Formation of radicals by irradiation of alkyl halides in the presence of triethylamine. Application to the synthesis of (±)-bisabolangelone

Article abstract of DOI:10.1016/S0040-4020(01)00357-X

The irradiation of unsaturated halides in the presence of triethylamine leads to the formation of the corresponding cyclized products. This photoreductive cyclization has been used to synthesize the bicyclic core of (±)-bisabolangelone.

Full text of DOI:10.1016/S0040-4020(01)00357-X

TETRAHEDRON
Pergamon
Tetrahedron 57 02001) 5173±5182
Formation of radicals by irradiation of alkyl halides
in the presence of triethylamine. Application to the synthesis
of ꢀ^)-bisabolangelone
p
Janine Cossy, Veronique Bellosta, Jean-Luc Ranaivosata and Barbara Gille
Â
Â
Laboratoire de Chimie Organique, Associe au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Dedicated to Professor Barry M. Trost on the occasion of his 60th birthday
Received 7 February 2001; revised 14 March 2001; accepted 15 March 2001
AbstractÐThe irradiation of unsaturated halides in the presence of triethylamine leads to the formation of the corresponding cyclized
products. This photoreductive cyclization has been used to synthesize the bicyclic core of 0^)-bisabolangelone. q 2001 Elsevier Science
Ltd. All rights reserved.
Studies on the photochemistry of alkyl iodides have shown
that the irradiation of alkyl halides in solution affords
mixtures of radical and ionic products with the latter usually
greatly predominant.1 As the ionic products are usually
obtained in high yield the reaction is of synthetic value.2
On the contrary, alkyl bromides lead to radical-derived
products in low yield.3 If photochemically generated ketyl
radicals are used as electron donors to halide derivatives,4
reagents such as trialkyltin hydrides or trialkyldistannanes
can be used for the subsequent reduction of C±Br and C±I
bonds.5 However, this reaction is troublesome as the
separation of the products from trialkyltin derivatives is
dif®cult. A partial solution to this problem has been found
by using polymer-supported organotin compounds.6
Scheme 1.
in 88% yield. It is worth noting that this photochemical
process is chemoselective as the ester function of 4 was
not reduced. Furthermore, when bromo ketone 59 was
irradiated, the only product that could be isolated, after
30 min, was ketone 10 060%). The unsaturated tricyclic
ketone 11 was obtained in 98% yield 0based on the
recovered starting material), when the unsaturated bromo
oxanorbornanone 6 was irradiated at 5£1022 M, for
30 min, in the presence of 5 equiv. of Et3N. It is worth
noting that no trace of alcohols10 such as 5 and 60 or an
Some years ago, we examined the photocyclization of
unsaturated halides.7 In this paper, we report that this photo-
chemical reaction is a fast, convenient and chemoselective
process that allows the formation of radicals either from
alkyl bromides or alkyl iodides and that this reaction can
be used in the synthesis of 0^)-bisabolangelone 0Scheme 1).
11
oxabridge opening products such as 500 and 600 were
Irradiation of compounds 1 and 2 at 254 nm in acetonitrile
01022 M), in the presence of triethylamine 010 equiv.) for
30 min leads to the formation of the cyclized product 78 in,
respectively, 94 and 90% yield. The reaction was
generalized to compounds 3 and 4. In the case of compound
3, two products 8 and 808a were formed in a ratio 85/15 and
in 80% yield. The irradiation of compound 4 afforded
compound 9, the result of a 5-exo-dig cyclization process,
detected when compounds 5 and 6 were irradiated in the
presence of 5 equiv. of Et3N for 30 min 0Scheme 2).
Under these photochemical conditions, the reduction of a
halide is faster than the reduction of a ketone. An amine±
halide exciplex is probably formed which leads to a radical
Rz and a halide-anion. The radical can be trapped very
ef®ciently by an internal p-bond system, or it can abstract
a hydrogen atom from the resulting amino radical±cation
intermediate12 when no unsaturation is present 0Scheme 3).
Keywords: radicals; photoreductive cyclization; bisabolangelone.
Corresponding author. Tel.: 133-1-40-79-44-29; fax: 133-1-40-79-46-
60; e-mail: janine.cossy@espci.fr
p
Due to the ef®cient formation of heterocyclic compounds
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020001)00357-X

5174
J. Cossy et al. / Tetrahedron 57 .2001) 5173±5182
Scheme 2. Irradiation of unsaturated halides in the presence of triethylamine.
Bisabolangelone is a sesquiterpene which was isolated from
umbelliferae such as Angelica silvestris L.,13,14 Angelica
koreana Max.,15 Angelica spp.,16 Pimpinella major
Huds.17 and Angelica pubescens f. biserrata.18 The structure
of bisabolangelone was established in 196614 and 1970.15
This compound shows antifeeding properties against insects
such as Mythimna unipuncta Haw. and Leptinotarsa
decemlineata Say.19,20 0^)-Bisabolangelone has been
previously synthesized in 17 steps via intermediate 21 by
using a dipolar 1,3-addition of acetonitrile oxide to
Scheme 3. Reduction of halides and the supposed mechanism.
from unsaturated halides when they are irradiated in the
presence of Et3N, the use of the photoreductive cyclization
was envisaged as a key step in a formal total synthesis of
0^)-bisabolangelone.
Scheme 4. Retrosynthetic analysis of 0^)-bisabolangelone.

J. Cossy et al. / Tetrahedron 57 .2001) 5173±5182
5175
5-methylcyclohex-2-enone 012) and the cyclization of a
g-acetylenic alcohol as the key steps.21
For our part, we envisaged the synthesis of the known inter-
mediate 21 from the unsaturated halide 14, as this
compound possesses the functional groups appropriate for
the synthesis of bisabolangelone 0Scheme 4).
The transformation of 5-methylcyclohex-2-enone 012)22 to
bromo ether 14 was achieved in 2 steps. Treatment of ketone
12 with ethylene glycol in the presence of p-toluenesulfonic
acid 0PTSA) 00.01 equiv.), in re¯uxing benzene for 3 h,23
afforded the expected 9-methyl-1,4-dioxaspiro[4.5]dec-6-ene
013) along with the undesired regioisomer 130. The forma-
tion of 130 was avoided when 12 was treated with ethylene
glycol in the presence of pyridinium p-toluenesulfonate
[PPTS 00.005 equiv.)] in gently re¯uxing benzene for 6 h.
Under these conditions, ketal 13 was isolated in 55% yield
0Scheme 5).
Scheme 5. Synthesis of ketal 13.
Ketal 13 reacted regioselectively and diastereoselectively
0dr: 92:8) with N-bromosuccinimide 0NBS) 01.25 equiv.)
and propargyl alcohol 036 equiv.) to produce the bromo
ether 14 in quantitative yield. The high regio- and diastereo-
selectivity can be explained by the formation of the bromo-
nium intermediate a which is attacked in a trans diaxial
fashion by propargyl alcohol on carbon C-3 due to the
presence of the ketal. It is worth noting that intermediate
b is not favored as the attack of b will lead to the twist
intermediate c 0Scheme 6).
The bicyclic structure of bisabolangelone was built up by
irradiation of 14 in the presence of Et3N 0hn, 254 nm; Et3N,
10 equiv.; CH3CN, 1022 M; 1 h). Under these conditions, a
5 exo-dig radical cyclization process takes place and affords
the bicyclic compound 15 in 88% yield. In compound 15,
the relative cis stereochemistry between H-3a, H-7a and the
methyl group on C-6, was con®rmed by NOE experiments
0Scheme 7).
