He and Ortiz de Montellano
m); 0.13 (1H, dd). 13C NMR (400 MHz, CDCl3) δ 209.4, 175.5,
166.7, 137.3, 112.6, 58.1, 42.7, 32.1, 28.4, 28.3, 19.7, 19.5, 17.2,
15.0. A high-resolution mass spectrum could not be obtained
due to the light sensitivity of the compound.
Syn th esis of Com p ou n d 16. 4-[[(R-Thujone)carbonyl]oxy]-
2(1H)-pyridinethione (16) was prepared as follows (Figure 2).
4,10-Deh yd r oth u jon e (11). 4,10-Dehydrothujone was syn-
thesized according to a published procedure.6b The structure
of the product was confirmed by NMR: 1H NMR (400 MHz,
CDCl3) δ 5.76 and 5.26 (2H, s, s); 2.51 (1H, dd, J ) 19 Hz);
2.31 (1H, dd, J ) 19 Hz); 2.02 (1H, dd, J ) 8 Hz, J ) 4 Hz);
1.49 (1H, m); 1.07 (1H, m); 0.94-1.00 (6H, 2d, J ) 6 Hz); 0.44
(1H, dd,).
F IGURE 8. Synthesis of carvotanacetone (4).
the thujone 4-hydroxylation catalyzed by cytochrome
P450 enzymes.
Exp er im en ta l P r oced u r es
10-Meth oxyth u jon e (12). 4,10-Dehydrothujone (11, 2 g,
14 mmol) was dissolved in methanol (20 mL) under N2. A
solution of sodium methoxide (0.5 M, in methanol, 2 mL) was
added, and the reaction mixture was stirred for 2 h before the
reaction mixture was neutralized and concentrated. The
residue was dissolved in ethyl acetate and extracted with
water and saturated NaCl. The organic layer was dried over
MgSO4, concentrated, and chromatographed using 1-5% ethyl
acetate in hexane: 1H NMR (400 MHz, CDCl3) δ 3.51 (2H, t,
J ) 6.0 Hz); 3.32 (3H, s); 2.49 (1H, dd, J ) 18 Hz, J ) 2.3 Hz);
2.38 (1H, m, J ) 6.0 Hz); 2.11 (1H, d, J ) 18 Hz); 1.36 (1H,
m); 1.31 (1H, dd, J ) 4 Hz); 0.93-1.01 (6H, 2d, J ) 6 Hz);
0.80 (1H, m, J ) 6 Hz, J ) 7.5 Hz, J ) 2.3 Hz); 0.12 (1H, dd,
J ) 6 Hz, J ) 4.5 Hz); 13C NMR (400 MHz, CDCl3) δ 219.1,
73.4, 58.9, 53.7, 41.7, 33.1, 29.9, 29.2, 22.0, 20.1, 19.4, 18.3;
HRMS (EI, m/z) calcd. for C11H18O2 (M+) 182.1293, found
182.1292.
Ma ter ia ls. Unless otherwise mentioned, all reagents, or-
ganic solvents, R-thujone (1r), and a mixture of R- and
â-thujone (1â) were purchased from a chemical supplier. All
the chemicals were used without further purification. GC and
GC-MS analyses were performed on a gas chromatograph
equipped with a J &W DB-1 phenyl-methylpolysiloxane capil-
lary column. NMR spectra were obtained with a 400 MHz
NMR spectrometer.
Syn th esis of Ca r vota n a ceton e (4). Compound 4 was
synthesized according to a published procedure15 (Figure 8):
1H NMR (400 MHz, CDCl3) δ 6.75 (1H, m); 2.0-2.8 (5H, m);
1.77 (3H, s, br); 1.58 (1H, m), 0.9 (6H).
