Cyclodextrin Homo- and Heterodimers
2237±2250
N,N'-Bis[mono(3-deoxy)-b-CD]-decane-1,10-diamide (2): Deprotection of
22 was performed as described for compound 1. Using dried dimer 22
(0.59 g) and a solution of TBAF (2.70 mL, 1.0m) in THF yielded the pure
product after work up. Yield: 0.31 g (88%). M.p.: 246 ± 2488C; Rf(E) 0.1;
1H NMR (600 MHz, D2O): see Table 1. 13C NMR (100 MHz, D2O): d
addition of 2-(4'-aminophenyl)ethyl alcohol (2.0 g, 14.6 mmol), the reac-
tion mixture was refluxed for 72 h. On cooling a precipitate was formed,
which was removed by filtration. After recrystallization (twice) from water,
the resulting slightly yellow solid was collected and dried in vacuo. Yield:
1.40 g (53%). M.p.: > 3508C; 1H NMR (90 MHz, D2O:[D6]DMSO, 10:1,
v/v): d 8.3 (s, 1H; H Ar), 8.0 (d, 1H; H Ar), 7.7 (m, 2H; H Ar), 7.5 (m,
2H; H Ar), 7.3 (m, 4H; H Ar), 3.8 (t, 2H, CH2 OH), 2.8 (t, 2H,
CH2 Ar); MS (FAB): m/z: 365 [M1]; C18H16NSO4Na: calcd C 59.17, H
4.41, N 3.83; found C 58.95, H 4.30, N 3.81.
177.84 and 176.98 (C O), 105.02 ± 102.30 (C-1), 82.41 ± 80.05 and 77.86 ±
69.06 (C-2, C-3, C-4, C-5), 61.90 ± 60.71 (C-6), 52.45 and 52.13 (C NH),
37.62, 36.87, 30.28, 30.16, 29.12, 28.77, 26.95 and 26.32 (8 Â CH2 ± spacer); IR
(KBr): nÄ 1670 ± 1610, 1560 ± 1550 cm 1 (amide I and II); MS (FAB): m/z:
2430.5 [M 2]; C94H156N2O70 ´ 7H2O: calcd C 44.10, H 6.69, N 1.09; found C
44.01, H 6.91, N 1.17.
2-(p-(3',6',9'-Trioxa-11'-hydroxyundecane)anilino)-6-naphthalene
sulfo-
nate (TENS, 7): 2-Amino-6-naphthalene sulfonate (98 mg, 0.40 mmol)
and NaOH (16 mg, 1 equiv) were dissolved in water (5 ml). This solution
was added to compound 37 (107 mg, 1 equiv). After addition of sodium
bisulphite (2.5 g), the reaction mixture was refluxed for 48 h. Hereafter,
water (25 mL) was added and the aqueous solution was extracted with ethyl
acetate to remove unconverted 37. The water layer was concentrated in
vacuo, and the resulting residue was extracted by stirring with ethanol (3Â),
and the combined ethanol fractions were concentrated to a small volume.
This solution was poured into hexane, and the resulting red precipitate was
collected by centrifugation. Yield: 13.9 mg (7%). M.p.: > 3508C; 1H NMR
(90 MHz, D2O): d 8.1 ± 6.6 (m, 10H; Ar H), 3.8 ± 3.1 (m, 14H; CH2 O),
2.8 (t, 2H; CH2 Ar); MS (FAB): m/z: 520 [MNa]; C24H28NSO7Na ´
4H2O: calcd C 49.23, H 6.20, N 2.39, S 5.47; found C 49.09, H 6.04, N
2.74, S 5.96.
N-[Mono(3-deoxy)-b-CD]-N'-[mono(3-deoxy)-a-CD]-butane-1,4-diamide
(3): To a solution of compound 25 (140 mg) in THF (10 mL) was added
TBAF (0.57 mL of a 1.0m stock solution in THF, 15 equiv). The mixture
was refluxed (24 h) until the reaction was completed according to TLC
(eluent E). The reaction mixture was concentrated in vacuo, and the
residue was dissolved in a minimum amount of water. This solution was
poured into acetone yielding a white precipitate. Repeating this procedure
twice afforded pure compound 3. Yield: 42 mg (50%). M.p.: >2808C
1
(decomp); Rf(E) 0.1; H NMR (400 MHz, D2O): d 5.06 (m, 3H; H-1),
5.00 (m, 6H; H-1), 4.95 (m, 2H; H-1), 4.89 (m, 2H; H-1), 4.17 ± 4.13 (m,
4H), 3.93 ± 3.76 and 3.64 ± 3.52 (2 Â m, ca. 74H; H-2, H-3, H-4, H-5, H-6),
2.56 (br.s, 4H; CH2 ± spacer); 13C NMR (100 MHz, D2O): d 176.07
(C O), 105.48 and 105.00 (C-1A and C-1A'), 103.16 ± 101.62 (C-1), 82.79 ±
81.21, 79.75, 77.28, 74.37 ± 72.43, 71.36 and 71.06 (C-2, C-3, C-4, C-5), 62.01 ±
60.91 (C-6), 52.19 and 51.98 (C NH), 32.25 (CH2--spacer); IR (KBr): nÄ
Hexakis(6-O-tert-butyldimethylsilyl)-a-CD (10): This compound was pre-
pared as compound 11, except for some modifications: To dried a-
cyclodextrin (19.0 g, 1008C, 0.05 mmHg, 9 h) in THF (350 mL) was added,
1
1680 ± 1610, 1560 ± 1520 cm (amide I and II); MS (FAB): m/z: 2189
at 08C over
a period of 1 h, tert-butyldimethylsilyl chloride (22.6 g,
[M1]; C82H134N2O65 ´ 5H2O: calcd C 43.24, H 6.37, N 1.23; found C 43.08,
H 6.30, N 1.30.
