Regioselective benzoylation of sugars mediated by excessive Bu₂SnO: observation of temperature promoted migration

Abstract

Regioselective benzoylation of carbohydrates using an excess of dibutyltin oxide (Bu₂SnO) at increased reaction temperatures has been developed for the synthesis of several glycoside benzoates with one or two free hydroxyl groups, including galactosides, glucosides, mannosides and lactosides in high yields. These compounds are useful as building blocks for the synthesis of complex saccharides and derivatives.

Introduction

Oligosaccharides with immense molecular diversity can be created from a few common monosaccharides through a linear or branched connection between each multifunctional sugar unit. However, creating such a high degree of molecular diversity requires the design of building blocks with orthogonal protecting groups for use in glycosylation reactions. Development of new methods for the synthesis of carbohydrate building blocks for this application is thus of current interest.

Recently, the use of organotin reagents such as tributyltin oxide, (Bu₃Sn)₂O, or dibutyltin oxide, Bu₂SnO, has been widely explored.1., 2., 3., 4. Regioselective alkylation,5., 6. silylation,⁷ acylation8., 9., 10. and even regioselective glycosylation11., 12., 13. have been reported with such reagents. It is believed that the reactivity of a hydroxyl group can be enhanced by forming a stannylene complex and, in most cases, the stannylene complex of a sugar exists as cyclic acetals, which can be selectively protected with an alkyl or acyl group. Most of the studies, however, use a stoichiometric or slightly excessive amount of the tin reagent. Our interest in this subject is to exploit the use of excess organotin reagents to mediate the regioselective protection of the hydroxyl groups of a sugar to give a product with one free hydroxyl group, as these building blocks are useful for selective glycosylation.

As suggested by previous studies,³ if the galactoside shown in Fig. 1 is treated with 3 equiv. of Bu₂SnO followed by 3 equiv. of BzCl, it is expected to generate the stannylene intermediate A and then give the 2,3,6-tri-O-benzoyl product B. To our surprise, some unexpected results were observed (Table 1). For example, p-methoxyphenyl β-d-galactoside 1¹⁴ was first treated with 3 equiv. of Bu₂SnO in toluene–benzene (1:1) followed by azeotropic removal of water to give a clear solution of the stannylene complex. Treatment of this complex with 3 equiv. of BzCl at room temperature, however, gave only the diprotected 3,6-O-di-benzoyl derivative 10 in 93% yield (Table 1). This result appears to be consistent with an early study with 1.5 equiv. of (Bu₃Sn)₂O and 3 equiv. of BzCl at room temperature.¹⁰ We thought that a higher temperature might facilitate additional benzoylation. Therefore, in a second experiment the tin complex was treated with 3 equiv. of BzCl at 100°C. While additional benzoylation was observed, the 3,4,6-tri-OBz derivative 11 was obtained in 86% yield instead of the expected 2,3,6-derivative. It is known that, in general, the 2-OH position is more reactive than the 4-OH in a β-galactoside series,¹⁵ even in the tin complex case.¹⁰

To confirm this unusual regioselectivity, galactosides 2 and 3 were also tested under this condition, and compounds 13 and 14 were obtained with the same selectivity in 89 and 91% yield, respectively (Table 1, entries 3 and 4). We were excited by these results, since there was no known synthetic method that would give this type of compound in few steps. To further study these reactions, we carefully followed the reaction at room temperature by TLC. We observed that the 3,6-di-OBz derivative 10 was first formed after only a few minutes. When the tin complex was treated with 2.2 equiv. of benzoyl chloride at room temperature followed by 100°C, a new spot with low R_f appeared after approximately 10 min, then disappeared during the formation of the 3,4,6-tri-Obz derivative 11. We finally isolated the first intermediate and confirmed by NMR and high-resolution mass spectrometry this to be the 4,6-O dibenzoate 12.

