H-3), 4.97 (d, J = 3.6 Hz, 1H, H-1), 4.81 (dd, J = 3.6 Hz, 10.0 Hz, 1H, H-2), 4.29 (dd, J = 2.0 Hz, 12.0 Hz, 1H, H-6a), 4.21 (dd, J = 5.6 Hz, 12.0 Hz, 1H, H-6b), 4.06−3.95 (m, 1H, H-5), 3.80 (t, J = 10.0 Hz, 1H, H-4), 3.38 (s, 3H, OMe), 2.31 (s, 3H, SAc), 1.23 (s, 9H, OPiv), 1.16 (s, 9H, OPiv), 1.11 (s, 9H, OPiv) ppm; 13C NMR (100 MHz, CDCl3) δ = 192.5, 178.1, 177.6, 176.9, 96.9, 72.1, 68.5, 67.7, 63.3, 55.5, 43.9, 38.8, 38.7, 38.7, 30.5, 27.1, 27.0, 26.9 ppm. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C24H40O9SNa 527.2291, found 527.2298. 13

Bis(methyl 2,3,6-tri-O-pivaloyl-4-thio-4-deoxy-α-D-glucopyranoside)-4,4′-disulfide (34). To a solution of methyl 2,3,6-tri-Opivaloyl-4-S-acetyl-α-D-glucopyranoside 33 (65 mg, 0.13 mmol) in CH3CN (1 mL) was added I2 (82 mg, 0.325 mmol) and NIS (73 mg, 0.325 mmol). The reaction mixture was stirred at room temperature for 2.5 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were washed with 5% Na2S2O3, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/ petroleum ether = 1:7) afforded the disulfide 34 as colorless oil (53 mg, 89% yield). 1H NMR (400 MHz, CDCl3) δ = 5.51 (t, J = 10.0 Hz, 2H, H-3),4.92 (d, J = 3.6 Hz, 2H, H-1), 4.79 (d, J = 12.0 Hz, 2H, H6a), 4.70 (dd, J = 3.6 Hz, 10.0 Hz, 2H, H-2), 4.44 (dd, J = 7.2 Hz, 12.0 Hz, 2H, H-6b), 4.09−4.00 (m, 2H, H-5), 3.32 (s, 6H, OMe), 2.88 (t, J = 10.0 Hz, 2H, H-4), 1.23 (s, 18H, OPiv), 1.19 (s, 18H, OPiv), 1.16 (s, 18H, OPiv) ppm; 13C NMR (100 MHz, CDCl3) δ = 177.9, 177.8, 176.9, 96.7, 72.4, 68.7, 68.0, 63.7, 55.5, 38.9, 38.8, 38.7, 27.3, 27.2, 26.9 ppm. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C44H74O16S2Na 945.4316, found 945.4327. Methyl 2,4,6-tri-O-pivaloyl-3-S-acetyl-β-D-gulopyranoside (35). To a solution of methyl 2,4,6-tri-O-pivaloyl-β-D-galactopyranoside (0.3 g, 0.67 mmol) in CH2Cl2 was added pyridine (133 mg) at −30 °C. Trifluoromethanesulfonic anhydride (0.48 g) in CH2Cl2 (5 mL) was added dropwise, and the mixture was stirred while allowing to warm from −30 to 10 °C for 2 h. The resulting mixture was subsequently diluted with CH2Cl2 and washed with 1 M HCl, aqueous NaHCO3, water, and brine. The organic phases were dried with MgSO4 and concentrated in vacuo at low temperature. The residue was solved in dry toluene (3.0 mL), which was used directly in the next step. TBASAc (5.0 equiv) was added to the solution. After stirring at room