European Journal of Organic Chemistry
10.1002/ejoc.201700609
1
amorphous solid. H NMR (400 MHz, CDCl
3
): δ = 3.50 (3H, s), 3.90 (3H, s), 5.24 (2H,
nBu
3
SnH (0.14 mL, 0.51 mmol) and 2,2′-azobis(isobutyronitrile) (AIBN) (1.7 mg,
s), 6.61 (1H, d, J = 2.4 Hz), 6.68 (1H, dd, J = 8.3, 2.0 Hz), 7.79 (1H, d, J = 8.8 Hz),
0.010 mmol) were added to a stirred solution of 30 (56.9 mg, 0.10 mmol) in benzene (2
mL) at room temperature. To degas the reaction mixture, it was frozen by using liquid
nitrogen, then the reaction vessel was placed under vacuum for 30 min and then filled
with dry argon. The mixture was heated at reflux under argon for 2 h. After cooling, the
reaction mixture was concentrated in vacuo to give a residue, which was purified by
column chromatography (hexane/EtOAc, 8:1) to give 31 (40.3 mg, 85% over 2 steps) as
1
3
1
1
1
0.31 ppm (1H, s). C NMR (100 MHz, CDCl
19.7, 130.5, 163.5, 163.8, 188.3 ppm. IR (neat): ν = 2943, 2853, 1678, 1601, 1499,
3
): δ = 55.6, 56.3, 94.1, 99.5, 108.1,
−
1
465, 1422, 1397, 1261, 1154, 1079, 999, 925, 838, 813 cm . HRMS (EI): calcd for
+
10 12 4
C H O [M] 196.0736; found 196.0738.
2
5
1
a colorless viscous liquid. [α]
δ = 0.66 (3H, d, J = 6.8 Hz), 0.82 (3H, s), 1.05 (3H, s), 1.25–1.51 (6H, m), 1.39 (3H, t, J
6.8 Hz), 1.59–1.68 (5H, m), 1.79 (1H, d, J = 12.7 Hz), 2.58 (1H, d, J = 13.2 Hz), 2.78
D
3 3
= −3.9 (c = 1.2, CHCl ). H NMR (400 MHz, CDCl ):
2
-Methoxy-4-(methoxymethoxy)phenol (28): m-Chloroperoxybenzoic acid (mCPBA;
5% purity, 5.56 g, 21 mmol) was added to a stirred solution of 27 (3.56 g, 18 mmol) in
6
=
CH
reaction was quenched with saturated aqueous Na
resulting mixture was extracted with CHCl (3 × 30 mL). The combined extracts were
washed with brine (2 × 40 mL), then dried with MgSO . Concentration of the solvent in
vacuo afforded a residue, which was dissolved in MeOH (84 mL). K CO (4.63 g, 34
mmol) was added to the mixture, and the resulting mixture was stirred for 15 min at
room temperature. The reaction was quenched with saturated aqueous NH Cl (40 mL),
2
Cl
2
(80 mL) at 0 ºC, and the mixture was stirred for 20 h at room temperature. The
(
(
1H, d, J = 13.2), 3.48 (3H, s), 3.76 (3H, s), 3.79–3.91 (4H, m), 4.00–4.05 (2H, m), 5.08
1H, d, J = 6.8 Hz), 5.11 (1H, d, J = 6.8 Hz), 6.70 (1H, d, J = 9.3 Hz), 6.77 ppm (1H, d,
2 2 3
S O
(40 mL) at 0 ºC, and the
3
1
3
J = 8.8 Hz). C NMR (100 MHz, CDCl
3
): δ = 15.1, 15.8, 16.8, 18.5, 22.4, 23.3, 28.3,
9.9, 30.9, 36.8, 39.5, 42.5, 44.1, 48.0, 56.0, 59.8, 64.8, 65.1, 65.2, 95.3, 108.6, 112,8,
13.7, 125.1, 146.8, 150.0, 151.6 ppm. IR (neat): ν = 2932, 2871, 1558, 1474, 1382,
4
2
1
1
2
3
−
1
248, 1152, 1130, 1098, 1049, 1012, 948, 922, 772 cm . HRMS (EI): calcd for
4
+
27 42 6
C H O [M] 462.2981; found 462.2970.
and the resulting mixture was concentrated in vacuo until the solvent volume was
reduced to almost halve. The resulting solution was extracted with EtOAc (3 × 50 mL).
The combined extracts were washed with brine (2 × 50 mL), then dried with Na
2
SO
4
.
