8730 J . Org. Chem., Vol. 64, No. 23, 1999
Notes
acetate as eluant to afford pure 4 (19 g, 0.091 mol, 75%) as a
colorless oil: [R]20D +12° (c 1.5, CHCl3); FT-IR (film) 1720, 1651,
1456, 723 cm-1; EI-MS m/z 209 (M+ + 1, 19), 208 (M+, 5), 193
(M+ - Me, 8), 163 (M+ - OEt, 20), 135 (M+ - COOEt, 100); 1H
NMR (250 MHz, CDCl3) δ 7.15 (1H, d, J ) 15.6 Hz); 5.80 (1H,
d, J ) 15.6 Hz); 5.68-5.57 (1H, m); 5.57-5.48 (1H, m); 4.20 (2H,
q, J ) 6.7 Hz); 2.76-2.10 (2H, m), 1.30 (3H, t, J ) 6.7 Hz), 1.08
(3H, s), 0.97 (3H, s), 0.85 (3H, s). Anal. Calcd for C13H20O2
(208.30): C, 74.96; H, 9.68. Found: C, 75.10; H, 9.65.
treated with NaBH4 (760 mg, 20 mmol), stirring for 1 h. The
reaction was diluted with ethyl acetate (60 mL) and 5% aqueous
HCl solution (60 mL). The layers were separated, and the
aqueous phase was extracted with ethyl acetate (3 × 20 mL).
The combined organic portions were washed with brine (40 mL),
dried over sodium sulfate, filtered, and concentrated under
reduced pressure. The residue was chromatographed on a silica
gel column eluting with 9:1 hexane/ethyl acetate to obtain phenol
7 (2.15 g, 7.8 mmol, 91%) as white crystals: [R]20 +77.6° (c 1,
D
3-[(1R)-1,2,2-Tr im eth ylcyclop en t-3-en yl]p r op -2-en a l (5).
DIBAH (0.17 mol, 1 M solution in THF) was added dropwise to
a 0 °C solution of ester 4 (16 g, 77 mmol) in dry THF (100 mL),
and the solution was stirred for 1 h. The reaction mixture was
quenched with 5% aqueous HCl solution (80 mL). The separated
aqueous layer was extracted with diethyl ether (3 × 50 mL).
The combined organic phases were washed with brine (60 mL),
dried over sodium sulfate, filtered, and concentrated under
reduced pressure. The obtained allylic alcohol was treated under
stirring with MnO2 (35 g, 400 mmol) in CH2Cl2 at reflux for 24
h. After filtration of the oxidant the solvent was removed under
reduced pressure. The residue was purified by chromatography
on silica gel column using 95:5 hexane/ethyl acetate as eluant
to afford pure aldehyde 5 (10.4 g, 63 mmol, 82%) as a colorless
oil: [R]20D + 16.7° (c 1.7, CHCl3); FT-IR (film) 1694, 1629, 1456,
CHCl3); FT-IR (film) 3343, 1682, 1608, 882, 772, 710 cm-1; EI-
MS m/z 275 (M+ + 1, 66), 274 (M+, 100), 229 (M+ - OEt, 37);
1H NMR (250 MHz, CDCl3) δ 7.52 (2H, m), 7.38 (1H, d, J ) 8
Hz), 6.20 (1H, bs), 5.81 (1H, m), 5.63 (1H, m), 4.35 (2H, q, J )
6.9 Hz), 3.17 (1H, d, J ) 17 Hz), 2.48 (1H, d, J ) 17 Hz), 1.48
(3H, s), 1.37 (3H, t, J ) 6.9 Hz), 1.26 (3H, s), 0.73 (3H, s). Anal.
Calcd for C17H22O3 (274.36): C, 74.42; H, 8.08. Found: C, 74.45;
H, 8.10.
