Journal of Medicinal Chemistry
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overlapping, 2H, 2-H of 3b and 3c), 5.41 (m as d, J = 3.5 Hz, 2H, 8-H
of 3b and 3c), 3.54 (q, J = 7.0 Hz, 2H, 1′-H of 3b and 3c), 3.19 (dd, J
= 16.0 Hz, J = 4.0 Hz, 2H, 10α-H of 3b and 3c), 2.68 (td, J = 11.0 Hz,
J = 4.0 Hz, 2H, 10a-H of 3b and 3c), 2.18−2.08 (m, 2H, 7α-H of 3b
and 3c), 1.88−1.73 (m, 6H, 10β-H, 7β-H, 6a-H of 3b and 3c), 1.67 (s,
6H, 9-CH3 of 3b and 3c), 1.43 (d, J = 7.0 Hz, 3H, C1′-CH3 of 3b),
1.41 (d, J = 7.0 Hz, 3H, C1′-CH3 of 3c), 1.37 (s, 6H, 6β-CH3 of 3b
and 3c), 1.08 (s, 6H, 6α-CH3 of 3b and 3c); mass spectrum (ESI) m/z
(relative intensity) 317 (M+ + H, 48), 271 (100).
and boron tribromide (16.0 mL, 16.0 mmol, 1 M solution in CH2Cl2)
in dry CH2Cl2 (40 mL) and gave 22 (685 mg, 79% yield).
Spectroscopic and physical data were identical to those of the pure
enantiomer 12.
(2S)-2-[(6aR,10aR)-6a,7,10,10a-Tetrahydro-1-hydroxy-6,6,9-
trimethyl-6H-dibenzo[b,d]pyran-3-yl]propanoic Acid (3c). The
synthesis was carried out as described for 3a using 22 (250 mg, 1.37
mmol), (+)-cis/trans-p-mentha-2,8-dien-1-ol (230 mg, 1.51 mmol),
and p-TSA (50 mg, 0.26 mmol), in refluxing CHCl3 (4 h) and gave 3c
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(178 mg, 41% yield) as a light yellow gum. H NMR (500 MHz,
2-[(6aR,10aR)-6a,7,10,10a-Tetrahydro-1-hydroxy-6,6,9-tri-
methyl-6H-dibenzo[b,d]pyran-3-yl]propanoic Acid Butyl Ester
(18). The synthesis was carried out as described for 2a using 17 (175
mg, 0.55 mmol), bromobutane (114 mg, 0.83 mmol), and sodium
bicarbonate (55 mg 0.65 mmol) in DMF (2 mL) and gave 18 as an
equally populated mixture of diasteromers 2b and 2c (146 mg, 71%
yield, light yellow gum). IR (neat) 3398, 2961, 1732, 1708 (s, >C
CDCl3) δ 6.37 (d, J = 1.5 Hz, 1H, 4-H), 6.24 (d, J = 1.5 Hz, 1H, 2-H),
5.41 (m as d, J = 3.5 Hz, 1H, 8-H), 3.54 (q, J = 7.0 Hz, 1H, 1′-H), 3.19
(dd, J = 16.0 Hz, J = 4.0 Hz, 1H, 10α-H), 2.68 (td, J = 11.0 Hz, J = 4.0
Hz, 1H, 10a-H), 2.18−2.08 (m, 1H, 7α-H), 1.88−1.73 (m, 3H, 10β-H,
7β-H, 6a-H), 1.67 (s, 3H, 9-CH3), 1.41 (d, J = 7.0 Hz, 3H, C1′-CH3),
1.37 (s, 3H, 6β-CH3), 1.08 (s, 3H, 6α-CH3); mass spectrum (ESI) m/
z (relative intensity) 317 (M+ + H, 100), 271 (19); mass spectrum
(EI) m/z (relative intensity) 316 (M+, 92), 301 (48), 248 (19), 233
(100), 227 (22), 195 (18); exact mass (EI) calculated for C19H24O4
(M+), 316.1675; found 316.1670. HPLC (4.6 mm × 250 mm, Supelco
Discovery column, acetonitrile/water) showed purity of 97.4% and
retention time of 9.2 min for 3c. Anal. (C19H24O4) C, H.