Ozonolysis of 15 in a mixture of CH2Cl2/MeOH 01/1) led to
the corresponding ketone 16 084% yield). The seleno
compound 16f, from alkylation±selenation of ketone 16,
was envisaged as a precursor of diene 17. When 16 was
treated with LDA 01.2 equiv., THF, 2788C) followed by
Scheme 6. Attack of the bromonium intermediate a by propargyl alcohol.
Scheme 7. Synthesis of compound 15 and NOE experiments.

5176
J. Cossy et al. / Tetrahedron 57 .2001) 5173±5182
Scheme 8. Alkylation and selenation of 16.
the addition of 4-bromo-2-methyl-2-butene in the presence
of sodium iodide, the starting material 16 was entirely
recovered. When the reaction was conducted at 08C then
warmed up to rt for 12 h, two inseparable compounds 16a
and 16b, were isolated in 27% yield in the ratio 40/60. Due
to the non-selective alkylation reaction, the selenation of 16
was achieved ®rst. After treatment of ketone 16 with LDA
01.2 equiv., THF, 08C), phenylselenyl chloride was added
and the reaction mixture allowed to warm slowly to room
temperature 012 h). Under these conditions, two seleno
regioisomers 16c and 16d were isolated in 30% yield and
in a ratio of 1:1. Treatment of this mixture with LDA
01.2 equiv., THF, 08C) followed by the addition of
4-bromo-2-methyl-2-butene 008C!rt; 12 h), led to the
recovery of compound 16c 050%) and to the formation of
the alkylated product 16e 041%) separable by chromato-
graphy. As the desired compound 16f could not be prepared
through seleno derivatives, an aldol condensation followed
by a dehydration was envisaged as an alternative route
0Scheme 8).
Scheme 9. Transformation of 16 to 0^)-bisabolangelone.

J. Cossy et al. / Tetrahedron 57 .2001) 5173±5182
5177
Scheme 10. Synthesis of 0^)-bisabolangelone.
The aldol condensation was achieved by treatment of ketone
16 with LDA 02788C; 30 min; THF) followed by addition
of 3-methyl-2-butenal 02 equiv.; 2788C; 15 min). After
acidic work-up 0AcOH, ether, 2788C), the condensation
product 17 was isolated in 97% yield 0based on the
recovered starting material; conversion: 70%). Compound
17 was then treated with tri¯uoroacetic anhydride 03 equiv.)
in the presence of Et3N 06 equiv.) and a catalytic amount of
4-DMAP 008C; 2 h; 08C!rt; 20 h; then rt; 24 h) to produce
diene 18 083% yield).24 The introduction of the methyl
group at C-3 was achieved by addition of methylmagnesium
bromide 07 equiv.) in the presence of CeCl3 06 equiv.),
producing the tertiary alcohol 19 which was isolated in
96% yield. After silylation of the tertiary alcohol 0AgNO3;
TESCl; DMF)25 and deprotection of the ketal by using ceric
ammonium nitrate 0CAN)26 00.03 equiv.; CH3CN; 608C,
borate±HCl buffer) ketone 21 was obtained with an overall
yield of 58% for the two steps 0Scheme 9).
of 18.5%. 0Scheme 10). Since 21 has been converted to
0^)-bisabolangelone,21 the present synthesis constitutes a
short formal total synthesis. It is worth noting that, as
0S)-5-methylcyclohex-2-enone can be obtained in optically
pure form,27 natural 01)-bisabolangelone could be prepared
ef®ciently by using our strategy.
1. Experimental
1.1. General procedures
Unless otherwise speci®ed, materials were purchased from
commercial suppliers and used without further puri®cation.
THF and diethyl ether were distilled from sodium/benzo-
phenone ketyl immediately before use. Benzene, dichloro-
methane,
acetonitrile,
DMF,
triethylamine
and
diisopropylamine were distilled from calcium hydride
under argon. Moisture sensitive reactions were conducted
in oven or ¯ame-dried glassware under an argon atmo-
sphere. Flash-chromatography was carried out on Kieselgel
60 0230±400 mesh, Merck) and analytical thin-layer
chromatography was performed on Merck precoated silica
The photoreductive cyclization of unsaturated halides
affords heterocyclic compounds in good yields. By using
this reaction as a key step, 5-methylcyclohex-2-enone was
transformed to ketone 21 in nine steps with an overall yield

5178
J. Cossy et al. / Tetrahedron 57 .2001) 5173±5182
gel 060 F254). Melting points are uncorrected. Microanalyses
were performed at the Service de Microanalyse de
0d, Jˆ4.4 Hz, 1H) 4.26 0ddt, Jˆ12.9, 5.2, 1.5 Hz, 1H); 4.05
0ddt, Jˆ12.9, 6.3, 1.5 Hz, 1H), 4.03±3.89 0m, 2H); 3.59 0m,
1H), 2.41 0m, 1H), 2.00±1.89 0m, 2H), 1.54 0m, 1H); 13C
NMR 0CDCl3, 75 MHz): d 133.8, 117.4, 100.0, 68.7, 62.5,
49.1, 30.1, 23.3; EI MS m/z 0relative intensity) 222±220
0M1,1), 181±179 03), 165±163 050), 135±133 032), 55
0100).
Â
l'Universite Pierre et Marie Curie in Paris. Mass spectra
were obtained by GC/MS with electron impact ionization
by using a 5971 Hewlett Packard instrument at 70 eV: only
selected ions are reported. HRMS were performed at the
Laboratoire de Spectrochimie de l'Ecole Normale
Â
1
Superieure in Paris. H and 13C spectra were respectively
recorded on a Bruker AC 300 spectrometer at 300 and
75 MHz. Spectra were recorded in CDCl3 as solvent, and
chemical shifts 0d) were expressed in ppm relative to
1.2. General procedure for the irradiation
After dissolving the halide in freshly distilled CH3CN
01022 M), triethylamine 010 equiv.) was added. The
resulting solution was irradiated in 10 mm B quartz tubes
in a merry-go-round apparatus equipped with eight low
pressure Phillips TUV 15 lamps 0lirr: 254 nm). After
30 min or 1 h at 258C, the solvent was evaporated in
vacuo. The residue was puri®ed by ¯ash chromatography
on silica gel.
1
residual CHCl3 at dˆ7.27 for H and to CDCl3 at dˆ77.1
for 13C. 1H NMR J values are given in Hz. IR spectra were
recorded as neat ®lms 0NaCl cell) and KBr pellets for solids
on a Perkin±Elmer 298 or FT-IR 1600. Compounds 4,28 5,9
6,28 12,22 were prepared following known procedures.
1.1.1. trans-3-Bromo-2-ꢀpropargyloxy)tetrahydropyran
ꢀ1).29 To a solution of N-bromosuccinimide 01.28 g,
7.13 mmol, 1.2 equiv.) in propargyl alcohol 010 mL) at
2308C, a solution of dihydropyran 00.50 g, 0.54 mL,
5.90 mmol) in CH2Cl2 05 mL) was added dropwise. After
2 h at 2208C and 12 h at rt, an aqueous solution of NaOH
01N, 10 mL) was added and the reaction mixture was
extracted with CH2Cl2 03£20 mL). The organic phase was
washed with an aqueous NaOH solution 01N, 10 mL), dried
over MgSO4 and ®ltered. After evaporation of the solvent in
vacuo, the crude residue was puri®ed by ¯ash chromato-
graphy on silica gel 0Et2O/petroleum ether) to afford 1
01.10 g, 5.02 mmol, 85% yield). Spectral data were
consistent with those previously reported.27 1H NMR
0CDCl3, 300 MHz): d 4.83 0d, Jˆ3.7 Hz, 1H), 4.32 0dd,
Jˆ15.5, 2.6 Hz, 1H), 4.25 0dd, Jˆ15.5, 2.6 Hz, 1H), 4.00
0dt, Jˆ5.9, 4.0 Hz, 1H), 3.87 0ddd, Jˆ11.8, 8.5, 3.3 Hz, 1H),
3.59 0m, 1H), 2.47 0t, Jˆ2.6 Hz, 1H), 2.37 0m, 1H), 2.03±
1.88 0m, 2H), 1.50 0m, 1H); 13C NMR 0CDCl3, 75 MHz): d
98.7, 78.7, 74.8, 62.1, 54.5, 48.5, 29.2, 22.5; EI MS m/z
0relative intensity) 220±218 0M1, 3), 165±163 035), 136
0100).
