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Synlett 2008(5): 715-719  
DOI: 10.1055/s-2008-1042803
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Aminocyclodextrin Carboxylic Acids

Stephen Hanessian*a, Céline Hocqueletb, Christopher K. Jankowskib,c
a Department of Chemistry, Université de Montréal, CP 6128, Montréal, QC, H3C 3J7, Canada
e-Mail: stephen.hanessian@umontreal.ca;
b Service de la Chimie Moléculaire, DRECAM, bat. 125, Commissariat à l’Énergie Atomique de Saclay, 91191 Gif-sur-Yvette, France
c Département de Chimie et Biochimie, Université de Moncton, Moncton, NB, E1A 3E9, Canada
Further Information

Publication History

Received 24 September 2007
Publication Date:
26 February 2008 (online)

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Abstract

Synthesis of aminocyclodextrin carboxylic acids (6-amino-6′-carboxylic acid) via selective amination and oxidation of 6A,6D-dihydroxy α- and β-cyclodextrins, respectively, is reported.

Keywords

α- and β-cyclodextrin amino acids - azido cyclodextrin carboxylic acids - amination

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6 A - O - tert -Butyldimethylsilyl-2 A-G ,3 A-G ,6 B,C,E,F,G -nonadecakis- O -benzyl Cyclomaltoheptaose (5)To a solution of compound 2 (200 mg, 70.2 µmol, 1 equiv) dried overnight under vacuum and dissolved in anhyd CH2Cl2 (2 mL) was added Et3N (21 µL). The mixture was cooled to 0 °C. TBSOTf (17.7 µL, 1.1 equiv) was added and the reaction was stirred overnight at r.t. The reaction mixture was evaporated, diluted in CH2Cl2, washed with distilled H2O, and dried with MgSO4. After removal of the solvent, the crude product was purified by chromatography on a silica gel column, eluting with cyclohexane-EtOAc (5:1, 4:1 then pure EtOAc) to obtain compound 5 as a white powder (80 mg, 40%). Starting material 2 (54.5%) was recovered. R f = 0.33 (cyclohexane-EtOAc, 3:1). 1H NMR (500 MHz, CDCl3): δ = 7.06-7.33 (m, 95 H, Harom.); anomeric protons: total integration of seven protons split into two series of signals doubled for inseparable isomers A,D and A,E: 5.51 (d, J H1-H2 = 3.2 Hz, 1 H, H-1), 5.44-5.46 (m, 2 H, H-1), 5.38 (d, J H1-H2 = 3.5 Hz, 1 H, H-1), 5.33 (d, J H1-H2 = 3.2 Hz, 1 H, H-1), 5.31 (d, J H1-H2 = 3.2 Hz, 1 H, H-1), 4.93 (d, 1 H, H-1), and seven anomeric protons between 4.95-5.27 mixed together with benzylic signals (m, CHPh plus 7 × H-1), 4.66-4.87 (m, CHPh), 4.39-4.62 (m, CHPh), 3.84-4.18 (m, H-3, H-4, H-5, H-6), 3.39-3.79 (m, 14 × H-2 and H-6), 0.90 [s, 12 H, SiC(CH3)], 0.88 [s, 12 H, SiC(CH3)], 0.00 (m, 12 H, SiCH3). 13C NMR (125 MHz, CDCl3): δ = 137.81-139.36 (Carom.), 126.70-128.32 (CHarom.), 97.66, 97.84, 97.92, 98.10, 98.20, 98.34, 98.51 (14 × C-1), 77.14-81.15 (C-2, C-3, C-4), 72.33-76.09 (CHPh, 2 × C-5), 71.37-71.90 (C-5), 68.62-69.34 (C-6), 61.51-62.51 (C-6), 25.98, 25.99 [SiC(CH3)3], 18.34,18.36 (SiC), -5,4, -5,2 (2 × SiCH3). MALDI-TOF MS: m/z calcd for C181H197O35SiNa: 2984.61; found: 2984.01 [M]+.

