Synthesis of a Highly Hindered Hydrindanone via α-Carbonyl Radical Cyclization: Enantiospecific Formal Syntheses of (-)-Pinguisenol and (-)-α-Pinguisene

Article abstract of DOI:10.1021/jo035008g

An enantiospecific synthesis of Schinzer's ketone 3 from (R)-(+)-pulegone via α-carbonyl radical cyclization was accomplished. This work also constitutes an enantiospecific formal syntheses of (-)-pinguisenol and (-)-α-pinguisene. The intermediate ketone 4 would be useful for the synthesis of other pinguisane-type sesquiterpenes.

Full text of DOI:10.1021/jo035008g

SCHEME 1
Syn th esis of a High ly Hin d er ed
Hyd r in d a n on e via r-Ca r bon yl Ra d ica l
Cycliza tion : En a n tiosp ecific F or m a l
Syn th eses of (-)-P in gu isen ol a n d
(-)-r-P in gu isen e
Chin-Kang Sha,* Hau-Wei Liao, Ping-Chang Cheng, and
Shih-Chieh Yen
Department of Chemistry, National Tsing Hua University,
Hsinchu 300, Taiwan, ROC
cksha@mx.nthu.edu.tw
Received J uly 12, 2003
As a continuation of our work on R-carbonyl radical
cyclization,9 we envisaged an application of our method
toward an enantiospecific synthesis of Schinzer’s ketone
3 from (R)-(+)-pulegone. The racemic form of 3 is the key
intermediate in the total synthesis of racemic pinguisenol
(1) and R-pinguisene (2) by Schinzer7 and Srikrishna.8
The retrosynthetic analysis is outlined in Scheme 1.
Schinzer’s ketone 3 might be obtained from ketone 4 by
a 1,3-carbonyl transposition. Ketone 4 might be obtained
from 5 by an R-carbonyl radical cyclization9 followed by
desilylation and hydrogenation. The radical precursor,
iodo ketone 5, would be prepared according to our
method9a from (4R)-(+)-2,3,4-trimethylcyclohexenone (6),
which can be readily synthesized from (R)-(+)-pulegone
(7).10
Abstr a ct: An enantiospecific synthesis of Schinzer’s ketone
3 from (R)-(+)-pulegone via R-carbonyl radical cyclization
was accomplished. This work also constitutes an enantiospe-
cific formal syntheses of (-)-pinguisenol and (-)-R-pin-
guisene. The intermediate ketone 4 would be useful for the
synthesis of other pinguisane-type sesquiterpenes.
The Porella species of liverworts produce various
terpenoids including a large group of pinguisane-type
sesquiterpenes.1 These liverworts show a broad spectrum
of biological activity including allergenic contact derma-
titis,2 anticancer,3 antimicrobial,4 and antifeedant activi-
ties.5 The pinguisanoids, such as (-)-pinguisenol (1) and
(-)-R-pinguisene (2),6 have a unique carbon skeleton
incorporating two vicinal quaternary carbon atoms and
four methyl groups on four contiguous carbon atoms
orientated in an all-cis fashion. Because of this highly
hindered hydrindanone structure, the pinguisane class
of natural products has attracted much attention from
synthetic chemists. Schinzer used a propargylsilane-
terminated cyclization in the key step for the total
synthesis of racemic pinguisenol (1) and R-pinguisene
(2).7 Srikrishna employed an ortho ester Claisen rear-
rangement followed by intramolecular diazo ketone cy-
clopropanation for the total syntheses of racemic 1, 2,
(+)-2, and the analogues.8
(R)-(+)-Pulegone (7)11 was first treated with lithium
cyclohexylisopropylamide and then iodomethane12 to give
a single diastereomer 8. Reaction of 8 with methyllithium
afforded 9. Ozonolysis of the double bond in 9 gave
compound 10. Dehydration of 10 with pTSA gave chiral
enone 6, [R]24D +53.6.10a CuI-mediated conjugate addition
of 4-(trimethylsilyl)-3-butynylmagnesium chloride (11) to
enone 6, followed by trapping the resulting enolate with
chlorotrimethylsilane, yielded trimethylsilyl enol ether
12. Without purification, crude 12 was treated with a
mixture of NaI and m-CPBA to afford unstable iodo
ketone 5. Treatment of iodo ketone 5 with a benzene
solution of tributyltin hydride and AIBN with a syringe
pump at 65 °C during 6 h afforded the expected cycliza-
tion product 13 (Scheme 2).
