T. Sato et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5504–5507
5507
0.67 (hexane/EtOAc = 4:1); 1H NMR (300 MHz, CDCl3) d 6.31 (1H, d, J = 1.8 Hz,
H18), 6.21 (1H, d, J = 3.4 Hz, H13), 6.01 (1H, d, J = 2.0 Hz, H18), 5.61 (1H, d,
J = 3.1 Hz, H13), 5.45 (1H, s, H15), 5.26 (1H, s, H15), 5.13–5.07 (2H, m, H8/14),
4.92 (1H, s, H14), 4.49 (1H, t, J = 7.6 Hz, H3), 4.39 (2H, t, J = 1.7 Hz, H19), 4.25
(1H, dd, J = 9.6 Hz, H6), 3.21 (1H, m, H7), 2.95 (1H, m, H1), 2.83 (1H, m, H5),
2.66 (1H, dd, J = 14.3 Hz, H9), 2.35 (1H, dd, J = 14.2 Hz, H9), 2.07 (1H, m, H2),
1.68 (1H, m, H2), 0.96–0.87 (18H, m, TBS), 0.12–0.09 (12H, m, TBS).
(1R,3S,5R,6R,7R,8S)-3-(tert-Butyldimethylsilyloxy)-8-hydroxy-13,14,15-trimethy-
lene-decahydroazuleno[6,7-b]furan-12-one (10): To a solution of 9 (31.1 mg,
0.054 mmol, 1.0 equiv) in THF (0.05 mL), 2 N NaOH (0.5 mL) was added. After
stirring for 28 h at room temperature, the mixture was diluted with EtOAc, and
(3.1523 g, 28.1 mmol, 5.0 equiv) were added. After stirring for 24 h, the
mixture was diluted with Et2O, and quenched with a saturated NaCl solution.
The aqueous layer was then extracted with Et2O. The combined organic layers
were washed with brine, dried over Na2SO4, and concentrated in vacuo. The
crude product was used in the next reaction, without further purification.
To a solution of 13 (674.0 mg, 5.61 mmol, 1.0 equiv) and imidazole (2.2943 g,
33.7 mmol, 6.0 equiv) in CH2Cl2, TIPSCl (2.61 mL, 12.3 mmol, 2.2 equiv) was
added at 0 °C. After stirring for 30 min, the solution was warmed to room
temperature and stirred for another 30 min. The mixture was diluted with
CH2Cl2, and quenched with a saturated NH4Cl solution. The aqueous layer was
then extracted with CH2Cl2. The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated in vacuo. Purification by silica gel
column chromatography (hexane/EtOAc = 40:1) afforded crude 14 as a color-
less oil. The crude product was used in the next reaction without further
purification; EI-HRMS (m/z) calcd for C11H17D4O3Si [MÀCH(CH3)2]+ 233.1511,
found 233.1504.
quenched with
a saturated NH4Cl solution. The aqueous layer was then
extracted with EtOAc. The combined organic layers were washed with brine,
dried over Na2SO4, and then concentrated in vacuo. Purification by silica gel
column chromatography (hexane/EtOAc = 2:1) afforded 10 as a white solid
(13.5 mg, 0.036 mmol, 67%); Rf 0.28 (hexane/EtOAc = 2:1); IR (neat, cmÀ1),
3740, 3426, 2945, 2856, 2362, 1741, 1644, 1465, 1281, 1164, 1100, 983, 894,
832; 1H NMR (300 MHz, CDCl3) d 6.27 (1H, d, J = 2.8 Hz, H13), 6.15 (1H, d,
J = 3.1 Hz, H13), 5.44 (1H, s, H15), 5.24 (1H, s, H15), 5.11 (1H, s, H14), 4.95 (1H,
s, H14), 4.47 (1H, m, H3), 4.16 (1H, t, J = 10.3, H6), 3.92 (1H, m, H8), 2.96 (1H, m,
H1), 2.84–2.77 (2H, m, H5/7), 2.67 (1H, dd, J = 13.8 Hz, H9), 2.26 (1H, dd,
J = 13.8 Hz, H9), 2.07 (1H, m, H2), 1.74 (1H, m, H2), 0.92–0.90 (9H, m, TBS), 0.09
(6H, m, TBS); 13C NMR (75 MHz, CDCl3) d 151.8, 143.0, 137.7, 122.9, 116.3,
111.3, 79.2, 73.7, 71.7, 50.2, 49.6, 44.6, 41.4, 40.1, 25.6, 17.9; ESI-HRMS (m/z)
calcd for C21H32NaO4Si [M+Na]+ 399.1970, found 399.1968.
17-((Triisopropylsilyloxy)methyl)acrylic acid-d4 (15): To
a solution of 14
(609.7 mg, 2.20 mmol, 1.0 equiv) in THF/H2O (1:1, 5.4 mL) LiOH (210.8 mg,
8.80 mmol, 4.0 equiv) was added at room temperature. After stirring for 24 h,
the mixture was diluted with Et2O, and quenched with 5% HCl solution. The
aqueous layer was then extracted with Et2O. The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification
by silica gel column chromatography (hexane/EtOAc = 10:1) afforded 15 as a
colorless oil (71.4 mg, 0.27 mmol, 12%, over three steps); Rf 0.15 (hexane/
EtOAc = 20:1); 1H NMR (300 MHz, CDCl3) d 1.30–1.04 (21H, m, TIPS).
