Y. Yi et al. / European Journal of Medicinal Chemistry 101 (2015) 179e184
183
saturated aqueous NaHCO
overnight. Before the synthesis of compounds 6g and 6h, the amino
of valine should be protected by ditertbutyl dicarbonate (BOC O).
After treatment with NaHCO and brine, the residue was treated
3
and brine, and then dried with Na
2
SO
4
J ¼ 8.4 Hz, 1H), 5.33e5.22 (m, 2H), 5.14 (d, J ¼ 17.4 Hz, 1H), 3.86 (d,
J ¼ 8.8 Hz, 3H), 3.79e3.61 (m, 2H), 3.32 (d, J ¼ 6.2 Hz,1H), 2.36e1.93
(m, 5H), 1.74e1.50 (m, 3H), 1.47e1.14 (m, 9H), 1.15e1.04 (m, 4H),
2
13
3
0.84 (d, J ¼ 6.9 Hz, 3H), 0.71 (d, J ¼ 6.8 Hz, 3H); C NMR (101 MHz,
with a mixture of 10 mL trifluoroacetic acid (TFA) and 10 mL DCM at
CDCl 217.16, 170.12, 168.02, 164.87, 164.37, 163.23, 139.16, 132.67,
3
) d
room temperature for 30 min. The reaction mixture was quenched
120.85, 117.09, 113.96, 91.10, 74.61, 69.74, 58.17, 55.57, 45.45, 44.49,
43.97, 41.88, 36.77, 35.99, 34.48, 34.06, 30.43, 26.87, 26.36, 24.82,
18.41, 16.82, 14.90, 11.44; HRMS (ES) calcd [M þ H]þ for
with 25% aqueous NaHCO
3
(15 mL) and washed with water, dried
with anhydrous Na SO overnight and rotary evaporated to dry-
2
4
ness. The crude residue obtained was purified by silica gel column
chromatography (petroleum ether: ethyl acetate 1:2 v/v) to afford
the desired compounds.
34 43 3 7
C H N O S 638.2894, found 638.2892.
4.2.8. 14-O-[(4-(Piperidine-2-L(-)carboxamide)-6-
hydroxypyrimidine-2-yl) thioacetyl] mutilin) (6e)
4
.2.4. 14-O-[(4-Acetamido-6-hydroxypyrimidine-2-yl) thioacetyl]
mutilin (6a)
White solid, 0.80 g (yield 73%); IR (KBr): 3448, 2931, 1779, 1729,
627, 1588, 1549, 1459, 1400, 1372, 1299, 1201, 1162, 1117, 1030, 981,
White solid, 0.62 g (yield 50%); IR(KBr): 3448, 2918, 2849, 1729,
1654, 1617, 1458, 1438, 1279,1362, 1265, 1151, 1240, 1115, 1042, 1081,
ꢀ11
984, 957, 747 cm . H NMR (400 MHz, CDCl3)
d
6.49 (dd, J ¼ 17.2,
1
9
1
11.3 Hz, 1H), 5.96 (s, 1H), 5.73 (d, J ¼ 8.5 Hz, 1H), 5.32 (d, J ¼ 11.0 Hz,
1H), 5.30e5.01 (m, 3H), 4.29e3.99 (m, 1H), 3.79 (dd, J ¼ 41.0,
16.3 Hz, 2H), 3.35 (s, 1H), 2.27 (s, 6H), 2.06 (d, J ¼ 17.5 Hz, 5H), 1.63
(d, J ¼ 10.3 Hz, 5H), 1.45e1.17 (m, 9H), 1.14 (s, 4H), 0.86 (d, J ¼ 6.8 Hz,
-1 1
39 cm ; H NMR (400 MHz, CDCl
H), 5.73 (d, J ¼ 7.9 Hz, 1H), 5.32 (d, J ¼ 10.8 Hz, 1H), 5.17 (d,
3
)
d
6.47 (dd, J ¼ 17.2, 11.0 Hz,
J ¼ 17.5 Hz, 2H), 4.69 (s, 2H), 3.85 (d, J ¼ 16.4 Hz, 1H), 3.78e3.56 (m,
H), 3.34 (d, J ¼ 4.6 Hz, 1H), 2.16 (ddd, J ¼ 75.4, 48.8, 32.3 Hz, 5H),
.75 (d, J ¼ 13.9 Hz, 2H), 1.63 (d, J ¼ 9.1 Hz, 3H), 1.28 (dd, J ¼ 45.4,
13
3
1
3
3
3H), 0.74 (d, J ¼ 6.7 Hz, 3H); C NMR (101 MHz, CDCl
3
) d 216.99,
170.41, 167.89, 167.61, 164.80, 139.28, 129.94, 128.13, 117.06, 90.73,
74.66, 69.73, 60.39, 58.20, 45.48, 44.54, 44.01, 41.92, 36.81, 36.04,
9.0 Hz, 9H), 1.13 (s, 4H), 0.86 (d, J ¼ 6.2 Hz, 3H), 0.71 (d, J ¼ 6.4 Hz,
13
H); C NMR (101 MHz, CDCl
3
)
d
216.96, 167.08, 166.35, 162.71,
34.49, 34.09, 30.47, 26.93, 26.40, 24.86, 21.41, 16.84, 16.55, 14.91,
þ
160.59, 139.24, 117.18, 84.18, 74.59, 70.05, 58.41, 58.11, 45.44, 44.32,
14.21, 11.43; HRMS (ES) calcd [M þ H] for C32
46 4 6
H N O S 615.3210,
4
1
3.95, 41.86, 36.70, 36.01, 34.45, 33.29, 30.40, 26.89, 26.34, 24.82,
found 615.3213.