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6 A -Azido-6 A deoxy-6 D - O - tert -butyldimethylsilyl-2 A-G ,3 A-G ,6 B,C,E,F,G -nonadecakis- O -benzyl Cyclomaltoheptaose (8)To a solution of compound 5 (322 mg, 108.7 µmol, 1 equiv) in pyridine (3.6 mL), DMAP (39.8 mg, 326.1 µmol, 3 equiv) was added and the reaction mixture was placed at 0 °C. After addition of MsCl (33.6 µL, 434.7 µmol, 4 equiv), the reaction was stirred 3 h. The mixture was diluted in CH2Cl2, treated with H2O, the organic phase was dried (MgSO4) and evaporated to dryness. The residue is then dissolved in DMF (3.6 mL), NaN3 (99 mg, 1.52 mmol, 14 equiv) was added and the mixture was heated at 70 °C overnight. The mixture was evaporated to dryness, diluted with CH2Cl2 and distilled H2O. The organic phase was dried (MgSO4). The crude product was purified by chromatography on a silica gel column, eluting with cyclohexane-EtOAc (7:1, 6.5:1) to give compound 8 as a white powder (228 mg, 70%). R f = 0.46 (cyclohexane-EtOAc, 3:1). IR (KBr): 2100 (N3) cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.03-7.30 (m, 95 H, Harom.), 5.42 (d, J H1-H2 = 3.2 Hz, 1 H, H-1), 5.35 (d, J H1-H2 = 3.3 Hz, 1 H, H-1), 5.31 (d, J H1-H2 = 3.4 Hz, 1 H, H-1), 5.20 (m, 2 H, H-1), 5.18 (d, J H1-H2 = 3.3 Hz, 1 H, H-1), 5.16 (d, J H1-H2 = 3.3 Hz, 1 H, H-1), 4.96-5.14 (m, H-1, CHPh), 4.66-4.85 (m, CHPh), 4.34-4.60 (m, CHPh), 3.80-4.24 (m, H-3, H-4, H-5, H-6), 3.37-3.71 (m, 14 × H-2 and H-6), 0.845 [s, 12 H, SiC(CH3)], 0.84 [s, 12 H, SiC(CH3)], -0.02 (m, 12 H, SiCH3). 13C NMR (125 MHz, CDCl3): δ = 137.3-139.5 (Carom.), 127.06-128.49 (CHarom.), 97.91, 98.04, 98.11, 98.32, 98.42, 98.46, 98.51, 98.55, 98.70, 98.79, 98.82, 98.98 (14 × C-1), 78.88-81.42 (C-CD), 72.62-75.99 (C-6, CH2Ph), 70.89-71.91 (C-CD), 68.30-69.55 (C-CD), 62.55 (C-6), 52.42 (C-6), 26.17 [SiC(CH3)3], 18.5 (SiC), -5.3 (SiCH3). MALDI-TOF MS: m/z calcd for C181H201O34Si: 2987.65; on sinapinic acid matrix found: 2981.56 [M - 5]+; on DHB matrix found: 2961.44 [M - 26].

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6 A -Azido-6 A deoxy-2 A-G ,3 A-G ,6 B,C,E,F,G -nonadecakis- O -benzyl Cyclomaltoheptaose (11)To a solution of compound 8 (228 mg, 76.3 µmol, 1 equiv) in THF (14 mL), TBAF (152 µL, 2 equiv) was added and the mixture was stirred for 5 h at r.t., then diluted in CH2Cl2 and processed as described above. After removal of the solvent, the crude product was purified by chromatography on a silica gel column, eluting with cyclohexane-EtOAc (6:1 then 4:1) to give compound 11 as a white powder (90%). R f = 0.24 (cyclohexane-EtOAc, 3:1). IR (KBr): 2100 (N3) cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.09-7.37 (m, 95 H, Harom.), 5.57 (d, J H1-H2 = 2.9 Hz, 1 H, H-1), 5.50 (d, J H1-H2 = 2.9 Hz, 1 H, H-1), 5.39 (d, J H1-H2 = 2.9 Hz, 1 H, H-1), 5.37 (d, J H1-H2 = 3.3 Hz, 1 H, H-1), 5.04-5.32 (m, CHPh, 6 × H-1), 5.02 (d, 2 H, H-1), 4.99 (d, 1 H, H-1), 4.96 (d, 1 H, H-1), 4.43-4.90 (m, CHPh), 3.85-4.20 (m, H-3, H-4, H-5, H-6), 3.44-3.83 (m, 14 × H-2, H-6). 13C NMR (100 MHz, CDCl3): δ = 137.77-139.31 (Carom.), 126.75-128.30 (CHarom.), 97.57-98.89 (C-1), 77.21-81.17 (C-2, C-3, C-4), 72.37-76.00 (CHPh), 70.58-71.77 (C-5), 68.58-69.63 (C-6), 61.40 (C-6), 51.96-52.20 (C-6A). MALDI-TOF MS: m/z calcd for C175H184O34N3: 2873.38; on sinapinic acid matrix found: 2867.23 [M - 5]+; on DHB matrix found: 2895.01 [MNa]+, 2868.28 [M - 26 + Na]+, 2846.02 [M - 26]+.

