α-Carbonyl Radical Cyclization Approach toward Angular Triquinanes: Total Synthesis of Enantiomerically Pure (-)-5-Oxosilphiperfol-6-ene

Article abstract of DOI:10.1021/jo9723570

An α-carbonyl radical cyclization approach toward synthesis of angular triquinanes is described. As a model study, conjugate addition of 4-(trimethylsilyl)-3-butynylmagnesium chloride to enone 7 followed by trapping of the enolate with chlorotrimethylsilane gave trimethysilyl enol ether 8. Iodination of 8 with a mixture of NaI and m-CPBA afforded iodo ketone 6. Radical cyclization of 6 effected by Bu₃SnH and AIBN gave 5. Epoxidation of 5 with m-CPBA yielded epoxy ketone 9. Desilylation and rearrangement of 9 by formic acid gave aldehyde 4. Aldol condensation and dehydration furnished angular triquinane skeleton 3. Total synthesis of (-)-5-oxosilphiperfol-6-ene (1) was accomplished in 12 steps starting from keto ester 14 based on this route. Conjugate addition of 3-hexynylmagnesium bromide to chiral ester 13 followed by treatment with chlorotrimethylsilane gave intermediate 15. Iodination of 15 with a mixture of NaI and m-CPBA gave α-iodo ester 12. Intramolecular radical cyclization of 12 gave ester 11. Reduction of 11 by LiAlH₄ yielded alcohol 16. On treatment with m-CPBA, alcohol 16 was converted to the corresponding epoxide 17, which was subjected to the epoxy-ketone rearrangement using BF₃ etherate as a catalyst to give ethyl ketone 18. Subsequent oxidation of 18 with PCC afforded aldehyde 10. Intramolecular aldol condensation of 10 yielded tricyclic compound 19. Methylation of 19 gave 20. Conjugate addition of lithium dimethylcuprate to 20 followed by trapping of the resulting enolate with chlorotrimethylsilane gave 21. Oxidation of 21 by DDQ afforded enantiomerically pure (-)-5-oxosilphiperfol-6-ene (1). Racemic (±)-1 was also synthesized in the same manner in order to determine the optical purity of chiral product (-)-1. The gas chromatographic analysis with a chiral column proved that 1 has high enantiomeric purity. A single-crystal X-ray analysis of 2,4-dinitrophenylhydrazone 22 was performed to unambiguously confirm the stereochemistry of 19.

Full text of DOI:10.1021/jo9723570

J . Org. Chem. 1998, 63, 2699-2704
2699
r-Ca r bon yl Ra d ica l Cycliza tion Ap p r oa ch tow a r d An gu la r
Tr iqu in a n es: Tota l Syn th esis of En a n tiom er ica lly P u r e
(-)-5-Oxosilp h ip er fol-6-en e
Chin-Kang Sha,* K. C. Santhosh, and Shin-Hong Lih
Department of Chemistry, National Tsing Hua University Hsinchu 300, Taiwan, R. O. C.
Received December 31, 1997
An R-carbonyl radical cyclization approach toward synthesis of angular triquinanes is described.
As a model study, conjugate addition of 4-(trimethylsilyl)-3-butynylmagnesium chloride to enone 7
followed by trapping of the enolate with chlorotrimethylsilane gave trimethysilyl enol ether 8.
Iodination of 8 with a mixture of NaI and m-CPBA afforded iodo ketone 6. Radical cyclization of
6 effected by Bu3SnH and AIBN gave 5. Epoxidation of 5 with m-CPBA yielded epoxy ketone 9.
Desilylation and rearrangement of 9 by formic acid gave aldehyde 4. Aldol condensation and
dehydration furnished angular triquinane skeleton 3. Total synthesis of (-)-5-oxosilphiperfol-6-
ene (1) was accomplished in 12 steps starting from keto ester 14 based on this route. Conjugate
addition of 3-hexynylmagnesium bromide to chiral ester 13 followed by treatment with chlorotri-
methylsilane gave intermediate 15. Iodination of 15 with a mixture of NaI and m-CPBA gave
R-iodo ester 12. Intramolecular radical cyclization of 12 gave ester 11. Reduction of 11 by LiAlH4
yielded alcohol 16. On treatment with m-CPBA, alcohol 16 was converted to the corresponding
epoxide 17, which was subjected to the epoxy-ketone rearrangement using BF3 etherate as a
catalyst to give ethyl ketone 18. Subsequent oxidation of 18 with PCC afforded aldehyde 10.
Intramolecular aldol condensation of 10 yielded tricyclic compound 19. Methylation of 19 gave
20. Conjugate addition of lithium dimethylcuprate to 20 followed by trapping of the resulting enolate
with chlorotrimethylsilane gave 21. Oxidation of 21 by DDQ afforded enantiomerically pure (-)-
5-oxosilphiperfol-6-ene (1). Racemic (()-1 was also synthesized in the same manner in order to
determine the optical purity of chiral product (-)-1. The gas chromatographic analysis with a
chiral column proved that 1 has high enantiomeric purity. A single-crystal X-ray analysis of 2,4-
dinitrophenylhydrazone 22 was performed to unambiguously confirm the stereochemistry of 19.
In tr od u ction
6-ene (1) and silphiperfol-6-ene (2) have also appeared.4
5-Oxosilphiperfol-6-ene (1) and silphiperfol-6-ene (2),
isolated from the stem of Espeletiopsis guacharaca1a and
the root of Silphium perfoliatum,1b are structurally
related angular triquinanes. This class of natural prod-
ucts with the multiply fused five-membered ring skeleton
has been a challenging target for total synthesis. Various
approaches toward the total syntheses of triquinanes
have been reported.2 Particularly, free radical cycliza-
tions are among the most effective methodologies for the
synthesis of angular and linear triquinanes.3 A few
elegant total and formal syntheses of 5-oxosilphiperfol-
We have recently reported R-carbonyl radical cyclization
reactions and their applications toward total syntheses
of natural products such as (()-modhephene and (-)-
dendrobine.5 As a continuation of our study in this area,
we here report the application of R-carbonyl radical
(1) (a) Bohlmann, F.; Suding, H.; Cuatrecasas, J .; Robinson, H.;
King. R. M. Phytochemistry 1980, 19, 2399. (b) Bohlmann, F.; J ak-
upovic, J . Phytochemistry 1980, 19, 259.