(4aS,5R,6S,8aS)-5-(3-Ethoxy-6-hydroxy-2-methoxybenzyl)-5,6,8a-
Concentration of the solvent in vacuo afforded a residue, which was purified by column
trimethyloctahydronaphthalen-1(2H)-one (32): 3 M HCl (2.9 mL) was added to a
stirred solution of 31 (105 mg, 0.23 mmol) in MeOH (8.6 mL) at 0 ºC, and the mixture
was stirred for 48 h at room temperature. The reaction was quenched with saturated
chromatography (hexane/EtOAc, 3:1) to give 28 (3.13 g, 93%) as a yellow viscous
1
liquid. H NMR (400 MHz, CDCl
3
): δ = 3.49 (3H, s), 3.86 (3H, s), 5.10 (2H, s), 5.33
(
1H, s), 6.55 (1H, dd, J = 8.5, 2.4 Hz), 6.62 (1H, d, J = 2.4 Hz), 6.80 ppm (1H, d, J =
aqueous NaHCO
mL). The combined extracts were washed with brine (2 × 20 mL), then dried over
Na SO . Concentration of the solvent in vacuo afforded a residue, which was purified
by column chromatography (hexane/EtOAc 3:1) to give 32 (72.5 mg, 85%) as a
3
(10 mL), and the resulting mixture was extracted with EtOAc (3 × 20
1
3
8
1
1
.3 Hz). C NMR (100 MHz, CDCl
46.9, 151.0 ppm. IR (neat): ν = 3432, 2944, 2829, 1613, 1510, 1452, 1367, 1267, 1230,
3
): δ = 55.8, 55.9, 95.5, 101.3, 108.3, 114.3, 140.7,
2
4
−
1
+
9 12 4
150, 1075, 1010, 924, 838, 794 cm . HRMS (EI): calcd for C H O [M] 184.0736;
2
5
1
found 184.0732.
colorless solid. M.p. 186–189 ºC. [α]
CDCl ): δ = 0.88 (3H, d, J = 6.3 Hz), 0.95 (3H, s), 1.15 (3H, s), 1.20–1.30 (2H, m),
.32–1.51 (4H, m), 1.39 (3H, t, J = 6.8 Hz), 1.54–1.73 (2H, m), 1.97–2.19 (3H, m),
.54–2.67 (3H, m), 3.74 (3H, s), 3.96 (2H, q, J = 6.8 Hz), 4.56 (1H, s), 6.39 (1H, d, J =
D
3
= −27.9 (c = 1.0, CHCl ). H NMR (400 MHz,
3
1
2
8
1
1
1
1
-Ethoxy-2-methoxy-4-(methoxymethoxy)benzene (24): EtI (4.1 mL, 51 mmol) was
added to a stirred solution of 28 (3.13 g, 17 mmol) in DMF (85 mL) containing K CO
6.68 g, 51 mmol) at room temperature, and the mixture was stirred at 60 ºC for 3 h.
2
3
1
3
3
.8 Hz), 6.66 ppm (1H, d, J =8.8 Hz). C NMR (100 MHz, CDCl ): δ = 15.1, 17.3, 18.4,
(
8.9, 22.6, 25.9, 27.5, 32.3, 35.5, 37.6, 37.8, 43.2, 49.7, 50.0, 59.8, 65.1, 109.5, 113,3,
After cooling to room temperature, H
2
O (100 mL) was added to the mixture. The
O (3 × 80 mL), and the combined extracts were
washed with brine (2 × 60 mL), then dried over Na SO . Concentration of the solvent in
vacuo afforded residue, which was purified by column chromatography
21.0, 145.8, 149.6, 150.4, 217.1 ppm. IR (neat): ν = 3384, 2975, 2931, 1686, 1597,
495, 1466, 1424, 1383, 1293, 1258, 1215, 1159, 1126, 1056, 968, 952, 795, 754 cm
resulting mixture was extracted with Et
2
−
1
.
2
4
+
34 4
HRMS (EI): calcd for C23H O [M] 374.2457; found 374.2462.
a
1
(
hexane/EtOAc 4:1) to give 24 (3.55 g, 98%) as a yellow viscous liquid. H NMR (400
MHz, CDCl
3
): δ = 1.41 (3H, t, J = 7.1 Hz), 3.49 (3H, s), 3.85 (3H, s), 4.02 (2H, q, J =
4-Ethoxy-3-methoxy-2-{[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-
7
.0 Hz), 5.12 (2H, s), 6.57 (1H, dd, J = 8.5, 2.7 Hz), 6.63 (1H, d, J = 2.4 Hz), 6.79 ppm
methylenedecahydronaphthalen-1-yl]methyl}phenol (23): A stirred suspension of
tBuOK (217 mg, 1.9 mmol) and methyltriphenylphosphonium bromide (692 mg, 1.9
mmol) in benzene (20 mL) was heated at reflux under argon for 1 h. A solution of 32
(72.5 mg, 0.19 mmol) in benzene (4 mL) was added to the above mixture, and the
resulting solution was heated at reflux for 2 h under argon. After cooling, the reaction
1
3
(
1H, d, J = 8.8 Hz). C NMR (100 MHz, CDCl
3
): δ = 14.9, 55.8, 55.9, 65.1, 95.2, 102.2,
06.9, 114.0, 143.5, 150.3, 151.9 ppm. IR (neat): ν = 2935, 1595, 1509, 1454, 1396,
1
1
−
1
260, 1224, 1189, 1152, 1077, 1016, 921, 837, 795, 712, 658, 641, 612 cm . HRMS
+
(
EI): calcd for C11
H
16
O
4
[M] 212.1049; found 212.1049.
