University of Groningen
Regioselective modification of carbohydrates for their application as building blocks in
synthesis
Zhang, Ji
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Zhang, J. (2019). Regioselective modification of carbohydrates for their application as building blocks in synthesis. Rijksuniversiteit Groningen.
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Chapter 6
Protecting group-free reductive chlorination of
glycosides via trityl hydrazones
The chapter focuses on the reductive chlorination of glycosides at C3.
Catalytic oxidation of glycosides is carried out with [(neocuproine)Pd(
μ
-OAc)]
2[OTf]
2to afford 3-ketone glycosides selectively, followed by the
transformation to the corresponding 3-trityl hydrazones with trityl
hydrazine HCl salt. The addition of tBuOCl to the 3-trityl hydrazone leads
to a diazene, which is unstable and decomposes upon heating. The
formed
-chloro radical formed accepts a hydrogen from a suitable
hydrogen donor and provides the 3-chloro glycoside as an epimeric
mixture.
6.1 Introduction
In the chemistry of monosaccharides, the conversion of a hydroxyl group into a leaving group is a frequently applied procedure. The leaving group, either a sulfonate ester(preferably triflate) or halogen (except for fluoride), is used to invert the stereochemistry at that position, for the synthesis of aminosugars1-2, thiosugars3-4 or deoxysugars5 and even to construct a glycosidic bond in the preparation of oligosaccharides.6-7 In special cases, as in artificial sweeteners, the chloro substituent is part of the final product.8 In order to obtain regioselectivity, a protecting group strategy is mostly used to single out the desired hydroxyl group. This is illustrated in Scheme 1, Panel A, for the synthesis of 3-chloro glucose.9-12 Although it would be more efficient to directly convert one of the hydroxyl groups in glucose into a good leaving group, in the presence of the other hydroxyl groups, up till now this has shown to be very problematic.
Panel A: Reported chlorination of glycosides via protection and deprotection
Panel B: Our reductive chlorination with glycosides Scheme 1. Reductive chlorination of glycosides
Although a series of recent papers showed the (more or less) regioselective esterification or etherification of hydroxyl groups in readily available monosaccharides,13-15 this apparently did not work for sulfonate ester synthesis. Besides, esters and ethers are not good leaving groups.
As shown in the previous chapters, selective oxidation of the C3-hydroxyl group in common pyranosides is now readily achieved.16-21 I have shown that this carbonyl function could be converted by reduction, reductive amination and in carbon-carbon bond forming reactions in the presence of the other hydroxyl groups. It would be very fruitful if the regioselectivity of this catalytic oxidation could be used for selective introduction of a leaving group. However, for this to happen, a method is required to convert ketones directly into a leaving group--in essence a reduction combined with a substitution. The common approach, namely reduction of the ketone to a hydroxyl group followed by its conversion into a leaving group is obviously not feasible here! Methods that effect this synthetic transformation are rare in literature, and procedures with demonstrated compatibility with hydroxyl groups are absent.
In 2016, the group of Rawal reported a study on the reductive chlorination of trityl hydrazones.22 The work built on much older work by sir Jack E. Baldwin et al. who studied the reactivity of (trityl) hydrazones.23 Upon treatment with tert-butyl hypochlorite, trityl hydrazones act as nucleophiles on carbon and form an intermediate diazo compound (Scheme 2).22 This intermediate is not stable and decomposes, forming the relatively stable trityl radical, dinitrogen, and the corresponding α-chloro radical. If a suitable hydrogen atom donor is present, the product is the corresponding chloride.22
Scheme 2. Reductive chlorination (for the mechanism see Figure 3).
We hypothesized that this method could meet the challenge of the selective introduction of a leaving group in unprotected carbohydrates. All the more so because we have shown already that hydrazone formation in our substrates is successful. (Figure 1) In this chapter it is shown that the approach as reported by Reyes and Rawal can be applied successfully to prepare 3-chloro substituted mono- and disaccharides from the corresponding keto saccharides.
Here we will report a method to introduce a chlorine substituent at C3 of glycosides based on site-selective palladium-catalyzed oxidation of unprotected glycosides (Scheme 1 Panel B).
. Catalytic oxidation of glycosides
Reductive chlorination of a trityl hydrazone
Figure 1. Catalytic oxidation of glycosides and reductive chlorination of a trityl hydrazone
6.2 Results and discussion
Synthesis of the starting glucosides
The scope of the substrates varies from monosaccharides to disaccharides as shown in Table 1. For convenience in the purification, we introduced a bulky group at the anomeric carbon of 1, 4 and 5 to make the substrate less polar. Monosaccharide 1 is synthesized from N-acetyl glucosamine with isopropyl alcohol and acetyl chloride (to generate HCl in situ) at reflux. Substrates 2 and 3 can be prepared in methanol mixed with Amberlite 120 H+ at reflux.
Disaccharide substrate 4 and 5 are synthesized via the route as shown Scheme 3.D-maltose and D-cellobiose were peracetylated using acetic anhydride and a catalytic amount of perchloric acid. Selective deacetylation at the anomeric position in 22 and 26 with methylamine gave the products 23 and 27 in 56% and 53% isolated yield over two steps respectively. The free hydroxyl function in 23 and in 27 was reacted with benzyl bromide in the presence of Ag2O to obtain the
-anomer of 24 and 28, as the major product. A small amount of -anomer was formed as well, but it could be removed by column chromatography. The reactions were slow and took 72 h at room temperature. De-acetylation of 19 and
24 in the presence of a catalytic amount of NaOMe in methanol afforded 4 and 5
in yields over 90%.
Oxidation of the glycosides and preparation of the trityl hydrazones
Having prepared the required starting materials, we started to carry out the oxidation of the substrates. Generally, the oxidation reactions are performed in DMSO, CH3CN/H2O or DMSO/1,4-dioxane, but the removal of these solvents after the reaction is time consuming. In an attempt to simplify purification, the oxidation of 1 was performed in trifluoroethanol according to Waymouth et al.13 Upon completion of the reaction, trifluoroethanol could be removed in vacuo and the crude was purified by flash column to afford 3-keto GlcNAc 6 with 89% yield. We next focused our attention on the oxidation of the other glycosides depicted in the table. In the meantime it had been found in our group that also MeOH can be used as the solvent in the selective catalytic oxidation of methyl α-D-glucopyranoside with only 0.5 mol% of catalyst and 1.25 eq benzoquinone. These conditions provide full conversion within 1 h and therefore the same conditions were applied for methyl α-D-xylopyranoside to afford 8. This was successful and the methanol was readily removed. The compound turned out to be a crystalline solid and crystals suitable for X-ray diffraction were obtained. The structure is provided in Fig. 5. Remarkably, the use of methanol as solvent in the oxidation of 1, benzyl -D-maltoside 4 and benzyl -D-cellobioside 5 made the reactions very slow. In trifluoroethanol, side products were formed as well, except in the case of 1, and therefore the oxidations were carried out with in a mixture of DMSO and 1,4-dioxane (4:1) which provided the products pure and in good yields.
Next, the keto products were converted into the corresponding 3-trityl hydrazones.
Table 1: Preparation of 3-trityl hydrazone
# Substrate 3-ketone 3-trityl hydrazone
1
3
4
5
Dissolving the ketones 6-10 in a mixture of water, MeOH and DCM and reacting the mixture with trityl hydrazine HCl salt in the presence of NaOAc provided the trityl hydrazones smoothly as a mixture of E/Z isomers. Note that trityl hydrazine has to be prepared from trityl chloride and hydrazine and is not stable as its free base. As HCl salt its stability is sufficient. The E and Z isomers of 13 and 15 could be separated and I was able to grow crystals of the E-isomer of 13 suitable for X-ray (Fig 4). The trityl hydrazones 12 and 13 give the Z isomer as the major isomer, the E/Z ratio of 12 and 13 is 1 : 3 and 0.6 : 1, respectively. For the trityl hydrazones 14 and 15, NMR showed overlap in the diagnostic signals so it was not possible to determine accurately the ratio of E/Z. It was shown that the E and Z isomers of 11 slowly interconvert. Upon dissolution of pure Z-11 in deutero methanol, only one set of signals is observed but over a period of 8 days this changed into a (E/Z 1 : 5) ratio of both isomers.