(2) (a) Paquette, L. A.; Doherty, A. M. Polyquinane Chemistry.
Reactivity and Structure Concepts in Organic Chemistry;
Springer-Verlag: Berlin, 1989; Vol 26. (b) Trost, B. M. Chem. Soc. Rev.
1982, 11, 141. (c) Paquette, L. A. Top. Curr. Chem. 1984, 110, 1. (d)
Hudlicky, T. In Studies in Natural Products Chemistry; Rahman, A.,
Ed.; Stereoselective Synthesis (part B); Elsevier: New York, 1989; Vol
3, pp 3-72. (e) Mehta, G.; Srikrishna, A. Chem. Rev. 1997, 97, 671.
(3) For radical cyclization approaches to triquinanes, see: (a)
Beckwith, A. L. J .; Roberts, D. H.; Schiesser, C. H.; Wallner, A.
Tetrahedron Lett. 1985, 26, 3349. (b) Curran, D. P.; Kuo, S.-C.
Tetrahedron 1987, 43, 5653. (c) Curran, D. P.; Rakiewicz, D. M. J . Am.
Chem. Soc. 1985, 107, 1448. (d) Winkler, J . D.; Sridar, V. J . Am. Chem.
Soc. 1986, 108, 1708. (e) Meyers, A. I.; Lefker, B. A. Tetrahedron 1987,
43, 5663. (f) Little, R. D.; Muller, G. W.; Venegas, M. G.; Carrol. G. L.;
Bukhari, A.; Patton, L.; Stone, K. Tetrahedron 1981, 37, 4371. (g)
Schwartz, C. E.; Curran, D. P. J . Am. Chem. Soc. 1990, 112, 9272. (h)
Hollingworth, G. J .; Pattenden, G.; Schultz, D. J .; Aust. J . Chem. 1995,
48, 381.
(4) Earlier reports on the total synthesis of 1: (a) Demuth, M.;
Hinsken, W. Helv. Chim. Acta 1988, 71, 569. (b) Kakiuchi, K.; Ue, M.;
Tsukahara, H.; Shimisu, T.; Miyao, T.; Tobe, Y.; Odaira, Y.; Yasuda,
M.; Shima, K. J . Am. Chem. Soc. 1989, 111, 3707. For total synthesis
of the closely related natural product silphiperfol-6-ene see: ref 2b and
(c) Paquette, L. A.; Roberts, R. A.; Drtina, G. J . J . Am. Chem. Soc.
1984, 106, 6690. (d) Curran, D. P.; Kuo, S.-C. J . Am. Chem. Soc. 1986,
108, 1106. (e) Dickson, J . K., J r.; Fraser-Reid, B. J . Chem. Soc. Chem.
Commun. 1990, 1440. (f) Vo, N. H.; Snider, B. B. J . Org. Chem. 1994,
59, 5419. (g) Wender, P. A.; Singh, S. K. Tetrahedron Lett. 1985, 26,
5987. (h) Wender, P. A.; Ternansky, R.; deLong, M.; Singh, S.; Olivero,
A.; Rice, K. Pure Appl. Chem. 1990, 62, 1597. (i) Demuth, M.; Hinsken,
W. Angew. Chem., Int. Ed., Engl. 1985, 24, 973.
(5) (a) Sha, C.-K.; J ean, T.-S.; Wang, D.-C. Tetrahedron Lett. 1990,
31, 3745. (b) Sha, C.-K.; Shen, C.-Y.; J ean, T.-S.; Chiu, R.-T.; Tseng,
W.-H. Tetrahedron Lett. 1993, 34, 7641. (c) Sha, C.-K.; Chiu, R.-T.;
Yang, C.-F.; Yao, N.-T.; Tseng, W,-H.; Liao, F.-L.; Wang, S.-L. J . Am.
Chem. Soc. 1997, 119, 4130.
S0022-3263(97)02357-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/25/1998

2700 J . Org. Chem., Vol. 63, No. 8, 1998
Sha et al.
Sch em e 1
Sch em e 3
Sch em e 2
synthetic analysis is shown in Scheme 3. The key step
would be the radical cyclization of 12, which would give
cis-fused bicyclic intermediate 11. Compound 11 could
be readily transformed into 10 in a few steps. Aldol
condensation of 10 would afford an angular triquinane
skeleton, which could be converted to (-)-1 by further
transformations. The starting material ethyl (4R)-4-
methyl-2-oxocyclohexane-1-carboxylate was prepared from
(R)-pulegone by the method of Djerassi.9 Compound 14
was treated with tert-butyl hypochlorite in methanol
followed by heating with Na2CO3 and glass powder in
xylene to give chiral ester 13 according to the method of
Takeda.10 Copper(I) iodide-mediated conjugate addition
of 3-hexynylmagnesium bromide to 13 followed by trap-
ping of the resulting enolate with chlorotrimethylsilane
gave ketene acetal 15 (Scheme 4). Without isolation, the
crude product 15 was immediately treated with a mixture
of NaI and m-CPBA in THF to afford R-iodo ester 12 (60%
from 13). Radical cyclization of 12 effected by syringe
pump addition of a solution of tributyltin hydride and
AIBN in benzene at reflux yielded ester 11 (73%, geo-
metrical isomers 3:1). Reduction of 11 with LiAlH4
afforded alcohol 16 (80%). Compound 16 was epoxidized
with m-CPBA to give epoxide 17. The crude product 17
was subjected to an epoxy-ketone rearrangement using
1 equiv of boron triflouride etherate to give 18 (57% from
16). Oxidation of keto alcohol 18 with pyridinium
chlorochromate furnished aldehyde 10. Aldol condensa-
tion of 10 with 5% KOH8 produced enone 19 (70% from
18). Enone 19 was subjected to alkylation with lithium
diisopropylamide and iodomethane to give enone 20
(82%). Conjugate addition of lithium dimethylcuprate to
20 followed by trapping of the resulting enolate with
chlorotrimethylsilane gave the trimethylsilyl enol ether
21. We assumed that the oxidation of 21 to 1 using Pd-
(OAc)2 would be a straightforward reaction. To our
surprise this reaction did not furnish the desired product.
