Asymmetric synthesis of 7-EPI-γ-eudesmanol

Article abstract of DOI:10.1081/SCC-100103319

A facile and efficient asymmetric synthesis of 7-epi-γ-eudesmanol (1) starting from (-)-dihydrocarvone is described.

Full text of DOI:10.1081/SCC-100103319

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ASYMMETRIC SYNTHESIS OF 7-
EPI-γ-EUDESMANOL
Zhe Zhang a , Gang Zhou a , Xiaolei Gao a , Yulin Li
b & Renan Liao c
a National Laboratory of Applied Organic
Chemistry and Institute of Organic Chemistry,
Lanzhou University , Lanzhou, 730000, P. R. China
b National Laboratory of Applied Organic
Chemistry and Institute of Organic Chemistry,
Lanzhou University , Lanzhou, 730000, P. R. China
c National Laboratory of Elemento-Organic
Chemistry , Nankai University , Tianjin, 300071, P.
R. China
Published online: 09 Nov 2006.
To cite this article: Zhe Zhang , Gang Zhou , Xiaolei Gao , Yulin Li & Renan
Liao (2001) ASYMMETRIC SYNTHESIS OF 7-EPI-γ-EUDESMANOL, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 31:6, 847-851, DOI: 10.1081/SCC-100103319
To link to this article: http://dx.doi.org/10.1081/SCC-100103319
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SYNTHETIC COMMUNICATIONS, 31(6), 847–851 (2001)
ASYMMETRIC SYNTHESIS OF
7-EPI-c-EUDESMANOL
Zhe Zhang,1 Gang Zhou,1 Xiaolei Gao1, Yulin Li,1,*
and Renan Liao2
1National Laboratory of Applied Organic Chemistry and
Institute of Organic Chemistry, Lanzhou University,
Lanzhou 730000, P. R. China
2National Laboratory of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, P. R. China
ABSTRACT
A facile and efficient asymmetric synthesis of 7-epi-
ꢀ-eudesmanol (1) starting from (ꢀ)-dihydrocarvone is
described.
Naturally occurring eudesmane sesquiterpenoids have drawn consid-
erable attention due to their wide spectrum of biological activities,
such as antifeedant, cell growth inhibitory, plant growth regulation, and
so on.1–3
7-epi-ꢀ-Eudesmanol (1), a novel eudesmane derivative, was isolated
recently from a traditional herbal plant, Laggera alate, by Ramanoelina
and co-workers.4
In continuation of our on going project on the synthesis of bioactive
sesquiterpenoids, we report the asymmetric synthesis of 1.
* Corresponding author.
847
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

848
ZHANG ET AL.
Scheme 1. a) (R)-(þ)-ꢀ-Phenylethylamine, toluene, reflux; b) i) EVK, THF, r.t.; ii)
50% HOAc, r.t.; c) NaOMe/MeOH, reflux; d) 10% H2SO4, THF, reflux; e) AlCl2H,
ether, 0ꢀC.
Our synthesis started from (ꢀ)-dihydrocarvone (2). Asymmetric
Micheal condensation of chiral imine 3 prepared in situ by the condensation
of (R)-(þ)-ꢁ-phenylethylamine (from Aldrich, 99% ee) with 2, with ethyl
vinyl ketone (EVK) to give dione 45 in 77% yield, which was subjected to
Robinson annulation by treatment with NaOMe in MeOH to afford the key
intermediate 7-epi-ꢁ-cyperone (5) in 95% yield (de >95%, determined
by GC). Selective hydration of 5 by 10% H2SO4 in THF gave 6 in 85%
yield (based on recovered starting material), which was deoxygenated reduc-
tively with AlCl2H6 to give the title compound 1. The synthetic 1 have
shown identical spectral data with those of reported for the natural prod-
uct.4 The overall yield of the synthesis from 2 is 47%. During our synthetic
work, we produced the key intermediate 5 in an excellent diasoselectivity. It
can be changed into many other eudesmane-typed compounds by functional
group transformation, so what we do is to give a general synthetic route of
this kind of natural products in an much efficient and simple way.
EXPERIMENTAL
For column chromatography, silica gel (200–300 mesh) and light
petroleum ether (PE, b.p. 60–90ꢁC) was used. IR spectra were recorded
on a Nicolet FT-170SX spectrometer as liquid films. 1H NMR spectra
were taken on a Bruker AM-400 spectrometer with TMS as an internal
standard and CDCl3 as solvent. Mass spectra were determined on a VG

