´
M. Bukvic Krajacic et al. / European Journal of Medicinal Chemistry 42 (2007) 138e145
ꢀ ´
144
84 (C-5), 73.7 (C-6), 27.8 (C-8), 78.1 (C-11), 75 (C-12), 78.1
(C-13), 21.8 (C-14), 11.3 (C-15), 101.7 (C-10), 70.0 (C-20),
64.8 (C-30), 40.1 (30 NMe2), 30.1 (C-40), 66.8 (C-50), 95.8
(C-100), 34.9 (C-200), 72.8 (C-300), 48.9 (300 OMe), 77.4 (C-
400), 65.0 (C-500), 14.6 (2 Me), 8.2 (4 Me), 28 (6 Me), 20.2
(8 Me), 13.6 (12 Me), 21.3 (50 Me), 21.1 (300 Me), 18.5 (500
Me), 155.6 (NCONH), 170 (isoxazolyl, c0), 160 (isoxazolyl,
a0), 14.0 (isoxazolyl, Me), 144.7 (phenyl, a), 132.0 (phenyl,
d), 127.2 (phenyl, b), 119 (phenyl, c).
e0), 7.74 (2H, phenyl, b), 7.64 (1H, phenyl, c0), 7.42 (2H, phe-
nyl, c), 7.38 (1H, pyridyl, b0), 6.80 (1H, pyridyl, d0); 13C NMR
(CDCl3) d 176 (C-1), 44.7 (C-2), 75.3 (C-3), 38.1 (C-4), 90
(C-5), 74.1 (C-6), 29.1 (C-8), 74.1 (C-12), 78.4 (C-13), 20.9
(C-14), 10.4 (C-15), 105.4 (C-10), 68.9 (C-20), 64.6 (C-30),
39.6 (30 NMe2), 27.4 (C-40), 69.9 (C-50), 15.5 (2 Me), 7.0 (4
Me), 27 (6 Me), 19 (8 Me), 16.3 (12 Me), 20.2 (50 Me),
155.8 (NCONH), 142.8 (phenyl, a), 141.5 (pyridyl, e0),
140.8 (pyridyl, c0), 133.3 (phenyl, d), 127.4 (phenyl, b),
117.9 (phenyl, c), 114.5 (pyridyl, d0), 114.1 (pyridyl, b0).
4.1.1.5.
nosulfonyl)phenyl]carbamoyl}-9a-aza-9a-homoerythronolide
5-O-Desosaminyl-9-deoxo-9-dihydro-9a-{N0-[4-(ami-
4.1.1.8. 5-O-Desosaminyl-9-deoxo-9-dihydro-9a-N-{N0-[4-(5-
methyl-3-isoxazolylaminosulfonyl)phenyl]carbamoyl}-9a-aza-
9a-homoerythronolide A (7d). Yield 54.4%. 1H NMR (CDCl3)
d 2.66 (1H, H-2), 3.87 (1H, H-3), 3.47 (1H, H-5), 1.8 (1H, H-
8), 4.60 (1H, H-13), 1.95, 1.59 (2H, H-14), 0.92 (3H, H-15),
4.36 (1H, H-10), 3.32 (1H, H-20), 2.47 (1H, H-30), 2.33 (6H,
30 NMe2), 1.71, 1.33 (2H, H-40), 3.56 (1H, H-50), 1.30 (3H,
2 Me), 0.93 (3H, 4 Me), 1.31 (3H, 6 Me), 1.06 (1H, H-8
Me), 1.13 (3H, 12 Me), 1.20 (3H, 50 Me), 7.64 (2H, phenyl,
b), 7.40 (2H, phenyl, c), 6.16 (1H, isoxazolyl, c0), 2.32 (3H,
isoxazolyl, c0-Me); 13C NMR (CDCl3) d 176 (C-1), 44 (C-
2), 74.6 (C-3), 38.6 (C-4), 90 (C-5), 74.1 (C-6), 29 (C-8), 74
(C-12), 77.1 (C-13), 21.4 (C-14), 10.8 (C-15), 105.6 (C-10),
69.3 (C-20), 64 (C-30), 40.1 (30 NMe2), 28.8 (C-40), 69 (C-
50), 16.0 (2 Me), 7.4 (4 Me), 26 (6 Me), 19 (8 Me), 16.7 (12
Me), 20.8 (50 Me), 156.1 (NCONH), 170.6 (isoxazolyl, c0),
157.6 (isoxazolyl, a0), 142 (phenyl, a), 133 (phenyl, d),
128.1 (phenyl, b), 117.9 (phenyl, c), 95.5 (isoxazolyl, b’),
12.6 (isoxazolyl, c’-Me).
A
1
(7a). Yield 28.8%. H NMR (pyridine) d 3.02 (1H, H-2), 4.30
(1H, H-3), 1.69 (1H, H-4), 4.41 (1H, H-5), 2.2 (1H, H-8), 4.3
(1H, H-11), 5.7 (1H, H-13), 2.36, 1.77 (2H, H-14), 1.01 (3H,
H-15), 5.1 (1H, H-10), 3.61 (1H, H-20), 2.62 (1H, H-30), 2.21
(6H, 30 NMe2), 1.53, 1.19 (2H, H-40), 3.49 (1H, H-50), 1.58
(3H, 2 Me), 1.26 (3H, 4 Me), 1.76 (3H, 6 Me), 1.15 (1H, H-8
Me), 1.40 (3H, 12 Me), 1.16 (3H, 50 Me), 8.16 (2H, phenyl,
b), 7.92 (2H, phenyl, c); 13C NMR (pyridine) d 176 (C-1),
45.6 (C-2), 77 (C-3), 39.1 (C-4), 92.8 (C-5), 74 (C-6), 40.3 (C-
7), 28 (C-8), 75 (C-12), 78 (C-13), 23.1 (C-14), 11.4 (C-15),
103.3 (C-10), 69.9 (C-20), 65.4 (C-30), 40.3 (30 NMe2), 29.2 (C-
40), 69.2 (C-50), 16.7 (2 Me), 8.9 (4 Me), 27 (6 Me), 21.1 (8
Me), 19.9 (12 Me), 21.5 (50 Me), 156.7 (NCONH), 138 (phenyl,
a), 127.6 (phenyl, b), 118 (phenyl, c), 144.8 (phenyl, d).
