Journal of Medicinal Chemistry
Article
×
1). The organic layer was dried over Na SO and concentrated in
2968, 2937, 2885, 1766, 1736, 1462, 1379, 1317, 1286, 1238, 1169,
2
4
1
vacuo. The crude product was purified by flash column chromatog-
1095, 1032, 997, 924, 899, 762. H NMR (500 MHz, CD OD): 8.40
3
raphy (only CHCl ) to afford 22 (88.8 mg, 0.178 mmol, 32%) as a
colorless solid and 23 (112.0 mg, 0.225 mmol, 41%) as a colorless
(s, 1H), 7.68 (s, 1H), 7.11 (s, 1H), 5.92 (s, 1H), 5.38 (dd, J = 10.9, 1.2
Hz, 1H), 5.29 (dd, J = 11.5, 2.3 Hz, 1H), 4.13 (dd, J = 16.0, 2.3 Hz,
1H, H-13), 3.98 (dd, J = 16.0, 2.3 Hz), 3.66 (t, J = 2.9 Hz, 1H), 3.51
(d, J = 2.3 Hz, 1H), 3.44 (d, J = 4.0 Hz, 1H), 3.17 (dq, J = 13.5, 6.9
Hz, 1H), 2.60 (t, J = 2.6 Hz, 1H), 2.44 (m, 1H), 2.18 (m, 1H), 2.03
(m, 1H), 1.93 (m, 1H), 1.72 (dd, J = 15.5, 8.6 Hz, 1H), 1.54 (m, 1H),
1.51 (s, 3H), 1.46 (s, 3H), 1.28 (d, J = 15.5 Hz, 1H), 1.22 (s, 3H), 1.21
3
solid.
2
2: Mp 198−205 °C. [α]D +5.2 (c 1.0, MeOH). IR (KBr) ν cm−1:
2
6
3
1
545, 3489, 3381, 3249, 2983, 2962, 2931, 2885, 2854, 1724, 1460,
381, 1335, 1259, 1219, 1169, 1086, 1032, 889, 800, 690. H NMR
1
(
500 MHz, CD OD) δ (ppm) 5.90 (s, 1H), 5.23 (dd, J = 11.2, 2.6 Hz,
3
1
3
1
2
1
H), 4.28 (dd, J = 15.5, 2.3 Hz, 1H), 4.22 (dd, J = 15.5, 2.3 Hz, 1H),
.63 (app t, J = 2.9 Hz, 1H), 3.52 (d, J = 2.9 Hz, 1H), 3.47 (dd, J =
0.6, 1.5 Hz, 1H), 3.24 (d, J = 3.4 Hz, 1H), 2.73 (t, J = 2.3 Hz, 1H),
.67 (m, 1H), 2.16 (m, 1H), 2.10 (m, 1H), 2.01 (m, 1H), 1.90 (m,
H), 1.78 (dd, J = 15.5, 9.2 Hz, 1H), 1.51 (m, 1H), 1.49 (s, 3H), 1.42
(
(
s, 3H, 6-CH ), 1.21 (d, J = 6.9 Hz, 3H), 1.18 (d, J = 6.9 Hz, 3H), 0.98
d, J = 7.5 Hz, 3H), 0.85 (t, J = 7.5 Hz, 3H). C NMR (125 MHz,
3
13
CD OD) δ (ppm): 174.5, 150.2, 138.9, 131.0, 119.0, 103.1, 85.1, 85.0,
8
2
3
1.6, 79.7, 78.5, 76.4, 75.3, 74.9, 71.6, 59.1, 44.0, 38.5, 35.6, 33.7, 31.7,
+
8.0, 26.7, 24.3, 22.5, 20.0, 16.9 (2C), 15.6, 10.9, 8.9. HRMS (ESI )
(s, 3H), 1.28 (m, 1H), 1.26 (s, 3H), 1.22 (d, J = 6.9 Hz, 3H), 1.20 (d, J
+
m/z: 615.3252 [M + Na] ; calcd for C H N NaO , 615.3258. HPLC
31
48
2
9
=
6.9 Hz, 3H), 1.19 (s, 3H), 0.98 (d, J = 7.5 Hz, 3H), 0.95 (d, J = 7.5
analysis (method A): retention time = 7.20 min; peak area, 95%.