(7) (a) Schinzer, D.; Ringe, K.; J onse, P. G.; Doring, D. Tetrahedron
Lett. 1995, 36, 4051. (b) Schinzer, D.; Ringe, K. Tetrahedron 1996, 52,
7475
(8) (a) Srikrishna, A.; Vijaykumar, D. J . Chem. Soc., Perkin Trans.
1 1997, 3295. (b) Srikrishna, A.; Vijaykumar, D. J . Chem. Soc., Perkin
Trans. 1 1999, 1265. (c) Srikrishna, A.; Vijaykumar, D. Tetrahedron
Lett. 1998, 39, 4901.
(9) (a) Sha, C.-K.; Yang, J .-J .; J ean, T.-S. J . Org. Chem. 1987, 52,
3919. (b) Sha, C.-K.; J ean, T.-S.; Wang, D.-C. Tetrahedron Lett. 1990,
31, 3745. (c) Sha, C.-K.; Shen, C.-Y.; J ean, T.-S.; Chiu, R.-T.; Tseng,
W.-H. Tetrahedron Lett. 1993, 34, 7641. (d) Sha, C.-K.; Chiu, R.-T.;
Yang, C.-F.; Yao, N.-T.; Tseng, W.-H.; Liao, F.-L. and Wang, S.-L. J .
Am. Chem. Soc. 1997, 119, 4130.
(10) (a) For the synthesis of enantiopure 6, see: Dudley, G. B.;
Takaki, K. S.; Cha, D. D.; Danheiser, R. L. Org. Lett. 2000, 2, 3407.
(b) For the synthesis of racemic 6, see: Cory, R. M.; Buton, L. P. J .;
Chan, D. M.; Mclaren, F. R.; Rastall, M. H.; Renenboog, R. M. Can. J .
Chem. 1984, 62, 1908.
(1) Asakawa, Y. In Progress in the Chemistry of Organic Natural
Products; Herz, W.; Kirby, G. W.; Moore, R. E.; Steglich, W.; Tamm,
Ch., Eds.; Springer: Wien, New York, 1995; Vol .65, p 1.
(2) Asakawa, Y.; Muller, J . C.; Ourisson, G.; Foussereau, J .; Du-
combs, G. Bull. Soc. Chim. Fr. 1976, 1465.
(3) Belkin, M.; Fitzgerald, D.; Felix, M. D. J . Nation. Cancer 1952-
53, 13, 741.
(4) (a) McCleary, J . A.; Walkington, D. A. Rev. Briol. Lichenol 1966,
34, 309. (b) Wolters, B. Planta 1964, 62, 88.
(5) Wada, K.; Munakata, K. Agr. Biol. Chem. 1971, 35, 115.
(6) (a) Asakawa, Y.; Toyota, M.; Aratani, T. Tetrahedron Lett. 1976,
3691. (b) Asakawa, Y.; Toyota, M.; Takemoto, T. Phytochemistry 1978,
17, 457. (c) We found that the name R-pinquisene or â-pinquisene was
used for the same natural product in the refs 2-5.
(11) (+)-(R)-Pulegone, purchased from Aldrich, was distilled. HPLC
analysis with a chiral column indicates that it has 92% ee.
(12) Zair, T.; Santelli-Rouvier, C.; Santelli, M. J . Org. Chem. 1993,
58, 2686
10.1021/jo035008g CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/09/2003
8704
J . Org. Chem. 2003, 68, 8704-8707

SCHEME 2
SCHEME 3
151 mmol) in THF (80 mL) was added n-BuLi (1.85 M, 76.6 mL)
dropwise at 0 °C. After being stirred for 30 min, the reaction
mixture was cooled to -78 °C. To this solution was added
dropwise (R)-(+)-pulegone (7) (21.3 mL, 131 mmol). After the
mixture was stirred for 60 min at -78 °C, CH3I (25.8 mL, 414
mmol) was added. The reaction mixture was allowed to warm
to room temperature and stirred for 30 min. The reaction
mixture was then cooled to 0 °C. Saturated NaHCO3 solution
(60 mL) was added. The reaction mixture was extracted with
Et2O (30 mL × 3). The combined organic layer was washed with
saturated NaHCO3 solution and brine and dried with MgSO4.
