M. Tarleton et al. / European Journal of Medicinal Chemistry 54 (2012) 573e581
579
1
1
2
H), 5.37e5.23 (m, 2H), 5.13 (d, J ¼ 4.8 Hz, 1H), 4.92 (d, J ¼ 4.8 Hz,
H), 4.46e4.40 (m, 1H), 4.17e4.10 (m, 1H), 2.89 (d, J ¼ 8.4 Hz, 1H),
1H), 4.84 (d, J ¼ 4.5 Hz,1H), 4.70 (d, J ¼ 4.5 Hz,1H), 3.80 (m, 1H), 3.53
(m,1H), 2.91 (d, J ¼ 8.0 Hz,1H), 2.50 (dd, J ¼ 1.7, 8.0 Hz,1H),1.79e1.33
13
13
.72e2.68 (m, 1H), 1.86e1.71 (m, 2H), 1.57e1.43 (m, 2H). C NMR
(m, 8H), 0.92 (t, J ¼ 7.3 Hz, 3H). C NMR (CDCl
3
) (75 MHz): d 175.9,
(
CDCl
3
) (75 MHz):
d
174.8, 132.5, 117.7, 102.4, 78.7, 76.0, 70.8, 51.1,
107.0, 79.7, 79.0, 69.2, 50.4, 49.8, 30.9, 28.0, 27.3, 18.6, 13.2; IR (KBr)
ꢂ1
ꢂ1
4
6.6, 27.6, 27.5; IR (KBr)
nmax/cm : 2988 (CeH), 1747 (C]O), 1638
nmax/cm : 2952 (CeH), 2870 (CeH), 1772 (C]O), 1122 (CeO); m/z
(
C]C), 1150 (CeO); m/z (APCI M þ H) 211. HRMS calculated for
(APCI M þ H) 227. HRMS calculated for M þ H; C12
19 4
H O ; 227.1278.
M þ H; C11 ; 211.0965.
14 4
H O
6.2.9. (3S,3aR,4S,7R,7aS)-3-(Pentyloxy)hexahydro-4,7-
6.2.5. (3S,3aR,4S,7R,7aS)-3-((E)-But-2-en-1-yloxy)hexahydro-4,7-
epoxyisobenzofuran-1(3H)-one (13)
epoxyisobenzofuran-1(3H)-one (8) and (3R,3aR,4S,7R,7aS)-3-((E)-
but-2-en-1-yloxy)hexahydro-4,7-epoxyisobenzofuran-1(3H)-one (9)
Synthesised as per the general microwave procedure above
from 3 and but-2-en-1-ol to afford the title compounds (6:1) as
Synthesised as per the general microwave procedure above
from 3 and pentan-1-ol to afford the title compound as a yellow oil
1
(53%); H NMR (CDCl
3
) (300 MHz):
d
5.22 (d, J ¼ 1.7 Hz, 1H), 4.79 (d,
J ¼ 4.6 Hz, 1H), 4.66 (d, J ¼ 4.6 Hz, 1H), 3.75 (m, 1H), 3.48 (m, 1H),
2.88 (d, J ¼ 7.9 Hz, 1H), 2.46 (dd, J ¼ 1.7, 7.9 Hz, 1H), 1.75e1.25 (m,
ꢁ
1
a white crystalline solid (R
300 MHz):
5.78 (dq, J ¼ 15.2, 6.4 Hz, 1H), 5.55 (dt, 15.2, 6.0 Hz,
H), 5.30 (d, J ¼ 1.1 Hz, 1H), 4.83 (d, J ¼ 4.5 Hz, 1H), 4.69 (d,
J ¼ 4.5 Hz, 1H), 4.24 (dd, J ¼ 6.0, 0.8 Hz, 1H), 4.01 (dd, J ¼ 7.1, 0.8 Hz,
H), 2.91 (d, J ¼ 7.9 Hz, 1H), 2.50 (dd, J ¼ 7.9, 1.1 Hz, 1H), 1.80e1.45
f
0.81) (42%), m.p. 78 C; H NMR (CDCl )
3
13
(
d
10H), 0.86 (t, J ¼ 6.3 Hz, 3H). C NMR (CDCl
3
) (75 MHz): d 175.6,
1
106.9, 79.7, 79.0, 69.5, 50.4, 49.8, 28.5, 28.0, 27.5, 27.2, 21.8, 13.4; IR
ꢂ1
(film)
n
max/cm : 2938 (CeH), 1777 (C]O), 1122 (CeO); m/z (APCI
1
M þ H) 241.0. HRMS calculated for M þ H; C13
21 4
H O ; 241.1434.
