Journal of Medicinal Chemistry
ARTICLE
(ddd, J = 14.2, 7.6, 2.3 Hz, 1H), 1.82 (t, J = 11.3 Hz, 1H), 1.73 (d, J = 14.3
Hz, 2H), 1.68ꢀ1.62 (m, 1H), 1.57 (dd, J = 15.2, 5.0 Hz, 1H), 1.52ꢀ1.42
(m, 1H), 1.36 (dd, J = 14.9, 7.7 Hz, 1H), 1.31 (d, J = 6.2 Hz, 3H), 1.28 (s,
3H), 1.23 (s, 3H), 1.21 (d, J = 6.1 Hz, 4H), 1.19 (d, J = 7.5 Hz, 4H), 1.13
(d, J = 6.5 Hz, 3H), 1.07 (s, 3H), 1.04 (d, J = 7.5 Hz, 3H), 0.92 (d, J = 6.9
Hz, 3H), 0.88 (t, J = 7.4 Hz, 4H). 13C NMR (500 MHz, CDCl3) δ
178.95, 103.10, 94.93, 83.43, 78.28, 78.04, 78.01, 73.93, 73.88, 73.16,
73.08, 70.97, 68.87, 65.92, 65.63, 57.47, 56.93, 49.58, 45.50, 42.33, 40.49,
34.87, 30.00, 28.83, 27.58, 22.04, 21.73, 21.51, 21.12, 18.40, 16.24, 15.04,
14.09, 11.28, 9.24. ESI mass spectrum: calcd (MHþ) 735.5; found 735.6.
N9-Propylazithromycin, 9. 9-Deoxo-9a-aza-homoerythromycin
A 8 (204 μmol, 150 mg) and propionaldehyde (1021 μmol, 59 mg) were
dissolved in DMF (1.5 mL). Acetic acid (2041 μmol, 123 mg) and sodium
cyanoborohydride (306 μmol, 19 mg) were added to the reaction mixture.
The mixture was stirred for 7 h at 70 °C. The crude mixture was diluted into
CH2Cl2 and was washed three times with saturated NaHCO3 (aq) and was
dried over Na2SO4. After evaporation of the solvent, the resulting product
was purified by flash chromatography, eluting with a step gradient ranging
from 3% to 10% MeOH/CH2Cl2 containing 0.1% NH4OH (aq) to yield 9
(38 mg, 24%) as a white powder. 1H NMR (500 MHz, CDCl3) δ 5.05 (d, J
= 4.5 Hz, 1H), 4.70 (dd, J = 9.7, 2.1 Hz, 1H), 4.43 (d, J = 7.3 Hz, 1H), 4.20
(dd, J= 5.3, 2.3 Hz, 1H), 4.12 (s, 1H), 4.07 (dt, J= 15.3, 6.1 Hz, 1H), 3.76 (s,
1H), 3.64 (d, J = 6.9 Hz, 1H), 3.54ꢀ3.45 (m, 1H), 3.38 (s, 1H), 3.32 (s,
3H), 3.23 (dd, J = 10.1, 7.3 Hz, 1H), 3.02 (t, J = 8.7 Hz, 1H), 2.86 (td, J =
12.9, 4.5 Hz, 1H), 2.81ꢀ2.71 (m, 3H), 2.63 (s, 1H), 2.53 (td, J = 13.0, 4.3
Hz, 1H), 2.45 (td, J = 12.2, 3.8 Hz, 1H), 2.34 (d, J = 15.2 Hz, 1H), 2.28 (s,
6H), 2.20 (d, J = 9.8 Hz, 1H), 2.09ꢀ1.96 (m, 3H), 1.87 (dtd, J = 22.0, 7.6,
2.6 Hz, 1H), 1.73 (d, J = 14.2 Hz, 1H), 1.65 (dd, J = 11.0, 1.8 Hz, 1H), 1.57
(dd, J = 15.2, 4.9 Hz, 2H), 1.51ꢀ1.38 (m, 3H), 1.37ꢀ1.33 (m, 1H), 1.32 (s,
1H), 1.31 (s, 4H), 1.23 (t, J = 5.1 Hz, 5H), 1.21 (t, J = 6.7 Hz, 7H), 1.13 (d, J
= 6.8 Hz, 3H), 1.06 (d, J = 9.1 Hz, 6H), 0.91 (d, J = 7.3 Hz, 3H), 0.88 (d, J =
7.4 Hz, 2H), 0.82 (t, J = 7.3 Hz, 3H). 13C NMR (500 MHz, CDCl3) δ
178.23, 133.57, 103.24, 95.67, 95.27, 83.85, 78.61, 78.19, 77.86, 75.04, 74.26,
73.90, 72.98, 71.01, 68.97, 65.77, 65.73, 65.14, 61.83, 52.16, 49.57, 45.04,
42.07, 41.32, 40.50, 35.03, 29.82, 28.91, 28.48, 27.32, 22.54, 21.72, 21.67,
21.49, 20.46, 18.38, 16.57, 15.06, 12.25, 11.45, 9.61. ESI mass spectrum: calcd
(MHþ) 777.5; found 777.5.
