SnCl4 Promoted Efficient Cleavage of Acetal/Ketal Groups with the Assistance of Water in CH2Cl2

Acetalization and deacetalation are a pair of routine manipulations to protect and deprotect the 4- and 6-hydroxyl groups of glycosides in the synthesis of glycosyl building blocks. In this study, we found that treatment of SnCl4 with various carbohydrates containing acetal/ketal groups with the assistance of water in CH2Cl2 led to deacetalization/deketalization products in almost quantitative yields. In addition, for substrates containing both acetal/ketal and p-methoxylbenzyl groups, we also found that the p-methoxylbenzyl group was selectively cleaved by the use of a catalytic amount of SnCl4, while the acetal/ketal groups remained. Furthermore, based on this, 4,6-benzylidene glycosides can be conveniently converted to 4,6-OAc or 4-OH, 6-OAc glycosides.


Results
We first evaluated the potential of SnCl4 to rem glycosides using methyl 2,3-di-O-benzyl-4,6-O-benz model compound. Thus, 1a was allowed to react wi estingly, as the used amount of SnCl4 was gradually the yield of the deacetalation product 2 increased fr (Entries 1-3). These results seem to support an equi Scheme 1. Application of SnCl 4 -promoted cleavage of acetal/PMB in this study.

Results
We first evaluated the potential of SnCl 4 to remove the 4,6-O-benzylidene group of glycosides using methyl 2,3-di-O-benzyl-4,6-O-benzylidene-α-D-glucopyranoside 1a as a model compound. Thus, 1a was allowed to react with SnCl 4 in DCM at rt (Table 2). Interestingly, as the used amount of SnCl 4 was gradually increased from 0.2 equiv to 2.5 equiv, the yield of the deacetalation product 2 increased from 19% to a nearly quantitative yield (Entries 1-3). These results seem to support an equilibrium reaction. The reaction mechanism is proposed in Figure 1a, where the coordination of SnCl 4 to the 4,6-oxygen atoms of 1a leads to the cleavage of the benzylidene group, and the formation of the intermediate M and dichlorotoluene. However, we failed when we tried to capture dichlorotoluene by an NMR experiment to support this mechanism ( Figure S1 in SI). The fact that benzaldehyde was captured instead of dicholorotoluene supports the mechanism shown in Figure 1b, where trace amounts of water play an indispensable role in the cleavage of the benzylidene group. The mechanism also explained why it is not feasible to use a catalytic amount of SnCl 4 in the reaction. When the solvent used in the reaction was changed from DCM to the more polar methanol and acetonitrile, the yields of 2 were greatly reduced (Entry 4). The reason must be due to the competitive coordination of SnCl 4 with polar solvents. es 2022, 27,8258 of SnCl4 in the reaction. When the solvent used in the reaction the more polar methanol and acetonitrile, the yields of 2 wer The reason must be due to the competitive coordination of Sn  of SnCl4 in the reaction. When the solvent used in the reaction was changed from DCM to the more polar methanol and acetonitrile, the yields of 2 were greatly reduced (Entry 4). The reason must be due to the competitive coordination of SnCl4 with polar solvents.  As can be seen from the NMR spectrum ( Figure S1 in SI), the reaction was terminated when the trace amounts of water in the d-choloroform was consumed. We then tried using water to assist this reaction (Entries 5-8). As can be seen, optimal conditions were to use 1.2-1.5 equiv of SnCl4 and 1.0-1.5 equiv of water; reaction at rt for 10 min under these conditions led to 2 in a nearly quantitative yield (Entry 8). Similar results for Entries 5 and 6 indicate that the simultaneous addition of SnCl4 and water had no adverse effect on the yield of 2. However, methanol used as a hydrogen source instead of water in the reaction proved to be ineffective (Entry 9). The use of HCl, SnCl2, FeCl3, CuCl2 and Cu(OTf )2 instead of SnCl4 in the reaction resulted in varying degrees of reduced yields of 2 (Entries 10-12). We also envisaged that the reaction of AcCl/Ac2O with M might produce selec- As can be seen from the NMR spectrum ( Figure S1 in SI), the reaction was terminated when the trace amounts of water in the d-choloroform was consumed. We then tried using water to assist this reaction (Entries 5-8). As can be seen, optimal conditions were to use 1.2-1.5 equiv of SnCl 4 and 1.0-1.5 equiv of water; reaction at rt for 10 min under these conditions led to 2 in a nearly quantitative yield (Entry 8). Similar results for Entries 5 and 6 indicate that the simultaneous addition of SnCl 4 and water had no adverse effect on the yield of 2. However, methanol used as a hydrogen source instead of water in the reaction proved to be ineffective (Entry 9). The use of HCl, SnCl 2 , FeCl 3 , CuCl 2 and Cu(OTf ) 2 instead of SnCl 4 in the reaction resulted in varying degrees of reduced yields of 2 (Entries 10-12). We also envisaged that the reaction of AcCl/Ac 2 O with M might produce selectively acetylated products. Therefore, AcCl/Ac 2 O instead of water was added to the reaction. However, the addition of AcCl led to the formation of a complex mixture (Entry 13), and the addition of Ac 2 O led to the formation of 4,6-OAc product 2a as the main product (Entry 14), indicating poor selectiveacetylations.
We also noticed that the 4-methoxylbenzyl (PMB) protecting group could be deprotected in the presence of catalytic amounts of SnCl 4 [36]. The catalytic mechanism involved the formation of the desired alcohol, the release of a PMB cation, and the subsequent formation of a lipophilic side product through the Friedel-Crafts alkylation of the PMB cation with another PMB ether [37,38]. Indeed, after treatment of methyl 2,4,6-tri-O-acetyl-3-O-PMB-galactoside/mannoside 27/29 with 0.2 equiv of SnCl 4 in DCM at rt for 10 min, the PMB-removed products 28/30 were obtained in 92/98% yield (Entries 9 and 10). Since the reactivity for removing PMB is much higher than that for removing acetal/ketal by SnCl 4 , we guessed that PMB should be preferentially removed from substrates containing both PMB and acetal/ketal in the presence of catalytic amounts of SnCl 4 . Therefore, four substrates 31, 33, 35 and 37 containing both PMB and acetal/ketal were treated with 0.2-0.5 equiv of SnCl 4 in DCM at rt for 5 min, leading to the selective PMB-removed products 32, 34, 36 and 38 in 80-85% yields (Scheme 2).

