N. Kojima et al. / Bioorg. Med. Chem. 23 (2015) 1276–1283
1281
Purification by flash column chromatography over silica gel with
4.42–4.48 (m, 1H), 5.14 (br s, 1H), 5.33 (d, 1H, J = 7.3 Hz), 6.45 (br
s, 1H), 7.18 (d, 1H, J = 7.3 Hz), 7.28–7.30 (m, 1H), 7.41 (d, 1H,
J = 4.9 Hz), 7.50–7.56 (m, 2H), 7.89 (d, 1H, J = 2.4 Hz), 8.23 (d, 1H,
J = 7.3 Hz), 8.32 (d, 1H, J = 8.5 Hz), 8.53 (d, 1H, J = 8.5 Hz); 13C NMR
(125 MHz, CDCl3) (major isomer) d: 18.47, 18.53, 21.0, 25.7, 26.1,
26.7, 28.1 (2C), 28.17, 28.21, 28.3, 28.5, 28.7, 29.0, 29.3, 29.5,
39.7, 43.1, 45.3 (2C), 64.1, 66.4, 75.1, 77.8, 80.8, 82.3, 86.4, 87.2,
115.1, 118.7, 123.1, 126.1 (2C), 127.9, 128.2, 129.4, 129.6, 129.8,
EtOAc as eluent yielded 10 (307 mg, 99%) as colorless solids.
24
[
a]
ꢀ25.2 (c 1.40, CHCl3); 1H NMR (500 MHz, CDCl3) d: 1.24–
D
1.40 (m, 8H), 1.49 (qn, 2H, J = 7.3 Hz), 1.59 (qn, 2H, J = 7.3 Hz),
1.84–1.94 (m, 2H,), 2.02 (dt, 1H, J = 11.0, 7.3 Hz), 2.10 (s, 3H),
2.14 (td, 1H, J = 7.3, 3.7 Hz), 2.19 (td, 2H, J = 7.3, 2.4 Hz), 2.65 (br
s, 1H), 2.72 (br s, 1H), 3.41 (td, 2H, J = 7.3, 6.1 Hz), 3.54–3.59 (m,
1H), 3.64–3.70 (m, 2H), 4.05–4.09 (m, 1H), 4.17 (q, 1H,
J = 7.3 Hz), 5.35 (dd, 1H, J = 7.3, 2.4 Hz), 6.20 (br s, 1H), 7.33 (dd,
1H, J = 4.9, 2.4 Hz), 7.39 (d, 1H, J = 4.9 Hz), 7.87 (d, 1H, J = 2.4 Hz);
13C NMR (125 MHz, CDCl3) d: 18.6, 21.0, 26.8, 27.6, 28.16, 28.22,
28.6, 28.8, 29.1, 29.6, 39.8, 64.6, 66.3, 72.7, 74.9, 80.2, 80.7, 87.5,
126.0, 126.4, 127.9, 137.7, 163.2, 170.1; IR (NaCl) cmꢀ1: 3322,
1740, 1634; MS (FAB) m/z: 466 [M+H]+; HRMS (FAB) m/z: Calcd
for C24H36NO6S: 466.2263. Found: 466.2267 [M+H]+.
130.2, 134.9, 137.7, 151.9, 163.1, 169.9; IR (NaCl) cmꢀ1
:
3525, 1746, 1641, 1317, 1142; MS (FAB) m/z: 806 [M+H]+; HRMS
(FAB) m/z: Calcd for C44H60N3O7S2: 806.3873. Found: 806.3855
[M+H]+.
4.10. (R)-1-((2R,5R)-5-{(R)-10-[5-(Dimethylamino)naphthalene-
1-sulfonamido]-1-hydroxydecyl})tetrahydrofuran-2-yl)-11-
(thiophene-3-carboxamido)undecyl acetate (13a)
4.7. (R)-1-[(2R,5R)-5-Formyltetrahydrofuran-2-yl]-11-(thiophene-
3-carboxamido)undec-2-ynyl acetate (11)
A solution of 12a (20.4 mg, 0.0253 mmol) in benzene/MeOH
(1:1, 0.5 mL) was hydrogenated on Rh(PPh3)3Cl (9.4 mg,
0.0101 mmol) for 6 h with stirring at rt under 1 atm pressure of
hydrogen. The solvent was evaporated under the reduced pressure.
Purification by flash column chromatography over flash silica gel
NaIO4 (202 mg, 0.943 mmol) was added to a solution of 10
(275 mg, 0.590 mmol) in THF/H2O (3:1, 5.9 mL) at rt. After stirred
for 1.5 h, water was added to the reaction mixture. The mixture
was extracted with CH2Cl2 prior to drying and solvent evaporation.