4.1.1.6.
5-O-Desosaminyl-9-deoxo-9-dihydro-9a-N-{N0-[4-
(phenylaminosulfonyl)phenyl]-carbamoyl}-9a-aza-9a-homoer-
1
ythronolide A (7b). Yield 20.0%. H NMR (CDCl3) d 2.67
(1H, H-2), 3.86 (1H, H-3), 3.57 (1H, H-5), 1.9 (1H, H-8),
4.59 (1H, H-13), 1.96, 1.56 (2H, H-14), 0.93 (3H, H-15),
4.35 (1H, H-10), 3.31 (1H, H-20), 2.55 (1H, H-30), 2.30 (6H,
30 NMe2), 1.70, 1.30 (2H, H-40), 3.57 (1H, H-50), 1.30 (3H,
2 Me), 0.94 (3H, 4 Me), 1.31 (3H, 6 Me), 1.07 (1H, 8 Me),
1.13 (3H, 12 Me), 1.20 (3H, 50 Me), 7.57 (2H, phenyl, b),
7.37 (2H, phenyl, c), 7.21 (2H, phenyl, c0), 7.09 (2H, phenyl,
b0), 7.06 (1H, phenyl, d0); 13C NMR (CDCl3) d 178.2 (C-1),
44.7 (C-2), 75.4 (C-3), 38.1 (C-4), 90 (C-5), 74.1 (C-6), 58
(C-9), 27.6 (C-8), 74.1 (C-12), 78.4 (C-13), 20.9 (C-14),
10.4 (C-15), 105.3 (C-10), 68.9 (C-20), 64.6 (C-30), 39.6 (30
NMe2), 27.6 (C-40), 69.8 (C-50), 15.5 (2 Me), 7.0 (4 Me), 27
(6 Me), 19.6 (8 Me), 16.3 (12 Me), 20.4 (50 Me), 155.8
(NCONH), 152.8 (phenyl, a0), 143.3 (phenyl, a), 136.3 (phe-
nyl, d), 128.7 (phenyl, c0), 127.8 (phenyl, b), 124.5 (phenyl,
d0), 120.9 (phenyl, b0), 117.8 (phenyl, c).
4.1.2. General procedure for the hydrolysis of 6a and 6b
The suspension of 6a or 6b (0.55 mmol) in 1 M hydro-
chloric acid (5 ml) was stirred for 12 h at room temperature;
the pH was adjusted to 9.5e10 by adding 1 M NaOH and
was extracted with CH2Cl2 (3 ꢂ 4 ml). The combined organic
layers were washed with water, dried over anhydrous Na2SO4,
evaporated to dryness under reduced pressure to give crude
product wherefrom by chromatography on silica gel column
using CH2Cl2:CH3OH:NH3(25%) ¼ 90:9:1.5 as eluents pure
7a or 7b was obtained. The spectroscopic data of so obtained
compound were identical to the spectroscopic data of 7a or 7b
obtained by the general procedure for preparation of 6ae6d
and 7ae7d.
4.2. Acid stability of 6a and 6b
4.2.1. Preparation of 6a hydrolyzate in 0.01 M HCl
4.1.1.7. 5-O-Desosaminyl-9-deoxo-9-dihydro-9a-N-{N0-[4-(2-
pyridylaminosulfonyl)phenyl]-carbamoyl}-9a-aza-9a-homoery-
thronolide A (7c). Yield 47.0%. 1H NMR (CDCl3) d 2.63 (1H,
H-2), 3.84 (1H, H-3), 3.65 (1H, H-5), 1.8 (1H, H-8), 3.5 (1H,
H-11), 4.61 (1H, H-13), 1.94, 1.55 (2H, H-14), 0.92 (3H, H-
15), 4.34 (1H, H-10), 3.31 (1H, H-20), 2.6 (1H, H-30), 2.29
(6H, 30 NMe2), 1.71, 1.26 (2H, H-40), 3.59 (1H, H-50), 1.29
(3H, 2 Me), 0.93 (3H, 4 Me), 1.29 (3H, 6 Me), 1.07 (1H, 8
Me), 1.12 (3H, 12 Me), 1.22 (3H, 50 Me), 8.30 (1H, pyridyl,
Solution of 6a in 0.01 M HCl of concentration 1 mg/ml
(100 ml) was stirred for 10 h at room temperature. After isola-
tion and purification procedures, described in Section 4.1.2,
1
the pure 7a was obtained. Its H and 13C NMR spectra were
identical to the spectra of the 7a authentic sample.
4.2.2. HPLC assay and decay data
The solution of 6a or 6b in 0.01 M HCl aqueous hydro-
chloric acid (concentration of 1 mg/ml) was held at 25 ꢀC,