Finally, we carried out the oxidation of 21 with freshly
recrystallized 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) in the presence of N,O-bis(trimethylsilyl)-2,2,2-
trifluoroacetamide (BSTFA)4a to afford (-)-5-oxosilphip-
erfol-6-ene (1) (38% from 20). All spectral data of
synthetic (-)-1 were found to be in good agreement11 with
those reported in the literature.1a,4a However, our syn-
cyclization toward a general synthesis of angular
triquinanes as well as a total synthesis of enantiomeri-
cally pure (-)-5-oxosilphiperfol-6-ene (1).
Resu lts a n d Discu ssion
The retro-synthetic analysis of angular triquinane
skeleton 3 based on R-carbonyl radical cyclization is
outlined in Scheme 1. Radical cyclization of R-iodo
ketone 6 would afford cis-fused bicyclic intermediate 5.
Compound 5 could be coverted to aldehyde 4 by epoxi-
dation and acid-catalyzed rearrangement. The third ring
would be annulated by aldol condensation of 4 to give
angular triquinane skeleton 3.
Copper(I) iodide-mediated conjugate addition of 4-(tri-
methylsilyl)-3-butynylmagnesium chloride to enone 76
followed by trapping of the resulting enolate with chlo-
rotrimethylsilane gave trimethylsilyl enol ether 8 (Scheme
2). Treatment of 8 with NaI and m-CPBA afforded iodo
ketone 6.7 Radical cyclization of 6 was effected by
tributyltin hydride and AIBN by syringe pump addition
to yield 5 as a mixture of geometrical isomers (4:1) with
a cis ring juncture. The major isomer of 5 was isolated
by silica gel chromatography and was epoxidized with
m-CPBA to give epoxide 9. Exposure of 9 with formic
acid resulted in desilylation and rearrangement to afford
aldehyde 4. The final ring closure was carried out by
the aldol condensation of 4 with 5% KOH8 followed by
dehydration, which gave enone 3 in low yield (26% from
9). However, attempts to improve the yield of enone 3
were futile.
thetic (-)-1 exhibited higher specific rotation {[R]D
)
Therefore we devised another synthetic route for the
total synthesis of enantiomerically pure (-)-1. The retro-
(9) Djerassi, C.; Burakevich, J .; Chamberlin, J . W.; Elad, D.; Toda,
T.; Stork, G. J . Am. Chem. Soc. 1964, 86, 465.
(10) Takeda, A.; Shinhama, K.; Tsuboi, S. Bull. Chem. Soc. J pn.
1977, 50, 1831.
(6) Hudlicky, T.; Srnak, T. Tetrahedron Lett. 1981, 22, 3351.
(7) Sha, C.-K.; Young, J .-J .; J ean, T.-S. J . Org. Chem. 1987, 52, 3919.
(8) Paquette, L. A.; Stevens, K. E. Tetrahedron Lett. 1981, 22, 4393.
(11) 1H and 13C NMR, IR, and MS of 1 are in good agreement with
those spectra received from Professor M. Demuth.

Total Synthesis of (-)-5-Oxosilphiperfol-6-ene
J . Org. Chem., Vol. 63, No. 8, 1998 2701
Sch em e 4
F igu r e 1. Analysis of the optical purity of (-)-1 by gas
chromatography with a chiral column (SGE 25QC2/CYDEX-B
0.25; temperature, 125 °C isothermal). Gas chromatogram of
(a) enantiomerically pure (-)-1, (b) racemic (()-1, (c) 1:1
mixture of (-)-1 and (()-1.
F igu r e 2. Molecular drawing of 2,4-dinitrophenylhydrazone
22 generated by SHELXTL PLUS.
-82.2 (c ) 1.3)} in comparison to the literature values
{[R]D ) -40 (c ) 1.3),1a [R]D ) -39.5 (c ) 0.34)4a}.
To check the enantiomeric purity of our product, we
also synthesized racemic (()-1 starting from racemic (()-
14 by the same route. The gas chromatographic analysis
of the enantiomerically pure (-)-1, racemic (()-1, and the
1:1 mixture of (-)-1 and (()-1 with a chiral column is
shown in Figure 1. The result confirmed that our product
is of high enantiomeric purity (>99%). Furthermore, to
unambiguously establish the absolute stereochemistry of
our product, we tried to synthesize a crystalline deriva-
tive of (-)-1 for X-ray analysis. However, we were not
successful in making the crystalline derivative of (-)-1,
but we did finally synthesize 2,4-dinitrophenylhydrazone
22 from 19, whose single-crystal X-ray analysis is shown
in Figure 2. The crystal structure drawing of 22 clearly
verifies the relative and absolute configuration of all the
stereogenic centers in compound 19. These results and
all the spectral data confirmed the structure and optical
purity of (-)-1.
Con clu sion
We have developed a general method toward the total
synthesis of angular triquinanes based on an R-carbonyl
radical cyclization reaction, and a total synthesis of
enantiomerically pure (-)-5-oxosilphiperfol-6-ene (1) has
been accomplished. Gas chromatography analysis of
racemic (()-1 and (-)-1 with a chiral column clearly
demonstrated that our product has high optical purity.

2702 J . Org. Chem., Vol. 63, No. 8, 1998
Sha et al.
J ) 12.0 Hz, J ) 7.6 Hz, 1 H), 2.37-2.54 (m, 2 H), 2.68-2.74
(m, 1 H), 5.29 (t, J ) 2.0 Hz, 1 H); 13C NMR (CDCl3, 100.6
MHz) δ -0.5, 25.7, 26.0, 31.7, 33.5, 33.6, 36.4, 47.4, 74.3, 121.0,
165.5, 208.8; IR (neat) 1700, 1615 cm-1; MS (EI) m/z 236 (M+,
47), 221 (100), 193 (37), 73 (44); HRMS calcd for C14H24OSi
236.1596, found 236.1589.
The single-crystal X-ray analysis of 22 provided ad-
ditional evidence for the absolute stereochemistry of our
chiral product (-)-1. This method is potentially useful
for the total synthesis of more complex angular triquinanes
and related natural products.