Purification by flash column chromatography over silica gel with
n-hexane/EtOAc (1:2) as eluent yielded 11 (235 mg, 92%) as a
colorless oil. The aldehyde was unstable and therefore used
immediately in the next reaction.
with n-hexane/EtOAc (3:2) as eluent yielded 13a (15.9 mg, 77%,
24
dr = 87:13) as a pale green oil. [
a]
+9.3 (c 0.88, CHCl3); 1H NMR
D
(500 MHz, CDCl3) (major isomer) d: 1.06–1.40 (m, 30H), 1.41–
1.49 (m, 1H), 1.52–1.74 (m, 6H), 1.92–2.02 (m, 2H), 2.08 (s, 3H),
2.89 (q, 2H, J = 6.1 Hz), 2.89 (s, 6H), 3.37 (q, 1H, J = 6.1 Hz), 3.40
(td, 2H, J = 7.3, 6.1 Hz), 3.80 (td, 1H, J = 7.3, 6.1 Hz), 3.98 (dt, 1H,
J = 7.3, 6.1 Hz), 4.64 (br s, 1H), 4.87 (dt, 1H, J = 7.3, 6.1 Hz), 6.04
(br s, 1H), 7.19 (d, 1H, J = 7.3 Hz), 7.32 (dd, 1H, J = 4.9, 2.4 Hz),
7.37 (d, 1H, J = 4.9 Hz), 7.52 (dd, 1H, J = 8.5, 7.3 Hz), 7.56 (dd, 1H,
J = 8.5, 7.3 Hz), 7.84 (d, 1H, J = 2.4 Hz), 8.24 (d, 1H, J = 7.3 Hz),
8.29 (d, 1H, J = 8.5 Hz), 8.54 (d, 1H, J = 8.5 Hz); 13C NMR
(125 MHz, CDCl3) (major isomer) d: 21.1, 25.3, 25.5, 26.4, 26.9,
28.2, 28.4, 28.9, 29.2 (2C), 29.32, 29.35, 29.37, 29.38, 29.39, 29.5,
29.6, 29.7, 30.8, 33.5, 39.8, 43.3, 45.4 (2C), 73.8, 75.1, 79.6, 82.3,
115.2, 118.8, 123.2, 126.0, 126.4, 127.8, 128.3, 129.6, 129.7,
4.8. (R)-1-((2R,5R)-5-{(R)-10-[5-(Dimethylamino)naphthalene-
1-sulfonamido]-1-hydroxydec-2-ynyl}tetrahydrofuran-2-yl)-
11-(thiophene-3-carboxamido)undec-2-ynyl acetate (12a)
The procedure was the same as that used for preparation of 8a,
25
giving 12a (80%, dr = 87:13). Pale green amorphous; [
a]
ꢀ11.8 (c
D
1.36, CHCl3); 1H NMR (500 MHz, CDCl3) (major isomer) d: 1.06–
1.15 (m, 4H), 1.16–1.23 (m, 2H), 1.26–1.39 (m, 12H), 1.47 (qn,
2H, J = 7.3 Hz), 1.58 (qn, 2H, J = 7.3 Hz), 1.81–1.89 (m, 1H), 1.90–
1.98 (m, 1H), 2.01–2.15 (m, 2H), 2.08 (s, 3H), 2.10–2.14 (m, 3H),
2.19 (td, 2H, J = 7.3, 2.4 Hz), 2.88 (q, 2H, J = 6.5 Hz), 2.88 (s, 6H),
3.38 (td, 2H, J = 7.3, 6.1 Hz), 4.06–4.24 (m, 3H), 5.10 (br s, 1H),
5.35 (d, 1H, J = 7.3 Hz), 6.43 (br s, 1H), 7.18 (d, 1H, J = 7.3 Hz),
7.30 (m, 1H), 7.42 (d, 1H, J = 4.9 Hz), 7.52 (dd, 1H, J = 8.5, 7.3 Hz),
7.55 (dd, 1H, J = 8.5, 7.3 Hz), 7.89 (d, 1H, J = 2.4 Hz), 8.23 (d, 1H,
J = 7.3 Hz), 8.31 (d, 1H, J = 8.5 Hz), 8.54 (d, 1H, J = 8.5 Hz); 13C
NMR (125 MHz, CDCl3) (major isomer) d: 18.5, 18.6, 21.0, 26.1,
26.7, 27.5, 28.0, 28.08, 28.11, 28.2, 28.3, 28.5, 28.8, 29.0, 29.3,
29.5, 39.7, 43.1, 45.3 (2C), 65.4, 66.3, 75.1, 78.0, 80.1, 82.9, 86.3,
87.3, 115.1, 118.8, 123.1, 126.1 (2C), 127.9, 128.2, 129.4, 129.6,
129.9, 130.3, 134.9, 137.8, 152.0, 163.1, 170.9; IR (NaCl) cmꢀ1
:
3325, 1738, 1640, 1312, 1144; MS (FAB) m/z: 814 [M+H]+; HRMS
(FAB) m/z: Calcd for C44H68N3O7S2: 814.4499. Found: 814.4493
[M+H]+.