was quenched with saturated aqueous NH
extracted with EtOAc (3 × 20 mL). The combined extracts were washed with brine (2 ×
0 mL), then dried with Na SO . Concentration of the solvent in vacuo afforded a
residue, which was purified by column chromatography (hexane/CHCl , 8:1) to give 23
4
Cl (10 mL), and the resulting mixture was
Mixture
of
(R)-(3-ethoxy-2-methoxy-6-
2
2
4
(
methoxymethoxy)phenyl){(4a′S,5′R,6′S,8a′S)-5′,6′,8a′-trimethyloctahydro-2′H-
3
spiro[[1,3]dioxolane-2,1′-naphthalen]-5′-yl}methanol and (S)-isomer (29):
A
2
5
1
(
58.7 mg, 81%) as a colorless amorphous solid. [α]
D
= −42.8 (c = 1.0, CHCl
3
). H
solution of nBuLi (1.6M in n-hexane; 0.37 mL, 0.59 mmol) was added dropwise to a
stirred solution of 24 (126 mg, 0.59 mmol) in THF (6 mL) at 0 ºC under argon. After 1h,
a solution of 6 (52.8 mg, 0.20 mmol) in THF (2 mL) was added to the mixture, and
stirring was continued for 30 min at 0 ºC. The reaction was quenched with saturated
NMR (400 MHz, CDCl
3
): δ = 0.80 (3H, d, J = 6.3 Hz), 0.88 (3H, s), 1.05 (3H, s), 1.06
(
1H, dd, J = 12.0, 2.0 Hz), 1.28–1.42 (4H, m), 1.38 (3H, t, J = 6.8 Hz), 1.44–1.58 (3H,
m), 1.82–1.88 (1H, m), 1.94 (1H, d, J = 12.7 Hz), 2.06–2.11 (1H, m), 2.35 (1H, td, J =
3.7, 5.4 Hz), 2.56 (1H, d, J = 13.7 Hz), 2.64 (1H, d, J = 13.7 Hz), 3.75 (3H, s), 3.99
2H, q, J = 7.0 Hz), 4.44–4.46 (2H, m), 4.51 (1H,s), 6.41 (1H, d, J =8.8 Hz), 6.66 ppm
1
aqueous NH
20 mL). The combined extracts were washed with brine (2 × 20 mL), then dried with
Na SO . Concentration in vacuo afforded a residue, which was purified by column
chromatography (hexane/EtOAc, 3:1) to give 29 (83.9 mg, 88%) as colorless
): δ = 0.70–0.77 (1H, m), 0.78 (3H, d, J =
.8 Hz), 0.88 (3H, s), 1.05 (3H, s), 1.19–1.67 (12H, m), 1.84–2.00 (2H, m), 3.51 (3H, s),
4
Cl (10 mL) at 0 ºC, and the resulting mixture was extracted with EtOAc (3
(
(
×
1
3
1H, d, J = 8.8 Hz). C NMR (100 MHz, CDCl
8.8, 33.1, 36.3, 36.6, 38.9, 40.6, 43.0, 52.0, 59.8, 65.2, 102.5, 109.5, 113.3, 121.7,
145.9, 149.5, 150.4, 160.5 ppm. IR (neat): ν = 3419, 2977, 2926, 2859, 1633, 1492,
3
): δ = 15.1, 16.4, 18.5, 20.4, 23.8, 28.6,
2
4
2
a
1
amorphous solid. H NMR (400 MHz, CDCl
3
−
1
1
465, 1423, 1382, 1291, 1255, 1214, 1166, 1120, 1094, 1054, 991, 952, 888, 792 cm .
6
3
4
+
36 3
HRMS (EI): calcd for C24H O [M] 372.2664; found 372.2664.