(9S)-9-Dihydro-9,11-O-isopropylidene-3-O-((4-(N-
methylcarbamoylguanidyl)butyl)carbamoyl)-5-O-propargyl-
erythronolide A: 26. To a solution of 25 (30.0 mg, 0.0506 mmol) in
THF (0.55 mL) was added dropwise over 15 min a solution of 1,4-
diaminobutane (22.3 mg, 0.253 mmol) in THF (0.55 mL). The
reaction mixture was stirred at room temperature for 3 h. The mixture
was diluted with EtOAc (10 mL) and added to saturated aqueous
13
Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H). C NMR (125 MHz, CD OD) δ
3
(
ppm) 176.7, 103.0, 88.4, 81.7 (2C), 78.2, 77.7, 75.3, 75.0, 74.8, 71.6,
5
1
9.1, 45.6, 39.3, 35.6, 33.7, 31.9, 28.0, 26.6, 24.3, 22.6, 20.0, 16.90,
+
+
6.87, 16.2, 10.8, 8.5. HRMS (ESI ): 521.3082 [M + Na] ; calcd for
C H NaO , 521.3090. HPLC analysis (method C): retention time =
2
+48.8 (c 1.0, MeOH). IR (KBr) ν
cm : 3437, 2976, 2937, 1732, 1631, 1460, 1379, 1230, 1169, 1074,
27
46
8
5.4 min; peak area, 98%.
25
2
3: Mp 157−161 °C. [α]
D
−
1
NH Cl (5 mL) and separated. The organic layer was washed with
saturated aqueous NH Cl (5 mL × 2), and then the organic layer was
dried over Na SO and concentrated in vacuo. The crude product was
4
1
1
2
1
034, 924. H NMR (500 MHz, CD OD) δ (ppm) 5.19 (dd, J = 11.5,
3
4
.3 Hz, 1H), 4.41 (dd, J = 15.5, 2.3 Hz, 1H), 4.35 (dd, J = 15.5, 2.3 Hz,
H), 3.67 (d, J = 9.8 Hz, 1H), 3.64 (dd, J = 2.9, 2.9 Hz, 1H), 3.57 (d, J
2
4
used for the next step without further purification. To a solution of the
crude product in THF (1.1 mL) were added DIPEA (44.0 μL, 0.253
mmol) and 15 (42.3 mg, 0.253 mmol). The reaction mixture was
stirred at 55 °C for 14 h. The crude mixture was concentrated and
purified by preparative TLC (CHCl /MeOH/30% NH OH = 7/1/
0
1
2
1
=
3.5 Hz, 1H), 3.50 (d, J = 2.3 Hz, 1H), 2.87 (t, J = 2.3 Hz, 1H), 2.74
(
dq, J = 10.3, 6.9 Hz, 1H), 2.17 (m, 1H), 1.99 (m, 1H), 1.96 (m, 1H),
1.89 (m, 1H), 1.74 (dd, J = 15.5, 8.6 Hz, 1H), 1.51 (m, 1H), 1.49 (s,
3H), 1.44 (s, 3H), 1.29 (d, J = 15.5 Hz, 1H), 1.26 (d, J = 6.9 Hz, 3H),
1.22 (s, 3H), 1.20 (d, J = 6.9 Hz, 3H), 1.17 (s, 3H), 0.99 (d, J = 6.9
3
4
.1) to afford 26 (22.1 mg, 61% over 2 steps) as a colorless solid. Mp
13
Hz, 3H), 0.98 (d, J = 7.5 Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H). C NMR
