S.M. Seyedi et al. / Tetrahedron 66 (2010) 6754e6760
6759
Anal. Calcd for C10H18N2O3: C, 52.17; H, 7.83; N, 12.17. Found: C,
52.34; H, 7.80; N, 12.22.
1.53e1.62 (m, 2H, 2CHCH2CH(CH3)2), 1.82 (s, CH3-acetyl), 3.6e3.75
(m, 4H, 2NCH2CO), 4.17e4.20 (m, 1H, NCHCO), 4.28e4.32 (m, 1H,
NCHCO), 7.74 (d, J¼8.4 Hz, 1H, NH), 8.05e8.09 (dd, J1¼7.4 Hz,
J2¼7.4 Hz, 1H, NH), 8.1e8.24 (m, 2H, 2NH), 12.5 (br s, 1H, COOH)
Anal. Calcd for C18H32N4O6: C, 53.98; H, 8.05; N, 13.99. Found: C,
53.72; H, 7.99; N, 14.01.
4.3.2. N-Acetyl-
L-leucylglycyl-L-leucine (c). Isobutyl chloroformate
(1.4 mL, 11 mmol) was added dropwise to a solution of N-acetyl-
L-
leucylglycine (b) (2.30 g, 10 mmol) and DBU (1.6 mL) in chloroform
(50 mL) while stirring in ice-water. After removing the ice-bath, the
reaction mixture was stirred at room temperature for 1 h. Leucine
methyl ester (1.81 g, 10 mmol) was then added and stirring con-
tinued for 3 h. The resulting solution was washed with 1 M NaOH
(2ꢄ30 ml), 1 M HCl (2ꢄ30 ml), and water (1ꢄ30 ml). The organic
layer was dried over anhydrous magnesium sulfate. After removing
the solvent under reduced pressure, the residue was recrystallized
4.4. General procedure for the synthesis of 3aed
Compound heptakis (6-bromo-6-deoxy)-b-cyclodextrin (2) was
synthesized according to the method reported in the literature.12 A
mixture of compound 2 (0.50 g, 0.32 mmol), one of the peptides
aed (4.0 mmol) and DBU (0.64 mL, 4.2 mmol) in DMF (10 mL) was
heated at 70e80 ꢃC for 12e48 h (for a and b 12 h and for c and
d 48 h). After cooling, the reaction mixture was then poured in to
a solution of saturated NaCl (40 mL). The precipitated solids were
collected and washed with water and potassium carbonate 5% and
then oven dried to give products 3aed.
from ethyl acetate/hexane to give N-acetyl-
L
-leucylglycyl-
L-leucine
methyl ester (b0) (1.58 g, 69%).
White crystal, mp: 133e135 ꢃC; 1H NMR: (CD3OCD3)
d
0.80e0.97
(m, 12H, 4CH3), 1.5e1.7 [m, 6H, 2CHCH2CH(CH3)2], 1.91 (s, 3H, CH3-
acetyl), 3.60 (s, 3H, OCH3), 3.70e3.90 (m, 2H, NCH2CO), 4.20e4.40
(m, 1H, NCHCO), 7.40e7.53 (m, 2H, 2NH), 7.70e7.85 (br m, 1H, NH).
Anal. Calcd for C17H31N3O5: C, 57.12; H, 8.74; N, 11.76. Found: C,
56.49; H, 8.70; N, 11.77.
4.4.1. Heptakis [6-O-(N-acetyl-
L
-leucyl)]-
b
-cyclodextrin (3a). White
A suspension of b0 (0.89 g, 2.5 mmol) in solution of NaOH (2 g) in
methanol (30 mL) was stirred at room temperature for 2 h. Then
water (10 mL) was added and after removing of methanol, acidified
with HCl 6 M. The precipitated crystals were collected and washed
with water. The crystals were recrystallized from acetone and oven
solid (0.34 g, 68%), mp: 197e198 ꢃC; 1H NMR: (DMSO-d6)
d
0.86 (d,
J¼6 Hz, 42H, 14CH3), 1.45e1.55 (m, 14H, 7CHCH2CH(CH3)2),
1.60e1.66 (m, 7H, 7CHCH2CH(CH3)2), 1.85 (s, 21H, CH3-acetyl),
3.40e3.48 (m, 14H, H-2, H-4), 3.60e3.69 (m, 7H, H-3), 3.80e3.89
(m, 7H, H-5), 4.03e4.10 (m, 7H, 7NCHCO), 4.22e4.28 (m, 14H, 2H-
6), 4.80e4.85 (m, 7H, H-1), 5.89e5.96 (m, 14H, OH-2 and OH-3),
dried to give N-Acetyl-L-leucylglycyl-L-leucine (c) (0.68 g, 77%).
