Ring-closing metathesis in the synthesis of BC ring-systems of taxol

Article abstract of DOI:10.1002/chem.200800774

BC ring-systems of taxol with different or no protecting group for the C1,C2-diol moiety have been efficiently synthesized. The eight-membered B ring is formed by a ring-closing metathesis reaction (RCM) between the C10 and C11 carbon atoms. The influence

Full text of DOI:10.1002/chem.200800774

DOI: 10.1002/chem.200800774
Ring-Closing Metathesis in the Synthesis of BC Ring-Systems of Taxol
Cong Ma,[a] StØphanie Schiltz,[a] Xavier F. Le Goff,[b] and Jolle Prunet*[a]
Abstract: BC ring-systems of taxol with different or no protecting group for the
C1,C2-diol moiety have been efficiently synthesized. The eight-membered B ring
is formed by a ring-closing metathesis reaction (RCM) between the C10 and C11
carbon atoms. The influence of the 1,2-diol protecting group on the RCM reaction
has been studied in detail.
Keywords: metathesis
chemistry · ruthenium · synthesis ·
taxol
·
organic
Introduction
Taxol (1) and Taxotere (2) are very effective agents for the
treatment of breast and ovarian cancer worldwide.[1] In spite
of numerous synthetic approaches, including six total syn-
theses,[2] they still constitute a remarkable challenge for or-
ganic chemists because of their sterically hindered and
highly functionalized structures.
Ring-closing metathesis (RCM) has been shown to be a
very versatile and efficient tool for the synthesis of natural
products.[3] During our previous studies towards the synthe-
sis of taxol, we observed the first formation of a trans cyclo-
octene by RCM, which closed the B-ring between C9 and
C10.[4] We then envisioned a semiconvergent retrosynthesis
of compound 3, which is an intermediate described by
Holton in his synthesis of taxol (Scheme 1). The A ring
would be formed at a late stage by performing an intramo-
lecular aldol reaction between the two ketone groups at C11
and C13 in compound 4.[5] The B ring of 5 would be formed
by ring-closing metathesis between the two alkenes at C10
and C11. The metathesis precursor 6 would be prepared by
a Shapiro reaction between the lithium derivative of hydra-
zone 8 and aldehyde 7. Here, we wish to report the synthesis
Scheme 1. Retrosynthesis of taxol.
[a] C. Ma, Dr. S. Schiltz, Dr. J. Prunet
Laboratoire de Synth›se Organique
CNRS UMR 7652, École Polytechnique, DCSO
91128 Palaiseau Cedex (France)
of models of compound 5, with no alkoxy group at C7 and
no ketal function at C13. In addition to our preliminary
study,[6] the influence of the group protecting the C1,C2-diol
moiety has been thoroughly studied.
Fax : (+33)169-335-972
E-mail: joelle.prunet@polytechnique.fr
[b] Dr. X. F. Le Goff
Laboratoire HØtØtoØlØments et Coordination
CNRS UMR 7653, École Polytechnique, DCPH
91128 Palaiseau Cedex, (France)
Results and Discussion
Aldehyde 9 was prepared as a racemic mixture, according to
our previous work.[6] Ketone 10 was synthesized in an excel-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800774.
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lent overall yield by a Barbier reaction between prenyl bro-
mide and valeraldehyde,[7] followed by oxidation of the re-
sulting alcohol with iodoxybenzoic acid.[8] Transformation of
this ketone to aldehyde 9 was effected by conversion to cya-
nohydrin 11 with trimethylsilyl cyanide in the presence of
ZnI2, and reduction of the latter by DIBAL-H (Scheme 2).[9]
Scheme 2. Synthesis of racemic aldehyde 9: a) Prenyl bromide, Zn, aq.
NH4Cl, THF, 208C; b) IBX, THF, 208C, 98% over 2 steps; c) TMSCN,
ZnI2, CH2Cl2, reflux, 97%; d) DIBAL-H, CH2Cl2, À78–08C; silica gel,
À208C, 85%. IBX=iodoxybenzoic acid, TMSCN=trimethylsilyl cya-
nide, DIBAL-H=diisobutyl aluminum hydride.
Scheme 4. Diastereoselective Shapiro coupling reaction. a) tBuLi, THF,
À788C; b) HCl (1n), 208C, 43% for 15a, 37% for 15b, respectively.
As shown in Scheme 3, the synthesis of optically active
hydrazone 12 began with known diol 13,[10] which could be
synthesized according to dꢁAngeloꢁs method.[11] Protection
were produced in 71% combined yield after hydrolysis of
the TMS ether. The present route saves two steps, and the
Shapiro coupling, although a delicate reaction to perform,
leads to the desired diols in a high yield (80%).
The coupling reaction is very diastereoselective in favor
of the trans diols (two isomers are obtained because the al-
dehyde 9 is racemic).[12] This high diastereoselectivity had al-
ready been obtained for similar coupling reactions realized
during previous studies on taxol precursors in our laboratory
(Scheme 4).[13] The structure of diol 15b was determined by
X-ray analysis;[6] this diastereomer possesses the configura-
tion found in taxol at the C1, C2, and C8 stereocenter. The
structure of compound 15a was secured by X-ray analysis of
its triol derivative 16a (Scheme 5).[6]
Scheme 3. Synthesis of enantiopure hydrazone (À)-12: a) DMAP·TrCl,
CH2Cl2, reflux; IBX, THF, 208C, 77% over 2 steps; b) TrisNHNH2,
concd HCl, THF, 208C, 96%. DMAP=4-dimethylaminopyridine, Tr=
trityl, Tris=triisopropylbenzenesulfonyl.
of the primary alcohol of compound 13 as its trityl ether, fol-
lowed by oxidation of the secondary alcohol provided
ketone 14, which was efficiently converted to hydrazone 12
with trisyl hydrazine under acidic conditions.
The Shapiro coupling reaction of racemic aldehyde 9 and
enantiopure hydrazone 12 was then studied. Although
nBuLi is a common choice for the base employed in the
Shapiro reaction, use of tBuLi was proven necessary in our
case. An unsuccessful trial with MeLi confirmed the impact
of the pKa of the base on our Shapiro coupling. The desired
product was obtained as a mixture of two diastereomers.
Deprotection of the tertiary hydroxy site by removal of the
TMS group was then immediately performed to provide
diols 15a and 15b, which were easily separated by column
chromatography in very good yield (Scheme 4).
In our preliminary study,[6] ketone 14 was converted into
the corresponding vinyl bromide in three steps, and the cou-
pling reaction effected by lithium–halogen exchange to form
the required vinyl lithium intermediate. Diols 15a and 15b
Scheme 5. Synthesis of metathesis precursors, carbonates 18a and 18b:
a) Amberlyst H-15, MeOH, 208C; b) PBu3, o-nitrophenylselenocyanate,
THF, 208C; c) carbonyl diimidazole, toluene, reflux; d) H2O2, THF, 208C.
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J. Prunet et al.
Both isomers 15a and 15b were converted to substrates
for the metathesis reaction, to evaluate the influence of the
relative stereochemistry of the diol motif and the C8 stereo-
center on the metathesis reaction. All the following reac-
tions have been performed on the two diastereomers sepa-
rately. The primary trityloxy group had to be converted into
a terminal olefin. For this purpose, triols 16a and 16b were
first obtained by treatment of 15a and 15b with Amberlyst-
15 resin in methanol (Scheme 5). The terminal olefin was
then obtained by using Griecoꢁs method: after selective
transformation of the primary alcohol into the correspond-
ing selenide (which also served as a temporary protecting
group), diols 17a and 17b were protected as their carbonate
derivatives, and final treatment with H2O2 led to the meta-
thesis precursors 18a and 18b. The three steps (from the
triols) were performed without any intermediate purifica-
tion. This sequence is slightly more efficient than the one
we previously used (protection of the diol as the carbonate,
hydrolysis of the trityl group, and elimination of the alcohol
with Griecoꢁs procedure).[6]
As shown in Scheme 8, direct transformation of triol 16a
into the corresponding diene by Griecoꢁs method led to the
corresponding epoxide product 21a in modest yield, along
with decomposition products. However, use of ammonium
molybdate tetrahydrate in H2O2 at À108C for 5 min for the
oxidation step afforded the desired dienes 22a and 22b in
excellent yields.
Metathesis precursors 19a and 19b, in which the diol
moiety is protected as an acetonide were also synthesized
(Scheme 6). Treatment of triols 16a and 16b with 2,2-dime-
Scheme 8. Synthesis of metathesis precursors 22a and 22b: a) PBu3, o-ni-
trophenylselenocyanate, THF, 208C; b) H2O2, THF, 208C, 20%; c) PBu3,
o-nitrophenylselenocyanate, THF, 208C; d) H2O2, (NH4)6Mo7O24·4H2O,
THF, À108C.
The ring-closing metathesis experiments were first per-
formed with the carbonate substrates. Diastereomer 18a,
which possesses the wrong stereochemistry for taxol at C1
Scheme 6. Synthesis of metathesis precursors, acetonides 19a and 19b:
a) 2,2-Dimethoxypropane, CSA, 208C; b) PBu3, o-nitrophenylselenocya-
nate, THF, 208C; c) H2O2, THF, 208C. CSA=camphor-10-sulfonic acid.
and C2, did not furnish any cyclized product, either with
[14]
Grubbs first-(Grubbs 1)
or second-generation (Grubbs
2)[15] catalysts in 1,2-dichloroethane at reflux. Longer reac-
tion time (several days) with the latter complex only result-
ed in decomposition. However, when the other diastereomer
18b was exposed to 30 mol% of Grubbs 1 catalyst, the cor-
responding cyclooctene 23b was obtained in 65% yield as
the Z isomer exclusively after several days at ambient tem-
perature (Table 1). No trans cyclooctene was detected, con-
trary to our previous study in which the metathesis closed
the B ring between C9 and C10.[4a] Use of second-generation
thoxypropane and CSA furnished the corresponding aceto-
nides, then Griecoꢁs method afforded the desired products
19a and 19b in good overall yields. Once again, no inter-
mediate purification was necessary.
