Selective acylation and sulfonylation of 4,6-O -benzylidene-1-deoxy- 1-(2-oxo-2-phenylethyl)- β - D -glucopyranose

Selective acylation and sulfonylation of 4,6-O -benzylidene-1-deoxy-1-(2-oxo-2-phenylethyl)- β - D -glucopyranose were systematically studied by introducing different electrophiles under the action of catalysts DMAP or Ag 2 O. As a result, 18 novel mono-protected compounds at the 2-or 3-position of the C -glucoside were prepared and their structures were confirmed by 1 H-NMR, 13 C-NMR, 2D NOEs and HRMS analysis. The results showed that electrophiles play a significant role in determining the product distribution


Introduction
Considerable efforts have been devoted to the synthesis of C-glycosyl compounds owing to their natural occurrence, biological interest, and synthetic utility. 1 C-Glycosides are of special interest because of their conformational differences compared to O-glycosides or N-glycosides; they are resistant to enzymatic and acidic hydrolysis since the anomeric center has been transformed from acetal to ether. 2 In the past few decades, the regioselective manipulation of carbohydrate hydroxyl groups has been addressed with challenging strategies.The presence of multiple reactive sites on saccharide molecules means the synthesis of carbohydrate derivatives often relies on extensive protecting group manipulations or bio-enzyme methods 3 .Oligosaccharides with 1-2 and/or 1-3 linkages are abundant in nature 4,5 such as SLeX analogs, 6 Globo-H, 7 and other bioactive oligosaccharides. 8,9ppropriate protected glycosides with one free hydroxyl group at the 2-or 3-position are very useful building blocks for the synthesis of bioactive oligosaccharide.Therefore we studied the regioselective protection of 2-or 3-position which have similar reactivity in carbohydrate derivatives with great interest.Nevertheless, small differences between the reactivity of 2-or 3position can be utilized to achieve the desired protection pattern in one or a few steps. 10Most studies had been focused on changing the hydrogen bond to an activated hydroxyl group at specific sites, 11 such as, methods employing DMAP 12,13 or functionalized DMAP, 14 organoboron, 15 organotin, 16 organosilicon, 17 The procedure also involves the use of inorganic catalysts like Ag 2 O, 18 metal salts 19 and chiral copper(II) complex 20 .However, such strategies are, for the most part, dependent on O-glycosides, regioselective strategies for C-glycosides are very limited in the literature.The accessibility of new building blocks by an efficient and simple way represents an outstanding challenge in glycochemistry.Therefore, the preparation of selectively protected monosaccharide units bearing a single strategically positioned free hydroxyl group (a nucleophilic acceptor) symbolizes a breakthrough in carbohydrate synthesis together with the stereoselective glycosylation 21,22 .
Our team has been engaged in the exploration of using simple sugar to synthesize corresponding drug intermediates, such as the synthesis of natural product D-mannoheptulose, 23 the stereocontrolled formation of protected aminodeoxyalditols, 24 synthesis of topiramate 25 and asymmetric catalyst derived from D-fructose. 26 Originally we reported the efficient synthesis of aryl ketone β-C-glycosides, 27 studying the regioselectivity of such compounds could make ways for the synthesis of bioactive oligosaccharides which can expand their application range.In this paper, we chose two different catalysts, DMAP and Ag 2 O, due to their lower toxicity and easy availability.We reasoned that electrophilic reagents with different steric and electronic effects could modulate the reactivity of the secondary hydroxyl groups which is an important method to evaluate the regioselectivity using these two catalysts under mild conditions.

Synthesis of the substrate
Benzylidene, as widely used in carbohydrate chemistry, was chosen as the 4,6-O protecting group to selectively mask the C-4 and C-6 hydroxy groups.The selective cleavage of the 4,6-Obenzylidene group with various reagents allows entry into three types of structure. 28The scheme used to prepare the benzylidene derivatives 3 is shown in Scheme 1, the approach is based on reported produres. 27,29heme 1.General synthetic scheme to prepare target C-glycoside 3 from D-glucose 1 Acetylation as a model reaction First, the relative reactivity of the free hydroxyl groups of partially protected D-glucose derivatives was assessed using acetylation as a model reaction.The parameters that can affect the regioselectivity of the reaction are the reaction conditions and the chemical nature of the protecting groups.Solvents like CH 2 Cl 2 , THF, CH 3 CN and CHCl 3 , widely used for glycosylation reaction that we wish to model, were chosen.As a result, acylation of the compound 3 gave a mixture of monosubstituted and fully substituted products in which the 3-O functionalized derivatives predominated.The data summarized in Table 1 clearly indicates that the solvent effect were negligible since similar regioselectivities were achieved.There's no improvement to the regioselectivity when increase the polarity of the solvent.By comparison of the results in entry 1 with the others in Table 1, dichloromethane appeared to be the most suitable solvent.