(1R,3S,5R,6R,7R,8S)-3-(tert-Butyldimethylsilyloxy)-13,14,15-trimethylene-12-
oxododecahydroazuleno[6,7-b]furan-8-yl 17-((triisopropylsilyloxy)methyl)acry-
late (11): To a solution of 6 (20.4 mg, 0.0791 mmol, 2.0 equiv) in toluene
(1R,3S,5R,6R,7R,8S)-3-(tert-Butyldimethylsilyloxy)-13,14,15-trimethylene-12-
oxododecahydroazuleno[6,7-b]furan-8-yl 17-((triisopropylsilyloxy)methyl)acry-
late-d4 (16): To a solution of 15 (67.7 mg, 0.258 mmol, 1.0 equiv) in toluene
(0.5 mL), 2,4,6-trichlorobenzoyl chloride (13.6
l
L, 0.0870 mmol, 2.2 equiv) and
(0.6 mL), 2,4,6-trichlorobenzoyl chloride (44.2
lL, 0.283 mmol, 1.1 equiv) and
Et3N (22.0 L, 0.158 mmol, 4.0 equiv) were added. After stirring for 1 h at room
l
Et3N (71.9 L, 0.516 mmol, 2.0 equiv) were added. After stirring for 1 h at room
l
temperature, a solution of 10 (14.9 mg, 0.0395 mmol, 1.0 equiv) and DMAP
(12.6 mg, 0.103 mmol, 2.6 equiv) in toluene (1.5 mL) was added to the reaction
mixture. After stirring for 25 h under reflux, the mixture was diluted with
EtOAc, and quenched with saturated NaHCO3 solution. The aqueous layer was
then extracted with EtOAc. The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated in vacuo. Purification by silica gel
column chromatography (hexane/EtOAc = 10:1) afforded 11 as a yellow oil
(16.0 mg, 0.0259 mmol, 66%); Rf 0.92 (hexane/EtOAc = 2:1); IR (neat, cmÀ1),
2944, 2864, 1773, 1716, 1640, 1463, 1389, 1260, 1096, 1014, 962, 882, 835,
776, 683; 1H NMR (300 MHz, CDCl3) d 6.34 (1H, s, H18), 6.21 (1H, d, J = 3.4 Hz,
H13), 6.09 (1H, s, H18), 5.61 (1H, d, J = 3.1 Hz, H13), 5.45 (1H, s, H15), 5.26 (1H,
s, H15), 5.13–5.07 (2H, m, H8/14), 4.92 (1H, s, H14), 4.49 (3H, m, H3/19), 4.25
(1H, t, J = 9.8 Hz, H6), 3.21 (1H, m, H7), 2.96 (1H, m, H1), 2.84 (1H, m, H5), 2.67
(1H, dd, J = 14.1 Hz, H9), 2.35 (1H, dd, J = 14.1 Hz, H9), 2.10–2.06 (1H, m, H2),
1.71–1.64 (1H, m, H2), 1.44–0.95 (21H, m, TIPS), 0.91–0.89 (9H, m, TBS), 0.09–
0.07 (6H, m, TBS); 13C NMR (75 MHz, CDCl3) d 168.9, 164.5, 151.4, 142.0, 139.4,
137.0, 124.7, 122.6, 117.1, 111.5, 79.0, 73.8, 61.3, 49.6, 46.8, 44.4, 39.6, 37.5,
25.6, 17.9, 11.7, 0.74, À5.0, À8.4; ESI-HRMS (m/z) calcd for C34H56NaO6Si2 [M
+Na]+ 639.3513, found 639.3491.
temperature, a solution of 10 (97.0 mg, 0.258 mmol, 1.0 equiv) and DMAP
(40.9 mg, 0.335 mmol, 1.3 equiv) in toluene (2.0 mL) was added to the reaction
mixture. After stirring for 2 h at 40 °C, the mixture was diluted with EtOAc, and
quenched with saturated NaHCO3 solution. The aqueous layer was then
extracted with EtOAc. The combined organic layers were washed with brine,
dried over Na2SO4, and concentrated in vacuo. Purification by silica gel column
chromatography (hexane/EtOAc = 10:1) afforded 16 as
(112.6 mg, 0.181 mmol, 70%); Rf 0.92 (hexane/EtOAc = 2:1); IR (neat, cmÀ1),
3747, 2944, 2892, 1773, 1715, 1462, 1385, 1258, 1104, 1013, 881, 834, 679; 1
a colorless oil
H
NMR (300 MHz, CDCl3) d 6.21 (1H, d, J = 3.4 Hz, H13), 5.61 (1H, d, J = 3.1 Hz,
H13), 5.45 (1H, s, H15), 5.25 (1H, s, H15), 5.13–5.07 (2H, m, H14/H8), 4.91 (1H,
s, H14), 4.49 (1H, t, J = 11.3 Hz, H3), 4.25 (1H, dd, J = 10.0 Hz, H6), 3.21 (1H, m,
H7), 2.95 (1H, m, H1), 2.86 (1H, m, H5), 2.65 (1H, dd, J = 14.1 Hz, H9), 2.35 (1H,
dd, J = 14.1 Hz, H9), 2.10–2.06 (1H, m, H2), 1.71–1.64 (1H, m, H2), 1.28–1.05
(21H, m, TIPS), 0.99–0.85 (9H, TBS), 0.11–0.06 (6H, TBS); 13C NMR (75 MHz,
CDCl3) d 169.4, 165.1, 151.8, 142.2, 139.4, 137.4, 122.8, 117.8, 112.0, 79.3, 74.1,
50.0, 47.2, 44.8, 40.0, 37.8, 26.0, 18.0, 12.4, À4.6; ESI-HRMS (m/z) calcd for
C
34H52D4NaO6Si2 [M+Na]+ 643.3764, found 643.3737.
