An efficient stereocontrolled synthesis of (-)-10-epi-5β,11- dihydroxyeudesmane and (-)-4,10-epi-5β,11-dihydroxyeudesmane

Article abstract of DOI:10.1016/S0957-4166(98)00141-4

A concise and efficient synthesis of (-)-10-epi-5β,11- dihydroxyeudesmane 1 and (-)-4,10-epi-5β,11-dihydroxyeudesmane 2, via (-)- 10-epi-y-eudesmol 5, was accomplished starting from (+)-dihydrocarvone. The salient feature of our synthesis is the utilization of substrate-directable epoxidation and homogeneous hydrogenation to control the stereochemistry at the C-4 and C-5 positions of the title compounds.

Full text of DOI:10.1016/S0957-4166(98)00141-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1525–1530
An efficient stereocontrolled synthesis of (−)-10-epi-5β,11-
dihydroxyeudesmane and (−)-4,10-epi-5β,11-
dihydroxyeudesmane
∗
Zhaoming Xiong, Gang Zhou, Jiong Yang, Yonggang Chen and Yulin Li
National Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry, Lanzhou University, Lanzhou 730000,
PR China
Received 20 February 1998; accepted 26 March 1998
Abstract
A concise and efficient synthesis of (−)-10-epi-5β,11-dihydroxyeudesmane 1 and (−)-4,10-epi-5β,11-
dihydroxyeudesmane 2, via (−)-10-epi-γ-eudesmol 5, was accomplished starting from (+)-dihydrocarvone.
The salient feature of our synthesis is the utilization of substrate-directable epoxidation and homogeneous
hydrogenation to control the stereochemistry at the C-4 and C-5 positions of the title compounds. © 1998
Published by Elsevier Science Ltd. All rights reserved.
1. Introduction
Eudesmane derivatives have been drawing considerable attention due to their wide spectrum of biolog-
1
,2
ical properties, particularly antifeedant, cell growth inhibitory and plant growth regulating activities.
3
In 1987, Itokawa and coworkers reported the isolation of a new eudesmane derivative (−)-4,10-epi-
5
β,11-dihydroxyeudesmane 2 and determination of its structure by spectroscopic methods and chemical
4
conversion. (−)-10-epi-5β,11-Dihydroxyeudesmane 1, 4-epimer of 2, was isolated in 1989 by Mathela
et al. and its absolute configuration was determined by X-ray diffraction. Herein, we report a concise
synthesis of two diastereomers 1 and 2 from (+)-dihydrocarvone in six and seven steps, respectively,
using substrate-directable epoxidation and homogeneous hydrogenation as key reactions. Our synthetic
strategy (outlined in Scheme 1) is to use epoxide 3 as a key intermediate.
5
(
−)-10-epi-γ-Eudesmol 5 is also a natural product isolated from the rhizome of Alpinia japonira
6
and the essential oil of Amyris balsamifera. Before its isolation two similar synthetic routes to 5 were
reported in the literature. We have developed a more facile procedure for the preparation of 5 by a
7,8
modification of the procedure of Marshall and Pike.7
∗
Corresponding author. Fax: (+86) 931 8911100; e-mail: liyl@lzu.edu.cn
0957-4166/98/$19.00 © 1998 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00141-4

1526
Z. Xiong et al. / Tetrahedron: Asymmetry 9 (1998) 1525–1530
Scheme 1.
2. Results and discussion
9
Our synthesis started with (+)-dihydrocarvone (Scheme 2). By the published method, (−)-10-epi-α-
cyperone 6 was easily prepared from (+)-dihydrocarvone in 71% yield by a two-step procedure using
7
(
S)-(−)-α-phenylethylamine as a chiral auxiliary. Epoxidation of 6 gave epoxide 7 in excellent yield.
10
Compound 7 was reduced first with LiAlH and then with AlCl H in one pot to give (−)-10-epi-
4
2
1
1
γ-eudesmol 5 in 70% yield. This result is remarkable, since cleavage of oxirane and deoxygenation
at C-3 in compound 7 are completed in one step. AlCl H is usually used for deoxygenation of α,β-
2
10
unsaturated carbonyl compounds and allylic alcohols. It can also reduce epoxides in a complementary
way to LiAlH to give the less substituted alcohols. So it is necessary to cleave oxirane in 7 first with
12
4
LiAlH (to give a tertiary alcohol) and then deoxygenate at the C-3 position by addition of AlCl H to the
4
2
7,8
reaction mixture. Our synthetic route to 5 is more efficient than those described in the literature.
