Cycloaddition of allylsilanes. Part 20: Organosilicon-mediated total synthesis of (±)-cameroonanol

Article abstract of DOI:10.1016/j.tet.2009.01.115

We describe a seven-step total synthesis of the triquinane sesquiterpene (±)-cameroonanol using a Lewis acid-promoted [3+2] cycloaddition of an allylsilane and a modified Fleming-Tamao oxidation as key reactions.

Full text of DOI:10.1016/j.tet.2009.01.115

Tetrahedron 65 (2009) 5484–5490
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cycloaddition of allylsilanes. Part 20: Organosilicon-mediated total
synthesis of (ꢀ)-cameroonanolq
Arndt W. Schmidt, Thomas Olpp, So¨ren Schmid, Anne Ja¨ger, Hans-Joachim Kno¨lker
*
Department Chemie, Technische Universita¨t Dresden, Bergstraße 66, 01069 Dresden, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe a seven-step total synthesis of the triquinane sesquiterpene (ꢀ)-cameroonanol using
a Lewis acid-promoted [3þ2] cycloaddition of an allylsilane and a modified Fleming–Tamao oxidation as
key reactions.
Received 21 January 2009
Received in revised form 30 January 2009
Accepted 31 January 2009
Available online 14 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
The angular triquinanes are a group of structurally related ses-
quiterpenes consisting of three annelated cyclopentanes. Bio-
genetically they derive from farnesyl pyrophosphate 1 (Scheme 1).2
Cyclization of farnesyl pyrophosphate 1 to the carbenium ion 2
followed by a sequence of various rearrangement steps affords the
presilphiperfolanyl cation 3, which is considered as the crucial
precursor in the biogenesis of angular triquinanes. Wagner–Meer-
wein rearrangement of 3 following path ‘a’ provides the carbenium
ion 4. Elimination of a proton provides (ꢁ)-silphinene 5. Whereas
shift of the angular hydrogen to the carbenium ion 6 followed by
a methyl shift affords the carbenium ion 7. Elimination of a proton
a
b
H
–
–HP2O7
H
H
OP2O6H
1
2
3
H
H
a
– H+
5 (–)-Silphinene
4
leads either to (ꢁ)- -isocomene 8 or to (ꢁ)-isocomene 9. Wagner–
b
Meerwein rearrangement of 3 following path ‘b’ affords the car-
benium ion 10. Shift of a methyl group and subsequent elimination
of a proton provide (ꢁ)-silphiperfol-6-ene 11. Nucleophilic attack of
water at the carbenium ion 10 leads to (ꢁ)-cameroonanol (ꢁ)-12.3
(ꢁ)-Cameroonanol (ꢁ)-12 has been isolated in 1998 by Weyerstahl
et al. on their investigation of the essential oil of Echinops giganteus
var. lelyi, an endemic species of Cameroon and Nigeria.3 Although
a large variety of sesquiterpenes has been found in the essential oil
of E. giganteus, (ꢁ)-cameroonanol (ꢁ)-12 appeared to represent the
major factor of its patchouli-like, woody fragrance. The structure
and absolute configuration have been assigned based on NMR
spectroscopy, comparison with other compounds from the same
source and rearrangement to derivatives of known structure.2b,3
Because of their unique structure, triquinane sesquiterpenes
became attractive synthetic targets for demonstrating the utility
and scope of novel methodologies for cyclopentane annelations.4,5
~ H
– H+
8 (−)-β-Isocomene
~ Me
– H+
6
7
9 (−)-Isocomene
3
b
OH
9
11
H
H
H
H2O
– H+
~ Me
– H+
1
7
5
4
q
See Ref. 1.
11 (–)-Silphiperfol-6-ene
10
(−)-12 (−)-Cameroonanol
* Corresponding author. Fax: þ49 351 463 37030.
Scheme 1. Biosynthetic route to the angular triquinane sesquiterpenes.
E-mail address: hans-joachim.knoelker@tu-dresden.de (H.-J. Kno¨lker).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.115

A.W. Schmidt et al. / Tetrahedron 65 (2009) 5484–5490
5485
OH
and alkoxysilanes, can be readily transformed into the corre-
sponding hydroxy compounds by oxidative cleavage of the carbon–
silicon bond via the well-established Fleming–Tamao oxidation.11
We have developed a modified Fleming–Tamao oxidation, espe-
cially for the oxidative cleavage of sterically highly hindered orga-
nosilicon compounds containing the tert-butyldiphenylsilyl and the
diisopropylphenylsilyl group.12 The oxidative cleavage of the tert-
butyldiphenylsilyl group proceeds smoothly if a double proto-
desilylation is achieved in the first step. Protodesilylation of the
triquinanes 16 using the boron trifluoride–acetic acid complex for 2
days at 83 ꢂC to the intermediate tert-butyldifluorosilyl compound
18 followed by oxidationwith buffered hydrogenperoxide for 3 days
at 65 ꢂC provided the desired hydroxytriquinane 19 (Scheme 4).
Replacement of hydrogen peroxide by water in the second step
transformed the intermediate difluorosilyl compound 18 into the
tert-butyldihydroxysilyl compound 20. At this stage, an unequivocal
confirmation of the relative stereochemistry of our triquinanes has
been obtained by crystallization of the major diastereoisomer anti-
20 and X-ray crystal structure determination (Fig. 1). The formation
of compound 20 emphasizes the replacement of both phenyl groups
with fluorine in the first step to afford 18 by double proto-
desilylation. Subsequent double nucleophilic substitution of the
difluorosilyl compound 18 with water affords the dihydroxysilyl
compound 20. Oxidative cleavage of 20 led to the hydroxy-
triquinane almost quantitatively. Based on our earlier study on the
oxidative cleavage of the methyldiphenylsilyl group,12 we have
proposed that the cleavage of the tert-butyldiphenylsilyl group by
the modified Fleming–Tamao oxidation proceeds via dihydroxy-
silanes as intermediates. The present results confirm our mecha-
nistic proposal for cleavage of the tert-butyldiphenylsilyl group.
Using TPAP (tetrapropylammonium perruthenate) and
N-methylmorpholine N-oxide as stoichiometric oxidant,13 oxida-
tion of carbinol 19 led to the diketone 21 in 84% yield (Scheme 5).