7.7 equiv) in dry pyridine (50 mL). After stirring for 24 h at room
temperature, the reaction mixture was poured into ice/water (1 L) and
stirred for 15 min. The white precipitate was filtered over Celite and
dissolved in dichloromethane. The solution was washed twice with HCl
(1m), once with a saturated NaHCO3 solution (100 mL), and once with
brine. The organic layer was dried (MgSO4) and concentrated in vacuo to
yield a crude product (40 g). Repeated column chromatography (1.6 kg
silica, eluent A) resulted in a TLC-pure compound. Yield: 22.6 g (69%
yield ). M.p.: 3318C (decomp), (ref. [25] 323 ± 3268C, (decomp); Rf(C) 0.4;
1H NMR (400 MHz, CDCl3): d 4.88 (d, 6H; H-1), 4.01 (t, 6H; H-3), 3.91
(dd, 6H; H-6), 3.84 (d, 6H; H-6), 3.75 (d, 6H; H-5), 3.64 (dd, 6H; H-2),
3.59 (t, 6H; H-4), 0.89 (s, 54H; CH3 C), 0.03 (s, 36H; CH3 Si); 13C NMR
(100 MHz, CDCl3): d 101.39 (C-1), 81.40, 74.45, 73.04, and 72.19 (C-2,
N-[Mono(3-deoxy)-b-CD]-N'-[mono(3-deoxy)-a-CD]-decane-1,10-diamide
(4): Deprotection of compound 4 was achieved as described for 3. Starting
with compound 26 (140 mg), a crude product was obtained after removal of
the solvent. This was dissolved in a minimum amount of water and poured
into ethanol (analytical grade), yielding a white precipitate. Repeating this
precipitation afforded compound 4, which was still contaminated with
tetrabutylammonium salts. The latter salts could be removed by running
the compound, dissolved in water, over a cation exchange column in the
NH4 form. Yield: 60 mg (71%). M.p.: > 3108C (decomp); Rf(E) 0.1; H
NMR (400 MHz, [D6]DMSO): d 4.90 ± 4.57 (5 Â m, 13H; H-1), 4.03 (m,
4H), 3.90 (m, 2H), 3.76 ± 3.25 (2 Â m, ca. 74H; H-2, H-3, H-4, H-5, H-6),
2.06 (br.t, 4H; CH2 CO) 1.48 (br.s, 4H; CH2 ± spacer), 1.24 (br.s, 8H;
CH2 ± spacer), see also Table 2 and 3 for 800 MHz spectrum in D2O; 13C
1
C-3, C-4, C-5), 61.95 (C-6), 25.97 (CH3 C), 18.42 (CH3 C),
5.19
NMR (100 MHz, [D6]DMSO): d 172.21 and 172.03 (2 Â C O), 104.72
(CH3 Si). MS (FAB): m/z: 1681 [M1]; C72H144O30Si6: calcd C 52.15, H
and 104.35 (C-1A and C-1A'), 102.49 ± 101.15 (C-1), 82.92, 81.96 ± 80.53,
79.66, 79.47, 76.59, 73.54 ± 71.72, 70.58 (C-2, C-3, C-4, C-5), 59.92 ± 59.45
(C-6), 50.20 and 49.63 (CH2 CO spacer), 35.65, 28.87 and 25.27 (CH2 ±
8.75; found C 52.39, H 8.53.