Besides the two precursors 18 and 19, which possess a
five-membered protecting group for the C1,C2- diol, we de-
cided to prepare two other types of precursors, in which the
diol moiety was monoprotected or not protected at all, to
test the influence of the conformation of the dienes on the
ring-closing metathesis reaction. Simple treatment of dienes
18a and 18b with PhLi provided ring-opened products 20a
and 20b, respectively (Scheme 7).
Table 1. Metathesis of carbonates 18b.[a]
Catalyst ([mol%])
T [8C]
t
Yield [%]
Grubbs 1 (30)
Grubbs 2 (10)
20
80
80
5 d[b]
1 h
1 h
65
69
72
[RulMes] (5)
[a] Reaction conditions: a) catalyst, 1,2-dichloroethane. [b] The reaction
was started with 10 mol% Grubbs 1, and 5 mol% additional catalyst was
added every day.
Scheme 7. Synthesis of metathesis precursors 20a and 20b: a) PhLi, THF,
À788C.
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catalysts Grubbs 2 or [RuIMes][16] also led to 23b in a com-
parable yield (69 and 72%, respectively), but the reaction
was complete in only 1 h.
The acetonide derivatives were then subjected to Grubbs
2 catalyst. After 30 min in CH2Cl2 at reflux, diastereomer
19a only led to dimeric products 24 and 25 in a 3:1 ratio, fa-
voring the head-to-head dimer (Scheme 9). This result con-
ethane at reflux for 36 h or with Grubbs 2 in dichlorome-
thane at reflux for 18 h furnished the same cyclooctene 27a
in 71 and 84% yield, respectively. No product was observed
at a lower temperature. Diastereomer 20b (the desired dia-
stereomer), when reacted with Grubbs 1 and 2, also afford-
ed the corresponding cyclooctene 27b, but the reaction con-
ditions were milder. Bicycle 27b was obtained in 78% yield
by treatment with Grubbs 1 at 408C and in quantitative
yield by treatment with Grubbs 2 at ambient temperature
after only 15 min (Table 2).
Finally, diols 22a and 22b were exposed to the different
Grubbs catalysts. Unfortunately diol 22a (the wrong diaste-
reomer) only led to decomposition. However, diastereomer
22b (the desired diastereomer) was successfully converted
into the corresponding cyclooctene 28b as colorless needle
crystals in quantitative yield after 1 h in dichloromethane at
reflux (Scheme 10). The structure of this cyclooctene was
confirmed by X-ray analysis.[17] The decomposition or low
reactivity[18] or occasional loss of methylene[19] in ring-closing
metathesis reactions in the presence of a diol were not ob-
served in our case.
Scheme 9. Metathesis of acetonides 19a and 19b: a) 5 mol% Grubbs 2,
CH2Cl2, reflux, 87% for the mixture of 24 and 25; b) 5 mol% Grubbs 2,
1,2-dichloroethane, reflux, quant.
firmed that the less-hindered C10 olefin is the site of initial
carbene formation. A prolonged reaction time did not show
a significant effect. Cyclization of the other diastereomer
19b was exceptionally rapid, and bicycle 26b was obtained
in quantitative yield after only 5 min in 1,2-dichloroethane
at reflux.
Our attempt at the ring-closing reaction with dienes 20a
and 20b showed an interesting conformation/reactivity rela-
tionship. Treatment of benzoate 20a (wrong diastereomer)
with both Grubbs 1 and 2 catalysts provided the desired cy-
clized product (Table 2). These results tend to prove that
the cyclic protecting groups lock the metathesis precursors
in an unfavorable conformation for cyclization of the wrong
diastereomer. Heating 20a with Grubbs 1 in 1,2-dichloro-
Scheme 10. Metathesis of diol 22b: a) 5 mol% Grubbs 2, CH2Cl2, reflux,
quant.; b) LiAlH4, THF, 08C, 83%.
The 1H NMR spectrum of cyclooctene 27b exhibits a
broadening of signals for the protons at C4 and C10, which
is probably due to the presence of rotamers induced by the
benzoate group. The expected NMR spectrum could be ob-
served by heating 27b at 658C in deuterated DMSO. This
compound was also correlated to cyclic diol 28b by reduc-
tion of the benzoate ester with LiAlH4 (Scheme 10).
Table 2. Metathesis of monoprotected benzoates 20a and 20b.
Isomer series
Catalyst ([mol%])
T [8C]
t
Yield [%]
An unusual oxidative fragmentation of the 1,2-diol moiety
was observed in our attempt to form bicycle 28b from un-
purified diol 22b. As shown in Scheme 11, the metathesis re-
action on unpurified diol 22b led to the desired cyclized
product 28b in 71% yield, along with keto aldehyde 29 in
a
Grubbs 1 (5)
Grubbs 2 (5)
Grubbs 1 (5)
Grubbs 2 (5)
80
40
40
20
36 h
18 h
12 h
15 min
71
84
78
b
quant.
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J. Prunet et al.
cyclic protecting groups, such as a carbonate or an aceto-
nide, seem to lock the undesired diastereomer in a confor-
mation which is unfavorable for cyclization, and only the
monobenzoate 20a is a good substrate for metathesis.
These results are in sharp contrast with those observed in
our previous route involving a metathesis to close the B-ring
between the C9 and the C10 carbon atom.[4] In this case, the
cyclic protecting groups were mandatory for both diastereo-
mers to obtain good yields in the RCM step.
We are currently synthesizing metathesis precursors with
all the functionalities required for the ABC tricyclic core of
taxol.
Scheme 11. Oxidative cleavage of diol 22b catalyzed by Grubbs 2 cata-
lyst: a) 5 mol% Grubbs 2, o-nitrophenylselenocyanate (residue), CH2Cl2,
reflux, 71% for 28b, 22% for 29, respectively; b) 5 mol% Grubbs 2, ben-
zeneseleninic acid, CH2Cl2, reflux, 67%.
Experimental Section
22% yield. We assumed that this oxidative cleavage was
mediated by a high oxidation state ruthenium complex de-
rived from the Grubbs 2 catalyst and the residual o-nitro-
phenyl seleninic acid from the Grieco reaction, which is the
only oxidant present in the reaction.[20] To check this hy-
pothesis, reaction of diol 28b with Grubbs 2 catalyst was
then carried out in the presence of stoichiometric phenyl se-
leninic acid, and the oxidized product 29 was obtained in
67% yield (Scheme 11).[21]
Finally, molecular modeling has been performed to try to
explain the difference in behavior between the two diaste-
reomers of the metathesis precursors bearing a cycling pro-
tecting group for the diol moiety. Systematic energy minimi-
zation experiments[22] led to the preferred conformations of
carbonates 18a and 18b (Figure 1). Comparison between
the C10–C11 distances in both diastereomers clearly shows
that cyclization should be favored in the case of 18b.
Materials and methods: All solvents were reagent grade. Diethyl ether
(Et2O) and THF were freshly distilled from sodium/benzophenone under
nitrogen. Dichloromethane, DMSO, toluene, and 1,2-dichloroethane
were freshly distilled from calcium hydride. All reagents were purchased
from commercial sources. Reactions were magnetically stirred and moni-
tored by TLC with 0.25 mm precoated silica-gel plates. Flash chromatog-
raphy was performed with silica gel (particle size 0.040–0.062 mm).
Yields refer to chromatographically and spectroscopically pure com-
pounds, unless otherwise noted. IR spectra were recorded on a FTIR in-
strument. 1H and 13C NMR spectra were recorded on a 400 MHz spec-
trometer. Chemical shifts are reported relative to either chloroform (d=
1
7.26 ppm) or [D6]DMSO (d=2.50 ppm) for H NMR spectra and chloro-
form (d=77.0 ppm) for 13C NMR spectra. Optical rotations were mea-
sured on a polarimeter. X-ray structures were obtained on a diffractome-
ter.
3,3-Dimethyloct-1-en-4-one (10): 1-Bromo-3-methylbut-2-ene (6.35 g,
42.6 mmol, 1.20 equiv) was added to a solution of valeraldehyde (3.8 mL,
36 mmol) in THF (20 mL). This was followed by the addition of aqueous
ammonium chloride (sat. 100 mL). The resulting mixture was cooled to
08C, and activated zinc dust (6.96 g, 106 mmol, 3.00 equiv) was slowly
added. The mixture was then stirred vigorously at room temperature for
1 h (no inert atmosphere is necessary). After completion of the reaction,
the mixture was filtered through a pad of Celite, the two phases were
separated and the aqueous phase was extracted with diethyl ether. The
combined organic fractions were washed with brine, dried over magnesi-
um sulfate, filtered, and the solvent was removed at reduced pressure. A
solution of IBX (22 g, 100 mmol, 1.2 equiv) in DMSO (150 mL) was
added slowly at 208C to a stirred solution of the crude product (13 g,
83 mmol) in THF (150 mL). The resulting mixture was stirred at 208C
overnight. When the reaction was complete, water was added and the or-
ganic phase was diluted with diethyl ether. The biphasic system was
stirred for at least 3 h. The white salts were then filtered through a pad
of Celite. The aqueous phase was extracted with diethyl ether and the
combined organic fractions were washed with water and brine, dried over
magnesium sulfate, filtered, and the solvent was removed at reduced
pressure. Purification of the crude product by flash chromatography (di-
ethyl ether/petroleum ether 5:95 then 10:90) afforded the desired product
10 (12.6 g, 98% over two steps) as a pale-yellow oil. 1H NMR (CDCl3,
400 MHz): d=5.90 (dd, J=17.5, 10.5 Hz, 1H), 5.15–5.11 (d, m, 2H), 2.44
(t, J=7.2 Hz, 2H), 1.53–1.46 (m, 2H), 1.29–1.21 (m, 2H), 1.21 (s, 6H),
0.88 ppm (t, J=7.2 Hz, 3H); 13C NMR (CDCl3, 100.6 MHz): d=213.2,
142.7, 114.1, 65.8, 50.8, 37.1, 26.1, 23.5, 15.2, 13.9 ppm; IR (film): n˜ =
3087, 2961, 2933, 2873, 1711, 1636, 1466, 1413, 1379, 1364, 1260 cmÀ1; MS
(CI, NH3): m/z: 172 [M+NH4]+, 155 [M+H]+, 105.