1.2.1. ꢀ^)-ꢀ3aRS,7aSR)-3-Methylidenehexahydro-4H-
furo[2,3-b]pyran ꢀ7).8 7 was prepared by irradiation of 1
or 2. Spectral data of 7 thus obtained were in good agree-
ment with the reported data.8b Yield .90%. 1H NMR
0CDCl3, 300 MHz): d 5.15 0d, Jˆ3.7 Hz, 1H), 5.06 0m,
1H), 4.96 0dd, Jˆ5.3, 2.8 Hz, 1H), 4.58 0dq, Jˆ12.9,
2.2 Hz, 1H), 4.49 0dq, Jˆ12.9, 2.2 Hz, 1H), 3.86 0m, 1H),
3.44 0td, Jˆ11.4, 2.6 Hz, 1H), 2.64 0m, 1H), 2.03 0m, 1H),
1.91 0m, 1H), 1.62 0m, 1H), 1.29 0m, 1H); 13C NMR 0CDCl3,
75 MHz): d 146.7, 103.7, 101.4, 70.8, 64.4, 42.1, 22.2, 20.3;
EI MS m/z 0relative intensity) 140 0M1,1), 111 09), 94 041),
79 0100).
1.2.2. ꢀ^)-ꢀ3aRS,7aSR)-3-Methylhexahydro-4H-furo[2,3-
b]pyran ꢀ8) and ꢀ80).8a Structural data of 8 and 80 prepared
by irradiation of 3 are identical to those previously reported in
the literature.8a Yield: 80%. 1H NMR 0CDCl3, 300 MHz): d
5.29, 5.00 0d, Jˆ3 Hz, 1H), 4.30±3.50 0m, 4H), 2.78±2.20
0m, 1H), 2.10±1.20 0m, 5H), 1.00, 0.97 0d, Jˆ7.0 Hz, 3H); EI
MS m/z 0relative intensity) major isomer 142 0M1, 13), 141
0100), 127 02), 112 021), 97 052); minor isomer 142 0M1, 12),
141 0100), 127 02), 112 019), 97 034).
1.1.2. trans-3-Iodo-2-ꢀpropargyloxy)tetrahydropyran ꢀ2).
A similar procedure as for 1 was used. N-iodosuccinimide
01.60 g, 7.13 mmol, 1.2 equiv.), dihydropyran 00.50 g,
0.54 mL, 5.9 mmol), and propargyl alcohol 010 mL) afforded
2 01.26 g, 4.7 mmol, 80% yield) after puri®cation by ¯ash
1.2.3. Methyl ꢀ^)-ꢀ3aSR,4SR,6RS,6aRS)-6-methoxy-3-
methylidenehexahydrofuro[3,4-b]furan-4-acetate ꢀ9).
Irradiation of 0^)-428 00.92 g, 3.0 mmol) afforded after
¯ash chromatography 0Et2O, petroleum ether) 9 00.60 g,
1
chromatography on silica gel 0Et2O/petroleum ether). H
2.6 mmol, 88% yield). IR 0neat) 1735, 1660 cm21; H
1
NMR 0CDCl3, 300 MHz): d 4.75 0d, Jˆ2.6 Hz, 1H), 4.35
0dd, Jˆ15.1, 2.6 Hz, 1H), 4.29 0dd, Jˆ15.1, 2.6 Hz, 1H),
4.12 0dt, Jˆ7.4, 4.4 Hz, 1H), 3.88 0td, Jˆ11.0, 3.3 Hz, 1H),
3.63 0m, 1H), 2.46 0t, Jˆ2.6 Hz, 1H), 2.38 0m, 1H), 1.89±
1.76 0m, 2H), 1.57 0m, 1H); 13C NMR 0CDCl3, 75 MHz): d
96.6, 78.7, 74.8, 63.1, 54.6, 30.2, 28.1, 24.8; EI MS m/z
0relative intensity) 266 0M1, 3), 211 012), 182 047), 154
0100).
NMR 0CDCl3, 300 MHz): d 5.11 0m, 1H), 4.92 0m, 1H),
4.91 0s, 1H), 4.62±4.55 0m, 2H), 4.29±4.18 0m, 2H), 3.71 0s,
3H), 3.42 0dd, Jˆ7.0, 6.9 Hz, 1H), 3.33 0s, 3H), 2.64 0dd,
Jˆ16.5, 7.3 Hz, 1H), 2.56 0dd, Jˆ16.5, 7.0 Hz, 1H); 13C
NMR 0CDCl3, 75 MHz): d 171.3, 146.3, 108.4, 107.5,
88.2, 75.2, 72.3, 54.2, 51.6, 49.3, 35.9; EI MS m/z 0relative
intensity) 197 0M1231, 10), 168 020), 165 025), 126 0100),
108 038). Anal. calcd for C11H16O5 0228.24): C, 57.89; H,
7.07. Found: C, 58.18; H, 7.25.
1.1.3. trans-3-Bromo-2-ꢀallyloxy)tetrahydropyran ꢀ3).30
Same procedure as for the preparation of 1 starting with
dihydropyran 00.50 g, 0.54 mL, 5.9 mmol), N-bromosucci-
nimide 01.28 g, 7.13 mmol, 1.2 equiv.), and allyl alcohol
010 mL). Spectral data were consistent with those
previously reported.28 1H NMR 0CDCl3, 300 MHz): d 5.93
0dddd, Jˆ17.3, 10.3, 5.9, 5.2 Hz, 1H), 5.33 0ddd, Jˆ17.3,
3.3, 1.5 Hz, 1H), 5.21 0ddd, Jˆ10.3, 2.9, 1.1 Hz, 1H), 4.66
1.2.4. ꢀ^)-ꢀ1RS,4SR,6SR)-6-endo-Benzyloxy-7-oxabicy-
clo[2.2.1]heptan-2-one ꢀ10). Irradiation of the 7-oxabicy-
clo[2.2.1]-heptan-2-one 59 00.100 g, 0.37 mmol) afforded
after ¯ash chromatography 10 00.048 g, 0.22 mmol, 60%
1
yield). IR 0neat) 1765 cm21; H NMR 0CDCl3, 300 MHz):
d 7.30±7.42 0m, 5H), 4.87 0dd, Jˆ5.9, 5.5 Hz, 1H), 4.61 0d,

J. Cossy et al. / Tetrahedron 57 .2001) 5173±5182
5179
Jˆ11.0 Hz, 1H), 4.47 0d, Jˆ5.9 Hz, 1H), 4.44 0d,
Jˆ11.0 Hz, 1H), 4.26 0m, 1H), 2.57 0m, 1H), 2.38 0dddd,
Jˆ12.9, 9.6, 5.5, 2.6 Hz, 1H), 2.23 0d, Jˆ17.6 Hz, 1H), 1.67
0dd, Jˆ12.9, 2.6 Hz, 1H); 13C NMR 0CDCl3, 75 MHz): d
208.4, 137.0, 128.4, 128.4, 128.0, 127.9, 126.9, 81.0, 76.3,
76.0, 72.1, 43.7, 36.4; EI MS m/z 0relative intensity) 218
0M1, 1), 200 00.5), 190 00.6), 172 02), 91 0100).
