A Formal Total Synthesis of Salvadione
FULL PAPER
was quenched by addition of half-saturated aqueous NH4Cl solu-
tion (100 mL), the layers were separated, and the aqueous layer
was extracted with diethyl ether (3×70 mL). The combined organic
layers were washed with diluted Na2S2O5 solution (50 mL) and
brine (25 mL), dried with MgSO4, filtered, and concentrated in
vacuo. Purification of the crude product by flash chromatography
(petroleum ether/ethyl acetate, 20:1) provided the desired coupling
product 36 (2.0 g, 5.6 mmol, 70%) as a colorless oil together with
some unreacted iodide 35 (0.56 g, 2.0 mmol, 25%).
HRMS (EI): [M]+ calcd. for C23H36O4 376.261342, found
376.259678.
2-[2-(3-Isopropyl-2,4,5-trimethoxyphenyl)ethyl]-3,3-dimethylcyclo-
hexanone (38): A solution of epoxide 37 (25 mg, 66 µmol,
1.0 equiv.) in dry dichloromethane was treated with BF3·Et2O
(9 µL, 69 µmol, 1.05 equiv.) at room temperature followed by stir-
ring of the mixture at room temperature overnight. Thereafter, the
mixture was diluted with diethyl ether (5 mL) and water (5 mL).
After separation of the layers, the aqueous phase was extracted
with diethyl ether (3×5 mL). The combined organic layers were
washed with brine (2 mL), dried with MgSO4, filtered and concen-
trated in vacuo. Purification of the residue by flash chromatography
(petroleum ether/ethyl acetate, 10:1) provided ketone 38 (6 mg,
17 µmol, 26%) and the pyran 39 (4 mg, 11 µmol, 17%) as colorless
oils.
Data for Coupling Product 36: Rf = 0.46 (petroleum ether/ethyl ace-
1
tate, 20:1). H NMR (400 MHz, CDCl3): δ = 0.83 (s, 3 H, CH3),
0.93 (s, 3 H, CH3), 1.18–1.28 (m, 1 H, 3ЈЈa-H), 1.33 [d, J = 7.1 Hz,
3 H, CH(CH3)2], 1.34 [d, J = 7.1 Hz, 3 H, CH(CH3)2], 1.42–1.49
(m, 1 H, 3ЈЈb-H), 1.50–1.57 (m, 2 H, 4ЈЈ-H), 1.63–1.76 (m, 2 H, 2Ј-
H), 1.80 (dd, J = 11.1, 3.1 Hz, 1 H, 1ЈЈ-H), 2.02–2.08 (m, 1 H, 5ЈЈa-
H), 2.13–2.20 (m, 1 H, 5ЈЈb-H), 2.27 (ddd, J = 11.3, 8.1, 5.6 Hz, 1
H, 1Јa-H), 2.57 (ddd, J = 11.3, 8.7, 5.1 Hz, 1 H, 1Јb-H), 3.40 [sept,
J = 7.1 Hz, 1 H, CH(CH3)2], 3.64, 3.82, 3.83 (3 s, 3 H each, OCH3),
4.67 (d, J = 2.1 Hz, 1 H, C=CH2), 4.83 (d, J = 2.1 Hz, 1 H,
C=CH2), 6.55 (s, 1 H, CHar) ppm. 13C NMR (100 MHz, CDCl3):
δ = 22.0 [CH(CH3)2], 23.7 (C-4ЈЈ), 26.1 (CH3), 26.3 [CH(CH3)2],
27.9 (C-2Ј), 28.4 (CH3), 29.4 (C-1Ј), 32.5 (C-5ЈЈ), 35.0 (C-2ЈЈ), 36.3
(C-3ЈЈ), 54.5 (C-1ЈЈ), 55.9, 60.6, 61.9 (3 OCH3), 109.0 (C=CH2),
111.2 (CHar), 130.9 (C-1), 134.9 (C-3), 146.8 (C-5), 149.3 (C=CH2),
Data for Ketone 38: Rf = 0.40 (petroleum ether/ethyl acetate, 10:1).