1-{(3a S*,6a R*)-3-[1-(Tr im et h ylsilyl)-1,2-ep oxym et h -
ylid en e]p er h yd r o-3-p en t a len yl}-1-et h a n on e (9). To a
solution of the major isomer of 5 (132 mg, 0.56 mmol) in
dichloromethane (8 mL) was added a solution of m-CPBA (106
mg, 0.62 mmol) in CH2Cl2 (5 mL) dropwise at 0 °C. The
reaction mixture was allowed to warm to room temperature
and stirred for 3 h. After washing with saturated NaHCO3
solution, the organic layer was dried (MgSO4). Concentration
and silica gel chromatography (hexanes-ethyl acetate, 10:1)
gave a mixture of two diastereomers, 9, as a colorless liquid
(106 mg, 76%): 1H NMR (CDCl3, 400 MHz) δ 0.07 (s), 0.12 (s,
4.5 H), 1.18-1.29 (m, 1 H), 1.34-1.43 (m, 1 H), 1.48-1.72 (m,
5.5 H), 1.87-2.26 (m, 3 H), 2.10 (s, 1.5 H), 2.15 (s, 1.5 H), 2.40-
2.47 (m, 0.5 H), 2.61-2.68 (m, 0.5 H), 2.84 (q, J ) 6.8 Hz, 0.5
H); 13C NMR (CDCl3, 100.6 MHz) δ -2.4, -2.2, 26.3, 26.6, 26.7,
27.7, 29.0, 30.6, 30.7, 31.2, 33.5, 33.6, 34.4, 34.7, 46.9, 48.5,
52.3, 52.9, 69.2, 69.9, 70.0, 73.6, 207.3, 210.1; IR (neat) 1730,
1701, 1250 cm-1; MS (El), m/z 252 (M+, 2), 209 (100), 193 (11),
119 (27), 91 (25), 73 (59); HRMS calcd for C14H24O2Si 252.1545,
found 252.1556.
Exp er im en ta l Section
Gen er a l Meth od . Melting points were determined with
an open capillary tube and were uncorrected. 1H NMR spectra
were recorded in CDCl3 solution at 300 or 400 MHz. 13C NMR
were recorded at 100.6 MHz. Mass spectra were recorded by
electron impact (70 eV) or FAB ionization. IR spectra were
recorded on an FT-IR spectrometer using NaCl film with neat
samples. Optical rotations were measured at room tempera-
ture (25 °C) on a J ASCO DIP-360 polarimeter. Single-crystal
X-ray analysis was performed on a Siemens SMART CCD
diffractometer. Gas chromatographic analysis was performed
with a chiral column (SGE 25QC2/CYDEX-B 0.25).
1-{(2R*)-1-Iod o-2-[4-(t r im et h ylsilyl)-3-b u t yn yl]cyclo-
p en tyl}-1-eth a n on e (6). To magnesium turnings (336 mg,
13.8 mmol) in THF (2 mL) was added 1,2-dibromoethane (0.01
mL). The mixture was heated to reflux. To this mixture were
added 4-chloro-1-trimethylsilyl-1-butyne (1.14 g, 7.12 mmol)
and 1,2-dibromoethane (0.1 mL) in THF (10 mL) by a syringe
pump (0.1 mL/min). After the addition, the reaction mixture
was heated to reflux for an additional hour and cooled to -78
°C. CuI (1.34 g, 7.04 mmol) was added and the reaction
mixture was stirred for 30 min. To this mixture was added 7
(313 mg, 2.85 mmol) in THF (8 mL) dropwise, followed by
chlorotrimethylsilane (0.43 mL, 3.40 mmol) and triethylamine
(0.4 mL, 2.89 mmol). The reaction mixture was allowed to
warm to room temperature and stirred for 12 h. After
filtration, the reaction mixture was washed with saturated
Na2CO3 solution and brine and then dried (MgSO4). Filtration
and concentration gave crude product 8 (205 mg). The crude
product was not purified and used for the next step.
To a solution of 8 (195 mg) and NaI (110 mg, 0.73 mmol) in
anhydrous THF (10 mL) was added m-CPBA (134 mg, 0.77
mmol) in THF (4 mL) dropwise at 0 °C. After warming to room
temperature, the reaction mixture was stirred for 30 min and
then diluted with ether (10 mL). The solution was washed
with water, saturated Na2S2O3, saturated Na2CO3, and brine.
The organic solution was dried (MgSO4). Concentration and
silica gel chromatography (hexanes-ethyl acetate, 20:1) af-
forded a yellow liquid 6 (125 mg, 74% from 7): 1H NMR
(CDCl3, 400 MHz) δ 0.09 and 0.10 (2s, 9 H), 1.16-1.50 (m, 3
H), 1.65-1.81 (m, 2 H), 1.89-2.03 (m, 2 H), 2.07-2.43 (m, 4
H), 2.47 and 2.55 (2s, 3 H); 13C NMR (CDCl3, 100.6 MHz) δ
0.05, 0.10, 18.2, 18.7, 20.5, 21.2, 26.5, 26.7, 28.1, 28.3, 29.4,
37.1, 38.1, 42.1, 47.0, 51.0, 65.0, 68.5, 84.6, 85.6, 105.8, 107.0,
202.69, 202.74; IR (neat) 2173, 1700, 1696 cm-1; MS (FAB)
m/z 363 (M+ + H, 30), 347 (23), 147 (100); HRMS (FAB) calcd
for C14H23IOSi (M+ + H) 363.0643, found 363.0637.
