J. Bjerre, T. Hauch Fenger, L. G. Marinescu, M. Bols
FULL PAPER
241 polarimeter at room temperature. IR spectra were recorded on
2 H), 4.77–4.61 (m, 7 H), 4.58–4.48 (m, 5 H), 4.42–4.21 (m, 24
H), 3.99–3.62 (m, 23 H), 3.56–3.24 (m, 12 H). 13C NMR (CDCl3,
100 MHz): δC = 139.75, 139.68, 139.63, 139.02, 138.81, 138.73,
138.58, 138.46, 138.40, 138.38 (C-ipso), 128.38, 128.35, 128.31,
128.29, 128.27, 128.24, 128.21, 128.18, 128.15, 128.03, 127.94,
127.88, 127.36, 127.33, 127.29, 127.24, 127.22, 127.19, 127.14,
1
a Perkin–Elmer FT-IR PARAGON 1000. H, 13C and 19F NMR
spectra were recorded on a Varian Mercury 400 MHz spectrometer.
Chemical shifts are given in ppm and referenced to internal SiMe4
(δH, δC = 0.00). J values are given in Hz. MALDI-TOF Mass spec-
tra were recorded on a Bruker Daltonics mass spectrometer
(Bruker) using a α-cyano-4-hydroxycinnamic acid (HCCA) matrix. 127.12, 127.08, 127.05 (C-Ph), 99.12, 99.04, 98.95, 98.90, 98.84,
98.74, 98.42 (C-1), 82.31, 82.12, 81.98, 79.89, 79.76, 79.34, 79.10,
78.84, 78.53, 78.11, 76.53, 75.91, 75.23, 73.87, 73.68, 73.02, 72.83,
71.98, 69.23 (CH, CH2).
6A,6D-Di-C-trifluoromethyl-2A–G,3A–G,6B,6C,6E,6F,6G-nonadecakis-
Undodecakis-O-benzyl-β-cyclodextrin (5): β-Cyclodextrin (3.76 g,
3.31 mmol) was dissolved in DMSO (100 mL) under N2. NaH
(5.46 g, 55%, 125 mmol) was added and stirred for 30 min. Benzyl
chloride (18.7 g, 147.7 mmol) was added at 0 °C and left stirring
O-benzyl-β-cyclodextrin (8): Nonadecabenzylated β-cyclodextrind-
icarbaldehyde 7 (3 g, 1.06 mmol) was dissolved in dry DMF (6 mL)
under nitrogen atmosphere. Arduengo carbene (107 mg,
0.317 mmol, 0.3 equiv.) and TMSCF3 (3.12 mL, 21.1 mmol,
20 equiv.) were added, yielding a clear orange solution which was
left stirring at room temperature under nitrogen atmosphere for
1.5 hours. The reaction progress was monitored by TLC (silica, elu-
ent EtOAc/pentane, 1:3). Upon completion, water (50 mL) was
added and the reaction was extracted with diethyl ether
(5ϫ40 mL). The combined organic phases were washed with satd.