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6 D -Azido-6 D -deoxy-2 A-G ,3 A-G ,6 B,C,E,F,G -nonadecakis- O -benzyl Cyclomaltoheptaose-6 A -carboxylic Acid (14)To a solution of compound 11 (154 mg, 53 µmol, 1 equiv) in anhyd CH2Cl2 (6 mL), Dess-Martin periodinane reagent (68 mg, 160.8 µmol, 3 equiv) was added and the reaction mixture was stirred for 5 h at r.t., then diluted with Et2O, and aq NaHCO3 containing Na2S2O3 was added. This mixture was stirred for 15 min, extracted successively with NaHCO3 and H2O. The organic phases were dried (MgSO4) and evaporated to dryness. To the residue dissolved in THF-BuOH (1.8:4.2 mL), were added successively of 2-methyl-2-butene (1.8 mL), NaH2PO4 (119 mg) in H2O (1.8 mL) and of NaClO2 (107 mg). The reaction was stirred overnight, diluted in EtOAc and extracted with H2O. Organic phases were dried (MgSO4). The crude product was purified by chromatography on a silica gel column, eluting with pentane-EtOAc, (4:1 then 4:1 with 1% AcOH) to give 120 mg of compound 14; yield 79%. R f = 0.40 (pentane-EtOAc, 3:1, +1% AcOH). IR (KBr): 2100 (N3), 3063, 3030, 2926 (COOH), 1728 (COOH); cm-1. 1H NMR (400 MHz, CDCl3): δ = 10.02 (COOH), 6.97-7.37 (m, 95 H, Harom.), 5.72 (d, J H1-H2 = 3.5 Hz, 1 H, H-1), 5.70 (d, J H1-H2 = 3.9 Hz, 1 H, H-1), 5.63 (d, J H1-H2 = 3.4 Hz, 1 H, H-1), 5.46 (d, J H1-H2 = 3.3 Hz, 1 H, H-1), 4.24-5.37 (m, H-1, CHPh), 3.20-4.19 (m, H-2, H-3, H-4, H-5, H-6). 13C NMR (100 MHz, CDCl3): δ = 171,90 (C=O), 137.5-139.4 (Carom.), 97.14-99.75 (C-1), 77.92-81.36 (C-2, C-3, C-4), 72.47-76.44 (CH2Ph, C-6), 70.42-72.08 (C-5), 68.45-69.89 (C-6), 51.76 (C-6D). MALDI-TOF MS: m/z calcd for C175H181O35N3: 2886.36; on DHB matrix found: 2860.16 [M - 26]+.

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6 D -Amino-6 D -deoxy-cyclomaltoheptaose-6 A -carboxylic Acid (17)To a solution of compound 14 (35 mg, 12 µmol, 1 equiv) in THF-H2O (2.5:1 mL), Pd/C 10% (30 mg) and a catalytic amount of TFA were added and the reaction mixture was stirred overnight under hydrogen atmosphere. The suspension was filtered over Celite® and evaporated to give the desired product 17; yield 90%. 1H NMR (300 MHz, DMSO): δ = 7.98 (COOH), 4.78-44.96 (H-1), 4.00 (m, H-5, H-6), 3,25-3.89 (H-2, H-3, H-4, H-5, H-6), 3.05 (m, H-2, H-6), 2.82 (H-6). HRMS-ESI+: m/z calcd for C42H69O35N: 1148.3716; found: 1148.3722 [MH]+.

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6 A - O - tert -Butyldimethylsilyl-2 A-G ,3 A-G ,6 B,C,E,F,G -nonadecakis- O -methyl Cyclomaltoheptaose (6)To compound 3 (200 mg, 143 µmol, 1 equiv) dissolved in anhyd CH2Cl2 (4 mL) was added Et3N (1.6 mL). To the reaction was added TBSOTf (36 µL, 1.1 equiv) at 0 °C. The mixture was stirred overnight at r.t., diluted in CH2Cl2 and processed as described above. Purification by chromatography on a silica gel column, eluting with CH2Cl2-MeOH (97:3) gave 97 mg (45%) of compound 6. R f = 0.3 (CH2Cl2-MeOH, 96:4). 1H NMR (400 MHz, CDCl3): δ = 5.05-5.21 (m, 12 H, H-1), 5.02 (d, J H1-H2 = 3.4 Hz, 2 H, H-1), 3.62-4.05 (m, H-4, H-5, H-6, OCH3), 3.45-3.61 (m, H-3, H-4, H-5, H-6, OCH3), 3.34-3.42 (m, OCH3), 3.16-3.22 (m, 12 H, H-2), 3.14 (d, J H1-H2 = 3.3 Hz, 1 H, H-2), 3.11 (d, J H1-H2 = 3.5 Hz, 1 H, H-2), 0.90 [s, 9 H, SiC(CH3)3], 0.89 [s, 9 H, SiC(CH3)3], 0.05 (m, 12 H, SiCH3). 13C NMR (100 MHz, CDCl3): δ = 97.83-99.07 (C-1), 79.85-82.47 (C-2, C-3, C-4), 78.24-79.02 (C-4), 70.40-71.86 (C-5, C-6), 61.3 (C-6), 60.71-61.40 (OCH3-3), 58.55-58.95 (OCH3-2), 57.72-58.32 (OCH3-6), 25.60, 25.62 [SiC(CH3)3], 18.1 (SiC), -5.56, -5.37, -5.33 (SiCH3). ESI-MS+: m/z calcd for C67H122035Si: 1515.77; found: 1515.6 [M]+.