N9-Allylazithromycin, 10. 9-Deoxo-9a-aza-homoerythromycin A
8 (204 μmol, 150 mg) was mixed with allyl acetate (10 204 μmol, 1021
mg). TEA (539 μmol, 55 mg) and tetrakis(triphenylphosphine)palla-
dium(0) (20 μmol, 24 mg) was added to the reaction mixture at rt under
N2. The mixture was stirred for 7 h at 80 °C and further stirred for 15 h at
rt under N2. The crude mixture was diluted into CH2Cl2 and was washed
three times with saturated NaHCO3 (aq) and was dried over Na2SO4.
After evaporation of the solvent, the resulting product was purified by
flash chromatography, eluting with a step gradient ranging from 3% to
10% MeOH/CH2Cl2 containing 0.1% NH4OH (aq) to yield 4 (41 mg,
26%) as a white powder. 1H NMR (500 MHz, CDCl3) δ 6.00 (dq, J =
10.0, 6.8 Hz, 1H), 5.15ꢀ5.02 (m, 3H), 4.70 (dd, J = 10.0, 2.0 Hz, 1H),
4.43 (d, J = 7.3 Hz, 1H), 4.38 (s, 1H), 4.24ꢀ4.20 (m, 1H), 4.07 (dq, J =
12.4, 6.1 Hz, 1H), 3.75 (s, 1H), 3.64 (d, J = 6.9 Hz, 1H), 3.64ꢀ3.57 (m,
1H), 3.50 (dd, J = 9.8, 5.4 Hz, 1H), 3.41ꢀ3.34 (m, 1H), 3.32 (s, 3H),
3.23 (dd, J = 10.1, 7.4 Hz, 1H), 3.02 (t, J = 9.2 Hz, 2H), 2.79 (dt, J = 10.8,
7.1 Hz, 3H), 2.70 (s, 1H), 2.48ꢀ2.41 (m, 1H), 2.35 (d, J = 15.1 Hz, 1H),
2.27 (s, 6H), 2.18 (d, J = 10.2 Hz, 1H), 2.04ꢀ1.97 (m, 3H), 1.87 (dqd, J
= 15.2, 7.5, 2.5 Hz, 1H), 1.71 (d, J = 14.3 Hz, 1H), 1.67ꢀ1.62 (m, 1H),
1.57 (dd, J = 15.2, 5.0 Hz, 1H), 1.52ꢀ1.42 (m, 1H), 1.31ꢀ1.32 (m, 6H),
1.23 (s, 3H), 1.19ꢀ1.22 (m, 6H), 1.14 (d, J = 6.8 Hz, 3H), 1.07 (s, 3H),
1.06 (d, J = 7.5 Hz, 3H), 0.88 (t, J = 7.5 Hz, 3H), 0.86 (d, J = 5.9 Hz, 3H).