Cynaropicrin-d4 (2): To a solution of 16 (56.8 mg, 0.091 mmol, 1.0 equiv) in THF
(1.6 mL), TBAF (129.0 L, 0.455 mmol, 5.0 equiv) was added at 0 °C. After
stirring for 4 h at room temperature, the mixture was diluted with EtOAc, and
quenched with saturated NH4Cl solution. The aqueous layer was then
Cynaropicrin (1) (via TBS route): To a solution of 11 (3.7 mg, 0.006 mmol,
1.0 equiv) in THF (0.2 mL), was added TBAF (8.5 lL, 0.030 mmol, 5.0 equiv) at
l
0 °C. After stirring for 4 h at room temperature, the mixture was diluted with
EtOAc and quenched with a saturated NH4Cl solution. The aqueous layer was
then extracted with EtOAc. The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated in vacuo. Purification by silica gel
column chromatography (hexane/EtOAc = 1:2) afforded 1 as a colorless oil
(1.5 mg, 0.004 mmol, 75%); Rf 0.20 (hexane/EtOAc = 1:1); 1H NMR (300 MHz,
CDCl3) d 6.39 (1H, s, H18), 6.23 (1H, d, J = 3.4 Hz, H13), 5.96 (1H, s, H18), 5.62
(1H, d, J = 3.1 Hz, H13), 5.51 (1H, s, H15), 5.37 (1H, s, H15), 5.18–5.12 (2H, m,
H8/14), 4.95 (1H, s, H14), 4.57 (1H, t, J = 7.2 Hz, H3), 4.39 (2H, s, H19), 4.26 (1H,
dd, J = 10.6 Hz, H6), 3.24–3.17 (1H, m, H7), 3.01–2.95 (1H, m, H1), 2.85 (1H, t,
J = 10.3 Hz, H5), 2.72 (1H, dd, J = 14.8 Hz, H9), 2.41 (1H, dd, J = 14.4 Hz, H9),
2.30–2.20 (1H, m, H2), 1.79–1.69 (1H, m, H2).
a
extracted with EtOAc. The combined organic layers were washed with brine,
dried over Na2SO4, and concentrated in vacuo. Purification by silica gel column
chromatography (hexane/EtOAc = 1:2) afforded 2 as a colorless oil (13.6 mg,
0.039 mmol, 43%); Rf 0.20 (hexane/EtOAc = 1:1); IR (neat, cmÀ1), 3742, 3413,
3081, 2931, 2362, 1765, 1712, 1647, 1456, 1272, 1174, 1046, 961, 910, 756,
634; 1H NMR (300 MHz, CDCl3) d 6.23 (1H, d, J = 3.4 Hz, H13), 5.62 (1H, d,
J = 3.1 Hz, H13), 5.49 (1H, s, H15), 5.36 (1H, s, H15), 5.17–5.11 (2H, m, H14/H8),
4.94 (1H, s, H14), 4.56 (1H, t, J = 7.2 Hz, H3), 4.26 (1H, dd, J = 10.3 Hz, H6), 3.23–
3.16 (1H, m, H7), 3.00–2.94 (1H, m, H1), 2.85 (1H, t, J = 10.3 Hz, H5), 2.72 (1H,
dd, J = 14.8 Hz, H9), 2.41 (1H, dd, J = 14.4 Hz, H9), 2.32–2.22 (1H, m, H2), 1.79–
1.68 (1H, m, H2); 13C NMR (75 MHz, CDCl3) d 152.3, 141.9, 137.4, 118.4, 113.8,
78.6, 74.4, 73.9, 51.5, 47.7, 45.4, 39.2, 37.2; EI-HRMS (m/z) calcd for C19H18D4O6
[M]+ 350.1667, found 350.1654.
Methyl 2-((triisopropylsilyloxy)methyl)acrylate-d4 (14):
A
solution of
paraformaldehyde-d2 (916.9 mg, 28.1 mmol, 5.0 equiv) in a mixture of 1,4-
dioxane/H2O (1:1, 4 mL) was stirred for 30 min at room temperature. To the
mixture, methyl acrylate-d3 12 (500.0 mg, 5.61 mmol, 1.0 equiv) and DABCO