13 00.308 g; 2.0 mmol, 1.0 equiv.) in propargyl alcohol
04 mL), at 08C, was added NBS 00.45 g, 2.50 mmol,
1.25 equiv.) in small portions. The reaction mixture was
stirred at 0±108C for 2 h. After removal of the excesss of
propargyl alcohol in vacuo, the reaction mixture was
quenched with saturated aqueous NaHCO3 solution
010 mL) and extracted with Et2O 02£10 mL). The combined
organic phases were dried over MgSO4, ®ltered and
evaporated. After ®ltration on silica gel of the crude reaction
mixture 0CH2Cl2), the solvent was removed in vacuo to
afford 14 00.576 g, 2.0 mmol, quantitative yield) as a
colorless liquid which crystallizes when cooled. Compound
14 was used in the following step without further puri®ca-
tion. Diastereomeric ratio 098:2) was measured by GC/MS
analysis. Rf: 0.4 0Et2O/petroleum ether: 1/2); IR 0neat) 3290,
1.2.5. ꢀ^)-ꢀ3aSR,4SR,7SR,7aRS)-3-Methylenehexahydro-
4,7-epoxybenzofuran-6ꢀ7H)-one ꢀ11). Irradiation of
compound 628 00.100 g, 0.41 mmol) in CH3CN
05£1022 M), for 30 min, in the presence of Et3N 05 equiv.)
afforded after ¯ash chromatography 0petroleum ether/
AcOEt: 3/2) 1100.042 g, 0.25 mmol) 098% yield, based on
1
recovered 6). IR 0neat) 1760, 1660, 1405 cm21; H NMR
1
2120 cm21; H NMR 0CDCl3, 300 MHz): d 4.25±4.21 0m,
0CDCl3, 300 MHz): d 5.08 0dt, Jˆ2.2, 2.1 Hz, 1H), 5.04 0td,
Jˆ2.4, 1.9 Hz, 1H), 4.92 0dddd, Jˆ8.5, 5.4, 1.1, 0.6 Hz,
1H), 4.89 0ttd, Jˆ5.9, 1.1, 1.0 Hz, 1H), 4.54 0m, 2H), 4.37
0dddd, Jˆ5.4, 1.1, 1.1, 0.6 Hz, 1H), 3.64 0m, 1H, H-3a), 2.46
0ddddd, Jˆ17.9, 5.9, 1.0, 0.9, 0.6 Hz, 1H), 2.35 0ddd,
Jˆ17.9, 1.0, 0.6 Hz, 1H); 13C NMR 0CDCl3, 75 MHz): d
207.4, 145.0, 107.9, 84.5, 82.6, 78.7, 76.9, 51.8, 39.6; EI MS
m/z 0relative intensity) 166 0M1, 6); 148 02); 137 011); 124
012); 109 036); 95 0100). HRMS calcd for C9H10O3
166.062992, found 166.06301.
2H), 4.11±3.90 0m), 2.44 0dd, Jˆ2.6, 2.2 Hz, 1H)), 2.12±
1.55 0m, 5H), 0.97 0d, Jˆ7.0 Hz, 3H); 13C NMR 0CDCl3,
75 MHz): d 108.3, 79.6, 78.1, 74.6, 65.5, 64.6, 56.8, 53.9,
38.6, 33.8, 25.0, 20.9; EI MS m/z 0relative intensity) 290±
288 0M1, 1), 275±273 0M2CH3, 2), 235 07), 233 09), 209
04), 179 013), 155 068), 113 0100). HRMS calcd for
C12H18O3Br 289.0439 079Br) 291.0420 081Br), found
289.0428 079Br) 291.0438 081Br).
1.3.4. ꢀ^)-ꢀ3aRS,6SR,7aSR)-6-Methyl-3-methylenehexa-
hydrospiro[benzofuran-4ꢀ2H),20-[1,3]dioxolane] ꢀ15).
Irradiation of 14 at 254 nm 00.722 g, 2.5 mmol, 1.0 equiv.)
for 1 h in CH3CN 0250 mL), in the presence of Et3N
03.5 mL, 25.0 mmol, 10.0 equiv.) afforded after ¯ash
chromatography on silica gel 0Et2O/petroleum ether: 1/2)
the bicyclic compound 15 00.462 g, 2.2 mmol, 88% yield)
as a colorless oil. Rf: 0.36 0Et2O/petroleum ether: 1/2); IR
0neat) 1670 cm21; 1H NMR 0CDCl3, 300 MHz): d 5.03 0m,
1H), 4.83 0m, 1H), 4.36 0br. d, Jˆ12.9 Hz, 1H), 4.10 0dm,
Jˆ12.9 Hz, 1H), 4.00 0m, 1H), 3.92±3.72 0m), 2.56 0br. d,
Jˆ4.4 Hz, 1H), 2.05±1.90 0m, 2H), 1.64 0dt, Jˆ12.5,
2.2 Hz, 1H), 1.21±1.10 0m, 1H), 1.02 0t, Jˆ12.5 Hz, 1H),
0.85 0d, Jˆ6.6 Hz, 3H); 13C NMR 0CDCl3, 75 MHz): d
149.0, 109.8, 105.8, 78.8, 70.9, 65.9, 64.1, 51.0, 43.1,
35.6, 24.3, 21.6; EI MS m/z 0relative intensity) 210 0M1,
11), 195 0M2CH3, 1), 181 03), 167 05), 148 09), 139 04), 122
0100), 113 068), 86 035).
1.3. Bisabolangelone intermediates
1.3.1. 9-Methyl-1,4-dioxaspirol[4.5]dec-6-ene ꢀ13). A
solution of 1222 03.3 g, 30.0 mmol, 1.0 equiv.), ethylene
glycol 02.0 mL, 36.0 mmol, 1.2 equiv.), PPTS 00.038 g,
0.005 equiv.) in benzene 080 mL) was heated for 6 h
under moderate re¯ux in a Dean±Stark unit. After cooling
the reaction mixture at rt, a saturated aqueous NaHCO3
solution 010 mL) was added. After dilution with Et2O
0100 mL), the organic layer was washed with brine
03£10 mL). After drying over MgSO4, the solvent was
removed in vacuo to afford an oil which was puri®ed by
¯ash chromatography on silica gel 0Et2O/petroleum ether:
1/4) to give 13 01.34 g, 8.7 mmol) 055% yield, based on
recovered 12). Rf: 0.56 0Et2O/petroleum ether: 1/4); IR
1
0neat) 1655 cm21; H NMR 0CDCl3, 300 MHz): d 5.87
0ddd, Jˆ10.1, 5.3, 2.2 Hz, 1H), 5.51 0dm, Jˆ10.1 Hz,
1H), 3.98±3.79 0m, 4H), 2.15±2.00 0m, 1H), 2.00±1.83
0m, 1H), 1.82±1.73 0m, 1H), 1.65±1.51 0m, 1H), 1.40 0t,
Jˆ13.1 Hz, 1H), 0.93 0d, Jˆ6.6 Hz, 3H); 13C NMR 0CDCl3,
75 MHz): d 131.9, 127.0, 106.3, 64.4, 64.1, 41.8, 33.4, 27.7,
21.5; Anal. calcd for C9H14O2: C, 70.10; H, 9.15. Found C,
69.81; H, 9.22.
1.3.5. ꢀ^)-ꢀ3aRS,6SR,7aSR)-6-Methyltetrahydrospiro-
[benzofuran-4ꢀ5H),20-[1,3]dioxolan]-3ꢀ2H)-one ꢀ16).