Using PCC (pyridinium chlorochromate) and CeliteÒ as reagents,14
the diketone 21 was obtained in 94% yield. CeliteÒ, which has the
same effect on oxidations with PCC as molecular sieves,15 leads to
shorter reaction times and easier work-up. A simple filtration over
silica gel removes the chromium residues.
Sit-BuPh2
=
–
+
13
14
Scheme 2. Allyl-tert-butyldiphenylsilane 13 as synthetic equivalent for the 2-hydroxy-
substituted 1,3-dipole 14.
In 2000, Coates et al. described the first total synthesis of
(ꢀ)-cameroonanol (ꢀ)-12.6 We reported the second total synthesis
of (ꢀ)-cameroonanol (ꢀ)-12 in 2007.7 Our methodology combines
the Lewis acid-promoted [3þ2] cycloaddition of allyl-tert-butyldi-
phenylsilane 13 with a subsequent modified Fleming–Tamao oxi-
dation. Thus, allyl-tert-butyldiphenylsilane 13 is exploited as
synthetic equivalent for the 2-hydroxy-substituted 1,3-dipole 14
(Scheme 2).8–10
Lewis acid-promoted [3þ2] cycloadditions of allylsilanes found
diverse applications in organic synthesis.8–10 In the present paper,
we describe full experimental details of our improved synthetic
route to (ꢀ)-cameroonanol (ꢀ)-12.
2. Results and discussion
The triquinane framework was assembled in the first step by the
titanium tetrachloride-promoted [3þ2] cycloaddition of allyl-tert-
butyldiphenylsilane 13 (Scheme 3).
Paquette et al. have used the bicyclo[3.3.0]octenone 15 as pre-
cursor in their synthesis of silphinene.4b We prepared compound 15
using a modification of Paquette’s original procedure reported by
Coates et al.6 The Lewis acid–Lewis base complex of titanium tet-
rachloride and compound 15 has been generated at ꢁ20 ꢂC. Sub-
sequent addition of allyl-tert-butyldiphenylsilane 13 at ꢁ78 ꢂC
afforded the triquinane 16 as a 7:1 mixture of the anti and the syn
diastereoisomer (syn and anti denote the relative stereochemistry of
the silyl substituent tothe carbonyl function). As a minor by-product
we isolated the bicyclo[3.3.0]octenone 17 (6% yield). Compound 17
is quite unusual and has been isolated as a single diastereoisomer. It
is presumed to result from addition of a second equivalent of allyl-
tert-butyldiphenylsilane 13 at the intermediate siliranium ion and
subsequent 1,5-hydride shift instead of cyclization. The mechanism
of formation as well as the stereochemistry of 17 are currently under
investigation. Based on our previous findings,8g,8h the relative con-
figuration of the silyl groupof the triquinane 16 has been assigned by
the chemical shift of the 13C NMR signal for the CH group in the
We envisaged a regio- and stereoselective alkylation of the
diketone 21 for introduction of the methyl group at C-9. Using
a bulky lithium base, preferential deprotonation should take place
at C-9 because of the steric hindrance at C-11 caused by the
annulated cyclopentanone. Electrophilic attack at the resulting
9,10-enolate should occur from the exo-face and thus give rise to
the desired diastereoselectivity. Deprotonation using lithium di-
isopropylamide and subsequent treatment with iodomethane in
the presence of DMPU (N,N0-dimethyl-1,3-propylene urea) and
catalytic amounts of dimethylzinc afforded the mono-C-alkylated
cyclopentane ring
a to silicon. Moreover, an X-ray crystal structure
determination at a later stage of the synthesis confirmed this as-
signment. For our synthetic route towards (ꢀ)-cameroonanol
(ꢀ)-12, we could use the diastereoisomeric mixture of triquinane 16.
In the following step, the silyltriquinane had to be converted into
a hydroxytriquinane. Organosilanes, like dimethylphenylsilanes
OH
Sit-BuPh2
Sit-BuF2
O
O
O
O
a
b
H
H
H
a
Sit-BuPh2
+
15
13
16
18
19
Sit-Bu(OH)2
Ph2t-BuSi
c
d
O
Sit-BuPh2
Sit-BuPh2
H
O
O
O
Ph2t-BuSi
H
H
+
+
20
Scheme 4. Reagents and conditions: (a) BF3$2AcOH, 1,2-C2H4Cl2, reflux, 46 h; (b) CsF,
KHCO3, H2O2, THF/MeOH (1:1), reflux, 3 days, 59% (two steps); (c) CsF, KHCO3, H2O,
THF/MeOH (1:1), reflux, 12 h, 27% (two steps); (d) CsF, KHCO3, H2O2, THF/MeOH (1:1),
reflux, 7 days, 96%.
anti-16
syn-16
17
Scheme 3. Reagents and conditions: (a) 1. TiCl4, CH2Cl2, ꢁ20 ꢂC, 10 min; 2. 13, ꢁ78 ꢂC,
24 h, 43% 16 (ratio of anti-16/syn-16¼7:1), 6% 17.

5486
A.W. Schmidt et al. / Tetrahedron 65 (2009) 5484–5490
Figure 2. Molecular structure of 23 in the crystal: triclinic, P1.
