2,3,4,6-Tetra-O-benzyl-1-C-phenyl-α-D-glucopyranosyl 2,3,4,6-Tetra-O-benzyl-α-D-glucopyranoside

Abstract

The title compound 1 was synthesized by the coupling reaction of 2,3,4,6-tetra-O-benzyl-1-C-phenyl-α-d-glucopyranose (2) with 2,3,4,6-tetra-O-benzyl-d-glucopyranose (3) in the presence of 5 mol% bismuth(III) triflate in dichloromethane at 0 °C.

Trehalose is a non-reducing disaccharide which is composed of two glucopyranosyl units linked to each other in α-configuration. Trehalose is well-known for its various biological functions, and current attention is focused on the biologically novel functions of trehalose analogs, such as binding potentials to E-selectin and shiga toxins, and antibacterial activities [1,2,3]. Therefore, it is of increasing importance to design and synthesize novel non-reducing disaccharides which are structurally-classified as trehalose analogs.

Our recent studies showed the synthetic approaches to two types of non-reducing disaccharides from aldoses and/or ketoses by bismuth(III) triflate (Bi(OTf)₃)-catalyzed dehydrative glycosidations [4,5,6]. One was non-reducing disaccharides composed of two aldoses which linked with each other by self-condensations [5]. The other was a hybrid type of non-reducing disaccharides composed of aldose and ketose by the cross-condensations [6]. The latter condensation was the ketosylation reaction that utilized the ketohexopyranoses carrying the methyl group at the anomeric centers, i.e., the 1-C-methyl-hexopyranose derivatives, as the glycosyl donors by using only 5 mol% Bi(OTf)₃. Since some ketohexopyranose derivatives having a functional group such as an alkyl, alkynyl, alkene, and aryl group at the anomeric carbon centers are readily prepared from the corresponding glycono-1,5-lactone derivatives and appropriate organometallic reagents, it is expected that various kinds of structurally novel non-reducing disaccharides can be created using such ketohexopyranose derivatives. We also achieved the synthesis of a non-reducing disaccharide using the 1-C-butyl-d-glucopyranose derivative employing the same procedure [7].

We designed a novel non-reducing disaccharide using the 1-C-phenyl-d-glucopyranose derivative as a trehalose analog. This paper describes the synthesis of 2,3,4,6-tetra-O-benzyl-1-C-phenyl-d-glucopyranosyl 2,3,4,6-tetra-O-benzyl-d-glucopyranoside (1) by the Bi(OTf)₃-catalyzed ketosylation of 2,3,4,6-tetra-O-benzyl-1-C-phenyl-d-glucopyranose (2) [8,9] into 2,3,4,6-tetra-O-benzyl-d-glucopyranose (3) [10].

The ketosylation of 2 with 3 was investigated using Bi(OTf)₃ as shown in Scheme 1. The condensation reaction of 2 with 3 in the presence of 5 mol% Bi(OTf)₃ in dichloromethane at 0 °C for 15 h afforded 1 in a good yield of 55%. The benzyl 2,3,4,6-tetra-O-benzyl-1-C-phenyl-α-d-glucopyranoside (4) was obtained in 11% yield as a major by-product. Compound 4 would be formed by the reaction of 2 with benzyl alcohol generated by the degradation of 2 and/or 3. A similar reaction at room temperature reduced the yield of 1 (12%) and increased the yield of 4 (26%).

The configuration of the two glycosidic linkages of 1 was determined by NOE and ¹H-NMR experiments. The NOE interaction between aromatic-ortho H and H-2' as shown in Figure 1 was observed. This observation inevitably indicated the equatorial orientation of the phenyl group and determined the α-ketopyranosidic linkage. The α-aldopyranosidic linkage was confirmed by the coupling constant (J = 3.4 Hz) of H-1. Thus, both the glycosidic linkages of 1 were α. The ketopyranosidic linkage of 4 was similarly determined as an α by the NOE interaction.

Experimental

2,3,4,6-Tetra-O-benzyl-1-C-phenyl-α-d-glucopyranosyl 2,3,4,6-tetra-O-benzyl-α-d-glucopyranoside (1)