Reductive chlorination of the trityl hydrazones
To prepare the desired chlorides, we subjected the trityl hydrazones to the conditions described by Rawal.22 Trityl hydrazone 11 was studied first. This hydrazone was reacted with (prepared) tBuOCl at -20 °C to form the chlorodiazene. Thermolysis of the chlorodiazene in the presence of an excess of EtSH as the hydrogen donor at 40 °C afforded a major product in 69% yield that according to mass analysis indeed contained one chloride. NMR-analysis established the structure of 16 as a mixture of epimers but with a clear preference for the equatorial chloride. Excited about this result, we next applied the same reaction conditions to trityl hydrazone 12. Instead of the 3-chloro glucoside, however, we isolated the thioether 29 as the major product. Only small amounts of the 3-chloride were isolated as shown in figure 2. In other words, EtSH did not
only serve as the H-atom donor, but also performed a nucleophilic substitution on the chloride. A similar result was obtained when trityl hydrazone 13 was subjected to the same conditions. Given the large excess of EtSH used and the fact that thiols are very good nucleophiles, this undesired follow-up reaction is not so surprising (in facts its absence in the reaction with substrate 11 is more surprising). To overcome this undesired side reaction, it was essential to find a new suitable H-atom donor for these and the other substrates.
Figure 2. Reductive chlorination of trityl hydrazone 7 with EtSH
According to a review by Renaud et al.24 thiols are efficient H-atom donors. This, and given the observation that Reyes and Rawal apparently required such a large excess of EtSH, made us focusing on thiols as well. We tried to find an alkyl thiol that serves as H-atom donor, but is bulky enough to avoid subsequent substitution of the chloride. Thermolysis of the chlorodiazene in the presence of tBuSH was carried out, and gratifyingly, this time there was no substitution product observed and the 3-chloro products were isolated in moderate to good yields. Therefore, also the other substrates depicted in the Table 2 were subjected to these new reaction conditions and all the products were obtained in good yield as a mixture of “allo and gluco” configured 3-chlorides. Interestingly, the diastereomeric ratio of the products differed quite drastically in the shift from EtSH to tBuSH. Reductive chlorination of 11 in the presence of EtSH gave preferentially the 3-equatorial chloride with a ratio of approximately 3:1. On the contrary, the axial chloride is the major product when substrates
12-15 (entries 2 to 5 in table 2) were reacted under the new reaction conditions with
tBuSH. In order to establish the configuration of the products beyond reasonable
doubt (literature NMR data on chloro-substituted carbohydrates is scarce), X-ray structures of both 3-axial 16 and 3-axial 17 were determined (Fig 4).
We speculated that after the decomposition of the chlorodiazene and formation of the -chlorocarbinyl radical, the bulky tert-butyl thiol prefers to transfer its hydrogen atom from the top face of the ring as shown in Fig. 3B. This is due to the steric shielding of the bottom face by the axial substituent on the
anomeric position. We therefore expected that the stereochemical outcome in the reaction of 11 with EtSH would invert upon the use of tBuSH.
Table 2: Reductive chlorination of 3-trityl hydrazones
# Substrate product Yield[%] ratio of equitorial and axial 1 69%a (3:1) (1:0.7)b 2 67% b (1:3.5) 3 51% b (1:3.5) 4 56% b (1:2.5) 5 61% b (1:2.5)
[a] Method A: trityl hydrazone (0.5 mmol), t-BuOCl (1.1 eq), EtSH (80 eq), THF, 0.1 M. [b] Method B: trityl hydrazone (0.5 mmol), t-BuOCl (1.1 eq), t-BuSH (80 eq), THF, 0.1 M.
Figure 3. Proposed mechanism for the formation of 11 and 12
We observed, however, that the ratio of the equatorial and axial chloride changed from 3 : 1 to 1 : 0.7. This means the 3-equatorial chloride is still the major product in this particular case (Fig. 3A). Apparently, the structure of the substrate also plays an important role in the outcome of the reaction of the radical with the H-donor. In substrate 12 to 15, the substituents at C2 and C4 are all equatorial hydroxyl groups, but in 11, the substituent at C2 is an equatorial acetamide group. Apparently this makes a difference although it is not clear how. There is an intriguing analogy with the observation that reduction of 3-keto N-acetyl glucosamine with NaBH4 produces mainly the NAc-glucosamine whereas the same reaction with 3-keto glucose produces allose with reasonable selectivity. An in depth study is required to establish whether these observations are connected. In order to study the influence of the temperature on the diastereomeric ratio in the products, we used substrate 12 as a model substrate. After the corresponding chlorodiazene had formed, thermolysis in the presence of tBuSH at 40 °C, 50 °C and 60 °C was carried out, and the results are shown in table 3. It is clear that the selectivity for the axial chloride increases with temperature, a trend (increasing selectivity with increasing temperature) that is somewhat counterintuitive, in particular if the selectivity should arise from steric hindrance.
Temperature Yield Ratio of equatorial and axial
40°C 44% 1 : 2.2
50°C 67% 1 : 3.3
60°C 66% 1 : 3.5
The reaction was carried out on 0.5 mmol scale
The isomers of 16, 17 and 18 could be separated by column chromatography. For the products 19 and 20, only the 3-axial chloride was isolated pure.
6.3 Conclusion
In conclusion, we have developed a novel method for the site-selective (regioselective) reductive chlorination of glycosides. Our methodology involves site-selective palladium-catalyzed oxidation of glycosides, conversion of the 3-ketose to the corresponding trityl hydrazone, and reductive chlorination of this trityl hydrazone with tert-butyl hypochlorite and ethane thiol or tert-butyl thiol. The 3-chloro saccharides are obtained as mixtures of the equatorial and the axial chloride. The ratio can be influenced by the choice of the H-atom donor and the temperature. Most of the products with an axial chloride can be obtained pure, we are currently trying to isolate also the equatorial chloride disaccharides from the mixture. Additional experiments can be designed to figure out how to influence the ratio of equatorial and axial reductive chlorination. As we mentioned in the previous part, EtSH acts as a nucleophile substituting the chloride in the case of trityl hydrazone 7. NMR shows that upon substitution, a mixture of equatorial and axial thioether product is obtained, but it was not possible to determine the ratio from the NMR spectrum of the mixture. Probably HPLC is a better technique to approach this problem. Admittedly, the large excess of tBuSH currently used in the reaction is also not ideal, in particular because of its impressive stench. It should be noted that the mechanism of the thermolysis reaction, a homolytic fragmentation, should be studied as well. Although Reyes and Rawal provide evidence for a radical mechanism, an ionic mechanism is difficult to rule out as the trityl cation and a carbanion next to a chloride are both readily formed. This pathway could provide an alternative rationale for the observed diastereoselectivity. Nevertheless, the excellent regio- and site selectivity of the palladium-catalyzed oxidation has been transferred to the introduction of a leaving group at the same position. This leaving group in principle can be used in substitution reactions, of which the formation of
glycosidic bonds and the introduction of 18F (for PET studies) are probably the most exciting. The fact that this reductive chlorination can be carried out on disaccharides (and therefore probably also on oligosaccharides as well) strongly adds to the applicability of the method.
8 8 (E)-trityl hydrazone 13 (E)-trityl hydrazone 13 16 (3-axial) 16 (3-axial)
17 (3-axial)
17 (3-axial)
Figure 4. X-ray structure of 8, (E)-13, 16 (3-axial) and 17 (3-axial)
6.4 Experimental Section
6.4.1 General information
All solvents used for reaction, extraction, filtration, and chromatography were of commercial grade and used without further purification. [(neocuproine)Pd(μ-OAc)]2(OTf)2 was prepared according to the literature procedure25. Flash chromatography was performed on a Reveleris® X2 Flash Chromatography, using Grace® Reveleris Silica flash cartridges (4 grams, 12 grams, 15 grams, 24 grams, 40 grams, 80 grams and 120 grams) and Scorpius Diol (OH) 48 grams. 1 H-, 13C-, APT-, HSQC-, and COSY-NMR were recorded on a Varian AMX400 spectrometer (400, 100 MHz, respectively) using DMSO-d6, D2O or methanol-d4 as solvent. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (DMSO-d6: δ 2.50 for 1H, δ 39.52 for 13C, CD3OD: δ 3.31 for 1H, δ 49.15 for 13C; D2O: δ 4.80 for 1H). Data are reported as follows: chemical shifts (δ), multiplicity (s = singlet, d = doublet, dd = double doublet, ddd = double double doublet, t = triplet, appt = apparent triplet, q =quartet, m = multiplet), coupling constants J (Hz), and integration. High Resolution Mass measurements were performed using a ThermoScientific LTQ OribitrapXL spectrometer.