White crystal, mp: 174e175 ꢃC; 1H NMR: (DMSO-d6) 0.80e0.87
(m, 12H, 4CH3), 1.4e1.48 (m, 4H, 2CHCH2CH(CH3)2), 1.54e1.62 (m,
2H, 2CHCH2CH(CH3)2), 1.82 (s, 3H, CH3-acetyl), 3.62e3.73 (m, 2H,
NCH2CO), 4.14e4.22 (m, 1H, NCHCO), 4.26e4.32 (m, 1H, NCHCO),
7.94e8.04 (m, 1H, 2NH), 8.05e8.07 (m, 1H, NH), 8.16e8.32 (m, 1H,
NH), one exchangeable proton is missing.
8.22e8.24 (m, 7H, 7NH). 13C NMR (DMSO-d6)
d 21.56, 22.63, 23.28,
24.91(CH3 and CH isobutyl, CH3 acetyl), 40.39 (CH2 isobutyl), 50.66
(HNCHCO), 63.63, 69.59, 72.67, 73.18 (C6, C5, C3, and C2), 81.94 (C4),
102.65 (C1),169.99 (CONH),172.66 (COO). IR (KBr disc)
n 1738 (C]O
ester) and 1682 (C]O amide) cmꢀ1
.
Anal. Calcd for C98H161N7O49: C, 52.99; H, 7.31; N, 4.41. Found: C,
52.70; H, 7.10; N, 4.25.
Anal. Calcd for C16H29N3O5: C, 55.98; H, 8.45; N, 12.24. Found: C,
55.77; H, 8.49; N, 12.20.
4.4.2. Heptakis [6-O-(N-acetyl-
White solid (0.31 g, 62%), mp: 210e212 ꢃC; 1H NMR: (DMSO-d6)
0.84 (d, 42H, 14CH3), 1.35e1.50 (m, 14H, 7CHCH2CH(CH3)2),
1.53e1.63 (m, 7H, 7CHCH2CH(CH3)2), 1.84 (s, 21H, 7CH3-acetyl),
3.40e3.46 (m, 14H, H-2, H-4), 3.58e3.64 (m, 7H, H-3), 3.79e3.87
(m, 21H, H-5, and 7NCH2CO), 4.19e4.31 (m, 21H, 2H-6, 7NCHCO),
4.80e4.90 (m, 7H, H-1), 5.80e6.00 (m, 14H, OH-2, and OH-3),
7.91e8.00 (m, 7H, 7NH), 8.25e8.39 (m, 7H, 7NH). 13C NMR (DMSO-
L-leucylglycyl)]-b-cyclodextrin (3b).
4.3.3. N-Acetyl-
formate (1.4 mL, 11 mmol) was added dropwise to a solution of N-
acetyl- -leucylglycyl- -leucine (c) (3.43 g, 10 mmol) and of DBU
(1.6 mL) in chloroform (50 mL) while stirring in ice-water. After
removing the ice-bath, the reaction mixture was stirred at room
temperature for 1 h. Glycine ethyl ester (1.81 g, 10 mmol) was then
added and stirring continued for 3 h. The resulting solution was
washed with 1 M NaOH (2ꢄ30 mL), 1 M HCl (2ꢄ30 mL), and water
(1ꢄ30 mL). The organic layer was dried over anhydrous magnesium
sulfate. After removing of the solvent under reduced pressure, the
L-leucylglycyl-L-leucylglycine (d). Isobutyl chloro-
d
L
L
d6)
d 21.97, 22.94, 23.49, 24.62 (CH3 and CH isobutyl, CH3 acetyl),
41.03, 41.27 (CH2 isobutyl, HNCH2CO), 51.16 (HNCHCO), 63.84,
69.33, 72.64, 73.28 (C6, C5, C3, and C2), 81.95 (C4), 102.67 (C1),
residue was recrystallized from hexane to give N-acetyl-
glycyl-
-leucine methyl ester (c0) (2.16 g, 63%).