(2S)-2-[(6aR,10aR)-6a,7,10,10a-Tetrahydro-1-hydroxy-6,6,9-
trimethyl-6H-dibenzo[b,d]pyran-3-yl]propanoic Acid Butyl
Ester (2c). The synthesis was carried out as described for 2a using
3c (150 mg, 0.47 mmol), bromobutane (180 mg, 1.31 mmol), and
sodium bicarbonate (60 mg, 0.71 mmol) in DMF and gave 2c (111
mg, 63% yield) as a light yellow gum. IR (neat) 3406, 2962, 1707 (s,
>CO), 1621, 1583, 1429, 1182 cm−1; 1H NMR (500 MHz, CDCl3)
δ 6.35 (d, J = 1.5 Hz, 1H, 4-H), 6.28 (d, J = 1.5 Hz, 1H, 2-H), 5.42 (m
as d, J = 4.5 Hz, 1H, 8-H), 5.24 (s, 1H, OH), 4.08 (m, 2H, -OCH2-),
3.54 (qt, J = 7.5 Hz, J = 3.5 Hz, 1H, 1′-H), 3.20 (dd, J = 15.0 Hz, J =
5.0 Hz, 1H, 10α-H), 2.69 (td, J = 10.5 Hz, J = 5.0 Hz, 1H, 10a-H),
2.18−2.10 (m, 1H, 7α-H), 1.87−1.73 (m, 3H, 10β-H, 7β-H, 6a-H),
1.69 (s, 3H, 9-CH3), 1.57 (quintet, J = 7.0 Hz, 2H, -CH2- of the side
chain), 1.42 (d, J = 7.5 Hz, 3H, -CH(CH3)-), 1.37 (s, 3H, 6β-CH3),
1.30 (quintet, J = 7.5 Hz, 2H, -CH2- of the side chain), 1.09 (s, 3H, 6α-
CH3), 0.87 (t, J = 7.5 Hz, 3H, 7′-H); 13C NMR (100 MHz, CDCl3) δ
175.2 (>CO), 155.5 (C-1 or C-5), 155.2 (C-5 or C-1), 140.2, 135.0,
119.2, 112.3, 109.8 (C-2 or C-4), 106.3 (C-4 or C-2), 77.0 (C-6), 65.0
(-OCH2-), 45.3, 45.0, 36.0, 31.8, 30.8, 28.1, 27.8, 23.7, 19.3, 18.7, 18.5,
13.9 (C-7′); mass spectrum (EI) m/z (relative intensity) 372 (M+,
100), 357 (M+ − 15, 17), 329 (35), 304 (21), 289 (98), 271 (26), 251
(17), 227 (25); exact mass (EI) calculated for C23H32O4 (M+),
372.2301; found 372.2299. HPLC (4.6 mm × 250 mm, Supelco
Discovery column, acetonitrile/water) showed purity of 97.3% and
retention time of 13.4 min for 2c. Anal. (C23H32O4) C, H.
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O), 1182 cm−1; H NMR (500 MHz, CDCl3) δ 6.36 (d, J = 1.5 Hz,
1H, 4-H of 2b), 6.35 (d, J = 1.5 Hz, 1H, 4-H of 2c), 6.30 (d and d
overlapping, 2H, 2-H of 2b and 2c), 5.74 (s, 2H, OH of 2b and 2c),
5.42 (m as d, J = 4.5 Hz, 2H, 8-H of 2b and 2c), 4.08 (m, 4H,
-OCH2− of 2b and 2c), 3.54 (qt and qt overlapping, 2H, 1′-H of 2b
and 2c), 3.20 (dd, J = 15.0 Hz, J = 5.0 Hz, 2H, 10α-H of 2b and 2c),
2.69 (td, J = 10.5 Hz, J = 5.0 Hz, 2H, 10a-H of 2b and 2c), 2.19−2.09
(m, 2H, 7α-H of 2b and 2c), 1.87−1.73 (m, 6H, 10β-H, 7β-H, 6a-H of
2b and 2c), 1.69 (s, 6H, 9-CH3 of 2b and 2c), 1.57 (quintet, J = 7.0
Hz, 4H, -CH2- of the side chain of 2b and 2c), 1.44 (d, J = 7.5 Hz, 3H,
-CH(CH3)- of 2b), 1.42 (d, J = 7.5 Hz, 3H, -CH(CH3)- of 2c),1.37 (s,
6H, 6β-CH3 of 2b and 2c), 1.30 (quintet, J = 7.5 Hz, 4H, -CH2- of the
side chain of 2b and 2c), 1.09 (s, 6H, 6α-CH3 of 2b and 2c), 0.88 (t, J
= 7.5 Hz, 3H, 7′-H of 2b), 0.87 (t, J = 7.5 Hz, 3H, 7′-H of 2c); mass
spectrum (ESI) m/z (relative intensity) 373 (M+ + H, 100), 329 (48).
(4S)-3-[2-(3,5-Dimethoxyphenyl)acetyl]-4-isopropyloxazoli-
din-2-one (19).35 The synthesis was carried out as described for 9
using (S)-4-isopropyloxazolidin-2-one (23, 1.7 g, 13.2 mmol), n-BuLi
(8.3 mL, 13.3 mmol, 1.6 M solution in hexane), and 8 (2.6 g, 12.1
mmol) in dry THF (45 mL) and gave 19 (2.4 g, 65% yield) as a
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colorless viscous oil. H NMR (500 MHz, CDCl3) δ 6.47 (d, J = 2.5
Hz, 2H, 2-H, 6-H, ArH), 6.37 (t, J = 2.5 Hz, 1H, 4-H, ArH), 4.43
(ddd, J = 8.5 Hz, J = 4.0 Hz, J = 3.5 Hz, 1H, >N-CH<), 4.29 (d, J =
14.5 Hz, 1H, -CH2-C(O)-), 4.25 (d, J = 8.5 Hz, 1H, -CH2OC(O)-),
4.20 (dd, J = 8.5 Hz, J = 3.5 Hz, 1H, -CH2OC(O)-), 4.16 (d, J = 14.5
Hz, 1H, -CH2-C(O)-), 3.77 (s, 6H, -OMe), 2.35 (septet of d, J = 7.0
Hz, J = 3.5 Hz, 1H, (CH3)2CH-), 0.88 (d, J = 7.0 Hz, 3H,
(CH3)2CH‑), 0.81 (d, J = 7.0 Hz, 3H, (CH3)2CH-); mass spectrum
(ESI) m/z (relative intensity) 308 (M+ + H, 28), 179 (100), 130 (10);
exact mass (EI) calculated for C16H21NO5 (M+), 307.1420; found
307.1418.
