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H.-Y. Kim et al. / Bioorg. Med. Chem. 18 (2010) 809–821
the mixture turned from orange to dark brown in color. After cool-
ing acetone (20 mL) was added, and the resulting precipitates were
removed by filtration. This procedure was repeated until no more
precipitate was produced, and the filtrates then concentrated. Puri-
fication by silica gel chromatography (EtOAc/Hx, 1:7) afforded a
light-yellow oil (1.08 g, yield 26%; 80:20 to branched aldehyde).
1H NMR (300 MHz, CDCl3) dppm 9.72 (s, 1H), 7.57 (d, J = 8.4 Hz,
2H), 6.90 (d, J = 8.1 Hz, 2H), 2.56 (t, J = 7.8, 7.2 Hz, 2H), 2.41 (td,
J = 7.2, 1.2 Hz, 2H), 1.89 (p, J = 7.2, 7.5 Hz, 2H). 13C NMR (75 MHz,
CDCl3) dppm 202.0, 141.0, 137.5, 130.6, 101.78, 81.24, 72.43,
69.74, 68.93, 59.61, 21.23.
4.1.15. Per-6-(phthalimidoethylthio)-6-deoxy-b-cyclodextrin (14)
Compound 14 was synthesized according to literature proce-
dures27,56 as
a
white solid (112 mg, 17% yield). 1H NMR
(400 MHz, DMSO-d6) dppm 7.71 (s, 4H), 5.84 (d, J = 23 Hz, 2 Hz,
2H), 4.86 (s, 1H), 3. 94 (br s, 1H), 3.81 (m, 2H), 3.59 (m, 1H),
3.42–3.33 (m, overlaps with DOH), 3.04 (d, J = 11.6 Hz, 1H), 2.91–
2.78 (m, 3H). 13C NMR (100 MHz, DMSO-d6) dppm 167.4, 134.2,
131.3, 122.9, 102.1, 84.2, 72.5, 72.2, 71.2, 36.9, 33.0, 30.8. MALDI-
TOF: calcd for C112H119N7O42S7 2459.66, found [M+Na]+ 2482.62.
4.1.16. Per-6-(2-aminoethylthio)-6-deoxy-b-cyclodextrin (15)
Compound 15 was prepared by literature procedures27 as a
white powder (50 mg, 81% yield). 1H NMR (400 MHz, DMSO-d6)
dppm 5.45 (d, J = 24, 4 Hz, 2H), 4.51 (br s, 1H), 3.40 (br s, 1H), 3.
19 (t, J = 8.4 Hz, 8.8 Hz, 1H), 3.02–2.48 (m, overlaps with DOH),
2.09 (s, 1H). 13C NMR (100 MHz, DMSO-d6) dppm 102.1, 84.5, 72.6,
72.2, 71.4, 38.6, 32.8, 29.7. MALDI-TOF: calcd for C56H105N7O28S7
1548.94, found [M]+ 1548.90.
4.1.11. 17a-[(4-Butanalphenyl)]ethynyl-estra-1,3,5 (10)-triene-
3,17b-diol (10)
Compound 10 was prepared by literature procedures25 as a
light-yellow powder (900 mg, 60% yield). 1H NMR (400 MHz,
CD3CN) dppm 9.75 (s, 1H), 7.45 (d, J = 8 Hz, 2H), 7.25 (d, J = 8 Hz,
2H), 7.20 (d, J = 8 Hz, 2H), 6.91 (s, 1H), 6.69 (d, J = 8 Hz, 1H), 6.62
(s, 1H), 3.64 (s, 1H), 2.85 (m, 2H), 2.69 (t, J = 8 Hz, 2H), 2.48–2.46
(m, 4H), 1.96–1.86 (m, 6H), 1.49–1.34 (m, 4H), 0.98 (s, 3H). 13C
NMR (100 MHz, DMSO-d6) dppm 203.2, 154.9, 141.8, 137.1, 131.2,
130.3, 128.6, 126.1, 120.5, 114.9, 112.7, 94.5, 84.0, 78.6, 49.4,
47.3, 43.4, 42.3, 40.4, 39.0, 34.2, 32.9, 29.2, 27.0, 26.3, 23.2, 12.9.
APCI-MS: calcd C30H32O3 442.25, found [MꢁH]ꢁ 442.10.
4.1.17. Per-6-(estradiol-17-(4-((2-(propylthio)ethylamino)-
methyl)phenyl)ethynyl)-6-deoxy-b-cyclodextrin (16)
Compounds 15 (40 mg, 0.0258 mmol) and 4 (310 mg, 0.774
mmol) were dissolved in DMF, and stirred at 60–70 °C for 10 days.
2 mL of aqueous NaOH (1 N in MeOH) and stirred for a further
2.5 h. After cooling and concentration, the residue was precipitated
in acetone (25 mL) giving a beige powder that was repeatedly
washed and filtered until no trace of 4 was detected by TLC. The pre-
cipitates were dried to give a light-yellow solid product containing
16 as the major product in a heterogeneous mixture. MALDI-TOF:
calcd for C245H301N7O42S7 4240.49, found [M+H2O+H]+ 4259.84.
4.1.12. Per-6-(4-iodobenzylamino)-6-deoxy-b-cyclodextrin (11)
ACD 3 (50 mg, 0.044 mmol) and 4-iodobenzaldehyde (85.1 mg,
0.352 mmol) were dissolved in DMF (0.1 mL), and the reaction
mixture was stirred at 60–70 °C for 18 h under N2 atmosphere.
