Journal of Natural Products
Article
144.4, 136.1, 133.8, 111.2, 75.4, 60.2, 48.8, 46.2, 40.0, 35.7, 31.8, 29.1,
26.1, 18.3, −4.4.
by column chromatography on silica gel (Biotage: step gradient
elution 1% to 10% EtOAc−hexanes) to obtain diol as a solid: 0.19 g
(79% yield). The spectroscopic data matched the previous
reports.11,12 1H NMR (400 MHz, CD3OD+CDCl3) δ 5.02 (d, J =
5.3 Hz, 1H), 4.27 (td, J = 7.3, 5.3 Hz, 1H), 3.99 (s, 3H), 3.83 (s, 3H),
3.39 (dd, J = 16.6, 7.1 Hz, 1H), 3.07 (ddt, J = 16.9, 7.5, 1.3 Hz, 1H),
2.96 (ABq, J = 17.1 Hz, νA‑B = 27.9 Hz, 2H), 2.73 (s, 2H), 1.14 (s,
3H), 1.10 (s, 3H); 13C NMR (100 MHz, CD3OD+CDCl3) δ 168.8,
158.0, 150.8, 145.5, 133.8, 131.8, 119.6, 73.6, 72.4, 60.2, 51.7, 49.9,
45.2, 40.4, 39.7, 29.1, 29.0; HRMS (ESI) calcd for C17H21O5 [M −
H]− 305.1394, found 305.1395.
1,2-Dihydroxy-8-methoxy-6,6-dimethyl-1,2,3,5,6,7-hexahy-
dro-s-indacene-4-carboxylic Acid. Methyl 1,2-dihydroxy-8-me-
thoxy-6,6-dimethyl-1,2,3,5,6,7-hexahydro-s-indacene-4-carboxylate
(the diol from the previous experiment, illustrated on p S11; 0.17 g,
0.56 mmol) was dissolved in a methanolic solution of KOH (2 M,
11.1 mL, 22.2 mmol, 40 equiv). The reaction mixture (purple color)
was heated to 80 °C and stirred for 2.5 h, and the resulting yellow
mixture was cooled to room temperature. The resulting mixture was
acidified by using phosphate buffer pH 2.6 and extracted with EtOAc
(5×). The combined EtOAc was washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The crude
product was used in the next step without further purification. The
spectroscopic data matched the previous reports.11,12 1H NMR (400
MHz, CD3OD) δ 4.91 (d, J = 5.3 Hz, 1H), 4.14 (ddd, J = 8.0, 7.1, 5.3
Hz, 1H), 3.90 (s, 3H), 3.32 (ddd, J = 16.9, 7.2 Hz, 1H), 3.07 (ddt, J =
16.9, 8.0, 1.0 Hz, 1H), 2.89 (ABq, J = 17.1 Hz, νA‑B = 23.8 Hz, 2H),
2.64 (s, 2H), 1.04 (s, 3H), 1.01 (s, 3H); HRMS (ESI) calcd for
C16H19O5 [M − H]− 291.1238, found 291.1239.
Methyl Ether of Illudalic Acid (IA-25). 1,2-Dihydroxy-8-
methoxy-6,6-dimethyl-1,2,3,5,6,7-hexahydro-s-indacene-4-carboxylic
acid (the acid from the previous experiment, illustrated on p S12; 0.17
g, 0.58 mmol) was dissolved in 30% aqueous dioxane (16.0 mL, 57
mM), and NaIO4 (0.15 g, 0.70 mmol, 1.2 equiv) was added. The
reaction mixture was stirred at room temperature for 2 h. Then, the
resulting mixture was diluted with water and extracted with DCM
(5×). The DCM layers were combined, washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel
(Biotage: step gradient elution 1% to 10% EtOAc−hexanes) to
obtain the methyl ether of illudalic acid IA-25 as a solid: 0.15 g (89%
yield). The spectroscopic data matched the previous reports.11,12 1H
NMR (400 MHz, CDCl3) δ 10.51 (s, 1H), 5.88 (t, J = 3.9 Hz, 1H),
4.00 (s, 3H), 3.73−3.51 (m, 3H), 3.23 (s, 2H), 2.88 (s, 2H), 1.19 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 191.8, 164.1, 163.9, 157.7,
139.0, 134.3, 124.4, 117.5, 94.8, 61.1, 49.5, 44.9, 39.9, 31.6, 28.8;
HRMS (ESI) calcd for C16H17O5 [M − H]− 289.1081, found
289.1082.
