Total synthesis of (-)-elegansidiol by using an abnormal Beckmann fragmentation of Hajos ketone oxime as a key step

Article abstract of DOI:10.1016/j.tet.2007.03.123

Abnormal Beckmann fragmentation of Hajos ketone oxime regioselectively forms of a chiral 1-oxygenated 2,2-dimethyl-4-methylene-cyclohexan skeleton. Using this transformation as a key step, the total synthesis of (-)-elegansidiol, an oxygenated mono-carboc

Full text of DOI:10.1016/j.tet.2007.03.123

Tetrahedron 63 (2007) 5036–5041
Total synthesis of (L)-elegansidiol by using an abnormal
Beckmann fragmentation of Hajos ketone oxime as a key step
*
Liya Cao, Jianwei Sun, Xinyan Wang, Rui Zhu, Haijian Shi and Yuefei Hu
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, PR China
Received 30 January 2007; revised 20 March 2007; accepted 21 March 2007
Available online 24 March 2007
Abstract—Abnormal Beckmann fragmentation of Hajos ketone oxime regioselectively forms of a chiral 1-oxygenated 2,2-dimethyl-4-meth-
ylene-cyclohexan skeleton. Using this transformation as a key step, the total synthesis of (ꢀ)-elegansidiol, an oxygenated mono-carbocyclic
sesquiterpenoid, was achieved.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
challenge,7,8 (ꢀ)-elegansidiol (1) is a very good target for
total synthesis.
(ꢀ)-Elegansidiol (1, Chart 1) is an oxygenated mono-
carbocyclic sesquiterpenoid isolated from the aerial parts
of Santolina elegans. Its structure was first established
by Barrero1 in 1999 and the absolute configuration was
determined by Monti et al.2 in 2001. Structurally, (ꢀ)-
elegansidiol is a 3-substituted chiral 2,2-dimethyl-4-
methylene-cyclohexanol and many known oxygenated
mono-carbocyclic terpenoids,3–6 such as achilleol A (2),3
achilleol B (3),4 and farnesiferol B (4),5 can be considered
as its derivatives.
Two different strategies have been employed to build the
skeleton of 2,2-dimethyl-4-methylene-cyclohexanol in the
total synthesis of elegansidiol (1). The synthesis of rac-
elegansidiol (rac-1) was accomplished by using an intra-
molecular epoxy-ene cyclization,1,7f while (ꢀ)-elegansidiol
(1) was synthesized starting from a chiral karahana lac-
tone.2,9 For efficient syntheses of oxygenated mono-carbo-
cyclic terpenoids, there remains a great need to develop more
practical methods and routes. Herein, we report a new ap-
proach toward the total synthesis of enantiopure (ꢀ)-elegan-
sidiol (1), in which an abnormal Beckmann fragmentation of
Hajos ketone (5) oxime was used as a key step to construct
the chiral 2,2-dimethyl-4-methylene-cyclohexanol skeleton.
Since the chiral 2,2-dimethyl-4-methylene-cyclohexanol
unit also is a widely used building block in other terpenoidal
syntheses7 and its construction still remains a synthetic
4
3
1
OH
2
HO
HO
HO
(-)-Elegansidiol (1)
Achilleol A (2)
H
O
O
O
HO
Achilleol B (3)
Farnesiferol B (4)
Chart 1.
Keywords: Total synthesis; (ꢀ)-Elegansidiol; Abnormal Beckmann fragmentation; Hajos ketone.
* Corresponding author. Tel.: +86 10 62795380; fax: +86 10 62771149; e-mail: yfh@mail.tsinghua.edu.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.123

L. Cao et al. / Tetrahedron 63 (2007) 5036–5041
5037
2. Results and discussion
oxidation, ꢀ60 ꢁC, 90%). When the mixture of 11,
NH2OH$HCl, and NaOAc in EtOH was refluxed for 2 h,
the oxime 12 was obtained in almost quantitative yield.
Enantiopure Hajos ketone (5) is a commercially available
product that can also be easily prepared on a 100-g scale
in the laboratory.10 It has been employed as a versatile build-
ing block in the synthesis of many complex products,11 in
which its angular methyl group has to be an essential com-
ponent in the target molecule. Thus, the application of Hajos
ketone in organic synthesis has been seriously limited be-
cause no suitable method can efficiently modify or remove
its angular methyl group. Recently, we have developed a
novel abnormal Beckmann fragmentation procedure, which
involves treatment of steroid-17-one oximes with TFA/
CH(OMe)3 in boiling THF for 2 h to convert the angular
18-Me into the corresponding methylene in moderate to
high yields.12 Therefore, the dimethyl derivative of Hajos
ketone oxime (12) can be expected to give the desired 3-
substituted chiral 2,2-dimethyl-4-methylene-cyclohexanone
(14) under similar conditions. This reaction was featured in
a proposed retro-synthetic route for (ꢀ)-elegansidiol (1)
(Scheme 1).