White crystal, mp: 140e141 ꢃC; 1H NMR: (DMSO-d6, ppm)
L
-leucyl-
169.74, 169.92 (CONH), 173.28 (COO). IR (KBr disc)
n 1731 (C]O
L
ester) and 1680 (C]O amide) cmꢀ1
.
d
0.81
Anal. Calcd for C112H182N14O56: C, 51.33; H, 7.00; N, 7.48. Found:
C, 51.96; H, 7.19; N, 7.81.
(d, J¼6.5 Hz, 6H, 2CH3), 0.86 (d, J¼6.5 Hz, 6H, 2CH3), 1.14 (t, J¼10 Hz,
3H, OCH2CH3), 1.39e1.47 (m, J¼7.3 Hz, 4H, 2CHCH2CH(CH3)2),
1.55e1.6 (m, J¼7 Hz, 2H, 2CHCH2CH(CH3)2), 1.82 (s, 3H, CH3-acetyl),
3.65e3.79 (m, 4H, 2NCH2CO), 4.05 (q, J¼7.1 Hz, 2H, OCH2CH3),
4.16e4.22 (m, 1H, NCHCO), 4.25e4.32 (m, 1H, NCHCO), 7.78 (d,
J¼8.35 Hz, 1H, NH), 8.03 (dd, J¼10, 5.35 Hz, 1H, NH), 8.19e8.22 (m,
1H, NH), 8.4 (t, J¼8 Hz, 1H, NH).
4.4.3. Heptakis [6-O-(N-acetyl-
(3c). White solid (0.33 g, 67%), mp: 197e199 ꢃC; 1H NMR: (DMSO-
d6)
L-leucylglycyl-leucyl)]-b-cyclodextrin
d
0.85 (d, J¼10 Hz, 84H, 28CH3), 1.43e1.59 (m, 42H, 14CHCH2CH
(CH3)2), 1.84 (s, 21H, 7CH3-acetyl), 3.35e3.38 (m, 14H, H-2 and H-3,
H-4), 3.64e3.89 (m, 28H, H-3 and H-5, and 7NHCH2CO), 4.1e4.32
(m, 28H, H-6, and 14NCHCO), 4.81e4.87 (m, 7H, H-1), 5.89e6.06
(m, 14H, OH-2, and OH-3), 8.00e8.31 (m, 21H, 21NH). 13C NMR
Anal. Calcd for C20H36N4O6: C, 56.06; H, 8.47; N, 13.07.Found: C,
55.79; H, 8.44; N, 12.99.
A suspension of c0 (1.07 g, 2.5 mmol) in solution of NaOH (2 g) in
ethanol (30 mL) was stirred at room temperature for 2 h. Then
water (10 mL) was added and after removing of ethanol, acidified
with HCl 6 M. The precipitated crystals were collected and washed
with water. The crystals were recrystallized from acetone and oven
(DMSO-d6) d 21.60, 22.00, 22.09, 22.92, 23.31, 23.44, 24.60 (CH3 and
CH isobutyl, CH3 acetyl), 40.96, 40.23 (CH2 isobutyl, HNCH2CO
covered by DMSO pick), 50.53, 51.74, 52.00 (HNCHCO), 63.66, 69.51,
72.61, 73.26 (C6, C5, C3, and C2), 81.76 (C4), 102.69 (C1), 169.36,
170.14, 172.40 (CONH), 173.03 (COO). (KBr disc)
n 1733 (C]O ester)
dried to give N-Acetyl-
L
-leucylglycyl-
L
-leucine (d) (0.76 g, 71%).
and 1681 (C]O amide) cmꢀ1
.
White crystal, mp: 170e171 ꢃC; 1H NMR: (DMSO-d6, ppm)
Anal. Calcd for C154H259N21O63: C, 54.20; H, 7.65; N, 8.26. Found:
C, 53.13; H, 7.27; N, 8.15.
d
0.80e0.87 (m, 12H, 4CH3), 1.40e1.48 (m, 4H, 2CHCH2CH(CH3)2),