S. Acherar, G. Audran, F. Fotiadu, H. Monti
FULL PAPER
mg, 3.08 mmol) and tert-butyldimethylsilyl chloride (232 mg, 1.54
mmol) were added, and the mixture was stirred at room temp. for
1 h. The solution was then poured into water and extracted with
of a 1.6 solution in hexane)] in 10 mL of dry diethyl ether. The
reaction mixture was stirred at this temperature for 2 h. Methyl
iodide (0.72 mL, 11.6 mmol) was then added to the reaction mix-
diethyl ether. The combined organic extracts were washed with ture, which was slowly warmed up to 0 °C and stirred overnight.
water, brine, dried, filtered, and concentrated. Column chromatog-
raphy gave 413 mg (99%) of (ϩ)-8 as an oil. [α]2D5 ϭ ϩ33.6 (c ϭ
1.0, CHCl3). IR (neat): ν˜ ϭ 3044, 1752, 1209, 1033 cmϪ1. 1H NMR
The reaction mixture was partioned between diethyl ether and,
sequentially, 5% aqueous HCl and 10% aqueous NaHCO3. The
organic layers were dried (MgSO4), concentrated, and chromato-
(300 MHz, CDCl3): δ ϭ 7.11 (d, J ϭ 2.1 Hz, 1 H), 7.00 (dd, J ϭ graphed to give the alkylated ester (Ϫ)-10 (136 mg, 65% yield) as
8.3, 2.1 Hz, 1 H), 6.78 (d, J ϭ 8.3 Hz, 1 H), 4.50 (quint, J ϭ 7.5
Hz, 1 H), 4.11 (dq, J ϭ 10.8, 7.2 Hz, 2 H), 3.95 (dq, J ϭ 14.2, 7.2
an oil. [α]2D5 ϭ Ϫ27.5 (c ϭ 1.0, CHCl3). IR (neat): ν˜ ϭ 3089, 3051,
1
1746, 1197 cmϪ1. H NMR (300 MHz, CDCl3): δ ϭ 7.04 (d, J ϭ
Hz, 1 H), 3.81 (s, 3 H), 3.41 (dd, J ϭ 10.4, 8.7 Hz, 1 H), 2.52 (dd, 1.9 Hz, 1 H), 6.92 (dd, J ϭ 8.1, 1.5 Hz, 1 H), 6.69 (d, J ϭ 8.1 Hz,
J ϭ 13.2, 8.3 Hz, 1 H), 2.28 (s, 3 H), 2.23Ϫ2.16 (m, 2 H), 1.68 (dd, 1 H), 3.72 (s, 3 H), 3.62 (m, 2 H), 2.63 (br. q, J ϭ 9.6 Hz, 1 H),
J ϭ 13.4, 6.6 Hz, 1 H), 1.42 (s, 3 H), 1.12 (t, J ϭ 7.0 Hz, 3 H),
2.25 (s, 3 H), 2.33Ϫ2.19 (m, 1 H), 1.95Ϫ1.73 (m, 3 H), 1.73Ϫ1.62
0.91 (s, 9 H), 0.07 (s, 3 H), 0.06 (s, 3 H) ppm. 13C NMR (75 MHz, (m, 1 H), 1.46 (s, 3 H), 1.34 (s, 3 H), 0.83 (t, J ϭ 7.2 Hz, 3 H)
CDCl3): δ ϭ 173.9 (C), 155.1 (C), 136.0 (C), 129.0 (C), 127.9 (CH), ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 177.7 (C), 155.9 (C), 136.2
127.4 (CH), 111.1 (CH), 72.0 (CH), 59.7 (CH2), 54.9 (CH), 50.0
(C), 128.7 (C), 128.3 (CH), 127.0 (CH), 111.0 (CH), 59.5 (CH2),
(CH2), 49.9 (CH), 45.5 (C), 38.0 (CH2), 25.9 (3 ϫ CH3), 24.7 55.5 (CH3), 54.6 (C), 52.1 (C), 41.1 (CH2), 40.5 (CH2), 23.9 (CH3),
(CH3), 20.8 (CH3), 18.2 (C), 14.2 (CH3), Ϫ4.7 (2 ϫ CH3-Si) ppm. 21.9 (CH2), 21.7 (CH3), 20.7 (CH3), 13.5 (CH3) ppm. C18H26O3
C23H38O4Si (406.6): calcd. C 67.94, H 9.42; found C 67.81, H 9.37. (290.4): calcd. C 74.45, H 9.02; found C 74.07, H 8.95.