Unfortunately, treatment of 12 with TFA/CH(OMe)3 in boil-
ing THF gave a mixture of three isomers (exo-14, and two
inseparable endo-isomers 15 and 16, Scheme 3) without
any regioselectivity. Controlled experiments15 revealed that
this may result from the fact that intermediate 13 (a ring-
opened intermediate of 12) does not have a fixed conforma-
tion like that of the steroid. Thus, at high temperature, the
proton elimination can occur from any of the three carbons
connected to the carbonium16 (13). Based on this analysis,
we hypothesized that the regioselectivity of the abnormal
Beckmann fragmentation of 12 may be improved by lower-
ing the reaction temperature.
1'
PCl5, 2,6-Dimethylpyridine
CH2Cl2, < -10 °C, 10 min
5
CN
4
-H+
O
1
3
2
12
O
H
13
O
CN
CN
+
CN
+
OH
O
O
O
HO
O
O
O
O
Hajos Ketone (5)
(-)-Elegansidiol (1)
15 (11%)
16 (0%)
14 (75%)
Scheme 3.
NOH
Abnormal Backmann
Fragmentation
After many attempts, we found that Magnus’ procedure17 (a
suspension of PCl5 and 2,6-dimethylpyridine in Et2O at
room temperature) gave better regioselectivity providing
14 in 50% yield, but it did not work when the reaction tem-
perature was dropped below 0 ꢁC. By simple replacement
of Et2O with CH2Cl2, we obtained a transparent solution of
PCl5 and 2,6-dimethylpyridine in CH2Cl2. This new set of
conditions was so powerful that the abnormal Beckmann
fragmentation could be promoted efficiently even at ꢀ10 ꢁC.
When oxime 12 was used as a substrate, the desired isomer
14 was obtained in 75% isolated yield within 15 min at
ꢀ10 ꢁC. It was interesting to observe that the reaction at
ꢀ10 ꢁC resulted in the endo-isomer 15 (11%), but not the
endo-isomer 16. When the reaction was carried out at room
temperature, both 15 and 16 were obtained in 20% and
13% yields, respectively. These temperature-controlled re-
gioselectivities may be a result of the rigid conformation
of 13 at ꢀ10 ꢁC, which makes it difficult to form the
endo-double bonds (for 15 and 16). At low temperature,
4
3
O
O
1
2
CN
O
O
14
12
Scheme 1.
Compounds 6 and 7 were prepared according to previously
reported procedures.13 Although the preparation of com-
pounds 8–11 has been reported in Ref. 14, our improved pro-
cedures were carried out under more convenient conditions
resulting in products whose physical data differ from those
in the references. By known procedures (Scheme 2),14 the
cis-ring fused product 9 was obtained by dimethylation of
7 followed by Pd–C catalyzed hydrogenation of 8. After
a highly efficient cleavage of tert-butyl ether 9 with aqueous
HCl (lit.14a BF3$Et2O, 100%), the ketone in product 10 was
protected with ethylene glycol. Without purification, the
crude ketal was oxidized by PCC in the presence of NaOAc
to provide 11 in 84% yield over two steps (lit.14a Swern
O
OBu-t
OBu-t
OH
i
iii
iv
ii
71%
87%
98%
99%
O
O
O
O
7
5
6
8
OH
O
NOH
OBu-t
vi
84%
v
vii
99%
O
O
99%
O
O
H
O
H
O
H
H
10
9
11
12
Scheme 2. Reagents and conditions: (i) NaBH4, EtOH, 0 ꢁC, 30 min; (ii) Me2C]CH2, H3PO4, BF3.Et2O, CH2Cl2, rt, 1 h; (iii) t-BuOK, t-BuOH, MeI, rt,
45 min; (iv) H2, Pd–C, EtOAc, rt, 30 min; (v) aq HCl, EtOH, reflux, 2 h; (vi) (a) HOCH2CH2OH, p-TsOH, benzene, reflux, 3 h; (b) PCC, NaOAc, CH2Cl2,
rt, 2 h; (vii) NH2OH$HCl, NaOAc, EtOH, reflux, 2 h.