With (−)-10-epi-γ-eudesmol 5 in hand, the next task was the stereoselective functional group trans-
formation at the C-4 and C-5 positions of compound 5. In our synthesis, the stereochemistry of C-4
and C-5 in the title compounds 1 and 2 was stereospecifically controlled by using substrate-directable
epoxidation and homogeneous hydrogenation as key reactions.13 In the presence of a catalytic amount
of VO(acac) , compound 5 was epoxidized with t-BuOOH to give 3 in quantitative yield and 100%
2
14
15
diastereoselectivity. The cleavage of the oxirane ring in 3 can not be achieved by reduction with
LiAlH in ether at room temperature due to the steric effects with a tetra-substituted oxirane. Compound 1
4
16
was obtained by reduction of 3 with LiAlH –AlCl3 in ether or with LiAlH in refluxing THF. Epoxide 3
4
4
was treated with LDA in ether and afforded allylic alcohol 4 in 70% yield. In the presence of Wilkinson’s
1
7
catalyst, RhCl(PPh ) , directed hydrogenation of allylic alcohol 4 gave the alcohol 2 stereospecifically
3
3
18
in 83% yield; its 4-epimer 1 was not detected in this reaction. The spectral data of synthetic products
match with those of natural products. Thus the title compounds 1 and 2 were efficiently synthesized
3,4
from (+)-dihydrocarvone in six and seven steps with overall yields of 33% and 27%, respectively.
7
Marshall and Pike reported that the epoxidation of 5 with m-chloroperoxybenzoic acid gave 4-
hydroxydihydroagarofuran 8 instead of the normal epoxide (Scheme 3). They assumed that epoxide 9 is
formed initially, but the geometry of 9 renders subsequent acid-catalyzed cyclization to 8 an exceedingly
5
favourable process. In 1985, Itokawa et al. also reported that the epoxidation of naturally-occurring
(−)-10-epi-γ-eudesmol with m-chloroperoxybenzoic acid gave 8. In our experiment, we found addition

Z. Xiong et al. / Tetrahedron: Asymmetry 9 (1998) 1525–1530
1527
Scheme 2.
of NaHCO to the reaction mixture can prevent the cyclization of 9 in the epoxidation of 5 with m-
3
chloroperoxybenzoic acid, and epoxide 9 was obtained as a major product along with a mixture of
compound 3 and 8 as minor products. Epoxide 9 is acid-sensitive and it can be cyclized to 8 on a
chromatography column of silica gel. During purification of 9 by chromatography on silica gel, some
drops of triethylamine must be added to the eluent to prevent its isomerization. These results verify the
assumption of Marshall and Pike.
Scheme 3.
3. Experimental
Melting points are uncorrected. For column chromatography, 200–300 mesh silica gel and 60–90°C
petroleum ether (PE) were used. Elemental analyses were performed on an Italian 1106 analyzer. IR

1528
Z. Xiong et al. / Tetrahedron: Asymmetry 9 (1998) 1525–1530
1
spectra were recorded on a Nicolet FT-170SX as liquid films. H NMR spectra were measured on a
Bruker AM-400 or a Varian FT-80A spectrometer (TMS, CDCl ). Mass spectra were determined on a
3
V.G.ZAB-HS spectrometer (EI, 70 eV).
3.1. (−)-10-epi-γ-Eudesmol 5
To a suspension of LiAlH (70 mg) in dry ether (5 mL) was added a solution of epoxide 7 (120 mg)
4
in dry ether (4 mL) at 0°C under argon. The mixture was stirred at room temperature for 7 h. Then a
10
solution of AlCl H (1 M in ether, 18 mL) was added to the reaction miture via a syringe at 0°C. After
2
stirring at this temperature for an additional 6 h, the reaction was poured into crushed ice. The organic
layer was separated and the aqueous layer was extracted with ether (2×15 mL). The combined organic
fractions were washed with water (2×10 mL), sat. aq. NaHCO (2×10 mL), brine (2×10 mL), and dried
3
(
MgSO ). After removal of the solvents, the oily residue was chromatographed on silica gel eluting with
4
21
5
PE:ether (10:1) to give 5 (80 mg, 70% yield) as a colourless oil. [α]
−55.6 (c 0.72, CHCl ), [lit.