1-{(3a S*,6a R*)-3-[(E)- or -(Z)-1-(Tr im eth ylsilyl)m eth -
ylid en e]p er h yd r o-3-p en ta len yl}-1-eth a n on e (5). A solu-
tion of 6 (821 mg, 2.27 mmol) in benzene (113 mL) was heated
to reflux. To this refluxing solution was added a solution of
tributyltin hydride (0.67 mL, 2.49 mmol) and AIBN (19 mg,
0.12 mmol) in benzene (31 mL) by a syringe pump over a period
of 6 h. The reaction mixture was then refluxed for an
additional hour and cooled to room temperature. After
concentration, the residue was dissolved in Et2O (20 mL). To
the Et2O solution was added saturated KF solution (10 mL)
and the mixture stirred for 2 h. The organic layer was
separated and the aqueous layer was extracted again by ether
(20 mL × 2). The combined organic layer was washed with
saturated NaHCO3 solution and brine. The solution was then
dried (MgSO4). Concentration and silica gel chromatography
(hexanes-ethyl acetate, 10:1) gave 5 (48 mg, ratio of isomers
) 4:1, 81%). The major isomer was separated and purified
by silica gel chromatography. Data for the major isomer: 1H
NMR (CDCl3, 400 MHz) δ 0.06 (s, 9 H), 1.34-1.63 (m, 5 H),
1.69-1.78 (m, 1 H), 1.98-2.07 (m, 1 H), 2.06 (s, 3 H), 2.3 (dt,
(3a S*,5a R*,8a S*)-1,3a ,4,5,5a ,6,7,8-Octa h yd r ocyclop en -
ta [c]p en ta len -1-on e (3). To compound 9 (91 mg, 0.37 mmol)
was added formic acid (98%, 2.2 mL). The reaction mixture
was stirred for 50 min and then diluted with Et2O (20 mL).
The organic layer was washed with saturated NaHCO3 solu-
tion and dried (MgSO4). Concentration gave crude product 4
(63 mg).
To a mixture of 5% KOH (5 mL), Bu4NOH (0.2 mL), and
THF (10 mL) were added a solution of 4 (63 mg) in Et2O (5
mL). The reaction mixture was heated to reflux for 16 h. After
cooling to room temperature, the reaction mixture was poured
into water (5 mL). The resulting mixture was extracted with
Et2O (10 mL × 2). The organic layer was dried (MgSO4).
Concentration and silica gel chromatography (hexanes-ethyl
acetate, 7:1) afforded 3 as a colorless liquid (15 mg, 26% from
9): 1H NMR (CDCl3, 400 MHz) δ 1.31-1.34 (m, 1 H), 1.49-
1.58 (m, 2 H), 1.59-1.63 (m, 2 H), 1.68-1.77 (m, 2 H), 1.88-
1.94 (m, 2 H), 2.01-2.08 (m, 1 H), 2.33-2.36 (m, 1 H), 2.88-
2.91 (m, 1 H), 6.09 (dd, J ) 5.6 Hz, J ) 1.3 Hz, 1 H), 7.41 (dd,
J ) 5.6 Hz, J ) 2.6 Hz, 1 H); 13C NMR (CDCl3, 100.6 MHz) δ
27.9, 28.1, 30.2, 33.2, 35.7, 50.1, 56.1, 65.9, 133.4, 165.8, 214.7;
MS (EI) m/z 162 (M+, 50), 12 (100); HRMS calcd for C11H14
O
162.1045, found 162.1052.
Eth yl (3R)-3-Meth yl-1-cyclopen ten e-1-car boxylate (13).
To a solution of 14 (6.59 g, 35.8 mmol) in methanol (53 mL)
was added t-BuOCl (4.6 mL, 40.7 mmol) dropwise in a salt-
ice bath. The mixture was stirred for 1 h and kept in the
refrigerator at 0 °C for 40 h. After warming to room temper-
ature, the mixture was stirred for additional 4 h. Concentra-
tion and distillation under reduced pressure (0.06 mmHg, 60
°C) yielded a colorless liquid (7.7 g). This liquid (7.7 g, 35.2
mmol) was dissolved in xylene (53 mL). To this solution were
added anhydrous Na2CO3 (8.3 g) and glass powder (32 g). The
reaction mixture was heated to reflux for 40 h. Filtration,
concentration and silica gel chromatography (hexanes-ethyl
acetate, 20:1) gave 13 as a colorless liquid (4.38 g, 81%): 1H
NMR (CDCl3, 400 MHz) δ 1.06 (d, J ) 6.4 Hz, 3 H), 1.26 (t, J
) 7.2 Hz, 3 H), 1.40-1.49 (m, 1 H), 2.10-2.20 (m, 1 H), 2.44-
2.53 (m, 1 H), 2.55-2.64 (m, 1 H), 2.82-2.92 (m, 1 H), 4.16 (q,
J ) 7.2 Hz, 2 H), 6.62 (q, J ) 2.2 Hz, 1 H); 13C NMR (CDCl3,
100.6 MHz) δ 14.2, 19.8, 30.9, 31.9, 40.6, 60.0, 135.4, 148.6,
165.6; MS (EI) m/z 154 (M+, 8), 139 (2), 125 (4), 109 (19), 81
(100); [R]D ) 101.2 (c ) 1.1, CHCl3).
Eth yl (2S,3R)-2-(3-Hexyn yl)-1-iod o-3-m eth ylcyclop en -
ta n e-1-ca r boxyla te (12). To a suspension of magnesium
powder (110 mg, 4.52 mmol) in THF (6 mL) was added 1,2-
dibromoethane (0.01 mL). The mixture was stirred at room
temperature for 20 min and then cooled to 0 °C. To this
mixture was added 1-bromo-3-hexyne (365 mg, 2.22 mmol) in

Total Synthesis of (-)-5-Oxosilphiperfol-6-ene
J . Org. Chem., Vol. 63, No. 8, 1998 2703
THF (1 mL) over a period of 3 h by a syringe pump and the
mixture was stirred for an additional 30 min. The mixture
was cooled to -78 °C and CuI (108 mg, 0.56 mmol) was added.
After stirring for 30 min, compound 13 (100 mg, 0.65 mmol)
in THF (1 mL) was added dropwise followed by chlorotrim-
ethylsilane (0.14 mL, 0.67 mmol) and triethylamine (0.18 mL,
1.3 mmol). The mixture was allowed to warm to room
temperature and stirred for 12 h. This reaction mixture was
added dropwise to a solution of NaI (446 mg, 2.98 mmol) and
m-CPBA (87%, 589 mg, 2.97 mmol) in THF (14 mL) at 0 °C.