1H NMR (400 MHz, CDCl3): δ = 0.76 (s, 3 H, CH3), 0.99 (s, 3 H,
CH3), 1.32 [d, J = 7.1 Hz, 6 H, CH(CH3)2], 1.52–1.64 (m, 2 H, 1Јa-
H, 4-H), 1.75–1.95 (m, 2 H, 5-H), 1.96–2.03 (m, 1 H, 1Јb-H), 2.14
(dm, J = 10.5 Hz, 1 H, 2-H), 2.25–2.33 (m, 1 H, 6a-H), 2.35–2.42
(m, 2 H, 6b-H, 2Јa-H), 2.55 (ddd, J = 13.5, 10.5, 4.6 Hz, 1 H, 2Јb-
H), 3.39 [sept, J = 7.1 Hz, 1 H, CH(CH3)2], 3.63, 3.81, 3.82 (3 s, 3
H each, OCH3), 6.58 (s, 1 H, CHar) ppm. 13C NMR (100 MHz,
CDCl3): δ = 22.0 [CH(CH3)2], 22.1 (CH3), 23.2 (C-5), 25.4 (C-1Ј),
26.0 [CH(CH3)2], 29.4 (CH3), 29.4 (C-2Ј), 39.2 (C-4), 39.9 (C-3),
41.3 (C-6), 55.8 (OCH3), 60.5 (C-2), 60.6 (OCH3), 61.9 (OCH3),
111.2 (C-6ЈЈ), 130.1 (C-1ЈЈ), 134.9 (C-3ЈЈ), 146.8 (C-5ЈЈ), 149.4 (C-
149.4 (C-4), 149.7 (C-2) ppm. IR (film): ν = 2935 (s), 2867 (m),
˜
1482 (s), 1456 (m), 1427 (m), 1344 (m), 1225 (s), 1116 (s), 1044 (s),
1016 (m) cm–1. MS (EI): m/z (%) = 360 (46) [M]+, 236 (100), 221
(85), 208 (66), 193 (25), 179 (24), 161 (18). HRMS (EI): [M]+ calcd.
for C23H36O3 360.26645, found 360.26900.
4ЈЈ), 149.7 (C-2ЈЈ), 213.5 (C-1) ppm. IR (film): ν = 2956 (s), 2871
˜
(m), 1709 (s), 1482 (s), 1458 (m), 1428 (m), 1227 (s), 1114 (m), 1043
(s), 1014 cm–1. MS (EI): m/z (%) = 362 (32) [M]+, 331 (2), 236
(100), 221 (40), 208 (26), 193 (9), 179 (10), 161 (8). HRMS (EI):
[M]+ calcd. for C22H34O4 362.245692, found 362.247185.
4-[2-(3-Isopropyl-2,4,5-trimethoxyphenyl)ethyl]-5,5-dimethyl-1-oxa-
spiro[2.5]octane (37) (2:1 Diastereomeric Mixture): A solution of
alkene 36 (0.18 g, 0.50 mmol, 1.0 equiv.) in dry dichloromethane
(1 mL) was treated with mCPBA (0.17 g, 1.0 mmol, 2.0 equiv.) fol-
lowed by stirring of the mixture at room temperature for 5 min.
Then the mixture was diluted with dichloromethane (2 mL) and
stirred at room temperature overnight. For the workup, a saturated
NaHCO3 solution (5 mL) was added, and stirring continued for
30 min, before diethyl ether was added (15 mL). After separation
of the layers, the organc layer was washed with brine (5 mL), dried
with MgSO4, filtered, and concentrated in vacuo. Purification of
the residue by flash chromatography (petroleum ether/ethyl acetate,
10:1) provided the epoxide 37 (0.12 g, 0.32 mmol, 65%) as a color-
Data for Pyran 39 [3-(3-Isopropyl-2,4,5-trimethoxyphenyl)-5,5-di-
methyloctahydro-1H-isochromene]: Rf = 0.69 (petroleum ether/ethyl
acetate, 10:1). 1H NMR (400 MHz, CDCl3): δ = 0.85 (s, 3 H, CH3),
0.87 (s, 3 H, CH3), 0.82–0.86 (m, 1 H, 8-H), 1.14–1.20 (m, 1 H, 4a-
H), 1.19–1.27 (m, 1 H, 6-H), 1.26–1.32 (m, 1 H, 4-H), 1.32 [d, J =
7.1 Hz, 3 H, CH(CH3)2], 1.33 [d, J = 7.1 Hz, 3 H, CH(CH3)2],
1.41–1.46 (m, 1 H, 6-H), 1.49–1.56 (m, 2 H, 8-H, 7-H), 1.56–1.65
(m, 1 H, 8a-H), 1.79 (d, J = 12.9 Hz, 1 H, 4-H), 3.20 (dd, J = 11.0,
10.9 Hz, 1 H, 1-H), 3.39 [sept, J = 7.1 Hz, 1 H, CH(CH3)2], 3.68
(s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 3.20