epi-Herbertenolide [(؉)-11]: A solution of BBr3 (1 in CH2Cl2,
Ethyl (1S,2S)-2-(2-Methoxy-5-methylphenyl)-2-methylcyclopentane-
459 µL, 0.459 mmol) was slowly added at Ϫ70 °C to a solution of
(Ϫ)-10 (100 mg, 0.344 mmol) in CH2Cl2 (10 mL), and the mixture
was allowed to warm to room temp. and stirred for 5 h. The reac-
tion mixture was extracted with CH2Cl2, washed with water and
carboxylate [(؉)-9]: Alcohol (ϩ)-6 (1.00 g, 3.42 mmol) was added
to a suspension of sodium hydride (275 mg, 6.88 mmol, 60% dis-
persion) in 20 mL of THF at 0 °C. After stirring the mixture at 0
°C for 30 min, carbon disulfide (1.60 g, 1.27 mL, 13.8 mmol) and
saturated NaCl solution, and dried with MgSO4. After evaporation
iodomethane (3.90 g, 1.71 mL, 27.4 mmol) were added. The re-
of the solvent, the residue was chromatographed on silica gel to
sulting mixture was stirred for another 1 h, then carefully poured
afford (ϩ)-11 (71 mg, 90%) as an oil. [α]2D5 ϭ ϩ33.9 (c ϭ 1.0,
onto ice and extracted with diethyl ether. The organic layer was
CHCl3). IR (neat): ν˜ ϭ 1761, 1615, 1235, 1108 cmϪ1 1H NMR
.
separated, dried (MgSO4), filtered, and concentrated under reduced
pressure to give an oily residue, which was immediately used for
(300 MHz, CDCl3): δ ϭ 7.11 (d, J ϭ 1.6 Hz, 1 H), 7.01 (dd, J ϭ
8.1, 2.1 Hz, 1 H), 6.89 (d, J ϭ 8.1 Hz, 1 H), 2.33 (s, 3 H), 2.42Ϫ2.31
(m, 1 H), 2.13Ϫ2.04 (m, 1 H), 1.90Ϫ1.57 (m, 4 H), 1.25 (s, 3 H),
1.22 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 173.7 (C),
147.5 (C), 134.0 (C), 128.6 (CH), 128.5 (C), 126.8 (CH), 116.4
(CH), 50.9 (C), 47.6 (C), 38.8 (CH2), 35.7 (CH2), 21.7 (CH3), 21.0
(CH3), 20.0 (CH2), 18.0 (CH3) ppm. C15H18O2 (230.3): calcd. C
78.23, H 7.88; found C 78.53, H 7.81.
1
the next step. H NMR (300 MHz, CDCl3): δ ϭ 7.13 (d, J ϭ 2.1
Hz, 1 H), 7.02 (dd, J ϭ 8.1, 1.7 Hz, 1 H), 6.79 (d, J ϭ 8.4 Hz, 1
H), 6.02 (qd, J ϭ 7.5, 6.4 Hz, 1 H), 4.06 (m, 2 H), 3.84 (s, 3 H),
3.56 (dd, J ϭ 10.6, 7.7 Hz, 1 H), 2.88 (dd, J ϭ 14.2, 8.2 Hz, 1 H),
2.56 (s, 3 H), 2.54Ϫ2.38 (m, 2 H), 2.28 (s, 3 H), 1.97 (dd, J ϭ 14.2,
5.3 Hz, 1 H), 1.45 (s, 3 H), 1.14 (t, J ϭ 7.2 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ ϭ 215.1 (C), 173.3 (C), 155.0 (C), 134.4
(C), 129.1 (C), 127.8 (CH), 127.7 (CH), 111.3 (CH), 83.8 (CH),
59.9 (CH2), 55.1 (CH), 49.8 (CH3), 46.3 (CH2), 45.4 (C), 34.0
(CH2), 23.7 (CH3), 20.7 (CH3), 18.8 (CH3), 14.1 (CH3) ppm. Tri-
n-butyltin hydride (1.58 g, 1.44 mL, 5.43 mmol) was added to a
solution of crude xanthate (1.19 g, 3.40 mmol) and AIBN (30 mg)
in toluene (20 mL) and the reaction mixture heated under reflux
for 40 min, then cooled and concentrated in vacuo. Rapid purifi-
cation of the residue on a silica gel column furnished 926 mg of
(ϩ)-9 [98% from the alcohol (ϩ)-6]. [α]2D5 ϭ ϩ55.1 (c ϭ 1.0,
(R,S)-1,14-Herbertenediol (؉)-1: A solution of (ϩ)-11 (50 mg,
0.217 mmol) in dry diethyl ether (5 mL) was slowly added to a
stirred slurry of LiAlH4 (28 mg, 0.738 mmol) in dry diethyl ether
(2 mL) at 0 °C. The solution was allowed to rise to room temp.