Figure 1. Conformations of carbonates 18a and 18b.
Conclusion
We have synthesized highly functionalized cyclooctenes by
using a ring-closing metathesis reaction at C10–C11 to form
the B ring. This key step was highly efficient for the dia-
steromer possessing the desired configuration for the C1
and C2 stereocenters of taxol, regardless of the diol protect-
ing group. We even performed the RCM reaction on the un-
protected diol in an excellent yield. On the other hand, the
2-(1,1-Dimethylallyl)-2-trimethylsiloxyhexanenitrile (11):
A
catalytic
amount of zinc iodide was added to a solution of 10 (3.33 g, 21.6 mmol)
in freshly distilled dichloromethane (70 mL). Then, TMSCN (4.32 mL,
32.4 mmol, 1.50 equiv) was added dropwise. The resulting mixture was re-
fluxed for 2 h. The solvents and excess TMSCN were then evaporated at
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Ring-Closing Metathesis
FULL PAPER
reduced pressure (with a NaOCl/NaOH trap). Purification of the crude
product by flash chromatography (diethyl ether/petroleum ether 2:100
then 5:100) afforded the desired nitrile 11 (5.33 g, 97%) as a pale-yellow
oil. 1H NMR (CDCl3, 400 MHz): d=5.96 (dd, J=17.3, 11.0 Hz, 1H),
5.14–5.09 (m, 2H), 1.67–1.61 (m, 2H), 1.52–1.46 (m, 2H), 1.38–1.30 (m,
2H), 1.16 (s, 3H), 1.13 (s, 3H), 0.92 (t, J=7.3 Hz, 3H), 0.25 ppm (s, 9H);
13C NMR (CDCl3, 100.6 MHz): d=142.4, 120.4, 114.4, 79.7, 45.2, 36.5,
27.5, 22.7, 22.6, 22.4, 14.0, 1.73 ppm; IR (film): n˜ =3087, 2961, 2875, 2361,
2342, 1639, 1468, 1417, 1381, 1365, 1254, 1127, 1112, 1066, 1005 cmÀ1; MS
(CI, NH3): m/z: 271 [M+NH4]+, 227, 172, 91; elemental analysis calcd
(%) for C14H27NOSi: C 66.34, H 10.74; found: C 66.31, H 10.87.
crude product by flash chromatography (diethyl ether/petroleum ether
20:80) yielded the desired pure hydrazone 12 as white crystals (1.62 g,
96%). M.p. 75–778C; [a]2D0 =À59.6 (c=1.67 in CH2Cl2); 1H NMR
(CDCl3, 400 MHz): d=7.42–7.39 (m, 7H), 7.31–7.22 (m, 9H), 7.11 (s,
2H), 4.19 (septet, J=6.7 Hz, 2H), 2.88 (t, J=6.2 Hz, 2H), 2.81 (septet,
J=6.9 Hz, 1H), 2.38 (dt, J=14.5, 4.6 Hz, 1H), 1.93 (ddd, J=14.6, 11.2,
5.1 Hz, 1H), 1.78–1.69 (m, 1H), 1.68–1.49 (m, 4H), 1.48–1.36 (m, 2H),
1.24 (dd, J=10.4, 6.7 Hz, 12H), 1.17 (dd, J=6.9, 2.8 Hz, 6H), 0.90 ppm
(s, 3H); 13C NMR (CDCl3, 100.6 MHz): d=163.0, 152.9, 151.0, 146.8,
144.3, 131.3, 128.6, 127.6, 126.8, 123.3, 86.2, 63.9, 41.7, 39.2, 34.3, 34.0,
29.8, 25.8, 24.8, 24.2, 24.0, 23.5, 23.5, 22.8, 20.8, 14.0 ppm; IR (film): n˜ =
3243, 2957, 2869, 1600, 1563, 1496, 1454, 1384, 1323, 1152, 1108, 911,
733 cmÀ1; MS (CI, NH3): m/z: 539 [M+H]+, 449, 300, 276, 259, 151, 108,
91.
2-(1,1-Dimethylallyl)-2-trimethylsiloxyhexanal (9): The nitrile 11 (2.28 g,
8.99 mmol) was dissolved in diethyl ether (40 mL) and cooled to À788C.
DIBAL-H (22.1 mL, 1m in hexanes, 22.1 mmol, 2.50 equiv) was then
added dropwise. The reaction mixture was warmed to 08C and stirred for
2 h. The reaction was quenched by the addition of ethyl acetate, diluted
with diethyl ether, and allowed to warm to 208C. Silica (40 g) was added
to the solution, which was then placed at À208C overnight. After com-
pletion of the reaction, the mixture was warmed to 208C and the silica
was filtered off. Solvents were evaporated at reduced pressure. Purifica-
tion of the crude product by flash chromatography (diethyl ether/petrole-
um ether 1:99) afforded the desired product 9 (1.96 g, 85%) as a colorless
oil. 1H NMR (CDCl3, 400 MHz): d=9.58 (s, 1H), 6.01 (dd, J=17.5,
10.9 Hz, 1H), 5.07–4.99 (m, 2H), 1.83–1.76 (m, 1H), 1.65–1.57 (m, 2H),
1.29–1.23 (m, 3H), 1.04 (s, 3H), 1.03 (s, 3H), 0.87 (t, J=7.2 Hz, 3H),
0.16 ppm (s, 9H); 13C NMR (CDCl3, 100.6 MHz): d=204.8, 144.0, 113.2,
87.7, 44.3, 31.9, 26.3, 23.2, 22.8, 22.4, 14.0, 2.9 ppm; IR (film): n˜ =3086,
2960, 2874, 1735, 1638, 1468, 1416, 1380, 1364, 1254 cmÀ1; MS (CI, NH3):
m/z: 274 [M+NH4]+, 257 [M+H]+, 91; elemental analysis calcd (%) for
C14H28O2Si: C 65.57, H 11.00; found: C 65.38, H 10.99.
AHCTRE(UGN 1R,2R)-2-(1,1-Dimethylallyl)-1-[(6S)-6-methyl-6-(3-trityloxypropyl)cy-
clohex-1-enyl]hexane-1,2-diol (15a) and (1S,2S)-2-(1,1-dimethylallyl)-1-
[(6S)-6-methyl-6-(3-trityloxypropyl)cyclohex-1-enyl]hexane-1,2-diol
(15b): tert-Butyllithium (2.48 mL, 4.51 mmol, 2.20 equiv, titrated 1.82m)
was added dropwise to a solution of hydrazone 13 (1.42 g, 2.05 mmol,
1.00 equiv) in THF (10 mL) at À788C. The solution turned red and was
stirred at À788C for 30 min until the color turned dark red, then the tem-
perature was allowed to warm to 08C. When nitrogen evolution was fin-
ished and the color had turned to pale red, the solution was cooled again
to À788C. A cooled solution of aldehyde 5 (526 mg, 2.05 mmol) in THF
(5.0 mL) was added dropwise by cannula. The resulting mixture became
light yellow and was stirred at À788C for 30 min. The reaction was
quenched by addition of saturated aqueous sodium hydrogen carbonate.
The phases were separated and the aqueous phase was extracted with di-
ethyl ether. The combined organic fractions were washed with brine,
dried over magnesium sulfate, filtered, and the solvent was removed at
reduced pressure. Aqueous HCl (1n, 3.08 mL, 3.08 mmol, 1.50 equiv)
was added at 08C to a solution of the crude product in THF (20 mL).
The resulting mixture was allowed to warm to 208C over 1 h and stirred
overnight. The reaction was quenched by addition of saturated aqueous
sodium hydrogen carbonate. The phases were separated and the aqueous
phase was extracted with diethyl ether. The combined organic fractions
were washed with brine, dried over magnesium sulfate, filtered, and the
solvent was removed at reduced pressure. Purification of the crude prod-
uct by flash chromatography (diethyl ether/petroleum ether 10:90) al-
lowed separation of the two diastereomers to afford the desired diols dia-
steromer 15a (364 mg, 43%) as a pale-yellow oil and diasteromer 15b
(313 mg, 37%) as a white solid (80% global yield over two steps).