(+)-3-Hyd r oxycu p a r en e (8). The phenolic ester 7 (1.2 g, 4.4
mmol) in dry THF (30 mL) was reduced with LiAlH4 (170 mg,
4.5 mmol) at 0 °C, stirring for 2 h. Methanol (10 mL) was slowly
added, and then 5% aqueous HCl solution (50 mL) was added
and the layers were separated. The aqueous layer was extracted
with ethyl acetate (3 × 30 mL). The combined organic portions
were washed with brine (50 mL), dried over sodium sulfate,
filtered, and concentrated under reduced pressure. The crude
benzylic alcohol was dissolved in ethyl acetate (100 mL) and
hydrogenated at atmospheric pressure (36 h) using 10% Pd/C
(100 mg) as catalyst. After removal of the catalyst by filtration,
the filtrate was concentrated in vacuo. The residue was purified
by chromatography on silica gel column using 9:1 hexane/ethyl
acetate as eluant to afford pure (+)-3-hydroxycuparene (8) (900
mg, 4.1 mmol, 93%): [R]20D +61° (c 1, CHCl3); FT-IR (film) 3527,
1617, 1462, 1411, 949, 809 cm-1; EI-MS m/z 217 (M+ + 1, 83),
216 (M+, 5), 215 (M+ - 1, 24), 148 (100); 1H NMR (250 MHz,
CDCl3) δ 7.19 (1H, d, J ) 8 Hz), 6.69 (1H, bd, J ) 8 Hz), 6.49
(1H, s), 4.70 (1H, bs), 2.68-2.50 (1H, m), 2.27 (3H, s), 2.00-
1.48 (5H, m), 1.42 (3H, s), 1.19 (3H, s), 0.77 (3H, s). Anal. Calcd
for C15H22O (218.34): C, 82.52; H, 10.16. Found: C, 82.71; H,
10.23.
(+)-Cu p a r en e (9). (+)-3-Hydroxycuparene (8) (400 mg, 1.83
mmol) in dry THF (20 mL) with stirring was treated with NaH
(85 mg of 60% dispersion in oil, 2 mmol) and diethyl phospho-
rochloridate (350 mg, 2 mmol) keeping the temperature under
20 °C. After 2 h the mixture was poured onto crushed ice and
extracted with ethyl acetate. The organic phase was dried over
sodium sulfate and concentrated under reduced pressure. The
obtained crude phosphate ester was dissolved in diethyl ether
(10 mL) and added to cooled liquid ammonia (-78 °C) under
nitrogen. Lithium powder (100 mg, 14 mmol) was added and
the mixture stirred for 20 min. The reaction was quenched by
adding solid NH4Cl (3.2 g, 60 mmol), and the ammonia was then
removed by warming at room temperature. The residue was
treated with water (50 mL) and extracted with diethyl ether (100
mL). The organic phase was concentrated under reduced pres-
sure and the crude product purified on a silica gel column eluting
with 95:5 hexane/ethyl acetate. Bulb to bulb distillation afforded
pure (+)-cuparene (9) (220 mg, 1.09 mmol, 60%) as a colorless
oil: [R]20D +66.4° (c 1.5, CHCl3), lit.16 [R]20D +65° (c 5.9, CHCl3);
FT-IR (film) 1516, 1460, 812 cm-1; EI-MS m/z 203 (M+ + 1, 6),
202 (M+, 25), 132 (100); 1H NMR (250 MHz, CDCl3) δ 7.23 (2H,
d, J ) 8.1 Hz), 7.08 (2H, d, J ) 8.1 Hz), 2.48 (1H, m), 2.31 (3H,
s), 1.84-1.45 (5H, m), 1.24 (3H, s), 1.05 (3H, s), 0.56 (3H, s).
Anal. Calcd for C15H22 (202.34): C, 89.04; H, 10.96. Found: C,
89.13; H, 10.92.
717 cm-1; EI-MS m/z 165 (M+ + 1, 57), 164 (M+, 25), 135 (M+
-
COH, 59), 82 (100); 1H NMR (250 MHz, CDCl3) δ 9.55 (1H, d, J
) 7.7 Hz), 7.02 (1H, d, J ) 15.8 Hz), 6.10 (1H, dd, J ) 15.8, 8
Hz), 5.62 (1H, m), 5.54 (1H, m), 2.49 (1H, dt, J ) 16.2, 2.3 Hz),
2.26 (1H, dt, J ) 16.2, 2.3 Hz), 1.13 (3H, s), 1.00 (3H, s), 0.88
(3H, s). Anal. Calcd for C11H16O (164.25): C, 80.44; H, 9.82.