7-EPI-c-EUDESMANOL
849
ZAB-HS spectrometer (EI, 70 eV). Elemental analysis was performed on an
Italian 1106 analyzer.
(2S,5S)-2-Methyl-2-(3-pentanonyl)-5-isopropenylhexanone (4)
A mixture of (–)-dihydrocarvone (2) (0.94 g, 6.18 mmol) and (R)-(þ)-
ꢁ-phenylethylamine (0.8 g, 1.05 equiv.) in toluene (15 mL) was heated at
refluxing temperature under argon atmosphere with azeotropic removal of
water for 24 h. The resulting mixture was cooled in an ice bath and ethyl
vinyl ketone (0.55 g, 1.05 equiv.) was added with a syringe under argon. The
mixture was stirred and heated at 40ꢁC under argon for 24 h. To the yellow
solution, cooled in an ice bath, was added a 50% aq. Acetic acid (4 mL) and
the resulting mixture was stirred at room temperature for 2 h. The reaction
mixture was poured into brine and extracted with ether (3 Â 20 mL). The
organic layer was washed with 10% hydrochloric acid (2 Â 15 mL), water
(20 mL), and brine (2 Â 15 mL), and dried (MgSO4). After evaporation of
the solvents under reduced pressure, the oily residue was chromatographed
on silica gel, eluting with PE:ether (15:1) to give diketone 4 (1.12 g, 77%
from 2) as a light yellow oil. (Found: C, 76.04; H, 10.16. C15H24O2 requires
10
C, 76.23; H, 10.23); ½ꢁŠD ꢀ92.8 (c 1.2, CHCl3); ꢂ/cmꢀ1 1715, 1423, 1362, 899;
ꢃH(400 MHz) 0.95(s, 3H, 2-Me), 0.98(t, 7.3 Hz, 3H, MeCH2), 1.69(s, 3H,
MeC¼C), 4.67(br, s, 1H, C¼CH2), 4.72(br, s, 1H, C¼CH2); m/z 236(Mþ,
4), 207(1), 152(11), 109(18), 81(28), 67(61), 57(100).
(þ)-7-epi-a-Cyperone (5)
To a solution of diketone 4 (1.00 g, 4.24 mmol) in dry methanol
(15 mL) was added a 25% sodium methoxide in methanol (1 mL) under
argon, and the mixture was refluxed for 5 h. After being cooled, the resulting
pink solution was neutralized with acetic acid. After removal of the solvent,
the residue was dissolved in water (15 mL) and extracted with ether
(3 Â 20 mL). The organic phases were washed with brine (2 Â 10 mL) and
dried (MgSO4). The solvent was removed under reduced pressure and the
crude product was purified by silica gel chromatography to yield 5 (878
xmg, 95%) as a light yellow oil. (Found: C, 82.41; H, 10.09. C15H22O
10
requires C, 82.52; H, 10.16%), ½ꢁŠ þ 169.9 (c 0.8, CHCl3); ꢂ/cmꢀ1 3004,
D
1716, 901; ꢃH(400 MHz) 1.20(s, 3H, 10-Me), 1.68(s, 3H, 11-Me), 1.77(s, 3H,
4-Me), 4.57(br, s, 1H, 12-H), 4.60(br, s, 1H, 12-H); m/z 218 (Mþ, 32),
200(19), 175(42), 147(74), 91(100).

850
ZHANG ET AL.
3-Oxo-7-epi-c-eudesmanol(6)
To a solution of 5 (800 mg, 3.67mmol) in THF (15 mL) was added
10% aq. H2SO4 (10 mL) and the mixture was refluxed for 4 h. After being
cooled, the heterogeneous mixture was extracted with ether (3 Â 20 mL),
washed with saturated NaHCO3 (2 Â 10 mL), water (2 Â 10 mL), and brine
(2 Â 10 mL), and dried (MgSO4). The solvent was removed and the crude
product was purified by silica gel chromatography to yield 6 (322 mg, 85%,
based on recovered material) as a colorless oil, 450 mg of 5 was
recovered. 6: (Found: C, 76.11; H, 10.14, C15H24O2 requires C, 76.23;
10
H, 10.23%), ½ꢁŠ þ 33.1 (c 0.7, CHCl3); ꢂ/cmꢀ1 3444(OH), 1645, 1379,
D
1084; ꢃH(400 MHz) 1.15, 1.20, 1.22(s, 3H each, 11-Me  2, 10-Me), 1.78(s,
3H, 4-Me); m/z 236(Mþ, 1), 218(3), 177(16), 165(23), 149(35), 137(20),
123(23), 109(26), 67(26), 43(100).
7-epi-c-Eudesmanol(1)
To a solution of AlCl2H6 in dry ether (1 M, 20 mL) was added a
solution of 7 (120 mg, 0.51 mmol) in dry ether (2 mL) dropwise at 0ꢁC
under argon. The resulting mixture was stirred at this temperature for
an additional 2 h. The mixture was poured into crushed ice, extracted
with ether (3 Â 20 mL), washed with water (2 Â 10 mL), sat. aq. NaHCO3
(2 Â 10 mL), and brine (2 Â 10 mL), and dried (MgSO4). After removal of
the solvents, the oily residue was chromatographed on silica gel eluting with
PE:ether (10:1) to give 1 (87 mg, 77%) as a colorless oil. (Found: C, 80.96;
10
H, 11.70. C15H26O requires C, 81.02; H, 11.78%); ½ꢁŠD ꢀ30.1 (c 0.7, CHCl3);
25
D
(lit.4 ½ꢁŠ ꢀ23.3, c 1.2, CHCl3); ꢂ/max 3375(OH), 2927, 1458, 1378; ꢃH(400
MHz) 1.07(s, 3H, 10-Me), 1,17(s, 3H, 11-Me), 1.23(s, 3H, 11-Me), 1.66(s,
3H, 4-Me); ꢃC(400 MHz) 18.92, 19.61, 22.57, 25.37, 25.94, 27.86, 29.79,
32.71, 34.42, 38.11, 39.44, 44.14, 74.50, 125.89, 134.99; m/z 222(Mþ, 2),
204(4), 189(5), 149(100), 112(10), 91(10), 59(27), 43(30).
ACKNOWLEDGMENTS
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 29732060).
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7-EPI-c-EUDESMANOL
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Received in Japan April 4, 2000