Filtration and concentration gave crude product 8 (19.6 g). This
crude product 8 (19.6 g) was dissolved in dry THF (50 mL). To
this solution was added CH3Li (2 M, 59 mL) dropwise at -78
°C. After the mixture was stirred for 1 h, water (30 mL) and
Et2O (30 mL) were added. The organic layer was separated and
washed with saturated NaHCO3 solution and brine and dried
with MgSO4. Concentration and flash column chromatography
(SiO2, EtOAc/hexane ) 1:35) afforded 9 as colorless liquid (16.1
g, 68%): 1H NMR (300 MHz, CDCl3) δ 2.59-2.50 (m, 1 H), 1.95
(s, 3 H), 1.91-1.73 (m, 2 H), 1.62, (s, 3 H), 1.64-1.52 (m, 1 H),
1.35-0.95 (m, 2 H), 1.15 (s, 3 H), 0.92 (d, 3 H, J ) 6.5 Hz), 0.86
(d, 3 H, J ) 6.3 Hz); 13C NMR (75 MHz, CDCl3) δ 137.4 (C),
123.8 (C), 77.3 (C), 51.1 (CH), 35.7 (CH), 34.1 (CH2), 27.8 (CH2),
23.3 (CH3), 22.2 (CH3), 21.0 (CH3), 20.7 (CH3),12.6 (CH3); IR
(neat) 3476, 2923, 1455, 1374 cm-1; MS (EI) m/z 182 (M+, 4),
Desilylation of compound 13 with trifluoroacetic acid
afforded ketone 14. Hydrogenation of 14 in methanol
using palladium on carbon as catalyst furnished ketone
4 as a single isomer with all-cis-methyl groups (Scheme
3). Compound 4 was then converted into tosylhydrazone
15. Treatment of 15 with n-butyllithium gave compound
16. Subsequent allylic oxidation13 of 16 with chromium
trioxide in the presence of 3,5-dimethylpyrazole gave
enone 17. Reduction of the conjugate double bond in 17
by catalytic hydrogenation afforded Schinzer’s ketone 3,
[R]24 +28.4.14 All spectral data of 3 are in good agree-
D
ment with those reported in the literature.7,8
In summary, enantiospecific synthesis of the highly
hindered hydrindanone 3 has been accomplished employ-
ing the R-carbonyl radical cyclization as the key step.
Because racemic 3 has been converted into (()-pinguise-
nol (1) and (()-R-pinguisene (2),7,8 this work also consti-
tutes a formal enantiospecific synthesis of (-)-1 and (-)-
2. In addition, intermediate 4 might be useful for the
synthesis of other natural products of the pinguisane
family, such as deoxopinguisone 1815 and pinguisanene
19.16 Total synthesis of 18 and 19 using 4 as the key
intermediate is under current investigation.
165 (100), 137 (20), 109 (67); HRMS (EI) m/z calcd for C12H22
O
182.1671, found 182.1664; [R]24 +61.0 (c 1.00, CHCl3).
D
(3R,4R)-2-Hyd r oxy-2,3,4-tr im eth ylcycloh exa n -1-on e (10).
To a solution of compound 9 (10.0 g, 55.5 mol) in CH2Cl2 (60
mL) was bubbled with O3 at -78 °C until the blue color
appeared. The reaction was followed by thin-layer chromatog-
raphy. When the starting material was consumed, the reaction
mixture was bubbled with N2 for 10 min, and then (CH3)2S (4.1
mL) was added. The cooling bath was removed. The reaction
mixture was allowed to warm to room temperature and stirred
for 12 h. Concentration and flash column chromatography (SiO2,
EtOAc/hexane ) 1:25) gave 10 as a colorless liquid (6.5 g, 76%):
1H NMR (300 MHz, CDCl3) δ 3.94 (s, 1 H), 2.65-2.53 (m, 1 H),
Exp er im en ta l Section
(2S,3R)-1,2,3-Tr im eth yl-6-(1-m eth yleth ylid en e)cycloh ex-
a n -1-ol (9). To a solution of isopropylcyclohexylamine (25.5 mL,
(13) Mateos, A. F.; Barrueco, O. F.; Gonzalea, R. R. Tetrahedron Lett.
1990, 31, 4343.
(15) Krutov, S. M.; Samek, Z.; Benesova, V.; Herout, V. Phytochem-
istry 1973, 12, 1405.
(16) Asakawa, Y.; Suire, C.; Toyota, M.; Togunoga, N.; Takemoto,
T.; Hattori, S.; Mitzutani, M. J . Hattori Bat. Lab. 1980, 46, 77.