6.4.2 Synthesis procedure
2,3,6,2',3',4',6'-Hepta-O-acetyl-maltose (23)
To a stirred suspension of D-maltose (5 g, 14.6 mmol) in acetic anhydride (25 mL) at 0 °C was added HClO4 (3 drops, 70% aq.) dropwise. The mixture was stirred at room temperature for 1 h, after which the solution was diluted with EtOAc (200 mL). The solution was washed with NaHCO3(aq) and brine, and dried over MgSO4. The organic layer was concentrated in vacuo to afford the crude per-acetylated product, which was dissolved in THF (100 mL) and treated with methylamine solution (40% in water, 2.5 mL). The reaction was stirred at room temperature till complete consumption of D-maltose octylacetate was observed, the reaction mixture was concentrated in vacuo and purified by flash column on a 120 g silica cartridge with pentane/EtOAc (linear gradient: 0 to 90% EtOAc in 35 min, the product eluted at 56% EtOAc). The product was obtained as a white solid (5.35 g, 58%). The spectral data matched literature.26 HRMS (ESI) m/z calcd for C26H36O18Na[M+Na]+: 659.1794; found: 659.1773; 1H NMR (400 MHz, Chloroform-d) δ 5.57 (dd, J = 10.1, 8.9 Hz, 1H), 5.42 (d, J = 4.0 Hz, 1H), 5.36 – 5.33 (m, 2H), 5.06 (t, J = 9.9 Hz, 1H), 4.85 (dd, J = 10.5, 4.0 Hz, 1H), 4.76 (dd, J = 10.1, 3.5 Hz, 1H), 4.52 – 4.45 (m, 1H), 4.29 – 4.18 (m, 3H), 4.04 (dd, J = 12.5, 2.4 Hz, 1H), 3.99 – 3.94 (m, 2H), 2.13 (s, 3H), 2.09 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 170.7, 170.63, 170.58, 170.2, 169.95, 169.94, 169.5, 95.5, 90.0, 72.6, 72.3, 71.5, 70.0, 69.4, 68.4, 68.0, 67.7, 62.8, 61.4, 20.9, 20.8, 20.7, 20.7, 20.6, 20.6. Benzyl--D-heptaacetyl-maltoside (24)
To an anomeric mixture of 2,3,6,2',3',4',6'-hepta-O-acetyl-maltose (4.72 g, 7.41 mmol) suspended in acetonitrile (35 mL) in the dark, was added silver oxide (5.15 g, 22.2 mmol) while stirring. After 15 min, benzyl bromide (2.6 mL, 22.2 mmol) was added and the mixture was left to stir for 72 h. Afterwards, the reaction mixture was diluted with dichloromethane (100 mL), filtered through a plug of celite, and evaporated in vacuo. The crude product was purified by Grace flash chromatography on a 120 g silica cartridge with eluent pentane/EtOAc (linear gradient: 0% to 60% EtOAc in 35 min; the product eluted at 40% EtOAc to yield white solid (3.97 g, 74%). HRMS (ESI) m/z calcd for C33H42O18Na [M+Na]+: 749.2263; found: 749.2261; 1H NMR (400 MHz,
5.21 (t, J = 9.1 Hz, 1H), 5.04 (t, J = 9.9 Hz, 1H), 4.92 – 4.82 (m, 3H), 4.63 – 4.55 (m, 2H), 4.50 (dd, J = 12.1, 2.8 Hz, 1H), 4.24 (ddd, J = 12.1, 4.2, 2.7 Hz, 2H), 4.07 – 3.99 (m, 2H), 3.96 (ddd, J = 10.2, 4.0, 2.4 Hz, 1H), 3.65 (ddd, J = 9.6, 4.4, 2.8 Hz, 1H), 2.15 (s, 3H), 2.10 (s, 3H), 2.02 (s, 6H), 1.99 (s, 6H), 1.98 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 170.5, 170.5, 170.2, 169.9, 169.6, 169.4, 136.6, 128.4, 128.0, 127.8, 98.7, 95.5, 75.4, 72.7, 72.1, 72.1, 70.7, 70.0, 69.3, 68.5, 68.0, 62.8, 61.5, 20.9, 20.8, 20.7, 20.6, 20.6, 20.6, 20.5. Benzyl--D-maltoside (4)
To a suspension of benzyl -D-heptaacetyl-maltoside (3.97 g, 5.46 mmol) in MeOH (55 mL) was added NaOMe (30 mg, 0.55 mmol, 0.1 equiv.). The reaction mixture was allowed to stir overnight, after which TLC (eluent: actontrile/H2O = 85/15) showed complete consumption of starting material. Amberlite 120 H+ was added to quench the reaction. The reaction was filtered and finally concentrated in vacuo to provide the crude product. Purification by Grace flash chromatography on a 40 g silica cartridge with eluent DCM/MeOH (linear gradient: 0 to 20% MeOH in 25 min; the product eluted at 15% MeOH) yielded the product as a colorless oil (2.16 g, 91%). HRMS (ESI) m/z calcd for C19H29O11 [M+H]+: 433.1704 and C19H28O11Na: 455.1529; found: 433.1717 and 455.1529; 1H NMR (400 MHz, Methanol-d4) δ 7.44 – 7.40 (m, 2H), 7.36 – 7.30 (m, 2H), 7.29 – 7.25 (m, 1H), 5.17 (d, J = 3.8 Hz, 1H), 4.92 (d, J = 11.8 Hz, 1H), 4.66 (d, J = 11.8 Hz, 1H), 4.38 (d, J = 7.8 Hz, 1H), 3.92 (dd, J = 12.2, 2.1 Hz, 1H), 3.86 – 3.80 (m, 2H), 3.72 – 3.53 (m, 5H), 3.44 (dd, J = 9.7, 3.8 Hz, 1H), 3.37 (ddd, J = 9.4, 4.8, 2.1 Hz, 1H), 3.33-3.31 (m, 1H), 3.30 – 3.24 (m, 1H). 13C NMR (101 MHz, Methanol-d4) δ 139.2, 129.4, 129.3, 128.8, 103.4, 103.0, 81.4, 78.0, 76.8, 75.2, 74.9, 74.9, 74.3, 71.9, 71.6, 62.9, 62.4. 2,3,6,2',3',4',6'-Hepta-O-acetyl-cellobiose (27)
To a stirred suspension of D-(+)-cellobiose (5 g, 14.6 mmol) in acetic anhydride (40 mL) at 0°C was added HClO4 (3 drops, 70% aq.) dropwise, after which the reaction was stirred at room temperature for 1 h. Then, the solution was diluted with EtOAc (200 mL). The resulting organic layer was washed with NaHCO3(aq) and brine and the organic layer was dried over MgSO4. The organic layer was concentrated in vacuo to afford the crude, which was dissolved in THF (100 mL) and treated with methylamine solution (40% in water, 2.5 mL). The reaction was