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6 A -Azido-6 A deoxy-6 D - O - tert -butyldimethylsilyl-2 A-G ,3 A-G ,6 B,C,E,F,G -nonadecakis- O -methyl Cyclomaltoheptaose (9)A solution of compound 6 (75 mg, 49.5 µmol, 1 equiv) in pyridine (1.6 mL) and DMAP (18 mg, 148.5 µmol, 3 equiv) was placed at 0 °C and MsCl (15 µL, 198 µmol, 4 equiv) was added. After 3 h of stirring, the mixture was diluted in CH2Cl2, extracted with H2O, and organic phases were dried (MgSO4) and evaporated to dryness. The residue was then dissolved in DMF (3.6 mL), NaN3 (99 mg, 1.52 mmol, 14 equiv) was added, and the mixture was heated at 70 °C overnight. The solution was evaporated to dryness, diluted in CH2Cl2 and washed twice with distilled H2O. The organic phases were dried (MgSO4), and the crude product was purified by chromatography on a silica gel column, eluting with CH2Cl2-MeOH (97:3) to give 54 mg of compound 9 (71%). R f = 0.37 (CH2Cl2-MeOH, 96:4). IR (KBr): 2100 (N3) cm-1. 1H NMR (400 MHz, CDCl3): δ = 5.05-5.20 (m, 14 H, H-1), 4.04-4.11 (m, H-6), 3.60-3.98 (m, H-4, H-5, H-6, OCH3), 3.44-3.58 (m, H-3, H-4, H-5, H-6, OCH3), 3.36-3.42 (m, OCH3), 3.15-3.22 (m, 12 H, H-2), 3.13 (dd, J H1-H2 = 3.0 Hz, J H2-H3 = 9.7 Hz, 2 H, H-2), 0.90 [m, 18 H, SiC(CH3)3], 0.06 (m, 12 H, SiCH3). 13C NMR (100 MHz, CDCl3): δ = 98.09-99.49 (C-1), 81.29-82.18 (C-2, C-3), 79.05-80.65 (C-4), 72.14, 72.22 (C-5), 71.17-71.52 (C-6), 70.76-70.96 (C-5), 62.47, 62.46 (C-6D), 61.20-61.63 (OCH3-3), 58.90-58.99 (OCH3-2), 58.37-58.67 (OCH3-6), 52.01, 53.38 (C-6A), 25.90 [SiC(CH3)3], 18.34, 18.36 (SiC), -5.27, -5.1 (SiCH3). ESI-MS+: m/z calcd for C67H121034N3Si: 1540.78; found: 1540.8 [M]+.

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6 A -Azido-6 A -deoxy-2 A-G ,3 A-G ,6 B,C,E,F,G -nonadecakis- O -methyl Cyclomaltoheptaose (12)To a solution of compound 9 (54 mg, 35 µmol, 1 equiv) in THF (6.7 mL), TBAF (70 µL, 2 equiv) was added and the mixture was stirred 5 h at r.t. Then, H2O was added and the organic phase was separated. After removal of the solvent, the crude product was purified by chromatography on a silica gel column, eluting with CH2Cl2-MeOH (97:3) to give compound 12 (90%). R f = 0.27 (CH2Cl2-MeOH, 96:4). IR (KBr): 2100 (N3) cm-1. 1H NMR (400 MHz, CDCl3): δ = 5.21 (d, J H1-H2 = 3.6 Hz, 2 H, H-1), 5.16 (d, J H1-H2 = 3.6 Hz, 1 H, H-1), 5.12 (d, J H1-H2 = 3.8 Hz, 1 H, H-1), 5.07-5.10 (m, 7 H, 7 × H-1), 5.05 (d, J H1-H2 = 3.6 Hz, 1 H, H-1), 5.02 (d, J H1-H2 = 3.4 Hz, 2 H, H-1), 3.57-4.00 (m, H-4, H-5, H-6, OCH3), 3.41-3.56 (m, H-3, H-4, H-5, H-6, OCH3), 3.34-3.40 (m, OCH3), 3.15-3.22 (m, 14 H, H-2). 13C NMR (100 MHz, CDCl3): δ = 98.49-99.45 (C-1), 79.71-82.28 (C-2, C-3, C-4), 78.38, 78.44 (C-4), 70.68-71.76 (C-5, C-6), 61.60 (C-6), 60.96-61.67 (OCH3-3), 60.35 (C-6), 58.11-59.14 (OCH3-2, OCH3-6), 51.99, 52.07, 52.30 (C-6). ESI-MS+: m/z calcd for C61H107034N3: 1426.52; found: 1426.8 [M]+.

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6 D -Azido-6 D -deoxy-2 A-G ,3 A-G ,6 B,C,E,F,G -nonadecakis- O -methyl Cyclomaltoheptaose-6 D -carboxylic Acid (15)To a solution of compound 12 (42 mg, 29.5 µmol, 1 equiv) in anhyd CH2Cl2 (1.5 mL), Dess-Martin periodinane reagent (70 mg, 165 µmol, 5 equiv) was added. The reaction mixture was stirred 5 h at r.t., diluted in Et2O, and NaHCO3 containing Na2S2O3 was added. The solution was stirred 15 min, then extracted successively with NaHCO3 and H2O. The organic phases were dried over MgSO4 and evaporated to dryness. To a solution of the residue dissolved in THF-BuOH (0.9:2 mL), were added of 2-methyl-2-butene (0.9 mL), NaH2PO4 (60.2 mg) in H2O (0.9 mL) and NaClO2 (53 mg). The solution was stirred overnight, diluted in EtOAc and extracted with H2O. The organic phases were dried (MgSO4) to give 35 mg of compound 15; yield 77%. IR (KBr): 2100 (N3), 3030, 2929, (COOH), 1732 (COOH) cm-1. ESI-MS+: m/z calcd for C61H105035N3: 1440.50; found: 1440.8 [M].