2-(3,5-Dimethoxyphenyl)-2-methylpropanenitrile (24a).54
To a stirred suspension of sodium hydride (6.7 g, 169.0 mmol) in
dry DMF (40 mL) at 0 °C under an argon atmosphere was added
dropwise a solution of 4 (10.0 g, 56.4 mmol) and iodomethane (10.5
mL, 169.0 mmol) in dry DMF (40 mL). The reaction temperature
rose to 25 °C over a 15 min period, and stirring was continued for 2 h.
The reaction mixture was quenched with saturated aqueous NH4Cl
solution and diluted with diethyl ether. The organic layer was
separated, and the aqueous layer was extracted with diethyl ether. The
combined organic layer was washed with water and brine, dried
(MgSO4), and concentrated in vacuo. Purification by flash column
chromatography on silica gel (25% ethyl acetate in hexane) gave the
(4S)-3-[(2S)-2-(3,5-Dimethoxyphenyl)propanoyl]-4-isopro-
pyloxazolidin-2-one (20).35 The synthesis was carried out as
described for 10 using 19 (2.3 g, 7.48 mmol), sodium bis-
(trimethylsilyl)amide (8.0 mL, 8.0 mmol, 1 M in THF), and
iodomethane (2.35 mL, 37.7 mmol) in THF and gave 20 (1.97 g,
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82% yield) as a colorless viscous oil. H NMR (500 MHz, CDCl3) δ
6.51 (d, J = 2.5 Hz, 2H, 2-H, 6-H, ArH), 6.34 (t, J = 2.5 Hz, 1H, 4-H,
ArH), 5.10 (q, J = 7.0 Hz, 1H, (MeO)2Ph-CH(CH3)-), 4.36 (ddd, J =
8.5 Hz, J = 4.0 Hz, J = 3.5 Hz, 1H, >N-CH<), 4.15 (dd, J = 8.0 Hz, J =
3.5 Hz, 1H, -CH2OC(O)-), 4.14 (d, J = 8.0 Hz, 1H, -CH2OC(O)-),
3.76 (s, 6H, -OMe), 2.43 (septet of d, J = 7.0 Hz, J = 3.5 Hz, 1H,
(CH3)2CH-), 1.49 (d, J = 7.0 Hz, 3H, (MeO)2Ph-CH(CH3)-), 0.92
(d, J = 7.0 Hz, 3H, (CH3)2CH-), 0.90 (d, J = 7.0 Hz, 3H,
(CH3)2CH‑); mass spectrum (ESI) m/z (relative intensity) 322 (M+ +
H, 98), 278 (100), 222 (27), 193 (77), 165 (63); exact mass (EI)
calculated for C17H23NO5 (M+), 321.1576; found 321. 1579.
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title compound (11.0 g, 95% yield) as a colorless oil. H NMR (500
MHz, CDCl3) δ 6.61 (d, J = 2.0 Hz, 2H, ArH), 6.40 (t, J = 2.0 Hz, 1 H,
ArH), 3.81 (s, 6 H, -OCH3), 1.71 (s, 6 H, -C(CH3)2-); mass spectrum
(ESI) m/z (relative intensity) 206 (M+ + H, 100).
(2S)-2-(3,5-Dimethoxyphenyl)propanoic Acid (21).35 The
synthesis was carried out as described for 11 using 20 (1.90 g, 5.91
mmol) and lithium hydroxide (400 mg, 16.7 mmol) in THF (20
mL):H2O (20 mL) and gave 21 (1.12 g, 90% yield). Spectroscopic and
physical data were identical to those of the pure enantiomer 11.
(2S)-2-(3,5-Dihydroxyphenyl)propanoic Acid (22). The syn-
thesis was carried out as described for 6 using 21 (1.0 g, 4.76 mmol)
1-(3,5-Dimethoxyphenyl)cyclobutanecarbonitrile (24b).23,36
The synthetic procedure was reported previously, along with physical
and spectral data.23
2-(3,5-Dimethoxyphenyl)-2-methylpropanoic Acid (25a).54
The synthesis was carried out as described for 5 using 24a (4.0 g, 19.5
mmol) and sodium hydroxide (1.9 g, 47.5 mmol) in 3 mL of n-
butanol/water (2:1 ratio) and gave 25a (4.0 g, 93% yield) as a white
L
dx.doi.org/10.1021/jm4016075 | J. Med. Chem. XXXX, XXX, XXX−XXX