Rearrangement of 4,5-epoxy-9-trimethylsilyldecalines. Application to the synthesis of the natural eremophilane (-)-aristolochene

Article abstract of DOI:10.1021/jo060643i

Several 4,5-epoxy-9-trimethylsilyl-eudesmanes and 15-nor-eudesmanes, having different relative stereochemistry and substitution at the oxirane ring, have been prepared starting from (-)-carvone and subjected to acid-promoted rearrangement. The presence of

Full text of DOI:10.1021/jo060643i

Rearrangement of 4,5-Epoxy-9-trimethylsilyldecalines. Application
to the Synthesis of the Natural Eremophilane (-)-Aristolochene
Gonzalo Blay, Luz Cardona, Ana M. Collado, Begon˜a Garc´ıa, and Jose´ R. Pedro*
Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica, UniVersitat de Vale`ncia,
46100 Burjassot (Vale`ncia), Spain
jose.r.pedro@uV.es
ReceiVed March 24, 2006
Several 4,5-epoxy-9-trimethylsilyl-eudesmanes and 15-nor-eudesmanes, having different relative stereo-
chemistry and substitution at the oxirane ring, have been prepared starting from (-)-carvone and subjected
to acid-promoted rearrangement. The presence of the silicon at C9 favors two different main reaction
pathways involving C14-methyl or C1-methylene migration through the stabilization of a C10 carbocation
intermediate. Selective 1,2-migration of the bridgehead methyl group takes place with trisubstituted
â-epoxide and tetrasubstituted R-epoxide, yielding 4-hydroxy-eremophilane and 15-nor-eremophilane
compounds, while the trisubstituted R-epoxide suffers successive rearrangements to give a 1-hydroxy-
15-nor-eremophilane through a pathway involving the initial migration of the C1 methylene. The synthetic
utility of these rearrangements is shown by the synthesis of natural (-)-aristolochene.
Introduction
carrying out this kind of rearrangement in the laboratory to
obtain eremophilane or spiranic sesquiterpenes.5 This task,
however, has been shown to be difficult, and only very few
successful examples have been described in the literature.
Among them, we can mention the photochemical rearrangement
of dienones leading to 1,2-methylene or 1,2-methyl migration
products,6 the thermal or acid-catalyzed rearrangements of
eudesmanes with special structural features such as hydroxy
enones to spirovetivanes3 and R,â-epoxy ketones to spiroveti-
vanes or eremophilanes,7 and the rearrangement of an epoxy
eudesmanolide to an eremophilanolide.8 In particular, the
rearrangement of 4,5- or 5,6-epoxy eudesmanes or related
compounds would be of great interest because their rearrange-
ments lead to compounds functionalized at C4 or C6, which
will allow further synthetic modifications at these positions. The
acid-catalyzed rearrangements of simple 4,5-epoxy eudesmanes
have been studied by different authors who have reported
noncoincidental results. However, no products with eremo-
philane or spiranic structures resulting from these reactions have
been reported in any case (Scheme 1).9,10
Skeletal rearrangements via carbocations are involved in many
biogenetic pathways leading to natural products. In the early
past century, Robinson suggested that eremophilanes were
formed in nature from C5 cationic eudesmane precursors via a
route involving methyl migration.1 Similar rearrangements
involving C1- or C9-methylene migrations with concomitant
contractions of the A or B rings, respectively, have been
proposed for the biosynthesis of sesquiterpenes bearing the
spiro[4,5]decane framework, that is, spiroaxanes and spiroveti-
vanes (Figure 1).2 The hypothesis of a common biogenetic
pathway for these kind of compounds is supported by the
simultaneous presence of eudesmane, eremophilane, and spiroveti-
vane sesquiterpenes in some plant species.3
Because of the extensive synthetic work carried out on
eudesmane sesquiterpenes,4 there is a considerable interest in
* To whom correspondence should be addressed. Tel.: +34 963544329.
Fax: +34 96354 4328.
(1) (a) Dewick, P. M. Nat. Prod. Rep. 2002, 19, 181-222 and previous
reviews in this series. (b) Marshall, J. A.; Brady, S. F.; Andersen, N. H.
Fortschr. Chem. Org. Naturst. 1974, 31, 283-285. (c) Robinson, R. The
structural relations of natural products; Clarendon: Oxford, 1955; p 12.
(2) Eggers, M. D.; Sinnwell, V.; Stahl-Biskup, E. Phytochemistry 1999,
51, 987-990.
(5) Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J. R. In Studies in Natural
Products Chemistry: BioactiVe Natural Products; Atta-Ur-Rahman, Ed.;
Elsevier: Amsterdam, 2000; Vol. 24, Part E, pp 53-129.
(6) Caine, D.; Graham, S. L. J. Org. Chem. 1980, 45, 3790-3797.
(7) Ceccherelli, P.; Curini, M.; Marcotullio, M. C.; Rosati, O. Tetrahedron
1989, 45, 3809-3818.
(3) Andersen, N. H.; Falcone, M. S.; Syrdal, D. D. Tetrahedron Lett.
1970, 21, 1759-1762.
(8) Kitagawa, I.; Yamazoe, Y.; Takeda, R.; Yosioka, I. Tetrahderon Lett.
1972, 48, 4843-4846.
(4) Coates, R. M. Fortschr. Chem. Org. Naturst. 1976, 33, 73-230.
10.1021/jo060643i CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/02/2006
J. Org. Chem. 2006, 71, 4929-4936
4929