To a suspension of Bi(OTf)₃ (4.7 mg, 0.007 mmol), 2 (47.3 mg, 0.09 mmol) and CaSO₄ (ca. 100 mg) in CH₂Cl₂ (3.5 mL) was added 3 (83.2 mg, 0.13 mmol) at 0 °C under an Ar atmosphere. The resulting mixture was stirred for 15 h. The reaction was then quenched by addition of a sat. NaHCO₃ solution (5 mL). The reaction mixture was extracted with CH₂Cl₂, and the organic layer was washed with water and a sat. NaCl solution. After the organic layer was dried over Na₂SO₄, the solvent was evaporated under reduced pressure. The crude product was purified by preparative silica gel TLC (ethyl acetate/hexane = 1/3) to give 1 (R_f = 0.58, 55.3 mg, 55%) and 4 (R_f = 0.65, 10.1 mg, 11%) both as colorless oils. Compound 1: [α]_D²¹ +49° (c 0.74, CHCl₃). ¹H-NMR (600 MHz, CDCl₃): δ 3.32 (1H, d, J = 9.7 Hz, H-2'), 3.33–3.37 (2H, m, H_a-6, H_a-6'), 3.42 (1H, dd, J = 3.4 Hz, J = 10.3 Hz, H-2), 3.47 (1H, dd, J = 2.8 Hz, J = 11.0 Hz, H_b-6'), 3.62–3.64 (1H, m, H_b-6), 3.65 (1H, t, J = 8.9 Hz, H-4), 3.80 (1H, t, J = 9.6 Hz, H-4'), 4.121 (1H, t, J = 9.6 Hz, H-3), 4.124 (1H, d, J = 11.0 Hz, CH₂Ph), 4.16 (1H, t, J = 9.7 Hz, H-3'), 4.28–4.30 (1H, m, H-5), 4.35 (1H, d, J = 12.3 Hz, CH₂Ph), 4.44–4.62 (8H, m, H-5', CH₂Ph), 4.75 (1H, d, J = 11.0 Hz, CH₂Ph), 4.83–4.92 (5H, m, CH₂Ph), 4.99 (1H, d, J = 11.0 Hz, CH₂Ph), 5.03 (1H, d, J = 3.4 Hz, H-1), 7.14–7.33 (43H, m, Ph), 7.83 (2H, d, J = 7.6 Hz, Armatic ortho-H). ¹³C-NMR (150 MHz, CDCl₃): δ 68.2 (C-6), 68.6 (C-6'), 70.5 (C-5), 71.4 (C-5'), 73.2 (CH₂Ph), 73.3 (CH₂Ph), 73.4 (CH₂Ph), 74.7 (CH₂Ph), 75.0 (CH₂Ph), 75.1 (CH₂Ph), 75.47 (CH₂Ph), 75.51 (CH₂Ph), 78.21 (C-4), 78.22 (C-4'), 80.5 (C-2), 81.8 (C-3), 83.1 (C-3'), 85.5 (C-2'), 92.1 (C-1), 101.3 (C-1'), 127.1–128.4 (Ph), 138.0–138.7 (Ph). HRMS (ESI): m/z calcd for C₇₄H₇₄O₁₁Na⁺: 1161.5123; found: 1161.5142. Anal. Calcd for C₇₄H₇₄O₁₁·H₂O: C, 76.79; H, 6.62. Found: C, 76.97; H, 6.82. Compound 4: [α]_D²⁴ +41° (c 0.55, CHCl₃). ¹H-NMR (600 MHz, CDCl₃): δ 3.38 (1H, d, J = 9.6 Hz, H-2), 3.74 (1H, d, J = 10.3 Hz, H_a-6), 3.80–3.85 (3H, m, H-4, H_b-6, CH₂Ph), 3.90 (1H, dd, J = 3.4 Hz, J = 10.3 Hz, H-5), 4.25 (1H, t, J = 8.9 Hz, H-3), 4.37 (2H, s, CH₂Ph), 4.46 (1H, d, J = 10.3 Hz, CH₂Ph), 4.61 (1H, d, J = 12.3 Hz, CH₂Ph), 4.63 (1H, d, J = 13.1 Hz, CH₂Ph), 4.70 (1H, d, J = 12.4 Hz, CH₂Ph), 4.86–4.88 (2H, m, CH₂Ph), 4.94 (1H, d, J = 11.0 Hz, CH₂Ph), 7.10–7.41 (28H, m, Ph), 7.72 (2H, d, J = 8.2 Hz, Armatic ortho-H). ¹³C-NMR (150 MHz, CDCl₃): δ 63.7 (CH₂Ph), 68.9 (C-6), 72.3 (C-5), 73.4 (CH₂Ph), 75.1 (CH₂Ph), 75.5 (CH₂Ph), 75.7 (CH₂Ph), 78.6 (C-4), 83.1 (C-3), 85.8 (C-2), 101.5 (C-1), 127.3–128.4 (Ph), 138.3–138.8 (Ph). HRMS (ESI): m/z calcd for C₄₇H₄₆O₆Na⁺: 729.3187; found: 729.3216. Anal. Calcd for C₄₇H₄₆O₆·2/3H₂O: C, 78.53; H, 6.64. Found: C, 78.42; H, 6.61.