After warming to room temperature, the mixture was stirred
for 2 h and then diluted with Et2O (20 mL). The mixture was
washed with water, saturated Na2S2O3 solution, saturated
NaHCO3 solution, and brine and dried (MgSO4). Concentra-
tion and silica gel chromatography (hexanes-ethyl acetate,
40:1) gave 12 (142 mg, 60%) as a mixture of two diastereo-
mers: 1H NMR (CDCl3, 400 MHz) δ 0.81-0.93 (m, 1 H), 1.03-
1.17 (m, 5 H), 1.21-1.39 (m, 4 H), 1.50-1.58 (m, 1 H), 1.69-
2.01 (m, 3 H), 2.06-2.29 (m, 6 H), 2.34-2.39 (m, 1 H), 4.13-
4.20 (m, 2 H); 13C NMR (CDCl3, 100.6 MHz) δ 12.3, 13.7, 13.8,
14.2, 14.3, 17.2, 17.7, 20.7, 21.9, 31.50, 31.7, 33.0, 37.8, 38.3,
39.0, 42.6, 42.6, 48.2, 55.0, 58.8, 59.6, 61.7, 61.8, 78.6, 79.0,
81.8, 82.2, 171.5, 172.0; IR (neat) 1724, 1246 cm-1; MS (FAB)
m/z 363 (M+ + H, 28), 289 (36), 235 (100), 161 (83); HRMS
(FAB) calcd for C15H23IO2 363.0823 (M+ + H), found 363.0840.
Eth yl (1R,3a S,6a S)-1-Meth yl-4-[(E)-p r op ylid en e]p er -
h yd r o-3a -p en ta len e-ca r boxyla te a n d Eth yl (1R,3a S,6a S)-
1-Meth yl-4-[(Z)-p r op ylid en e]p er h yd r o-3a -p en ta len eca r -
boxyla te (11). A solution of 12 (89 mg, 0.25 mmol) in benzene
(13 mL) was heated to reflux. To this solution was added
slowly Bu3SnH (0.08 mL, 0.29 mmol) and AIBN (4.6 mg, 0.03
mmol) in benzene (3.6 mL) by a syringe pump over a period of
6 h. The mixture was refluxed for an additional hour. After
cooling to room temperature, benzene was removed under
reduced pressure. The residue obtained was dissolved in Et2O
(8 mL) and saturated KF solution was added. The mixture
was stirred at room temperature for 2 h. After filtration, the
filtrate was extracted with Et2O (5 mL × 2). The combined
organic layer was washed with saturated NaHCO3 solution
and brine and dried (MgSO4). Concentration and silica gel
chromatography (hexanes-ethyl acetate, 40:1) gave 11 as a
colorless liquid (42 mg, 73%). Compound 11 was found to be
a mixture of geometrical isomers (3:1): 1H NMR (CDCl3, 400
MHz) δ 0.86 (t, J ) 7.4 Hz, 2.25 H), 0.90 (t, J ) 7.4 Hz, 0.75
H), 0.94 (d, J ) 6.6 Hz, 0.75 H), 0.95 (d, J ) 6.6 Hz, 2.25 H),
1.16-1.30 (m, 0.75 H), 1.19 (t, J ) 6.8 Hz, 0.75 H), 1.20 (t, J
) 6.8 Hz, 2.25 H), 1.41-2.07 (m, 8 H), 2.21-2.64 (m, 3 H),
2.76 (ddd, J ) 13.0 Hz, J ) 7.2 Hz, J ) 2.2 Hz, 0.75 H), 4.03-
4.16 (m, 2 H), 5.14 (tt, J ) 7.2 Hz, J ) 1.8 Hz, 0.75 H), 5.24
(tt, J ) 7.2 Hz, J ) 2.4 Hz, 0.25 H); 13C NMR (CDCl3, 100.6
MHz) δ 13.9, 14.0, 14.1, 14.9, 18.7, 19.2, 22.4, 22.9, 28.5, 28.9,
33.6, 34.7, 34.9, 36.0, 36.2, 36.9, 40.46, 40.54, 57.7, 60.2, 60.3,
61.7, 61.8, 64.0, 123.6, 124.0, 147.3, 147.4, 172.6, 177.4; IR
(neat) 1724, 1242 cm-1; MS (EI) m/z 236 (M+, 15), 208 (4), 163
(100); HRMS calcd for C15H24O2 236.1776, found 236.1777.
{(1R,3a S,6a S)-1-Meth yl-4-[(E)-p r op ylid en e]p er h yd r o-
3-p en t a len yl}m et h a n ol a n d {(1R ,3a S,6a S)-1-Met h yl-4-
[(Z)-p r op ylid en e]p er h yd r o-3-p en ta len yl}m eth a n ol (16).
To a suspension of LiAlH4 (30 mg, 0.79 mmol) in Et2O (5 mL)
was added a solution of 11 (130 mg, 0.55 mmol) in Et2O (2
mL). The mixture was heated to reflux for 3 h. After cooling
to room temperature, the reaction mixture was quenched with
5% HCl solution (3 mL). The mixture was extracted with Et2O
(5 mL × 2). The organic layer was washed with brine and
dried (MgSO4). Concentration and silica gel chromatography
(hexanes-ethyl acetate, 5:1) gave 16 as a colorless liquid (86
mg, 80%). Compound 16 was found to be a mixture of E and
Z isomers: 1H NMR (CDCl3, 400 MHz) δ 0.92 (t, J ) 7.4 Hz,
2.25 H), 0.93 (t, J ) 7.4 Hz, 0.75 H), 0.95 (d, J ) 6.8 Hz, 0.75
H), 0.96 (d, J ) 6.8 Hz, 2.25 H), 1.14-1.26 (m, 1 H), 1.36-
1.44 (m, 1 H), 1.49-1.92 (m, 7 H), 1.97-2.08 (m, 2 H), 2.25-
2.47 (m, 2 H), 3.44 (AB, J ) 10.6 Hz, 1.5 H), 3.63 (AB, J )
10.6 Hz, 0.5 H), 5.14 (tt, J ) 7.2 Hz, J ) 2.4 Hz, 0.25 H), 5.26
(tt, J ) 7.6 Hz, J ) 2.0 Hz, 0.75 H); 13C NMR (CDCl3, 100.6
MHz) δ 14.4, 14.8, 18.9, 19.2, 22.2, 22.9, 27.9, 28.0, 28.8, 35.0,
35.2, 35.5, 36.1, 36.4, 40.5, 41.0, 56.0, 58.7, 59.0, 59.7, 69.15,
69.19, 123.1, 124.6, 147.5, 148.5; IR (neat) 3350 cm-1; MS (EI)
m/z 194 (M+, 3), 176 (8), 163 (75), 147 (15), 57 (100); HRMS
calcd for C13H22O 194.1671, found 194.1676.