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6 A - O - tert -Butyldimethylsilyl-2 A-F ,3 A-F ,6 B,C,E,F -hexadecakis- O -benzyl Cyclomaltohexaose (4)The same procedure was used as for 5 starting with compound 1 (1.5 g, 621 µmol) to give 600 mg (42%) of compound 4 after purification by column chromatography. R f = 0.40 (cyclohexane-EtOAc, 3:1). 1H NMR (800 MHz, CDCl3): δ = 7.08-7.33 (m, 80 H, Harom.), 5.57 (d, J H1-H2 = 3.5 Hz, 1 H, H-1), 5.48 (d, J H1-H2 = 3.5 Hz, 1 H, H-1), 5.36 (d, 2 J CH2 = 10.6 Hz, 1 H, CHPh), 5.32 (d, 2 J CH2 = 10.6 Hz, 1 H, CHPh), 5.23 (d, 2 J CH2 = 10.6 Hz, 1 H, CHPh), 5.19 (d, 2 J CH2 = 10.9 Hz, 1 H, CHPh), 5.04 (d, J H1-H2 = 3.2 Hz, 1 H, H-1), 4.96 (d, 2 J CH2 = 11.1 Hz, 1 H, CHPh), 4.90-4.97 (m, CH2Ph), 4.89 (d, J H1-H2 = 3.7 Hz, 2 H, H-1), 4.84 (d, J H1-H2 = 3.1 Hz, 1 H, H-1), 4.83 (d, 2 J CH2 = 10.4 Hz, 1 H, CHPh), 4.81 (d, 2 J CH2 = 10.8 Hz, 1 H, CHPh), 4.80 (d, 2 J CH2 = 11.1 Hz, 1 H, CHPh), 4.71 (d, 2 J CH2 = 12.0 Hz, 1 H, CHPh), 4.68 (d, 2 J CH2 = 12.1 Hz, 1 H, CHPh), 4.57 (d, 2 J CH2 = 12.4 Hz, 1 H, CHPh), 4.38-4.54 (m, CH2Ph), 4.36 (d, 2 J CH2 = 12.1 Hz, 1 H, CHPh), 4.06-4.26 (m, 12 H, 3 × H-6, 3 × H-4, 6 × H-3), 3.85-3.99 (m, 11 H, 3 × H-6, 5 × H-5, 3 × H-4), 3.81 (m, 1 H, H-5), 3.70-3.72 (m, 3 H, 3 × H-6), 3.66 (m, 1 H, H-6), 3.59-3.61 (m, 2 H, 1 × H-2, 1 × H-6), 3.55 (dd, J H1-H2 = 3.6 Hz, J H2-H3 = 9.9 Hz, 1 H, H-2), 3.47-3.49 (m, 2 H, 1 × H-2, 1 × H-6), 3.44 (dd, J H1-H2 = 3.3 Hz, J H2-H3 = 9.9 Hz, 1 H, H-2), 3.40 (dd, J H1-H2 = 3.6 Hz, J H2-H3 = 9.7 Hz, 1 H, H-2), 3.35 (dd, J H1-H2 = 3.1 Hz, J H2-H3 = 9.8 Hz, 1 H, H-2), 2.59 (br s, 1 H, OH), 0.87 [s, 12 H, SiC(CH3)], 0.00 (s, 6 H, SiCH3). 13C NMR (200 MHz, CDCl3): δ = 137.90, 137.93, 138.04, 138.06, 138.14, 138.22, 138.34, 138.45, 138.51, 139.13, 139.21, 139.25, 139.31, 139.38 (Carom. quat.), 126.81-128.33 (CHarom.), 97.75, 97.87, 97.92, 98.00, 98.07, 98.76 (6 × C-1), 79.78, 80.81, 80.84, 80.98, 81.28, 81.37 (6 × C-3 and C-4), 80.02, 80.52 (2 × C-4), 79.55 (1 × C-2), 79.41 (1 × C-4), 78.16, 78.53, 78.93, 79.11, 79.21 (5 × C-2), 75.97, 76.08 (CH2Ph), 75.75, 75.84 (C-4), 72.41, 72.58, 72.89, 72.92, 72.98, 73.04, 73.29, 73.33, 74.64, 74.77, 75.64, 75.71 (CH2Ph), 71.33, 71.38, 71.63, 71.78, 71.89, 72.21 (6 × C-5), 61.4, 62.55, 68.83, 69.2, 69.26, 69.29 (6 × C-6), 26.01 [3 × SiC(CH3)], 18.32 (SiC), -4.85, -4.71 (2 × SiCH3). MALDI-TOF MS: m/z calcd for C154H169O30SiNa: 2551.08; found: 2551.08 [MNa]+.