(14) HPLC analysis of 4 with a chiral column shows that it has 83%
ee. The antipod (-)-3, [R]24 -38, was synthesized by Srikrishna et
D
al.4
J . Org. Chem, Vol. 68, No. 22, 2003 8705

2.43-2.36 (m, 1 H), 2.01-1.92 (m, 1 H), 1.66-1.53 (m, 1 H),
1.40-1.25 (m, 2 H), 1.19 (s, 3 H), 1.02 (d, 3 H, J ) 6.8 Hz), 0.91
(d, 3 H, J ) 6.4 Hz); 13C NMR (75 MHz, CDCl3) δ 214.6 (C),
77.9 (C), 50.7 (CH), 36.8 (CH2), 35.2 (CH), 35.0 (CH), 19.8 (CH3),
19.0 (CH3), 12.4 (CH3); IR (neat) 3484, 1714, 1455, 1376, 1143,
1039 cm-1; MS (EI) m/z 155 (M - 1+, 3), 126 (29), 111(22), 69
(26), 55 (37), 43 (100); HRMS (EI) m/z calcd for C9H16O2
solution of 5a ,b (1.7 g, 4.4 mmol) in benzene (267 mL) at 65 °C
was added a solution of Bu3SnH (1.4 mL, 5.3 mmol) and AIBN
(90 mg, 0.5 mmol) in benzene (80 mL) with a syringe pump
during 6 h. The reaction mixture was heated at reflux further
for 2 h and then cooled to room temperature. Benzene was
removed with a rotary evaporator. Et2O (25 mL) and saturated
KF solution (25 mL) were added. The mixture was stirred for
18 h. Concentration and column chromatography (SiO2, EtOAc/
hexane ) 1:50) gave 13a (355 mg, 30%) and 13b (560 mg, 48%)
as yellow liquids. Data for 13a : 1H NMR (300 MHz, CDCl3) δ
5.32 (t, 1 H, J ) 2.1 Hz), 2.89-2.66 (m, 2 H), 2.58-2.49 (m, 1
H), 2.16 (dt, 1 H, J ) 12.3, 3.1 Hz), 1.94-1.69 (m, 3 H), 1.61-
1.44 (m, 2 H), 1.06 (s, 3 H), 0.88 (d, 3 H, J ) 6.6 Hz), 0.73 (s, 3
H), 0 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 214.2 (C), 167.5 (C),
121.8 (C), 64.4 (C), 56.7 (C), 40.5 (CH2), 35.0 (CH2), 34.3 (CH),
33.1 (CH2), 32.7 (CH2), 19.1 (CH3), 16.6 (CH3), 13.8 (CH3), 0.9
(CH3); IR (neat) 2956, 1703, 1606, 1247, 842 cm-1; MS (EI) m/z
264 (M+, 18), 249 (28), 211 (100), 175 (12), 73 (89); HRMS (EI)
m/z calcd for C16H28OSi 264.1909, found 264.1919. Data for
13b: 1H NMR (300 MHz, CDCl3) δ 5.00 (t, 1 H, J ) 2.5 Hz),
2.66-2.52 (m, 2 H), 2.48 (dt, 1 H, J ) 9.9, 2.2 Hz), 2.18-2.11
(m, 2 H), 1.89-1.67 (m, 3 H), 1.61-1.48 (m, 2 H), 1.02 (s, 3 H),
0.91 (d, 3 H, J ) 6.8 Hz), 0.78 (s, 3 H), 0.03 (s, 3 H); 13C NMR
(75 MHz, CDCl3) δ 214.0 (C), 166.7 (C), 120.2 (CH), 66.6 (C),
52.7 (C), 38.7 (CH2), 34.3 (CH2), 34.0 (CH), 30.8 (CH2), 29.3
(CH2), 20.2 (CH3), 16.7 (CH3), 14.2 (CH3), -0.6 (CH3); IR (neat)
1702, 1614, 1247, 1012, 880, 840 cm-1; MS (EI) m/z 264 (M+,
14), 249 (71), 222 (30), 211 (77), 175 (100), 73 (55); HRMS (EI)
m/z calcd for C16H28OSi 264.1909, found 264.1902.