1-[(3aS,4R,6aS)-6a-(Hydr oxym eth yl)-4-m eth ylper h ydr o-
1-p en ta len yl]-1-p r op a n on e (18). To a solution of 16 (42 mg,
0.22 mmol) in CH2Cl2 (4 mL) was added m-CPBA (87%, 85
mg, 0.43 mmol) in CH2Cl2 (1 mL) at 0 °C. The mixture was
allowed to warm to room temperature and stirred for 4 h. After
being washed with saturated NaHCO3 solution, the organic
layer was dried (MgSO4). Concentration gave crude epoxide
17 (96 mg). To a solution of 17 (96 mg) in benzene (2 mL)
was added BF3‚OEt2 (0.06 mL, 0.49 mmol) at room tempera-
ture. The reaction mixture was stirred for 30 min and then
washed with saturated NaHCO3 and dried (MgSO4). Concen-
tration and silica gel chromatography (hexanes-ethyl acetate,
3:1) gave 18 as a yellowish liquid (26 mg, 57%): 1H NMR
(CDCl3, 400 MHz) δ 0.88-1.12 (m, 1 H), 0.94 (d, J ) 6.8 Hz,
3 H), 0.98 (t, J ) 7.4 Hz, 3 H), 1.36-1.42 (m, 2 H), 1.44-1.56
(m, 2 H), 1.63-1.66 (m, 1 H), 1.72-1.76 (m, 1 H), 1.86-1.93
(m, 3 H), 2.40-2.62 (m, 3 H), 3.34 (ABd, J ) 10.6 Hz, J ) 3.2
Hz, 1 H), 3.54 (ABd, J ) 10.6 Hz, J ) 6.4 Hz, 1 H), 3.72-3.75
(m, 1 H); 13C NMR (CDCl3, 100.6 MHz) δ 7.3, 19.1, 27.9, 29.1,
31.9, 34.4, 35.9, 42.3, 55.7, 57.9, 60.2, 70.1, 215.5; IR (neat)
3417, 1695 cm-1; MS (EI) m/z 210 (M+, 2), 192 (12), 163 (20),
135 (100); HRMS calcd for C13H22O2 210.1620, found 210.1631.
(3a R,5a S,6R,8a S)-2,6-Dim eth yl-3,3a ,4,5,5a ,6,7,8-octa h y-
d r ocyclop en ta [c]p en ta len -3-on e (19). To a mixture of PCC
(630 mg, 2.92 mmol) and a small amount of Celite (0.5 g) in
CH2Cl2 (20 mL) was added 18 (309 mg, 1.46 mmol) in CH2Cl2
(3.5 mL) at 0 °C. The mixture was allowed to warm to room
temperature and stirred for 4 h. Filtration through a short
column of Florisil and concentration gave 10 as a colorless
liquid (279 mg). Without further purification, compound 10
was used for the next step.
To a mixture of 5% aqueous KOH (20 mL), Bu4NOH (0.02
mL), and THF (40 mL) was added 10 (279 mg) in Et2O (20
mL) dropwise. The mixture was heated to reflux for 16 h.
After cooling to room temperature, the reaction mixture was
poured into water (20 mL). The mixture was extracted with
Et2O (30 mL × 3). The combined organic layer was washed
with brine and dried (MgSO4). Concentration and silica gel
chromatography (hexanes-ethyl acetate, 10:1) gave 19 as a
colorless liquid (198 mg, 70%): 1H NMR (CDCl3, 400 MHz) δ
0.94 (d, J ) 6.4 Hz, 3 H), 1.19-1.39 (m, 2 H), 1.46-1.51 (m, 1
H), 1.55-1.72 (m, 3 H), 1.67 (d, J ) 1.6 Hz, 3 H), 1.77-1.97
(m, 4 H), 2.22-2.25 (m, 1 H), 7.05 (q, J ) 1.6 Hz, 1 H); 13C
NMR (CDCl3, 100.6 MHz) δ 9.9, 20.0, 27.85, 27.88, 35.4, 35.9,
39.4, 56.9, 59.1, 62.0, 138.6, 164.9, 213.1; IR (neat) 1702, 1634
cm-1; MS (EI) m/z 190 (M+, 100), 175 (16), 162 (36), 135 (68),
108 (78); HRMS calcd for C13H18O 190.1358, found 190.1367;
[R]D ) -72.8 (c ) 0.52, CHCl3).
Din itr op h en ylh yd r a zon e (22). To 2,4-dinitrophenylhy-
drazine (125 mg) suspended in CH3OH (5 mL) was added
concentrated H2SO4 (0.3 mL). To this solution was added a
solution of 19 (50 mg, 0.026 mmol) in methanol (2 mL) and
the reaction mixture was heated to 60 °C. The orange
precipitate formed was filtered and washed with aqueous CH3-
OH. The crude product was recrystallized (EtOH) to yield 22
(82 mg, 84%) as orange needles: mp ) 127-128 °C; 1H NMR
(CDCl3, 400 MHz) δ 0.98 (d, J ) 6.4 Hz, 3 H), 1.15-1.20 (m,
1 H), 1.60-1.90 (m, 8 H), 1.92 (d, J ) 2 Hz, 3 H), 2.11-2.40
(m, 2 H), 3.82 (d, J ) 9.6 Hz, 1 H), 6.29 (br, 1 H), 7.94 (d, J )
10.4 Hz, 1 H), 8.26 (d, J ) 10.4 Hz, 1 H), 9.03 (s, 1 H), 11.13
(s, 1 H); 13C NMR (CDCl3, 100.6 MHz) δ 11.0, 19.7, 27.5, 29.8,
34.7, 36.5, 39.0, 51.8, 57.8, 66.9, 116.2, 123.6, 129.8, 136.0,
137.3, 144.9, 152.0, 169.8; IR (KBr) 3308, 1621, 1591 cm-1
;
MS (EI) m/z 370 (M+, 39), 319 (100), 318 (36), 228 (18), 226
(3); HRMS calcd for C19H22O4N4 370.1641, found 370.1658
(3a R,5a S,6R,8a S)-2,3a ,6-Tr im eth yl-3,3a ,4,5,5a ,6,7,8-oc-
ta h yd r ocyclop en ta [c]p en ta len -3-on e (20) To a solution of
diisopropylamine (0.25 mL, 1.78 mmol) in THF (3 mL) was
added n-BuLi (2.1 M in hexane, 0.74 mL, 1.55 mmol) at -20
°C. After warming to 0 °C, the mixture was stirred for 30 min
and then was cooled to -78 °C. To this solution was added

2704 J . Org. Chem., Vol. 63, No. 8, 1998
Sha et al.