Effect of different electrophilic reagents
The effect of various electrophilic reagents was another factor we considered and the results were summarized in Table 2.All reactions proceeded effectively under the same conditions: at 25 ºC catalyzed by either DMAP or Ag 2 O. Conversion rates between 70 to 95% were observed.
The data summarized in Table 2 clearly indicated the differentiation of the reactivity of each hydroxyl, as well as the existence of steric and electronic effects of the electrophiles.To our surprise, these electrophiles showed a higher preference for position 3 except for tosylation, using DMAP or Ag 2 O as the catalyst.In the case of tosylation, the C-2-protected product was predominant and no fully protected product was formed (Table 2, entries 15, 16).Accordingly, we presume that steric hindrance was involved.To verify the guess, we tried mesylation, which has relative lower steric hindrance.As a result, C-3, as expected, was preferentially protected and the fully protected product arose (Table 2, entries 17, 18), which was different from tosylation.
Then we further studied introduction of the benzenesulfonyl group; the result was the same as ptoluenesulfonylation with C-2-protected product predominant; data are not reported in Table 2.
Thus we came to the conclusion that sulfonylation with higher steric hindrance, such as tosylation, may preferentially generate the C-2 substituted compound, after which the C-3 position was more difficult to substitute, and thus no fully protected products were generated.The nature and position of substituents in the aromatic ring result in effects on the regioselectivity.The amount of C-3-protected products was slightly enhanced in the case of the substituted aromatic ring with the electron-withdrawing substituent groups (i.e., p-chloro, m-nitro and 3,5-dinitro groups).Data collected in Table 2 also revealed that C-3-protected products increased or C-2-protected products decreased (the ratio of a/b decreased) with the increase of the steric hindrance in acylation.Eventually, results indicated that strong electron-withdrawing and higher steric hindrance lead regioselectivity product to 3-substituted ester in acylation.

Structure assignment
The mono-substituted products which are of comparable reactivity were evaluated by 1 H NMR. Changes in chemical shifts of crucial signals in starting materials and products were compared for structure characterization and product identification.NMR signal of H-2′ in regioselectivity product 2-OAc (3a) was obviously shifted downfield from 3.50 ppm to 5.00 ppm, together with the adjacent proton signals of H-1′ and H-3′ from 4.10 ppm to 4.30 ppm and 3.81 ppm to 4.00 ppm respectively.We also got the NOESY spectrum (500 MHz, CDCl 3 ) of products 8b and 10a for further confirmation.NOEs signals indicated spatial proximity of H-1′, H-3′ and H-5′ on one side of the ring and of H-2′ and H-4′ on the other side, respectively.We can see the NOE correlation at the same side.The significant nuclear NOE correlation between H-3′ (not H-2′) with H-5′ and H-3′ with H-1′ in 8b and the downfield shifted signal of H-3′ indicated that compound 8b were 3-OAc (Figure 1), other NOE correlation can also be found.Similarly, a significant nuclear Overhauser effect between H-2′ with H-4′ can be observed in compound 10a (Figure 2), and the other relevant signal can also be found, all of these indicated that compound 10a was 2-OTs not 3-OTs.

Experimental Section
General.Melting points were determined in open glass capillaries using a Griffin melting point apparatus.Solvents were distilled and dried by standard methods.All commercially available reagents were used without further purification.The progress of the reactions was monitored by thin-layer chromatography (TLC) over silica gel, and spots were visualized with UV light or iodine. 1 H, 13 C NMR and NOESY spectra were recorded in CDCl 3 or DMSO-d 6 on a Bruker Avance III 500MHz spectrometer.Proton chemical shifts are reported in ppm relative to the internal standard tetramethylsilane (δ TMS = 0 ppm) or solvents (δ DMSO = 2.50 ppm), and carbon chemical shifts are reported in ppm relative to the solvents (δ CDCl3 = 77.00,δ DMSO = 39.7).Data were recorded and evaluated using TOPSPIN 3.1 (Bruker Biospin).All chemical shifts are given in ppm relative to tetramethylsilane.The resonance multiplicity is indicated as s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), m (multiplet), or combinations of these.HRMS spectra analyses were performed on an Agilent 6540Q-TOF MS.

Table 1 .
Optimization of solvent for acetylation reaction