Product 15a: [a]D20 =+9.48 (c=1.12 in CH2Cl2); 1H NMR (CDCl3,
400 MHz): d=7.47–7.43 (m, 6H), 7.33–7.23 (m, 6H), 7.23–7.15 (m, 3H),
6.24–6.16 (m, 2H), 5.06–5.00 (m, 2H), 4.17 (d, J=4.4 Hz, 1H), 3.18 (s,
1H), 3.11–3.00 (m, 2H), 2.05–1.99 (m, 2H), 1.86 (d, J=4.4 Hz, 1H),
1.69–1.47 (m, 6H), 1.47–1.31 (m, 6H), 1.31–1.11 (m, 2H), 1.07, 1.06 (2s,
6H), 0.97 (s, 3H), 0.87 ppm (t, J=7.2 Hz, 3H); 13C NMR (CDCl3,
100.6 MHz): d=147.1, 146.9, 144.4, 129.0, 128.7, 128.2, 127.7, 126.8, 112.1,
86.4, 78.1, 69.5, 64.4, 47.0, 37.1, 36.4, 35.1, 33.3, 27.0, 25.9, 25.7, 24.5, 23.7,
22.9, 22.8, 18.8, 14.1 ppm; IR (CaF2, CCl4, 1 mgmLÀ1): n˜ =3610, 3534,
2959, 2931, 2871, 2289, 2002, 1854, 1549, 1449, 1380, 1252, 1217,
1067 cmÀ1; MS (CI, NH3): m/z: 243 [Ph3C]+.
(2S)-2-Methyl-2-(3-trityloxypropyl)cyclohexanone (14): 4-Dimethylami-
no-N-triphenylmethyl pyridinium chloride (11.3 g, 27.9 mmol, 1.20 equiv)
was added at 208C to a solution of diol 13 (4.0 g, 23 mmol) in dichloro-
methane (60 mL). The resulting mixture was refluxed overnight. After
cooling, diethyl ether (30 mL) was added, and the white salts were fil-
tered off. The solution was dried over magnesium sulfate, filtered, and
the solvent was evaporated at reduced pressure. A solution of IBX
(7.79 g, 27.9 mmol, 1.20 equiv) in DMSO (15 mL) was added slowly at
208C to a stirred solution of the crude product in THF (15 mL). The re-
sulting mixture was stirred at 208C overnight. When the reaction had
gone to completion, water was added and the organic phase was diluted
with diethyl ether. The biphasic system was stirred for 3 h. The white
salts were then filtered on a pad of Celite. The phases were separated
and the aqueous phase was extracted with diethyl ether. The combined
organic fractions were washed with water then brine, dried over magnesi-
um sulfate, filtered, and the solvent was removed at reduced pressure.
Purification of the crude product by flash chromatography (diethyl ether/
petroleum ether 50:50) afforded the desired product 14 (7.38 g, 77%
over two steps) as a white solid. M.p. 117–1188C; [a]2D0 =À32.0 (c=2.76
in CH2Cl2); 1H NMR (CDCl3, 400 MHz): d=7.45–7.42 (m, 6H), 7.32–
7.28 (m, 6H), 7.25–7.21 (m, 3H), 3.07–3.03 (m, 2H), 2.44–2.28 (m, 2H),
1.92–1.86 (m, 1H), 1.80–1.73 (m, 4H), 1.71–1.53 (m, 3H), 1.46–1.31 (m,
2H), 1.05 ppm (s, 3H); 13C NMR (CDCl3, 100.6 MHz): d=216.1, 144.3,
128.7, 127.7, 126.8, 86.4, 64.0, 48.4, 39.3, 38.8, 33.9, 27.5, 24.4, 22.6,
21.1 ppm; IR (CaF2, CCl4, 1 mgmLÀ1): n˜ =3087, 3061, 3034, 2935, 2867,
2360, 1708, 1491, 1449, 1378, 1314 cmÀ1; MS (CI, NH3): m/z: 243 (Ph3C+);
elemental analysis calcd (%) for C29H32O2: C 84.43, H 7.82; found: C
84.21, H 8.08.
Product 15b: M.p. 102–1058C; [a]2D0 =+9.42 (c=1.00 in CH2Cl2);
1H NMR (CDCl3, 400 MHz): d=7.53–7.48 (m, 6H), 7.38–7.32 (m, 6H),
7.32–7.26 (m, 3H), 6.31 (t, J=4.0 Hz, 1H), 6.25 (dd, J=17.6, 10.8 Hz,
1H), 5.08 (d, J=17.6 Hz, 1H), 5.03 (d, J=10.8 Hz, 1H), 4.28 (d, J=
4.4 Hz, 1H), 3.19 (s, 1H), 3.14–3.09 (m, 2H), 2.12–2.05 (m, 2H), 1.89 (d,
J=4.4 Hz, 1H), 1.70–1.52 (m, 8H), 1.52–1.40 (m, 3H), 1.35–1.14 (m,
3H), 1.15–1.10 (m, 9H), 0.89 ppm (t, J=7.6 Hz, 3H); 13C NMR (CDCl3,
100.6 MHz): d=147.9, 147.1, 144.4, 128.6, 127.7, 127.0, 126.8, 112.1, 86.2,
78.1, 70.0, 64.0, 46.9, 36.7, 36.2, 35.0, 33.4, 27.0, 25.7, 25.1, 24.4, 23.6, 22.9,
22.8, 18.6, 14.1 ppm; IR (CaF2, CCl4, 1 mgmLÀ1): n˜ =3610, 3537, 3061,
2959, 2930, 2871, 2291, 2004, 1856, 1550, 1449, 1379, 1252, 1217,
1067 cmÀ1; MS (CI, NH3): m/z: 243 [Ph3C]+.
N-[(S)-2-Methyl-2-(3-trityloxypropyl)cyclohex-1-ylidene]-N’-(2,4,6-triiso-
propylbenzenesulfono)hydrazone (12): Two drops of concentrated hydro-
chloric acid were added to a solution of ketone 14 (1.00 g, 2.42 mmol)
and triisopropylbenzenesulfonyl hydrazine (723 mg, 2.42 mmol,
1.00 equiv) in THF (5.0 mL). The resulting solution was stirred at 208C
for 1 h, and the reaction was quenched by the addition of saturated aque-
ous sodium hydrogen carbonate. The phases were separated and then the
aqueous phase was extracted with diethyl ether. The combined organic
fractions were washed with brine, dried over magnesium sulfate, filtered,
and the solvent was removed at reduced pressure. Purification of the
AHCTRE(UGN 1R,2R)-2-(1,1-Dimethylallyl)-1-[(S)-6-(3-hydroxypropyl)-6-methylcyclo-
hex-1-enyl]hexane-1,2-diol (16a) and (1S,2S)-2-(1,1-dimethylallyl)-1-[(S)-
6-(3-hydroxypropyl)-6-methylcyclohex-1-enyl]hexane-1,2-diol (16b): Diol
Chem. Eur. J. 2008, 14, 7314 – 7323
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7319

J. Prunet et al.
15a (251 mg, 0.43 mmol) was dissolved in MeOH (5 mL) at 208C. Am-
berlyst H-15 (40 mg) was then added, and the mixture was stirred over-
night at 208C. The resin was filtered off and the solvents were removed
in vacuo. Purification of the crude product by flash chromatography (di-
ethyl ether/petroleum ether 20:80 then 50:50 then 80:20) afforded the de-
sired alcohol 16a (128 mg, 88%) as a white solid. The same procedure re-
peated with 223 mg of diol 15b afforded the desired alcohol 16b
(104 mg, 80%) as a yellow oil.
Product 16a: M.p. 47–498C; [a]2D0 =+1.03 (c=1.56 in CH2Cl2); 1H NMR
(CDCl3, 400 MHz): d=6.27 (t, J=4.0 Hz, 1H), 6.18 (dd, J=17.6, 10.9 Hz,
1H), 5.06 (m, 2H), 4.18 (s, 1H), 3.70–3.65 (m, 1H), 3.58–3.53 (m, 1H),
3.01 (brs, 1H), 2.50 (brs, 1H), 2.12 (brs, 1H), 2.02–1.98 (m, 2H), 1.66–
1.48 (m, 6H), 1.46–1.40 (m, 2H), 1.38–1.31 (m, 4H), 1.27–1.12 (m, 2H),
1.08 (s, 3H), 1.07 (s, 3H), 0.98 (s, 3H), 0.85 ppm (t, J=7.3 Hz, 3H);
13C NMR (CDCl3, 100.6 MHz): d=146.9, 145.9, 128.0, 112.2, 78.2, 69.3,
63.1, 47.0, 37.4, 35.9, 35.2, 33.3, 27.1, 27.0, 26.7, 25.8, 23.6, 23.1, 22.8, 18.9,
14.1 ppm; IR (CaF2, CCl4, 1 mgmLÀ1): n˜ =3380, 2955, 2870, 1460, 1377,
785, 705, 603 cmÀ1; HRMS: m/z: calcd for C21H38O3: 338.2821; found:
338.2832.
23.2, 22.3, 20.8, 18.2, 13.8 ppm; IR (film): n˜ =3575, 3076, 2960, 2368,
1984, 1790, 1638, 1538, 1456, 1417, 1380, 1326, 1198, 1042 cmÀ1; MS (CI,
NH3): m/z: 364 [M+NH4]+, 347 [M+H]+, 303, 285; HRMS: m/z: calcd
for C22H34O3: 346.2508; found: 346.2524.