stirred at room temperature till complete consumption of D-(+)-cellobiose octylacetate (indicated by TLC eluent: 70% EtOAc/pentane). Upon completion, the reaction mixture was concentrated in vacuo and purified by flash column on a 80 g silica cartridge with pentane/EtOAc (linear gradient: 0 to 90% EtOAc in 35 min; the product eluted at 60% EtOAc) affording the product as a white solid (4.94 g, 53%). HRMS (ESI) m/z calcd for C26H36O18Na[M+Na]+: 659.1794; found: 659.1768; 1H NMR (400 MHz, Chloroform-d) δ 5.49 (dd, J = 10.2, 9.3 Hz, 1H), 5.35 (d, J = 3.6 Hz, 1H), 5.12 (d, J = 9.3 Hz, 1H), 5.07 (d, J = 9.7 Hz, 1H), 4.92 (dd, J = 9.1, 8.0 Hz, 1H), 4.81 (dd, J = 10.2, 3.6 Hz, 1H), 4.54-4.49 (m, 2H), 4.38-4.33 (m, 1H), 4.18-4.13 (m, 1H), 4.10 (dd, J = 11.9, 4.5 Hz, 1H), 4.04 (dd, J = 12.4, 2.2 Hz, 1H), 3.76-3.73 (m, 1H), 3.68-3.63 (m, 1H), 2.12 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 2.01 (s, 6H), 2.00 (s, 3H), 1.97 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 170.6, 170.4, 170.31, 170.27, 169.7, 169.3, 169.0, 100.6, 90.0, 76.5, 73.0, 71.9, 71.6, 71.2, 69.3, 68.2, 67.8, 61.7, 61.6, 20.9, 20.7, 20.64, 20.60, 20.53, 20.51. Benzyl--D-heptaacetyl-cellobioside (28)
To an anomeric mixture of 2,3,6,2',3',4',6'-hepta-O-acetyl-cellobiose (4.86 g, 7.64 mmol) suspended in acetonitrile (34 mL) in the dark, was added silver oxide (5.49 g, 23.7 mmol) while stirring. After 15 min, benzyl bromide (2.8 mL, 23.7 mmol) was added and the mixture left to stir for 72 h. The reaction mixture was diluted with dichloromethane (150 mL), filtered through a plug of celite, and evaporated in vacuo. The resulting crude product was purified by Grace flash on a 120 g silica cartridge with pentane/EtOAc (linear gradient: 0 to 75% EtOAc in 35 min; the product eluted at 56% EtOAc). Only part of the product (1.91 g) turned out to be pure. The remaining product fractions contained impurities and these were therefore collected, concentrated and further purified by Grace flash chromatography on a 80 g silica cartridge with DCM/EtOAc (linear gradient: 0 to 30% EtOAc in 35 min, the product eluted at 13% EtOAc to afford white solid 2.29 g). The pure product was combined with the pure product from the first column (combined yield: 4.2 g, 76%). HRMS (ESI) m/z calcd for C33H42O18Na[M+Na]+: 749.2263; found: 749.2245;
1H NMR (400 MHz, Chloroform-d) δ 7.36 – 7.29 (m, 3H), 7.28 – 7.24 (m, 2H) , 7.25 (d, J = 1.7 Hz, 1H), 5.14 (t, J = 9.4 Hz, 2H), 5.05 (t, J = 9.6 Hz, 1H), 4.97 (dd, J = 9.6, 7.9 Hz, 1H), 4.91 (dd, J = 9.3, 7.9 Hz, 1H), 4.85 (d, J = 12.3 Hz, 1H), 4.59 (d, J = 12.3
1H), 4.36 (dd, J = 12.5, 4.4 Hz, 1H), 4.10 (dd, J = 12.0, 4.9 Hz, 1H), 4.04 (dd, J = 12.4, 2.3 Hz, 1H), 3.79 (t, J = 9.5 Hz, 1H), 3.65 (ddd, J = 9.9, 4.5, 2.3 Hz, 1H), 3.56 (ddd, J = 9.9, 4.9, 2.1 Hz, 1H), 2.14 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.97 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 170.4, 170.3, 170.2, 169.8, 169.5, 169.3, 169.0, 136.6, 128.4, 128.0, 127.7, 100.7, 99.1, 76.4, 72.9, 72.7, 72.5, 72.0, 71.6, 71.5, 70.7, 67.8, 61.8, 61.5, 20.9, 20.6, 20.6, 20.52, 20.51. Benzyl--D-cellobioside (5)
To a suspension of benzyl -D-heptaacetyl-cellobiose (4.125 g, 5.676 mmol) in MeOH (57 mL) was added NaOMe (31 mg, 0.57 mmol, 0.1 equiv.) and the resulting mixture was allowed to stir overnight. TLC (eluent: actontrile/H2O = 85/15) showed complete consumption of the starting material. Amberlite 120 H+ was added to quench the reaction and the mixture was filtered. The filtrate was concentrated in vacuo to afford the product (2.47 g, 100%) as white solid. HRMS (ESI) m/z calcd for C19H29O11 [M+H]+: 433.1704; found: 433.1707; 1H NMR (400 MHz, Methanol-d4) δ 7.43 – 7.38 (m, 2H), 7.35 – 7.24 (m, 3H), 4.91 (d, J = 11.8 Hz, 1H), 4.66 (d, J = 11.8 Hz, 1H), 4.41 (d, J = 7.8 Hz, 1H), 4.38 (d, J = 7.8 Hz, 1H), 3.95 – 3.84 (m, 3H), 3.66 (dd, J = 11.9, 5.3 Hz, 1H), 3.59 (t, J = 9.1 Hz, 1H), 3.53 – 3.47 (m, 1H), 3.42 – 3.30 (m, 5H), 3.25 – 3.19 (m, 1H). 13C NMR (101 MHz, Methanol-d4) δ 139.1, 129.4, 129.3, 128.8, 104.7, 103.3, 80.9, 78.2, 78.0, 76.6, 76.5, 75.02, 74.96, 71.9, 71.5, 62.6, 62.0. Isopropyl-2-acetamido-2-deoxy-α-D-ribo-hexapyranoside-3-ulose (6) Isopropyl-2-acetamido-2-deoxy--D-glucopyranoside (3.33 g, 12.7 mmol) and benzoquinone (2.05 g, 18.97 mmol) were dissolved in 2,2,2-trifluoroethanol (126 ml). The catalyst [(neocuproine)Pd(μ-OAc)]2(OTf)2 (133 mg, 1 mol%) was added and the mixture was stirred at 60 °C for 1 h. Next, the solvent was evaporated and the crude product was purified by flash chromatography on a 80 g silica cartridge with pentane/EtOAc, (linear gradient: 0 to 100% EtOAc; the product eluted at 88% of EtOAc). The ketoproduct was obtained as a white solid (2.95 g, 89%), m.p.: 125-126 °C; HRMS (ESI) m/z calcd for C11H20NO6 ([M+H]+): 262.129 and C11H19NO6Na ([M+Na]+): 284.110 ; found: 262.129 and 284.111; 1H NMR (400 MHz, Methanol-d4) δ 5.34 (d, J = 4.2 Hz, 1H), 4.86 (dd, J = 4.4, 1.3 Hz, 1H), 4.28 (dd, J = 9.0, 1.3 Hz, 1H), 3.93 (p, J = 6.2 Hz, 1H), 3.89 – 3.79 (m, 3H), 2.03 (s, 3H), 1.19 (d, J = 6.3 Hz, 3H), 1.13 (d, J = 6.1 Hz, 3H); 13C NMR (101 MHz, methanol-d4) δ 203.9, 173.5, 99.5, 77.2, 73.9, 71.8, 62.7, 60.4, 23.5, 22.4, 21.6.