Blay et al.
FIGURE 1. Proposed biogenetic pathways from eudesmane to eremophilane, spiroaxane, and spirovetivane sesquiterpenes.
SCHEME 1. Acid-Promoted Rearrangements of Simple 4,5-Epoxyeudesmanes
SCHEME 2. Rearrangement of
Epoxytrimethylsilyldecalines
Three main concerns may be encountered during the acid-
catalyzed rearrangement of this kind of epoxides: (a) lack of
selectivity of the migrating group, (b) 1,2-elimination of the
hydroxyl group before rearrangement,11 and (c) a Grob-type
rearrangement of the 1,3-hydroxycarbocations that result after
the initial rearrangement in the case of epoxides.9,10 In previous
work, we have shown that some of these problems can be
overcome and selectivity during migration can be gained by
introducing a TMS group in the vicinity of the migrating group.
In the case of simple decalines, we found that methylene
migration was preferred if the epoxide and the TMS group were
on the same ring, while methyl migration was the main pathway
if both groups were on different rings of the decalin system.12
It is believed that the TMS group promotes migration of the
methyl or methylene groups in â to the TMS group by
stabilizing the resulting carbocation at C10 (â-effect), and at
the same time, it prevents further rearrangements in the resulting
carbocation by rapidly eliminating the TMS group to form a
double bond (super proton behavior).13 The success of this
approach has been shown by the synthesis of different spiro-
cyclic sesquiterpenes with spirovetivane14 or spiroaxane15
skeleton (Scheme 2).
As a continuation of our research on silicon-guided rear-
rangements of epoxy decalines, we report here the synthesis
and acid-promoted rearrangement of several 4,5-epoxy-9-
trimethylsilyl-eudesmanes and 15-nor-eudesmanes and the ap-
plication of such rearrangements in a total synthesis of (-)-
(9) Hikino, H.; Kohama, T.; Takemoto, T. Tetrahedron 1969, 25, 1037-
1045.
(10) Mehta, G.; Chetty, G. L.; Nayak, U. R.; Dev, S. Tetrahedron 1968,
aristolochene, an eremophilane sesquiterpene that has been
isolated from Aristolochia indica,16 Bixa orellana,17 and Du-
mortiera hirsuta18 and which is a component of the defensive
secretion of some termites.19 (-)-Aristolochene has been
24, 3775-3786.
(11) Coxon, J. M.; Lindley, N. B. Aust. J. Chem. 1976, 29, 2207-2217.
(12) Blay, G.; Cardona, L.; Collado, A. M.; Garc´ıa, B.; Pedro, J. R.
Tetrahedron Lett. 2003, 44, 8117-8119.
(13) Colvin, E. W. Silicon Reagents in Organic Synthesis; Academic
Press: London, 1988.
(14) (a) Blay, G.; Collado, A. M.; Garc´ıa, B.; Morcillo, V.; Pedro, J. R.
J. Org. Chem. 2004, 69, 7294-7302. (b) Hwu, J. R.; Wetzel, J. M. J. Org.
Chem. 1992, 57, 922-928.
(15) Blay, G.; Collado, A. M.; Garc´ıa, B.; Pedro, J. R. Tetrahedron 2005,
61, 10853-10860.
(16) Govindachari, T. R.; Mohamed, P. A.; Parthasarathy, P. C.
Tetrahedron 1970, 26, 615-619.
(17) Lawrence, B. M.; Hogg, J. W. Phytochemistry 1973, 12, 2995.
(18) Saritas, Y.; Bulow, N.; Fricke, C.; Konig, W. A.; Muhle, H.
Phytochemistry 1998, 48, 1019-1023.
4930 J. Org. Chem., Vol. 71, No. 13, 2006