temperature for 24 h under nitrogen atmosphere, the mixture was diluted by ethyl acetate, and washed with brine. The organic phases were dried with MgSO4 and concentrated in vacuo. Purification of the residue by flash column chromatography (ethyl acetate/ petroleum ether, 1:10) afforded compound 35 (251 mg, 81%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ = 5.14 (dd, J = 4.8 Hz, 6.8 Hz, 1H, H-2), 5.04 (dd, J = 2.4 Hz, 4.8 Hz, 1H, H-4), 4.50 (d, J = 6.8 Hz, 1H, H-1), 4.36 (dd, J = 4.8 Hz, 1H, H-3), 4.27 (dd, J = 7.6 Hz, 11.2 Hz, 1H, H-6a), 4.20−4.06 (m, 2H, H-6b, H-5), 3.52 (s, 3H, OMe), 2.38 (s, 3H, SAc), 1.28 (s, 9H, OPiv), 1.21 (s, 9H, OPiv), 1.18 (s, 9H, OPiv) ppm; 13C NMR (100 MHz, CDCl3) δ = 191.3, 178.0, 176.9, 176.7, 100.6, 71.8, 69.4, 68.3, 62.1, 56.7, 43.7, 39.1, 38.8, 38.7, 30.6, 27.1, 27.0, 26.9 ppm. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C24H40O9SNa 527.2291, found 527.2294. Bis(methyl 2,4,6-tri-O-pivaloyl-3-thio-3-deoxy-β-D-gulopyranoside)-3,3′-disulfide (36). To a solution of methyl 2,4,6-tri-Opivaloyl-3-S-acetyl-β-D-gulopyranoside 35 (68 mg, 0.14 mmol) in CH3CN (1 mL) was added I2 (86 mg, 0.34 mmol) and NIS (76 mg, 0.34 mmol). The reaction mixture was stirred at room temperature for 2.5 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were washed with 5% Na2S2O3, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:10) afforded the disulfide 36 as colorless oil (55 mg, 89% yield). 1H NMR (400 MHz, CDCl3) δ = 5.30 (dd, J = 2.0 Hz, 4.8 Hz, 2H, H-4), 5.05 (dd, J = 4.8 Hz, 7.6 Hz, 2H, H-2), 4.60 (d, J = 7.6 Hz, 2H, H-1), 4.37 (ddd, J = 2.0 Hz, 4.8 Hz, 8.0 Hz, 2H, H-5), 4.31 (dd, J = 8.0 Hz, 11.2 Hz, 2H, H-6a), 4.21 (dd, J = 4.8 Hz, 11.2 Hz, 2H, H-6b), 3.72 (t, J = 4.8 Hz, 2H, H-3), 3.51 (s, 6H, OMe), 1.26 (s, 18H, OPiv), 1.25 (s, 18H, OPiv), 1.23 (s, 18H, OPiv) ppm; 13C NMR (100 MHz, CDCl3) δ = 178.0, 177.0, 176.9, 99.5, 70.4, 69.7, 69.1, 62.5, 56.7, 39.0, 38.9, 38.7, 27.2, 27.1, 27.0 ppm. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C44H74O16S2Na 945.4316, found 945.4322. 2,3,4,6-Tetra-O-acetyl-1-thio-α-D-mannopyranose (37).9f To a solution of bis(2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranosyl)1,1′-disulfide 2 (81 mg, 0.11 mmol), in DMF (1.0 mL) was added TCEP·HCl (48 mg, 0.17 mmol). The reaction mixture was stirred at room temperature for 30 min. When TLC indicated full conversion of 12619

