HETEROCYCLES

Communication | Special issue | Vol. 88, No. 1, 2014, pp. 201-206
Received, 24th June, 2013, Accepted, 30th July, 2013, Published online, 7th August, 2013.
DOI: 10.3987/COM-13-S(S)44

■ Formation of 1,2-cis-α-Aryl-glycosidic Linkages Directly from 2-Acetamido-2-deoxy-D-glucopyranosyl Acetate by the Mixed Activating System Using Ytterbium(III) Triflate and Catalytic Boron Trifluoride Diethyl Etherate Complex

Takashi Yamanoi,* Masanobu Midorikawa, and Yoshiki Oda

Research Department, The Noguchi Institute, 1-8-1, Kaga, Itabashi-ku, Tokyo 173-0003, Japan

Abstract

We found that a mixed activating system using ytterbium(III) triflate and a catalytic boron trifluoride diethyl etherate complex efficiently promoted glycosidation of the 2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-α-D-glucopyranosyl acetate in dichloromethane at room temperature to afford 2-acetamido-2-deoxy-D-glucopyranosides in good yields along with the formation of a considerable amount of α-isomers. Glycosylations of the aryl alcohols as the acceptors stereoselectively afforded aryl α-glycosides without producing any β-isomers.

Ytterbium(III) triflate (Yb(OTf)3) is one of the useful activators in some glycosidation reactions.1 Our investigation into the Yb(OTf)3-promoted glycosidation showed that Yb(OTf)3 was effective for several glycosyl acetates.2 In addition, we found that a mixed activating system based on the combined use of Yb(OTf)3 and a catalytic amount of boron trifluroride diethyl etherate (BF3·OEt2) was useful for glycosidation using some of the less reactive glycosyl acetates.3-5 Our attention was recently directed toward the formation of 2-acetamido-2-deoxy-D-glucopyranosidic linkages, and we conducted a preliminary investigation on glycosidation using 2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-α-D-glucopyranosyl acetate (1)6 as the glycosyl donor using a mixed activating system. The mixed activating system using Yb(OTf)3 (1 equiv.)-BF3·OEt2 (0.03 equiv.) successfully promoted the glycosidation of 1 with phenethyl alcohol (2) to produce the phenethyl 2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-D-glucopyranosides (3) in a high yield of 95% with an α/β ratio of 40/60. Interestingly, this resulted in the production of a considerable amount of α-glycoside. It is known that glycosidations using 2-acetamido-2-deoxy-D-glucopyranosyl donors having a natural N-acetyl protecting group usually forms corresponding β-glycosides by the following mechanism. Stable oxazoline derivatives are generated by the effect of the neighboring-group participation of a C-2 acetamido function, and the consequent SN2-like nucleophilic substitution of an alcohol to the oxazoline derivatives (or oxazolinium cation intermediate) under severe reaction conditions when using a strong Lewis or Brϕnsted acid leads to the production of the β-glycosides.7 To the best of our knowledge, there have been no reports of glycosidations that directly produce 1,2-cis-α-glycosidic linkages from a 2-acetamido-2-deoxy-D-glucopyranosyl donor. The unusual reactivity and stereoselectivity of the glycosidation between 1 and 2 using our mixed activating system suggest that it may involve a different pathway that does not generate oxazoline intermediates.
2-Acetamido-2-deoxy-α-D-glucopyranosidic linkages are found in the O-glycans of gastric mucins,8 lipopolysaccharides of bacteria,9 tunicamycin,10 etc.11 Therefore, developing a convenient method for forming 1,2-cis-α-glycosidic linkages directly from 2-acetamido-2-deoxy-D-glucopyranose derivatives is one important goal in synthetic carbohydrate chemistry.12 This study describes the detailed glycosidation properties involved in the formation of the 1,2-cis-α-glycosidic linkages from 1 by a mixed activating system using Yb(OTf)3 and catalytic BF3·OEt2.

