Total synthesis and stereochemistry of 13-hydroxy-α-eudesmol

Article abstract of DOI:10.1016/S0957-4166(98)00184-0

The first total synthesis of both C-11 epimers of 13-hydroxy-α-eudesmol 1a and 1b by the use, as a key reaction, of the Sharpless asymmetric dihydroxylation of alkene 7 is presented. The absolute configuration of natural 13-hydroxy-α-eudesmol is established through comparison of the ¹H NMR spectrum of natural diol and synthetic diols. In our synthesis another natural product (+)-α-selinene 2 has also been accomplished.

Full text of DOI:10.1016/S0957-4166(98)00184-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1923–1928
Total synthesis and stereochemistry of 13-hydroxy-α-eudesmol
Yonggang Chen, Zhaoming Xiong, Gang Zhou, Lijun Liu and Yulin Li∗
National Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry, Lanzhou University, Lanzhou 730000,
PR China
Received 27 March 1998; accepted 6 May 1998
Abstract
The first total synthesis of both C-11 epimers of 13-hydroxy-α-eudesmol1a and 1b by the use, as a key reaction,
of the Sharpless asymmetric dihydroxylation of alkene 7 is presented. The absolute configuration of natural 13-
1
hydroxy-α-eudesmol is established through comparison of the H NMR spectrum of natural diol and synthetic
diols. In our synthesis another natural product (+)-α-selinene 2 has also been accomplished. © 1998 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Eudesmane type compounds are widely distributed in the plant kingdom. Due to their wide spectrum
of biological properties, particularly antifeedant, cell growth inhibitory and plant growth regulating
activities,1,2 these kinds of compounds have been attracting considerable attention.
Recently, 13-hydroxy-α-eudesmol 1a was first isolated from C. uncata Cunn. by King and Robinson
et al.,3 and its structure was determined by high field NMR techniques, however, the absolute config-
uration of C-11 remained unsolved. Herein, we report the first total synthesis and determination of the
stereochemistry of 13-hydroxy-α-eudesmol. In our synthesis (+)-α-selinene has also been accomplished.
In recent years, the osmium-catalysed asymmetric dihydroxylation reaction of substituted alkenes with
AD-mixes-α and -β has emerged as one of the most powerful and practical methods for controlling
relative and absolute stereochemistry in secondary and tertiary alcohol derivatives4 and the face-selection
rule of Sharpless et al. has now become established as a reliable method for predicting absolute
∗
Corresponding author. Fax: (+86) 931 8911100; e-mail: liyl@lzu.edu.cn
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00184-0

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stereochemistry in the AD process.4,5 Therefore we designed the following synthetic route to accomplish
the first total synthesis of 13-hydroxy-α-eudesmol, by the use of the AD reaction as the key step
(Scheme 1).
Scheme 1. Reagents and conditions: (a) Ref.,6 50%; (b) Li, liq. NH3, −78°C, 25 min, 86%; (c) LiAl(OBut)3H, THF, 18 h, 92%;
(d) PPh3–NCS, THF, 3 h, 88%; (e) LiBr–Li2CO3, DMF, 138–140°C, 5 h, 86%; (f) AD-mix-α, t-BuOH–H2O, 0°C, 88%; (g)
LiBr–Li2CO3, DMF, 138–140°C, 5 h, 84%; (h) AD-mix-β, t-BuOH–H2O, 0°C, 88%
2. Results and discussion
By the published method, (+)-α-cyperone 4 was stereoselectively prepared from (+)-dihydrocarvone 3
in two steps with an overall yield of 50%.6 Stereoselective lithium–liquid ammonia reduction of 4, using
ammonium chloride as the proton donor, gave the dihydro-α-cyperone 5.7 Utilizing the steric hindrances
of 10β-methyl, stereoselective reduction of 5 by tri-t-butoxyaluminium hydride gave alcohol 6 in high
yield. In a stereospecific manner, alcohol 6 was converted into its 3α-chloro derivative 7 by PPh3–NCS in
THF under milder conditions.8 Oxidation of 7 with commercially available AD-mix-α in t-BuOH–H2O
provided 8a (45% de) in 88% yield.4 The diastereoselectivity for (−)-8a was determined by analysis
1
of the H NMR (400 MHz) data.9 The absolute configuration of (−)-8a, predicted by the Sharpless
model, was assigned to be 11S. The mixture of 8a and 8b, as well as the sequent mixture of 1a and
1b, cannot be separated by chromatography on silica gel. Elimination of the halide of (−)-8a (45% de)
1
with LiBr–LiCO3–DMF gave (−)-(11S)-13-hydroxy-α-eudesmol 1a (39% de, determined by H NMR
spectrum) in 84% yield. Similarly, dihydroxylation of 7 with AD-mix-β instead of AD-mix-α followed
by elimination of the halide to afford (−)-(11R)-13-hydroxy-α-eudesmol 1b (33% de, determined by
1H NMR spectrum) gave an overall yield of 74%. Oxidation of 7 with a catalytic amount of OsO4,
K3Fe(CN6)6 as reoxidant, followed by elimination of the halide, gave a mixture of 1a and 1b in a ratio
of 1:1.
In the earlier stage of our studies, by elimination of the halide from 7, we obtained (+)-α-selinene 2 in
86% yield, which was known to occur in a number of essential oils10 and also in the defense secretions of