Figure 1. Molecular structure of anti-20 in the crystal: triclinic, P1.
regioselectively to the dithioketal 23. An X-ray crystal structure
analysis of compound 23 unambiguously confirmed the regio- and
stereochemical assignment for the methylation (Fig. 2).
compound 22 as major product. Addition of catalytic amounts of
dimethylzinc, originally described by Noyori, was essential for the
regio- and stereoselective methylation.16 According to a GC–MS
chromatogram the crude product contained about 60% of the de-
sired monomethylated product 22, two monomethylated isomers,
two dialkylated products, and some starting material 21. Simple
flash chromatography on silica gel using hexane/tert-butyl methyl
ether (10:1) as eluent provided pure 22 in 54% yield. The relative
configuration was assigned by 2D NMR spectroscopy (COSY, HSQC,
HMBC, and NOESY). A chemoselective deoxygenation of the car-
bonyl group at C-7 was feasible by exploiting the sterical hindrance
of the carbonyl group at C-10 caused by two neighboring quater-
nary carbon centers. Thus, thioketalization of compound 22 by
reaction with boron trifluoride and 1,3-propanedithiol led
Raney-nickel hydrogenation of the dithioketal 23 afforded
(ꢀ)-cameroonanone (ꢀ)-24. Previously, Weyerstahl et al. obtained
(ꢁ)-cameroonanone (ꢁ)-24 by oxidation of natural (ꢁ)-camer-
oonanol (ꢁ)-12.3 (ꢀ)-Cameroonanone (ꢀ)-24 served as an in-
termediate in the synthetic route described by Coates et al.6 Both
groups described a low diastereoselectivity for the reduction of
cameroonanone 24 to cameroonanol 12. We have investigated the
diastereoselectivity of the reduction of (ꢀ)-cameroonanone (ꢀ)-24
to (ꢀ)-cameroonanol (ꢀ)-12 by variation of the reaction conditions
(Table 1).
By reduction of (ꢀ)-cameroonanone (ꢀ)-24 with lithium alu-
minum hydride in diethyl ether at 0 ꢂC, Coates et al. obtained a ratio
of 1.4:1 for (ꢀ)-cameroonanol (ꢀ)-12 and (ꢀ)-epi-cameroonanol
(ꢀ)-epi-12.6 Using the same reaction conditions, Weyerstahl et al.
reported a ratio of 2.3:1 by reduction of (ꢁ)-cameroonanone
(ꢁ)-24.3 Using tetrahydrofuran as solvent, we have determined
a ratio of 2.7:1, however, at a lower yield. Finally, using diisobutyl-
aluminum hydride at ꢁ78 ꢂC as reducing agent,17 we have obtained
(ꢀ)-cameroonanol (ꢀ)-12 and (ꢀ)-epi-cameroonanol (ꢀ)-epi-12 in
a ratio of 3.7:1 and 88% yield. A separation of the two epimeric
alcohols (ꢀ)-12 and (ꢀ)-epi-12 has been achieved by flash chro-
matography on silica gel (eluent: pentane/diethyl ether, 25:1) to
provide pure (ꢀ)-cameroonanol (ꢀ)-12. The spectroscopic data of
our synthetic (ꢀ)-cameroonanol (ꢀ)-12 were in full agreement
with those reported by Weyerstahl for the natural product.3
O
OH
O
O
O
O
a
b
H
H
H
19
21
22
S
S
O
O
c
d
e
H
H
Table 1
23
24
Results for the reduction of (ꢀ)-cameroonanone 24 to (ꢀ)-cameroonanol (ꢀ)-12 and
(ꢀ)-epi-cameroonanol (ꢀ)-epi-12
Reagent
Solvent
T [ꢂC]
Yield [%]
Ratioa
OH
OH
1.4:1b
2.3:1c
2.7:1
3.2:1
3.7:1
H
H
LiAlH4
LiAlH4
LiAlH4
DIBAL-H
DIBAL-H
Et2O
Et2O
THF
CH2Cl2
CH2Cl2
0
0
0
86
81
67
61
88
+
ꢁ78 to rt
( )-12
( )-epi-12
ꢁ78
a
Scheme 5. Reagents and conditions: (a) PCC, Celite, CH2Cl2, 25 ꢂC, 5 h, 94%; (b) 1. BuLi,
i-Pr2NH, THF, ꢁ5 ꢂC, 6 h; 2. MeI, ZnMe2, DMPU, THF, ꢁ78 to 25 ꢂC, 40 h, 54%; (c)
HS(CH2)3SH, BF3$Et2O, CH2Cl2, 25 ꢂC, 24 h, 83%; (d) Raney-Ni, EtOH, 25 ꢂC, 4 h, 71%; (e)
DIBAL-H, CH2Cl2, ꢁ78 ꢂC, 20 h, 88% [ratio of (ꢀ)-12/(ꢀ)-epi-12¼3.7:1].
Ratio of (ꢀ)-cameroonanol (ꢀ)-12 and (ꢀ)-epi-cameroonanol (ꢀ)-epi-12 as de-
termined by gas chromatography.
b
Result for the reduction of (ꢀ)-24 reported by Coates et al.6
c
Result for the reduction of (ꢁ)-24 reported by Weyerstahl et al.3

A.W. Schmidt et al. / Tetrahedron 65 (2009) 5484–5490
5487
3. Conclusion
Compound 16: IR (neat):
n
¼3071, 2959, 2933, 2858, 1722, 1471,
1427, 1392, 1380, 1362, 1307, 1273, 1194, 1153, 1107, 999, 986, 910,
The Lewis acid-promoted [3þ2] cycloaddition of allyl-tert-
butyldiphenylsilane is a useful method for the stereoselective
construction of tricyclopentanoid frameworks. Using our modified
Fleming–Tamao oxidation, the resulting silylcyclopentanes can be
converted to cyclopentanols. Thus, this sequence of reactions pro-
vides a direct route to cyclopentanoid natural products. In the
present work, the triquinane sesquiterpene (ꢀ)-cameroonanol
(ꢀ)-12 has been obtained in seven linear steps and 5% overall yield
based on bicyclo[3.3.0]octenone 15. Moreover, isolation of the tert-
butyldihydroxysilyl derivative 20 provided circumstantial evidence
for the mechanism previously proposed by us for the oxidative
cleavage of the tert-butyldiphenylsilyl group via the modified
Fleming–Tamao oxidation. Formation of the disilyl-substituted
bicyclo[3.3.0]octenone 17 shows another interesting novel aspect
of the Lewis acid-promoted reactions of allylsilanes with enones.