DOI: 10.1021/acs.joc.7b02367 J. Org. Chem. 2017, 82, 12613−12623

Article

The Journal of Organic Chemistry

5.35 (dd, J = 3.0 Hz, 0.8 Hz, 1H, H-4’), 5.18 (t, J = 9.6 Hz, 1H, H-3), 5.10 (dd, J = 9.6 Hz, 8.0 Hz, 1H, H-2), 4.94 (dd, J = 9.6 Hz, 3.0 Hz, 1H, H-3′), 4.88 (dd, J = 9.6 Hz, 8.0 Hz, 1H, H-2’), 4.58−4.36 (m, 3H, H-1, H-1′, H-6’a), 4.22−4.00 (m, 3H, H-6a, H-6b, H-6’b), 3.87 (m, 1H, H-5′), 3.80 (dd, J = 10.0 Hz, 9.6 Hz, 1H, H-4), 3.64 (ddd, J = 10.0 Hz, 5.2 Hz, 2.0 Hz, 1H, H-5), 2.26 (d, J = 9.6 Hz, 1H, SH), 2.16 (s, 3H, OAc), 2.14 (s, 3H, OAc), 2.08 (s, 3H, OAc), 2.07 (s, 3H, OAc), 2.06 (s, 3H, OAc), 2.05 (s, 3H, OAc), 1.97 (s, 3H, OAc) ppm. 3,4,6-Tri-O-acetyl-1-thio-2-acetamido-2-deoxy-β-D-glucopyranose (42).9f To a solution of bis(3,4,6-tri-O-acetyl-2-N-acetyl-1thio-β-D-glucosamine)-1,1′-disulfide 22 (56 mg, 0.08 mmol), in DMF (0.5 mL) was added TCEP·HCl (34 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 1 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/ petroleum ether = 1:1) afforded the glycosyl thiol 42 as colorless oil (53 mg, 96% yield). 1H NMR (600 MHz, CDCl3) δ = 6.05 (d, J = 9.6 Hz, 1H, NH), 5.15−5.08 (m, 2H, H-4, H-3), 4.63 (t, J = 10.0 Hz, 1H, H-1), 4.23 (dd, J = 12.4 Hz, 4.8 Hz, 1H, H-6a), 4.16−4.08 (m, 2H, H6b, H-2), 4.72 (ddd, J = 2.4 Hz, 4.8 Hz, 9.6 Hz, 1H, H-5), 2.56 (d, J = 10.0 Hz, 1H, SH), 2.09 (s, 3H, OAc), 2.04 (s, 3H, OAc), 2.02 (s, 3H, OAc), 1.98 (s, 3H, OAc) ppm. Methyl 2,3,4-tri-O-acetyl-6-thio-α-D-glucopyranoside (43).6a To a solution of bis(methyl 2,3,4-tri-O-acetyl-6-thio-α-D-glucopyranoside)-6,6′-disulfide 4 (87 mg, 0.13 mmol), in DMF (1.0 mL) was added TCEP·HCl (55 mg, 0.19 mmol). The reaction mixture was stirred at room temperature for 30 min. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/ petroleum ether = 1:4) afforded the glycosyl thiol 43 as colorless oil (85 mg, 98% yield). 