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6 A -Azido-6 A deoxy-6 D - O - tert -butyldimethylsilyl-2 A-F ,3 A-F ,6 B,C,E,F -hexadecakis- O -benzyl Cyclomaltohexaose (7)The same procedure was used as for 8 starting with compound 4 (600 mg, 245 µmol) to give 516 mg (85%) of compound 7 after purification by column chromatography. R f = 0.5 (cyclohexane-EtOAc, 3:1). IR (KBr): 2100 (N3) cm-1. 1H NMR (800 MHz, CDCl3): δ = 7.13-7.31 (m, 80 H, Harom.), 5.31 (d, J H1-H2 = 3.4 Hz, 1 H, H-1), 5.22 (d, 2 J CH2 = 10.9 Hz, 1 H, CHPh), 5.19 (d, 2 J CH2 = 10.9 Hz, 1 H, CHPh), 5.18 (d, 2 J CH2 = 10.9 Hz, 1 H, CHPh), 5.15-5.17 (m, 4 H, 3 × CHPh, 1 × H-1), 5.11 (d, 2 J CH2 = 11.0 Hz, 1 H, CHPh), 5.06 (d, J H1-H2 = 3.1 Hz, 2 H, H-1), 5.02 (m, 2 H, H-1), 4.90 (d, 2JCH2 = 10.9 Hz, 1 H, CHPh), 4.88 (d, 2 J CH2 = 10.9 Hz, 1 H, CHPh), 4.86 (d, 2 J CH2 = 11.3 Hz, 1 H, CHPh), 4.85 (m, 5 H, CH2Ph), 4.58 (d, 2 J CH2 = 12.3 Hz, 1 H, CHPh), 4.57 (d, 2 J CH2 = 12.3 Hz, 1 H, CHPh), 4.41-4.55 (m, 20 H, CH2Ph), 4.38 (d, 2 J CH2 = 12.0 Hz, 1 H, CHPh), 4.33 (d, 2 J CH2 = 12.0 Hz, 1 H, CHPh), 4.22 (dd, J H6-H6 ′ = 1.9 Hz, J H5-H6 = 11.6 Hz, 1 H, H-6D), 4.06-4.20 (m, 11 H, 6 × H-3, 3 × H-4, 2 × H-6), 3.94-4.05 (m, 7 H, 3 × H-4, 2 × H-5, 2 × H-6), 3.93 (m, 1 H, H-5), 3.91 (m, 1 H, H-5), 3.85 (m, 1 H, H-5), 3.79 (m, 1 H, H-5), 3.72 (m, 1 H, H-4), 3.70 (d, J H5-H6 = 11.3 Hz, 1 H, H-6′D), 3.65 (d, J H5-H6 = 10.2 Hz, 1 H, H-6), 3.63 (d, J H5-H6 = 10.6 Hz, 1 H, H-6), 3.58 (d, J H5-H6 = 10.6 Hz, 1 H, H-6), 3.54 (dd, J H1-H2 = 3.4 Hz, J H2-H3 = 9.7 Hz, 1 H, H-2), 3.51-3.54 (m, 3 H, 1 × H-2, H-6′A, 1 × H-6), 3.51 (dd, J H1-H2 = 3.2 Hz, J H2-H3 = 9.7 Hz, 1 H, H-2), 3.49 (dd, J H1-H2 = 3.5 Hz, J H2-H3 = 9.9 Hz, 1 H, H-2), 3.47 (dd, J H1-H2 = 3.4 Hz, J H2-H3 = 9.9 Hz, 1 H, H-2), 3.41-3.45 (m, 2 H, 1 × H-2, H-6A), 3.39 (dd, J H1-H2 = 3.3 Hz, J H2-H3 = 9.8 Hz, 1 H, H-2), 0.88 [s,12 H, SiC(CH3)], 0.00 (s, 6 H, SiCH3). 13C NMR (200 MHz, CDCl3): δ = 139.33, 139.29, 139.23, 139.16, 138.34, 138.28, 138.22, 138.19, 138.17, 138.15, 138.04, 138.01, 137.99 (Carom.), 126.86-128.35 (CHarom.), 97.69, 98.07, 98.37, 98.59, 98.62, 98.75 (C-1), 80.60, 80.72, 80.81, 80.99, 81.08, 81.17 [6 × (C-3 + C-4)], 80.03 (C-4), 78.63, 78.88, 78.94, 79.01, 79.04, 79.12, 79.17, 79.61 [6 × C-2, 4 × (C-3 + C-4)], 78.22 (C-3 and C-4), 72.61, 72.70, 72.79, 72.99, 73.35, 73.38, 73.42, 73.49, 75.35, 75.38, 75.64 (CH2Ph), 70.78, 71.40, 71.54, 71.60, 71.75, 72.43 (C-5), 68.77, 69.06, 69.13, 69.20 (C-6), 62.48 (C-6D), 52.11 (C-6A), 25.97 [SiC(CH3)], 18.31 (SiC), -5.12, -4.89 (SiCH3). MALDI-TOF MS: m/z calcd for C154H169O29N3Si: 2554.12; on sinapinic acid matrix found: 2548.95 [M - 5]+; on DHB matrix found: 2527.97 [M - 26]+, 2549.92 [M - 5]+.

