796 Medicinal Chemistry, 2012, Vol. 8, No. 5
Jin et al.
Cl3) ꢀ: 10.9, 15.4, 21.2, 22.6, 25.2, 29.8, 30.0, 33.6, 38.1,
40.8, 45.2, 45.9, 56.5, 66.9, 71.5, 72.2, 76.6, 77.7, 80.6, 84.0,
128.8, 129.6, 129.9, 130.5, 133.7, 144.6, 165.0, 165.7, 170.6,
170.8, 202.5; ESI Full MS m/z: [M]+ 635.8.
132.0, 133.0, 133.8, 138.2, 138.7, 165.1, 167.0, 170.4, 170.6,
172.6, 172.9, 202.9; ESI Full MS m/z: [M+Na]+ 928.3.
7-Ethanoyl-10-n-hexanoyl-10-deacetyl-1-deoxypaclitaxel
(4b)
7-Ethanoyl-1-deoxybaccatin III (15g)
1
White solid, yield 74%. H-NMR (CDCl3) ꢀ: 0.90 (3H, t,
White solid, yield 64%. 1H-NMR (CDCl3)ꢀ: 1.03 (3H, s),
1.21 (3H, s), 1.69 (1H, m), 1.77 (3H, s), 1.82 (1H, m), 1.95
(1H, dd, J = 9.0, 2.0 Hz), 2.03 (3H, s), 2.12 (3H, s), 2.16
(3H, s), 2.30 (3H, s), 2.52 (1H, td, J = 15.5, 9.5 Hz), 2.62
(1H, m), 3.83 (1H, d, J = 6.5 Hz), 4.13 (1H, d, J = 8.5 Hz),
4.38 (1H, d, J = 8.5 Hz), 4.67 (1H, t, J = 8.0 Hz), 5.01 (1H,
d, J = 9.0 Hz), 5.61 (2H, m), 6.23 (1H, s), 7.47 (2H, t, J =
7.5 Hz), 7.60 (1H, t, J = 7.5 Hz), 8.07 (2H, d, J = 7.5 Hz);
13C-NMR (CDCl3) ꢀ: 10.9, 15.3, 21.2, 22.6, 25.2, 29.9, 30.1,
33.6, 38.1, 45.3, 46.0, 56.5, 67.0, 71.7, 72.3, 76.3, 76.7, 80.8,
84.1, 128.7, 129.7, 129.9, 131.3, 133.7, 143.5, 165.0, 169.2,
170.6, 170.8, 203.3; ESI Full MS m/z: [M+Na]+ 635.3.
J = 7.0 Hz), 1.13 (3H, s), 1.25 (3H, s), 1.33 (4H, m), 1.62
(3H, s), 1.68 (2H, m), 1.71 (1H, dd, J = 15.5, 8.0 Hz), 1.79
(3H, s), 1.83 (3H, s), 1.86 (1H, m), 2.04 (3H, s), 2.06 (s, 1H),
2.37 (3H, s), 2.43 (2H, m), 2.59 (2H, m), 3.68 (1H, d, J = 5.0
Hz), 3.75 (1H, d, J = 6.5 Hz), 4.15 (1H, d, J = 8.5 Hz), 4.38
(1H, d, J = 8.5 Hz), 4.80 (1H, dd, J = 4.0, 2.5 Hz), 4.99 (1H,
d, J = 8.5Hz), 5.56 (1H, dd, J = 10.5, 7.5 Hz), 5.64 (1H, dd,
J = 6.5, 3.0 Hz), 5.80 (1H, dd, J = 9.0, 2.5 Hz), 5.96 (1H, t, J
= 8.5 Hz), 6.21 (1H, s), 7.11 (1H, d, J = 9.0 Hz), 7.33 (1H, t,
J = 7.0 Hz), 7.40 (4H, m), 7.49 (5H, m), 7.61 (1H, t, J = 7.5
Hz), 7.74 (2H, d, J = 8.0 Hz), 8.06 (2H, d, J = 8.0 Hz); 13C-
NMR (CDCl3) ꢀ: 11.1, 14.1, 14.8, 18.6, 21.2, 22.5, 22.7,
24.7, 25.7, 26.6, 30.0, 31.4, 33.7, 34.2, 38.5, 45.0, 46.0, 54.9,
56.6, 71.5, 71.9, 72.1, 73.4, 75.4, 76.8, 81.3, 84.0, 127.2,
127.2, 128.4, 128.9, 128.9, 129.1, 129.5, 130.0, 132.1, 133.1,
133.8, 138.2, 138.6, 165.1, 167.0, 170.4, 170.7, 171.9, 172.6,
202.7; ESI Full MS m/z: [M+Na]+ 958.3.