1H NMR (400 MHz, CDCl3) δ = 5.45 (t, J = 10.0 Hz, 1H, H-3), 4.98 (dd, J = 9.6 Hz, 1H, H-4), 4.92 (d, J = 3.6 Hz, 1H, H-1), 4.85 (dd, J = 3.6 Hz, 10.0 Hz, 1H, H-2), 3.85 (td, J = 5.2 Hz, 10.0 Hz, 1H, H-5), 3.43 (s, 3H, OMe), 2.66−2.59 (m, 2H, H-6a, H6b), 2.06 (s, 3H, OAc), 2.03 (s, 3H, OAc), 1.99 (s, 3H, OAc), 1.74 (t, J = 8.4 Hz, 1H, SH) ppm. Methyl 2,3,4-tri-O-acetyl-6-thio-β-D-glucopyranoside (44). To a solution of bis(methyl 2,3,4-tri-O-acetyl-6-thio-β-D-glucopyranoside)-6,6′-disulfide 6 (90 mg, 0.13 mmol), in DMF (1.0 mL) was added TCEP·HCl (55 mg, 0.19 mmol). The reaction mixture was stirred at room temperature for 30 min. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/ petroleum ether = 1:4) afforded the glycosyl thiol 44 as colorless oil (86 mg, 95% yield).1H NMR (400 MHz, CDCl3) δ = 5.20 (t, J = 9.6 Hz, 1H, H-3), 5.04−4.94 (m, 2H, H-2, H-4), 4.45 (d, J = 8.0 Hz, 1H, H-1), 3.57 (ddd, J = 4.8 Hz, 6.0 Hz, 10.4 Hz, 1H, H-5), 3.54 (s, 3H, OMe), 2.70−2.64 (m, 2H, H-6a, H-6b), 2.05 (s, 3H, OAc), 2.04 (s, 3H, OAc), 2.00 (s, 3H, OAc), 1.79 (t, J = 8.0 Hz, 1H, SH) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.3, 169.6, 169.5, 101.5, 74.4, 72.8, 71.4, 71.2, 57.1, 26.2, 20.7, 20.7, 20.6 ppm. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for C13H20O8SNa 359.0777, found 359.0789. Methyl 2,3,4-tri-O-acetyl-6-thio-α-D-galactopyranoside (45). To a solution of bis(methyl 2,3,4-tri-O-acetyl-6-thio-α-D-galactopyranoside)-6,6′-disulfide 8 (52 mg, 0.08 mmol), in DMF (0.5 mL) was added TCEP·HCl (34 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 30 min. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/ petroleum ether = 1:4) afforded the glycosyl thiol 45 as colorless oil (51 mg, 98% yield). 1H NMR (400 MHz, CDCl3) δ = 5.52 (dd, J = 1.2 Hz, 3.6 Hz, 1H, H-4), 5.36 (dd, J = 3.6 Hz, 10.8 Hz, 1H, H-3), 5.14