As proposed in Fig. 2, it is possible that the galactoside intermediate A was formed after reaction with 3 equiv. of Bu₂SnO. As stannylene complexes have different dimer and polymer forms,3., 16. we assume that the R′ group may be another tin moiety or sugar residue. The 3-O and 6-O positions of intermediate A are perhaps more reactive and readily benzoylated to give the 3,6-di-O-benzoyl derivative with a structure like compound C. This intermediate will then give the diprotected product 10. Under higher temperature, two pathways from intermediate C may be possible. One is a slow benzoylation reaction at the 2-O-position to give products B and H through intermediate G, which is often isolated in a small amount in each reaction. Another is a faster migration reaction, where the benzoyl group at 3-O migrates to the 4-O-position, presumably with an aid from the tin group at the 2-O position to give the newly formed 2,3-O stannylene acetal D. Further benzoylation would occur at the 3-O position as the 3-O position is more reactive than the 2-O position to give the hydrolyzed product F through intermediate E.

In order to further support this migration mechanism, we performed additional experiments. First, we treated compound 1 (Table 1) with 3 equiv. of Bu₂SnO, followed by 2.2 equiv. of BzCl at room temperature to form the 3,6-OBz intermediate 10 (see Fig. 2, C). Raising the reaction temperature to 100°C gave 4,6-di-benzoate 12 in 75% along with 20% of 3,4,6-OBz 11. This example shows that higher temperature is necessary for the migration. To support the hypothesis involving the assistance from the tin moiety at the 2-O position of intermediate C (Fig. 1), 2-(trimethylsilyl)ethyl 2,3,6-tri-O-benzoyl-β-d-galactopyranoside¹⁷ was treated with 1 equiv. of Bu₂SnO in refluxing benzene. After 10 h, only about 50% of the migrated product was formed. Moreover, when a complex of 2-azido-2-deoxy galactoside 4 and 2 equiv. of Bu₂SnO was treated with 3 equiv. of BzCl at room temperature, 3,6-di-benzoate 15 was obtained in 90% yield and with 2 equiv. of BzCl at 70–90°C for 1.5–3 h the migrated product 16 was obtained in 45% yield along with ∼20% of compound 15. All these examples show that the migration of Bz- from position 3-O to 4-O is very slow without the anchimeric effect from the tin moiety at the 2-O position.

The galactosides discussed above are β-linked compounds; however, a result from Ogawa's group indicated a different reaction pattern with an α-galactopyranoside.⁸ Treatment of methyl α-galactopyranoside 5 with 1.5 equiv. of (Bu₃Sn)₂O and 3 equiv. of BzCl gave a mixture of different di-OBz and tri-OBz compounds, and the 2,3,6-tri-OBz 17 was isolated in 40% yield as the major product. We obtained a mixture using 3 equiv. of Bu₂SnO and 3.3 equiv. of BzCl under a higher temperature (45°C) condition. Three major products, 2,3,6-tri-OBz 17, 2,4-6-tri-OBz 18 and 3,4,6-tri-OBz 19 were isolated in 42, 29 and 12, respectively (entry 8). A possible explanation for this is that a stannylene acetal at the 2-O position coordinates with the α-anomeric oxygen and reduces the extent of the 3-O to 4-O benzoyl migration (Scheme 1). In this case, the 2-O seems more reactive towards benzoylation than its β-isomer, consequently slowing down the 3-O to 4-O migration. In addition, compound 17 was synthesized in 65% yield by a direct benzoylation using 4.2 equiv. of BzCl in pyridine.¹⁵

A glucoside is a 4-epimer of galactoside. Ogawa et al. systematically studied the reactions of an α-glucoside with different ratios of (Bu₃Sn)₂O to BzCl.¹⁰ They found that 1.5 equiv. of (Bu₃Sn)₂O and 2–3 equiv. of BzCl gave 2,6-di-OBz 21 in 73–82%. A larger excess of (Bu₃Sn)₂O and BzCl gave the 2,3,6-O-tri-benzoate 20 in 63%. A higher yield (90%) was obtained with a modified procedure.¹⁸ We hypothesized that the stannylene complex of an α-glucoside with 3 equiv. of Bu₂SnO may be similar to the α-galactoside case. With our high temperature procedure, the methyl α-glucoside 6 was treated with 3 equiv. of Bu₂SnO, followed by 3.2 equiv. of BzCl at 70°C to give 2,3,6-O-tri-OBz 20 in 91% yield. TLC analysis of the reaction showed that the intermediate 2,6-di-OBz 21 was formed first. Based on these results, the reactivities of these hydroxy groups as tin derivatives in the α-glucoside seem to be 6-O>2-O>3-O>4-O, a trend similar to those found under imidazole benzoate treatment.¹⁹ This high regioselectivity makes this method attractive for preparation of tri-benzoates. We have also applied this procedure to the modification of 2-deoxy globotriosyl neo-glycosyl lipid.²⁰ We treated the 2-deoxy glucosyl lipid 7 (entry 10) with 3 equiv. of Bu₂SnO followed by 2.4 equiv of BzCl at 100°C for 5 min, giving the desired 3,6-dibenzoate in 85% yield.