5038
L. Cao et al. / Tetrahedron 63 (2007) 5036–5041
the reaction is more likely to be performed kinetically, which
makes it easier to deprotonate at C10 than C3 and C5
(Scheme 3).
3. Conclusion
In conclusion, we have found that the transparent solution
of PCl5 and 2,6-dimethylpyridine in CH2Cl2 is a powerful
reagent for the abnormal Beckmann fragmentation. It pro-
moted the fragmentation of Hajos ketone oxime derivative
at ꢀ10 ꢁC to regioselectively form a 1-oxygenated 2,2-di-
methyl-4-methylene-cyclohexane skeleton smoothly. By us-
ing this transformation as a key step, the total synthesis of
(ꢀ)-elegansidiol, an oxygenated mono-carbocyclic sesqui-
terpenoid, was achieved.
As shown in Scheme 4, routine alkaline hydrolysis of 14
yielded the corresponding carboxylic acid 17. Without
purification, crude acid 17 was treated with CH3Li to give
methyl ketone 18 in 77% yield (over two steps).18 It is
worthy to note that a large excess of CH3Li lowers the yield
of 18 dramatically, while 2.5 equiv of CH3Li gave the best
result. The reaction of 18 with H2C]CHMgBr was per-
formed in THF at 0 ꢁC for 1 h. For easy separation, the crude
product was directly converted into the acetate 19 as a 1:1
mixture of diastereomers in 75% yield (over two steps).
The acetate 19 underwent an allylic rearrangement catalyzed
by PdCl2(MeCN)2 to afford compound 20 as a mixture of
trans/cis isomers in the ratio of 95:5.19 By using our proce-
dure for deprotection of an O,O-ketal,20 20 was deprotected
with catalytic molecular iodide to provide 21 in 80% yield
(over two steps) within 5 min. Reduction of the ketone in
21 with different reducing reagents, such as NaBH4,
DIBAL-H or K-Selectride, showed that NaBH4 gave the
best stereoselectivity (1S/1R¼5.7:1.0) in 80% yield, while
K-Selectride gave the worst stereoselectivity (1S/1R¼
1.0:1.0) in 90% yield. However, when compound 21 was
treated with DIBAL-H at ꢀ78 ꢁC for 1 h, both ketone and
ester were reduced in one step in 95% yield with 1S/1R in
the ratio of 5.0:1.0.
4. Experimental
4.1. General methods
All melting points were determined on a Yanaco melting
point apparatus and are uncorrected. IR spectra were re-
corded on a Nicolet FTIR 5DX spectrometer. The 1H
NMR and 13C NMR spectra were recorded on a JEOL
JNM-ECA 300 spectrometer in CDCl3 with TMS as internal
reference. The J values are given in Hertz. MS was recorded
on a VG-ZAB-MS spectrometer with 70 eV. Optical rota-
tions were recorded on a Perkin-Elmer 343 polarimeter.
Elementary analysis data were obtained on a Perkin-
Elmer-241C apparatus. Compounds 6 and 7 were prepared
according to the previously reported procedures.13
4.1.1. (1R-cis)-1-tert-Butoxy-4,4,7a-trimethyl-1,2,4,6,7,
7a-hexahydro-inden-5-one (8). To a solution of metal K
(6 g, 154 mmol) in anhydrous t-BuOH (120 mL) was added
dropwise a solution of 7 (10.1 g, 50 mmol) in anhydrous
t-BuOH (30 mL) at room temperature under nitrogen. After
the mixture was stirred for 15 min, MeI (42.6 g, 300 mmol)
was added dropwise. The resultant mixture was stirred for
another 45 min and then was quenched with saturated
aqueous NH4Cl at 0 ꢁC. After most of t-BuOH was
removed in vacuum, the residue was diluted with Et2O
and washed with water. The aqueous layer was extracted
with Et2O and combined organic layers were washed
with brine and dried over Na2SO4. Removal of solvent
gave crude product, which was purified by chromatography
(PE/CH2Cl2/EtOAc¼16:4:1) to give 8 (8.9 g, 71.2%) as col-
orless crystals. It had mp 44.0–44.5 ꢁC, [a]D25 ꢀ60.7 (c 1.0,
CHCl3) [lit.14a enantioisomer: 40–42 ꢁC, [a]2D5 +49 (c 1.0,
ii
i
iii
O
O
14
COOH
O
O
O
O
17
18
iv
v
O
OAc
O
O
OAc
19
20
4
3
vi
1
2
OH
OAc
HO
O
(-)-Elegansidiol (1)
21
1
CHCl3)]. IR: n 2975, 2935, 1710, 1470, 1362 cmꢀ1; H
Scheme 4. Reagents and conditions: (i) KOH, aq EtOH, reflux, 12 h; (ii)
CH3Li, Et2O, 0 ꢁC, 1 h, 77% (14–18); (iii) (a) CH2]CH2MgBr, THF,
0 ꢁC, 0.5 h; (b) Ac2O, DMAP, Et3N, THF, reflux, 24 h, 75%; (iv)
PdCl2(MeCN)2, THF, rt, 1 h; (v) I2, acetone, rt, 5 min, 80% (19–21); (vi)
DIBAL-H, CH2Cl2, ꢀ78 ꢁC, 1 h, 95%.