the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:4) afforded the glycosyl thiol 37 as colorless oil (78 mg, 97% yield). 1H NMR (400 MHz, CDCl3) δ = 5.56 (d, J = 6.4 Hz, 1H, H-1), 5.38−5.27 (m, 3H, H-2, H-3, H-4), 4.42−4.34 (m, 1H, H-5), 4.30 (dd, J = 12.0 Hz, 4.8 Hz, 1H, H-6a), 4.12 (dd, J = 12.0 Hz, 2.0 Hz, 1H, H-6b), 2.28 (d, J = 6.4 Hz, 1H, SH), 2.17 (s, 3H, OAc), 2.11 (s, 3H, OAc), 2.06 (s, 3H, OAc), 2.00 (s, 3H, OAc) ppm. 2,3,4,6-Tetra-O-acetyl-1-thio-β-D-glucopyranose (38).9f To a solution of bis(2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranosyl)-1,1′disulfide 14 (94 mg, 0.13 mmol), in DMF (1.0 mL) was added TCEP· HCl (57 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 30 min. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:4) afforded the glycosyl thiol 38 as colorless oil (91 mg, 97% yield). 1H NMR (400 MHz, CDCl3) δ = 5.19 (t, J = 9.6 Hz, 1H, H-3), 5.10 (t, J = 9.6 Hz, 1H, H-4), 4.97 (t, J = 9.6 Hz, 1H, H-2), 4.54 (t, J = 9.6 Hz, 1H, H1), 4.25 (dd, J = 12.5 Hz, 4.8 Hz, 1H, H-6a), 4.13 (dd, J = 12.5 Hz, 2.4 Hz, 1H, H-6b), 3.73 (ddd, J = 9.6 Hz, 4.8 Hz, 2.4 Hz, 1H, H-5), 2.31 (d, J = 9.6 Hz, 1H, SH), 2.10 (s, 3H, OAc), 2.08 (s, 3H, OAc), 2.02 (s, 3H, OAc), 2.01 (s, 3H, OAc) ppm. 2,3,4,6-Tetra-O-acetyl-1-thio-β-D-galactopyranose (39).9f To a solution of bis(2,3,4,6-tetra-O-acetyl-6-thio-β-D-galactopyranosyl)1,1′-disulfide 16 (50 mg, 0.07 mmol), in DMF (0.5 mL) was added TCEP·HCl (30 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for 30 min. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:4) afforded the glycosyl thiol 39 as colorless oil (49 mg, 98% yield). 1H NMR (600 MHz, CDCl3) δ = 5.45 (dd, J = 3.6 Hz, 0.8 Hz, 1H, H-4), 5.20 (t, J = 10.0 Hz, 1H, H-2), 5.04 (dd, J = 10.0 Hz, 3.6 Hz, 1H, H-3), 4.55 (t, J = 10.0 Hz, 1H, H-1), 4.17−4.12 (m, 2H, H-6a, H-6b), 3.96 (ddd, J = 6.8 Hz, 0.8 Hz, 1H, H-5), 2.39 (d, J = 10.0 Hz, 1H, SH), 2.18 (s, 3H, OAc), 2.11 (s, 3H, OAc), 2.07 (s, 3H, OAc), 2.01 (s, 3H, OAc) ppm. 2,3,4,6-Tetra-O-acetyl-1-thio-β-D-mannopyranose (40).9f To a solution of bis(2,3,4,6-tetra-O-acetyl-1-thio-β-D-mannopyranosyl)1,1′-disulfide 18 (92 mg, 0.13 mmol), in DMF (1.0 mL) was added TCEP·HCl (55 mg, 0.19 mmol). The reaction mixture was stirred at room temperature for 30 min. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:4) afforded the glycosyl thiol 40 as colorless oil (89 mg, 97% yield). 1H NMR (600 MHz, CDCl3) δ = 5.45 (dd, J = 3.2 Hz, 0.8 Hz, 1H, H-2), 5.24 (t, J = 10.0 Hz, 1H, H-4), 5.09 (dd, J = 10.0 Hz, 3.2 Hz, 1H, H-3), 4.90 (dd, J = 9.6 Hz, 0.8 Hz, 1H, H-1), 4.26 (dd, J = 12.4 Hz, 5.6 Hz, 1H, H-6a), 4.15 (dd, J = 12.4 Hz, 2.4 Hz, 1H, H-6b), 3.72 (ddd, J = 10.0 Hz, 5.6 Hz, 2.4 Hz, 1H, H-5), 2.55 (d, J = 9.6 Hz, 1H, SH), 2.25 (s, 3H, OAc), 2.11 (s, 3H, OAc), 2.06 (s, 3H, OAc), 2.00 (s, 3H, OAc) ppm. 2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl-(1 → 4)-2,3,6tri-O-acetyl-1-thio-β-D-glucopyranose (41).9f To a solution of bis(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl(1 → 4)-2,3,6-tri-O-acetyl-1-thio-β-D-glucopyranose)-1,1′-disulfide 20 (85 mg, 0.07 mmol), in DMF (1.0 mL) was added TCEP·HCl (29 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for 1 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/petroleum ether = 1:2) afforded the glycosyl thiol 41 as colorless oil (81 mg, 96% yield). 1H NMR (400 MHz, CDCl3) δ = 12620