of 1
We also noticed that the 4-methoxylbenzyl (PMB) protecting group could be depro tected in the presence of catalytic amounts of SnCl4 [36]. The catalytic mechanism involved the formation of the desired alcohol, the release of a PMB cation, and the subsequent for mation of a lipophilic side product through the Friedel-Crafts alkylation of the PMB cat ion with another PMB ether [37,38]. Indeed, after treatment of methyl 2,4,6-tri-O-acetyl-3 O-PMB-galactoside/mannoside 27/29 with 0.2 equiv of SnCl4 in DCM at rt for 10 min, th PMB-removed products 28/30 were obtained in 92/98% yield (Entries 9-10). Since the re activity for removing PMB is much higher than that for removing acetal/ketal by SnCl we guessed that PMB should be preferentially removed from substrates containing both PMB and acetal/ketal in the presence of catalytic amounts of SnCl4. Therefore, four sub strates 31, 33, 35 and 37 containing both PMB and acetal/ketal were treated with 0.2-0. equiv of SnCl4 in DCM at rt for 5 min, leading to the selective PMB-removed products 32 34, 36 and 38 in 80-85% yields (Scheme 2). In the control experiment shown for Entry 14 in Table 2, the 4,6-benzylidene aceta was conveniently converted to 4,6-OAc for 1a when acetic anhydride was used instead o H2O during the SnCl4-promoted deacetalation; in addition, a 78% yield of 2a was obtained when acetic anhydride was directly added dropwise to the reaction mixture. Further ex periments indicate that the yield of 2a increased to 91% when a solution of acetic anhy was completed, the reaction mixture was dissolved in dichloromethane and extracted us-ing a saturated sodium bicarbonate solution and a saturated sodium potassium tartrate solution. The concentrated crude products were then dissolved in dry acetonitrile, followed by the addition of 1.1 equiv of Ac2O and 0.2 equiv of DIPEA [39]. The reaction proceeded at 40 °C for 12 h, resulting in 6-OAc products 44, 45, 46 and 47 in 70%, 64%, 69% and 65% yields, respectively (Scheme 3).

Conclusions
In this study, it was found that acetal and ketal protective groups could be efficiently removed in the presence of SnCl 4 for orthogonally protected carbohydrate substrates. The reaction can be completed in DCM within 10 min at room temperature, and a small amount of water has an obvious promoting effect on the reaction. It was also found that the PMB could be preferentially removed from the substrates containing both acetal/ketal and PMB by a catalytic amount of SnCl 4 . Based on SnCl 4 -promoted deacetalation, 4,6benzylidene glycosides can be conveniently converted to 4,6-OAc glycosides and 4-OH, 6-OAc glycosides. These methods provide efficient approaches to synthesizing orthogonally protected carbohydrate building blocks.

Materials and Methods
General Methods. All chemicals were purchased as reagent grade and used without further purification. The solvents were purified before use and CH 3 CN was distilled from CaH 2 . Chemical reactions were monitored by 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). Spots were visualized by UV light (254 nm) then by charring with a solution of H 2 SO 4 (5%) in ethanol. 1 H NMR spectra were recorded by 400 MHz or 600 MHz ( 1 H) and 100 MHz ( 13 C) at 298 K in CDCl 3 using the residual signals from CDCl 3 ( 1 H: δ = 7.26 ppm; 13 C: δ = 77.16 ppm) or CD 3 OD ( 1 H: δ = 3.31 ppm) as the internal standard. 1 H peak assignments were made by first order analysis of the spectra, supported by standard 1 H-1 H correlation spectroscopy (COSY). High-resolution mass spectra (HRMS) were obtained by TOF detection. Optical rotations were measured on an SGW-1 automatic polarimeter with [α] D values reported in degrees; concentration (c) is in g/100 mL.
General procedure A for SnCl 4 -mediated deacetalization. SnCl 4 (1.5 equiv) and H 2 O (1.0 equiv) were added to a solution of a carbohydrate substrate containing acetal/ketal in DCM (1 mL). The mixture was stirred at rt for 10 min and then poured onto a cold saturated NaHCO 3 solution. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3 × 10 mL). The combined organic phase was washed with saturated sodium potassium tartrate solution (1 × 15 mL), dried with anhydrous MgSO 4 , and concentrated in vacuo. The residue was purified by silica gel flash chromatography.
General procedure B for SnCl 4 -mediated removal of PMB. SnCl 4 (0.2-0.5 equiv) was added to a solution of a carbohydrate substrate containing PMB in DCM (1 mL). The mixture was stirred at rt for 5 min and then poured onto a cold saturated NaHCO 3 solution. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3 × 10 mL). The combined organic phase was washed with the saturated NaHCO 3 solution (1 × 15 mL), dried with anhydrous MgSO 4 , and concentrated in vacuo. The residue was purified by silica gel flash chromatography.