NMR: d 1.18 (3H, s), 1.19 (9H, s), 1.22 (3H, s), 1.28 (3H,
s), 1.61–1.93 (2H, m), 2.19–2.39 (3H, m), 2.62 (1H, m),
3.77 (1H, t, J¼8.1), 5.42 (1H, s); 13C NMR: d 17.9, 23.8,
28.1, 28.7, 33.9, 35.0, 38.2, 46.2, 48.3, 72.7, 80.8, 120.0,
154.1, 215.3; MS m/z (%): 250 (M+, 1), 110 (60), 57
(100); Anal. Calcd for C16H26O2: C, 76.75%; H, 10.47%.
Found: C, 76.97%; H, 10.39%.
After careful column chromatography and two successive
recrystallizations, pure (ꢀ)-elegansidiol (1) was obtained
in 70% yield. The spectral data (IR, H NMR, and 13C
1
NMR) of our synthetic sample were in full agreement with
those of the literature.1,2 Our synthetic sample is a white
crystalline solid with a melting point of 79.5 ꢁC (Et2O–
Petroleum ether) and [a]2D5 ꢀ22.9 (c 0.2, CHCl3), which are
in closer agreement to the data reported by Monti et al.2 [mp
82 ꢁC, [a]D25 ꢀ14.8 (c 1.0, CHCl3)]. Thus, we agree with the
conclusion suggested by Monti that the natural elegansidiol
(1) [lit.1 colorless oil, [a]D25 ꢀ4.0 (c 0.9, CHCl3)] is partially
racemic.
4.1.2. (1R)-1-tert-Butoxy-4,4,7a-trimethyl-octahydro-
inden-5-one (9). A stirred suspension of 8 (8.9 g, 35.6 mmol)
and 10% Pd–C (890 mg) in EtOAc (40 mL) was hydroge-
nated at atmospheric pressure and room temperature until
the absorption of hydrogen ceased completely (it was carried
out on an atmospheric pressure hydrogenator). Then the
catalyst was filtrated off and the solvent was evaporated. Re-
moval of the solvent gave a white solid, which was purified

L. Cao et al. / Tetrahedron 63 (2007) 5036–5041
5039
by chromatography (PE/CH2Cl2/EtOAc¼25:5:1) to give 9
(7.8 g, 87%) as white needless crystals. It had mp 75–
76 ꢁC, [a]D25 ꢀ51.08 (c 0.9, CHCl3) [lit.14a enantioisomer:
72–73 ꢁC, [a]D25 +64 (c 1.0, CHCl3)]. IR: n 2968, 2875,
(2.1 g, 8.8 mmol), NH2OH$HCl (1.96 g, 28 mmol), and an-
hydrous NaOAc (3.2 g, 39 mmol) in EtOH (40 mL) was re-
flux for 2 h under nitrogen. After evaporation of the solvent,
the residue was dissolved in H2O (60 mL). The aqueous
layer was extracted with CH2Cl2 and the combined organic
layers were washed with brine and dried over Na2SO4. Re-
moval of the solvent gave product 12 (2.2 g, quantitative
yield) as a white solid. It had mp 116–119 ꢁC, [a]D25 ꢀ6.76
(c 1.1, CHCl3). IR: n 3284, 2971, 2922, 2881, 1475,
1
1703, 1474, 1360 cmꢀ1; H NMR: d 0.96 (3H, s), 1.10
(3H, s), 1.13 (9H, s), 1.18 (3H, s), 1.20–1.50 (1H,
m), 1.60–1.72 (3H, m), 1.72–1.83 (3H, m), 2.11–2.24 (1H,
m), 2.45–2.55 (1H, m), 3.45–3.49 (1H, t, J¼6.5); 13C
NMR: d 23.5, 24.6, 26.6, 26.7, 28.6, 31.9, 32.0, 34.7,
42.1, 47.1, 54.7, 72.6, 79.3, 217.3; MS m/z (%): 252
(M+, 9), 196 (82), 71 (57), 57 (100); Anal. Calcd for
C16H28O2: C, 76.14%; H, 11.18%. Found: C, 75.46%; H,
10.89%.