Y. Chen et al. / Tetrahedron: Asymmetry 9 (1998) 1923–1928
1925
Table 1
1 H NMR spectral data of natural diol, 1a and 1b, and the mixture of 1a and 1b
termite soldiers in the genera Amitermes.11 Although there have been some successful examples of the
total synthesis of 2,12 the strategy described in this paper is more facile and is highly efficient. Our initial
synthetic design was to employ 2 as a key intermediate, by a regioselective dihydroxylation, to obtain 1a
and 1b. It failed due to the complex products obtained by dihydroxylation of 2 with AD-mix-α or -β.
With both C-11 epimers of 13-hydroxy-α-eudesmol 1a (39% de), 1b (33% de) and the mixture of 1a
and 1b in hand, the C-11 configuration of the natural product could be established through comparison
of the 1H NMR spectrum (Table 1) of the natural diol and those of the synthetic diols. It is worthwhile
to note that there is a remarkable difference between 1a and 1b in a chemical shift of 12-H and 15-H
(δ15H–δ12H: 1a: 0.44 ppm; 1b: 0.49 ppm). It is the ∆δ value of 1a that coincides with that of natural diol
(δ15H–δ12H=0.43 ppm). The mass spectra of synthetic (−)-1a is also identical to that of the natural diol.3
In conclusion, the present results have established the configuration of 13-hydroxy-α-eudesmol to be
those represented by stereoformula as (−)-1a.
3. Experimental section
Melting points are uncorrected. MS were performed on a V.G.ZAB-HS spectrometer (EI, 70 eV).
Elemental analyses were performed on a Carlo Erba-1106 instrument. IR spectra were recorded on a
1
Nicolet 170 SXFT-IR spectrometer. H NMR spectra were recorded on a Bruker AC-80 and AM-400
instruments. Chemical shifts are referred to TMS on the ‘δ’ scale. Standard flash chromatography was
employed to purify the crude reaction mixture using 200–300 mesh silica gel under a positive nitrogen
pressure.
3.1. Dihydro-α-cyperone 5
Pure α-cyperone 4 (600 mg, 2.75 mmol) in dry ether (30 ml) was added slowly into a stirred solution of
Li (340 mg, 24.3 mmol) in liq. NH3 (60 ml) over 5 min. After the mixture was stirred for 25 min, excess
NH4Cl was added and the NH3 was allowed to evaporate. The reaction mixture was diluted with water
(35 ml) and extracted with ether. The extracts were washed with brine. After drying over anhydrous
MgSO4, the solution was evaporated to dryness in vacuo. The crude products were purified by flash
16
chromatography. The compound 5 (520 mg, 86% yield) was isolated as a colorless liquid. [α]D −27.3
(c, 1.05, CHCl3); IR: 1711, 1642, 1458, 887 cm−1; 1H NMR (80 MHz): δ (ppm) 0.98 (d, 3H, J=5.6 Hz,
4-Me), 1.12 (s, 3H, 10-Me), 1.75 (s, 3H, 11-Me), 4.75 (brs, 2H, 13-H); EIMS m/z: 220 (M+, 86), 205
(16), 191 (13), 177 (43), 149 (38), 109 (80), 67 (79), 55 (100).