General Procedure for Preparation of Compounds 4a-g
To a stirred solution of 15a-g (0.10 mmol), 4-
dimethylaminopyridine (0.10 mmol) and 1-ethyl-3-(3-
dimethyllaminopropyl)carbodiimide
hydrochloride
7-Ethanoyl-10-propanoyl-10-deacetyl-1-deoxypaclitaxel
(4c)
(EDC·HCl) (0.20 mmol) in toluene (5 mL) was added
(4S,5R)-2,4-diphenyloxazoline-5-carboxylic acid (12, 54.6
o
White solid, yield 76%. 1H-NMR (CDCl3)ꢀ: 1.13 (3H, s),
1.19 (3H, t, J = 7.5 Hz), 1.25 (3H, s), 1.58 (3H, s), 1.71 (1H,
dd, J = 15.0, 8.5 Hz), 1.82 (1H, m), 1.83 (3H, s), 2.05 (3H,
s), 2.06 (1H, m), 2.38 (3H, s), 2.43 (2H, m), 2.60 (2H, m),
3.66 (1H, d, J = 4.5 Hz), 3.72 (1H, t, J = 7.0 Hz), 3.75 (1H,
d, J = 7.0 Hz), 4.15 (1H, d, J = 8.5 Hz), 4.38 (1H, d, J = 8.5
Hz), 4.80 (1H, dd, J = 3.5, 3.0 Hz), 4.99 (1H, d, J = 8.5 Hz),
4.80 (1H, dd, J = 3.5, 3.0 Hz), 5.64 (1H, dd, J = 6.5, 2.5
Hz), 5.81 (1H, dd, J = 9.0, 2.0 Hz), 5.96 (1H, t, J = 9.0 Hz),
6.22 (1H, s), 7.10 (1H, d, J = 9.0 Hz), 7.34 (1H, t, J = 7.0
Hz), 7.40 (4H, m),7.49 (5H, m), 7.61 (1H, t, J = 7.5 Hz),
7.75(2H, d, J = 7.0 Hz), 8.06 (2H, d, J = 7.0 Hz); 13C-NMR
(CDCl3) ꢀ: 11.1, 14.1, 14.8, 18.6, 21.2, 22.5, 22.7, 24.7,
25.7, 26.6, 30.0, 31.4, 33.7, 34.2, 38.5, 45.0, 46.0, 54.9, 56.6,
71.5, 71.9, 72.1, 73.4, 75.4, 76.8, 81.3, 84.0, 127.2, 127.2,
128.4, 128.9, 128.9, 129.1, 129.5, 130.0, 132.1, 133.1, 133.8,
138.2, 138.6, 165.1, 167.0, 170.4, 170.7, 171.9, 172.6, 202.7;
ESI Full MS m/z: [M+Na]+ 917.3.
mg, 0.20 mmol) at 50 C. The reaction was monitored by
TLC until complete, and quenched with 1 mL methanol. The
solvent was evaporated, followed by adding of EtOAc (12
mL), solids were removed by filtration, and the organic layer
was concentrate in vacuo. The crude residue was purified by
column chromatography on silica gel using EtOAc and pe-
troleum ether to afford the intermediate compounds. To a
stirred solution of the intermdiate compound (0.09 mmol) in
CH3OH (4 mL) was added dropwise 0.04 mol/L aqueous
HCl to maintain the pH 3-4 at room temperature. The reac-
o
tion temperature was then warmed to 60 C, and the reaction
was followed by TLC until complete. After cooling to room
temperature, the reaction mixture was neutralized with satu-
rated aqueous NaHCO3 solution, and extracted with EtOAc,
washed with water, and dried, and the solvent was evapo-
rated. The crude residue was purified by chromatography
using EtOAc and petroleum ether to afford the desired prod-
uct 4a-g.