24

6 A -Azido-6 A deoxy-2 A-F ,3 A-F ,6 B,C,E,F -hexadecakis- O -benzyl Cyclomaltohexaose (10)Same procedure was used as for 11 starting with compound 7 (496 mg, 194 µmol) to give 420 mg (90%) of compound 10 after purification by column chromatography. R f = 0.3 (cyclohexane-EtOAc, 3:1). IR (KBr): 2100 (N3) cm-1. 1H NMR (800 MHz, CDCl3): δ = 7.09-7.34 (m, 80 H, Harom.), 5.54 (d, J H1-H2 = 3.7 Hz, 1 H, H-1), 5.51 (d, J H1-H2 = 3.7 Hz, 1 H, H-1), 5.47 (d, 2 J CH2 = 10.5 Hz, 1 H, CHPh), 5.36 (d, 2 J CH2 = 10.5 Hz, 1 H, CHPh), 5.21 (d, 2 J CH2 = 10.8 Hz, 1 H, CHPh), 5.15 (d, 2 J CH2 = 10.8 Hz, 1 H, CHPh), 4.91 (d, 2 J CH2 = 10.2 Hz, 1 H, CHPh), 4.85-4.90 (m, 5 H, 1 × H-1, 4 × CHPh), 4.85 (d, J H1-H2 = 3.4 Hz, 1 H, H-1), 4.81-4.83 (m, 2 H, 1 × H-1, 1 × CHPh), 4.79-4.78 (m, 2 H, 2 J CH2 = 10.5 Hz, J H1-H2 = 3.7 Hz, 1 × H-1, 1 × CHPh), 4.72 (d, 2 J CH2 = 12.0 Hz, 1 H, CHPh), 5.57 (d, 2 J CH2 = 12.2 Hz, 1 H, CHPh), 4.56 (d, 2 J CH2 = 12.2 Hz, 1 H, CHPh), 4.35-4.55 (m, 16 H, CHPh), 4.34 (d, 2 J CH2 = 12.5 Hz, 1 H, CHPh), 4.17-4.20 (m, 2 H, H-3), 4.03-4.12 (m, 7 H, 4 × H-3, 1 × H-4, 1 × H-5, 1 × H-6), 3.92-4.03 (m, 2 × H-4, 2 × H-5, 3 × H-6), 3.77-3.92 (m, 6 H, 3 × H-4, 3 × H-5), 3.72-3.76 (m, 4 H, H-6′D, 3 × H-6), 3.63-3.65 (m, 1 H, H-6D), 3,56-3,60 (m, 4 H, 1 × H-6A, 1 × H-6, 2 × H-2), 3.47 (dd, J H1-H2 = 3.3 Hz, J H2-H3 = 10.0 Hz, 1 H, H-2), 3.45 (dd, J H1-H2 = 3.3 Hz, J H2-H3 = 10.0 Hz, 1 H, H-2), 3.42 (dd, J H1-H2 = 3.3 Hz, J H2-H3 = 9.8 Hz, 1 H, H-2), 3.36-3.39 (m, 2 H, 1 × H-2, H-6A), 13C NMR (200 MHz, CDCl3): δ = 137.79, 137.87, 137.93, 138.06, 138.21, 138.49, 139.07, 139.17, 139.20, 139.22, 139.25, 139.29 (Carom.), 126.49-128.36 (CHarom.), 97.99, 98.02, 98.12, 92.28, 98.35 (C-1), 80.39, 80.55, 80.62, 80.71, 80.76, 80.80, 80.90, 81.00, 81.11, 81.23 (6 × C-3, 4 × C-4), 77.91, 77.99, 78.98, 79.01, 79.44, 79.67 (C-2), 76.13, 76.62 (C-4), 72.32, 72.39, 72.92, 73.14, 73.30, 73.37, 73.40, 74.33, 74.41, 75.80, 75.92, 76.15, 76.18 (CH2-Ph), 70.42, 71.49, 71.68, 71.70, 71.75, 71.77 (C-5), 69.00, 69.30, 69.42, 69.48 (4 × C-6), 62.06 (C-6D), 51.98 (C-6A). MALDI-TOF MS: m/z calcd for C148H155O29N3: 2439.85; on sinapinic acid matrix found: 2434.34 [M - 5]+; on DHB matrix found: 2414.24 [M - 26]+, 2435.22 [M - 5]+, 2462.27 [MNa]+.