DOI: 10.1021/acs.joc.7b02367 J. Org. Chem. 2017, 82, 12613−12623

Article

The Journal of Organic Chemistry (dd, J = 3.6 Hz, 10.8 Hz, 1H, H-2), 4.98 (d, J = 3.6 Hz, 1H, H-1), 3.98 (m, 1H, H-5), 3.45 (s, 3H, OMe), 2.70 (ddd, J = 8.0 Hz, 10.0 Hz, 14.0 Hz, 1H, H-6a), 2.47 (ddd, J = 5.6 Hz, 10.0 Hz, 14.0 Hz, 1H, H-6b), 2.16 (s, 3H, OAc), 2.09 (s, 3H, OAc), 1.99 (s, 3H, OAc), 1.63 (dd, J = 7.6 Hz, 10.0 Hz, 1H, SH) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.5, 170.4, 169.9, 97.2, 70.3, 69.2, 68.2, 67.8, 55.6, 24.5, 20.9, 20.6 ppm. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for C13H20O8SNa 359.0777, found 359.0782. Methyl 2,3,4-tri-O-acetyl-6-thio-β-D-galactopyranoside (46). To a solution of bis(methyl 2,3,4-tri-O-acetyl-6-thio-β-D-galactopyranoside)-6,6′-disulfide 10 (50 mg, 0.08 mmol), in DMF (0.5 mL) was added TCEP·HCl (34 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 30 min. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/ petroleum ether = 1:4) afforded the glycosyl thiol 46 as colorless oil (49 mg, 98% yield). 1H NMR (400 MHz, CDCl3) δ = 5.50 (d, J = 0.8 Hz, 3.2 Hz, 1H, H-4), 5.19 (dd, J = 8.0 Hz, 10.4 Hz, 1H, H-2), 5.03 (dd, J = 3.2 Hz, 10.4 Hz, 1H, H-3), 4.40 (d, J = 8.0 Hz, 1H, H-1), 3.69 (t, J = 6.8 Hz, 1H, H-5), 3.54 (s, 3H, OMe), 2.79 (ddd, J = 6.8 Hz, 8.0 Hz, 14.0 Hz, 1H, H-6a), 2.54 (ddd, J = 6.8 Hz, 10.0 Hz, 14.0 Hz, 1H, H-6b), 2.16 (s, 3H, OAc), 2.06 (s, 3H, OAc), 1.99 (s, 3H, OAc), 1.64 (dd, J = 8.0 Hz, 10.0 Hz, 1H, SH) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.5, 170.1, 169.6, 102.1, 75.1, 71.1, 68.9, 68.0, 57.1, 24.3, 20.8, 20.7, 20.6 ppm. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for C13H20O8SNa 359.0777, found 359.0787. Methyl 2,3,4-tri-O-acetyl-6-thio-α-D-mannopyranoside (47). To a solution of bis(methyl 2,3,4-tri-O-acetyl-6-thio-α-D-mannopyranoside)-6,6′-disulfide 12 (108 mg, 0.16 mmol), in DMF (1.0 mL) was added TCEP·HCl (68 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 30 min. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/ petroleum ether = 1:4) afforded the glycosyl thiol 47 as colorless oil (105 mg, 97% yield). 1H NMR (400 MHz, CDCl3) δ = 5.31 (dd, J = 3.6 Hz, 10.0 Hz, 1H, H-4), 5.26−5.15 (m, 2H, H-2, H-3), 4.70 (d, J = 1.2 Hz, 1H, H-1), 3.82 (ddd, J = 2.4 Hz, 4.8 Hz, 10.0 Hz, 1H, H-5), 3.45 (s, 3H, OMe), 2.77−2.66 (m, 1H, H-6a), 2.66−2.57 (m, 1H, H6b), 2.15 (s, 3H, OAc), 2.06 (s, 3H, OAc), 1.99 (s, 3H, OAc), 1.81 (dd, J = 6.8 Hz, 10.0 Hz, 1H, SH) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.1, 169.9, 169.9, 98.4, 71.1, 69.6, 69.1, 68.9, 55.3, 26.2, 20.9, 20.8, 20.7 ppm. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for C13H20O8SNa 359.0777, found 359.0783. Methyl 2,3,6-tri-O-acetyl-4-thio-α-D-glucopyranoside (48). To a solution of bis(methyl 2,3,6-tri-O-acetyl-4-thio-α-D-glucopyranoside)-4,4′-disulfide 30 (50 mg, 0.08 mmol), in DMF (0.5 mL) was added TCEP·HCl (34 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 1.5 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/ petroleum ether = 1:4) afforded the glycosyl thiol 48 as colorless oil (48 mg, 96% yield). 1H NMR (400 MHz, CDCl3) δ = 5.29 (t, J = 10.0 Hz, 1H, H-3), 4.95 (d, J = 3.6 Hz, 1H, H-1), 4.84 (dd, J = 3.6 Hz, 10.0 Hz, 1H, H-2), 4.52−4.43 (m, 2H, H-6a, H-6b), 3.86 (dt, J = 3.2 Hz, 10.8 Hz, 1H, H-5), 3.40 (s, 3H, OMe), 2.88 (q, J = 10.8 Hz, 1H, H-4), 2.12 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.07 (s, 3H, OAc), 1.51 (d, J = 10.0 Hz, 1H, SH) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.7, 170.3, 170.1, 97.2, 71.9, 71.9, 74.4, 63.5, 55.4, 40.8, 20.8, 20.8, 20.7 ppm. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for C13H20O8SNa 359.0777, found 359.0790. Methyl 2,3,6-tri-O-benzoyl-4-thio-α-D-glucopyranosyl (49). To a solution of bis(methyl 2,3,6-tri-O-benzoyl-4-thio-α-D-glucopyranoside)-4,4′-disulfide 32 (109 mg, 0.11 mmol), in DMF (1.0 mL) was added TCEP·HCl (45 mg, 0.16 mmol). The reaction mixture was

