G. J. Tarver et al. / Bioorg. Med. Chem. 10 (2002) 1819–1827
1825
To a solution of octakis-per-6-O-(tert-butyldimethyl-
silyl)-g-CD (0.5 g, 0.225 mmol) in dimethylformamide
(20 mL) was added barium hydroxide octahydrate (0.5
g, 1.58 mmol) followed by barium oxide (0.9 g, 5.87
mmol). 2-(Trimethylsilyl)ethyl 4-iodomethylbenzoate (2
equiv per hydroxyl) was added and the reaction stirred
for 24 h. The reaction mixture was filtered to remove
barium oxide and poured into water to remove barium
hydroxide. The crude CD precipitate was dissolved in
dichloromethane and dried (sodium sulfate). The solu-
tion was filtered and the solvent evaporated to a small
volume. Methanol was added to triturate the compound
which was then filtered and dried in vacuo.
resin elutingwith pure water. The compound was dia-
lysed overnight and the water evaporated to give the
title compound. Analysis showed a 1:1 mixture of 2 and
3 substituted products, (100 mg, 3.3%): 1H NMR
(D2O): d 7.75 (m), 7.35 (m), 4.9 (m), 4.85 (m), 4.0–3.3
(m) ppm; 13C NMR d 130.0, 128.7, 102.1, 100.0, 80.6,
74.7, 73.7, 73.3, 72.7, 72.6, 72.0, 60.5 ppm. Electrospray
mass spectrum M+Na 1475.3; IR n (cmꢁ1) 1550
(CO2ꢁ).
2-O-Mono-carboxymethyl-ꢀ-CD ethyl ester (9). To a
solution of g-cyclodextrin (1 g, 0.77 mmol) in dimethyl-
formamide (20 mL) was added sodium hydride (33.88
mg, 60% in oil, 0.845 mmol). The reaction was stirred
for 15 min, ethyl-iodoacetate (100 mL, 0.84 mmol) was
added and the reaction heated at 55 ꢄC for 3 h. The
reaction was cooled and the product precipitated by
addition of acetone. The crude precipitate was filtered
and dried in vacuo to give the title compound, (1 g,
94%): 1H NMR (D2O) d 5.35 (H10), 3.6 (H20), 4.05
(H30), 4.45 (H70), 4.2 (H90), 1.25 (H100) ppm; 13C NMR
(D2O): d 102.0, 99.9, 80.7, 73.2, 72.7, 72.6, 72.2, 72.0,
69.2, 62.6, 60.6, 13.9 ppm. Electrospray mass spectrum
M+Na 1399.7.
Tetrabutyl ammonium fluoride (17.65 mL, 1.0 M solu-
tion in tetrahydrofuran, 17.6 mmol) was added to a
solution of per-2-O-[4-{2-(trimethylsilyl)ethylcarboxy}
benzyl]-6-O-(tert-butyldimethylsilyl)-g-cyclodextrin (2.4
g, 0.59 mmol) in tetrahydrofuran (30 mL). The reaction
mixture was refluxed for 2 h and allowed to cool to
room temperature. The solvent was removed under
reduced pressure and water (150 mL) added. The pH
was adjusted to 4 by addition of 2 M hydrochloric acid
and the solid formed was filtered off. Washingwith
acetone gave 1.2 g of per-2-O-(3-carboxybenzyl)-g-
cyclodextrin as a pale solid. To this was added methanol
(100 mL) and sodium hydroxide (0.16 g, 4.1 mmol) and
the suspension was stirred until dissolution had occur-
red. The solvent was removed under reduced pressure
and water was added (30 mL). This solution was dia-
lyzed and the water was removed under reduced pres-
sure to give a gum. Stirring with acetone gave a solid
which was filtered to give the title compound as a tan
solid (1.1 g, 73%). 1H NMR (D2O) d 7.9 (2H), 7.5 (2H),
5.1 (1H), 4.9 (2H), 4.7–3.95 (1H), 3.7 (3H), 3.55 (2H)
ppm. Electrospray mass spectrum M+ 2545.2.
2-O-Mono-(3-carboxybenzyl)-ꢀ-CD sodium salt (10).