4.11. (R)-1-((2R,5R)-5-{(S)-10-[5-(Dimethylamino)naphthalene-
1-sulfonamido]-1-hydroxydecyl}tetrahydrofuran-2-yl)-11-
(thiophene-3-carboxamido)undecyl acetate (13b)
The procedure was the same as that used for preparation of 13a,
24
giving 13b (85%, dr = 88:12). Pale green oil; [
a
]
+5.7 (c 0.84,
D
CHCl3); 1H NMR (500 MHz, CDCl3) (major isomer) d: 1.06–1.48
(m, 30H), 1.52–1.68 (m, 6H), 1.77–1.90 (m, 2H), 1.95–2.05 (m,
1H), 2.09 (s, 3H), 2.89 (q, 2H, J = 6.1 Hz), 2.89 (s, 6H), 3.40 (td,
2H, J = 7.3, 6.1 Hz), 3.77 (td, 1H, J = 6.1, 3.7 Hz), 3.87 (ddd, 1H,
J = 8.5, 6.1, 3.7 Hz), 4.02 (dt, 1H, J = 7.3, 6.1 Hz), 4.62–4.65 (m,
1H), 4.86 (dt, 1H, J = 7.3, 6.1 Hz), 6.03 (br s, 1H), 7.18 (d, 1H,
J = 7.3 Hz), 7.32 (dd, 1H, J = 4.9, 2.4 Hz), 7.37 (d, 1H, J = 4.9 Hz),
7.52 (dd, 1H, J = 8.5, 7.3 Hz), 7.56 (dd, 1H, J = 8.5, 7.3 Hz), 7.84 (d,
1H, J = 2.4 Hz), 8.25 (d, 1H, J = 7.3 Hz), 8.29 (d, 1H, J = 8.5 Hz),
8.54 (d, 1H, J = 8.5 Hz); 13C NMR (125 MHz, CDCl3) (major isomer)
d: 21.2, 24.8, 25.3, 25.9, 26.3, 26.9, 28.4, 28.86, 28.87, 29.2 (2C),
29.27, 29.34, 29.37, 29.39 (2C), 29.5, 29.7, 30.9, 32.6, 39.8, 43.3,
45.4 (2C), 71.6, 75.4, 80.2, 82.2, 115.2, 118.7, 123.2, 126.0, 126.4,
127.8, 128.3, 129.6, 129.7, 129.9, 130.3, 134.8, 137.8, 152.1,
163.1, 170.9; IR (NaCl) cmꢀ1: 3318, 1734, 1636, 1310, 1144; MS
(FAB) m/z: 814 [M+H]+; HRMS (FAB) m/z: Calcd for C44H68N3O7S2:
814.4499. Found: 814.4487 [M+H]+.
129.8, 130.2, 134.9, 137.6, 151.9, 163.1, 169.9; IR (NaCl) cmꢀ1
:
3325, 1744, 1640, 1316, 1142; MS (FAB) m/z: 806 [M+H]+; HRMS
(FAB) m/z: Calcd for C44H60N3O7S2: 806.3873. Found: 806.3856
[M+H]+.
4.9. (R)-1-((2R,5R)-5-{(S)-10-[5-(Dimethylamino)naphthalene-
1-sulfonamido]-1-hydroxydec-2-ynyl}tetrahydrofuran-2-yl)-
11-(thiophene-3-carboxamido)undec-2-ynyl acetate (12b)
The procedure was the same as that used for preparation of 8a by
use of (1S,2R)-N-methylephedrine, giving 12b (91%, dr = 88:12).
25
Pale green amorphous; [
a]
ꢀ8.5 (c 0.79, CHCl3); 1H NMR
D
(500 MHz, CDCl3) (major isomer) d: 1.06–1.40 (m, 18H), 1.48 (qn,
2H, J = 7.3 Hz), 1.57 (qn, 2H, J = 7.3 Hz), 1.89–1.96 (m, 1H), 2.01–
2.20 (m, 7H), 2.08 (s, 3H), 2.72 (br s, 1H), 2.86–2.90 (m, 8H), 3.38
(td, 2H, J = 7.3, 6.1 Hz), 4.12-4.18 (m, 1H), 4.23–4.27 (m, 1H),