Syn th esis of 8. 4-[[(â-Thujone)carbonyl]oxy]-2(1H)-pyridi-
nethione (8) was prepared as follows according to a published
procedure (Figure 2).9
â-Th u jon e-4-m eth yl Alcoh ol (6).9 â-Thujone-4-methyl
alcohol was synthesized according to a published procedure.9
4-Meth ylen em eth oxy-r-th u jon e (13). 10-Methoxythujone
(12, 550 mg) was dissolved in dry THF (15 mL) at -78 °C
under a nitrogen atmosphere. Sodium hexamethyldisilazide
(2 mL, 2 M solution in THF) was added dropwise to the stirred
solution. After 45 min, CH3I (0.5 mL, passed through neutral
alumina before being added) was added to the mixture over 1
min. The reaction mixture was warmed to 0 °C over 3 h before
it was quenched with saturated NH4Cl at 0 °C and concen-
trated. The residue was dissolved in ethyl acetate and washed
with saturated NaCl and 10% Na2CO3. The organic layer was
dried over MgSO4, concentrated, and chromatographed on
silica gel (ethyl acetate/hexanes:1:20). The yield was ∼90%.
The identity of the product was confirmed by 1H and 13C
NMR: 1H NMR (400 MHz, CDCl3) δ 3.39 and 3.27 (2H, dd, J
) 9.6 Hz); 3.37 (3H, s); 2.66 (1H, dd, J ) 18 Hz, J ) 2.4 Hz);
2.10 (1H, d, J ) 18 Hz); 1.41 (1H, m); 1.26 (1H, dd, J ) 4 Hz);
1.18 (3H, s); 0.94-1.02 (6H, 2d, J ) 6 Hz); 0.71 (1H, m, J ) 6
Hz, J ) 7.5 Hz, J ) 2.3 Hz); 0.23 (1H, dd, J ) 6 Hz, J ) 4.5
Hz). 13C NMR (400 MHz, CDCl3) δ 219.1, 75.5, 59.6, 40.2, 32.6,
28.4, 27.0, 22.2, 19.9, 19.7, 16.3. HRMS (EI, m/z) calcd. for
1
The identity of the product (1.75 g, 95%) was confirmed by H
and 13C NMR: 1H NMR (400 MHz, DMSO-d6) δ 4.86 (1H, t, J
) 5.3 Hz); 3.34 (2H, d, J ) 5.3 Hz); 2.54 (1H, dd, J ) 18 Hz,
J ) 2.3 Hz); 1.99 (1H, d, H-2R, J ) 18 Hz); 1.41 (1H, m); 1.33
(1H, dd, J ) 4 Hz); 0.9-1.0 (6H, 2d, J ) 6 Hz); 0.87 (3H, s);
0.61 (1H, m, J ) 6 Hz, J ) 7.5 Hz, J ) 2.3 Hz); 0.01 (1H, dd,
J ) 6 Hz, J ) 4.5 Hz). 13C NMR (400 MHz, CDCl3) δ 220.5,
89.9, 68.9, 42.0, 32.5, 27.6, 27.5, 19.8, 19.6, 16.4, 15.6.
â-Th u jon e-4-ca r boxylic Acid (7).9 â-Thujone-4-carboxylic
acid was synthesized according to a published procedure.9 The
1
identity of the product (1.55 g, 90%) was confirmed by H and
13C NMR: 1H NMR (400 MHz, CDCl3) δ 2.84 (1H, dd, J ) 18
Hz, J ) 2.5 Hz); 2.26 (1H, d, J ) 18 Hz); 1.71 (1H, dd, J ) 8
Hz, J ) 4 Hz); 1.48 (1H, m); 1.28 (3H, s); 0.93-1.15 (6H, 2d,
J ) 6 Hz); 0.77 (1H, m, J ) 6 Hz, J ) 7.5 Hz, J ) 2.5 Hz);
0.08 (1H, dd, J ) 6 Hz, J ) 4.5 Hz); -COOH not shown. 13C
NMR (400 MHz, CDCl3) δ 211.8, 177.4, 58.8, 42.1, 32.4, 29.0,
28.2, 19.7, 19.4, 16.7, 15.7.