stirred at room temperature for 1 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/ petroleum ether = 1:4) afforded the glycosyl thiol 49 as colorless oil (104 mg, 96% yield). 1H NMR (400 MHz, CDCl3) δ = 8.15−7.90 (m, 6H, Ph), 7.65−7.31 (m, 9H, Ph), 5.88−5.76 (m, 1H, H-3), 5.25−5.15 (m, 2H, H-1, H-2), 4.85−4.72 (m, 2H, H-6a, H-6b), 4.15 (dt, J = 3.6 Hz, 10.8 Hz, 1H, H-5), 3.45 (s, 3H, OMe), 3.20 (q, J = 10.8 Hz, 1H, H-4), 1.70 (d, J = 10.0 Hz, 1H, SH) ppm; 13C NMR (100 MHz, CDCl3) δ = 166.3, 166.0, 165.9, 133.4, 133.3, 129.9, 129.8, 129.8, 129.4, 129.1, 128.5, 128.4, 128.4, 97.4, 72.9, 72.7, 71.7, 64.2, 55.6, 41.3 ppm. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for C28H26O8SNa 545.1246 , found 545.1249. Methyl 2,3,6-tri-O-pivaloyl-4-thio-α-D-glucopyranosyl (50). To a solution of bis(methyl 2,3,6-tri-O-pivaloyl-4-thio-α-D-glucopyranoside)-4,4′-disulfide 34 (53 mg, 0.06 mmol), in DMF (0.5 mL) was added TCEP·HCl (44 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 6 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/ petroleum ether = 1:8) afforded the glycosyl thiol 50 as colorless oil (50 mg, 95% yield). 1H NMR (400 MHz, CDCl3) δ = 5.34 (t, J = 10.0 Hz, 1H, H-3), 4.94 (d, J = 3.6 Hz, 1H, H-1), 4.73 (dd, J = 3.6 Hz, 10.0 Hz, 1H, H-2), 4.53 (dd, J = 2.0 Hz, 12.0 Hz, 1H, H-6a), 4.36 (dd, J = 5.6 Hz, 12.0 Hz, 1H, H-6b), 3.88 (ddd, J = 2.0 Hz, 5.6 Hz, 10.0 Hz, 1H, H-5), 3.38 (s, 3H, OMe), 2.81 (q, J = 10.0 Hz, 1H, H-4), 1.44 (d, 1H, J = 10.0 Hz, SH), 1.23 (s, 9H, OPiv), 1.20 (s, 9H, OPiv), 1.16 (s, 9H, OPiv) ppm; 13C NMR (100 MHz, CDCl3) δ = 178.1, 177.7, 177.2, 97.0, 71.9, 71.5, 71.4, 63.8, 55.5, 41.3, 38.9, 38.8, 38.7, 27.2, 27.0 ppm. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for C22H38O8SNa 485.2185, found 485.2179. Methyl 2,4,6-tri-O-pivaloyl-3-thio-β-D-glucopyranosyl (51). To a solution of bis(methyl 2,4,6-tri-O-pivaloyl-3-thio-β-D-gulopyranoside)-3,3′-disulfide 36 (55 mg, 0.06 mmol), in DMF (0.5 mL) was added TCEP·HCl (43 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 6 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/ petroleum ether = 1:8) afforded the glycosyl thiol 51 as colorless oil (52 mg, 95% yield). 1H NMR (400 MHz, CDCl3) δ = 4.98−4.85 (m, 2H, H-2, H-4), 4.60 (d, J = 7.6 Hz, 1H, H-1), 4.53−4.45 (m, 1H, H-5), 4.26 (dd, J = 7.6 Hz, 11.2 Hz, 1H, H-6a), 4.12 (dd, J = 6.4 Hz, 11.2 Hz, 1H, H-6b), 3.80 (dd, J = 4.0 Hz, 9.6 Hz, 1H, H-3), 3.52 (s, 3H, OMe), 1.68 (d, 1H, J = 9.6 Hz, SH), 1.26 (s, 9H, OPiv), 1.24 (s, 18H, OPiv), 1.20 (s, 9H, OPiv) ppm; 13C NMR (100 MHz, CDCl3) δ = 177.9, 177.3, 177.0, 99.1, 71.5, 69.7, 69.5, 69.1, 62.0, 56.9, 39.5, 39.1, 39.0, 38.7, 27.2, 27.1, 27.0 ppm. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C22H38O8SNa 485.2185, found 485.2195. Methyl 3,4,6-tri-O-acetyl-2-thio-α-D-mannopyranoside (52). To a solution of bis(methyl 3,4,6-tri-O-acetyl-2-thio-α-D-mannopyranoside)-2,2′-disulfide 24 (110 mg, 0.16 mmol), in DMF:H2O (2:1, 1.5 mL) was added TCEP·HCl (184 mg, 0.64 mmol). The reaction mixture was stirred at 50 °C for 6 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/ petroleum ether = 1:4) afforded the glycosyl thiol 52 as colorless oil (83 mg, 75% yield). 1H NMR (400 MHz, CDCl3) δ = 5.42−5.32 (m, 2H, H-3, H-4), 4.84 (s, 1H, H-1), 4.23 (dd, J = 4.8 Hz, 12.0 Hz, 1H, H-6a), 4.13 (dd, J = 2.0 Hz, 12.0 Hz, 1H, H-6b), 4.01−3.90 (m, 1H, H-5), 3.58 (dd, J = 3.2 Hz, 9.2 Hz, 1H, H-2), 3.40 (s, 3H, OMe), 2.11 (s, 3H, OAc), 2.08 (s, 3H, OAc), 2.05 (s, 3H, OAc), 1.77 (d, J = 9.2 Hz, 1H, SH) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.7, 170.1, 12621