13C NMR (500 MHz, CDCl3) δ 178.38, 136.45, 117.66, 103.18, 95.21,
83.77, 78.46, 78.20, 77.80, 74.88, 74.36, 74.10, 73.00, 70.99, 68.95, 65.80,
65.75, 61.83, 53.57, 49.58, 45.12, 41.96, 41.52, 40.50, 34.98, 28.87, 27.80,
27.15, 22.19, 21.72, 21.60, 21.50, 18.39, 16.49, 15.01, 11.42, 9.85, 9.54.
ESI mass spectrum: calcd (MHþ) 775.5; found 775.4.
N9-Ethylamideazithromycin, 12. 9-Deoxo-9a-aza-homoery-
thromycin A 8 (88 μmol, 65 mg) was dissolved in toluene (1.8 mL).
Ethyl isocyanate (91 μmol, 6 mg) was added to the reaction mixture, and
the mixture was stirred for 1 h at rt. After evaporation of the solvent, the
crude mixture was diluted into CH2Cl2 and was washed three times with
saturated NaHCO3 (aq) and was dried over Na2SO4. The resulting
product was purified by flash chromatography, eluting with a step
gradient ranging from 3% to 10% MeOH/CH2Cl2 containing 0.1%
1
NH4OH (aq) to yield 12 (33 mg, 47%) as a white powder. H NMR
(500 MHz, CDCl3) δ 4.99 (dd, J = 9.3, 2.7 Hz, 1H), 4.83 (d, J = 4.2 Hz,
1H), 4.66 (s, 1H), 4.45 (d, J = 7.2 Hz, 1H), 4.05 (td, J = 12.7, 6.3 Hz,
1H), 4.01ꢀ3.98 (m, 1H), 3.75 (s, 1H), 3.59 (dd, J = 9.9, 4.8 Hz, 1H),
3.49 (d, J = 4.4 Hz, 1H), 3.44 (d, J = 14.3 Hz, 1H), 3.32 (dd, J = 10.5, 6.8
Hz, 1H), 3.27 (s, 3H), 3.24ꢀ3.16 (m, 3H), 3.02 (d, J = 7.3 Hz, 1H), 2.66
(dt, J = 12.4, 6.2 Hz, 1H), 2.59ꢀ2.49 (m, 2H), 2.29 (s, 6H), 2.34ꢀ2.25
(m, 9H), 2.14 (s, 2H), 1.91 (ddd, J = 14.1, 7. 5, 3.0 Hz, 2H), 1.70ꢀ1.61
(m, 2H), 1.55 (dd, J = 15.1, 4.9 Hz, 1H), 1.46 (ddd, J = 14.4, 9.2, 7.3 Hz,
1H), 1.30 (d, J = 6.9 Hz, 3H), 1.26 (d, J = 6.1 Hz, 6H), 1.24ꢀ1.20 (m,
9H), 1.13 (s, 2H), 1.11 (t, J = 7.2 Hz, 3H), 1.04 (t, J = 7.0 Hz, 6H), 0.89
(t, J = 7.4 Hz, 3H). 13C NMR (500 MHz, CDCl3) δ 159.86, 104.64,
96.84, 79.23, 78.23, 77.60, 74.68, 74.59, 74.17, 72.95, 70.84, 69.52, 66.36,
64.77, 49.46, 46.28, 41.36, 40.56, 35.91, 35.15, 29.41, 28.25, 22.46, 21.63,
21.33, 21.23, 17.91, 17.45, 15.46, 15.08, 12.57, 11.57, 10.40. ESI mass
spectrum: calcd (MHþ) 806.5; found 806.6.