(3a S,7R,7a S)-3a ,7,7a -Tr im eth yl-3-m eth ylen ep er h yd r o-4-
in d en on e (14). To a solution of 13a ,b (444 mg, 1.68 mmol) in
CH2Cl2 (10 mL) was added CF3CO2H (0.39 mL, 5.08 mmol)
dropwise at 0 °C. The reaction mixture was stirred for 3 h. NaOH
solution (2 N) was added to neutralize the reaction mixture. The
aqueous layer was separated and extracted with CH2Cl2 (10 mL
× 3). The combined CH2Cl2 layer was dried with MgSO4.
Concentration and column chromatography (SiO2, EtOAc/hexane
) 1:30) gave 14 (310 mg, 96%) as a pale yellow liquid: 1H NMR
(400 MHz, CDCl3) δ 4.81 (t, J ) 2.0 Hz, 1 H), 4.55 (t, J ) 2.8
Hz, 1 H), 2.69-2.61 (m, 1 H), 2.61-2.43 (m, 1 H), 2.22-2.14
(m, 2 H), 1.91-1.89 (m, 2 H), 1.89-1.68 (m, 1 H), 1.68-1.48 (m,
2 H), 1.06 (s, 3 H), 0.91 (d, J ) 6.4, 3 H), 0.79 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ 213.8 (C), 158.0 (C), 106.8 (CH2), 63.8 (C),
53.4 (C), 38.2 (CH2), 33.7 (CH), 33.7 (CH2), 30.7 (CH2), 28.9
(CH2), 20.0 (CH3), 16.5 (CH3), 14.0 (CH3); IR (neat) 1701, 1424,
1386, 887 cm-1; MS (EI) m/z 192 (M+, 14), 135 (32), 121 (22.4),
93 (100); HRMS (EI) m/z calcd for C13H20O 192.1514, found
192.1510.
(3R,3a S,7R,7a S)-3,3a ,7,7a -Tetr a m a th ylp er h yd r o-4-in d e-
n on e (4). To a solution of 14 (100 mg, 0.52 mmol) in MeOH (20
mL) was added 5% Pd on carbon (250 mg). The mixture was
bubbled with H2 gas at room temperature. The reaction was
followed by thin-layer chromatography until the starting mate-
rial 14 was fully consumed. Concentration and column chroma-
tography (SiO2, EtOAc/hexane ) 1:50) gave 4 as a colorless liquid
(104 mg, 82%): 1H NMR (400 MHz, CDCl3) δ 2.81-2.58 (m, 2
H), 2.2-2.18 (m, 1 H), 2.18-1.9 (m, 2 H), 1.82-1.77 (m, 2 H),
1.62-1.48 (m, 1 H), 1.48-1.23 (m, 2 H), 0.90 (d, J ) 6.4, 3 H),
0.853 (s, 3 H), 0.782 (s, 3 H), 0.771 (d, J ) 8.0 Hz, 3 H); 13C
NMR (125 MHz, CDCl3) δ 216.4 (C), 61.5 (C), 54.2 (C), 41.0 (CH),
37.6 (CH2), 35.7 (CH2), 34.2 (CH), 31.3 (CH2), 30.8 (CH2), 16.74
(CH3), 16.70 (CH3), 14.78 (CH3), 11.70 (CH2); IR (neat) 2957,
1699, 1455, 1380 cm-1; MS (EI) m/z 194 (M+, 8), 179 (43), 161
(26), 137 (40), 123 (31), 109 (75); HRMS (EI) m/z calcd for
C13H22O 194.1671, found 194.1674; [R]23D +74.5 (c 1.00, CHCl3).
N′1-[(3R,3a S,7R,7a S)-3,3a ,7,7a -Tetr a m eth ylp er h yd r o-4-
in d en ylid en e]-4-m eth yl-1-ben zen esu lfon oh yd r a zid e (15).
T o a solution of 4 (83 mg, 0.43 mmol) in MeOH (30 mL) were
added NH2NHTs (160 mg, 0.86 mmol) and concentrated HCl
(0.05 mL). The reaction mixture was heated at reflux for 2 h.
After the mixture was cooled to room temperature, concentration
and column chromatography (SiO2, EtOAc/hexane ) 1:5) gave
15 as a colorless liquid (142 mg, 91%): 1H NMR (400 MHz,
CDCl3) δ 7.83 (d, J ) 8.4 Hz, 2 H), 7.27 (d, J ) 8.0 Hz, 2 H),
156.1150, found 156.1155; [R]24 +44.1 (c 1.00, CHCl3).
