Synthesis of 6-Branched Cyclo-(1→3)-glucohexaose and Glucooctaose

Abstract

The cyclization precursors nonasaccharide 3 and dodecasaccharide 8 were obtained, respectively, from the corresponding 4-methoxyphenyl glycosides 1 and 6 via oxidative cleavage of 1-OMp followed by selective 1-O-trichloroacetimidate formation. TMSOTf-promoted cycloglycosylation of 3 and 8 went smoothly giving α-linked cyclized nonasaccharide 4 and dodecasaccharide 9. Finally, deacylation of 4 and 9 furnished the target cycloglucans 5 and 10 consisting of alternate β- and α-(1→3)-linked cycloglucohexaose backbone bearing three β-(1→6)-linked glucose side chains and cycloglucooctaose backbone bearing four β-(1→6)-linked glucose side chains, respectively. The side chains were ­attached at the glucose residue of the backbone with α-linkage.

cyclodextrin - cyclo-glycosylation - glucans

References

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Cyclization Procedure: Compound 3 (400 mg, 0.115 mmol) or 8 (400 mg, 0.087 mmol) was dried under high vacuum for 2 h, then dissolved in anhyd CH₂Cl₂ (15 mL). TMSOTf (5 µL) was added dropwise at -20 °C under N₂ protection. The reaction mixture was stirred for 3 h, during which time the temperature was gradually raised to ambient temperature. Then the mixture was neutralized with Et₃N. Concentration of the reaction mixture, followed by purification on a silica gel column with 2:1 petroleum ether-EtOAc as the eluent gave 4 (154 mg, 40.1%) or 9 (125 mg, 32.4%).

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All the new compounds involved in the study were identified by ¹H NMR and/or ¹³C NMR spectrometry, and elemental analyses. Selected data for some important compounds:
Compound 3: [α]_D +46.3 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 8.41 (s, 1 H, C=NH), 6.31 (d, 1 H, J _1,2 = 3.6 Hz, H-1), 4.97 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.92 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.88 (d, 1 H, J _1,2 = 3.6 Hz, H-1), 4.85 (d, 1 H, J _1,2 = 3.6 Hz, H-1), 4.79 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.61 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.56 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.50 (d, 1 H, J _1,2 = 7.9 Hz, H-1). ¹³C NMR (100 MHz, CDCl₃): δ = 101.5, 101.4, 100.7, 100.3, 100.0, 99.8 (6 β-C-1), 94.2, 93.9, 92.8 (3 α-C-1). Anal. Calcd for C₁₇₀H₁₇₀Cl₃NO₇₃: C, 58.46; H, 4.87. Found: C, 58.72; H, 4.99.
Compound 4: [α]_D +48.6 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 5.01 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.93 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.90 (d, 1 H, J _1,2 = 3.6 Hz, H-1), 4.80 (d, 1 H, J _1,2 = 3.6 Hz, H-1), 4.77 (d, 1 H, J _1,2 = 3.6 Hz, H-1), 4.70 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.55 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.50 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.46 (d, 1 H, J _1,2 = 7.9 Hz, H-1). ¹³C NMR (100 MHz, CDCl₃): δ = 102.0, 101.5, 101.4, 100.4, 100.4, 100.2 (6 β-C-1), 94.0, 92.1, 89.9 (3 α-C-1). MALDI-TOF MS: Calcd for C₁₆₈H₁₆₈O₇₂: 3339.1 [M]. Found: 3363 [M + Na].

Compound 5: [a]_D +16.7 (c 1.0, H₂O). ¹H NMR (400 MHz, CDCl₃): d = 5.39 (d, 3 H, J = 3.8 Hz, 3 H-1), 4.55 (d, 6 H, J = 7.9 Hz, 6 H-1), 4.30-4.20 (m, 4 H), 4.02-3.97 (m, 12 H), 3.86-3.70 (m, 20 H), 3.59-3.50 (m, 11 H), 3.45-3.33 (m, 7 H). ¹³C NMR (100 MHz, D₂O): d = 102.8 (6 C-1 for b bonds, J _C-H = 163.3 Hz), 99.1 (3 C-1 for a bond, J _C-H = 171.6 Hz), 85.1, 84.4, 76.4, 76.0, 75.9, 75.6, 73.4, 73.2, 73.1, 72.2, 71.5, 71.2, 71.0, 70.8, 70.3, 69.9, 69.6, 69.0, 68.8, 68.4, 67.7 (C-2,3,4,5,6, some signals were overlapped). MALDI-TOF MS: Calcd for C₅₄H₉₀O₄₅: 1459.3 [M]. Found: 1482.6 [M + Na].
Compound 8: [a]_D +37.5 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): d = 8.40 (s, 1 H, C=NH), 6.30 (d, 1 H, J _1,2 = 3.6 Hz, H-1), 4.96 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.93 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.90 (d, 1 H, J _1,2 = 3.6 Hz, H-1), 4.85 (d, 2 H, J _1,2 = 3.6 Hz, 2 H-1), 4.80 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.65 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.62 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.54 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.44 (d, 1 H, J _1,2 = 7.9 Hz, H-1). ¹³C NMR (100 MHz, CDCl₃): d = 101.8, 101.6, 101.5, 100.9, 100.5, 100.3, 100.1, 99.8 (8 b-C-1), 94.5, 94.1, 93.6, 92.7 (4 a-C-1). Anal. Calcd for C₂₂₆H₂₂₆Cl₃NO₉₇: C, 58.82; H, 4.90. Found: C, 60.07; H, 4.94.
Compound 9: [a]_D +42.8 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): d = 4.98 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.96 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.90 (d, 1 H, J _1,2 = 3.6 Hz, H-1), 4.86 (d, 2 H, J _1,2 = 3.6 Hz, 2 H-1), 4.81 (d, 1 H, J _1,2 = 3.6 Hz, H-1), 4.76 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.66 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.62 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.53 (d, 1 H, J _1,2 = 7.9 Hz, H-1), 4.45 (d, 1 H, J _1,2 = 7.9 Hz, H-1). ¹³C NMR (100 MHz, CDCl₃): d = 102.3, 101.7, 101.5, 101.5, 100.8, 100.5, 100.3, 99.9 (8 b-C-1), 94.7, 94.3, 93.7, 90.0 (4 a-C-1). MALDI-TOF MS: Calcd for C₂₂₄H₂₂₄O₉₆: 4452 [M]. Found: 4475 [M + Na].
Compound 10: [a]_D +24.1 (c 1.0, H₂O). ¹H NMR (400 MHz, CDCl₃): d = 5.24 (d, 4 H, J = 3.6 Hz, 4 H-1), 4.40 (d, 8 H, J = 8.0 Hz, 8 H-1), 4.13-4.05 (m, 12 H), 3.92-3.80 (m, 22 H), 3.70-3.54 (m, 26 H), 3.42-3.32 (m, 12 H). ¹³C NMR (100 MHz, D₂O): d = 102.8 (8 C-1 for b bonds, J _C-H = 164.3 Hz), 99.1 (4 C-1 for a bond, J _C-H = 173.1 Hz), 82.6, 81.9, 75.9, 75.6, 73.5, 73.2, 73.0, 72.8, 72.5, 72.4, 72.2, 71.8, 71.2, 70.8, 69.9, 69.6, 68.4, 67.7, 60.8, 60.5 (C-2,3,4,5,6, some signals were overlapped). MALDI-TOF MS: Calcd for C₇₂H₁₂₀O₆₀: 1945.7 [M]. Found: 1969.0 [M + Na].