1
1388 cmꢀ1; H NMR: d 0.64 (3H, s), 1.04 (3H, s), 1.23
(3H, s), 1.40–1.51 (1H, m), 1.51–1.7 (2H, m), 1.7–1.82
(1H, m), 1.82–2.01 (3H, m), 2.23–2.4 (1H, m), 2.58–2.72
(1H, m), 3.91 (4H, m), 8.69 (1H, s); 13C NMR: d 21.0,
23.2, 24.9, 25.0, 26.9, 27.0, 29.9, 40.5, 43.9, 55.9, 64.5,
65.0, 112.6, 171.4; MS m/z (%): 253 (M+, 4), 99 (100),
86 (60), 41 (62); Anal. Calcd for C14H23NO3: C, 66.37%;
H, 9.15%; N, 5.53%. Found: C, 66.43%; H, 9.22%; N,
5.61%.
4.1.3. (1R)-1-Hydroxy-4,4,7a-trimethyl-octahydro-
inden-5-one (10). A mixture of 9 (7.8 g, 31 mmol) and aque-
ous HCl (6.0 M, 10 mL) in EtOH (70 mL) was refluxed for
2 h under nitrogen. Then the mixture was neutralized with
solid Na2CO3 at 0 ꢁC. After evaporation of EtOH, the resi-
due was diluted by CH2Cl2. Then the organic layer was
washed with water, brine, and dried over Na2SO4. Removal
of the solvent gave crude product, which was purified by
chromatography (PE/EtOAc¼7:3) to give pure 10 (6.1 g,
quantitative yield) as a yellowish oil. [a]2D5 ꢀ29.2 (c 1.2,
CHCl3) [lit.14a enantioisomer: [a]D25 +22 (c 1.0, CHCl3)].
IR: n 3447, 2961, 2932, 1705, 1455, 1385 cmꢀ1; 1H NMR:
d 0.89 (3H, s), 1.21 (3H, s), 1.22 (3H, s), 1.38–1.53 (1H,
m), 1.66–1.73 (2H, m), 1.73–1.91 (1H, m), 1.91–2.03
(3H, m), 2.12–2.23 (1H, m), 2.54–2.66 (1H, m), 3.70–3.80
(1H, m); 13C NMR: d 23.2, 23.7, 26.8, 26.9, 31.1, 32.1,
34.5, 42.7, 47.0, 54.9, 81.1, 217.3; MS m/z (%): 196 (M+,
16), 97 (60), 55 (51), 43 (66), 41 (100); Anal. Calcd for
C12H20O2: C, 73.43%; H, 10.27%. Found: C, 73.85%; H,
10.22%.
4.1.6. 3-[(7R)-6,6-Dimethyl-8-methylene-1,4-dioxa-spiro-
[4,5]dec-7-yl]-propionitrile (14). To a stirred solution of
PCl5 (620 mg, 3.0 mmol) and 2,6-dimethylpyridine
(0.7 mL, 7 mmol) in anhydrous CH2Cl2 (30 mL) was added
compound 12 (500 mg, 2 mmol) dropwise in anhydrous
CH2Cl2 (10 mL) at ꢀ10 ꢁC under nitrogen. After stirring
for 15 min, the mixture was poured into anhydrous Et2O
(100 mL). The produced white solids were filtrated off and
the filtrate was washed with saturated aqueous Na2CO3
(50 mL), aqueous HCl (1.0 N, 50 mL), saturated aqueous
Na2CO3 (50 mL), brine (50 mL), and dried over Na2SO4.
Removal of the solvent gave crude product, which was puri-
fied by chromatography (PE/CH2Cl2/EtOAc¼20:4:1) to
give 14 (350 mg, 75%) as a colorless oil. [a]2D5 ꢀ18.4 (c
0.3, CHCl3). IR: n 3072, 2979, 2874, 2245, 1647, 1444,
1
1383 cmꢀ1; H NMR: d 0.89 (3H, s), 1.04 (3H, s), 1.55–
4.1.4. (7aR-cis)-5,5-Ethylenedioxy-4,4,7a-trimethyl-
octahydro-inden-1-one (11). A mixture of 10 (2.1 g,
10.7 mmol), ethylene glycol (5 mL), and p-TsOH
(100 mg) in benzene (80 mL) was refluxed with a Dean–
Stark apparatus. Two hours later, it was quenched with satu-
rated aqueous NaHCO3. The resultant mixture was extracted
with EtOAc and worked up as usual to give a yellow oil,
which was used in the next step without further purification.