Ozone was bubbled into a solution of 15 00.483 g,
2.3 mmol, 1.0 equiv.) in methanol 015 mL) and CH2Cl2
015 mL) at 2788C, until a light blue color was persistent
0about 30 min). The resulting blue solution was purged with
nitrogen until colorless, then the reaction was quenched
with dimethyl sul®de 02 mL) at 2788C, and the resulting
mixture was allowed to warm slowly to rt. After stirring for
30 min at rt, the mixture was concentrated under reduced
pressure, and the residue was puri®ed by ¯ash chromato-
graphy on silica gel 0Et2O/petroleum ether: 1/1) to afford
ketone 16 00.409 g, 1.93 mmol, 84% yield) as a colorless
solid. Mp: 59±608C; Rf: 0.40 0Et2O/petroleum ether: 1/1);
IR 0neat): 1755 cm21; 1H NMR 0CDCl3, 300 MHz): d 4.27
0m, 1H), 3.96 0br. d, Jˆ16.6 Hz, 1H), 3.92±3.68 0m, 4H),
3.63 0d, Jˆ16.6 Hz, 1H), 2.42 0d, Jˆ5.1 Hz, 1H), 2.02 0m,
1H), 1.97 0dm, Jˆ15.1 Hz, 1H), 1.62 0ddd, Jˆ13.0, 2.6,
1.8 Hz, 1H), 1.19 0tdd, Jˆ15.1, 3.5, 2.6 Hz, 1H), 0.99 0t,
1.3.2. 9-Methyl-1,4-dioxaspiro[4.5]dec-7-ene ꢀ130). Follow-
ing the same procedure as described above but with PTSA
00.01 equiv.) and under ef®cient re¯ux 03 h),23 the desired
compound 13 as well as 130 were isolated. Rf: 0.58 0Et2O/
petroleum ether: 1/4); IR 0neat) 1655 cm21; 1H NMR 0CDCl3,
300 MHz): d 5.55 0br. s, 2H)), 4.05±3.90 0m, 4H), 2.50 0m,
1H), 2.35±2.10 0m, 2H), 1.86 0m, 1H), 1.40 0dd, Jˆ12.9,
10.7 Hz, 1H), 1.07 0d, Jˆ7.0 Hz, 3H); 13C NMR 0CDCl3,
75 MHz): d 132.7, 122.8, 108.1, 64.1, 64.1, 39.6, 35.3,
30.3, 20.9.
1.3.3. ꢀ^)-ꢀ6RS,7SR,9SR)-6-Bromo-9-methyl-7-ꢀpropar-
gyloxy)-1,4-dioxaspiro[4.5]decane ꢀ14). To a solution of

5180
J. Cossy et al. / Tetrahedron 57 .2001) 5173±5182
1H, Jˆ13.0 Hz, 1H), 0.85 0d, Jˆ6.6 Hz, 3H); 13C NMR
0CDCl3, 75 MHz): d 214.1, 108.7, 77.5, 72.4, 65.3, 64.1,
52.6, 42.8, 35.4, 23.8, 21.4; EI MS m/z 0relative intensity)
212 0M1, 17), 197 0M2CH3, 4), 183 010), 155 012), 139 04),
127 05), 113 0100), 99 09), 86 045), 69 010), 68 07); Anal. calcd
for C11H16O4: C, 62.25; H, 7.60. Found C, 62.32; H, 7.63.
to rt 012 h). A saturated aqueous NH4Cl solution 010 mL)
and Et2O 050 mL) were added. The organic layer was
separated, washed with brine 02£5 mL), and dried over
MgSO4. After ®ltration and evaporation of the solvent, the
crude residue was puri®ed. Flash chromatography on silica
gel 0AcOEt/petroleum ether: 1/9) afforded an inseparable
mixture of 16c and 16d 00.31 g, 0.84 mmol, 30% yield) in
a ratio 050/50) and ketone 16 00.220 g, 1.04 mmol, 37%
yield). 16c116d: Rf: 0.55 0AcOEt/petroleum ether: 1/6).
1.3.6. ꢀ^)-6-Methyl-2-ꢀ3-methylbut-2-enyl)-tetrahydro-
spiro[benzofuran-4ꢀ5H),20-[1,3]dioxolan]-3ꢀ2H)-one
ꢀ16a) and ꢀ^)-6-methyl-3a-ꢀ3-methylbut-2-enyl)-tetra-
hydrospiro[benzofuran-4ꢀ5H),20-[1,3]dioxolan]-3ꢀ2H)-
one ꢀ16b). A solution of LDA was prepared by adding
n-BuLi 00.96 mL, 2.5 M in hexanes, 2.4 mmol, 1.2 equiv.)
to a solution of diisopropylamine 00.34 mL, 2.4 mmol,
1.2 equiv.) in THF 08 mL) at 08C. After 15 min at 08C,
LDA was added to a solution of ketone 16 00.424 g,
2.0 mmol, 1.0 equiv.) in THF 02 mL) at 08C and stirred
for 30 min before the addition of 4-bromo-2-methyl-2-
butene 00.28 mL, 2.4 mmol, 1.2 equiv.). After 1 h at 08C,
the reaction mixture was allowed to warm up to rt for
12 h. A saturated aqueous NH4Cl solution 010 mL) and
Et2O 050 mL) were added. The organic layer was separated,
washed with brine 02£5 mL), and dried over MgSO4. After
®ltration and evaporation of the solvent, the crude residue
was puri®ed. Flash chromatography on silica gel 0AcOEt/
petroleum ether: 1/9) afforded an inseparable mixture of 16a
and 16b 00.15 g, 0.54 mmol, 27% yield) in a ratio 040/60)
and ketone 16 00.16 g, 0.76 mmol, 38% yield). 16a116b:
Rf: 0.58 0AcOEt/petroleum ether: 1/6); IR 0neat) 1765,
1
16c: H NMR 0CDCl3, 300 MHz): d 7.65±7.18 0m, 5H),
4.64 0m, 1H), 4.15±3.69 0m, 5H), 2.55 0d, Jˆ5.2 Hz, 1H),
2.30±1.05 0m, 5H), 0.92 0d, Jˆ6.2 Hz, 3H); 13C NMR
0CDCl3, 75 MHz): d 208.8, 135.1, 128.9, 128.1, 127.9,
108.8, 84.6, 75.5, 65.5, 64.4, 52.6, 42.8, 34.8, 24.1, 21.4;
EI MS m/z 0relative intensity) 368 0M11, 4), 280 06), 211
1
034), 157 06), 113 0100), 86 020), 77 05). 16d: H NMR
0CDCl3, 300 MHz): d 7.65±7.18 0m, 5H), 5.22±4.90 0m,
1H), 4.15±3.69 0m, 5H), 3.38 0d, Jˆ16.6 Hz, 1H), 2.30±
1.05 0m, 5H), 0.98 0d, Jˆ6.6 Hz, 3H); 13C NMR 0CDCl3,
75 MHz): d 213.4, 137.6, 129.4, 129.2, 125.2, 110.9, 80.3,
68.4, 65.9, 65.0, 59.8, 41.1, 32.6, 24.2, 17.8; EI MS m/z
0relative intensity) 368 0M11, 2), 212 013), 211 0100),
157 07), 155 011), 125 021), 113 017), 87 028).