8.43, 16.81, 14.90, 11.47; HRMS (ES) calcd [M þ H]þ for
[C
29
H
41
N
3
O
5
S 560.2788, found 560.2784.
4.2.9. 14-O-[(4-(Piperidine-2-(
hydroxypyrimidine-2-yl) thioacetyl] mutilin (6f)
White solid, 0.60 g (yield 48%); IR(KBr): 3447, 1733, 1637, 1577,
D)-carboxamide)-6-
4.2.5. 14-O-[(4-(3-Chlorobenzamide)-6-hydroxypyrimidine-2-yl)
ꢀ
1
1
thioacetyl] mutilin (6b)
1560, 1541, 1508, 1457, 1245, 1151, 1116, 969, 547 cm
(400 MHz, CDCl
; H NMR
White solid, 0.53 g (yield 41%); IR (KBr): 3368, 3215, 2931, 1735,
3
)
d
6.48 (ddd, J ¼ 15.2, 11.0, 4.2 Hz, 1H), 5.96 (s, 1H),
ꢀ
1 1
1
(
1
625, 1586, 1547, 1459, 1283, 1240, 1116, 981, 739 cm
400 MHz, CDCl 8.20e7.91 (m, 2H), 7.73e7.34 (m, 2H), 6.49 (s,
H), 6.08 (s, 1H), 5.72 (s, 1H), 5.21 (dd, J ¼ 50.2, 22.6 Hz, 4H), 4.11 (d,
;
H NMR
5.74 (t, J ¼ 8.6 Hz,1H), 5.45e5.27 (m,1H), 5.23e5.10 (m, 3H), 4.11 (q,
J ¼ 7.1 Hz, 1H), 3.91e3.64 (m, 2H), 3.34 (d, J ¼ 6.3 Hz, 1H), 2.41e2.14
(m, 6H), 2.11e1.95 (m, 5H), 1.82e1.44 (m, 5H), 1.47e1.16 (m, 9H),
3
) d
1
3
J ¼ 6.7 Hz, 1H), 3.97e3.57 (m, 2H), 3.34 (d, J ¼ 6.1 Hz, 1H), 2.40e1.90
1.17e1.09 (m, 4H), 0.85 (d, J ¼ 7.0 Hz, 3H), 0.73 (t, J ¼ 6.4 Hz, 3H);
C
(
3
m, 6H), 1.63 (td, J ¼ 47.2, 13.3 Hz, 3H), 1.42 (s, 4H), 1.36e1.18 (m,
NMR (101 MHz, CDCl 216.90, 170.32, 167.87, 166.77, 164.80,
3
) d
13
H), 1.10 (s, 4H), 0.85 (d, J ¼ 5.5 Hz, 3H), 0.72 (s, 3H); C NMR
217.15, 170.39, 167.95, 165.03, 164.49, 162.37,
39.15, 134.89, 134.19, 130.37, 130.00, 129.70, 128.54, 117.12, 91.07,
139.22, 117.21, 117.08, 90.78, 83.91, 74.62, 69.70, 60.40, 58.17, 45.46,
44.47, 43.97, 41.88, 36.78, 36.67, 34.48, 34.06, 30.43, 26.90, 26.36,
24.83, 21.42, 21.05, 16.83, 14.89, 14.20, 11.45; HRMS (ES) calcd
(
3
100 MHz, CDCl ) d
1
74.63, 69.84, 60.42, 58.17, 45.46, 43.98, 41.89, 36.77, 36.00, 34.48,
[M þ H]þ for C32
H
46
N
4
O
6
S 615.3210, found 615.3202.
3
4.05, 30.43, 26.89, 26.37, 21.05,16.84,14.90,11.45; HRMS (ES) calcd
þ
[M þ H] for C33
H40ClN
3
O
6
642.2399, found 642.2397.