E/Z-Isopropyl-2-acetamido-2-deoxy-3-(trityl)hydrazone-α-D -ribo-hexapyranoside (11)
A 100 mL flask equipped with a magnetic stir bar was charged with Ph3CNHNH2·HCl (2.76 g, 8.88 mmol, 2.0 equiv.) and MeOH (11 mL), followed by the addition of NaOAc·3H2O (3.24 M in H2O, 2.74 mL, 8.88 mmol, 2.0 equiv.), isopropyl 2-acetamido-2-deoxy-α-D-ribo-hexapyranoside-3-ulose 6 (1.16 g, 4.44 mmol, 1.0 equiv.) and 34 mL DCM, the reaction immediately turned cloudy, and the system was subsequently evacuated and backfilled with N2 three times. Under N2 flow, away from light, the reaction was stirred overnight at ambient temperature for 24 h. Subsequently, the solvent was evaporated under reduced pressure. Purification by Grace flash chromatography on a 80 g silica cartridge with pentane/EtOAc followed by DCM/MeOH (linear gradient: 0% to 30% EtOAc in pentane in 10 min, then flush with DCM for 3 minutes, then linear gradient: 0% to 3% MeOH in DCM in 38 min, the product eluted at 2% of MeOH) provided the product (1.84 g, yield: 80%) as yellow solid. HRMS (ESI) m/z calcd for C30H35N3O5 [M+H]+: 518.2650 and C30H35N3NaO5 [M+Na]+: 540.2474; found: 518.2677 and 540.2493; 1H NMR (400 MHz, Methanol-d4) δ 7.45 – 7.02 (m, 15H), 6.46 (d, J = 6.8 Hz, 1H), 5.09 (d, J = 3.6 Hz, 1H), 4.44 (d, J = 9.8 Hz, 1H), 4.25 – 4.12 (m, 1H), 3.90 – 3.79 (m, 2H), 3.79 – 3.67 (m, 2H), 1.60 (s, 3H), 1.21 (d, J = 6.2 Hz, 3H), 1.03 (d, J = 6.1 Hz, 3H); 13C NMR (101 MHz, Methanol-d4) δ 170.8, 146.1, 135.3, 128.9, 127.2, 126.2, 95.6, 73.9, 72.7, 70.9, 69.9, 60.9, 53.7, 22.4, 21.2, 20.5. Isopropyl-2-acetmido-3-chloro-2,3-dideoxy--D-ribo-hexapyranoside (16)
An 100 mL flask equipped with a magnetic stir bar was charged with trityl hydrazone 11 (821 mg, 1.59 mmol) and THF (16 mL). The resulting light yellow green solution was evacuated and backfilled with N2 (3 times) and then cooled to -20°C (external temperature). Tert-butyl hypochlorite (1.24 M in DCM, 0.44 mL, 1.1 equiv.) at ambient temperature was added dropwise over 2 minutes to the cooled solution of hydrazone and the mixture was stirred for 15 minutes. The resulting light yellow solution was then frozen in a liquid N2 bath and degassed by two freeze-pump-thaw cycles, each time thawing in a -20°C bath. After backfilling with N2, the reaction was maintained at an external temperature ≤ -15 °C for at least 20 minutes. During this time EtSH was degassed in a separated flask by a single freeze-pump-thaw cycle. Excess EtSH (9 mL) at ambient temperature was added to the cooled reaction, and the reaction flask was subsequently transferred to a pre-heated 40 °C heating mantle. After 1.5 h, the reaction was allowed to cool to ambient temperature The solvent was evaporated and the product was purified by flash chromatography on a 24 g silica cartridge
with DCM/MeOH (linear gradient: 0 to 6% MeOH in DCM in 22 min; the product eluted at 4% MeOH). The title product was isolated as white solid (312 mg, yield: 70%, the ratio of equatorial to axial is 3:1). HRMS (ESI) m/z calcd for C11H21ClNO5 [M+H]+: 282.1103 and 284.1073; C11H21ClNO5Na [M+Na]+: 304.0922 and 306.0893; found: 282.1105, 284.1074, 304.0924 and 306.0893; 3-equatorial: 1H NMR (400 MHz, Methanol-d4) δ 4.89 (d, J = 3.4 Hz, 1H), 4.09 (dd, J = 11.6, 3.4 Hz, 1H), 4.02 (dd, J = 11.7, 8.8 Hz, 1H), 3.91 (p, J = 6.2 Hz, 1H), 3.84 – 3.66 (m, 3H), 3.55 (t, J = 9.1 Hz, 1H), 1.99 (s, 3H), 1.23 (d, J = 6.2 Hz, 3H), 1.14 (d, J = 6.1 Hz, 3H). 13C NMR (101 MHz, Methanol-d4) δ 173.4, 96.8, 74.7, 72.6, 71.5, 64.5, 62.8, 56.3, 23.7, 22.5, 21.7.
3-axial: 1H NMR (400 MHz, Methanol-d4) δ 4.86 (overlaps with the peak of CD3OD, 1H), 4.47 (t, J = 3.8 Hz, 1H), 4.42 (t, J = 4.2 Hz, 1H), 4.01-3.95 (m, 1H), 3.94 – 3.88 (m, 1H), 3.87 – 3.79 (m, 2H), 3.74 (dd, J = 11.9, 5.2 Hz, 1H), 2.04 (s, 3H), 1.24 (d, J = 6.3 Hz, 3H), 1.15 (d, J = 6.1 Hz, 3H). 13C NMR (101 MHz, Methanol-d4) δ 173.2, 96.0, 71.3, 69.1, 67.9, 64.6, 62.5, 51.2, 23.9, 22.6, 21.6.
Methyl--D-ribo-hexapyranoside-3-ulose (7)
Methyl -D-glucopyranoside (1 g, 5.15 mmol) and benzoquinone (696 mg, 6.44 mmol) were dissolved in MeOH (12.9 ml). The catalyst [(neocuproine)Pd(μ-OAc)]2(OTf)2 (27 mg, 0.5 mol%) was added and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and subsequent purification by Grace flash chromatography on a 24 g silica cartridge with pentane/EtOAc (linear gradient: 0 to 100% EtOAc in pentane in 22 min, followed by flushing with 100% EtOAc for 5 min; the product eluted with 100% EtOAc) afforded the product as a white solid (973 mg, yield: 98%). 1H NMR (400 MHz, Methanol-d4) δ 5.05 (d, J = 4.2 Hz, 1H), 4.40 (dd,
J = 4.3, 1.5 Hz, 1H), 4.22 (dd, J = 9.7, 1.5 Hz, 1H), 3.87 (dd, J = 12.1, 2.2 Hz, 1H), 3.80
(dd, J = 12.1, 4.6 Hz, 1H), 3.64 (ddd, J = 9.7, 4.7, 2.2 Hz, 1H), 3.40 (s, 3H). 13C NMR (101 MHz, Methanol-d4) δ 207.1, 104.0, 76.8, 76.2, 73.5, 62.6, 55.9.
A 100 mL flask equipped with a magnetic stir bar was charged with Ph3CNHNH2 · HCl (2.36 g, 7.58 mmol, 1.5 equiv.), NaOAc·3H2O (1.03 g, 7.58 mmol, 1.5 equiv.) and methyl--D -ribo-hexapyranoside-3-ulose (971 mg, 5.05 mmol, 1.0 equiv.). DCM (39 mL), H2O (3.1 mL) and CH3OH (12.5 mL) were added. The flask was subsequently evacuated and backfilled with N2 three times. Under N2 flow, away from light, the reaction was stirred overnight at ambient temperature for 24 h, then evaporated the solvent. Purification by Grace flash chromatography on a 80.0 g silica cartridge with pentane/EtOAc (linear gradient: 0% to 90% EtOAc in 38 min; the product eluted at 77% EtOAc) gave the hydrazone as a mixture of E/Z isomers as yellow semi solid (1.89 g, 83%), the ratio of E/Z is 1:3. HRMS (ESI) m/z calcd for C26H29N2O5 [M+H]+: 449.2071; found: 449.2072; 1H NMR (400 MHz, Methanol-d4) δ 7.36 – 7.15 (m, 15H), 4.71 (d, J = 3.7 Hz, 1H), 4.51 (d, J = 3.7 Hz, 1H), 3.72 – 3.67 (m, 2H), 3.60 (dd, J = 11.9, 5.5 Hz, 1H), 3.39 (s, 3H), 3.17 (ddd, J = 9.7, 5.5, 2.2 Hz, 1H). 13C NMR (101 MHz, Methanol-d4) δ 147.2, 141.5, 130.5, 128.7, 127.7, 102.5, 76.9, 75.1, 74.2, 68.7, 62.8, 55.5.