After 2 h, Celite (1 g) and Na2SO4·10H2O (1 g) were added and
the solution was stirred for a further 30 min. The mixture was fil-
tered through a pad of MgSO4 and concentrated. Purification of
the residue on a silica gel column furnished 1,14-herbertenediol
1
(ϩ)-1 (49 mg, 96%) as a solid compound which exhibited H and
CHCl3). IR (neat): ν˜ ϭ 3092, 3047, 1743, 1181 cmϪ1 1H NMR
.
13C NMR spectra identical to those of the natural product. M.p.
116Ϫ117 °C. [α]2D5 ϭ ϩ11.8 (c ϭ 1.0, CHCl3). IR (KBr): ν˜ ϭ 3161,
1613, 1227, 1029 cmϪ1. 1H NMR (300 MHz, CDCl3): δ ϭ 6.96 (d,
J ϭ 1.7 Hz, 1 H), 6.90 (dd, J ϭ 7.9, 1.7 Hz, 1 H), 6.72 (d, J ϭ 7.9
Hz, 1 H), 3.33 and 3.26 (AB, J ϭ 11.3 Hz, 2 H), 2.50Ϫ2.35 (m, 1
H), 2.26 (s, 3 H), 2.00Ϫ1.73 (m, 4 H), 1.55 (s, 3 H), 1.45Ϫ1.34 (m,
1 H), 1.31Ϫ1.24 (m, 1 H), 1.22 (s, 3 H) ppm. 13C NMR (75MHz,
CDCl3): δ ϭ 153.1 (C), 132.9 (C), 129.8 (C), 129.2 (CH), 128.0
(CH), 117.8 (CH), 70.7 (CH2), 50.9 (C), 48.9 (C), 42.3 (CH2), 36.0
(CH2), 24.0 (CH3), 21.2 (CH2), 21.0 (CH3), 20.5 (CH3) ppm.
C15H22O2 (234.3): calcd. C 76.88, H 9.46; found C 76.65, H 9.57.
(300 MHz, CDCl3): δ ϭ 7.14 (d, J ϭ 1.9 Hz, 1 H), 6.99 (dd, J ϭ
8.1, 1.5 Hz, 1 H), 6.78 (d, J ϭ 8.1 Hz, 1 H), 4.12 (dq, J ϭ 10.8,
7.0 Hz, 1 H), 4.00 (dq, J ϭ 10.8, 7.2 Hz, 1 H), 3.81 (s, 3 H), 3.44
(t, J ϭ 8.1 Hz, 1 H), 2.28 (s, 3 H), 2.28Ϫ2.17 (m, 1 H), 2.13Ϫ2.01
(m, 1 H), 1.98Ϫ1.71 (m, 4 H), 1.32 (s, 3 H), 1.15 (t, J ϭ 7.2 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 175.3 (C), 155.6 (C),
136.0 (C), 129.0 (C), 128.0 (CH), 127.3 (CH), 111.3 (CH), 59.6
(CH2), 55.0 (CH), 51.9 (CH3), 48.5 (C), 40.1 (CH2), 28.6 (CH2),
23.2 (CH2), 23.1 (CH3), 20.8 (CH3), 14.2 (CH3) ppm. C17H24O3
(276.4): calcd. C 73.88, H 8.75; found C 74.17, H 8.79.
Ethyl (1R,2R)-2-(2-Methoxy-5-methylphenyl)-1,2-dimethylcyclopen-
(1R,2S)-1-(Hydroxymethyl)-2-(2-methoxy-5-methylphenyl)-1,2-di-
tanecarboxylate [(Ϫ)-10]: HMPA (0.62 mL, 3.56 mmol) and a solu- methylcyclopentane [(؊)-12]: A solution of (Ϫ)-10 (100 mg, 0.344
tion of the ester (ϩ)-9 (200 mg, 0.724 mmol) in 3 mL of dry THF
were added successively over a period of 30 min to a cold (Ϫ90 °C)
magnetically stirred solution of LDA [prepared from diisopro-
mmol) in dry diethyl ether (5 mL) was slowly added to a stirred
slurry of LiAlH4 (30 mg, 0.790 mmol) in dry diethyl ether (4 mL)
at 0 °C. The solution was allowed to rise to room temp. After 1 h,
pylamine (0.50 mL, 3.57 mmol) and n-BuLi (2.89 mmol, 1.81 mL Celite (1 g) and Na2SO4·10H2O (1 g) were added and the solution
Eur. J. Org. Chem. 2004, 5092Ϫ5099