1.72 (2H, m), 1.8–2.4 (7H, m), 3.8–4.0 (4H, m), 4.70 (1H,
s), 4.91 (1H, s); 13C NMR: d 16.0, 19.5, 23.1, 24.8, 29.6,
31.5, 42.5, 53.3, 64.5, 65.2, 111.7, 111.9, 120.1, 145.5;
MS m/z (%): 235 (M+, 16), 99 (80), 86 (100), 41 (63);
Anal. Calcd for C14H21NO2: C, 71.46%; H, 8.99%; N,
5.95%. Found: C, 71.32%; H, 9.22%; N, 5.67%.
4.1.7. 3-[(7R)-6,6,8-Trimethyl-1,4,-dioxa-spiro[4,5]dec-8-
en-7-yl]-propionitrile (15). It was also obtained in 11%
yield (50 mg) as a colorless oil. IR: n 2977, 2879, 2243,
To a suspension of PCC (3.24 g, 15.1 mmol) and anhydrous
NaOAc (2.47 g, 30.1 mmol) in CH2Cl2 (50 mL), was added
dropwise a solution of the yellow oil in CH2Cl2 (10 mL). Af-
ter the mixture was stirred for 2 h at room temperature, it was
filtrated through a pad of silica gel. Removal of the solvent
gave a crude product, which was purified by a chromato-
graphy (PE/EtOAc¼5:1) to give 11 (2.1 g, 84%) as white
crystals. It had mp 66–68 ꢁC, [a]D25 ꢀ20.98 (c 0.4, CHCl3)
[lit.14a enantioisomer: oil, [a]D25 +15 (c 1.0, CHCl3)]. IR:
1
1732, 1383 cmꢀ1. H NMR: d 0.94 (s, 3H), 1.03 (s, 3H),
1.74 (s, 4H), 1.92 (s, 1H), 2.16 (s, 3H), 2.29–2.48 (m, 1H),
2.48–2.62 (m, 1H), 3.80–4.10 (m, 4H), 5.31 (s, 1H); 13C
NMR: d 18.0, 19.4, 22.7, 24.2, 24.9, 33.9, 40.8, 50.3, 65.0,
65.3, 111.4, 120.3 (2C), 134.9; Anal. Calcd for
C14H21NO2: C, 71.46%; H, 8.99%; N, 5.95%. Found: C,
71.50%; H, 9.03%; N, 5.66%.
n 2973, 2929, 2888, 1733, 1461, 1400, 1373 cmꢀ1
;
1H
4.1.8. 3-[(7R)-6,6-Dimethyl-8-methylene-1,4-dioxa-
spiro[4,5]dec-7-yl]butan-2-one (18). A solution of 14
(1.81 g, 7.7 mmol) and KOH (5 g, 89 mmol) in H2O
(15 mL) and EtOH (20 mL) was refluxed for 12 h under
nitrogen. Then it was acidified with aqueous HCl (1.0 M,
50 mL) at 0 ꢁC. The mixture was extracted with CH2Cl2
and combined organic layers were washed with brine and
dried over Na2SO4. Removal of the solvent gave crude prod-
uct 17 (quantitative yield) as a yellow oil, which was used in
the next step without further purification.
NMR: d 0.89 (3H, s), 1.11 (3H, s), 1.19 (3H, s), 1.2–2.4
(9H, m), 3.92 (4H, m); 13C NMR: d 20.8, 21.1, 23.6, 25.6,
26.5, 27.1, 35.6, 40.0, 47.6, 54.6, 64.3, 65.1, 112.2, 222.5;
MS m/z (%): 238 (M+, 5), 99 (100); Anal. Calcd for
C14H22O3: C, 70.56%; H, 9.30%. Found: C, 70.30%; H,
9.24%.