D
3
−1 1
[
3
α] −30.8 (c 0.16, EtOH)]; IR: 3403, 1459, 1375 cm ; H NMR (80 MHz, CDCl ): δ (ppm) 1.09 (s,
D
3
H, 10-Me), 1.19 (s, 3H, 11-Me), 1.25 (s, 3H, 11-Me), 1.45 (m, 4H), 1.68 (s, 3H, 4-Me), 1.91 (m, 3H),
+
2
.16 (m, 1H), 2.63, 2.82 (each br s, 1H); EIMS m/z (%): 222 (M , 10), 204 (49), 189 (72), 162 (18), 161
(55), 149 (49), 133 (39), 122 (20), 105 (38), 91 (48), 59 (73), 43 (100).
3.2. (−)-4β,5β-Oxido-10-epi-γ-eudesmol 3
To a solution of 10-epi-γ-eudesmol 5 (80 mg) in dry benzene (10 mL) was added a catalytic amount
of VO(acac) . Then a solution of t-BuOOH (3.1 M in toluene, 0.17 mL) was added to the mixture. After
2
stirring at ambient temperature for 3 h, the reaction mixture was diluted with ether (30 mL), washed with
water (3×10 mL) and brine (2×10 mL), and dried (MgSO ). The crude product was chromatographed
4
21
on silica gel (eluent PE:ether, 8:1) to yield 3 (85 mg, 99% yield) as a colourless oil. [α]
−56.3 (c
D
−1 1
0
1
.71, CHCl ); IR: 3609, 1457, 1381 cm ; H NMR (400 MHz, CDCl ): δ (ppm) 1.12 (s, 3H, 10-Me),
3
3
.22, 1.28 (each s, 3H, 11-Me), 1.31 (s, 3H, 4-Me), 1.54 (m, 2H), 1.74–1.83 (m, 4H), 1.89–2.06 (m, 3H);
+
EIMS m/z (%): 238 (M , 1), 223 (3), 221 (1), 220 (3), 205 (4), 187 (4), 165 (11), 162 (37), 147 (24), 122
36), 107 (37), 105 (37), 77 (30), 59 (50), 43 (100).
(
3.3. (−)-10-epi-5β,11-Dihydroxyeudesmane 1
Method A: To a solution of epoxide 3 (20 mg) in dry ether (2 mL) was added 2 mL of an ether
suspension of LiAlH –AlCl (3 mmol of LiAlH and 1.5 mmol of AlCl in 30 mL of dry ether) under
4
3
4
3
argon at room temperature. After stirring at ambient temperature for 1.5 h, the reaction mixture was
poured into crushed ice, and extracted with ether (3×10 mL). The extracts were washed with water
(
2×5 mL), sat. aq. NaHCO (2×5 mL), brine (2×5 mL), and dried (MgSO ). Silica gel chromatographic
3
4
8
purification eluting with PE:ether (6:1) afforded 1 (14 mg, 69%) as colourless crystals. [α] −12 (c
D
4
25
0
1
3
.60, CHCl ), mp 108–109°C, [lit. [α]
−9.0 (c 0.80, CHCl ), mp 120–121°C]; IR: 3438, 3315,
3
D
3
−1 1
464, 1458, 1418, 1378 cm ; H NMR (80 MHz, CDCl ): δ (ppm) 0.85 (d, 3H, J=6 Hz, 4-Me), 1.06 (s,
3
+
H, 10-Me), 1.26 (s, 6H, 11-Me), 1.34–1.65 (m, 6H), 1.83 (m, 2H); EIMS m/z (%): 240 (M , 19), 222
(11), 207 (27), 189 (13), 164 (34), 149 (61), 126 (84), 109 (59), 95 (39), 59 (77), 43 (100); anal. calcd
for C H O : C, 74.95; H, 11.74. Found: C, 74.82; H, 11.69%.
15
28
2
Method B: To a suspension of LiAlH (40 mg) in dry THF (6 mL) was added a solution of epoxide 3
4
(20 mg) in dry THF (4 mL) under argon. Then the mixture was heated at reflux for 24 h. After cooling,

Z. Xiong et al. / Tetrahedron: Asymmetry 9 (1998) 1525–1530
1529
0.1 mL of water was added to the reaction mixture followed by 0.1 mL of 10% aq. NaOH, and 0.1 mL of
water, and stirring was continued for an additional 0.5 h. The reaction mixture was filtered and the white
residue was washed with hot THF (10 mL), the combined filtrates were dried over MgSO . Purification
4
by chromatography on silica gel afforded 1 (13 mg, 64% yield) as colourless crystals, which is identical
to the product prepared by procedure A.