1.3.8. ꢀ^)-6-Methyl-2-ꢀ3-methylbut-2-enyl)-3a-ꢀphenyl-
seleno)-tetrahydrospiro[benzofuran-4ꢀ5H),20-[1,3]diox-
olan]-3ꢀ2H)-one ꢀ16e). A solution of LDA was prepared by
adding n-BuLi 00.48 mL, 2.5 M in hexanes, 1.2 mmol,
1.2 equiv.) to a solution of diisopropylamine 00.17 mL,
1.2 mmol, 1.2 equiv.) in THF 06 mL) at 08C. After 15 min
at 08C, the resulting solution of LDA was added to the
mixture of regioisomers 16c and 16d 00.37 g, 1.0 mmol,
1.0 equiv.) in THF 04 mL) at 08C and after 30 min, 4-
bromo-2-methyl-2-butene 00.14 mL, 1.2 mmol, 1.2 equiv.)
was added. After 1 h at 08C, the cooling bath was removed
and the reaction mixture was stirred for 12 h at rt. A
saturated aqueous NH4Cl solution 05 mL) and Et2O
050 mL) were then added. The organic layer was separated
and washed with brine 02£5 mL), and dried over 0MgSO4).
After ®ltration and evaporation of the solvent, the crude
residue was puri®ed. Flash chromatography on silica gel
0AcOEt/petroleum ether: 1/9) furnished 16e 00.173 g,
0.41 mmol, 41% yield) and recovered 16c 00.187 g,
0.50 mmol, 50% yield). Rf: 0.70 0AcOEt/petroleum ether:
1755, 1670, 1630 cm21
.
16a: 1H NMR 0CDCl3,
300 MHz): d 5.25±5.17 0m, 1H), 4.51±4.45 0m, 1H),
4.08±3.72 0m, 5H), 2.53 0d, Jˆ5.1 Hz, 1H), 2.35±2.00
0m, 4H), 1.75±0.80 0m, 9H), 0.95 0d, Jˆ6.6 Hz, 3H); 13C
NMR 0CDCl3, 75 MHz): d 215.3, 134.6, 119.1, 108.7, 81.5,
74.8, 65.4, 64.3, 53.1, 43.0, 35.6, 29.0, 25.7, 23.8, 21.6,
17.7; EI MS m/z 0relative intensity) 280 0M1, 5), 265
0M2CH3, 1), 238 05), 237 016), 212 026), 183 07), 155
073), 139 08), 124 08), 113 0100), 112 023), 111 017), 87
1
012), 86 018), 69 029). 16b: H NMR 0CDCl3, 300 MHz):
d 4.97±4.88 0m, 1H), 4.20 0br. t, Jˆ2.9 Hz, 1H), 4.11 0dd,
Jˆ16.7, 0.7 Hz, 1H), 4.08±3.72 0m, 4H), 3.66 0d,
Jˆ16.7 Hz, 1H), 2.77±2.66 0m, 1H), 2.35±2.00 0m, 3H),
1.75±0.80 0m, 9H), 0.96 0d, Jˆ6.6 Hz, 3H). 13C NMR
0CDCl3, 75 MHz): d 216.6, 134.9, 119.1, 110.7, 80.5,
72.6, 64.9, 64.3, 55.3, 40.8, 34.4, 26.9, 25.7, 24.2, 21.5,
17.7; EI MS m/z 0relative intensity) 280 0M1, 3), 265
0M2CH3, 1), 251 01), 237 01), 235 01), 222 03), 211 013),
207 03), 163 03), 137 04), 114 09), 113 0100), 86 029), 69 012).
1/6); IR 0neat) 1760, 1580 cm21
;
1H NMR 0CDCl3,
300 MHz): d 7.68±7.55 0m, 2H), 7.32±7.23 0m, 3H),
5.07±4.97 0m, 1H), 4.64±4.54 0m, 1H), 4.17±3.63 0m,
5H), 2.70 0dd, Jˆ14.9, 6.4 Hz, 1H), 2.24 0dd, Jˆ14.9,
9.4 Hz, 1H), 2.19±2.00 0m, 2H), 1.76±1.10 0m, 3H), 1.73
0br. s, 3H), 1.62 0br. s, 3H), 0.95 0d, Jˆ6.6 Hz, 3H); 13C
NMR 0CDCl3, 75 MHz): d 211.2, 135.2, 134.7, 129.0,
128.9, 128.6, 118.8, 110.7, 85.3, 78.2, 65.0, 64.4, 56.1,
40.8, 33.7, 27.0, 25.8, 24.4, 21.5, 17.8.
1.3.7. ꢀ^)-6-Methyl-2-ꢀphenylseleno)-tetrahydrospiro-
[benzofuran-4ꢀ5H),20-[1,3]dioxolan]-3ꢀ2H)-one ꢀ16c) and
ꢀ^)-6-methyl-3a-ꢀphenylseleno)-tetrahydrospiro[benzo-
furan-4ꢀ5H),20-[1,3]dioxolan]-3ꢀ2H)-one ꢀ16d). A solu-
tion of LDA was prepared by adding n-BuLi 01.34 mL,
2.5 M in hexanes, 3.35 mmol, 1.2 equiv.) to a solution of
diisopropylamine 00.47 mL, 3.36 mmol, 1.2 equiv.) in THF
010 mL) at 08C. After 15 min at 08C, the resulting solution
of LDA was added to a solution of ketone 16 00.593 g,
2.8 mmol, 1.0 equiv.) in THF 02 mL) at 08C and after
30 min at 08C, a solution of phenylselenyl chloride
00.804 g, 4.2 mmol, 1.5 equiv.) and NaI 00.021 g,
0.14 mmol, 0.05 equiv.) in THF 02 mL) was added. After
1 h at 08C, the reaction mixture was allowed to warm slowly
1.3.9. ꢀ^)-ꢀ3aRS,6SR,7aSR)-2-ꢀ1-Hydroxy-3-methylbut-2-
enyl)-6-methyltetrahydrospiro[benzofuran-4ꢀ5H),20-
[1,3]dioxolan]-3ꢀ2H)-one ꢀ17). To a solution of diisopro-
pylamine 00.348 mL, 2.49 mmol, 1.2 equiv.) in THF
032.6 mL), at 08C, was added n-BuLi 00.995 mL, 2.5 M in
hexanes, 2.49 mmol). The resulting solution was stirred
10 min at 08C and cooled to 2788C and a solution of ketone
16 00.440 g, 2.08 mmol, 1.0 equiv.) in THF 03.6 mL) was
added dropwise. The resulting mixture was stirred for

J. Cossy et al. / Tetrahedron 57 .2001) 5173±5182
5181
30 min at 2788C and a solution of 3-methyl-2-butenal
00.34 mL, 4.15 mmol, 2 equiv.) was added dropwise. After
15 min at 2788C, the reaction mixture was quenched by
addition of a solution of AcOH 00.15 mL, 2.49 mmol,
1.2 equiv.) in Et2O 01.4 mL). The reaction mixture was
then warmed up to rt and H2O 03 mL) was added. The
aqueous layer was extracted with Et2O 03£30 mL). The
combined organic phases were washed with brine
03£15 mL), dried over MgSO4 and ®ltered. The solvent
was removed in vacuo to afford an oil which was puri®ed
by ¯ash chromatography on silica gel 0Et2O/pentane: 1/1) to
give ketone 16 00.130 g, 0.61 mmol, 29.5% yield) and 17
00.421 g, 1.42 mmol, 68.5% yield) as a mixture of two
diastereomers in a ratio 050/50). Rf: 0.32 0Et2O/pentane:
methylbut-2enylidene)hexahydrospiro[benzofuran-
31
4ꢀ2H),20-[1,3]dioxolan]-3-ol ꢀ19). Anhydrous CeCl3 was
dried just before use 0vacuo ca. 0.1 Torr, 1408C, 2 h) and
anhydrous THF 047 mL) freshly distilled was added with
vigorous stirring. The resulting suspension was stirred over-
night at rt, and a solution of 18 00.242 g, 0.87 mmol,
1 equiv.) in THF 047 mL) was added. After 3 h at rt, methyl-
magnesium bromide 02.03 mL, 3 M in Et2O, 6.09 mmol,
7 equiv.) was added with vigorous stirring at 08C. After
15 min, the reaction was quenched with brine 010 mL) and
diluted with Et2O 040 mL). The organic layer was separated
and the aqueous layer was extracted with Et2O 03£40 mL).