Heptakis(6-O-tert-butyldimethylsilyl)-b-CD (11): Compound 11 was syn-
thesized according to modified literature methods refs. [2, 26]. b-Cyclo-
dextrin was dried (1008C, 0.05 mmHg, 10 h) yielding a product (33 g),
which was dissolved under vigorous stirring in dry pyridine (500 mL). At
08C, tert-butyldimethylsilyl chloride (37.28 g, 8.5 equiv) in dry pyridine
(100 mL) was added in 1.5 h. After stirring overnight at room temperature,
the reaction mixture was poured into ice/water (1 L) and stirred for 15 min.
The white precipitate was filtered (over Celite) and dissolved in ethyl
acetate (800 mL), washed twice with aqueous HCl (100 mL, 1m), once with
a saturated NaHCO3 solution (100 mL), and once with brine. The resulting
organic layer was dried (MgSO4) and concentrated in vacuo yielding 66 g of
crude product. Repeated column chromatography (1.4 kg silica, eluent A)
resulted in a TLC-pure compound 11 (in our hands, purification by
recrystallization as mentioned in refer. [26] did not yield a TLC-pure
1
spacer); IR (KBr): nÄ 1670 ± 1600, 1560 ± 1520 cm (amide I and II); MS
(FAB): m/z: 2271 [M 1]; C88H146N2O65 ´ 4H2O: calcd C 45.09, H 6.62, N
1.20; found C 45.12, H 6.49, N 1.24.
N,N'-Bis[mono(3-deoxy)-b-CD]-5,5'-dicarboxamide-2,2'-bipyridine
(5):
Compound 31 (640 mg) was dried (1 h, 0.05 mmHg, 408C) and dissolved
in THF (15 mL). After addition of a stock solution of TBAF (2.4 mL, 1.0m)
in THF (15.5 equiv), the reaction mixture was refluxed for 24 h. After
concentration in vacuo, the crude product was dissolved in a minimum
amount of water. This solution was poured into ethanol (analytical grade),
and the product was collected by centrifugation. Repeating this procedure
twice afforded pure compound 5 as a slightly purple precipitate. Yield:
260 mg (67%). M.p.: 325 ± 3278C (decomp); 1H NMR (400 MHz, D2O):
d 8.90 (s, 2H; Ar H), 8.24 (br.s, 2H; Ar H), 8.13 (br.s, 2H; Ar H),
5.08 ± 4.98 (m, 14H; H-1), 4.45, 4.21 (2 Â br.s, 2 Â 2H) and 4.07 ± 3.49 (2 Â
m, ca. 80H; H-2, H-3, H-4, H-5, H-6); 13C NMR (100 MHz, D2O): d 168.9
compound). Yield: 44.4 g (79% yield). M.p.: 287 ± 2898C (crystals from
1
MeOH/CHCl3, 95:5, v/v); Rf(C) 0.40; H and 13C NMR data were in close
agreement with reported literature values.[2] MS (FAB): m/z: 1957
[MNa], 2067 [MCs]; C84H168O35Si7 ´ 2H2O: calcd C 51.17; H 8.84; found
C 51.07; H 8.85.
(C O), 157.7 (bipy-C-2), 149.5 (bipy-C-6), 138.5 (bipy-C-4), 131.4 (bipy-
C-5), 123.3 (bipy-C-3), 105.0, and 103.2 ± 102.5 (C-1), 82.4, 82.1, 81.9, 81.4,
74.4 ± 72.6, and 71.07 (C-2, C-3, C-4, C-5), 61.5 ± 61.1 (C-6), 53.0 (C NH);
Mono(2-O-tosyl)hexakis(6-O-tert-butyldimethylsilyl)-a-CD (12): This
compound was synthesized from 10 as described for compound 13 from
11. Starting with a solution of compound 10 (2.87 g, dried at 808C,
0.05 mmHg, 6 h) in THF (150 mL) and a dispersion of NaH (103 mg,
1.5 equiv, 60%) in mineral oil, and tosyl chloride (495 mg, 1.5 equiv)
yielded a crude product (3.0 g), which was subjected twice to column
chromatography (first run 800 g silica, eluent A, second run 800 g silica,
eluent E). In this way, pure starting material 10 (600 mg, 21%) was
1
IR (KBr): nÄ 1625, 1510 cm (amide I and II, and bipyridine C C); MS
(FAB): m/z: 2477 [M1]; C96H146N4O70 ´ 10H2O: calcd C 43.41, H 6.30, N
2.11; found C 43.49, H 6.31, N 2.09.
2-(p-(2'-Hydroxyethyl)anilino)-6-naphthalene sulfonate (ENS, 6): The
synthesis of this compound was carried out as described by Cory et al.[6]
2-Amino-6-naphthalene sulfonate (1.75 g, 7.88 mmol), NaOH (291 mg,
7.28 mmol), and NaHSO3 (17 g) were dissolved in water (50 mL). After the
Chem. Eur. J. 1998, 4, No. 11
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