aq. NaHCO3 (3 ϫ 60 mL), brine (4 ϫ 50 mL) and water
(9ϫ70 mL). The organic layer was dried (MgSO4), filtered and
concentrated in vacuo, yielding 3.38 g crude silylated product as a
pale yellow foam. The silyl bonds were hydrolyzed by dissolving
the crude product in a mixture of 0.50% TFA in EtOAc/MeOH
(2:3, 50 mL). The solution was stirred vigorously at room tempera-
ture for 10 min and concentrated under reduced pressure. The
crude product was purified by flash chromatography (eluent gradi-
ent, EtOAc/pentane, 1:7 Ǟ 1:0) to afford the desired product
(847 mg, 27%) as a colorless solid. Two major product spots were
seen on the TLC plate and the shorter-running enantiomer mixture
was isolated and analyzed: [α]D = +35.3 (c = 1.0, CHCl3). IR
overnight at room temperature. Water (80 mL) was added slowly,
and the mixture was extracted with EtOAc (5ϫ100 mL). The com-
bined organic phases were washed with brine, dried with MgSO4
and concentrated. The residue was purified by flash chromatog-
raphy (EtOAc/pentane, 1:5) to give 9.59 g of compound 5[45] (95%
yield) as a colorless foam. 1H NMR (CDCl3 400 MHz): δH = 7.30–
7.15 (m, 105 H, Ph), 5.32 (d, J = 3.2 Hz, 7 H, 1-H), 5.18 (d, J =
9.8 Hz, 7 H, CH2Ph), 4.88 (d, J = 9.8 Hz, 7 H, CH2Ph), 4.62 (d, 7
H, CH2Ph), 4.58 (d, 7 H, CH2Ph), 4.52 (d, 7 H, CH2Ph), 4.46 (d,
7 H, CH2Ph), 4.20–4.06 (m, 28 H, 3-H, 5-H, 6-H), 3.68 (d, 7 H, J
= 10.3 Hz, 4-H), 3.60 (dd, 7 H, 2-H). 13C NMR (CDCl3,
100 MHz): δC = 138.17–137.09 (C-ipso), 127.07–125.86 (C-Ph),
97.37 (C-1), 79.83, 77.68 (OCH2Ph), 74.37, 72.19 (C-2), 72.19 (C-
4), 71.56 (C-3), 70.41 (C-6), 68.21 (C-5).
2A–G,3A–G,6B,6C,6E,6F,6G-Nonadecakis-O-benzyl-β-cyclodextrin
(6):[38–40] To a solution of compound 5 (7.56 g, 2.50 mmol) and 4-
Å molecular sieves (53 g) in toluene (350 mL), stirred under N2 for
1 h, was added DIBAL-H (1.5 ) (80 mL, 120 mmol) dropwise, and
left stirring overnight. The reaction was monitored by TLC
(EtOAc/pentane, 1:3) until no starting material (Rf = 0.55) and no
monool (Rf = 0.26) were observed, and only the diol occurred (Rf
= 0.13). The mixture was cooled to 0 °C before slowly adding water
(300 mL), and stirred for 30 min. EtOAc (300 mL) was added and
the mixture was filtered through Celite, washed with EtOAc
(5ϫ50 mL). The combined organic phases were washed with brine
(3ϫ50 mL), and dried with MgSO4. The residue was concentrated
and purified by flash chromatography (EtOAc/pentane, 1:4) to give
compound 6 (6.12 g, 86% yield) as a colorless foam. 1H NMR
(CDCl3 400 MHz): δH = 7.32–7.00 (m, 95 H, Ph), 5.60 (dd, 2 H),
5.24 (m, 4 H), 5.06 (m, 5 H), 4.95–4.67 (m, 12 H), 4.62–4.43 (m,
23 H), 4.11–3.90 (m, 28 H), 3.83–3.43 (m, 16 H), 2.78 (br. s, 1 H,
(KBr): ν = 3424, 3028, 2925, 2866, 1496, 1453, 1357, 1095, 1040,
˜
733, 696 cm–1; 1H NMR (CDCl3 400 MHz): δH = 7.26–6.86 (m, 95
H, H-Ph), 5.64 (d, 0.1 H, J1,2 = 3.6 Hz, 1-H), 5.40 (d, 0.1 H, J1,2
= 4.0 Hz, 1-H), 5.34 (d, 0.3 H, J1,2 = 4.0 Hz, 1-H), 5.26 (m, 0.1 H,