Methyl-3-chloro-3-deoxy-α-D-gulopyranoside (17)
An 100 mL flask equipped with a magnetic stir bar was charged with trityl hydrazone 12 (224 mg, 0.5 mmol) and THF (5 mL). The resulting light yellow green solution was evacuated and backfilled with N2 (3 times) and then cooled to -20 ℃ (external temperature).
tert-Butyl hypochlorite (1.24 M in THF, 0.443 mL, 1.1 equiv.) at ambient
temperature was added dropwise over 2 minutes to the cooled solution of hydrazone and stirred for 15 minutes. The resulting light yellow solution was then frozen in a liquid N2 bath and degassed by two freeze-pump-thaw cycles, each time thawing in a -20 ℃ bath. After backfilling with N2, the reaction was maintained at an external temperature ≤ -15 ℃ for at least 20 minutes. During this time tert-butylthiol was degassed in a separated flask by a single freeze-pump-thaw cycle. Excess tert-butylthiol (4.5 mL) at ambient temperature was added to the cooled reaction, and the reaction flask was subsequently transferred to a pre-heated 60 ℃ heating mantle. After half an hour, the reaction was allowed to cool to ambient temperature. Then the solvent was evaporated and the product was purified by Grace flash chromatography on a 15 g silica cartridge using pentane/EtOAc as eluent (linear gradient: 0 to 100% EtOAc in pentane in 20 min; the product eluted at 78% EtOAc). The product (71 mg, yield: 66%) was obtained as a colorless oil. The NMR shows the ratio of equatorial and axial is 1:3.5. HRMS (ESI) m/z calcd for C7H13ClO5Na[M+Na]+: 235.0344 and 237.0314; found: 235.0342 and 237.0312;
3-equatorial:1H NMR (400 MHz, Methanol-d4) δ 4.70 (d, J = 3.6 Hz, 1H), 3.94 (dd, J = 10.4, 9.2 Hz, 1H), 3.81 (dd, J = 11.9, 2.3 Hz, 1H), 3.71 (dd, J = 11.8, 4.9 Hz, 1H), 3.56 (dd, J = 10.4, 3.5 Hz, 1H), 3.54 – 3.51 (m, 1H), 3.50 – 3.45 (m, 1H), 3.42 (s, 3H). 13C NMR (101 MHz, Methanol-d4) δ 101.2, 74.2, 74.0, 72.2, 67.5, 62.6, 55.7. 3-axial: 1H NMR (400 MHz, Methanol-d4) δ 4.67 (d, J = 4.2 Hz, 1H), 4.50 (t, J = 3.5 Hz, 1H), 3.91 (t, J = 4.1 Hz, 1H), 3.87 – 3.78 (m, 3H), 3.72 (dd, J = 12.4, 5.4 Hz, 1H), 3.40 (s, 3H). 13C NMR (101 MHz, Methanol-d4) δ 100.8, 69.1, 69.0, 67.7, 66.8, 62.4, 56.2. Methyl -D-xylo-hexapyranoside-3-ulose (8)
Methyl -D-xylopyranoside (739 mg, 4.5 mmol) and benzoquinone (535 mg, 4.95 mmol) were dissolved in MeOH (0.4 M, 11.3 mL). The catalyst [(neocuproine)Pd(μ-OAc)]2(OTf)2 (24 mg, 0.5 mol %) was added and the mixture was stirred at rt for 1 h. After the reaction is completed as judged by TLC, the solvent was evaporated. Subsequent purification by Grace flash chromatography on a 40 g silica cartridge with pentane/EtOAc (linear gradient: 0 to 100% EtOAc in 25 min; the product eluted at 70% of EtOAc) afforded methyl -D-xylo-hexopyranoside-3-ulose as a colorless oil (520 mg, yield: 71%). 1H NMR (400 MHz, Methanol-d4) δ 5.01 (d, J = 4.3 Hz, 1H), 4.41 – 4.34 (m, 2H), 4.01 (dd, J = 10.3, 7.9 Hz, 1H), 3.58 (dd, J = 10.7, 10.1 Hz, 1H), 3.39 (s, 3H).13C NMR (101 MHz, Methanol-d4) δ 206.8, 104.6, 76.4, 73.3, 65.4, 55.9.
E/Z-Methyl-3-(trityl)hydrazone--D-xylo-hexapyranoside (13)
A 100 mL flask equipped with magnetic stir bar was charged with Ph3CNHNH2 · HCl (1.47 g, 4.74 mmol, 1.5 equiv.), NaOAc·3H2O (645 mg, 4.74 mmol, 1.5 equiv.), methyl -D -xylo-hexopyranoside-3-ulose (512 mg, 3.158 mmol, 1.0 equiv.). DCM (24 mL), H2O (1.9 mL) and CH3OH (7.8 mL) were added. The flask was subsequently evacuated and backfilled with N2 three times. Under N2 flow, away from light, the reaction was stirred overnight at ambient temperature for 24 h. Then, the solvent was evaporated. Purification by Grace flash chromatography on a 40 g silica cartridge with pentane/EtOAc (linear gradient: 0% to 50% EtOAc in 25 min; the product eluted at 25% EtOAc) provided the mixture of the E and the Z hydrazone (932 mg, yield: 71%) as yellow oil, the ratio of E/Z is 0.63:1. HRMS (ESI) m/z calcd for
C25H27N2O4 [M+H]+: 419.1965 and C25H26N2O4Na [M+Na]+: 441.1790; found: 419.1969 and 441.1788 Zisomer: 1H NMR (400 MHz, Methanol-d4) δ 7.34 – 7.18 (m, 15H), 4.64 (d, J = 3.7 Hz, 1H), 4.50 (d, J = 3.7 Hz, 1H), 3.88 (dd, J = 10.2, 6.0 Hz, 1H), 3.62 (dd, J = 10.1, 5.9 Hz, 1H), 3.37 (s, 3H), 3.11 (t, J = 10.1 Hz, 1H). 13C NMR (101 MHz, Methanol-d4) δ 147.3, 142.1, 130.5, 128.7, 127.8, 102.8, 74.9, 74.2, 68.6, 66.0, 55.6. Eisomer: 1H NMR (400 MHz, Methanol-d4) δ 7.32 – 7.16 (m, 15H), 4.58 (d, J = 3.5 Hz, 1H), 4.52 (t, J = 8.1 Hz, 1H), 3.89 (d, J = 3.5 Hz, 1H), 3.59 (d, J = 8.1 Hz, 2H), 3.31 (s, 3H). 13C NMR (101 MHz, Methanol-d4) δ 147.3, 142.1, 130.4, 128.8, 127.8, 101.8, 74.1, 71.4, 71.0, 65.3, 55.6. Methyl-3-chloro-3-deoxy--D-xylo-hexapyranoside (18)
An 100 mL flask equipped with a magnetic stir bar was charged with trityl hydrazone 13 (209 mg, 0.5 mmol) and THF (5 mL). The resulting light yellow green solution was evacuated and backfilled with N2 (3 times) and then cooled to -20 ℃ (external temperature), tert-Butyl hypochlorite (1.24 M in THF, 0.443 mL, 1.1 equiv.) at ambient temperature was added dropwise over 2 minutes to the cooled solution of hydrazone and stirred for 15 minutes. The resulting light yellow solution was then frozen in a liquid N2 bath and degassed by two freeze-pump-thaw cycles, each time thawing in a -20 ℃ bath. After backfilling with N2, the reaction was maintained at an external temperature ≤ -15 ℃ for at least 20 minutes. During this time tert-butylthiol was degassed in a separated flask by a single freeze-pump-thaw cycle. Excess tert-butylthiol (4.5 mL) at ambient temperature was added to the cooled reaction, and the reaction flask was subsequently transferred to a pre-heated 40 ℃ heating mantle. After 1 h, the reaction was allowed to cool to ambient temperature. Then, the solvent was evaporated and the crude product was purified by Grace flash chromatography on a 15 g silica cartridge using pentane/EtOAc (linear gradient: 0 to 70% EtOAc in 20 min; the product eluted at 50% EtOAc in pentane). The product was obtained as a yellow oil (47 mg, yield: 51%). The NMR shows the ratio of equatorial and axial is 1 : 3.5. HRMS (ESI) m/z calcd for C6H11ClO4Na [M+Na]+: 205.0238 and 207.0209; found: 205.0240 and 207.0210;