D
(4R)-2,3,4-Tr im eth yl-2-cycloh exen -1-on e (6). To a solution
of 10 (3.3 g, 21 mmol) in benzene (100 mL) was added pTSA‚
7H2O (4.1 g, 21.4 mmol). The reaction mixture was heated with
a Dean-Stark apparatus for 12 h. After the mixture was cooled
to room temperature, Et2O (50 mL) was added. The organic layer
was filtered through Celite, washed with saturated NaHCO3
solution and brine, and then dried with MgSO4. Concentration
and flash column chromatography (SiO2, EtOAc/hexane ) 1:30)
gave 6 as a colorless liquid (2.0 g, 68%): 1H NMR (400 MHz,
CDCl3) δ 2.51-2.43 (m, 1 H), 2.38-2.34 (m, 1 H), 2.31-2.24 (m,
1 H), 2.10-2.01 (m, 1 H), 1.87 (s, 3 H), 1.70 (s, 3 H), 1.68-1.64
(m, 1 H), 1.14 (d, 3 H, J ) 7.1 Hz); 13C NMR (100 Mz, CDCl3) δ
198.7 (C), 159.1 (C), 130.4 (C), 35.6 (CH), 34.0 (CH2), 29.4 (CH2),
19.7 (CH3), 12.7 (CH3), 11.0 (CH3); IR (neat) 2932, 1666, 1376,
1309, 1085 cm-1; MS (EI) m/z 138 (M+, 10), 109 (100), 111 (22),
81 (17), 43 (68); HRMS (EI) m/z calcd for C9H14O 138.1045, found
138.1050; [R]24 +53.6 (c 0.72, CHCl3).
D
(3S,4R)-2-Iod o-2,3,4-tr im eth yl-3-[4-(1,1,1-tr im eth ylsilyl)-
3-bu tyn yl]cycloh exa n -1-on e (5a ,b). To a suspension of Mg
turnings (1.46 g, 60.75 mmol) in THF (5 mL) was added 1,2-
dibromoethane (0.01 mL). The reaction mixture was heated to
reflux, and then a solution of 1,2-dibromoethane (0.5 mL) and
4-chloro-1-trimethylsilyl-1-butyne (4.9 g, 30.3 mmol) in THF (15
mL) was added dropwise. The reaction mixture was heated at
reflux for 2 h and then cooled to -78 °C. CuI (3.52 g, 18.2 mmol)
was added. After the mixture was stirred for 30 min, HMPA
(0.3 mL, 1.8 mmol) was added. The reaction mixture was stirred
for 10 min. A solution of compound 6 (1.7 g, 12.1 mmol) and
TMSCl (3.8 mL, 30 mmol) in THF (3 mL) was added dropwise
at -78 °C. After the mixture was stirred for 30 min, Et3N (4.22
mL, 30 mmol) was added. The reaction mixture was allowed to
warm to room temperature and stirred for 18 h. Hexane (50 mL)
was added. The organic layer was washed with saturated
NaHCO3 solution and brine and dried with MgSO4. Concentra-
tion gave crude product 12 (3.59 g, 92%). Crude 12 was used for
the next step without purification. To a solution of crude product
12 (3.59 g) and NaI (4.87 g, 32.8 mmol) in THF (60 mL) was
added a solution of m-CPBA (85% purity, 5.60 g, 32.5 mmol) in
THF (83 mL) dropwise at 0 °C. After the mixture was stirred at
0 °C for 2 h, Et2O (8 mL) was added. The organic layer was
washed with saturated NaHCO3 solution (10 mL × 3), Na2S2O3
solution (10 mL × 3), and brine (10 mL) and dried with MgSO4.