Product 18b: [a]D20 =À19.3 (c=1.01 in CH2Cl2); 1H NMR (CDCl3,
400 MHz): d=5.95 (dd, J=17.6, 11.2 Hz, 1H), 5.79 (t, J=4.1 Hz, 1H),
5.73 (ddt, J=17.2, 10.4, 7.1 Hz, 1H), 5.23 (d, J=11.2 Hz, 1H), 5.21 (d,
J=17.6 Hz, 1H), 5.06 (dd, J=17.0, 10.6 Hz, 2H), 5.02 (s, 1H), 2.14–2.00
(m, 4H), 1.89–1.80 (m, 1H), 1.74–1.55 (m, 4H), 1.50–1.18 (m, 5H), 1.16
(s, 3H), 1.14 (s, 3H), 1.07 (s, 3H), 0.88 ppm (t, J=7.6 Hz, 3H); 13C NMR
(CDCl3, 100.6 MHz): d=155.5, 141.9, 140.6, 133.8, 130.5, 118.1, 115.8,
90.6, 79.7, 46.5, 43.6, 36.9, 35.0, 31.1, 27.0, 25.7, 25.0, 23.2, 22.4, 20.8, 18.0,
13.8 ppm; IR (film): n˜ =3568, 3077, 2956, 2254, 1790, 1638, 1539, 1456,
1417, 1379, 1326, 1200, 1117, 1044 cmÀ1
; MS (CI, NH3): m/z: 364
[M+NH4]+, 347 [M+H]+, 285; elemental analysis calcd (%) for
C22H34O3: C 76.26, H 9.89; found: C 76.01, H 9.98.
AHCTREUNG
AHCTREUNG
Product 16b: [a]D20 =+0.35 (c=1.15 in CH2Cl2); 1H NMR (CDCl3,
400 MHz): d=6.24–6.17 (m, 2H), 5.08–5.03 (m, 2H), 4.20 (s, J=4.5 Hz,
1H), 3.60 (t, J=6.7 Hz, 2H), 3.11 (s, 1H), 2.03–1.99 (m, 2H), 1.85 (d, J=
4.7 Hz, 1H), 1.63–1.49 (m, 6H), 1.47–1.30 (m, 6H), 1.28–1.12 (m, 2H),
1.08–1.07 (m, 9H), 0.85 ppm (t, J=7.3 Hz, 3H); 13C NMR (CDCl3,
100.6 MHz): d=147.6, 147.1, 127.2, 112.1, 78.2, 70.2, 63.7, 46.9, 36.6, 35.3,
35.1, 33.5, 27.2, 27.0, 25.7, 25.2, 23.6, 22.9, 22.8, 18.6, 14.1 ppm; IR (film):
ACHTREUNG
lytic amount of CSA was added to triol 16a (38 mg, 0.111 mmol) at 208C,
and the resulting mixture was stirred overnight. After this time, the reac-
tion was quenched by the addition of saturated aqueous sodium hydro-
gen carbonate, the phases were separated, and the aqueous phase was ex-
tracted with diethyl ether. The combined organic fractions were washed
with brine, dried over magnesium sulfate, filtered, and the solvent was re-
moved at reduced pressure. The crude product was used for the next step
without purification. o-Nitrophenylselenocyanate (58 mg, 0.254 mmol,
2.4 equiv) was added in one portion at 208C to a solution of the crude
product (40 mg, 0.106 mmol) in THF (1.0 mL). Tributylphosphine (64 mL,
0.254 mmol, 2.4 equiv) was then added dropwise. The resulting mixture
was stirred at 208C for 20 min. Completion of the reaction was checked
by TLC. Water was then added, and the solution was diluted with diethyl
ether. The phases were separated and the aqueous phase was extracted
with diethyl ether. The combined organic fractions were washed with
brine, dried over magnesium sulfate, filtered, and the solvent was re-
moved at reduced pressure. The crude product thus obtained was then
dissolved in THF (1.0 mL) and aqueous hydrogen peroxide (0.5 mL,
35%wt solution in water) was added dropwise at 08C. The mixture was
stirred overnight. After this time, water was added and the solution was
diluted with diethyl ether. The phases were separated and the aqueous
phase was extracted with diethyl ether. The combined organic fractions
were washed with brine, dried over magnesium sulfate, filtered, and the
solvent was removed at reduced pressure. Purification of the crude prod-
uct by flash chromatography (diethyl ether/petroleum ether 10:90) af-
forded the desired diene 19a (25 mg, 63% over three steps) as a colorless
oil. The same procedure was repeated with 30 mg of alcohol 16b to
afford the desired diene 19b (23 mg, 71% over three steps) as a colorless
oil.
n˜ =3412, 2954, 2867, 1461, 1377, 1055, 1011, 842, 737, 686, 625 cmÀ1
HRMS: m/z: calcd for C21H38O3: 338.2821; found: 338.2834.
;
ACHTREUNG
ACHTREUNG
AHCTREUNG
trophenylselenocyanate (55 mg, 0.24 mmol, 2.4 equiv) was added in one
portion at 208C to a solution of alcohol 16a (34 mg, 0.10 mmol) in THF
(1.0 mL). Tributylphosphine (60 mL, 0.24 mmol, 2.4 equiv) was then
added dropwise. The resulting mixture was stirred at 208C for 20 min.
Completion of the reaction was checked by TLC. Water was then added,
and the solution was diluted with diethyl ether. The phases were separat-
ed and the aqueous phase was extracted with diethyl ether. The com-
bined organic fractions were washed with brine, dried over magnesium
sulfate, filtered, and the solvent was removed at reduced pressure. The
crude product was used for the next step without purification. Carbonyl
diimidazole (81 mg, 0.50 mmol, 5.0 equiv) was added at 208C to a solu-
tion of the crude product in toluene (5 mL). The resulting mixture was
refluxed for 3 d. After cooling, the reaction was quenched by addition of
saturated aqueous sodium hydrogen carbonate. The phases were separat-
ed and the aqueous phase was extracted with diethyl ether. The com-
bined organic fractions were washed with brine, dried over magnesium
sulfate, filtered, and the solvent was removed at reduced pressure. The
crude product was then dissolved in THF (1.0 mL). Aqueous hydrogen
peroxide (1.5 mL, 10%wt solution in water) was added dropwise at 08C.
The mixture was stirred overnight. After this time, water was added and
the solution was diluted with diethyl ether. The phases were separated
and the aqueous phase was extracted with diethyl ether. The combined
organic fractions were washed with brine, dried over magnesium sulfate,
filtered, and the solvent was removed at reduced pressure. Purification of
the crude product by flash chromatography (diethyl ether/petroleum
ether 10:90) afforded the desired diene 18a (32 mg, 57% over three
steps) as a pale-yellow oil. The same procedure repeated with 30 mg of
alcohol 16b afforded the desired diene 18b (16 mg, 52% over three
steps) as a pale-yellow oil.
Product 19a: [a]D20 =À21.4 (c=1.5 in CH2Cl2); 1H NMR (CDCl3,
400 MHz): d=6.20 (dd, J=17.6, 10.9 Hz, 1H), 6.03–5.98 (m, 1H), 5.89–
5.77 (m, 1H), 5.01–4.91 (m, 4H), 4.44 (s, 1H), 2.27 (d, J=7.0 Hz, 2H),
2.14–1.99 (m, 2H), 1.82–1.79 (m, 2H), 1.62–1.58 (m, 4H), 1.46 (s, 3H),
1.36 (s, 3H), 1.33–1.16 (m, 4H), 1.12–1.05 (m, 9H), 0.90 ppm (t, J=
7.3 Hz, 3H); 13C NMR (CDCl3, 100.6 MHz): d=146.9, 139.2, 136.2, 129.1,
116.5, 110.6, 104.3, 88.3, 77.1, 44.8, 43.3, 37.9, 35.9, 33.5, 28.0, 27.9, 26.3,
26.2, 26.1, 25.4, 24.0, 23.4, 17.9, 14.3 ppm; IR (film): n˜ =3076, 2959, 2933,
2872, 1636, 1461, 1372, 1247, 1212, 1016, 910, 862, 793, 764, 626, 486 cmÀ1
HRMS: m/z: calcd for C24H40O2: 360.3028; found: 360.3028.
;
Product 19b: [a]D20 =À1.23 (c=1.3 in CH2Cl2); 1H NMR (CDCl3,
400 MHz): d=6.19 (dd, J=17.7, 10.9 Hz, 1H), 5.92 (t, J=3.8 Hz, 1H),
5.82–5.72 (m, 1H), 5.05–4.92 (m, 4H), 4.44 (s, 1H), 2.32 (dd, J=13.9,
7.2 Hz, 1H), 2.19 (dd, J=13.9, 7.2 Hz, 1H), 2.10–2.05 (m, 2H), 1.82–1.76
(m, 2H), 1.65–1.53 (m, 4H), 1.46 (s, 3H), 1.37 (s, 3H), 1.32–1.22 (m, 4H),
1.09–1.08 (m, 9H), 0.89 ppm (t, J=7.3 Hz, 3H); 13C NMR (CDCl3,
100.6 MHz): d=146.9, 139.2, 135.5, 128.4, 116.9, 110.7, 104.3, 88.3, 77.7,
44.0, 43.4, 37.8, 35.6, 33.5, 27.9, 27.8, 26.5, 26.3, 26.0, 25.5, 23.9, 23.5, 17.8,
14.3 ppm; IR (film): n˜ =2959, 2931, 2869, 1636, 1459, 1373, 1253, 1017,
Product 18a: [a]D20 =+23.5 (c=0.92 in CH2Cl2); 1H NMR (CDCl3,
400 MHz): d=5.95 (dd, J=17.6, 10.6 Hz, 1H), 5.85 (t, J=4.1 Hz, 1H),
5.75 (ddt, J=17.6, 10.6, 7.6 Hz, 1H), 5.22 (d, J=10.5 Hz, 1H), 5.21 (d,
J=17.4 Hz, 1H), 5.10 (d, J=7.6 Hz, 1H), 5.06 (d, J=17.6 Hz, 1H), 4.98
(s, 1H), 2.32–2.26 (m, 1H), 2.19–2.02 (m, 3H), 1.85–1.50 (m, 4H), 1.50–
1.19 (m, 6H), 1.15 (s, 3H), 1.14 (s, 3H), 0.98 (s, 3H), 0.87 ppm (t, J=
7.6 Hz, 3H); 13C NMR (CDCl3, 100.6 MHz): d=155.7, 141.9, 139.3, 133.9,
131.2, 118.1, 115.7, 90.7, 79.0, 46.6, 44.9, 36.9, 35.7, 31.0, 27.0, 26.2, 25.6,
7320
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7314 – 7323

Ring-Closing Metathesis
FULL PAPER
857, 802, 713, 695, 648, 632, 524, 462 cmÀ1; HRMS: m/z: calcd for
C24H40O2: 360.3028; found: 360.3032.