1
3
(
1
m, 4H), 1.73 (d, J ¼ 6.4 Hz, 3H). C NMR (CDCl
3
) (75 MHz): d 175.5,
31.2, 125.0, 105.5, 79.7, 79.0, 69.6, 50.4, 49.8, 28.0, 27.2, 17.3; IR
6.2.10. (3S,3aR,4S,7R,7aS)-3-(Hexyloxy)hexahydro-4,7-
epoxyisobenzofuran-1(3H)-one (14)
Synthesised as per the general microwave procedure above
from 3 and hexan-1-ol to afford the title compound as a yellow oil
ꢂ1
nmax/cm : 2985 (CeH), 1752 (C]O),1617 (C]C), 1153 (CeO);
(
KBr)
m/z (APCI M þ H) 225. HRMS calculated for M þ H; C12
25.1121.
Isolated as a white solid (R
CDCl ) (300 MHz):
H
16
O
4
;
2
ꢁ
1
1
f
0.62) (9%), m.p. 116e118 C; H NMR
(31%); H NMR (CDCl
3
) (300 MHz):
d
5.24 (d, J ¼ 1.8 Hz, 1H), 4.82 (d,
(
3
d
5.76 (dq, J ¼ 15.3, 6.4 Hz, 1H), 5.57 (m, 1H),
J ¼ 4.7 Hz, 1H), 4.68 (d, J ¼ 4.7 Hz, 1H), 3.78 (m, 1H), 3.50 (m, 1H),
5
1
.56 (d, J ¼ 6.8 Hz, 1H), 5.11 (d, J ¼ 4.8 Hz, 1H), 4.90 (d, J ¼ 4.8 Hz,
2.90 (d, J ¼ 8.0 Hz, 1H), 2.48 (dd, J ¼ 1.8, 8.0 Hz, 1H), 1.85e1.22 (m,
13
H), 4.35 (m, 1H), 4.06 (m, 1H), 2.88 (d, J ¼ 8.3 Hz, 1H), 2.67 (dd,
12H), 0.88 (t, J ¼ 6.6 Hz, 3H). C NMR (CDCl
3
) (75 MHz): d 175.5,
13
J ¼ 6.8, 8.3 Hz, 1H), 1.85e1.38 (m, 4H), 1.73 (d, J ¼ 6.4 Hz, 3H).
C
106.9, 79.7, 79.0, 69.5, 50.4, 49.8, 28.8, 28.0, 27.3, 25.0, 21.9, 20.4,
ꢂ1
NMR (CDCl
3
) (75 MHz):
d
175.0, 130.6, 125.3, 102.1, 78.7, 76.0, 70.6,
13.4; IR (film)
n
max/cm : 2932 (CeH),1780 (C]O),1124 (CeO); m/z
ꢂ1
5
1.2, 46.6, 27.6, 27.5,17.2; IR (KBr)
O),1617 (C]C),1153 (CeO); m/z (APCI M þ H) 225. HRMS calculated
for M þ H; C12 ; 225.1121.
n
max/cm : 2985 (CeH),1752 (C]
(APCI M þ H) 255. HRMS calculated for M þ H; C14
23 4
H O ; 255.1591.
H
17
O
4
6.2.11. (3S,3aR,4S,7R,7aS)-3-(Octyloxy)hexahydro-4,7-
epoxyisobenzofuran-1(3H)-one (15)
6.2.6. (3S,3aR,4S,7R,7aS)-3-(Hex-5-yn-1-yloxy)hexahydro-4,7-
Synthesised as per the general microwave procedure above from
epoxyisobenzofuran-1(3H)-one (10)
3 and octan-1-ol to afford the title compound as a dark yellow oil
1
Synthesised as per the general microwave procedure above
(26%); H NMR (CDCl
3
) (300 MHz):
d
5.25 (d, J ¼ 1.7 Hz, 1H), 4.83 (d,
from 3 and hex-5-yn-1-ol to afford the title compound as a clear oil
J ¼ 4.6 Hz,1H), 4.69 (d, J ¼ 4.6 Hz), 3.80 (m,1H), 3.51 (m,1H), 2.90 (d,
1
(
80%); H NMR (Acetone-d
6
) (300 MHz):
d
5.32 (d, J ¼ 1.5 Hz, 1H),
J ¼ 8.0 Hz,1H), 2.49 (dd, J ¼ 1.7, 8.0 Hz, 1H), 2.04e1.25 (m, 16H), 0.88
13
4
3
1
1
8
.73 (d, J ¼ 4.2 Hz, 1H), 4.65 (d, J ¼ 4.2 Hz, 1H), 3.79e3.71 (m, 1H),
(t, J ¼ 6.2 Hz, 3H). C NMR (CDCl
3
) (75 MHz): d 175.4, 106.9, 79.7,
.62e3.55 (m, 1H), 3.00 (d, J ¼ 7.9 Hz, 1H), 2.53 (dd, J ¼ 7.9, 1.5 Hz,
79.0, 69.5, 50.4, 49.8, 31.2, 28.8, 28.7, 28.6, 28.0, 27.3, 25.4, 22.1, 13.5;
ꢂ1
H), 2.36e2.31 (m, 1H), 2.23e2.14 (m, 3H), 2.08e2.02 (m, 1H),
IR (film)
n
max/cm : 2938 (CeH),1782 (C]O),1123 (CeO); m/z (APCI
.74e1.51 (m, 6H). 13C NMR (Acetone-d
) (75 MHz):
d
175.2, 106.6,
M þ H) 283. HRMS calculated for M þ H; C16
6
27 4
H O ; 283.1904.