Concentration and column chromatography (SiO2, EtOAc/hexane
) 1:60 and 1:55) gave 5a (Rf ) 0.80, 1.17 g, 28%) and 5b (Rf )
0.76, 2.08 g, 50%) as yellow liquids. Data for 5a : 1H NMR (300
MHz, CDCl3) δ 2.94-2.79 (m, 2 H), 2.68-2.59 (m, 1 H), 2.18-
2.12 (m, 1 H), 1.92-1.83 (m, 2 H), 1.75-1.66 (m, 1 H), 1.58-
1.47 (m, 2 H), 1.09 (s, 3 H), 0.85 (d, 3 H, J ) 6.5 Hz), 0.67 (s, 3
H), 0.19 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 213.2 (C), 167.0
(C), 112.0 (C), 66.2 (C), 60.8 (C), 47.4 (CH2), 40.0 (CH2), 34.8-
(CH2), 34.2 (CH), 33.0 (CH2), 18.3 (CH3), 16.3 (CH3), 13.5 (CH3),
2.7 (CH3); IR (neat) 1705, 1316, 1250, 1158, 860 cm-1; MS (EI)
m/z 390 (M+, 0.1), 375 (5), 263 (57), 191 (73); HRMS (EI) m/z
calcd for C15H24OISi (M+ - CH3) 375.0719, found 375.0636. Data
for 5b: 1H NMR (300 MHz, CDCl3) 2.92-2.84 (m, 1 H), 2.77-
2.67 (m, 1 H), 2.54-2.45 (m, 1 H), 2.38-2.32 (m, 1 H), 1.99-
1.92 (m, 1 H), 1.85-1.78 (m, 2 H), 1.67-1.55 (m, 2 H), 1.16 (s,
3 H), 0.86 (d, 3 H, J ) 6.5 Hz), 0.68 (s, 3 H), 0.24 (s, 9 H); 13C
NMR (75 MHz, CDCl3) δ 213.9 (C), 165.4 (C), 101.0 (C), 70.6
(C), 56.4 (C), 42.0 (CH2), 35.3 (CH2), 34.4 (CH), 33.6 (CH2), 33.2
(CH2), 16.2 (CH3), 15.2 (CH3), 12.9 (CH3), 1.2 (CH3); IR (neat)
2969, 1704, 1249, 840 cm-1; MS (EI) m/z 390 (M+, 0.1), 375 (3),
263 (41), 185 (42), 161 (78); HRMS (EI) m/z calcd for C15H24
-
OISi (M+ - CH3) 375.0719, found 375.0640.
(3a S,7R,7a S)-3a ,7,7a -Tr im eth yl-3-[(E,Z)-1-(1,1,1-tr im eth -
ylsilyl) m eth ylid en e]p er h yd r o-4-in d en on e (13a ,b). To a
8706 J . Org. Chem., Vol. 68, No. 22, 2003

2.56-2.41 (m, 1 H), 2.40 (s, 3 H), 2.39-2.20 (m, 1 H), 2.00-1.54
(m, 6 H), 1.43-1.15 (m, 3 H), 0.804 (d, J ) 4.4 Hz, 3 H), 0.66 (s,
3 H), 034 (d, J ) 6.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ
163.95 (C), 143.24 (C), 134.82 (C), 128.78 (CH), 127.91(CH), 54.57
(C), 50.72 (C), 39.327 (CH), 34.48 (CH2), 33.31 (CH), 29.65 (CH2),
29.23 (CH2), 22.51 (CH2), 21.18 (CH3), 16.46 (CH3), 14.24 (CH3),
13.48 (CH3), 13.01 (CH3); IR (neat) 3211, 2963, 2873, 1598, 1292,
1165 cm-1; MS (EI) m/z 362 (M+, 7), 347 (18), 207 (96), 177 (100),
163 (54); HRMS (EI) m/z calcd for C20H30O2N2S 362.2028, found
362.2026.
(1R ,3a S ,4R ,7a R )-1,3a ,4,7a -Te t r a m e t h yl-2,3,3a ,4,5,7a -
h exa h yd r o-1H-in d en e (16). To a solution of 15 (142 mg, 0.39
mmol) in hexane (10 mL) was added TMEDA (1 mL) at 0 °C.
After the mixture was stirred for 10 min, n-BuLi (1.8 M, 0.5
mL) was added dropwise at 0 °C. The reaction was allowed to
warm to room temperature and stirred for 6 h. After the mixture
was cooled to 0 °C, water (10 mL) and hexane (20 mL) were
added. The aqueous layer was separated and washed with
hexane (10 mL × 3). The combined organic layer was washed
with saturated NaHCO3 solution and brine and dried with
MgSO4. Concentration and column chromatography (SiO2, hex-
ane) gave 16 as a colorless liquid (48 mg, 69%): 1H NMR (400
MHz, CDCl3) δ 5.53-5.41 (m, 2 H), 2.20-2.00 (m, 1 H), 1.97-
1.60 (m, 3 H), 1.40-1.10 (m, 4 H), 0.85 (d, J ) 6.4 Hz, 6 H), 0.72
(s, 3 H), 0.71 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 135.44 (CH),
123.74 (CH), 47.64 (C), 45.049 (C), 43.74 (CH), 33.66 (CH2), 32.50
(CH), 31.95 (CH2), 30.05 (CH2), 16.78 (CH3), 16.00 (CH3), 15.20
(CH3), 14.99 (CH3); IR (neat) 3014, 2958, 1465, 1374, 994, 708
cm-1; MS (EI) m/z 178 (M+, 10), 163 (18), 121 (70), 107 (100),
105 (27); HRMS (EI) m/z calcd for C13H22 178.1721, found
178.1719.