820, 764, 737, 702, 649, 608 cmꢁ1 1H NMR (500 MHz, CDCl3):
.
d
¼0.82 (s, 3H), 0.98 (dd, J¼9.6, 1.3 Hz, 1H), 1.06 (s, 3H), 1.081 (s, 9H),
1.085 (s, 3H), 0.94–1.27 (m, 2H), 1.40–1.44 (m, 1H), 1.56 (d,
J¼13.9 Hz, 1H), 1.58–1.74 (m, 2H), 1.66 (d, J¼13.9 Hz, 1H), 1.92 (ddd,
J¼12.8, 5.8, 2.2 Hz, 1H), 2.14–2.21 (m, 2H), 2.48–2.50 (m, 1H), 7.31–
7.40 (m, 6H), 7.59–7.67 (m, 4H). 13C NMR and DEPT (125 MHz,
CDCl3), anti-16:
d
¼18.57 (C), 24.55 (CH3), 25.35 (CH), 27.34 (CH3),
27.87 (CH3), 28.47 (3CH3), 29.45 (CH2), 35.57 (CH2), 38.36 (CH2),
40.01 (CH2), 44.94 (C), 47.21 (C), 48.03 (CH2), 55.03 (CH), 70.98 (C),
127.28 (2CH), 127.36 (2CH), 128.88 (2CH), 134.32 (C), 134.44 (C),
136.54 (2CH), 136.56 (2CH), 229.55 (C]O); syn-16:
d¼18.04 (C),
22.31 (CH3), 26.37 (CH3), 26.89 (CH2), 28.47 (3CH3), 28.60 (CH),
29.83 (CH3), 30.64 (CH2), 31.19 (CH2), 41.75 (CH2), 45.16 (C), 45.56
(CH), 46.70 (CH2), 48.90 (C), 68.11 (C), 127.45 (2CH), 134.82 (C),
135.29 (C), 136.13 (2CH), 136.25 (2CH), 136.54 (2CH), 136.56 (2CH),
223.41 (C]O). MS (EI): m/z (%)¼444 (1, Mþ), 387 (100), 199 (12),
197 (6), 183 (45), 181 (6), 135 (10), 105 (3), 83 (6), 81 (10). HRMS m/z
calcd for C30H40OSi: 444.2848, found: 444.2857.
4. Experimental section
4.1. General
Compound 17: UV (CHCl3):
IR (neat):
l¼227, 265 (
3
¼11.530 cm2 mmolꢁ1) nm.
n
¼3071, 3048, 2929, 2858, 1701, 1642, 1471, 1427, 1391,
All reactions were carried out in dry solvents under an inert at-
mosphere (argonornitrogen). THFanddiethylether weredriedusing
a solvent purification system (MBraun-SPS). Chemicals were used as
received from commercial sources. Flash chromatography: Merck
silica gel (0.040–0.063 mm). Melting points: Electrothermal IA9100.
UV spectra: Perkin–Elmer Lambda 2 (UV/VIS spectrometer). IR
1362, 1260, 1193, 1106, 999, 910, 866, 820, 736, 701, 606 cmꢁ1. 1H
NMR (500 MHz, CDCl3):
d
¼0.66–0.73 (m, 2H), 0.80–1.18 (m, 6H),
0.956 (s, 9H), 0.960 (s, 9H), 1.05 (s, 3H), 1.188 (s, 3H), 1.194 (s, 3H),
1.44–1.48 (m, 1H), 1.58–1.69 (m, 2H), 1.82 (dd, J¼12.0, 6.3 Hz, 1H),
1.86 (d, J¼12.8 Hz,1H), 2.03 (dd, J¼17.5, 8.4 Hz,1H), 2.15 (dd, J¼12.9,
7.5 Hz, 1H), 2.24 (dd, J¼12.9, 6.6 Hz, 1H), 2.46 (ddd, J¼17.3, 10.9,
6.3 Hz, 1H), 7.29–7.39 (m, 12H), 7.49–7.52 (m, 4H), 7.58–7.61 (m,
spectra: Thermo Nicolet Avatar 360 FT-IR;
Bruker DRX 500; chemical shifts in parts per million, coupling
n
in cmꢁ1. NMR spectra:
d
4H). 13C NMR and DEPT (125 MHz, CDCl3):
d¼10.02 (CH2), 14.23
constants J in hertz. Mass spectra: Finnigan MAT-95 (electron impact
EI, ionizationpotential:70 eV)orbyGC/MS-couplingusinganAgilent
Technologies 6890N GC System equipped with a 5973 Mass Selective
Detector (EI, 70 eV). Elemental analyses: EuroVector EuroEA3000. X-
ray analyses: Bruker-Nonius Kappa CCD with an Oxford Cryosystems
cooling device and STOE IPDS 2 image plate; Software: Collect
(Nonius BV, 1999), Dirax/lsq (Duisenberg, 1992), SHELXS-97 (Shel-
drick, G. M.,1900), EvalCCD (Duisenberg et al., 2003), SADABS version
2.10 (Sheldrick, G. M., Bruker AXS Inc., 2002), SHELX97-2 (Sheldrick,
G. M., 1997).
(CH2), 18.06 (C), 18.30 (C), 21.09 (CH2), 25.67 (CH3), 26.89 (CH3),
27.83 (3CH3), 27.87 (3CH3), 28.26 (CH3), 32.51 (CH), 36.41 (CH2),
38.65 (CH2), 40.71 (CH2), 44.15 (CH2), 49.42 (C), 50.07 (C), 51.44
(CH2), 127.41 (2CH), 127.45 (2CH), 127.48 (4CH), 128.86 (2CH),
128.92 (2CH), 128.96 (2CH), 134.98 (C), 135.14 (C), 135.88 (2C),
136.23 (4CH),136.26 (2CH),147.22 (C),153.95 (C), 207.60 (C]O). MS
(EI): m/z (%)¼667 (10, MþꢁC4H9), 429 (5), 401 (8), 387 (100), 199
(24), 197 (10), 183 (14), 135 (20). HRMS: m/z calcd for C45H55OSi2
(MþꢁC4H9): 667.3791, found: 667.3799.