A catalytic amount of BF3·OEt2 is essential for promoting glycosidation because glycosidation does not proceed at all without BF3·OEt2. We speculated that the ROH·BF3 complex formed in situ between BF3·OEt2 and an alcohol would work as a Brϕnsted acid and influence the glycosidation reactivity as we previously reported for the glycosidation using 1.13 The effect of the Brϕnsted acids, AcOH, and TfOH, as additives was then examined (Scheme 1). The addition of a 3 mol% amount of AcOH or TfOH to the glycosidation process using 1 (1.2 equiv.), phenethyl alcohol (1 equiv.), and Yb(OTf)3 (1 equiv.) in CH2Cl2 at room temperature produced the glycoside 3 in 72% or 68% yields with α/β ratios of 49/51 or 47/53, respectively. The addition of AcOH or TfOH was also effective for the promotion of glycosidation using 1 as well as BF3·OEt2, and these reactions produced a considerable amount of the α-glycoside. These results are shown in Table 1.

Next, we investigated the glycosidation of 1 with several types of alcohols under similar reaction conditions to examine the effect of alcohols on glycosidation’s stereoselectivities (Scheme 2, Figure 1). The reactions using primary and secondary alcohols 2, 4-10 gave the corresponding glycosides 3, 15-21, respectively in good yields with α/β ratios of ca. 1/1-1/5. Thus, each of these reactions gave a mixture of α- and β-glycosides. However, surprisingly, the reactions using aryl alcohols 11-14 gave aryl α-glycosides 22-25, respectively in good yields with no production of the β-glycosides. The steric and electronic effects of the alcohols influenced the glycosidation’s stereoselectivities. Table 2 summarizes these results and the 1H and 13C NMR data of H-1 and C-1, respectively from the α- and β-glycosides (3, 15-25) produced.

Furthermore, to clarify the difference in the reaction mechanism, we performed glycosidation using 3,4,6-tri-O-benzyl-1,2-oxazoline-glucopyranose (26),14 considered to be one of the glycosyl intermediates, under the same reaction conditions (Figure 2). The reactions of 26 (1.2 equiv.) with 2 or 11 were examined in the presence of Yb(OTf)3 (1 equiv.) and BF3·OEt2 (0.03 equiv.) in CH2Cl2 at room temperature. The reaction using 2 gave β-glycoside in 53% yield with no production of the α-glycoside, while the reaction using 11 did not produce glycoside at all. These results are shown in Table 3. The reactivity and stereoselectivity of glycosidation using 26 were found to be quite different from those of glycosidation using 1. In addition, we confirmed that the β-anomer of 22 was not isomerized to the α-anomer at all under the acidic conditions in the presence of Yb(OTf)3 (1 equiv.) and BF3·OEt2 (0.03 equiv.) in CH2Cl2 at room temperature. Therefore, the α-glycosides formed by the glycosidation using 1 are not a conversion product of in situ acid-catalyzed anomerization from the β-glycosides.

We speculated that the complex of ytterbium metal and 1 through the carbonyl group of 1 might be formed as a glycosyl cation intermediate, as shown in Figure 3. This complex formation would prevent the production of the oxazoline derivative because of the decrease in the Lewis basicity of the oxygen atom of the carbonyl group and allow an alcohol to attack the glycosyl cation intermediate from the α-face, resulting in the formation of the 1,2-cis-α-glycosidic linkages. However, we have not yet found a sufficient explanation for the high α-stereoselectivities of the glycosidations using aryl alcohols.
In summary, we found that several 2-acetamido-2-deoxy-D-glucopyranosides were directly synthesized from glycosyl acetate 1 in good yields along with the formation of a considerable amount of α-isomers by a mixed activating system using Yb(OTf)3-catalytic BF3·OEt2. The reactions using the aryl alcohols as acceptors only afforded aryl α-glycosides with no production of β-glycosides.15 This novel glycosidation approach for forming 2-acetamido-2-deoxy-D-glucopyranosidic linkages is applicable for the synthesis of natural products.

References

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