7-Ethanoyl-10-(5,6-dichloronicotinoyl)-10-deacetyl-1-
deoxypaclitaxel (4d)
7-Ethanoyl-10-cyclopropanoyl-10-deacetyl-1-
deoxypaclitaxel (4a)
White solid, yield 72%. 1H-NMR (CDCl3)ꢀ: 1.21 (3H, s),
1.34 (3H, s), 1.76 (1H, dd, J = 15.0, 8.5 Hz), 1.81 (3H, s),
1.87 (1H, m), 1.90 (3H, s), 2.10 (3H, s), 2.13 (1H, m), 2.40
(3H, s), 2.62 (2H, m), 3.65 (1H, d, J = 4.5 Hz), 3.78 (1H, d,
J = 6.5 Hz), 4.16 (1H, d, J = 8.5 Hz), 4.41 (1H, d, J = 8.5
Hz), 4.81 (1H, dd, J = 4.5, 2.5 Hz), 5.00 (1H, d, J = 10.0
Hz), 5.66 (m, 2H), 5.80 (1H, dd, J = 9.0, 2.0 Hz), 5.99 (1H,
t, J = 8.5 Hz), 6.49 (1H, s), 7.08 (1H, d, J = 9.0 Hz), 7.33
(1H, t, J = 7.5 Hz), 7.40 (4H, t, J = 7.5 Hz), 7.50 (5H, m),
7.62 (1H, t, J = 7.5 Hz), 7.74 (2H, d, J = 7.0 Hz), 8.08 (2H,
d, J = 7.0 Hz), 8.31 (1H, d, J = 2.0 Hz), 8.89 (1H, d, J = 2.0
Hz); 13C-NMR (CDCl3) ꢀ: 11.0, 14.9, 21.3, 22.7, 22.8, 26.1,
26.5, 29.8, 30.2, 33.8, 38.5, 45.0, 46.0, 55.0, 56.8, 71.4, 71.9,
71.9, 73.3, 76.7, 81.1, 83.9, 126.0, 127.1, 127.2, 128.4,
128.8, 128.9, 129.1, 129.4, 130.0, 131.0, 132.0, 132.1, 133.8,
1
White solid, yield 75%. H-NMR (CDCl3) ꢀ: 1.03 (1H,
m), 1.04 (1H, m), 1.05 (1H, m), 1.14 (3H, s), 1.25 (6H, d, J =
2.5 Hz), 1.68 (2H, m), 1.81 (1H, m), 1.79 (3H, s), 1.83 (3H,
s), 1.84 (1H, m), 2.00 (3H, s), 2.38 (3H, s), 2.04 (1H, m),
2.37 (3H, s), 2.58 (2H, m), 3.69 (1H, d, J = 4.0 Hz), 3.74
(1H, d, J = 6.5 Hz), 4.15 (1H, d, J = 8.0 Hz), 4.38 (1H, d, J =
8.5 Hz), 4.79 (s, 1H), 4.98 (1H, d, J = 9.0 Hz), 5.55 (1H, dd,
J = 10.5, 7.0 Hz), 5.63 (1H, dd, J = 6.5, 3.0 Hz), 5.80 (1H,
dd, J = 9.0, 2.0 Hz), 5.96 (1H, t, J = 8.5 Hz), 6.23 (1H, s),
7.13 (1H, d, J = 9.0 Hz), 7.33 (1H, t, J = 7.5 Hz), 7.40 (4H,
m), 7.49 (5H, m), 7.61 (1H, t, J = 7.5 Hz), 7.74 (2H, d, J =
7.5 Hz), 8.07 (2H, d, J = 7.5 Hz); 13C-NMR (CDCl3) ꢀ: 8.9,
9.0, 11.0, 13.0, 14.8, 21.2, 22.7, 25.8, 26.6, 29.8, 30.0, 33.7,
38.5, 45.0, 46.0, 54.9, 56.6, 71.4, 71.9, 72.1, 73.3, 75.3, 81.2,
84.0, 127.2, 127.2, 128.4, 128.8, 128.9, 129.1, 129.5, 130.0,