Another model structure studied was a methyl α-mannoside, 2-epimer of a glucoside. Based on the stannylene complex, we expected that the migration reaction would be involved in the benzolation process. Indeed, treatment of α-methyl mannoside 8 with 3 equiv. of Bu₂SnO followed by 3 equiv. of 3.3 BzCl at 90°C for 15 min gave the product 2,3,6-tri-OBz mannoside 23 in 89% yield. The 2,6-di-OBz 24 and 3,6-di-OBz 25 were also isolated in 6 and 3%, respectively. Using 2.2 equiv. of BzCl gave 3,6-O-di-OBz 24 in 61% yield which is comparable to a reported result (66%).¹⁰ Taking advantage of the observation, we treated the stannylene complex (3 equiv. of Bu₂SnO) with BzCl (2.2 equiv.) at room temperature for 2 h, then a higher temperature (100°C) for 20 min. We were able to isolate the 2,6-diester 24 in 74% yield together with 20% of the 2,3,6-tri-OBz 23. This procedure thus enables us to prepare three different partially protected building blocks by varying the amount of BzCl and temperature.

We have found an interesting trend under these conditions. In a pyranoside structure, when an equatorial hydoxy group is cis to an adjacent axial hydroxy group, this equatorial hydoxy group is much more reactive than another equatorial hydoxy group which is trans to an adjacent equatorial hydroxyl group. For instance, the 3-O group is more reactive than the 2-O group in the β-galactoside series, the 2-O group is more reactive than the 3-O and 4-O groups in the α-glucoside, and the 3-O group is more reactive than the 4-O group in the α-mannoside series.

Encouraged by these results, the disaccharide lactoside 9 was chosen as the substrate for multiple stannylation. We treated compound 9 with 6 equiv. of Bu₂SnO, followed by 9 equiv. of BzCl at 120°C for 2 h, and we isolated a major product (86% yield). The ¹H NMR spectrum of this product indicated the structure 2,6,3′,4′,6′-O-penta-benzoyl lactosylpyranoside 26. In another experiment, lactoside 9 was treated with 7 equiv. of Bu₂SnO, followed by 10 equiv. of BzCl at 120°C for a longer reaction time (7 h). Surprisingly, a new product, 2,6,2′,3′,4′,6′-hexa-benzoate 27 was isolated in 85% yield. The mechanisms in these two cases are unclear. Perhaps, with a longer reaction time and lager excess of Bu₂SnO at high temperature, an 8-membered stannylene acetal from the 3-O and 2′-O position of the 26 is formed (Scheme 2), but further studies are needed to understand the mechanism. The speculated existence of 3,2′-O-stannylene complex is based on the known structure of 3,2′-O-benzylidene lactoside.²¹ In the newly formed stannylene complex, the 2′-O position may be less hindered towards benzoylation to give the hexabenzoate 27. This result is different from Ogawa's early result, where they treated a free lactose with slightly more than 3 equiv. of (Bu₃Sn)₂O and 6.6 equiv. of BzCl at 45°C for 2 days and 2,6,3′6′-tetra-OBz lactose was isolated in 72% yield. In their procedure, no migration reaction is involved.¹⁰ Therefore, the high temperature induced migration procedure is crucial for the syntheses of compounds 26 and 27.

In summary, we have observed a different migration pattern in organotin-mediated benzoylations at high temperature using excess amounts of (Bu₃Sn)₂O and BzCl. We have used this method in preparation of building blocks that normally require many steps with traditional synthesis. High regioselectivities have been found in different sugar structures including galactosides, glucosides, mannosides, and even a disaccharide. The conditions used in this study represent a new method for the synthesis of partially benzoylated glycosides. The mechanisms of these transformations described above are speculative and require further investigation.