4-[[(â-Th u jon e)ca r bon yl]oxy]-2(1H)-pyr idin eth ion e (8).
â-Thujone-4-carboxylic acid (7, 0.51 g, 2.6 mmol), N-hydroxy-
pyridine-2-thione (0.33 g, 2.5 mmol), and p-(dimethylamino)-
pyridine (DMAP, 33 mg, 0.26 mmol) were dissolved in 25 mL
CH2Cl2 at room temperature in a vessel shielded from light.
To the mixture was added dropwise a solution of dicyclohexy-
lcarbodiimide (DCC, 0.63 g, 2.6 mmol) in 6 mL CH2Cl2 over
15 min. The mixture was stirred for 12 h in the dark. Unless
otherwise indicated, all the steps were conducted in the dark.
The reaction mixture was filtered and concentrated. The
residue was dissolved in 25 mL of ethyl acetate and sequen-
tially washed with 10% KHSO4, H2O, and 5% NaHCO3. The
organic layer was dried over MgSO4 and concentrated. The
residue was purified by silica gel chromatography with 50%
(v/v) ethyl acetate/hexanes as the solvent. The identity of the
product (0.41 g, 55%) was confirmed by NMR: 1H NMR (400
MHz, CDCl3) δ 7.66 (1H, d, J ) 9.2 Hz); 7.48 (1H, d, J ) 6.8
Hz); 7.19 (1H, t, J ) 6.8 Hz); 3.06 (1H, dd, J ) 18 Hz); 2.38
(1H, dd, J ) 18 Hz); 1.70 (1H, dd, J ) 8 Hz, J ) 4 Hz); 1.61
(1H, m); 1.49 (3H, s); 0.95-1.09 (6H, 2d, J ) 6 Hz); 0.84 (1H,
C
12H20O2 (M+) 196.1463, found 196.1464.
r-Th u jon e-4-m eth yl Alcoh ol (14). 4-Methylenemethoxy-
R-thujone (13, 530 mg, 2.7 mmol) was dissolved in CH2Cl2 at
-78 °C under N2 protection. BBr3 (2.5 mL, 26 mmol) was added
dropwise to the stirred solution. After 1 h, the reaction mixture
was warmed to -20 °C, and the temperature was kept at -20
°C for 3 h. The reaction was then quenched very slowly with
5% NaHCO3 at -20 °C. The mixture was extracted with CH2-
Cl2 (2 × 20 mL), and the organic layer was dried over MgSO4,
concentrated, and chromatographed on silica gel with ethyl
acetate and hexanes (10% ethyl acetate/hexanes). The yield
was 100%: 1H NMR (400 MHz, CDCl3) δ 3.72 and 3.51 (2H,
dd, J ) 9.6 Hz); 2.69 (1H, dd, J ) 18 Hz, J ) 2.4 Hz); 2.12
(1H, d, J ) 18 Hz); 1.40 (1H, m); 1.10 (1H, dd, J ) 4 Hz); 1.27
(3H, s); 0.95-1.02 (6H, 2d, J ) 6 Hz); 0.70 (1H, m, J ) 6 Hz,
J ) 7.5 Hz, J ) 2.3 Hz); 0.27 (1H, dd, J ) 6 Hz, J ) 4.5 Hz);
HRMS (EI, m/z) calcd. for C11H18O2 (M+) 182.1293, found
182.1293.
r-Th u jon e-4-ca r boxylic Acid (15). R-Thujone-4-carboxylic
acid (14, 100 mg, 0.55 mmol) was dissolved in dry acetone (5
mL) at 15 °C. J ones reagent (1 mL) was added. The reaction
mixture was stirred for 3 h at 15 °C (monitored by TLC) and
(15) Dos Santos, R. B.; Zanotto, P. R.; Brocksom, T. J .; Brocksom,
U. Flavour Fragr. J . 2001, 16, 303.
5688 J . Org. Chem., Vol. 69, No. 17, 2004