3-equatorial: 1H NMR (400 MHz, Methanol-d4) δ 4.63 (d, J = 3.6 Hz, 1H), 3.86 (dd, J = 10.3, 8.9 Hz, 1H), 3.66 – 3.59 (m, 2H), 3.56 – 3.51
(m, 1H), 3.49 – 3.41 (m, 1H), 3.40 (s, 3H). 13C NMR (101 MHz, Methanol-d4) δ 101.3, 74.0, 72.2, 67.1, 63.5, 55.8. 3-axial: 1H NMR (400 MHz, Methanol-d4) δ 4.44 (d, J = 2.4 Hz, 1H), 4.33 (t, J = 3.2 Hz, 1H), 3.92 (dd, J = 11.6, 6.0 Hz, 1H), 3.87 (t, J = 3.0 Hz, 1H), 3.86 – 3.83 (m, 1H), 3.50 (dd, J = 11.6, 2.7 Hz, 1H), 3.46 (s, 3H). 13C NMR (101 MHz, Methanol-d4) δ 102.2, 71.5, 69.3, 65.4, 63.1, 56.8. Benzyl--3-ketomaltoside (9)
Benzyl-β-maltose (1.07 g, 2.47 mmol, 1 equiv.) was dissolved in a dioxane/DMSO mixture (4 : 1 v/v, 8.3 mL, 0.3 M) and benzoquinone (294 mg, 2.72 mmol, 1.1 equiv.) and [(neocuproine)Pd(μ-OAc)]2(OTf)2 (26 mg, 1 mol%) were added. After 4 h, water (80 mL) was added and the mixture was lyophilized to afford the crude product. Subsequent purification by flash chromatography on a 25 g silica cartridge with DCM/MeOH (linear gradient: 0 to 10% MeOH in 20 min; the product eluted at 6% MeOH) afforded the product as a brown oil (625 mg, 59%). HRMS (ESI) m/z calcd for C19H26O11Na[M+Na]+: 453.1367; found: 453.1361; 1H NMR (400 MHz, Methanol-d4) δ 7.42-7.38 (m, 2H), 7.35 – 7.23 (m, 3H), 5.64 (d, J = 4.5 Hz, 1H), 4.91 (d, J = 11.8 Hz, 1H), 4.65 (d, J = 11.8 Hz, 1H), 4.45 (dd, J = 4.4, 1.5 Hz, 1H), 4.35 (d, J = 7.8 Hz, 1H),. 4.26 (dd, J = 9.5, 1.6 Hz, 1H), 3.91 – 3.74 (m, 5H), 3.65 – 3.54 (m, 2H), 3.35 – 3.32 (m, 1H), 3.30 – 3.26 (m, 1H). 13C NMR (101 MHz, Methanol-d4) δ 207.2, 139.1, 129.4, 129.3, 128.9, 104.9, 103.3, 80.6, 78.1, 77.7, 76.6, 76.5, 75.0, 73.4, 72.0, 62.7, 62.2.
Benzyl--3-(trityl)hydrazone maltoside (14)
A 25 mL flask equipped with magnetic stir bar was charged with Ph3CNHNH2·HCl (414 mg, 1.33 mmol, 1.5 equiv.), NaOAc·3H2O (181 mg, 1.33 mmol, 2.0 equiv.) and benzyl- -3-ketomaltoside (382 mg, 0.888 mmol, 1.0 equiv.). DCM (6.7 mL), H2O (410 μL) and CH3OH (2.3 mL) were added. The flask was subsequently evacuated and backfilled with N2 three times. Under N2 flow, away from light, the reaction was stirred overnight at ambient temperature for 48 h. Then, the solvent was evaporated. Purification by Grace flash chromatography on a 15 g silica cartridge with pentane/EtOAc (linear gradient: 0% to 30% EtOAc in 10 min) followed by flushing with DCM for 3 min, followed by DCM/MeOH (linear gradient: 0% to 4% MeOH in DCM in 20 min; the product eluted at 3% of
MeOH) provided the product as a yellow semi-solid (387 mg, yield: 64%). HRMS (ESI) m/z calcd for C38H43N2O10 [M+H]+: 687.2912; found: 687.2916; 1H NMR (400 MHz, Methanol-d4) δ 7.48 – 7.14 (m, 20H), 5.15 (d, J = 3.5 Hz, 1H), 4.93 (d, J = 11.7 Hz, 1H), 4.70 (d, J = 11.7 Hz, 1H), 4.59 (d, J = 3.9 Hz, 1H), 4.32 (d, J = 7.8 Hz, 1H), 3.85 – 3.80 (m, 1H), 3.78 – 3.71 (m, 2H), 3.71 – 3.66 (m, 1H), 3.62 (dd, J = 12.1, 5.8 Hz, 1H), 3.52-3.46 (m, 1H), 3.39 – 3.33 (m, 2H), 3.27 – 3.22 (m, 2H). 13C NMR (101 MHz, Methanol-d4) δ 147.0, 141.0, 139.0, 130.3, 130.3, 129.5, 128.90, 128.89, 127.8, 104.2, 102.9, 81.9, 78.0, 77.8, 76.5, 75.6, 74.6, 74.1, 71.8, 68.5, 62.9, 62.3.
Benzyl 3-chloro-3-deoxy--D-maltoside (19)
A 100 mL flask equipped with a magnetic stir bar was charged with trityl hydrazone 14 (343 mg, 0.5 mmol) and THF (5 mL). The resulting light yellow green solution was evacuated and backfilled with N2 (3 times) and then cooled to -20 ℃ (external temperature). Tert-Butyl hypochlorite (1.24 M in DCM, 443 μL, 1.1 equiv.) at ambient temperature was added dropwise over 2 minutes to the cooled solution of hydrazone and stirred for 15 minutes. The resulting light yellow solution was then frozen in a liquid N2 bath and degassed by two freeze-pump-thaw cycles, each time thawing in a -20℃ bath. After backfilling with N2, the reaction was maintained at an external temperature ≤ -15℃ for at least 20 minutes. During this time tert-butylthiol was degassed in a separated flask with a single freeze-pump-thaw cycle. Excess tert-butylthiol (4.5 mL) at ambient temperature was added to the cooled reaction, and the reaction flask was subsequently transferred to a pre-heated 55 ℃ heating mantle. After 1 h, the reaction was allowed to cool to ambient temperature, then the solvent was evaporated. The crude product was purified by Grace flash chromatography on a 15 g silica cartridge with DCM/MeOH (linear gradient: 0 to 5% MeOH in 20 min; the product eluted at 4% MeOH) affording the pure chlorides as a yellow oil (126 mg, yield: 56%, the ratio of equatorial and axial is 1 : 2.5). HRMS (ESI) m/z calcd for C19H27ClO10NH4 [M+NH4]+: 468.1631 and 470.1602; C19H27ClO10Na [M+Na]+: 473.1185 and 475.1156; found: 468.1633, 470.1602, 473.1182 and 475.1151. 3-axial: 1H NMR (400 MHz, Methanol-d4) δ 7.43-7.38 (m, 2H), 7.35-7.29 (m, 2H), 7.29 – 7.24 (m, 1H), 5.25 (d, J = 4.2 Hz, 1H), 4.92 (d, J = 11.8 Hz, 1H), 4.65 (d, J = 11.7 Hz, 1H), 4.51 – 4.47 (m, 1H), 4.37 (d, J = 7.8 Hz, 1H), 3.97-3.90 (m, 3H), 3.89 – 3.82 (m, 2H),
3.80-3.75 (m, 1H), 3.74-3.68 (m, 1H), 3.67 – 3.55 (m, 2H), 3.38-3.32 (m, 1H), 3.29 – 3.25 (m, 1H). 13C NMR (101 MHz, Methanol-d4) δ 139.2, 129.4, 129.3, 128.8, 103.4, 101.2, 79.5, 78.1, 76.9, 75.3, 71.9, 70.1, 69.5, 67.6, 66.5, 62.5, 62.3.