DOI: 10.1021/acs.joc.7b02367 J. Org. Chem. 2017, 82, 12613−12623

Article

The Journal of Organic Chemistry

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169.6, 102.2, 70.1, 68.7, 65.7, 62.4, 55.4, 42.4, 20.9, 20.8, 20.7 ppm. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for C13H20O8SNa 359.0777, found 359.0786. Methyl 3,4,6-tri-O-acetyl-2-thio-β-D-mannopyranoside (53). To a solution of bis(methyl 3,4,6-tri-O-acetyl-2-thio-α-D-mannopyranoside)-2,2′-disulfide 26 (63 mg, 0.1 mmol), in DMF:H2O (2:1, 1.5 mL) was added TCEP·HCl (108 mg, 0.38 mmol). The reaction mixture was stirred at 50 °C for 12 h. When TLC indicated full conversion of the starting material, the resulting mixture was diluted with water, then extracted with CH2Cl2. The combined organic phases were dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (ethyl acetate/ petroleum ether = 1:4) afforded the glycosyl thiol 53 as colorless oil (48 mg, 76% yield). 1H NMR (400 MHz, CDCl3) δ = 5.41 (t, J = 9.6 Hz, 1H, H-4), 5.08 (dd, J = 4.4 Hz, 9.2 Hz, 1H, H-3), 4.63 (d, J = 1.6 Hz, 1H, H-1), 4.27 (dd, J = 4.8 Hz, 12.0 Hz, 1H, H-6a), 4.18 (dd, J = 2.4 Hz, 12.0 Hz, 1H, H-6b), 3.78 (td, J = 1.6 Hz, 5.6 Hz, 1H, H-2), 3.66 (ddd, J = 2.4 Hz, 4.8 Hz, 9.6 Hz, 1H, H-5), 3.55 (s, 3H, OMe), 2.10 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.05 (s, 3H, OAc), 1.87 (d, J = 5.6 Hz, 1H, SH), ppm; 13C NMR (100 MHz, CDCl3) δ = 170.7, 170.1, 169.6, 102.2, 70.1, 68.7, 65.7, 62.4, 55.4, 42.4, 20.9, 20.7, 20.7 ppm. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for C13H20O8SNa 359.0777, found 359.0785. Spectroscopic data of known products were in accordance with those reported in the literature.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02367. 1 H NMR and 13C NMR spectra of compounds 2−53 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Hai Dong: 0000-0002-9794-1805 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was supported by the National Nature Science Foundation of China (Nos. 21772049). REFERENCES

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DOI: 10.1021/acs.joc.7b02367 J. Org. Chem. 2017, 82, 12613−12623

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DOI: 10.1021/acs.joc.7b02367 J. Org. Chem. 2017, 82, 12613−12623