3.4. (−)-10-epi-5β-Hydroxy-β-eudesmol 4
To a freshly prepared solution of LDA (0.5 M in ether, 5 mL) was added a solution of epoxide 3 (40
mg) in dry ether (4 mL) under argon at room temperature. The reaction mixture was stirred at ambient
temperature for 24 h and then some water was added to quench the reaction. After the usual work-up,
8
4
3
1
(28 mg, 70%) was obtained as colourless crystals: mp 110–112°C, [α] −81.1 (c 0.74, CHCl ); IR:
D
3
−1 1
295, 3076, 1382, 896 cm ; H NMR (80 MHz, CDCl ): δ (ppm) 0.92 (s, 3H, 10-Me), 1.32 (s, 6H,
1-Me), 1.73 (m, 2H), 1.87 (m, 3H), 1.99 (m, 3H), 2.19 (br t, J=3.6 Hz, 1H), 4.15 (br s, 2H, OH), 4.72
br t, J=1.3 Hz, 1H), 4.83 (br t, 1H, J=1.5 Hz); EIMS m/z (%): 238 (M , 6), 220 (20), 205 (42), 192 (25),
3
+
(
1
87 (17), 177 (18), 163 (29), 162 (72), 147 (100), 109 (47), 95 (94); anal. calcd for C H O : C, 75.58;
15 26 2
H, 10.99. Found: C, 75.76; H, 10.87%.
3.5. (−)-4,10-epi-5β,11-Dihydroxyeudesmane 2
Method A: A solution of allylic alcohol 4 (18 mg) and a catalytic amount of RhCl(PPh ) in dry
3
3
benzene (5 ml) was stirred under an atmospheric pressure of hydrogen at room temperature for 40 h.
The reaction mixture was then evaporated and the residue was chromatographed on silica gel (eluent
10
PE:ether, 6:1) to afford 2 (15 mg, 83%) as colourless crystals: mp 130–132°C, [α]D −46.2 (c 0.68,
3
−1
CHCl ), [lit. mp 130.0–132.0C, [α] −21.8 (c 0.12, CHCl )]; IR: 3235, 1458, 1157, 1016, 946 cm ;
3
D
3
1
H NMR (400 MHz, CDCl ): δ (ppm) 1.06 (d, J=7.6 Hz, 3H, 4-Me), 1.12 (s, 3H, 10-Me), 1.28 (s, 6H,
1-Me), 1.55–1.91 (m, 9H), 1.97 (dt, J=14.0, 5.0 Hz, 1H), 2.05 (dd, J=15.0, 7.5 Hz, 1H); EIMS m/z (%):
40 (M , 6), 222 (10), 207 (34), 189 (17), 164 (29), 149 (83), 126 (89), 109 (57), 59 (94), 43 (100); anal.
3
1
+
2
calcd for C H O : C, 74.95; H, 11.74. Found: C, 74.88; H, 11.79%.
15
28
2
Method B: A mixture of allylic alcohol 4 (25 mg), 10% Pd–C (10 mg) and triethylamine (0.1 mL) in
absolute ethanol (5 mL) was stirred under an atmospheric pressure of hydrogen at room temperature
for 45 h. The reaction mixture was then filtered and the filtrate was evaporated. The residue was
chromatographed on silica gel eluting with PE:ether (8:1) to give 1 (5 mg) and 2 (15 mg).
3.6. (−)-4α,5α-Oxido-10-epi-γ-eudesmol 9
To a mixture of (−)-10-epi-γ-eudesmol 5 (30 mg) and NaHCO (60 mg) in CH Cl (6 mL) was added
3
2
2
mCPBA (70%, 35 mg). After stirring at ambient temperature for 0.5 h, the reaction mixture was diluted
with ether (20 mL), washed with 5% aq. NaOH (2×5 mL), water (2×5 mL), brine (2×5 mL), and dried
(
MgSO ). After removal of the solvents, the residue was chromatographed on silica gel eluting with
4
5
1
PE:ether:Et N (8:1:0.005) to give a mixture of 8 and 3 (6 mg, 8:3=1:1.2, determined by their H NMR
3
8
spectra), and 9 (20 mg, 62%) as a colourless oil. [α] −43.1 (c 0.60, CHCl ); IR: 3443, 1463, 1377
D
3
−1 1
cm ; H NMR (80 MHz, CDCl ): δ (ppm) 1.07 (s, 3H, 10-Me), 1.18 (s, 3H, 11-Me), 1.21 (s, 3H, 11-
3
Me), 1.30 (s, 3H, 4-Me), 1.42–1.54 (m, 3H), 1.65 (m, 2H), 1.79 (m, 1H), 1.95 (m, 2H); EIMS m/z (%):
+
2
38 (M , 10), 223 (17), 220 (9), 205 (13), 187 (7), 177 (23), 162 (55), 159 (25), 149 (37), 135 (26), 119
(41), 107 (46), 93 (32), 84 (33), 59 (69), 43 (100).