Benzyl--3-ketocellobioside (10)
Benzyl-α-cellobioside (649 mg, 1.5 mmol, 1 equiv.) was dissolved in a dioxane/DMSO mixture (4 : 1 v/v, 5 mL, 0.3 M) and benzoquinone (178 mg, 1.65 mmol, 1.1 equiv.) and Pd-catalyst (40 mg, 2.5 mol%) were added. After 8 h, water (50 mL) was added and the mixture was lyophilized to afford the crude product. Subsequent purification by flash chromatography on a 25 g silica cartridge with DCM/MeOH (linear gradient: 0 to 15% MeOH in 21 min; the product eluted at 6% MeOH) afforded the product as a brown oil (416 mg, 64%). HRMS (ESI) m/z calcd for C19H27O11 [M+H]+: 431.1548 and C19H26O11Na [M+Na]+: 453.1373; found: 431.1553 and 453.1366. 1H NMR (400 MHz, Methanol-d4) δ 7.44 – 7.39 (m, 2H), 7.36 – 7.30 (m, 2H), 7.29 – 7.23 (m, 1H), 4.91 (d, J = 11.8 Hz, 1H), 4.66 (d, J = 11.8 Hz, 1H), 4.55 (d, J = 7.9 Hz, 1H), 4.40 (d, J = 7.9 Hz, 1H), 4.25 (dd, J = 10.1, 1.8 Hz, 1H), 4.18 (dd, J = 8.0, 1.8 Hz, 1H), 3.99 – 3.82 (m, 3H), 3.78 (dd, J = 12.1, 5.0 Hz, 1H), 3.68 (t, J = 9.3 Hz, 1H), 3.56 (t, J = 9.0 Hz, 1H), 3.44 – 3.32 (m, 3H). 13C NMR (101 MHz, Methanol-d4) δ 206.8, 139.1, 129.4, 129.3, 128.9, 105.9, 103.3, 80.5, 78.4, 78.4, 76.7, 76.6, 75.0, 73.6, 72.0, 62.5, 61.7. E/Z-Benzyl-3-(trityl)hydrazone--D-cellobioside (15)
A 25 mL flask equipped with magnetic stir bar was charged with Ph3CNHNH2·HCl (414 mg, 1.33 mmol, 1.5 equiv.), NaOAc·3H2O (181 mg, 1.33 mmol, 1.5 equiv.) and benzyl β-3-ketocellobioside (382 mg, 0.888 mmol, 1.0 equiv.). DCM (6.7 mL), H2O (410 μL) and CH3OH (2.3 mL) were added. The flask was subsequently evacuated and backfilled with N2 three times. Under N2 flow, away from light, the reaction was stirred overnight at ambient temperature for 48 h. Then, the solvent was evaporated. Purification by Grace flash chromatography on a 15 g silica cartridge with pentane/EtOAc (linear gradient: 0% to 30% EtOAc in 10 min) followed by flushing with DCM for 3 min and then DCM/MeOH (linear gradient: 0% to 4% MeOH in 20 min; the product eluted at 3% of MeOH) provided the product (421 mg, 69%) as yellow semi-solid. HRMS (ESI) m/z calcd for C38H43N2O10 [M+H]+: 687.2912; found: 687.2931;
1H NMR (400 MHz, Methanol-d4) δ 7.43-7.39 (m, 2H), 7.37 – 7.25 (m, 15H), 7.23 – 7.18 (m, 3H), 4.91 (d, J = 11.8 Hz, 1H), 4.66 (d, J = 11.8 Hz, 1H), 4.37 (d, J = 7.8 Hz, 1H), 4.33 – 4.26 (m, 2H), 3.90 (dd, J = 12.0, 2.4 Hz, 1H), 3.82 (dd, J = 12.1, 4.5 Hz, 1H), 3.75 – 3.70 (m, 2H), 3.61 – 3.53 (m, 2H), 3.49 (t, J = 9.0 Hz, 1H), 3.41 – 3.32 (m, 2H), 2.86 – 2.78 (m, 1H) (m, 1H). 13C NMR (101 MHz, Methanol-d4 δ 146.9, 142.3, 139.1, 130.2, 129.4, 129.3, 128.93, 128.86, 127.8, 105.3, 103.2, 81.0, 80.1, 76.7, 76.5, 76.0, 75.0, 74.4, 71.9, 68.8, 62.7, 62.1. 1H NMR (400 MHz, Methanol-d4) δ 7.43 – 7.38 (m, 2H), 7.36 – 7.19 (m, 17H), 7.13 – 7.09 (m, 1H), 4.91 (d, J = 11.8 Hz, 1H), 4.66 (d, J = 11.8 Hz, 1H), 4.47 (d, J = 9.8 Hz, 1H), 4.37 (d, J = 7.8 Hz, 1H), 4.01 (d, J = 7.1 Hz, 1H), 3.85 (dd, J = 12.1, 2.3 Hz, 1H), 3.78 (dd, J = 11.9, 2.3 Hz, 1H), 3.74 – 3.60 (m, 3H), 3.52 – 3.40 (m, 2H), 3.37 – 3.24 (m, 3H). 13C NMR (101 MHz, Methanol-d4) δ 145.4, 141.0, 137.6, 128.7, 127.9, 127.8, 127.4, 127.3, 126.3, 104.8, 101.7, 79.5, 78.0, 75.2, 74.9, 73.4, 72.8, 71.5, 70.4, 69.4, 60.5, 60.4. Benzyl-3-chloro-3-deoxy--D-cellobioside (20)
A 100 mL flask equipped with a magnetic stir bar was charged with trityl hydrazone 15 (387 mg, 0.564 mmol), THF (5.6 mL). The resulting light yellow green solution was evacuated and backfilled with N2 (3 times) and then cooled to -20 °C (external temperature). Tert-butyl hypochlorite (1.24 M in DCM, 0.5 mL, 1.1 equiv.) at ambient temperature was added dropwise over 2 minutes to the cooled solution of hydrazone and stirred was continued for 15 minutes. The resulting light yellow solution was then frozen in a liquid N2 bath and degassed by two freeze-pump-thaw cycles, each time thawing in a -20 °C bath. After backfilling with N2, the reaction was maintained at an external temperature ≤ -15 °C for at least 20 minutes. During this time tert-butylthiol was degassed in a separated flask with a single freeze-pump-thaw cycle. Excess tert-butylthiol (6.4 mL) at ambient temperature was added to the cooled reaction, and the reaction flask was subsequently transferred to a pre-heated 40 °C heating mantle. After 1 hour, the reaction was allowed to cool to ambient temperature. Then, the solvent was evaporated and the crude product was purified by Grace flash on a 15.0 g silica cartridge with DCM/MeOH (linear gradient: 0 to 4% MeOH in 20 min; the product eluted at 3% MeOH). The product was obtained as a yellow oil (155 mg, yield: 61%, the ratio of equatorial and axial is 1:2.5). HRMS (ESI) m/z calcd for C19H28ClO10 [M+H]+: 451.1366 and 453.1336; C19H27ClO10NH4 [M+NH4]+: 468.1631 and 470.1602; C19H27ClO10Na [M+Na]+:
473.1185 and 475.1156; found: 451.1380, 453.1336, 468.1644, 470.1613, 473.1185 and 475.1161. 3-axial: 1H NMR (600 MHz, Methanol-d4) δ 7.43-7.39 (m, 2H), 7.35 – 7.31 (m, 2H), 7.29 – 7.25 (m, 1H), 4.92 (d, J = 11.8 Hz, 1H), 4.82 (d, J = 7.8 Hz, 1H), 4.67 (d, J = 11.8 Hz, 1H), 4.60 (t, J = 2.7 Hz, 1H), 4.39 (d, J = 7.8 Hz, 1H), 3.92 (dd, J = 12.1, 2.6 Hz, 1H), 3.89 – 3.84 (m, 4H), 3.70 – 3.66 (m, 2H), 3.61 – 3.57 (m, 1H), 3.51 (t, J = 9.0 Hz, 1H), 3.39 (ddd, J = 9.7, 4.3, 2.5 Hz, 1H), 3.33 (dd, J = 9.3, 7.9 Hz, 1H). 13C NMR (151 MHz, Methanol-d4) δ 139.1, 129.4, 129.3, 128.9, 103.3, 102.1, 80.7, 76.62, 76.60, 76.0, 74.9, 71.9, 70.9, 69.2, 67.8, 62.3, 62.0.
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