compound 19 (97.0 mg, 0.51 mmol) in THF (0.5 mL) dropwise.
The mixture was allowed to warm to 0 °C and was stirred for
1 h at 0 °C. The mixture was cooled to -78 °C again and CH3I
(0.09 mL, 1.45 mmol) was added. The mixture was allowed
to warm to room temperature and stirred for 1 h. A saturated
solution of NH4Cl (2 mL) was added to quench the reaction.
The mixture was extracted with Et2O (10 mL × 2). The ether
layer was washed with brine and dried (MgSO4). Concentra-
tion and silica gel chromatography (hexanes-ethyl acetate,
10:1) gave 20 as a colorless liquid (76 mg, 82%) along with
some unreacted 19 (9 mg, 9%). Data for 20: 1H NMR (CDCl3,
400 MHz) δ 0.96 (d, J ) 6.4 Hz, 3 H), 0.98 (s, 3 H), 1.21-1.49
(m, 4 H), 1.57-1.68 (m, 2 H), 1.71 (d, J ) 1.4 Hz, 3 H), 1.73-
1.84 (m, 2 H), 1.95-2.00 (m, 1 H), 7.02 (q, J ) 1.4 Hz, 1 H);
13C NMR (CDCl3, 100.6 MHz) δ 10.0, 19.4, 20.8, 26.2, 30.6,
35.4, 36.1, 39.2, 57.7, 58.5, 64.1, 136.4, 165.1, 215.7; IR (neat)
1700, 1637 cm-1; MS (EI) m/z 204 (M+, 100), 189 (37), 176 (24),
135 (26); HRMS calcd for C14H20O 204.1514, found 204.1519;
[R]D ) -38.2 (c ) 1.3, CHCl3).
(-)-5-Oxosilp h ip er fol-6-en e (1). To a solution of CuI (380
mg, 2.0 mmol) in Et2O (16 mL) was added CH3Li (0.9 M in
Et2O, 4.4 mL, 3.96 mmol) dropwise at 0 °C. After stirring for
5 min, compound 20 (61 mg, 0.3 mmol) in Et2O (0.6 mL) and
chlorotrimethylsilane (0.15 mL, 1.19 mmol) were added drop-
wise in sequence. The mixture was stirred at 0 °C for 2 h and
then quenched with saturated NaHCO3 solution (15 mL). The
organic layer was separated and washed with brine and dried
(MgSO4). Concentration gave crude product 21, which was
used for the next step without further purification.
anes-ethyl acetate, 10:1) gave 1 as a colorless solid (25 mg,
38% from 20): mp ) 50-51 °C; 1H NMR (CDCl3, 400 MHz) δ
0.96 (d, J ) 6.0 Hz, 3 H), 0.96 (s, 3 H), 1.08-1.18 (m, 1 H),
1.20-1.44 (m, 3 H), 1.49-1.63 (m, 2 H), 1.62 (q, J ) 1.2 Hz, 3
H), 1.65-1.76 (m, 2 H), 1.81-1.88 (m, 1 H), 1.94 (q, J ) 1.2
Hz, 3 H), 1.95-1.99 (m, 1 H); 13C NMR (CDCl3, 100.6 MHz) δ
8.2, 13.1, 19.0, 21.1, 25.9, 28.7, 35.0, 36.6, 39.4, 57.6, 57.9, 67.1,
133.1, 173.7, 214.2; IR (neat) 1698, 1644 cm-1; MS (EI) m/z
(rel int) 218 (M+, 100), 203 (14), 190 (7), 175 (9), 163 (25), 136
(39); HRMS calcd for C15H22O 218.1671, found 218.1675; [R]D
) -82.2 (c ) 1.3, CHCl3). Gas chromatography of 1 with a
chiral column (SGE 25QC2/CYDEX-B 0.25; temperature, 125
°C isothermal) showed that product 1 is of high enantiomeric
purity (>99%, Figure 1).
Ack n ow led gm en t. Financial support by the Na-
tional Science Council of the Republic of China (NSC
87-2113-M007-043) is gratefully acknowledged. We
thank Professors M. Demuth and L. A. Paquette for
sending us the spectra of 5-oxosilphiperfol-6-ene for
comparison and Professor Sue-Lein Wang and Mrs. Fen-
Ling Liao for the single-crystal X-ray analysis of com-
pound 22.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data and molecular drawing of compound 22, 1H NMR
spectra of 1, 3, 5, 6, 9, 11-13, 16, 18-22, and 13C NMR spectra
of 1, 3, 5, 6, 9, 11-13, 16, 18-20 (37 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
To a solution of 21 (89 mg) and freshly recrystallized DDQ
(118 mg, 0.52 mmol) in benzene (7.5 mL) was added N,O-bis-
(trimethylsilyl)-2,2,2-trifluoroacetamide (BSTFA) (0.2 mL, 0.75
mmol). The mixture was heated to 45 °C and stirred for 48 h.
After cooling to room temperature, the mixture was diluted
with Et2O (15 mL), washed with saturated NaHCO3, and dried
(MgSO4). Concentration and silica gel chromatography (hex-
J O9723570