4.2.10. 14-O-[(4-(3-Methyl-2-(L)-amino-butyrylamide) -6-
hydroxypyrimidine-2-yl) thioacetyl] mutilin (6g)
4
.2.6. 14-O-[(4-(4-Methylbenzamide)-6-hydroxypyrimidine-2-yl)
White solid, 0.72 g (yield 60%); IR(KBr): 3462, 2931, 1733, 1605,
ꢀ
1
1
thioacetyl] mutilin (6c)
1544, 1432, 1275, 1152, 1117,1043, 785, 547 cm
(400 MHz, CDCl
;
H NMR
White solid, 0.53 g (yield 43%); IR (KBr): 3375, 2930,1735, 1624,
3
)
d
6.48 (ddd, J ¼ 15.2, 11.0, 4.2 Hz, 1H), 5.96 (s, 1H),
ꢀ1
1
(
1
(
586, 1458, 1298, 1255, 1166, 1117, 1071, 980, 745 cm ; 1H NMR
400 MHz, CDCl 8.06e7.97 (m, 2H), 7.29 (s, 1H), 6.59e6.36 (m,
H), 6.09 (dd, J ¼ 6.6, 3.0 Hz, 1H), 5.72 (d, J ¼ 6.3 Hz, 1H), 5.36e5.23
m, 1H), 5.21e5.06 (m, 2H), 3.91e3.67 (m, 2H), 3.33 (s, 1H), 2.44 (d,
5.73 (d, J ¼ 8.6 Hz, 1H), 5.40e5.24 (m, 1H), 5.17 (d, J ¼ 17.1 Hz, 3H),
4.11 (q, J ¼ 7.1 Hz, 1H), 3.92e3.63 (m, 2H), 3.34 (d, J ¼ 6.3 Hz, 1H),
2.40e2.13 (m, 5H), 2.05 (dd, J ¼ 17.3, 9.5 Hz, 4H), 1.69 (ddd, J ¼ 11.8,
11.2, 3.3 Hz, 6H), 1.55e1.20 (m, 12H), 1.13 (s, 4H), 0.85 (d, J ¼ 7.0 Hz,
3
) d
13
J ¼ 1.1 Hz, 2H), 2.33e2.01 (m, 5H),1.74 (d, J ¼ 14.5 Hz, 2H),1.66e1.50
3H), 0.74 (d, J ¼ 6.8 Hz, 3H); C NMR (101 MHz, CDCl
3
) d 216.92,
(
3
d
1
m, 3H), 1.51e1.18 (m, 9H), 1.16e1.04 (m, 4H), 0.85 (d, J ¼ 6.4 Hz,
167.05, 163.88, 159.63, 157.52, 139.20, 130.90, 128.84, 117.24, 94.45,
75.38, 74.59, 70.06, 67.78, 58.10, 45.44, 44.37, 43.95, 41.87, 36.72,
13
H), 0.73 (dd, J ¼ 4.3, 2.3 Hz, 3H); C NMR (101 MHz, CDCl
217.10, 170.22, 167.98, 164.83, 163.60, 145.16, 139.19, 130.52,
29.39, 125.89, 117.11, 91.10, 74.63, 69.72, 60.40, 58.18, 45.46, 43.98,
3
)
36.01, 34.45, 33.24, 30.41, 26.89, 26.27, 25.61, 24.83, 16.86, 14.88,
þ
11.47; HRMS (ES) calcd [M þ H] for C32
48 4 6
H N O S 617.3367, found
4
2
C
1.89, 36.79, 36.01, 34.49, 34.08, 30.45, 26.89, 26.36, 24.84, 21.81,
617.3360.
1.04, 16.84, 14.91, 11.45; HRMS (ES) calcd [M þ H]þ for
H
34 43
N
3
O
6
S 622.2945, found 622.2938.
4.2.11. 14-O-[(4-(3-Methyl-2-(D)-amino-butyrylamide) -6-
hydroxypyrimidine-2-yl) thioacetyl] mutilin (6h)
4
.2.7. 14-O-[(4-(4-Methoxylbenzamide)-6-hydroxypyrimidine-2-
White solid, 0.69 g (yield 58%); IR(KBr): 3463, 3363, 2922, 1731,
ꢀ
1
1
yl) thioacetyl] mutilin (6d)
1604, 1544, 1433, 1278, 1152, 1117, 1042, 785.40 cm
(400 MHz, CDCl
; H NMR
White solid, 0.59g (yield 46%); IR(KBr):3369, 2933, 1734, 1605,
3
)
d
6.48 (dd, J ¼ 17.3, 11.0 Hz, 1H), 5.74 (d, J ¼ 7.9 Hz,
1581, 1549, 1511, 1458, 1401, 1299, 1251, 1160, 1116, 1069, 1024,
1H), 5.46 (s, 1H), 5.33 (d, J ¼ 10.9 Hz, 1H), 5.23e4.95 (m, 3H), 4.01
(dd, J ¼ 14.5, 7.4 Hz, 1H), 3.93e3.62 (m, 2H), 3.34 (d, J ¼ 6.0 Hz, 1H),
2.42e2.09 (m, 5H), 2.00 (dd, J ¼ 15.7, 9.6 Hz, 4H), 1.69 (ddd, J ¼ 23.1,
ꢀ
1 1
8
46 cm ; H NMR (400 MHz, CDCl
3
)
d
8.07 (d, J ¼ 8.8 Hz, 2H), 6.94
(
d, J ¼ 8.8 Hz, 2H), 6.47 (dd, J ¼ 17.4,11.0 Hz,1H), 6.07 (s,1H), 5.70 (d,