.81 (3H, s), 3.87–4.09 (6H, m), 4.55 (0.3H, d, J = 11.2 Hz), 4.66 (0.7H, d, J = 11.2),
.97 (0.7H, d, J = 11.7 Hz), 5.06–5.15 (0.9H, m,), 5.16 (0.7H, d, J = 6.8 Hz), 5.27 (0.7H,
1
3
d, J = 6.8 Hz), 6.72–6.81 ppm (2H, m). C NMR for major isomer (100 MHz, CDCl
δ = 12.4, 15.0, 17.1, 18.0, 22.9, 23.4, 28.3, 29.8, 30.9, 35.5, 44.4, 44.5, 47.0, 56.5, 56.0,
4.8, 64.9, 65.2, 75.9, 95.0, 108.8, 112.8, 113.6, 126.2, 147.0, 148.1, 150.6 ppm. IR
neat): ν = 3545, 2932, 2873, 1588, 1474, 1384, 1254, 1229, 1154, 1094, 1049, 1004,
3
):
(4aS,7S,7aR,13aS)-10-Ethoxy-9-methoxy-4,4,7,7a-tetramethyl-1,2,3,4,4a,5,6,7,7a,8-
decahydrobenzo[d]xanthene (22): BF ·OEt (0.19 mL, 1.6 mmol) was added to a
stirred solution of 23 (58.7 mg, 0.16 mmol) in CH Cl (16 mL) at −78 °C under argon,
and the mixture was gradually warmed to 0 °C over 3 h. The reaction was quenched
with saturated aqueous NaHCO (6 mL) at 0 °C, and the resulting mixture was extracted
with CHCl (3 × 20 mL). The combined extracts were washed with brine (2 × 20 mL),
then dried with MgSO . Evaporation of the solvent in vacuo gave a residue, which was
purified by column chromatography (hexane/EtOAc, 8:1) to give 22 (56.0 mg, 95%) as
3
2
6
(
2
2
−
1
+
9
79, 924, 797 cm . HRMS (EI): calcd for C27
H
42
O
7
[M] 478.2931; found 478.2923.
3
3
4
(
4a′S,5′R,6′S,8a′S)-5′-[3-Ethoxy-2-methoxy-6-(methoxymethoxy)benzyl]-5′,6′,8a′-
trimethyloctahydro-2′H-spiro{[1,3]dioxolane-2,1′-naphthalene} (31): NaN(SiMe )
3 2
2
5
1
a yellow viscous liquid. [α]
0.78 (3H, s), 0.90 (3H, s), 1.05 (3H, s), 1.11 (3H, d, J = 7.3 Hz), 1.16–1.19 (1H, m),
.33–1.62 (5H, m), 1.39 (3H, t, J = 6.8 Hz), 1.66–1.86 (4H, m), 2.02–2.12 (2H, m), 2.17
1H, d, J = 17.6 Hz), 3.16 (1H, d, J = 17.6 Hz), 3.85 (3H, s), 3.98–4.03 (2H, m), 6.42
D
3 3
= +53.6 (c = 1.0, CHCl ). H NMR (400 MHz, CDCl ): δ
(
(
1.0 M in THF; 0.61 mL, 0.61 mmol) was added dropwise to a stirred solution of 29
48.9 mg, 0.10 mmol) in THF (2 mL) at −78 °C under argon. After 30 min, CS (0.12
=
2
1
(
(
mL, 2.0 mmol) was added dropwise to the mixture at −78 °C, and the resulting mixture
was stirred at −65 °C for 1 h. MeI (0.14 mL, 2.0 mmol) was added dropwise to the
mixture at −65 °C, and the resulting solution was further stirred for 2 h at the same
1
3
1H, d, J =8.8 Hz), 6.68 (1H, d, J = 8.8 Hz) ppm. C NMR (100 MHz, CDCl
3
): δ = 15.2,
1
8
1
7.4, 18.4, 20.3, 22.2, 27.9, 29.3, 29.9, 31.9, 32.5, 33.9 (2C), 37.6, 39.4, 44.0, 60.0, 65.0,
temperature. The reaction was quenched with saturated aqueous NH
and the resulting mixture was extracted with EtOAc (3 × 20 mL). The combined
extracts were washed with brine (2 × 20 mL), then dried with Na SO . Evaporation of
4
Cl (5 mL) at 0 °C,
2.0, 111.0, 113.1, 115.9, 144.6, 146.4, 147.3 ppm. IR (neat): ν = 2933, 2871, 1596,
488, 1475, 1386, 1325, 1298, 1254, 1223, 1187, 1107, 1083, 1060, 966, 950, 791, 771
2
4
−
1
+
36 3
cm . HRMS (EI): calcd for C24H O [M] 372.2664; found 372.2667.
the solvent in vacuo afforded methyl xanthate 30 (56.9 mg, 0.10 mmol), which was
used for the next reaction without further purification.
(
4aS,7S,7aR,13aS)-10-Ethoxy-4,4,7,7a-tetramethyl-1,2,3,4,4a,5,6,7,7a,8-
decahydrobenzo[d]xanthen-9-ol (21): nBuLi (2.6 M in n-hexane; 0.61 mL, 1.6 mmol)
was added to a stirred solution of nBuSH (0.17 mL, 1.6 mmol) in HMPA (8 mL) at
9
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