(dd, J = 11.0, 4.3 Hz, 1 H, 1-H), 4.64 (dd, J = 10.8, 1.6 Hz, 1 H,
3-H), 6.84 (s, 1 H, H aromatic) ppm. 13C NMR (100 MHz, CDCl3):
δ = 20.0 (CH3), 21.4 (C-7), 21.9 [CH(CH3)2], 26.0 [CH(CH3)2], 28.4
(C-8), 29.8 (CH3), 32.5 (C-5), 33.6 (C-4), 36.2 (C-8a), 41.9 (C-6),
50.2 (C-4a), 55.9 (OCH3), 60.6 (OCH3), 62.7 (OCH3), 74.3 (C-1),
75.5 (C-3), 108.1 (CH aromatic), 130.9 (C-1Ј), 134.6 (C-3), 148.2
1
less oil; Rf = 0.39 (petroleum ether/ethyl acetate, 10:1). H NMR
(400 MHz, CDCl3): δ = 0.86 (s, 2 H, CH3), 0.94 (s, 1 H, CH3), 0.99
(s, 1 H, CH3), 1.97 (s, 2 H, CH3), 1.10–1.30 (m, 3 H, 4-H, 6a-H,
1Јa-H), 1.33 [d, J = 7.1 Hz, 6 H, CH(CH3)2], 1.38–1.53 (m, 2 H,
1Јa-H, 2Јa-H, 6b-H), 1.54–1.81 (m, 4 H, 7a-H, 1Јb-H, 2Јb-H, 7b-
H), 2.44–2.55 (m, 1 H, 8a-H), 2.52 (d, J = 4.7 Hz, 0.67 H, 2a-H),
2.57 (d, J = 4.7 Hz, 0.33 H, 2a-H), 2.61–2.72 (m, 1 H, 8b-H), 2.66
(d, J = 4.7 Hz, 0.67 H, 2b-H), 2.68 (d, J = 4.7 Hz, 0.33 H, 2b-H),
3.39 [sept, J = 7.1 Hz, 1 H, CH(CH3)2], 3.65 (s, 2 H, OCH3), 3.66
(s, 1 H, OCH3), 3.81 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 6.55 (s,
0.67 H, CHar), 6.59 (s, 0.33 H, CHar) ppm. 13C NMR (100 MHz,
CDCl3): δ = 20.7 (C-7), 21.0 (C-7), 22.0 [CH(CH3)2], 25.4 (CH3),
26.1 [CH(CH3)2], 26.6 (CH3), 27.8 (2 peaks, C-2Ј), 28.2 (CH3), 28.9
(CH3), 31.0 (C-1Ј), 31.1 (C-8), 31.3 (C-8), 32.1 (C-1Ј), 35.7 (C-6),
(C-5Ј), 148.4 (C-2Ј), 149.9 (C-4) ppm. IR (film): ν = 2939 (s), 2870
˜
(m), 2844 (m), 1482 (s), 1456 (s), 1428 (m), 1367 (m), 1344 (m),
1222 (m), 1115 (s), 1042 (s), 1013 (m) cm–1. MS (EI): m/z (%) =
376 (100) [M]+, 345 (58), 237 (16), 223 (40), 208 (36), 195 (26), 149
(23), 84 (47). HRMS (EI): [M]+ calcd. for C23H36O4 376.261342,
found 376.264189.
1-{2-[2-(Bromomethyl)-6,6-dimethylcyclohex-2-en-1-yl]ethyl}-3-iso-
36.1 (C-5), 37.1 (C-6), 50.2 (C-4), 50.4 (C-4), 51.3 (C-2), 54.1 (C- propyl-2,4,5-trimethoxybenzene (40): A suspension of dry FeCl3
2), 55.9 (OCH3), 59.9 (C-3), 60.0 (C-3), 60.6 (OCH3), 61.9 (2 peaks, (0.034 g, 0.21 mmol, 1.05 equiv.) in dry THF (5 mL) was treated
OCH3), 111.2 (CHar), 130.4 (C-1ЈЈ), 130.6 (C-1ЈЈ), 134.9 (C-3ЈЈ), with bromine (0.011 mL, 0.21 mmol, 1.05 equiv.). After stirring at
135.0 (C-3ЈЈ), 146.9 (C-5ЈЈ), 147.0 (C-5ЈЈ), 149.4 (2 peaks, C-4ЈЈ),
room temperature for 45 min, compound 36 (0.071 g, 0.20 mmol,
1.0 equiv.) was added. The mixture was stirred at room temperature
for another 60 min, before it was diluted with diethyl ether (10 mL)
149.7 (C-2ЈЈ) ppm. IR (film): ν = 2938 (s), 2869 (m), 1482 (s), 1456
˜
(m), 1428 (m), 1226 (s), 1115 (s), 1043 (s), 1015 (m) cm–1. MS (EI):
m/z (%) = 376 (11) [M]+, 236 (100), 221 (61), 208 (13), 164 (12). and water (15 mL). The layers were separated, and the aqueous
Eur. J. Org. Chem. 2006, 4034–4043
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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