Methyl 1-((tert-Butyldimethylsilyl)oxy)-8-methoxy-6,6-di-
methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-carboxylate (9).
Aryl bromide 8 (0.64 g, 1.50 mmol) was dissolved in dry THF
(30.0 mL, 50 mM), and the solution was cooled to −78 °C. To this
mixture was slowly added n-BuLi in hexane (1.6 M, 1.40 mL, 2.50
mmol, 1.5 equiv). The mixture was stirred for 30 min; then methyl
chloroformate (0.35 mL, 4.50 mmol, 3 equiv) was slowly added
dropwise and stirred for another 30 min. The reaction mixture was
warmed to room temperature, stirred for another 1 h, then quenched
with water and extracted with EtOAc (3×). The combined EtOAc
was washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica gel (Biotage: step gradient elution 5% to
10% EtOAc−hexanes) to obtain ester 9 as a solid: 0.59 g (96% yield).
The spectroscopic data matched the previous report.12 1H NMR (400
MHz, CDCl3) δ 5.36 (dd, J = 6.5, 2.3 Hz, 1H), 3.89 (s, 3H), 3.84 (s,
3H), 3.32 (dt, J = 16.5, 7.9 Hz, 1H), 3.07 (ddd, J = 17.5, 8.8, 3.7 Hz,
1H), 3.00 (s, 3H), 2.85−2.72 (ABq, J = 15.3 Hz, νA‑B = 15.4 Hz, 2H),
2.29−2.17 (m, 1H), 2.04−1.97 (m, 1H), 1.16 (s, 3H), 1.12 (s, 3H),
0.90 (s, 9H), 0.15 (s, 3H), 0.12 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 168.1, 156.8, 150.3, 147.8, 135.3, 132.6, 119.0, 74.0, 59.7,
51.3, 49.1, 45.0, 40.1, 36.1, 31.9, 29.0, 26.1, 18.3, −4.41, −4.43.
Methyl 1-Hydroxy-8-methoxy-6,6-dimethyl-1,2,3,5,6,7-hex-
ahydro-s-indacene-4-carboxylate (2). Ester 9 (0.59 g, 1.45
mmol) was dissolved in dry THF (14.5 mL, 0.10 M), and the
resulting solution was cooled to 0 °C. To this mixture was added a
Tetra-n-butylammonium fluoride solution (1 M, 3.60 mL, 3.61 mmol,
2.5 equiv), and then the reaction mixture was warmed to room
temperature and stirred for 18 h. The reaction mixture was quenched
with water and extracted with EtOAc (3×). The EtOAc layers were
combined, washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The crude product was purified by column
chromatography on silica gel (Biotage: step gradient elution 5% to
40% EtOAc−hexanes) to obtain alcohol 2 as a solid: 0.35 g (85%
yield). The spectroscopic data matched the previous reports.11,12 1H
NMR (400 MHz, CDCl3) δ 5.41 (dt, J = 7.0, 3.4 Hz, 1H), 3.97 (s,
3H), 3.84 (s, 3H), 3.40−3.28 (m, 1H), 3.10−3.02 (m, 1H), 3.00 (s,
2H), 2.80 (s, 2H), 2.50−2.32 (m, 2H), 2.12−1.91 (m, 1H), 1.15 (s,
3H), 1.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.9, 156.3,
150.8, 147.1, 134.4, 131.9, 119.1, 74.1, 59.7, 51.4, 49.0, 45.0, 40.1,
34.4, 31.7, 29.0, 29.0.