Sodium hydride (0.31 g, 60% dispersion in mineral oil,
7.75 mmol) was added to a solution of g-cyclodextrin
(10 g, 7.71 mmol) in dimethylformamide (100 mL) and
the reaction mixture was stirred for 1 h. To this was
added (dropwise) a solution of 2-(trimethylsilyl)ethyl-
3-(iodomethyl)benzoate (2.79 g, 7.70 mmol) in dimethyl
formamide (50 mL) and stirringwas continued for 4 h.
The solvent was removed under reduced pressure and
the solid obtained was stirred in acetone. Filtration gave
10gof white solid which was dissolved in dimethyl
sulphoxide (80 mL). To this was added tetrabutyl
ammonium fluoride (13.06 mL, 1.0 M solution in tetra-
hydrofuran, 13.1 mmol) and the solution was stirred for
1 h. The solvent was removed under reduced pressure.
Chromatography on Sephadex DEAE A-25 resin elut-
ingwith water followed by 0.01 M sodium hydroxide
solution gave 1 g of white solid. This was dialyzed for 4
h and the water removed under reduced pressure. The
solid obtained was stirred in acetone and filtered to give
2-O-Per-(3-carboxybenzyl) ꢀ-CD sodium salt (3). This
compound was prepared in the similar way as described
above for compound 1, but with the alkylatingagent
1
2-(trimethylsilyl)ethyl 3-iodomethylbenzoate. H NMR
(D2O); d 32;3.47 (t, 8H), 3.54–3.57 (m, 8H), 3.67–3.74
(m, 24H), 3.86 (t, 8H), 4.70–4.75 (m, 8H), 4.84 (d, 8H),
5.07 (d, 8H), 7.50 (t, 8H), 7.56 (d, 8H), 7.88–7.90 (m,
16H) ppm. Electrospray MS (M+Na)+ 2393.1.
1
the title compound as a white solid (190 mg, 2%). H
2-O-Mono-(4-carboxybenzyl) ꢀ-CD sodium salt (2).
To a solution of octakis-per-6-O-(tert-butyldimethylsi-
lyl)-g-cyclodextrin (3 g, 1.35 mmol) in tetrahydrofuran
(90 mL) was added sodium hydride, (108 mg, 60%
in oil, 2.7 mmol) the reaction was stirred for 15 min.
(3-(Trimethylsilyl)ethyl)-4-(iodomethyl)benzoate (483 mg,
1.29 mmol) was added and the reaction stirred over-
night. Methanol was added and the solvents removed.
Water was then added and the compound precipitated.
The compound was then dried in vacuo. The white solid
(1 g, 0.42 mmol) was dissolved in dichlormethane (45
mL) and boron trifluoride diethyl etherate (1.33 mL,
10.1 mmol) was added. The reaction was stirred for 2 h
and then dilute sodium carbonate was added to quench
the reaction. The solvents were removed and acetone
added to precipitate the compound. The compound was
purified by chromatography on Sephadex DEAE A-25
NMR (D2O); d 3.50 (t, 1H), 3.59–3.67 (m, 15H), 3.83–
3.94 (m, 23H), 4.09 (t, 1H), 4.85 (d, 1H), 4.93 (d, 1H),
5.09–5.14 (m, 8H), 7.53 (t, 1H), 7.67 (d, 1H), 7.92 (d,
1H), 7.98 (s, 1H) ppm. Electrospray MS (M+H)+
1453.4, (M+Na)+ 1475.5.
2-O-Per-(4-carboxypiperidin-1-yl)carbonylmethyl-ꢀ-CD
sodium salt (14). Sodium hydride (2.72 g, 60% disper-
sion in mineral oil, 67.9 mmol) was added portionwise
to
a
solution of per-6-O-(tert-butyldimethylsilyl)-
g-cyclodextrin (15 g, 6.79 mmol) in tetrahydrofuran
(500 mL) at 0 ꢄC. The reaction mixture was allowed to
warm to room temperature and a solution of 4-piper-
idinecarboxylic acid, 1-(bromoacetyl)-, ethyl ester (18.88
g, 67.9 mmol) in tetrahydrofuran (30 mL) was added.
The reaction mixture was stirred for 48 h and the sol-
vent removed under reduced pressure. Chromatography