4.1.5. (7aR,3aS)-5,5-Ethylenedioxy-4,4,7a-trimethyl-
octahydro-inden-1-one oxime (12). The mixture of 11

5040
L. Cao et al. / Tetrahedron 63 (2007) 5036–5041
A stirred solution of 17 in dry ether (120 mL) was treated
with CH3Li (1.6 M THF solution, 13 mL, 20.8 mmol) at
0 ꢁC under nitrogen. After another 1 h, it was quenched
with saturated aqueous NH4Cl. The mixture was extracted
with ether and combined layers were washed with brine
and dried over Na2SO4. Removal of the solvent gave
crude product, which was purified by chromatography
(PE/EtOAc¼5:1) to give 18 (1.5 g, 77%) as a colorless
oil. [a]2D5 ꢀ10.4 (c 1.0, CHCl3). IR: n 2953, 2880, 1716,
The mixture of 20 and I2 (65 mg, 0.26 mmol) in acetone
(10 mL) was stirred at room temperature for 5 min. Then
the reaction was quenched with 5% aqueous solution of
Na2S2O3. After the mixture was poured into water, it was
extracted with CH2Cl2. The combined organic layers were
washed with brine and dried over Na2SO4. Removal of the
solvent to crude product, which was purified by chromato-
graphy (PE/EtOAc¼10:1) to give 21 (550 mg, 80%) as a
yellow oil. IR:
n 3072, 2958, 1738, 1708, 1444,
1
1
1642, 1445, 1359 cmꢀ1; H NMR: d 0.83 (3H, s), 1.00
1366 cmꢀ1; H NMR: d 1.05 (s, 3H), 1.10–1.27 (m, 1H),
1.20 (s, 3H), 1.60–2.20 (m, 6H), 1.63 (s, 3H), 2.06 (s, 3H),
2.15–2.72 (m, 4H); 13C NMR: d 16.5, 21.0, 21.2 (Z-), 21.3
(E-), 25.4, 27.2, 30.6, 37.3, 37.6, 49.0, 56.0, 61.3, 113.4,
118.5, 141.8, 144.7, 171.1, 215.2; HREI MS m/z:
278.1894 (calcd. for C17H26O3, 278.1882).
(3H, s), 1.55–1.75 (2H, m), 1.75–1.95 (3H, m), 2.11 (3H,
s), 2.11–2.19 (1H, m), 2.20–2.32 (2H, m), 2.38–2.52 (1H,
m), 3.8–4.0 (4H, m), 4.56 (1H, s), 4.84 (1H, s); 13C NMR:
d 19.3, 20.4, 23.9, 30.0, 30.8, 31.9, 42.9, 43.1, 52.7, 64.6,
65.2, 110.0, 112.3, 147.2, 209.4; MS m/z (%): 252 (M+,
21), 209 (75), 99 (55), 43 (100); Anal. Calcd for
C15H24O3: C, 71.39%; H, 9.59%. Found: C, 71.50%; H,
9.65%.
4.1.11. (1S,3R)-3-[(3E)-5-Hydroxy-3-methylpent-3-enyl]-
2,2-dimethyl-4-methylenecyclohexanol (elegansidiol, 1).
To a stirred solution of 21 (180 mg, 0.65 mmol) in CH2Cl2
was added a solution of DIBAL-H in hexane (1.0 M,
6.5 mL, 6.5 mmol) at ꢀ78 ꢁC. One hour later, the reaction
was quenched by saturated aqueous solution of NH4Cl.
The resultant mixture was extracted with CH2Cl2 and com-
bined organic layers were washed with H2O, brine, and dried
over Na2SO4. Removal of the solvent yielded crude product,
which was purified by chromatography (CH2Cl2/
EtOAc¼7:3) to give a mixture of (ꢀ)-elegansidiol (1) and
its isomers (146 mg, 95%) as a white solid. After it was re-
crystallized from Et2O–PE twice, pure elegansidiol (1)
(108 mg, 70%) was obtained as white crystals. It had mp
79.5 ꢁC, [a]D25 ꢀ22.9 (c 0.2, CHCl3) [lit.1 oil, [a]2D5 ꢀ4.0 (c
0.9, CHCl3); lit.2 mp 82 ꢁC, [a]D25 ꢀ14.8 (c 1.0, CHCl3)].
4.1.9. Acetic acid 1-[2-[(7R)-6,6-dimethyl-8-methylene-
1,4-dioxa-spiro[4,5]dec-7-yl]-ethyl]-1-methyl-allyl ester
(19). To a stirred solution of 18 (1.17 g, 4.64 mmol) in
dry THF (40 mL) was added dropwise vinylmagnesium
bromide (1.0 M THF solution, 6 mL, 6 mmol) at 0 ꢁC under
nitrogen. After another 1 h, it was quenched with saturated
aqueous NH4Cl. Then the mixture was poured into water
and extracted with ether. The combined organic layers
were washed with brine and dried over Na2SO4. Removal
of the solvent gave the crude allylic alcohols as a yellow
oil, which was used in the next step without further
purification.