The combined organic phases were washed with an aqueous
saturated NaHCO3 solution 015 mL) and brine 015 mL).
After drying over MgSO4 and evaporation of the solvent,
the crude residue was puri®ed by ¯ash chromatography on
silica gel 0Et2O/pentane: 1/1) to give 19 00.245 g,
0.84 mmol, 96% yield) as a solid. Mp 1518C; Rf: 0.38
1
1/1); IR 0neat) 3470, 1750, 1675 cm21; H NMR 0CDCl3,
300 MHz): d 5.37 0dm, Jˆ9.2 Hz, 0.5H), 5.29 0dm,
Jˆ9.2 Hz, 0.5H), 4.71±462 0m, 2£0.5H), 4.61±4.53 0m,
2£0.5H), 3.99±3.69 0m, 5H), 2.52 0br. d, Jˆ6.1 Hz,
0.5H), 2.51 0m, 0.5H), 2.50 0br. d, Jˆ6.1 Hz, 0.5H), 2.20
0m, 0.5H), 2.15±2.00 0m, 2H), 1.68 0m, 4H), 1.64 0d,
Jˆ1.5 Hz, 1.5H), 1.60 0d, Jˆ1.1 Hz, 1.5H), 1.26±1.12 0m,
1H), 1.13 0td, Jˆ12.9, Jˆ3.3 Hz, 1H), 0.90 0d, Jˆ6.6 Hz,
1.5H), 0.89 0d, Jˆ6.6 Hz, 1.5H); 13C NMR 0CDCl3,
75 MHz): d 214.3, 214.0, 137.0,123.2, 123.0, 108.8,
108.7, 83.9, 83.5, 77.2, 76.8, 69.4, 69.0, 65.4, 65.3, 64.3,
64.2, 53.5, 53.3, 53.1, 42.9, 35.8, 35.7, 25.8, 25.7, 23.7,
23.6, 21.4, 18.2; Anal. calcd for C16H24O5: C, 64.85; H,
8.16. Found C, 64.37; H, 7.88.
1
0Et2O/pentane: 1/1); IR 0KBr) 3510, 1680, 1635 cm21; H
NMR 0CDCl3, 300 MHz): d 6.05 0dm, Jˆ11.4 Hz, 1H), 5.32
0d, Jˆ11.4 Hz, 1H), 4.45 0m, 1H), 4.14±3.92 0m, 4H), 3.23
0br. s, 1H), 2.24 0d, Jˆ5.2 Hz, 1H), 2.17 0dm, Jˆ14.7 Hz,
1H), 1.98 0m, 1H), 1.84 0dm, Jˆ13.6 Hz, 1H), 1.78 0br. s,
3H), 1.71 0br. s, 3H), 1.49 0br. s, 3H), 1.26 0m, 1H),
0.98 0dd, Jˆ13.6, 11.8 Hz, 1H), 0.95 0d, Jˆ7.0 Hz, 3H);
13C NMR 0CDCl3, 75 MHz): d 161.3, 130.1, 118.3,
110.2, 91.6, 79.0, 77.5, 64.1, 62.1, 51.0, 40.8, 35.9,
28.7, 25.9, 23.6, 21.1, 18.0; EI MS m/z 0relative inten-
sity) 295 0M11, 19), 294 0M, 100), 277 06), 276 029),
189 011), 162 017), 161 014), 155 057), 154 019), 153
014), 139 015), 125 030), 113 096), 112 032), 111 086),
95021), 81 014), 69 022). HRMS calcd for C17H26O4
294.1831, found 294.1825.
1.3.10. ꢀ^)-ꢀ3aRS,6SR,7aSR)-6-Methyl-2-ꢀ3-methylbut-2-
enylidene)-tetrahydrospiro[benzofuran-4ꢀ5H),20-[1,3]-
dioxolan]-3ꢀ2H)-one ꢀ18). The mixture of aldols 17
00.222 g, 0.80 mmol, 1 equiv.) was dissolved in CH2Cl2
06 mL) and cooled at 08C. Triethylamine 00.67 mL,
4.8 mL, 6 equiv.), a catalytic amount of 4-DMAP were
added to the solution, and tri¯uoroacetic anhydride
00.34 mL, 2.4 mmol, 3 equiv.) in CH2Cl2 03 mL) was then
added dropwise at 08C over a period of 30 min. The mixture
was stirred at 08C for 2 h and then warmed up to rt very
slowly 020 h). After 24 h at rt, the reaction mixture was
quenched by addition of a saturated aqueous NaHCO3 solu-
tion 03 mL), water 03 mL) and Et2O 010 mL). The organic
layer was separated and the aqueous layer was extracted
with Et2O 03£15 mL). The combined organic phases were
washed with brine 010 mL), dried over MgSO4 and ®ltered.
The solvent was removed under reduced pressure and the
residue was puri®ed by ¯ash chromatography on silica gel
0Et2O/pentane: 1/3) to give 18 00.185 g, 0.67 mmol, 83%
yield) as a white solid. Mp: 148±1498C; Rf: 0.60 0Et2O/pen-
1.3.12. ꢀ^)-ꢀ3RS,3aRS,6SR,7aSR)-3,6-Dimethyl-2-ꢀ3-
methylbut-2-enylidene)-3-[ꢀtriethysilyl)oxy]-hexahydro-
spiro[benzofuran-4ꢀ2H),20-[1,3]dioxolane ꢀ20).
T o a
solution of alcohol 19 00.176 g, 0.60 mmol, 1 equiv.) in
DMF 04 mL) was added AgNO3 00.204 g, 1.2 mmol,
2 equiv.). When all the silver nitrate was dissolved 0about
2 min), triethylsilyl chloride 00.20 mL, 1.2 mmol, 2 equiv.)
was added dropwise. The reaction mixture was stirred for
1.5 h at rt, AgNO3 00.204 g, 1.2 mmol, 2 equiv.) and
triethylsilyl chloride 00.20 mL, 1.2 mmol, 2 equiv.) were
added again. After 1.5 h at rt, the reaction mixture was
diluted with Et2O 020 mL) and ®ltered into a cold 008C)
aqueous 5% NaHCO3 solution 016 mL). The organic
phase was separated and the aqueous layer was
extracted with Et2O 03£30 mL). The combined organic
phases were washed with H2O 03£10 mL), dried over
MgSO4 and ®ltered. The solvent was removed in vacuo to
afford an oil which was puri®ed by ¯ash chromatography on
silica gel 0Et2O/pentane: 1/5) to afford 20 00.220 g,
0.54 mmol, 90% yield) as an oil and alcohol 19 00.014 g,
0.05 mmol, 8% yield). Rf: 0.68 0Et2O/pentane: 1/5); IR
1
tane: 1/3); IR 0KBr) 1730, 1630 cm21; H NMR 0CDCl3,
300 MHz): d 6.25 0d, 1H, Jˆ12.1 Hz, 1H), 6.13 0dm, 1H,
Jˆ12.1 Hz, 1H), 4.58 0m, 1H), 4.07 0m, 1H), 3.92±3.74 0m,
3H), 2.72 0d, Jˆ6.3 Hz, 1H), 2.25 0dm, Jˆ14.7 Hz, 1H),
2.13 0m, 1H), 1.87 0br. s, 3H), 1.83 0br. s, 3H), 1.74 0dm,
Jˆ13.7 Hz, 1H), 1.44±1.10 0m, 2H), 0.99 0d, Jˆ6.6 Hz,
3H); 13C NMR 0CDCl3, 75 MHz): d 198.5, 147.6, 142.7,
118.6, 109.0, 102.5, 77.7, 65.6, 64.4, 52.2, 43.1, 35.4,
26.5, 23.7, 21.4, 18.7; EI MS m/z 0relative intensity) 279
0M11, 8), 278 0M, 45), 263 014), 155 038), 139 010), 113
0100), 96 038), 81 016). HRMS calcd for C16H22O4 278.1518,
found 278.1520.