125 MHz, CD OD) δ (ppm) 176.4, 103.0, 87.0, 81.7, 81.2, 81.0, 77.9,
28
−1
19−122 °C. [α]D +11.4 (c 1.0, MeOH). IR (KBr) ν cm : 3305,
(
3
968, 2937, 1732, 1724, 1720, 1612, 1514, 1458, 1379, 1255, 1169,
086, 1032, 754. H NMR (500 MHz, CD OD) δ (ppm): 5.24 (dd, J
7
2
4
6.00, 75.97, 75.0, 71.7, 60.4, 45.8, 39.0, 35.1, 33.9, 31.9, 28.0, 26.4,
4.3, 22.5, 19.9, 16.9 (2C), 16.3, 10.8, 9.2. HRMS (FAB, NBA):
99.3270 [M + H] ; calcd for C H O , 499.3271. HPLC analysis
1
3
=
11.5, 2.3 Hz, 1H), 4.98 (dd, J = 10.9, 1.2 Hz, 1H), 4.19 (dd, J = 16.0,
+
27
47
8
2
3
2
2
1
.3 Hz, 1H), 4.01 (dd, J = 16.0, 2.3 Hz, 1H), 3.63 (t, J = 2.9 Hz, 1H),
.51 (d, J = 2.3 Hz, 1H), 3.40−3.21 (m, 4H), 3.27 (d, J = 4.0 Hz, 1H),
.88 (m, 1H), 2.75 (t, J = 2.3 Hz, 1H), 2.70 (s, 3H), 2.25 (m, 1H),
.15 (m, 1H), 2.01 (m, 1H), 1.91 (m, 1H), 1.71 (q, J = 15.8, 8.9 Hz,
H), 1.58−1.45 (m, 1H), 1.49 (s, 3H), 1.43 (s, 3H), 1.35−1.25 (m,
(
method C): retention time = 8.35 min; peak area, >99%.
(
9S)-9-Dihydro-9,11-O-isopropylidene-5-O-((1-(2-(N-
methylcarbamoylguanidino)ethyl)-1H-1,2,3-triazol-4-yl)-
methyl)erythronolide A: 24. According to the preparation of 21, 22
(
20.0 mg, 0.0401 mmol) was converted to 24 (16.8 mg, 0.0246 mmol)
25
1H), 1.23 (s, 3H), 1.20 (d, J = 6.9 Hz, 3H), 1.18 (s, 3H), 1.13 (d, J =
6.9 Hz, 3H), 1.04 (d, J = 7.5 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H), 0.83 (t,
in 61% yield as a colorless solid. Mp 115−118 °C. [α] −1.80 (c 1.0,
MeOH). IR (KBr) ν cm : 3319, 2970, 2937, 1732, 1616, 1514, 1458,
1
D
−1
J = 7.5 Hz, 3H). 13C NMR (125 MHz, CD OD) δ (ppm): 175.4,
1
377, 1227, 1165, 1086, 1032. H NMR (500 MHz, CD OD) δ
3
3
1
4
1
59.1, 103.1, 86.5, 81.6, 81.1, 79.9, 78.1, 75.5, 75.2, 75.0, 71.6, 59.2,
4.6, 41.6 (2C), 38.5, 35.6, 33.7, 31.8, 28.0, 26.8, 26.6, 24.2, 22.5, 20.0,
6.91, 16.88, 15.6, 10.8, 9.0 (The peaks of −NHC(NH)-
(
ppm): 7.93 (s. 1H), 5.24 (dd, J = 11.5, 2.3 Hz, 1H), 4.82 (d, J = 12.0
Hz, 2H), 4.27−4.54 (m, 3H), 3.69 (brt, J = 5.7 Hz, 2H), 3.62 (t, J =
.9 Hz, 1H), 3.55−3.50 (m, 2H), 3.20 (d, J = 2.9 Hz, 1H), 2.75−2.67
2
13
+
NHCONHMe were not observed in C NMR). HRMS (ESI ) m/
z: 734.4315 [M + Na] ; calcd for C H N NaO , 734.4316. HPLC
analysis (method A): retention time = 6.20 min; peak area, >99%.