(CDCl3, 100.6 MHz): d=146.2, 134.2, 117.9, 112.6, 76.6, 67.7, 66.7, 60.7,
47.1, 43.2, 36.6, 32.7, 32.0, 27.6, 23.9, 23.9, 23.2, 22.3, 21.9, 16.1, 14.1 ppm;
IR (film): n˜ =3494, 2958, 2874, 1636, 1460, 1381, 1077, 1000, 907, 878,
826, 804, 771, 708, 632, 591 cmÀ1; HRMS: m/z: calcd for C21H36O3:
336.2665; found: 336.2665.
ACHTREUNG
A
of phenyllithium in ether (0.3m, 1.5 mL, 2.1 equiv) was added dropwise
to a solution of crude diene 18a, synthesized from 16a (49 mg), in THF
(5 mL) at À788C. After 10 min, the solution was poured into a saturated
aqueous solution of sodium hydrogen carbonate, the phases were sepa-
rated, and then the aqueous phase was extracted with diethyl ether. The
combined organic fractions were washed with brine, dried over magnesi-
um sulfate, filtered, and the solvent was removed at reduced pressure.
Purification of the crude product by flash chromatography (diethyl ether/
petroleum ether 5:95) afforded diene 20a (30 mg, 46% over four steps
from diol 16a) as a colorless oil. The same procedure was repeated with
41 mg of triol 16b to afford diene 20b (19.5 mg, 36% over four steps
from 16b) as a colorless oil.
Product 20a: [a]D20 =+1.6 (c=1.30 in CH2Cl2); 1H NMR (CDCl3,
400 MHz): d=7.97–7.95 (m, 2H), 7.57–7.53 (m, 1H), 7.45–7.42 (m, 2H),
6.43 (t, J=4.0 Hz, 1H), 5.96 (dd, J=17.6, 10.9 Hz, 1H), 5.77 (s, 1H),
5.71–5.61 (m, 1H), 4.98–4.92 (m, 3H), 4.77 (dd, J=10.9, 1.2 Hz, 1H),
2.59 (s, 1H), 2.40 (dd, J=14.0, 7.5 Hz, 1H), 2.12–2.07 (m, 3H), 1.68–1.58
(m, 3H), 1.55–1.39 (m, 2H), 1.33–1.18 (m, 5H), 1.11 (s, 3H), 1.09 (s, 3H),
1.06 (s, 3H), 0.90 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3, 100.6 MHz): d=
164.7, 145.1, 142.9, 135.1, 132.8, 131.0, 130.5, 129.6, 128.4, 117.1, 112.3,
79.3, 72.5, 46.6, 44.0, 36.9, 34.9, 33.3, 29.7, 26.9, 25.7, 25.5, 23.6, 23.2, 22.9,
18.0, 14.2 ppm; IR (film): n˜ =3965, 3807, 3711, 2928, 2280, 1793, 1710,
1576, 1484, 1427, 1316, 1262, 1078, 976, 944, 919, 857, 835, 817, 765, 685,
602, 571, 509 cmÀ1; HRMS: m/z: calcd for C28H40O3: 424.2978; found:
424.2985.
Product 20b: [a]D20 =+5.5 (c=1.30 in CH2Cl2); 1H NMR (CDCl3,
400 MHz): d=7.98–7.96 (m, 2H), 7.57–7.54 (m, 1H), 7.46–7.42 (m, 2H),
6.41 (t, J=3.9 Hz, 1H), 5.99 (dd, J=17.6, 10.9 Hz, 1H), 5.87–5.78 (m,
1H), 5.76 (s, 1H), 5.06–4.93 (m, 3H), 4.79 (dd, J=10.9, 1.2 Hz, 1H), 2.61
(s, 1H), 2.34 (dd, J=13.1, 7.0 Hz, 1H), 2.17–2.07 (m, 3H), 1.67–1.63 (m,
2H), 1.58–1.36 (m, 6H), 1.33–1.18 (m, 2H), 1.13 (s, 3H), 1.08 (s, 3H),
1.05 (s, 3H), 0.90 ppm (t, J=7.3 Hz, 3H); 13C NMR (CDCl3, 100.6 MHz):
d=165.0, 145.3, 142.8, 134.9, 132.8, 131.0, 130.7, 129.6, 128.4, 117.5, 112.3,
79.4, 73.9, 46.5, 44.5, 36.8, 35.8, 33.7, 26.8, 25.8, 25.7, 23.6, 23.4, 23.0, 18.0,
14.1 ppm; IR (film): n˜ =3681, 2931, 2275, 1714, 1636, 1454, 1316, 1265,
1108, 964, 937, 902, 864, 844, 725, 694, 524 cmÀ1; HRMS: m/z: calcd for
C28H40O3: 424.2978; found: 424.2964.
ACHTRE(UGN 1R,2R)-1-[(S)-6-Allyl-6-methylcyclohex-1-enyl]-2-(1,1-dimethylallyl)hex-
ane-1,2-diol (22a) and (1S,2S)-1-[(S)-6-allyl-6-methylcyclohex-1-enyl]-2-
(1,1-dimethylallyl)hexane-1,2-diol (22b): o-Nitrophenylselenocyanate
(282 mg, 1.24 mmol, 2.40 equiv) was added in one portion at 208C to a
solution of alcohol 16a (175 mg, 0.52 mmol) in THF (1.0 mL). Tributyl-
phosphine (49 mL, 0.2 mmol, 2.4 equiv) was then added dropwise. The re-
sulting mixture was stirred at 208C for 20 min. Completion of the reac-
tion was checked by TLC. Water was then added and the solution was di-
luted with diethyl ether. The phases were separated and the aqueous
phase was extracted with diethyl ether. The combined organic fractions
were washed with brine, dried over magnesium sulfate, filtered, and the
solvent was removed at reduced pressure. The crude product thus ob-
tained was dissolved in THF (1.0 mL) and aqueous ammonium molyb-
date in solution (6m) of hydrogen peroxide (1.5 mL, 10%wt solution in
water) was added dropwise at À108C. The mixture was then stirred for
5 min. Water was added and the solution was diluted with diethyl ether.
The phases were separated and the aqueous phase was extracted with di-
ethyl ether. The combined organic fractions were washed with brine,
dried over magnesium sulfate, filtered, and the solvent was removed at
reduced pressure. Purification of the crude product by flash chromatogra-
phy (diethyl ether/petroleum ether 20:80) afforded the desired diene 22a
(152 mg, 92%) as a pale-yellow oil. The same procedure was repeated
with 115 mg of alcohol 16b to afford the desired diene 22b (99 mg, 91%)
as a pale-yellow oil.
Product 22a: [a]D20 =+3.3 (c=1.0 in CH2Cl2); 1H NMR (CDCl3,
400 MHz): d=6.26–6.17 (m, 2H), 5.91–5.80 (m, 1H), 5.08–5.04 (m, 4H),
4.20 (d, J=3.4 Hz, 1H), 3.16 (s, 1H), 2.23 (dq, J=14.0, 7.4 Hz, 2H),
2.04–2.00 (m, 2H), 1.90 (d, J=3.8 Hz, 1H), 1.66–1.48 (m, 4H), 1.43–1.32
(m, 4H), 1.28–1.22 (m, 2H), 1.09 (s, 3H), 1.08 (s, 3H), 0.99 (s, 3H),
0.86 ppm (t, J=7.3 Hz, 3H); 13C NMR (CDCl3, 100.6 MHz): d=147.1,
146.2, 135.4, 128.1, 117.3, 112.1, 78.1, 69.5, 47.0, 45.1, 37.4, 35.6, 33.3, 27.0,
26.1, 25.7, 23.7, 22.9, 22.8, 18.6, 14.1 ppm; IR (film): n˜ =2929, 2278, 1587,
1511, 1450, 1328, 1304, 1096, 1030, 924, 890, 850, 810, 772, 648, 587,
532 cmÀ1; HRMS: m/z: calcd for C21H36O2: 320.2715; found: 320.2716.
Product 22b: [a]D20 =+4.6 (c=1.20 in CH2Cl2); 1H NMR (CDCl3,
400 MHz): d=6.28–6.19 (m, 2H), 5.85–5.74 (m, 1H), 5.10–5.01 (m, 4H),
4.22 (d, J=4.3 Hz, 1H), 3.09 (s, 1H), 2.09 (d, J=7.4 Hz, 2H), 2.02 (dt,
J=6.2, 4.2 Hz, 2H), 1.83 (d, J=4.5 Hz, 1H), 1.66–1.60 (m, 1H), 1.57–1.49
(m, 3H), 1.45–1.33 (m, 4H), 1.33–1.12 (m, 2H), 1.10 (s, 3H), 1.09 (s, 3H),
1.07 (s, 3H), 0.86 ppm (t, J=7.3 Hz, 3H); 13C NMR (CDCl3, 100.6 MHz):
d=147.1, 134.7, 127.5, 117.6, 112.2, 78.2, 70.1, 47.0, 44.0, 37.0, 35.2, 33.5,
27.0, 25.7, 25.2, 23.6, 22.9, 22.8, 18.4, 14.1 ppm; IR (film): n˜ =2956, 2867,
1716, 1638, 1587, 1508, 1328, 1300, 1095, 1026, 910, 859, 828, 782, 694,
642, 603, 517, 478 cmÀ1; HRMS: m/z: calcd for C21H36O2: 320.2715;
found: 320.2728.