25

6 D -Azido-6 D deoxy-2 A-F ,3 A-F ,6 B,C,E,F -hexadecakis- O -benzyl Cyclomaltohexaose-6 A -carboxylic Acid (13)The same procedure was used as for 14 starting with compound 10 (380 mg, 156 µmol) to give 325 mg (85%) of compound 13 after purification by column chromatography. R f = 0.2 (pentane-EtOAc, 3:1). IR (KBr): 2100 (N3) cm-1. 1H NMR (800 MHz, CDCl3): δ = 7.06-7.36 (m, 80 H, Harom.), 5.71 (d, J H1-H2 = 3.7 Hz, 1 H, H-1), 5.69 (d, J H1-H2 = 3.1 Hz, 1 H, H-1), 5.51 (d, 2 J CH2 = 10.2 Hz, 1 H, CHPh), 5.48 (d, 2 J CH2 = 10.2 Hz, 1 H, CHPh), 5.17 (d, 2 J CH2 = 10.5 Hz, 1 H, CHPh), 5.09 (d, 2 J CH2 = 10.9 Hz, 1 H, CHPh), 4.93 (d, 2 J CH2 = 10.2 Hz, 1 H, CHPh), 4.91 (d, 2 J CH2 = 10.8 Hz, 2 H, CHPh), 4.83-4.90 (m, 3 H, 1 × H-1, 2 × CHPh), 4.80 (d, 1 H, H-1), 4.78 (d, 2 J CH2 = 10.8 Hz, 1 H, CHPh), 4.76 (d, 2 J CH2 = 12.2 Hz, 1 H, CHPh), 4.74 (d, 1 H, CHPh), 4.72 (d, 2 J CH2 = 10.9 Hz, 1 H, CHPh), 4.68 (d, 1 H, H-1), 4.66 (d, 2 J CH2 = 12.6 Hz, 1 H, CHPh), 4.65 (d, 2 J CH2 = 12.0 Hz, 1 H, CHPh), 4.63 (d, 1 H, H-1), 4.60 (d, 2 J CH2 = 12.6 Hz, 3 H, CHPh), 4.55 (m, 2 H, CHPh), 4.47-4.52 (m, 5 H, 4 × CHPh, 1 × H-6), 4.41 (d, 2 J CH2 = 12.0 Hz, 1 H, CHPh), 4.27-4.37 (m, 2 × H-6, CHPh), 3.98-4.24 (m, 6 × H-3, H-5, 3 × H-6), 3.89-3.92 (m, 2 H, 2 × H-5), 3.80 (m, 1 H, H-5), 3.75 (d, 1 H, J H5-H6 = 11.1 Hz, H-6), 3.66 (d, J H5-H6 = 11.1 Hz, 1 H, H-6), 3.54-3.59 (m, 4 H, 2 × H-2, H-6D, 1 × H-6), 3.50 (dd, 1 H, H-2), 3.44-3.46 (m, 2 H, 2 × H-2), 3.31-3.35 (m, 2 H, H-6D, 1 × H-6), 3.29 (dd, J H1-H2 = 3.2 Hz, J H2-H3 = 10.1 Hz, 1 H, H-2), 3.24-3.26 (m, 1 H, H-4). 13C NMR (200 MHz, CDCl3): δ = 137.77-139.26 (Carom.), 126.19-128.65 (CHarom.), 96.12, 97.27, 97.68, 98.15, 98.77, 98.93 (6 × C-1), 83.31 (1 × C-4), 80.37-81.28 (C-3, C-4), 77.75, 77.80, 79.06, 79.10, 79.18, 79.79 (C-2), 76.14, 76.21, 76.40, 76.46 (CH2Ph), 75.41 (1 × CH), 72.18-74.20 (CH2-Ph, 1 × CH), 70.70, 71.22, 71.75 (4 × CH), 68.70, 68.80, 69.43, 70.22, 70.68 (5 × C-6), 51.39 (C-6D). MALDI-TOF MS: m/z calcd for C148H153O30N3: 2453.84; on sinapinic acid matrix found: 2455.50 [MH]+, 2471.47 [M + H2O]+; on DHB matrix found: 2427.10 [M - 26]+.

26

6 D -Amino-6 D -deoxy-cyclomaltohexaose-6 A -carboxylic Acid (16)Same procedure was used as for 17 starting with compound 13 (100 mg, 40.75 µmol) to give 36 mg (90%) of compound 16. 1H NMR (800 MHz, DMSO): δ = 4.95 (d, 1 H, H-1), 4.84 (d, 1 H, H-1), 4.81 (m, 2 H, H-1), 4.79 (d, 1 H, H-1), 4.69 (d, 1 H, H-1), 3.85 (m, 1 H, H-5), 3.70-3.81 (m, 5 × H-3, 1 × H-4), 3.56-3.68 (1 × H-3, 5 × H-5, 1 × H-6), 3.51-3.53 (1 × H-4), 3.36-3.46 (m, 3 × H-4, 1 × H-6), 3.27-3.34 (m, 6 H, 5 × H-2, 1 × H-6D), 3.19 (m, 2 H, 1 × H-2, 1 × H-4), 3.00 (m, 1 H, H-6D). 13C NMR (200 MHz, DMSO): δ = 100.70-101.87 (C-1), 81.72-84.06 (C-4), 71.40-73.04 (C-3, C-2, C-5), 68.36 (1 × C-5), 59.69-60.62 (5 × C-6), 46.33 (1 × C-6). HRMS-ESI+: m/z calcd for C36H60O30N: 986.3178 [M]; found: 986.3194 [MH]+.