(
1
1
m, 1H), 2.70 (s, 3H), 2.17−2.09 (m, 2H), 2.00 (m, 1H), 1.90 (m,
+
H), 1.77 (m, 1H), 1.56−1.47 (m, 1H), 1.48 (s, 3H), 1.42 (s, 3H),
35 61
5
10
.29 (m, 1H), 1.25 (d, J = 6.3 Hz, 3H), 1.20 (d, J = 4.5 Hz, 3H), 1.19
(
9S)-9-Dihydro-9,11-O-isopropylidene-3-O-((1-(2-(N-
(
3
s, 3H), 1.08 (s, 3H), 1.03 (d, J = 7.5 Hz, 3H), 0.95 (d, J = 6.9 Hz,
H), 0.84 (t, J = 7.5 Hz, 3H). 1 C NMR (500 MHz, CD OD) δ
3
methylcarbamoylguanidyl)ethyl)-1H-1,2,3-triazol-4-yl)-
methyl)erythronolide A: 27. According to the preparation of 21, 23
(
in 69% yield as a colorless solid. Mp 122−125 °C. [α] +28.6 (c
0.41, MeOH). IR (KBr) ν cm : 3398, 2972, 2937, 1732, 1620, 1562,
1
(
1
3
(
ppm): 176.8 167.2, 160.7, 146.2, 125.7, 103.0, 88.7, 81.7, 78.4, 77.8,
50.0 mg, 0.100 mmol) was converted to 27 (47.4 mg, 0.0693 mmol)
7
2
7
5.5, 75.0, 71.6, 64.9, 50.7, 45.6, 41.7, 39.4, 35.6, 33.7, 31.8, 28.0, 26.8,
2
D
7
+
6.5, 24.2, 22.6, 20.0, 16.9 (2C), 16.2, 10.8, 8.7. HRMS (ESI ):
−1
+
06.4106 [M + Na] ; calcd for C H N NaO , 706.4115. HPLC
32
57
7
9
1
512, 1462, 1379, 1311, 1227, 1169, 1078, 1032, 920, 756. H NMR
analysis (method A): retention time = 5.08 min; peak area, 99%.
9S)-9-Dihydro-3-imidazoylcarbonyl-9,11-O-isopropylidene-
-O-propargylerythronolide A: 25. To a solution of 22 (50.0 mg,
.100 mmol) in THF (2 mL) were added NaH (21.9 mg, 0.50 mmol)
500 MHz, CD OD) δ (ppm) 7.97 (s. 1H), 5.20 (dd, J = 10.9, 2.3 Hz,
(
3
H), 4.91−4.70 (m, 2H), 4.58 (t, J = 5.2 Hz, 2H), 3.70 (m, 3H), 3.65
5
0
(d, J = 2.9 Hz, 1H), 3.52 (t, J = 1.7 Hz, 1H), 3.50 (d, J = 3.4 Hz, 1H),
2.78 (m, 1H), 2.70 (s, 3H), 2.18 (m, 1H), 2.04−1.96 (m, 2H), 1.89
(m, 1H), 1.76 (m, 1H), 1.55−1.47 (m, 1H), 1.50 (s, 3H), 1.45 (s, 3H),
1.30 (d, J = 14.9 Hz, 1H), 1.27 (d, J = 6.9 Hz, 3H), 1.23 (s, 3H), 1.21
(d, J = 6.9 Hz, 3H), 1.18 (s, 3H), 1.00 (d, J = 4.6 Hz, 3H), 0.99 (d, J =
and carbonyldiimidazole (81.3 mg, 0.500 mmol) at room temperature
under N . The reaction mixture was stirred for 3 h. The mixture was
quenched with saturated aqueous NH Cl (30 mL) and extracted with
EtOAc (40 mL × 1), washed with saturated aqueous NH Cl (40 mL ×
2
and concentrated in vacuo. The crude product was purified by flash
column chromatography (CHCl /MeOH = only CHCl to 100/1) to
2
4
4
5.2 Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CD
OD)
) and brine (40 mL × 1). The organic layer was dried over Na SO4
3
2
δ (ppm) 176.5, 146.3, 125.6, 103.0, 88.0, 81.7, 80.8, 77.9, 76.0, 75.0,
71.7, 67.2, 50.8, 46.0, 41.7, 39.5, 35.1, 33.9, 31.9, 28.0, 26.8, 26.6, 24.3,
22.5, 19.9, 16.9 (2C), 16.3, 10.8, 9.4 (The peaks of −NHC(
3
3
afford 25 (52.4 mg, 0.088 mmol, 88%) as a colorless solid. Mp 221−
27
D
−1
13
+
222 °C. [α] +5.5 (c 1.0, MeOH). IR (KBr) ν cm : 3386, 3311,
NH)NHCONHMe were not observed in C NMR). HRMS (ESI )
J
J. Med. Chem. XXXX, XXX, XXX−XXX