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3.2. Dihydro-α-cyperol 6
Dry t-butanol (2.1 ml) was slowly added to a solution of LAH (398 mg, 10.5 mmol) in dry THF (42
ml) at 0°C. The solution of dihydro-α-cyperone 5 (450 mg, 2.05 mmol) in THF (21 ml) was added
with stirring and the mixture allowed to stand at 0°C for 30 min and then at room temperature for 18
h. The reaction mixture was poured into ice-cold 1 N HCL (60 ml) and extracted with petroleum ether.
The extracts were washed with sat. aq. NaHCO3 and brine. After drying over anhydrous MgSO4, the
solution was evaporated to dryness in vacuo. The crude products were purified by flash chromatography.
20
Compound 6 (420 mg, 92%) was obtained as white needles, m.p. 71–72°C. [α]D −5.7 (c, 2.96, CHCl3);
IR: 3342, 1644, 1451, 1377, 1025, 887 cm−1; 1H NMR (80 MHz): δ (ppm) 0.88 (s, 3H, 11-Me), 0.98 (d,
3H, J=5.5 Hz, 4-Me), 1.63 (brs, 3H, 12-Me), 3.14 (ddd, 1H, J=5.5, 9.5 and 9.6 Hz, 3-H), 4.71 (brs, 2H,
13-H); EIMS m/z (%): 222 (M+, 52), 204 (32), 189 (28), 175 (14), 161 (58), 122 (60), 41 (100).
3.3. 3α-Chloro-4β-H-eudesma-11,12-ene 7
To a magnetically stirred solution of NCS (239 mg, 1.80 mmol) in THF (2.2 ml), a solution of PPh3
(472 mg, 1.8 mmol) in THF (1 ml) was added dropwise. The solution was stirred at room temperature for
1 h. To this suspension, a solution of the alcohol 6 (350 mg, 1.58 mmol) in THF (3.5 ml) was added and
stirring was continued until most of the solid was dissolved (ca. 3 h). The reaction mixture was stripped
of solvent under reduced pressure and the residue was treated with water and ether. The organic layer was
washed with water, dried over anhydrous MgSO4, and evaporated. The crude products were purified by
26
flash chromatography. The compound 7 (334 mg, 88%) was obtained as a colourless oil. [α]D −68.8
(c, 3.9, CHCl3); IR: 1879, 1450, 886 cm−1; 1H NMR(400 MHz): δ (ppm) 0.85 (s, 3H, 10-Me), 0.94 (d,
3H, J=6.5 Hz, 4-Me), 1.73 (br s, 3H, 10-Me), 4.33 (br q, 1H, J=2.7 Hz, 3-H), 4.68 (br d, 1H, J=1.42
Hz, 13-H), 4.69 (br s, 1H, 13-H); EIMS m/z (%): 240 (M+, 64), 225 (15), 197 (89), 161 (44), 81 (100).
Found: C, 74.67%; H, 10.16%. Calcd for C15H25Cl: C, 74.81%; H, 10.46%.
3.4. (+)-α-Selinene 2
A suspension of compound 7 (42 mg, 0.18 mmol), LiBr (46 mg, 0.53 mmol) and Li2CO3 (52 mg,
0.7 mmol) in dry DMF (1.5 ml) was heated at 138–140°C for 5 h. After the solution was cooled, it was
diluted with ether and washed with water and brine. After drying over anhydrous MgSO4, the solution
was evaporated to dryness in vacuo. Purification by flash chromatography give pure 2 (31.6 mg, 86%).
[α]D8 +13.7 (c, 1.52, CHCl3, lit10 [α]D +15.7); IR: 2967, 2929, 2844, 1642, 1447, 1375, 1216, 887 cm−1
;
1H NMR (400 MHz): δ (ppm) 0.81 (s, 3H, 10-Me), 1.62 (brs, 3H, 11-Me) 1.77 (brs, 3H, 4-Me), 4.71 (s,
1H, 12-H), 4.74 (s, 1H, 12-H), 5.33 (brs, 1H, 3-H); EIMS m/z (%): 204 (M+, 69), 189 (100), 175 (31),
161 (41), 147 (36), 133 (63), 119 (40), 105 (66), 91 (85), 79 (67), 41 (82).
3.5. (−)-(11S)-3α-Chloro-13-hydroxy-α-eudesmol 8a
A 5 ml round-bottomed flask, equipped with a magnetic stirrer, was charged with 0.6 ml tert-butyl
alcohol, 0.6 ml of water, and 870 mg AD-mix-α. The mixture was stirred at room temperature until both
phases were clear, and then cooled at 0°C. Compound 7 (75 mg, 0.31 mmol) in 50% aqeous t-BuOH (1
ml) was added at once. The resulting mixture was stirred for 24 h at 0°C. Sodium sulfide (1.0 g) was added
to the mixture which was then warmed to room temperature and stirred for 1 h. The reaction mixture was
extracted several times with CH2Cl2. The extract was washed with 10% aqeous KOH, H2O and brine,