C6-Methoxyl-9-Deoxo-9a-aza-9a-homoerythromycin A,
14. Clarithromycin (5.4 mmol, 4 g), 50% hydroxylamine (7 mL), and
acetic acid (5 mL) in isopropanol was stirred for 5 days at 40 °C to yield
6-methoxyerythromycin A 9-oxime as a white solid (2.6 g, 64%). C6-
Methoxylerythromycin A 9-oxime (3.4 mmol, 2.6 g), toluene-p-sulfonyl
chloride (6.81 mmol, 1.3 g), and pyridine (6.81 mmol, 0.5 g) in THF was
stirred for 20 h at 40 °C to yield C6-methoxylerythromycin A 9,11-imino
ether (2 g, 80%). C6-Methoxylerythromycin A 9,11-imino ether (2.7
mmol, 2 g) in MeOH was reduced by adding acetic acid and sodium
borohydride (18.8 mmol, 0.7 g) to yield 14 as a white powder (460 mg,
23%). 1H NMR (500 MHz, CDCl3) δ 4.95 (d, J = 4.0 Hz, 1H), 4.86 (dd,
J = 10.8, 2.0 Hz, 1H), 4.47 (d, J = 7.3 Hz, 1H), 4.08ꢀ3.98 (m, 2H), 4.00
(dd, J = 7.2, 1.6 Hz, 1H), 3.82 (d, J = 6.4 Hz, 1H), 3.69ꢀ3.58 (m, 1H),
3.51 (dd, J = 9.8, 5.4 Hz, 2H), 3.35 (s, 3H), 3.32 (s, 3H), 3.18 (dd, J =
10.3, 7.3 Hz, 2H), 3.07ꢀ2.98 (m, 2H), 2.86 (dt, J = 14.8, 7.5 Hz, 1H),
2.76 (dd, J = 13.1, 6.5 Hz, 1H), 2.45ꢀ2.38 (m, 1H), 2.34 (d, J = 15.1 Hz,
1H), 2.27 (s, 6H), 2.22 (d, J = 10.7 Hz, 1H), 2.11 (t, J = 10.5 Hz, 1H),
1.92ꢀ1.82 (m, 3H), 1.70ꢀ1.61 (m, 3H), 1.58 (dd, J = 9.0, 5.6 Hz, 1H),
1.50 (ddd, J = 14.2, 10.9, 7.2 Hz, 1H), 1.38ꢀ1.34 (m, 3H), 1.33ꢀ1.28
(m, 1H), 1.30 (d, J = 6.2 Hz, 3H), 1.25 (s, 3H), 1.24ꢀ1.19 (m, 9H), 1.12
(t, J = 8.5 Hz, 1H), 1.07 (s, 3H), 1.06 (d, J = 7.6 Hz, 2H), 1.04ꢀ1.01 (m,
1H), 0.99 (d, J = 7.0 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H). 13C NMR (500
MHz, CDCl3) δ 177.62, 102.61, 96.05, 79.91, 79.16, 77.99, 73.77, 72.96,
72.74, 71.04, 68.85, 66.14, 65.71, 58.21, 57.23, 51.82, 49.55, 45.30, 40.46,
35.08, 29.83, 28.70, 28.05, 22.01, 21.65, 21.60, 20.90, 20.40, 18.75, 16.27,
16.03, 12.85, 11.06, 9.35. ESI mass spectrum: calcd (MHþ) 749.5;
found 749.5.
C6-Alloxyl-9-deoxo-9a-aza-9a-homoerythromycin A, 21.
Erythromycin A 9-oxime 1a (6.7 mmol, 5 g), pyridine hydrochloride (10
mmol, 1.2 g), and cyclohexane, diethyl ketal (16.7 mmol, 2.9 g) in
acetonitrile were stirred for 16 h under N2 to yield erythromycin A 9-(O-
ethoxycyclohexyl)oxime. The oxime (6.2 mmol, 5.4 g), pyridine hydro-
chloride (9.3 mmol, 1.1 g), and hexamethyldisilazane (25 mmol, 5.2 g)
in acetonitrile were stirred for 2 h to yield 20,400-O-bis(TMS) erythro-
mycin A-9-(1-(1-ethoxy)cyclohexyl)oxime (5.8 g, 92%). The protected
oxime (2 mmol, 2 g), allyl tert-butylcarbonate (2.4 mmol, 0.4 g),
Pd2(dba)3 (29.6 μmol, 37 mg), and dppb (39.2 μmol, 17 mg) in THF
was refluxed for 3 h under N2. After reflux, the protection groups
were removed by acetic acid (5.6 mL) in acetonitrile (20 mL) and
H2O (4 mL) to yield C6-alloxylerythromycin A 9-oxime (1.2 g, 80%).
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dx.doi.org/10.1021/jm101593u |J. Med. Chem. 2011, 54, 2792–2804