1-H), 5.20–4.75 (m, 9.7 H), 5.12 (d, J = 3.6 Hz), 5.08 (d, J =
3.6 Hz), 4.86 (d, J = 3.6 Hz), 4.78 (dd, J = 3.2 Hz, J = 7.6 Hz),
4.75–4.09 (m, 40 H), 4.01–3.57 (m, 22.6 H), 3.57–3.27 (m, 11.5 H),
3.24 (dd, 0.7 H, J1,2 = 3.2 Hz, J2,3 = 9.6 Hz, 2-H). 13C NMR
(100 MHz, CDCl3): δC = 139.6–137.4 (C-ipso), 128.6–126.7 (CH-
Ph), 100.1, 99.4, 99.3, 99.1, 98.9, 98.7, 98.4, 98.1, 97.8, 97.5 (10
C1), 83.1, 81.2, 81.1, 80.9, 80.7, 80.4, 80.1, 79.6, 79.4, 79.0, 78.8,
78.6, 78.3, 76.6, 76.5, 76.2, 76.0, 75.7, 75.4, 74.4, 74.0, 73.7, 73.6,
73.5, 73.4, 73.3, 73.2, 7.1, 73.0, 72.9, 72.7, 72.6, 72.5, 72.3, 72.1,
71.7, 71.6, 70.9, 70.4, 69.9, 69.5, 69.3, 69.0, 68.4, 67.9. 19F NMR
OH), 2.68 (br. s, 1 H, OH). 13C NMR (CDCl3, 100 MHz): δC
=
139.76, 139.62, 139.42, 139.02, 138.85, 138.56, 138.42, 138.35,
138.23, 138.18, 138.06 (Cipso), 128.12, 128.03, 128.01, 127.94,
127.91, 127.87, 127.85, 127.82, 127.80, 127.76, 127.74, 127.55,
127.53, 127.51, 127.49, 127.33, 127.21, 127.09, 127.01, 126.75,
126.63, 126.52 (CPh), 99.67, 99.63, 98.61, 98.58, 98.53, 98.12, 97.92
(C-1), 82.12, 81.82, 81.75, 81.70, 81.61, 81.49, 81.01, 80.85, 79.76,
76.25, 76.08, 75.81, 73.74, 73.02, 71.88, 69.72 (CH, CH2), 61.86
(CH2-OH).
3
(377 MHz, CDCl3): δF: –71.5 (d, JF,H-6 = 6.8 Hz), –72.0 (br. s), –
3
7 2 . 4 ( b r . s ) , – 7 3 . 9 ( d ,
J
= 6 . 8 H z ) ,
F , H - 6
3
3
–74.0 (d, JF,H-6 = 6.4 Hz), –74.5 (br. s), –74.7 (d, JF,H-6
6.8 Hz), –75.0 (d, JF,H-6 = 8.3 Hz). MALDI-TOF-MS, m/z calcd.
=
3
for C177H182F6O35Na 3004.2263, found 3004.6748.
2A–G,3A–G,6B,6C,6E,6,6G-Nonadecakis-O-benzyl-6A,6D-dioxo-β-cyclo- 6A,6D-Di-C-trifluoromethyl-β-cyclodextrin (2): Nonadecabenzylated
dextrin (7): Dess–Martin reagent was added to a solution of com-
pound 6 (4.42 g, 1.55 mmol) in DCM (200 mL), at 25 °C, under N2.
After 2 h, Et2O (200 mL), and satd. aqueous NaHCO3 (150 mL)
containing Na2S2O3 (6.5 g) was added and stirred for 1 h. The resi-
due was diluted with Et2O (150 mL), and washed with satd.
NaHCO3 (4ϫ40 mL) and water (3ϫ40 mL). The organic phases
were dried with MgSO4 and concentrated to give compound 6,[46]
di-trifluoromethylated β-cyclodextrin 8 (216 mg, 0.072 mmol) was
dissolved in EtOAc/MeOH (1:1, 15 mL). Pd(OH)2 (20%, 200 mg)
and TFA (cat.) were added and the mixture was stirred at room
temperature under hydrogen atmosphere until completion of the
reaction. Filtration through Celite and evaporation of the solvent
gave the desired product 2 (87 mg, 95%) as a colorless powder.
[α]D = +97.6 (c = 0.68, D O). IR (KBr): ν = 3404, 2934, 1678,
˜
2
with same Rf as the starting material, as a colorless foam in a quan- 1426, 1369, 1284, 1156, 1080, 1030, 945, 701, 578 cm–1. H NMR
1
titative yield. 1H NMR (CDCl3, 400 MHz): δH = 9.42 (s, 2 H,
CHO), 7.22–7.00 (m, 95 H, Ph), 5.18–4.98 (m, 10 H), 4.91–4.80 (m, H, 6-H(A,D)], 3.92–3.39 (m, 38 H). 19F NMR (377 MHz, D2O):
(400 MHz, D2O): δH = 5.00–4.95 (m, 7 H, 1-H), 4.04–4.00 [m, 2
708
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Eur. J. Org. Chem. 2007, 704–710