ACHTREUNG(1S,2R)-1-[(S)-2-Allyl-2-methyl-7-oxabicycloACHRTE[UGN 4.1.0]hept-1-yl]-2-(1,1-dime-
thylallyl)hexane-1,2-diol (21a): o-Nitrophenylselenocyanate (145 mg,
0.66 mmol, 2.40 equiv) was added in one portion at 208C to a solution of
alcohol 16a (90 mg, 0.28 mmol) in THF (5.0 mL). Tributylphosphine
(159 mL, 0.66 mmol, 2.39 equiv) was then added dropwise. The resulting
mixture was stirred at 208C for 20 min. Completion of the reaction was
checked by TLC. Water was added and the solution was diluted with di-
ethyl ether. The phases were separated and the aqueous phase was ex-
tracted with diethyl ether. The combined organic fractions were washed
with brine, dried over magnesium sulfate, filtered, and the solvent was re-
moved at reduced pressure. The crude product thus obtained was dis-
solved in THF (1.0 mL) and aqueous hydrogen peroxide (0.5 mL,
35%wt solution in water) was added dropwise at 08C. The mixture was
then stirred overnight. After this time, water was added and the solution
was diluted with diethyl ether. The phases were separated and the aque-
ous phase was extracted with diethyl ether. The combined organic frac-
tions were washed with brine, dried over magnesium sulfate, filtered, and
the solvent was removed at reduced pressure. Purification of the crude
product by flash chromatography (diethyl ether/petroleum ether 10:90)
(Z)-(2R,6S,11S)-6-Butyl-7,7,11-trimethyl-3,5-dioxatricycloACHTER[UNG 9.4.0.02]penta-
deca-1(15),8-dien-4-one (23b): Diene 18b (10 mg, 30 mmol) was dissolved
in 1,2-dichloroethane (2.0 mL). The mixture was thoroughly degassed
three times while stirring. Second-generation Grubbs catalyst (2.6 mg,
3.0 mmol, 10 mol%) was added and the mixture was refluxed for 1 h.
After cooling, the solvent was evaporated at reduced pressure. Purifica-
tion of the crude product by flash chromatography (diethyl ether/petrole-
um ether 10:90) afforded the desired product 23b (6.4 mg, 69%) as a
pale-yellow oil. The same procedure repeated with [RuIMes] catalyst
(1.3 mg, 1.5 mmol, 5 mol%) afforded compound 23b (6.6 mg, 72%).
[a]2D0 =+112.5 (c=1.17 in CH2Cl2); 1H NMR (CDCl3, 400 MHz): d=6.06
(t, J=4.4 Hz, 1H), 5.66 (ddd, J=11.8, 10.6, 8.1 Hz, 1H), 5.39 (s, 1H),
5.36 (d, J=11.8 Hz, 1H), 2.58 (dd, J=14.2, 10.6 Hz, 1H), 2.26 (dt, J=
18.7, 5.8 Hz, 1H), 2.12–1.70 (m, 8H), 1.46 (s, 3H), 1.33 (s, 3H), 1.32–1.25
(m, 4H), 1.18 (s, 3H), 0.93 ppm (t, J=7.2 Hz, 3H); 13C NMR (CDCl3,
100.6 MHz): d=138.3, 134.9, 129.7, 128.5, 93.5, 80.1, 40.4, 39.0, 38.8, 34.1,
31.1, 28.8, 28.5, 27.7, 24.5, 23.3, 21.8, 18.0, 13.9 ppm; IR (film): n˜ =3588,
2961, 2870, 2345, 1803, 1654, 1560, 1458, 1380, 1248 cmÀ1; MS (CI, NH3):
afforded the epoxide diene 21a (20 mg, 20%) as pale-yellow oil. [a]D20
=
1
À17.2 (c=1.40 in CH2Cl2); H NMR (CDCl3, 400 MHz): d=6.12 (dd, J=
17.4, 11.0 Hz, 1H), 5.88–5.78 (m, 1H), 5.09–5.01 (m, 4H), 4.05 (d, J=
5.3 Hz, 1H), 3.93 (t, J=2.4 Hz, 1H), 3.30 (d, J=5.3 Hz, 1H), 2.86 (s,
1H), 2.30 (dd, J=13.6, 7.5 Hz, 1H), 2.12 (dd, J=13.6, 7.5 Hz, 1H), 1.87–
1.83 (m, 2H), 1.60–1.48 (m, 2H), 1.47–1.37 (m, 4H), 1.36–1.17 (m, 4H),
1.09–1.05 (m, 6H), 1.03 (s, 3H), 0.92 ppm (t, J=7.3 Hz, 3H); 13C NMR
Chem. Eur. J. 2008, 14, 7314 – 7323
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7321

J. Prunet et al.
m/z: 336 [M+NH4]+, 319 [M+H]+, 258, 257; HRMS: m/z: calcd for
C20H30O3: 318.2195; found: 318.2206.
in dichloromethane (2.0 mL) refluxed for 12 h afforded the compound
27b (7.2 mg, 78%). [a]D20 =+42.3 (c=1.30 in CH2Cl2); 1H NMR (CDCl3,
400 MHz): d=8.04–8.02 (m, 2H), 7.58–7.54 (m, 1H), 7.47–7.43 (m, 2H),
6.13 (s, 1H), 6.11–6.05 (m, 1H), 5.74–5.60 (m, 1H), 5.48–5.36 (m, 1H),
2.80–2.60 (brs, 1H), 2.12–2.02 (m, 3H), 1.94 (t, J=12.5 Hz, 1H), 1.76–
1.66 (m, 2H), 1.62–1.58 (m, 2H), 1.54 (s, 3H), 1.36–1.31 (m, 2H), 1.36–
1.26 (m, 4H), 1.23 (s, 3H), 1.18 (s, 3H), 0.95 ppm (t, J=7.3 Hz, 3H);
13C NMR (CDCl3, 100.6 MHz): d=166.1, 142.4, 139.7, 132.8, 130.6, 129.7,
129.1, 128.4, 81.3, 77.2, 38.4, 31.9, 30.3, 28.1, 28.1, 27.6, 25.9, 25.8, 23.9,
22.7, 18.5, 14.2 ppm; IR (film): n˜ =3920, 3704, 3548, 2926, 2867, 2360,
Mixture of 24 and 25: Diene 19a (24 mg, 0.067 mmol) was dissolved in
dichloromethane (7.0 mL). The mixture was thoroughly degassed three
times while stirring. Second-generation Grubbs catalyst (2.8 mg,
3.3 mmol, 5 mol%) was added and the mixture was refluxed for 15 min.
After cooling, the solvent was evaporated at reduced pressure. Purifica-
tion of the crude product by flash chromatography (diethyl ether/petrole-
um ether 10:90) afforded the mixture of 24 (15 mg, E/Z 3:1) and 25
(5 mg, E/Z 3:1) (87% global yield) with a ratio of 3:1 as a pale-yellow
oil.
Fractions 24: 1H NMR (CDCl3, 400 MHz): d=6.37–6.12 (m, 2H), 6.04–
6.01 (m, 2H), 5.55–5.46 (m, 3H), 5.02–4.91 (m, 3H), 4.49 (s, 0.75H), 4.21
(s, 0.25H), 2.54–2.42 (m, 2H), 2.26–2.20 ppm (m, 2H).
Fractions 25: 1H NMR (CDCl3, 400 MHz): d=6.24–6.16 (m, 2H), 6.01–
5.96 (m, 2H), 5.50–5.48 (m, 0.5H), 5.40–5.38 (m, 1.5H), 4.98–4.90 (m,
4H), 4.43 (s, 2H), 2.34–2.26 (m, 2H), 2.21–2.13 ppm (m, 2H).
1723, 1656, 1599, 1454, 1273, 1110, 1025, 873, 857, 840, 697, 518 cmÀ1
;
HRMS: m/z: calcd for C26H36O3: 396.2665; found: 396.2678.