Found: C, 80.50; H, 9.79.
6-[(1R)-1,2,2-Tr im et h ylcyclop en t -3-en yl]-3-(et h oxyca r -
bon yl)-3,5-h exa d ien oic Acid (6). The aldehyde 5 (5.5 g, 33.6
mmol) in CHCl3 (80 mL) was treated with triphenyl(carbethoxy-
carboxyethyl)phosphonium betaine (15 g, 37 mmol) at reflux for
36 h. Removal of the solvent under reduced pressure and
purification of the residue on a silica gel column using 8:2
hexane/ethyl acetate as eluant afford the acid 6 (7.5 g, 25.7
mmol, 75%): [R]20 +13.7° (c 1.2, CHCl3); FT-IR (film) 3270,
D
1713, 1637, 985, 947, 773, 717 cm-1; EI-MS m/z 293 (M+ + 1,
37), 292 (M+, 100), 275 (M+ - OH, 46); 1H NMR (250 MHz,
CDCl3) δ 7.38 (1H, d, J ) 10.5 Hz), 6.40 (1H, d, J ) 14 Hz), 6.23
(1H, dd, J ) 14, 10.5 Hz), 5.64-5.57 (1H, m), 5.53-5.47 (1H,
m), 4.23 (2H, q, J ) 7 Hz), 3.50 (2H, s), 2.47 (1H, dt, J ) 16, 2.2
Hz), 2.16 (1H, bd, J ) 16 Hz), 1.28 (3H, t, J ) 7 Hz), 1.07 (3H,
s), 0.94 (3H, s), 0.82 (3H, s). Anal. Calcd for C17H24O4 (292.38):
C, 69.84; H, 8.27. Found: C, 69.73; H, 8.19.
4-[(1R)-1,2,2-Tr im eth ylcyclop en t-3-en yl]-3-h yd r oxyben -
zoic Acid Eth yl Ester (7).
(a ) ClCOOEt a s Activa tin g Agen t. ClCOOEt (0.8 g, 7.2
mmol) was added in one portion to a solution of acid 6 (1 g, 3.4
mmol) in dry THF (20 mL), and then Et3N (1 g, 10 mmol) was
added dropwise keeping the temperature under 20 °C. The
mixture was stirred for 10 min and then acidified with an excess
of 5% aqueous HCl and extracted with ethyl acetate. Concentra-
tion of the organic phase gave a residue which was treated with
ethanolic (40 mL) NaOH (0.4 g, 10 mmol) at room temperature
for 10 min. The reaction was diluted with ethyl acetate (60 mL)
and 5% aqueous HCl solution (50 mL). The layers were sepa-
rated, and the aqueous phase was extracted with ethyl acetate
(3 × 20 mL). The combined organic portions were washed with
brine (40 mL), dried over sodium sulfate, filtered, and concen-
trated under reduced pressure. The crude product was chro-
matographed on a silica gel column eluting with 9:1 hexane/
ethyl acetate to obtain the diethyl ester of acid 6 (160 mg, 0.5
mmol) and phenol 7 (655 mg, 2.4 mmol, 70%).
(b) (CF 3CO)2O a s Activa tin g Agen t. (CF3CO)2O (3.8 g, 18
mmol) was added in one portion to a solution of acid 6 (2.5 g,
8.6 mmol) in dry THF (25 mL), and then Et3N (2.6 g, 25.7 mmol)
was added dropwise. The mixture was stirred at room temper-
ature for 2 h and then acidified with an excess of 5% aqueous
HCl and extracted with ethyl acetate. The organic phase was
concentrated under reduced pressure and the residue dissolved
in ethanol (50 mL). The latter mixture was cooled to 0 °C and
Ack n ow led gm en t. The financial support of MURST
is acknowledged.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of
compounds 3-9. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O9909148