Y. Chen et al. / Tetrahedron: Asymmetry 9 (1998) 1923–1928
1927
dried over (MgSO4). After evaporation, the crude product was purified by flash chromatography to afford
12
8a (75 mg, 45% de) in 88% yield. [α]D −95.2 (c, 0.47, CHCl3); IR: 3364, 2937, 1450, 1380, 1040, 790
cm−1; 1H NMR (400 MHz, CDCl3): δ (ppm) 0.83 (s, 3H, 10-Me), 0.94 (d, 3H, J=6.6 Hz, 4-Me), 1.14 (s,
3H, 11-Me), 1.90 (dd, 1H, J=3.13, 14.6 Hz, 5-H), 3.44 (d, 1H, J=10.8, 13-H), 3.59 (d, 1H, J=10.6, 13-H),
4.33 (m, 1H, 3-H). MS m/z (%): 259 (M+−15, 1), 243 (100), 225 (58), 189 (24), 163 (7), 109 (11), 75
(20). Found: C, 65.38%; H, 9.76%. Calcd for C15H27O2Cl: C, 65.56%; H, 9.90%.
3.6. (−)-(11S)-13-Hydroxy-α-eudesmol 1a
A suspension of compound 8a (60 mg, 0.22 mmol), LiBr (57 mg, 0.66 mmol) and Li2CO3 (65 mg,
0.88 mmol) in dry DMF (2 ml) was heated to 138–140°C for 5 h. After the solution was cooled, it was
diluted with ether and washed with water and brine. After drying over anhydrous MgSO4, the solution
was evaporated to dryness in vacuo. Purification by flash chromatography give pure 1a (44 mg, 39% de)
in 84% yield. [α]D −6.8 (c, 0.735, CHCl3); IR: 3403, 2910, 1452, 1376, 1046 cm1; EIMS m/z (%):
10
238 (M+, 18), 220 (19), 207 (75), 189 (100), 107 (28), 84 (81). Found: C, 75.46%; H, 10.82%. Calcd for
C15H26O2: C, 75.58%; H, 11.00%.
3.7. (−)-(11R)-3α-Chloro-13-hydroxy-α-eudesmol 8b
By a procedure similar to the preparation of 8a, the reaction of 7 (70 mg, 0.29 mmol), AD-mix-β (812
8
mg), t-BuOH (1.1 ml) and H2O (1.1 ml), gave 8b (70 mg, 46% de) in 88% yield; [α]D −27.0 (c, 1.48,
CHCl3); IR: 3390, 2934, 1739, 1461, 1389, 1039 cm−1; 1H NMR (400 MHz, CDCl3): δ (ppm) 0.83 (s,
3H, 10-Me), 0.96 (d, 3H, J=6.6 Hz, 4-Me), 1.11 (s, 3H, 11-Me), 3.43 (d, 1H, J=10.9, 13-H), 3.58 (d, 1H,
J=10.9, 13-H), 4.33 (m, 1H, 3-H). EIMS m/z (%): 259 (M+−15, 1), 243 (100), 225 (39), 189 (16), 163
(6), 109 (9), 75 (17).
3.8. (−)-(11R)-13-Hydroxy-α-eudesmol 1b
A suspension of compound 8b (70 mg, 0.29 mmol), LiBr (67 mg, 0.77 mmol) and Li2CO3 (76 mg,
1.03 mmol) in dry DMF (2.5 ml) was heated at 138–140°C for 5 h. After the solution was cooled, it was
diluted with ether and washed with water and brine. After drying over anhydrous MgSO4, the solution
was evaporated to dryness in vacuo. Purification by flash chromatography give pure 1b (51 mg, 33% de)
in 84% yield. [α]D −3.0 (c, 0.78, CHCl3); IR: 3378, 2910, 1451, 1377, 1046 cm−1; EIMS m/z (%):
10
238 (M+, 7), 220 (10), 207 (32), 189 (48), 101 (100), 75 (49), 43 (59).
Acknowledgements
We are grateful for the financial support from National Natural Science Foundation of China (Grant
No. 29732060).
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9. The stereoselectivities of the asymmetric dihydroxylation of 1,1-disubstituted olefins vary from 30% to 95% in the
literature.4 In our experiments, we found: oxidation of 7 with a catalytic amount of OsO4, without chiral ligand, gave
a mixture of 8a and 8b in satisfactory yield within 10 h. Hydroxylation of 7 with AD-mixes by standard procedure
was not complete within 48 h. When two-times the amount of AD-mixes described in standard procedure was used, the
hydroxylation of 7 was completed within 24 h and gave diol 8 in satisfactory yield. Based on the above experimental facts,
we think that the deca-hydronaphthalene substitute in olefin 7 might be responsible for the low de values in dihydroxylation
of 7 with AD-mix. Because the deca-hydronaphthalene substitute is rigid and big, the diastereoselectivities and reaction
rates of dihydroxylation of 7 with AD-mix were lowered.
10. For a list see: Gildmeister, E.; Hoffmann, F. Atherischen Ole, (4th Edition revised by Triebs, W.; Merkel D.) Akademie-
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