The resulted brown imine solution was reduced in situ by freshly
prepared 0.1 M NaBH4 solution (2.1 mL) at 0 °C and allowed to stir
for 2 h. The warmed reaction mixture was poured into acetone
(25 mL) to precipitate the product as beige powder that was
repeatedly washed and filtered until no corresponding alcohol
from 4-iodobenzaldehyde was detected by TLC. The precipitates
were collected, and overnight drying gave a light-yellow powder
that by MALDI-TOF analysis gave signals corresponding to a mix-
ture of 1–7-fold substitution.
4.1.18. Mono-6-(p-tolylsulfonyl)-6-deoxy-b-cyclodextrin (17)
Compound 17 was prepared by adaptation of literature proce-
dures57 as a white powder was obtained (1 g, 10% yield). 1H NMR
(300 MHz, DMSO-d6) dppm 7.76 (d, J = 7.6 Hz, 2H), 7.44 (d,
J = 7.2 Hz, 2H), 5.71 (br s, 14H), 4.84 (s, 4H), 4.77 (s, 3H), 4.33 (d,
J = 10.4 Hz, 3H), 4.20 (m, 3H), 3.66–3.51 (m, overlaps with HOD),
3.38–3.22 (m, overlaps with HOD), 2.09 (s, 3H), 13C NMR
(100 MHz, DMSO-d6) dppm 144.9, 132.7, 129.9, 127.6, 102.0 (m),
81.5 (m), 73.1–72.8, 60.0, 21.3. MALDI-TOF: calcd C49H76O37
S
4.1.13. 17a-(4-Aminophenyl)ethynyl-estra-1,3,5 (10)-triene-
[M]+ 1289.19, found [M+Na]+ 1313.43.
3,17b-diol (12)53–55
A solution of Pd(OAc)2 (80.7 mg, 0.169 mmol) and P(Ph)3
(90.4 g, 0.338 mmol) in TEA (20 mL) was stirred under N2 for
10 min. CuI (65.7 mg, 0.338 mmol) and 4-iodoaniline (748 mg,
3.376 mmol) were added, and after 5 min, 17b-ethynylestradiol
(1 g, 3.376 mmol) was transferred. The dark brown mixture was
stirred at room temperature for 5 h. TEA was evaporated, and the
residue was purified by silica gel column chromatography
(CH2Cl2/MeOH, 20:1). After drying under vacuum, yellow powder
was obtained (1.10 g, 84% yield). 1H NMR (400 MHz, CD3CN) dppm
8.98 (s, 1H), 7.06 (s, 2H), 6.50 (d, J = 7.2 Hz, 2H), 6.43 (s, 1H), 5.39
(s, 2H), 5.25 (s, 1H), 3.33 (s, 1H), 2.70 (s, 2H), 2.31 (d, J = 9.6 Hz,
1H), 2.15–1.68 (m, 9H), 1.31 (m, 4H), 0.79 (s, 3H). 13C NMR
(100 MHz, CD3CN) dppm 154.9, 148.8, 137.1, 132.3, 130.3, 126.1,
114.9, 113.6, 112.7, 109.1, 91.4, 85.2, 78.6, 49.2, 47.1, 43.4, 32.9,
29.2, 27.0, 26.3, 22.6, 12.9. APCI-MS: calcd For C26H29NO2 387.2,
found [MꢁH]ꢁ 386.6.
4.1.19. Mono-6-azido-6-deoxy-b-cyclodextrin (18)57
Compound 17 (350 mg, 0.271 mmol) and NaN3 (189 mg,
2.90 mmol) were suspended in H2O (3.53 mL), which was heated
and to a clear solution with stirring at 80 °C for 15 h. The reaction
mixture was cooled, poured into acetone (60 mL) to precipitate the
product as a white powder that was dried in a drying pistol at 56 °C
under vacuum. A pure white solid was obtained (492.8 mg, 90%
yield). 1H NMR (400 MHz, DMSO-d6) dppm 5.73 (br s, 14 H), 4.84
(m, 7 H), 3.75–3.55 (m, 28 H), 3.41–3.28 (m, overlaps with HOD),
13C NMR (100 MHz, DMSO-d6) dppm 102.0 (m), 83.0, 81.6 (m),
73.0 (m), 72.4, 72.2, 72.1, 70.2, 60.2 (m), 51.1. MALDI-TOF: calcd
C42H69N3O34 [M]+ 1160.00, found [M+Na]+ 1183.74.
4.1.20. Mono-6-amino-6-deoxy-b-cyclodextrin hydrochloride
(19)57
Compound 18 (300 mg, 0.259 mmol) and PPh3 (116 mg,
0.442 mmol) were dissolved in DMF (5.6 mL) to which 30% NH4OH
(2.7 mL) was added by syringe. The reaction mixture was stirred at
room temperature for 18 h, and poured into acetone (50 mL)
yielding after successive washes and drying a white powder
(200.0 mg, 68% yield). 1H NMR (400 MHz, DMSO-d6) dppm 5.15 (br
s, 7 H), 4.06–4.00 (m, 21 H), 3.73–3.63 (m, 10 H). 13C NMR
(100 MHz, DMSO-d6) dppm 101.8, 101.5, 82.8, 81.0, 80.8, 73.1,
4.1.14. (2-Phthalimidoethyl) isothiouronium hydrobromide (13)
Compound 13 was synthesized according to literature proce-
dures.54,55 as a white solid (5.1, 79% yield). 1H NMR (400 MHz,
DMSO-d6) dppm 9.14 (s, 4H), 7.91 (m, 4H), 3.39 (t, J = 5.2 Hz,
6.4 Hz, 2H), 3.55 (t, J = 5.2 Hz, 6.4 Hz, 2H). 13C NMR (100 MHz,
DMSO-d6) dppm 169.2, 167.6, 134.7, 131.4, 123.2, 36.0, 29.3. APCI-
MS: calcd for C11H12BrN3O2S 328.98, found [MꢁHBr]+ 249.80.