4.3. (3a,5a,8a)-7-Hydroxy-2,2,3a-trimethyldecahydro-
4.2. (3a,5a,7,8a)-7-tert-Butyldiphenylsilyl-2,2,3a-
trimethyldecahydrocyclopenta[c]pentalen-1-one (anti-16),
(3a,5a,7,8a)-7-tert-butyldiphenylsilyl-2,2,3a-
trimethyldecahydrocyclopenta[c]pentalen-1-one (syn-16),
and 8-([5-tert-butyldiphenylsilyl]-[2-tert-
cyclopenta[c]pentalen-1-one (19)
Method A. Boron trifluoride–acetic acid complex (2.5 g, 1.8 mL,
13.14 mmol) was added to a solution of anti-/syn-16 (584 mg,
1.31 mmol) in anhydrous 1,2-dichloroethane (30 mL) and the
mixture was heated at reflux for 46 h. After cooling to room tem-
perature, the mixture was neutralized by addition of a saturated
sodium bicarbonate solution. The aqueous layer was separated,
extracted with diethyl ether three times, and the combined organic
layers were dried over magnesium sulfate. The solvent was re-
moved and the residue was dissolved in THF (25 mL). Cesium
fluoride (1.2 g, 7.88 mmol), KHCO3 (264 mg, 2.60 mmol), methanol
(25 mL), and a solution of hydrogen peroxide in water (35%, 2.3 mL,
22.34 mmol) were added. The mixture was heated at reflux for 3
days. After cooling to room temperature, water (100 mL) was
added. The aqueous layer was separated and extracted with diethyl
ether three times. The combined organic layers were washed with
a saturated aqueous solution of iron(II) sulfate, dried over magne-
sium sulfate, and the solvent was removed. Purification of the
residue by flash chromatography on silica gel (hexane/tert-butyl
methyl ether, 1:1) afforded the carbinol 19 as a colorless oil, yield:
170 mg (59%).
butyldiphenylsilylmethyl]pentyl)-3,3,5-
trimethylbicyclo[3.3.0]oct-1(8)-en-2-one (17)
A 1 M solution of titanium tetrachloride in dichloromethane
(7.31 mL, 7.31 mmol) was added to a solution of 3,3,5-trimethylbi-
cyclo[3.3.0]oct-1(8)-en-2-one (15) (1.00 g, 6.09 mmol) in anhy-
drous dichloromethane (40 mL) at ꢁ20 ꢂC. After stirring for 10 min,
the mixture was cooled to ꢁ78 ꢂC, allyl-tert-butyldiphenylsilane
(13) (3.42 g, 12.2 mmol) was added, and the mixture was stirred at
ꢁ78 ꢂC for 24 h. The reaction mixture was poured into a saturated
aqueous solution of ammonium chloride and stirred vigorously
until it turned yellow (approx. 10 min). The aqueous layer was
separated and extracted with dichloromethane three times. The
combined organic layers were dried over sodium sulfate and the
solvent was removed. Purification of the residue by flash chroma-
tography on silica gel (hexane/tert-butyl methyl ether, 40:1) affor-
ded as the less polar fraction a diastereoisomeric mixture of anti-16
and syn-16 (ratio: 7:1) as a colorless oil, yield: 1.17 g (43%). The
more polar fraction was the bicyclo[3.3.0]octenone 17, colorless oil,
yield: 284 mg (6%).
IR (neat):
1219, 1091, 1059, 995 cmꢁ1
3H), 1.07 (s, 3H), 1.09 (s, 3H), 1.24 (dt, J¼12.2, 8.9 Hz, 1H), 1.41 (dd,
n
¼3432, 2955, 2868,1726,1462,1380,1358,1307,1274,
.
1H NMR (500 MHz, CDCl3):
d¼1.04 (s,

5488
A.W. Schmidt et al. / Tetrahedron 65 (2009) 5484–5490
J¼12.6, 8.7 Hz, 1H), 1.46 (m, 1H), 1.59–1.79 (m, 4H), 1.83–1.91 (m,
1H), 1.95 (ddd, J¼12.6, 6.0, 1.6 Hz, 1H), 2.13–2.18 (m, 2H), 2.33 (dq,
J¼1.4, 8.8 Hz, 1H), 4.41 (m, 1H). 13C NMR and DEPT (125 MHz,
of the dihydroxysilyl compound 20 (60 mg, 185
(10 mL). After addition of aqueous hydrogen peroxide (35%; 293
m
mol) in THF
mL,
3.70 mmol), the reaction mixture was heated at reflux for 7 days.
Subsequently, the mixture was cooled to room temperature and
water (10 mL) was added. The aqueous layer was separated and
extracted with diethyl ether three times. The combined organic
layers were washed with a saturated aqueous solution of iron(II)
sulfate, dried over magnesium sulfate, and the solvent was re-
moved. Purification of the residue by flash chromatography on
silica gel (hexane/tert-butyl methyl ether, 1:1) provided the carbi-
nol 19 as a colorless oil, yield: 39.5 mg (96%).
CDCl3):
d
¼24.72 (CH3), 27.39 (CH3), 28.10 (CH3), 30.39 (CH2), 39.68
(CH2), 39.80 (CH2), 42.56 (CH2), 44.79 (C), 47.86 (C), 48.10 (CH2),
49.19 (CH), 68.60 (C), 73.59 (CH), 228.28 (C]O). MS (EI): m/z
(%)¼222 (22, Mþ), 207 (100), 179 (9), 167 (6), 165 (76), 152 (7), 151
(19), 149 (5), 95 (8), 94 (13), 79 (11), 77 (5). HRMS m/z calcd for
C14H22O2: 222.1620, found: 222.1611.
4.4. (3a,5a,7,8a)-7-tert-Butyldihydroxysilyl-2,2,3a-
trimethyldecahydrocyclopenta[c]pentalen-1-one (20)
Spectroscopic data, see above.
Boron trifluoride–acetic acid complex (15.5 g, 11.5 mL,
82.50 mmol) was added to a solution of anti-/syn-16 (3.41 g,
7.67 mmol) in anhydrous 1,2-dichloroethane (100 mL) and the
mixture was heated at reflux for 46 h. After cooling to room
temperature, the mixture was neutralized by addition of a satu-
rated sodium bicarbonate solution. The aqueous layer was sepa-
rated, extracted with diethyl ether three times, and the combined
organic layers were dried over magnesium sulfate. The solvent
was removed and the residue was dissolved in THF (70 mL). CsF
(7.5 g, 53.0 mmol), KHCO3 (1.7 g, 16.4 mmol), methanol (70 mL),
and water (15 mL) were added and the mixture was heated at
reflux for 12 h. After cooling to room temperature, water
(100 mL) was added. The aqueous layer was separated and
extracted with diethyl ether three times. The combined organic
layers were dried over magnesium sulfate and the solvent was
removed. Purification of the residue by flash chromatography on
silica gel (hexane/tert-butyl methyl ether, 1:1) afforded the
dihydroxysilane 20 as colorless crystals, yield: 670 mg (27%), mp
146 ꢂC.