1
The mixture of allylic alcohol, Ac2O (7 mL), DMAP
(400 mg), and Et3N (20 mL) in THF (60 mL) was refluxed
for 24 h. Then the reaction mixture was diluted with Et2O
at room temperature. The resultant mixture was washed
with aqueous HCl (1.0 M), saturated aqueous NaHCO3,
brine, and dried over Na2SO4. Removal of the solvent gave
crude product, which was purified by chromatography
(PE/EtOAc¼10:1) to give a diastereomeric mixture 19 in
the ratio of 1:1 (970 mg, 75%) as a yellow oil. IR: n 3083,
2977, 2879, 1736, 1646, 1446, 1368 cmꢀ1; 1H NMR (major
isomer): d 0.84 (s, 3H), 0.98 (s, 3H), 1.45–1.51 (m, 2H), 1.52
(s, 3H), 1.58–1.61 (m, 3H), 1.60–1.97 (m, 2H), 2.01 (s, 3H),
2.04–2.30 (m, 2H), 3.83–4.00 (m, 4H), 4.60 (s, 1H), 4.84
(s, 1H), 5.01 (d, 1H, J¼11.0), 5.03 (d, 1H, J¼17.5), 5.97
(dd, 1H, J¼17.5, 11.0); 13C NMR (major isomer): d 19.1,
19.8, 22.2, 23.2, 23.46 (1R or 1S), 23.57 (1R or 1S), 31.4,
31.9, 39.13 (R or S), 39.22 (R or S), 43.4, 52.7, 64.6, 65.1,
83.20 (R or S), 83.30 (R or S), 109.4, 112.4, 112.9, 141.93
(R or S), 142.05 (R or S), 147.3, 169.9; Anal. Calcd for
C19H30O4: C, 70.77%; H, 9.38%. Found: C, 70.81%; H,
9.57%.
IR: n 3566, 3292, 3078, 2939, 1647, 1024, 890 cmꢀ1; H
NMR: d 0.74 (s, 3H), 1.04 (s, 3H), 1.12 (t, 1H, J¼5.2,
–OH, disappears after addition of D2O), 1.34 (d, 1H, J¼5.5,
–OH, disappears after addition of D2O), 1.44–1.60 (m, 2H),
1.60–1.67 (m, 2H), 1.69 (s, 3H), 1.78–1.92 (m, 2H), 1.93–
2.09 (m, 1H), 2.09–2.21 (m, 1H), 2.30–2.40 (dt, 1H,
J¼13.1, 4.8), 3.42 (dd, 1H, J¼9.6, 4.1, a multiplet before
the addition of D2O), 4.16 (d, 2H, J¼6.9, a triplet before
the addition of D2O), 4.61 (s, 1H), 4.89 (s, 1H), 5.41 (t,
1H, J¼6.9); 13C NMR: d 15.7, 16.3, 23.6, 25.9, 32.2, 32.8,
38.5, 40.5, 51.2, 59.4, 77.2, 108.5, 123.2, 140.2, 147.2;
MS m/z (%): 220 (M+ꢀ18, 4), 205 (8), 187 (8), 159 (5),
135 (10), 107 (15), 96 (26), 81 (24), 44 (13), 43 (100), 41
(93); Anal. Calcd for C15H26O2: C, 75.58%. H, 10.99%.
Found: C, 75.61%; H, 10.93%.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (20025204) and the Key Subject
Foundation from Beijing Department of Education
(XK100030514).
4.1.10. Acetic acid (2E)-5-((1R)-2,2-dimethyl-6-methyl-
ene-3-oxo-cyclohexyl)-3-methylpent-2-enyl ester (21).
The mixture of 19 (800 mg, 2.48 mmol) and PdCl2(MeCN)2
(80 mg) in dry THF (15 mL) was stirred for 1 h at room tem-
perature under nitrogen. Then the reaction mixture was di-
luted with ether and was filtrated through a pad of silica
gel. Removal of the solvent gave crude product 20 as a yel-
low oil, which was utilized for the next step without further
purification.
Supplementary data
1H NMR and 13C NMR spectra for products 11–12, 14, 18–
19, 21 and 1 were supported. Supplementary data associated
with this article can be found in the online version, at
doi:10.1016/j.tet.2007.03.123.

L. Cao et al. / Tetrahedron 63 (2007) 5036–5041
5041
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