Methyl 8-Methoxy-2,2-dimethyl-1,2,3,5-tetrahydro-s-inda-
cene-4-carboxylate (10). A solution of alcohol 2 (0.32 g, 1.10
mmol) in dry toluene (9.1 mL) was heated at 80 °C using a preheated
aluminum block. p-Toluenesulfonic acid (1.6 mg, 8.5 μmol, 0.8 mol
%) was added, followed by stirring at 80 °C for 10 min. After cooling
to room temperature, the reaction mixture was concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica gel (Biotage: step gradient elution 1% to
10% EtOAc−hexanes) to obtain indene 10 as a solid: 0.26 g (85%
yield). The spectroscopic data matched the previous reports.11,12 1H
NMR (400 MHz, CDCl3) δ 7.02 (dt, J = 5.7, 1.9 Hz, 1H), 6.51 (dt, J
= 5.7, 1.9 Hz, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 3.70 (tt, J = 1.8, 0.9 Hz,
2H), 3.10 (s, 2H), 2.79 (s, 2H), 1.17 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 167.9, 153.0, 147.9, 146.0, 134.7, 133.6, 133.2, 127.6, 118.5,
60.4, 51.3, 49.4, 44.3, 41.6, 39.9, 29.1; HRMS (ESI) calcd for
C17H19O3 [M − H]− 271.1340, found 271.1342.
Methyl 1,2-Dihydroxy-8-methoxy-6,6-dimethyl-1,2,3,5,6,7-
hexahydro-s-indacene-4-carboxylate. To a solution of AD-mix-α
(1.10 g) in 5.1 mL of H2O and 5.1 mL of t-BuOH at 0 °C was added
methane sulfonamide (77 mg, 0.81 mmol, 1.05 equiv), followed by
stirring for 20 min. Indene 10 (0.21 g, 0.77 mmol) was added to the
mixture, which was then warmed to room temperature and stirred for
16 h. The reaction mixture was quenched by adding sodium sulfite
(1.17 g) and vigorously stirred for 30 min. The resulting mixture was
diluted with water and extracted with DCM (3×). The DCM layers
were combined, washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The crude product was purified
3,6-Dihydroxy-8,8-dimethyl-1-oxo-1,3,4,7,8,9-
hexahydrocyclopenta[h]isochromene-5-carbaldehyde (IA-30).
A solution of the methyl ether of illudalic acid IA-25 (44 mg, 0.15
mmol) in dry DCM (2.0 mL, 75 mM) was cooled to −78 °C. A
solution of BBr3 in DCM (1 M, 0.17 mL, 0.17 mmol, 1.1 equiv) was
added slowly, and the resulting mixture was warmed to room
temperature and then stirred for another 3 h. The reaction mixture
was carefully quenched with cold water and extracted with DCM
(3×). The DCM layers were combined, washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel
(Biotage: linear gradient elution 3% to 10% methanol−DCM) to
obtain illudalic acid IA-30 (recrystallization by diethyl ether) as a
solid: 0.15 g (84% yield). The spectroscopic data matched the
previous reports.11,12 1H NMR (400 MHz, CDCl3) δ 12.42 (s, 1H),
10.25 (s, 1H), 5.94 (s, 1H), 3.51 (d, J = 4.0 Hz, 2H), 3.24 (ABq, J =
1
18.7 Hz, νA‑B = 23.2 Hz, 2H), 2.72 (s, 2H), 1.18 (s, 6H); H NMR
(400 MHz, DMSO-d6) δ 12.04 (s, 1H), 10.32 (s, 1H), 7.73 (d, J = 5.7
Hz, 1H), 5.98−5.52 (m, 1H), 3.60−3.36 (m, 2H), 3.34 (s, 3H), 3.09
(s, 2H), 2.64 (s, 2H), 1.13 (s, 3H), 1.12 (s, 3H); 13C NMR (100
MHz, DMSO-d6) δ 195.4, 162.8, 161.5, 155.9, 142.2, 130.0, 116.8,
F
J. Nat. Prod. XXXX, XXX, XXX−XXX