4.6. (3a,5a,8a)-2,2,3a-Trimethyldecahydrocyclopenta[c]-
pentalene-1,7-dione (21)
A solution of the carbinol 19 (837 mg, 3.80 mmol) in dichloro-
methane (50 mL) was added to a suspension of PCC (1.80 g,
8.36 mmol) and CeliteÒ (4.6 g) in dichloromethane (70 mL). The
resulting mixture was stirred at room temperature for 5 h. Removal
of the chromium residues by filtration over silica gel (tert-butyl
methyl ether) and evaporation of the solvent afforded 21 as a light
yellow oil, yield: 787 mg (94%).
IR (neat):
1276, 1227, 1171, 1096, 1056, 1020, 895 cmꢁ1
CDCl3):
n
¼2959, 2935, 2870, 1746, 1468, 1402, 1382, 1360,
.
1H NMR (500 MHz,
d
¼1.06 (s, 3H), 1.11 (s, 3H), 1.16 (s, 3H), 1.46–1.49 (m, 1H),
1.65–1.69 (m, 1H), 1.75–1.80 (m, 1H), 1.78 (s, 2H), 1.91–2.00 (m, 2H),
2.28 (dd, J¼18.6, 1.8 Hz, 1H), 2.53–2.62 (m, 2H), 2.81 (m, 1H). 13C
NMR and DEPT (125 MHz, CDCl3):
d
¼25.59 (CH3), 27.13 (2CH3),
31.07 (CH2), 41.69 (CH2), 43.49 (CH2), 43.92 (CH2), 45.61 (C), 46.52
(CH), 47.35 (C), 49.76 (CH2), 66.86 (C), 217.06 (C]O), 225.86 (C]O).
MS (EI): m/z (%)¼220 (36, Mþ), 205 (15), 178 (23), 165 (100), 164
(13), 137 (25), 109 (15), 94 (22), 79 (12). HRMS m/z calcd for
C14H20O2: 220.1463, found: 220.1459.
IR (ATR):
1310, 1275, 1197, 1154, 1128, 1082, 987, 919, 886, 833, 816, 762,
612 cmꢁ1 1H NMR (500 MHz, DMSO-d6):
n
¼3391, 2933, 2856, 1726, 1705, 1465, 1380, 1360,
.
d
¼0.86 (s, 9H), 1.00 (s,
3H), 1.01 (s, 3H), 1.05 (s, 3H), 1.13–1.18 (m, 1H), 1.25–1.35 (m, 2H),
1.40 (t, J¼12.8 Hz, 1H), 1.55–1.71 (m, 5H), 1.78–1.83 (m, 1H), 1.98
(m, 1H), 2.31 (q, J¼8.7 Hz, 1H), 5.59 (s, 1H), 5.62 (s, 1H). 13C NMR
4.7. (3a,5a,6,8a)-2,2,3a,6-Tetramethyldecahydro-
cyclopenta[c]pentalene-1,7-dione (22)
and DEPT (125 MHz, CDCl3):
d
¼18.45 (C), 24.54 (CH3), 25.97
A 1.6 M solution of butyllithium in hexane (1.02 mL, 1.63 mmol)
was added to a solution of diisopropylamine in anhydrous THF
(5 mL) at ꢁ5 ꢂC and the mixture was stirred at that temperature for
15 min. A solution of 21 (300 mg, 1.36 mmol) in anhydrous THF
(2 mL) was added and the mixture was stirred at ꢁ5 ꢂC for 6 h. The
(3CH3), 26.89 (CH), 27.40 (CH3), 28.11 (CH3), 29.67 (CH2), 34.45
(CH2), 37.64 (CH2), 39.97 (CH2), 44.96 (C), 47.41 (C), 47.91 (CH2),
54.97 (CH), 71.25 (C), 229.47 (C]O). 29Si NMR (99 MHz, DMSO-d6):
d
¼ꢁ12.81. MS (EI): m/z (%)¼324 (3, Mþ), 307 (7), 306 (29), 291 (7),
267 (100), 251 (2), 249 (8), 211 (12), 193 (4), 187 (18), 183 (13), 147
(10), 77 (16). HRMS: m/z calcd for C18H32O3Si: 324.2121, found:
324.2092. Anal. Calcd for C18H32O3Si: C 66.62, H 9.94. Found: C
66.78, H 9.96.
solution was cooled to ꢁ78 ꢂC and DMPU (522 mg, 492
m
m
L,
L,
4.08 mmol) and a 1 M solution of dimethylzinc in heptane (272
272
m
mol) were added. After 15 min of stirring at ꢁ78 ꢂC, iodo-
methane (965 mg, 423 mL, 6.80 mmol) was added and the reaction
mixture was allowed to warm up to room temperature over a pe-
riod of 16 h. The reaction mixture was stirred for another 24 h at
room temperature and then quenched by addition of a saturated
aqueous solution of ammonium chloride (20 mL). Dichloromethane
(20 mL) was added, the aqueous layer was separated, and extracted
with dichloromethane three times. The combined organic layers
were dried over magnesium sulfate and the solvent was evapo-
rated. Purification of the residue by flash chromatography on silica
gel (hexane/tert-butyl methyl ether, 10:1) gave 22 as a colorless oil,
yield: 171 mg (54%).