1
0neat) 1665, 1630 cm21; H NMR 0CDCl3, 300 MHz): d
5.97 0dm, Jˆ11.0 Hz, 1H), 5.17 0d, Jˆ11.0 Hz, 1H), 4.51
0m, 1H), 3.90±3.79 0m, 4H), 2.13±1.91 0m, 4H), 1.72 0br. s,
3H), 1.65 0m, 1H), 1.64 0br. s, 3H), 1.51 0s, 3H), 1.31 0m,
1H), 0.98 0d, Jˆ7.0 Hz, 3H), 0.88 0t, Jˆ7.9 Hz, 9H), 0.57
0q, Jˆ7.9 Hz, 6H); 13C NMR 0CDCl3, 75 MHz): d 159.5,
130.7, 118.4, 110.6, 94.3, 78.9, 77.7, 64.1, 63.6, 54.1, 38.9,
34.5, 26.7, 26.1, 25.9, 19.9, 17.9, 6.9, 6.5; EI MS m/z
1.3.11. ꢀ^)-ꢀ3RS,3aRS,6SR,7aSR)-3,6-Dimethyl-2-ꢀ3-

5182
J. Cossy et al. / Tetrahedron 57 .2001) 5173±5182
6. Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.; Okawara, M.
J. Am. Chem. Soc. 1982, 104, 5564.
0relative intensity) 409 0M11, 29), 408 0M, 96), 394 014),
393 049), 305 07), 277 08), 251 010), 239 010), 226 019), 225
0100), 189 040), 157 030), 113 032), 87 014), 75 014). HRMS
calcd for C23H40O4Si 408.2696, found 408.2695.
7. Cossy, J.; Ranaivosata, J.-L.; Bellosta, V. Tetrahedron Lett.
1994, 35, 8161.
8. 0a) Torri, S.; Inokuchi, T.; Yukawa, T. J. Org. Chem. 1985, 50,
5875. 0b) Inokuchi, T.; Kawafuchi, H.; Aoki, K.; Yoshida, A.;
Torii, S. Bull. Chem. Soc. Jpn 1994, 67, 595.
1.3.13. ꢀ^)-ꢀ3RS,3aRS,6SR,7aSR)-3,6-Dimethyl-2-ꢀ3-
methylbut-2-enylidene)-3-[ꢀtriethysilyl)oxy]-hexahydro-
[benzofuran-4ꢀ2H)-one ꢀ21). Solid cerium ammonium
nitrate 00.004 g, 0.03 equiv.) was added to a solution of
ketal 20 00.090 g, 0.22 mmol, 1 equiv.) in CH3CN
00.4 mL) and borate±HCl buffered solution 0Merck, pH 8,
0.5 mL). The resulting solution was heated at 608C for 24 h.
After cooling to rt, H2O 01 mL) was added. The organic
layer was separated, and the aqueous phase was extracted
with CH2Cl2 03£5 mL). The combined organic extracts
were dried over MgSO4, ®ltered, and the solvent was
removed under vacuo. The crude residue was puri®ed by
¯ash chromatography on silica gel to afford 21 00.048 g,
0.13 mmol, 60% yield) as a colorless solid. Physical and
spectral data are identical to those reported previously.21b
Mp 64±658C 0lit.21b 65±668C); Rf: 0.42 0Et2O/petroleum
9. Reymond, J.-L.; Pinkerton, A. A.; Vogel, P. J. Org. Chem.
1991, 56, 2128.
10. Cohen, S. G. Chem. Rev. 1973, 73, 141.
11. 0a) Cossy, J.; Ranaivosata, J.-L.; Bellosta, V.; Ancerewicz, J.;
Ferritto, R.; Vogel, P. J. Org. Chem. 1995, 60, 8351.
0b) Cossy, J.; Ranaivosata, J.-L.; Bellosta, V. Tetrahedron
Lett. 1995, 36, 2067.
12. 0a) For the behaviour of the amino radical-cation see Ref. 11.
Â
0b) Guha, M. PhD Thesis, Universite Paris VI, France, 1996.
13. Khadzhai, Y. L.; Sokolova, V. E. Farmakol. i. Toksikol. 1960,
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55, 2920.
14. Novotny, L.; Samek, Z.; Sorm, F. Tetrahedron Lett. 1966, 30,
2541.
1
ether: 1/5); IR 0KBr) 1703, 1665, 1630 cm21; H NMR
15. Hata, K.; Kozowa, M.; Baba, K.; Konoshima, M.; Chi, H.
J. Tetrahedron Lett. 1970, 4379.
0CDCl3, 300 MHz): d 5.97 0dm, Jˆ11.4 Hz, 1H), 5.22 0d,
Jˆ11.4 Hz, 1H), 4.66 0ddd, Jˆ9.1, Jˆ8.8 and 6.0 Hz, 1H);
2.64 0d, Jˆ8.8 Hz, 1H), 2.47 0dd, Jˆ16.2, 5.5 Hz, 1H), 2.33
0m, 1H), 2.14±2.02 0m, 2H), 1.89 0m, 1H), 1.74 0s, 3H), 1.66
0br. s, 3H), 1.50 0s, 3H), 0.90, 0d, Jˆ7.4 Hz, 3H), 0.83 0t,
Jˆ7.8 Hz, 9H), 0.53 0q, Jˆ7.8 Hz, 6H); 13C NMR 0CDCl3,
75 MHz): d 209.1, 156.9, 132.5, 117.9, 95.9, 81.2, 78.0,
60.3, 48.0, 35.1, 26.1, 25.9, 24.9, 19.9, 18.0, 6.7, 6.1; EI
MS m/z 0relative intensity) 365 0M11, 8), 364 0M, 27), 349
09), 335 021), 239 09), 226 021), 225 0100), 211 04), 189 05),
103 08), 87 07), 75 011). HRMS calcd for C21H36O3Si
364.2434, found 364.2431.
16. Chi, H. J. J. Pharm. Soc. Korea 1975, 19, 115.
17. Stahl, E.; Herting, D. Phytochemistry 1976, 999.
18. Liu, J.-H.; Zschocke, S.; Bauer, S. Phytochemistry 1998, 49,
211.
19. Muckensturm, B.; Duplay, D.; Robert, P. C.; Simonis, M. T.;
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20. Navrot, J.; Harmatha, J.; Novotny, L. Biochem. Syst. Ecol.
1984, 12, 99.
21. 0a) Riss, B.; Muckensturm, B. Tetrahedron Lett. 1986, 27,
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2591.
22. Blanchard, J. P.; Goering, H. L. J. Am. Chem. Soc. 1951, 73,
5863.
23. Cavill, G. W. K.; Goodrich, B. S.; Laine, D. G. Aust. J. Chem.
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Acknowledgements
24. Narasaka, K. Org. Synth. 1987, 65, 12.
25. 0a) Hakimelahi, G. H.; Proba, Z. A.; Ogilvie, K. K.
Tetrahedron Lett. 1981, 22, 4775. 0b) Ogilvie, K. K.;
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Two of us 0J.-L. R.) and 0B. G.) thank the MRES for a grant.
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