(SiO2, EtOAc/hexane ) 1:20) gave 17 as a colorless liquid (35
mg, 66%): 1H NMR (400 MHz, CDCl3) δ 6.48 (d, J ) 10.4 Hz, 1
H), 5.85 (d, J ) 10 Hz, 1 H), 2.70 (q, J ) 6.4 Hz, 1 H), 2.58-2.40
(m, 1 H), 2.04-1.84 (m, 1 H), 1.83-1.76 (m, 1 H), 1.55-1.30 (m,
2 H), 1.04 (d, J ) 6.4 Hz, 3 H), 0.96 (d, J ) 6.8 Hz, 3 H), 0.89 (s,
3 H), 0.78 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 202 (C), 154.6
(CH), 126.3 (CH), 53.28 (C), 48.75 (C), 46.4 (CH), 41.5 (CH), 33.7
(CH2), 30.4 (CH2), 16.7 (CH3), 16.4 (CH3), 15.4 (CH3), 8.5 (CH3);
IR (neat) 1681, 1450, 1377, 1209, 1117, 827, 751 cm-1; MS (EI)
m/z 192 (M+, 26), 177 (25), 164 (63), 149 (30), 135 (62), 93 (62);
HRMS (EI) m/z calcd for C13H20O 192.1514, found 192.1512.
(1R,3a S,4S,7a S)-1,3a ,4,7a -Tetr a m a th ylp er h yd r o-5-in d e-
n on e (3). To a solution of 17 (35 mg, 0.18 mmol) in MeOH (15
mL) was added 5% Pd on carbon (250 mg). The solution was
bubbled with H2 gas at room temperature. The reaction was
followed by thin-layer chromatography until 17 was fully
consumed. Concentration and column chromatography (SiO2,
EtOAc/hexane ) 1:60) gave 3 as a colorless liquid (30 mg, 88%):
1H NMR (400 MHz, CDCl3) δ 2.60 (q, J ) 6.8 Hz, 1 H), 2.54-
2.38 (m, 2 H), 2.20-2.12 (m, 1 H), 1.97-1.80 (m, 2 H), 1.80-
1.45 (m, 2 H), 1.42∼1.35 (m, 1 H), 0.96 (d, J ) 6.8 Hz, 3 H), 0.93
(d, J ) 6.4 Hz, 3 H), 0.75 (s, 3 H), 0.70 (s, 3 H); 13C NMR (100
MHz, CDCl3) δ 214.4 (C), 53.0 (C), 48.3 (CH), 45.5 (C), 37.4 (CH2),
37.4 (CH), 35.3 (CH2), 32.3 (CH2), 29.6 (CH2), 18.3 (CH3), 16.5
(CH3), 14.8 (CH3), 8.7 (CH3); IR (neat) 1713, 1457, 1379, 1138,
1010 cm-1; MS (EI) m/z 194 (M+, 15), 179 (25), 123 (50), 109
(100), 93 (39), 91 (36), 67 (34); HRMS (EI) m/z calcd for C13H22
O
194.1671, found 194.1669; [R]23 +28.4 (c 0.20, CHCl3).
D
Ack n ow led gm en t. We thank the National Science
Council of Republic of China for financial support.
(1R ,3a S ,4S ,7a S )-1,3a ,4,7a -Te t r a m a t h yl-2,3,3a ,4,5,7a -
h exa h yd r o-1H-5-in d en on e (17). To a solution of 16 (48 mg,
0.27 mmol) in CH2Cl2 (10 mL) were added CrO3 (560 mg, 5.6
mmol) and 3,5-dimethylpyrazole (538 mg, 5.6 mmol). The
reaction was followed by thin-layer chromatography until 16 was
fully consumed. Florisil (3 g) was then added. The mixture was
stirred for 15 min. Concentration and column chromatography
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra of compounds 3-6, 9, 10, and 13-17. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O035008G
J . Org. Chem, Vol. 68, No. 22, 2003 8707