4.4.1. Crystal data for anti-20
C18H32O3Si, crystal size: 0.51ꢃ0.47ꢃ0.08 mm3, Mr¼324.53 g molꢁ1
,
ꢀ
triclinic, space group P1,
l
¼0.71073 Å, a¼12.186(3), b¼15.114(1),
c¼16.730(4) Å,
a
¼103.50(1)ꢂ,
b
¼95.17(2)ꢂ,
g
¼104.16(1)ꢂ, V¼
2869.5(10) Å3, Z¼6, rcalcd¼1.127 g cmꢁ3
,
m
¼0.133 mmꢁ1, T¼198(2) K,
q
range¼3.52–22.50ꢂ; reflections collected: 43,390, independent: 7450
(Rint¼0.0522). The structure was solved by direct methods and refined
by full-matrix least-squares on F2; R1¼0.0407, wR2¼0.1006 [I>2
s(I)];
maximal residual electron density: 0.464 e Åꢁ3. CCDC 636590 contains
the supplementary crystallographic data for this structure. These data
can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
IR (ATR):
n
¼2960, 2933, 2870, 1729, 1458, 1380, 1288, 1171, 1091,
1042, 974, 895, 582 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d
¼1.04 (s, 3H),
1.110 (d, J¼7.1, 3H), 1.112 (s, 3H), 1.14 (s, 3H), 1.54–1.58 (m, 1H), 1.66–
1.82 (m, 5H), 1.95 (m, 1H), 2.37 (br t, J¼7.8 Hz, 1H), 2.44–2.53 (m,
4.5. (3a,5a,8a)-7-Hydroxy-2,2,3a-trimethyldecahydro-
cyclopenta[c]pentalen-1-one (19)
2H). 13C NMR and DEPT (125 MHz, CDCl3):
d
¼14.90 (CH3), 25.84
(CH3), 26.25 (CH3), 26.99 (CH3), 29.04 (CH2), 42.31 (CH2), 44.07
(CH2), 46.04 (C), 46.26 (C), 49.10 (CH), 50.18 (CH2), 55.85 (CH), 64.41
(C), 218.76 (C]O), 226.94 (C]O). MS (EI): m/z (%)¼234 (23, Mþ),
219 (7), 178 (40), 165 (100), 150 (10), 137 (55), 121 (6), 114 (9), 109
Method B. Methanol (10 mL), cesium fluoride (168 mg,
1.11 mmol), and KHCO3 (37 mg, 370 mmol) were added to a solution

A.W. Schmidt et al. / Tetrahedron 65 (2009) 5484–5490
5489
(11), 107 (8), 94 (8), 79 (10). HRMS: m/z calcd for C15H22O2:
234.1620, found: 234.1623.
d
¼18.83 (CH3), 24.60 (CH3), 27.38 (CH3), 27.70 (CH3), 28.81 (CH2),
31.71 (CH2), 36.58 (CH2), 40.83 (CH2), 43.26 (CH), 44.97 (C), 47.62
(C), 48.37 (CH2), 61.17 (CH), 70.67 (C), 229.19 (C]O). MS (EI): m/z
(%)¼220 (52, Mþ), 205 (6), 192 (7), 165 (100), 164 (75), 134 (26), 135
(30), 121 (45), 110 (61), 109 (22), 95 (22), 94 (21), 79 (20), 69 (21).
HRMS: m/z calcd for C15H24O: 220.1827, found: 220.1845.
4.8. (3a0,5a0,60,8a0)-20,20,3a0,60-Tetramethyl-spiro[1,3-dithiane-
2,70-decahydrocyclopenta[c]pentalen]-10-one (23)
Boron trifluoride–diethyl ether complex (163 mg, 144
1.15 mmol) was added to a solution of 22 (257 mg, 1.10 mmol) and
1,3-propanedithiol (124 mg, 115 L, 1.15 mmol) in anhydrous
mL,
4.10. ( )-Cameroonanol [(1,3a,5a,6,8a)-2,2,3a,6-
m
tetramethyldecahydrocyclopenta[c]pentalen-1-ol] [( )-12]
and ( )-epi-cameroonanol [(1,3a,5a,6,8a)-2,2,3a,6-
tetramethyldecahydrocyclopenta[c]pentalen-1-ol] [( )-epi-12]
dichloromethane (10 mL). The mixture was stirred for 24 h at room
temperature. Then, an aqueous solution of sodium hydroxide (5%;
20 mL) and dichloromethane (20 mL) were added. The organic
layer was separated, washed with water, dried over magnesium
sulfate, and the solvent was evaporated. Purification of the residue
by flash chromatography on silica gel (hexane/tert-butyl methyl
ether, 10:1) provided 23 as colorless crystals, yield: 294 mg (83%),
mp 84 ꢂC.
A
1 M solution of diisobutylaluminum hydride (820 mL,
820
(60 mg, 272
m
mol) was added to a solution of (ꢀ)-cameroonanone (ꢀ)-24
m
mol) in anhydrous dichloromethane (5 mL) at ꢁ78 ꢂC
and the mixture was stirred at that temperature for 20 h. The
cooling was removed and methanol (1 mL) was added dropwise.
Water (1 mL) and diethyl ether (3 mL) were added, stirring was
continued for 30 min, and the precipitate was removed by filtration
over silica gel (diethyl ether). The filtrate was washed with water
and dried over magnesium sulfate. Evaporation of the solvent
provided a diastereoisomeric mixture of (ꢀ)-cameroonanol (ꢀ)-12
and (ꢀ)-epi-cameroonanol (ꢀ)-epi-12 (ratio: 3.7:1) as a colorless
oil, yield: 53.5 mg (88%). The diastereoisomers were separated by
flash chromatography on silica gel (pentane/diethyl ether, 25:1).