1530
Z. Xiong et al. / Tetrahedron: Asymmetry 9 (1998) 1525–1530
Acknowledgements
We are grateful for the financial support from the National Nature Science Foundation of China
Grant No. 29732060) and the National Laboratory of Elemento-Organic Chemistry at Nankai University
Tianjing, China).
(
(
References
1
2
3
4
5
6
7
8
9
. Van Beek, T. A.; De Grot, A. Recl. Trav. Chim. Pays-Bas, 1986, 105, 513.
. Ando, M.; Isogai, K.; Azami, H.; Hirata, N.; Yanagi, Y. J. Nat. Prod., 1991, 54, 1017.
. Itokawa, H.; Morita, H.; Watanabe, K. Chem. Pharm. Bull., 1987, 35, 1460.
. Mathela, C. S.; Melkani, A. B.; Pant, A.; Dev, V.; Nelson, T. F.; Hope, H.; Bottini, A. T. Phytochemistry, 1989, 28, 936.
. Itokawa, H.; Morita, H.; Watanabe, K.; Mihashi, S.; Iitaka, Y. Chem. Pharm. Bull., 1985, 33, 1148.
. Van Beek, T. A.; Kleis, R.; Posthumus, M. A.; Veldhuizen, A. V. Phytochemistry, 1989, 28, 1909.
. Marshall, J. A.; Pike, M. T. J. Org. Chem., 1968, 33, 435.
. Baker, R.; Evans, D. A.; McDowell, P. G. J. Chem. Soc., Chem. Commun., 1977, 111.
. Xiong, Z.-M.; Li, Y.-L.; Liao, R.-A.; Li, Z.-M. J. Chem. Res. (S), 1996, 477.
10. Brewster, J. H.; Bayer, H. O. J. Org. Chem., 1964, 29, 105; 116.
1
1. For reviews of deoxygenation of carbonyl compounds, see: (a) Yamamura, S.; Nishiyama, S. In Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I., Ed.; Pergamon Press: New York, 1991; Vol. 8, p. 307; (b) Hutchins, R. O.; Hutchins,
M. K. ibid, Vol. 8, p. 327.
12. Xiong, Z.-M.; Li, Y.-L., to be published.
13. For a review of substrate-directable chemical reactions, see: Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev., 1993,
93, 1307.
3
14. Epoxidation of 5 with mCPBA in the presence of NaHCO gave the epoxide 9 of opposite configuration as a major product,
see Scheme 3 in the text.
15. For a review of reduction of epoxides, see: Murai, S.; Murai, T.; Kato, S. In Comprehensive Organic Synthesis; Trost, B.
M.; Fleming, I., Ed.; Pergamon Press: New York, 1991; Vol. 8, p. 871.
1
1
6. Andrejevic, V.; Bjelakovic, M.; Mihailovic, M. M.; Mihailovic, M. L. Helv. Chim. Acta, 1985, 68, 2030.
7. (a) Hoeger, C. A.; Johnston, A. D.; Okamura, W. H. J. Am. Chem. Soc., 1987, 109, 4690. (b) Nakata, M.; Toshima, K.;
Kai, T.; Kinoshita, M. Bull. Chem. Soc. Jpn, 1985, 58, 3457. (c) For reviews of directed homogeneous hydrogenation, see:
Brown, J. M. Angew Chem. Int. Ed. Engl., 1987, 26, 190; and Ref. 13.
1
8. Hydrogenation of 4 can also be catalyzed by 10% palladium on charcoal in the presence of triethylamine in ethanol, which
gave an epimeric mixture of 2 and 1 with a ratio of 3:1 in a combined yield of 79%. This reaction must be performed in
the presence of triethylamine, otherwise the products are more complex and the yields of 1 and 2 are very low.