(Z)-(5S,6S,10aS)-6-Butyl-7,7,10a-trimethyl-1,2,3,5,6,7,10,10a-octahydro-
benzocyclooctene-5,6-diol (28b): Diene 22b (6 mg, 19 mmol) was dis-
solved in dichloromethane (2.0 mL). The mixture was thoroughly de-
gassed three times while stirring. Second-generation Grubbs catalyst
(0.8 mg, 1.0 mmol, 5 mol%) was added and the mixture was refluxed for
1 h. The solvent was evaporated at reduced pressure. Purification of the
crude product by flash chromatography (diethyl ether/petroleum ether
20:80) afforded the desired bicycle 28b (6 mg, quantitative yield) as pale-
yellow needles. Bicycle 27b (9.0 mg, 21 mmol) in THF (1.0 mL) was
added dropwise to a suspension of LiAlH4 (2.0 mg, 53 mmol, 2.3 equiv) in
THF (5 mL) at 08C, and the resulting mixture was stirred for 15 min at
08C. Ethyl acetate was then added, and the reaction was quenched by ad-
dition of aqueous sodium and potassium tartrate solution (10%, 10 mL),
and the mixture was stirred for 3 h. The phases were separated and the
aqueous phase was extracted with diethyl ether. The combined organic
fractions were washed with brine, dried over magnesium sulfate, filtered,
and the solvent was removed at reduced pressure. Purification of the
crude product by flash chromatography (diethyl ether/petroleum ether
20:80) afforded the same bicycle 28b (5.5 mg, 83%) as pale-yellow nee-
(Z)-(2S,6S,11S)-6-Butyl-4,4,7,7,11-pentamethyl-3,5-dioxatricycloACHTRE[UGN 9.4.0.02]-
pentadeca-1(15),8-diene (26b): Diene 19b (20 mg, 56 mmol) was dis-
solved in 1,2-dichloroethane (5.0 mL). The mixture was thoroughly de-
gassed three times while stirring. Second-generation Grubbs catalyst
(2.4 mg, 2.8 mmol, 5 mol%) was added and the mixture was refluxed for
5 min. After cooling, the solvent was evaporated at reduced pressure. Pu-
rification of the crude product by flash chromatography (diethyl ether/pe-
troleum ether 10:90) afforded the desired bicycle 26b (19 mg, quantita-
tive yield) as
a
pale-yellow oil. [a]2D0 =+124.0 (c=1.3 in CH2Cl2);
1H NMR (CDCl3, 400 MHz): d=6.04 (m, 1H), 5.55–5.47 (m, 1H), 5.34
(d, J=12.0 Hz, 1H), 4.69 (s, 1H), 2.65 (dd, J=13.7, 10.7 Hz, 1H), 2.15
(dt, J=18.3, 5.0 Hz, 1H), 1.98–1.90 (m, 1H), 1.87–1.62 (m, 5H), 1.59–
1.51 (m, 2H), 1.47 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H), 1.30–1.22 (m, 4H),
1.17 (s, 3H), 1.12 (s, 3H), 0.86 ppm (t, J=7.2 Hz, 3H); 13C NMR (CDCl3,
100.6 MHz): d=141.2, 137.6, 127.7, 125.8, 104.5, 89.1, 75.5, 40.5, 38.9,
38.8, 34.4, 34.4, 29.7, 29.6, 28.8, 28.3, 26.5, 24.9, 24.0, 22.5, 18.4, 14.2 ppm;
IR (film): n˜ =2929, 2866, 2360, 1701, 1666, 1594, 1458, 1372, 1247, 1041,
897, 833, 738, 539 cmÀ1; HRMS: m/z: calcd for C22H36O2: 332.2715;
found: 332.2714.
1
dles. M.p. 105–1078C; [a]D20 =+28.5 (c=1.0 in CH2Cl2); H NMR (CDCl3,
400 MHz): d=5.96 (dd, J=4.8, 2.8 Hz, 1H), 5.62–5.55 (m, 1H), 5.35 (d,
J=11.7 Hz, 1H), 4.51 (s, 1H), 2.66–2.38 (brs, 1H), 2.36–1.92 (m, 4H),
1.84–1.48 (m, 4H), 1.34 (s, 3H), 1.29–1.24 (m, 6H), 1.18 (s, 3H), 1.15 (s,
3H), 0.91 ppm (t, J=7.3 Hz, 3H); 13C NMR (CDCl3, 100.6 MHz): d=
145.8, 140.1, 128.8, 126.5, 81.4, 73.0, 42.3, 38.4, 31.4, 30.3, 29.7, 28.2, 27.7,
25.6, 23.9, 22.7, 22.3, 18.6, 14.2 ppm; IR (film): n˜ =3791, 3477, 2927, 2866,
(Z)-(5R,6R,10aS)-6-Butyl-6-hydroxy-7,7,10a-trimethyl-1,2,3,5,6,7,10,10a-
octahydrobenzocycloocten-5-ylbenzoate (27a): Diene 20a (15 mg,
35 mmol) was dissolved in dichloromethane (2.0 mL). The mixture was
thoroughly degassed three times while stirring. Second-generation
Grubbs catalyst (1.5 mg, 1.8 mmol, 5 mol%) was added and the mixture
was refluxed for 18 h. After cooling, the solvent was evaporated at re-
duced pressure. Purification of the crude product by flash chromatogra-
phy (diethyl ether/petroleum ether 5:95) afforded the desired bicycle 27a
(13 mg, 84%) as a pale-yellow oil. The same procedure repeated with
first-generation Grubbs catalyst (1.5 mg, 1.8 mmol, 5 mol%) in 1,2-di-
chloroethane (2.0 mL) refluxed for 36 h afforded compound 27a (9.0 mg,
1718, 1588, 1514, 1452, 1330, 1265, 914, 885, 810, 788, 718, 685, 572 cmÀ1
;
HRMS: m/z: calcd for C19H32O2: 292.2402; found: 292.2405.
(S)-6-[(Z)-4,4-Dimethyl-5-oxonon-2-enyl]-6-methylcyclohex-1-enecarbal-
dehyde (29): Benzeneseleninic acid (12 mg, 66 mmol, 2.0 equiv) was
added to a solution of bicycle 28b (9.6 mg, 33 mmol) in dichloromethane
(5 mL) followed by second-generation Grubbs catalyst (2.8 mg, 3.3 mmol,
10 mol%) at 208C, and the mixture was refluxed for 6 h. The solvent was
evaporated at reduced pressure. Purification of the crude product by
flash chromatography (diethyl ether/petroleum ether 10:90) afforded ke-
toaldehyde 29 (6.4 mg, 67%) as a colorless oil. [a]2D0 =À7.5 (c=0.4 in
1
71%). [a]2D0 =+0.5 (c=1.10 in CH2Cl2); H NMR (CDCl3, 400 MHz): d=
1
CH2Cl2); H NMR (CDCl3, 400 MHz): d=9.32 (s, 1H), 6.81 (t, J=3.9 Hz,
8.10–8.08 (m, 2H), 7.62–7.58 (m, 1H), 7.51–7.47 (m, 2H), 5.95–5.91 (m,
1H), 5.83 (s, 1H), 5.80–5.72 (m, 1H), 5.42 (d, J=11.7 Hz, 1H), 3.26 (t,
J=11.9 Hz, 1H), 2.20–2.12 (m, 1H), 2.05–1.94 (m, 1H), 1.86–1.78 (m,
2H), 1.72–1.67 (m, 2H), 1.61 (s, 3H), 1.54 (s, 3H), 1.29–1.20 (m, 7H),
0.99 (s, 3H), 0.84 ppm (t, J=7.1 Hz, 3H); 13C NMR (CDCl3, 100.6 MHz):
d=166.0, 139.8, 138.0, 133.0, 132.8, 131.5, 130.4, 129.8, 128.6, 83.5, 80.2,
43.3, 41.3, 37.6, 36.7, 31.9, 30.9, 29.4, 25.5, 23.8, 23.4, 18.3, 14.1 ppm; IR
(film): n˜ =3544, 3435, 2926, 2866, 2360, 1722, 1453, 1264, 1099, 913, 861,
842, 778, 655, 563, 532 cmÀ1; HRMS: m/z: calcd for C26H36O3: 396.2665;
found: 396.2656.
1H), 5.45 (dt, J=11.5, 2.1 Hz, 1H), 5.19–5.13 (m, 1H), 2.52 (ddd, J=
15.7, 5.2, 2.4 Hz, 1H), 2.46 (t, J=7.5 Hz, 2H), 2.37–2.27 (m, 2H), 2.09
(ddd, J=15.7, 8.8, 1.3 Hz, 1H), 1.67–1.58 (m, 4H), 1.34–1.25 (m, 4H),
1.23 (s, 3H), 1.22 (s, 3H), 1.17 (s, 3H), 0.90 ppm (t, J=7.4 Hz, 3H);
13C NMR (CDCl3, 100.6 MHz): d=214.3, 194.6, 155.1, 146.8, 135.8, 129.4,
128.0, 49.1, 37.6, 36.7, 35.8, 27.2, 26.5, 26.3, 25.9, 25.6, 22.5, 18.0,
14.1 ppm; IR (film): n˜ =3532, 2930, 2869, 2360, 1688, 1516, 1368, 1333,
998, 954, 908, 829, 802, 788, 755, 664, 624, 542, 493 cmÀ1; HRMS: m/z:
calcd for C19H30O2: 290.2246; found: 290.2244.
(Z)-(5S,6S,10aS)-6-Butyl-6-hydroxy-7,7,10a-trimethyl-1,2,3,5,6,7,10,10a-
octahydrobenzocycloocten-5-ylbenzoate (27b): Diene 20b (9.0 mg,
21 mmol) was dissolved in dichloromethane (2.0 mL). The mixture was
thoroughly degassed three times while stirring. Second-generation
Grubbs catalyst (0.9 mg, 1.1 mmol, 5 mol%) was added and the mixture
was stirred for 15 min at 208C. The solvent was evaporated at reduced
pressure. Purification of the crude product by flash chromatography (di-
ethyl ether/petroleum ether 5:95) afforded the desired bicycle 27b
(9.0 mg, quantitative yield) as a pale-yellow oil. The same procedure re-
peated with first-generation Grubbs catalyst (0.9 mg, 1.1 mmol, 5 mol%)
Acknowledgements
Financial support was provided by the CNRS (UMR 7652) and the Ecole
Polytechnique. C.M. thanks the DRE of Ecole Polytechnique for a fel-
lowship. S.S. thanks the DØlØgation GØnØrale pour l’Armement (DGA)
for a fellowship. We gratefully acknowledge Dr. J.-P. FØrØzou for fruitful
discussions and molecular modeling.
7322
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7314 – 7323

Ring-Closing Metathesis
FULL PAPER
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[12] Diols 15a and 15b would be trans if the B ring were closed.
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Received: April 23, 2008
Published online: July 4, 2008
Chem. Eur. J. 2008, 14, 7314 – 7323
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7323