(ꢀ)-Cameroonanol [(ꢀ)-12]: colorless crystals, mp 42–45 ꢂC. IR
IR (ATR):
n
¼2959, 2943, 2924, 2904, 2866, 2824, 1729, 1453,
1414,1377,1358,1305,1276,1241,1189,1133,1084,1055,1033,1002,
987, 953, 929, 902, 872, 780, 717, 683, 656, 607, 567, 548 cmꢁ1. 1H
NMR (500 MHz, CDCl3):
d
¼1.05 (s, 3H), 1.07 (s, 3H), 1.08 (s, 3H), 1.15
(d, J¼6.8 Hz, 3H), 1.47 (dd, J¼13.2, 6.1 Hz, 1H), 1.60–1.76 (m, 5H),
1.81–1.91 (m, 2H), 2.08–2.13 (m, 1H), 2.12 (d, J¼14.1 Hz, 1H), 2.50
(dd, J¼10.2, 7.8 Hz, 1H), 2.80 (dt, J¼14.1, 3.9 Hz, 1H), 2.85 (dt, J¼14.4,
4.1 Hz, 1H), 2.98 (d, J¼14.1 Hz, 1H), 3.12–3.21 (m, 2H). 13C NMR and
DEPT (125 MHz, CDCl3):
d
¼13.69 (CH3), 25.27 (CH3), 25.74 (CH2),
26.78 (CH2), 27.11 (CH3), 27.52 (CH3), 28.02 (CH2), 28.79 (CH2),
40.29 (CH2), 44.29 (C), 47.14 (CH2), 47.80 (C), 49.16 (CH2), 52.47
(CH), 58.69 (CH), 60.77 (C), 68.16 (C), 225.62 (C]O). MS (EI): m/z
(%)¼324 (96, Mþ), 291 (7), 255 (9), 250 (18), 240 (100), 228 (6), 217
(73), 194 (37), 166 (66), 146 (9), 134 (16), 133 (75), 119 (14), 105 (20),
93 (9), 91 (27), 79 (24). HRMS: m/z calcd for C18H28OS2: 324.1582,
found: 324.1581. Anal. Calcd for C18H28OS2: C 66.61, H 8.70, S 19.76.
Found: C 66.60, H 8.48, S 19.68.
(ATR):
n
¼3604, 3479, 2929, 2864, 1458, 1374, 1242, 1163, 1077, 1051,
997, 976, 910, 782, 667 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d¼0.90 (s,
3H), 0.96 (s, 3H), 0.99 (d, J¼6.6 Hz, 3H), 1.03 (s, 3H), 1.18–1.27 (m,
1H), 1.30–1.34 (m, 1H), 1.38–1.45 (m, 3H), 1.50–1.67 (m, 5H), 1.73–
1.81 (m,1H),1.90 (t, J¼8.2 Hz,1H), 3.68 (br s,1H). 13C NMR and DEPT
(125 MHz, CDCl3):
d¼19.37 (CH3), 23.79 (CH3), 25.67 (CH3), 28.99
(CH2), 32.45 (CH3), 35.33 (CH2), 36.11 (CH2), 38.64 (C), 39.97 (CH2),
43.82 (CH), 47.56 (C), 51.36 (CH), 52.60 (CH2), 67.10 (C), 89.71 (CH).
MS (EI): m/z (%)¼222 (7, Mþ), 207 (11), 204 (39), 189 (27), 176 (13),
166 (40), 148 (50), 135 (100), 124 (49), 109 (24), 96 (41), 95 (36), 93
(29), 81 (32). HRMS: m/z calcd for C15H26O: 222.1984, found:
222.1971. Anal. Calcd for C15H26O: C 81.02, H 11.79. Found: C 81.05,
H 11.74.
4.8.1. Crystal data for 23
C18H28OS2, crystal size: 0.46ꢃ0.34ꢃ0.28 mm3, Mr¼324.52 g molꢁ1
,
ꢀ
triclinic, space group P1,
l
¼0.71073 Å, a¼7.486(2), b¼9.117(2), c¼
13.246(3) Å,
a
¼85.58(3)ꢂ,
b
¼77.34(3)ꢂ,
g
¼87.08(3)ꢂ, V¼878.9(4) Å3,
Z¼2, rcalcd¼1.226 g cmꢁ3
,
m
¼0.301 mmꢁ1, T¼198(2) K,
range¼3.52–
q
(ꢀ)-epi-Cameroonanol [(ꢀ)-epi-12]: colorless oil. 1H NMR
25.41ꢂ; reflections collected: 11,484, independent: 3126 (Rint¼0.0295).
(500 MHz, CDCl3):
d
¼0.81 (s, 3H), 0.91 (d, J¼6.6 Hz, 3H), 0.96 (s,
3H), 1.03 (s, 3H), 1.19–1.88 (m, 12H), 3.35 (br s, 1H). 13C NMR and
DEPT (125 MHz, CDCl3):
The structure was solved by direct methods and refined by full-matrix
least-squares on F2; R1¼0.0351, wR2¼0.0769 [I>2
s(I)]; maximal
d
¼19.01 (CH3), 21.49 (CH3), 25.66 (CH2),
residual electron density: 0.273 e Åꢁ3. CCDC 636591 contains the
supplementary crystallographic data for this structure. These data can
be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
26.40 (CH2), 28.44 (CH3), 28.51 (CH3), 36.75 (CH2), 38.13 (CH), 41.75
(C), 43.48 (CH2), 48.36 (C), 52.71 (CH2), 62.73 (CH), 65.70 (C), 88.24
(CH). GC–MS (EI): m/z (%)¼222 (8, Mþ), 204 (41), 189 (27), 175 (34),
166 (55), 148 (42), 135 (100), 124 (46), 119 (37), 107 (40), 95 (40), 93
(40), 91 (53), 79 (45).
4.9. ( )-Cameroonanone [(3a,5a,6,8a)-2,2,3a,6-tetramethyl-
decahydrocyclopenta[c]pentalen-1-one] [( )-24]
Acknowledgements
A suspension of Raney-nickel in water (5 g) was washed with
absolute ethanol until it became active. A solution of the thioketal
23 (75 mg, 231 mmol) in absolute ethanol was added to a suspen-
sion of activated Raney-nickel in absolute ethanol (25 mL). The
suspension was stirred at room temperature for 4 h, the solid was
removed by filtration over silica gel (tert-butyl methyl ether), and
the solvent was evaporated. Purification of the residue by flash
chromatography on silica gel (hexane/tert-butyl methyl ether, 10:1)
provided (ꢀ)-cameroonanone (ꢀ)-24 as a colorless oil, yield: 36 mg
(71%).
We are grateful to the Wacker Chemie AG, Burghausen, for
a generous gift of tert-butylchlorodiphenylsilane. We thank Sigrid
Goutal for her contribution.
References and notes
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1223, 1194, 1128, 1087, 1067, 1038, 976, 913 cmꢁ1
(500 MHz, CDCl3):
n
¼2951, 2933, 2866, 1725, 1458, 1378, 1358, 1304, 1272,
.
1H NMR
d
¼0.97 (d, J¼6.1 Hz, 3H), 1.05 (s, 3H), 1.06 (s, 3H),
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