3.2, 79.5, 78.8, 68.7, 68.1, 50.0, 49.2, 27.8, 27.5, 27.0, 24.4, 17.0; IR
ꢂ1
(film)
n
max/cm : 3325 (C^CeH), 2933 (CeH), 2145 (C^C), 1779
6.2.12. (3S,3aR,4S,7R,7aS)-3-Isopropoxyhexahydro-4,7-
epoxyisobenzofuran-1(3H)-one (16)
(
C]O), 1124 (CeO); m/z (APCI M þ H) 251. HRMS calculated for
M þ H; C14
H
19
O
4
; 251.1278.
Synthesised as per the general microwave procedure above
from 3 and isopropanol to afford the title compound as a white
ꢁ
1
6.2.7. (3S,3aR,4S,7R,7aS)-3-Ethoxyhexahydro-4,7-
solid (49%), m.p. 74e76 C; H NMR (CDCl ) (300 MHz): d 5.36 (d,
3
epoxyisobenzofuran-1(3H)-one (11)
J ¼ 1.6 Hz, 1H), 4.83 (d, J ¼ 4.3 Hz, 1H), 4.68 (d, J ¼ 4.3 Hz, 1H), 3.98
(sept, J ¼ 6.2 Hz, 1H), 2.91 (d, J ¼ 8.0 Hz, 1H), 2.47 (dd, J ¼ 1.6, 8.0 Hz,
Synthesised as per the general microwave procedure above
from 3 and ethanol to afford the title compound as a white solid
13
1H), 1.79e1.75 (m, 2H), 1.59e1.46 (m, 2H), 1.22e1.21 (m, 6H).
C
ꢁ
1
(
80%), m.p. 71e72 C; H NMR (CDCl
3
) (300 MHz):
d
5.27 (d,
NMR (CDCl
28.1, 27.6, 22.7, 21.0; IR (KBr)
3
) (75 MHz):
d
175.7, 105.2, 79.7, 79.0, 71.5, 50.8, 50.0,
ꢂ1
J ¼ 1.5 Hz, 1H), 4.84 (d, J ¼ 4.7 Hz, 1H), 4.70 (d, J ¼ 4.7 Hz, 1H), 3.87
n
max/cm : 2964 (CeH), 2984 (CeH),
(
1
m, 1H), 3.60 (m, 1H), 2.91 (d, J ¼ 8.0, 1H), 2.50 (dd, J ¼ 1.5,8.0 Hz,
1732 (C]O), 1124 (CeO); m/z (APCI M þ H) 212. HRMS calculated
1
3
H), 1.81e1.76 (m, 2H), 1.60e1.50 (m, 2H), 1.23 (t, J ¼ 7.1 Hz, 3H).
C
for M þ H; C11 ; 213.1121.
17 4
H O
NMR (CDCl
2
3
) (75 MHz):
d
175.6, 106.7, 79.7, 79.0, 64.9, 50.5, 49.8,
ꢂ1
8.1, 27.3, 14.4; IR (KBr)
n
max/cm : 2979 (CeH), 2881 (CeH), 1752
6.2.13. (3S,3aR,4S,7R,7aS)-3-(Tert-butoxy)hexahydro-4,7-
epoxyisobenzofuran-1(3H)-one (17)
(
C]O), 1190 (CeO); m/z (APCI M þ H) 199. HRMS calculated for
M þ H; C10 ; 199.0965.
H
15
O
4
Synthesised as per the general microwave procedure above
from 3 and tert-butanol to afford the title compound as a white
ꢁ
1
6.2.8. (3S,3aR,4S,7R,7aS)-3-Butoxyhexahydro-4,7-
solid (76%), m.p. 127e128 C; H NMR (CDCl ) (300 MHz): d 5.47 (d,
3
epoxyisobenzofuran-1(3H)-one (12)
J ¼ 1.3 Hz, 1H), 4.83 (d, J ¼ 3.9 Hz, 1H), 4.64 (d, J ¼ 3.5 Hz, 1H), 2.88
(d, J ¼ 8.0 Hz, 1H), 2.45 (dd, J ¼ 1.3, 7.0 Hz, 1H), 1.76e1.27 (m, 13H).
Synthesised asper the general microwave procedure above from 3
and butan-1-ol to afford the title compound as pale yellow solid
13
C NMR (CDCl
3
) (75 MHz):
d
175.7, 102.2, 79.6, 79.0, 76.9 51.7, 50.0,
ꢁ
1
ꢂ1
(
23%), m.p. 46e47 C; H NMR (CDCl
3
) (300 MHz):
d
5.26 (d, J ¼ 1.7 Hz,
28.2, 28.0, 27.1; IR (KBr)
n
max/cm : 2985 (CeH), 2878 (CeH), 1759