Rearrangement of 4,5-Epoxy-9-trimethylsilyldecalines
SCHEME 3. Synthesis of Compounds 7a, 7b, 13, and 14a
a (a) (Me3Si)2 (2.5 equiv), MeLi (2 equiv), THF-HMPA; ref 15. (b) (1) MVK (2 equiv), Ph3CSbCl3 (0.05 equiv), 0 °C; (2) 1 M KOH/MeOH; ref 15.
(c) (1) EVK (1.5 equiv), KOH (0.25 equiv), MeOH, reflux. (2) Pyrrolidine (0.12 equiv), Bz, reflux. (d) Wilkinson’s catalyst, Bz, H2. (e) (CH2SH)2 (4 equiv),
BF3‚Et2O (cat), AcOH. (f) Ca, NH3. (g) m-CPBA (1.5 equiv), NaOAc (2.5 equiv), CHCl3, 0 °C. (h) NaBH4 (4 equiv), MeOH, 0 °C. (i) (1) Ph3P (3 equiv),
PhCO2H (3 equiv), DEAD (2 equiv), THF, 0 °C; (2) LiAlH4 (1 equiv), THF, 0 °C. (j) Ti(i-PrO)4 (5 equiv), t-BuOOH (2 equiv), Bz. (k) (1) MsCl (4.5 equiv),
Et3N (6 equiv), CH2Cl2, -10 °C; (2) NaBH4 (4 equiv), (PhSe)2 (4 equiv), AcOH (1.8 equiv), DMF; then mesylate. (l) 30% aq H2O2 (2 equiv), THF, 0 °C
to room temperature. (m) N2H4‚H2O (22 equiv), 30% aq H2O2 (11 equiv), EtOH, 0 °C.
synthesized in racemic form20 and also in enantiomerically pure
6a by using different indirect epoxidation approaches23 were
unsuccessful, as they resulted in decomposition mixtures.
To prepare epoxide 13, we used a modification of the
Sharpless epoxidation of allylic alcohols. It is known that allylic
and homoallylic hydroxyl groups have a cis directing effect in
the metal-catalyzed epoxidation of alkenes.24 Therefore, we
thought that it could be possible to direct the epoxidation of
the C4-C5 double bond by a hydroxyl group at C3. Reduction
of enone 4a with NaBH4 gave two epimeric alcohols 8 and 9
in 4 and 91% yields, respectively. The stereochemistry of the
new stereogenic center in compounds 8 and 9 was initially
assigned according to the shape of the H3 signal in the
corresponding H NMR spectra. Thus, in the H NMR of the
minor alcohol 8, H3 appeared as a broad singlet (δν1/2 ≈ 9.6
Hz), characteristic for an equatorial proton, while in the 1H NMR
of compound 9, the signal for H3 appeared as a multiplet
(δν1/2 ≈ 20 Hz), characteristic for an axial proton. The
form starting from (+)-valencene.21
Results and Discussion
1. Synthesis of 4,5-Epoxy-9-trimethylsilyldecalines. The
starting point for the synthesis of epoxides 7a and 13 was enone
4a, which can be readily prepared in three steps from R-(-)-
carvone (1; Scheme 3).15 To prepare epoxide 7a, deoxygenation
of the carbonyl group at C3 was achieved in two steps involving
formation of a thioketal 5a by treatment with ethanedithiol in
acetic acid containing BF3‚Et2O followed by reductive desul-
furization with calcium in liquid ammonia22 to give alkene 6a
in 88% yield for the two steps. Epoxidation of the double bond
was carried out by treatment with m-CPBA to afford exclusively
epoxide 7a in 89% yield, which resulted from the attack of the
epoxidating reagent from the less sterically congested side of
the double bond opposite to the C7-isopropyl chain. All attempts
to prepare the diastereomeric epoxide 13 directly from alkene
1
1
(23) (a) Cun˜at, A. C.; D´ıez-Mart´ın, D.; Ley, S. V.; Montgomery, F. J. J.
Chem. Soc., Perkin Trans. 1 1996, 611-620. (b) Fritsch, W.; Kohl, H.;
Stache, U.; Haede, W.; Radscheit, K.; Ruschig, H. Liebigs Ann. Chem. 1969,
727, 110-120. (c) Sanseverino, A. M.; de Mattos, M. C. S. Synth. Commun.
1998, 28, 559-572. (d) Toshimitsu, A.; Aoai, T.; Owada, H.; Uemura, S.;
Okano, M. J. Chem. Soc., Chem. Commun. 1980, 412-413. (e) Labar, D.;
Krief, A.; Hevesi, L. Tetrahedron Lett. 1978, 3967-3970.
(19) Baker, R.; Coles, H. R.; Edwards, M.; Evans, D. A.; Howse, P. E.;
Walmsley, S. J. Chem. Ecol. 1981, 7, 135-145.
(20) Piers, E.; Geraghty, M. B. Can. J. Chem. 1973, 51, 2166-2173.
(21) Cane, D. E.; Salaski, E. J.; Prabhakaran, P. C. Tetrahedron Lett.
1990, 31, 1943-1944.
(22) Hwu, J. R.; Chua, V.; Schroeder, J. E.; Barrans, R. E., Jr.; Khourdary,
K. P.; Wang, N.; Wetzel, J. M. J. Org. Chem. 1986, 51, 4731-4733.
(24) Rao, A. S. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1993; Vol. 7.
J. Org. Chem, Vol. 71, No. 13, 2006 4931

Blay et al.
SCHEME 4. Acid-Promoted Rearrangement of
4,5-Epoxy-9-trimethylsilyldecalines 7a, 7b, and 13a
a (a) BF3‚Et2O (1.25 equiv), CH3CN, -25 °C.
C-O bond by radical procedures via thiocarbonates, mesylates,
and related derivatives were unsuccessful because they gave
rise to mixtures of rearranged products.27 Therefore, we planned
a sequence involving elimination of the hydroxyl group and
hydrogenation of the resulting double bond. Elimination of the
hydroxyl group was achieved by its transformation into a
phenylselenide: treatment of compound 10 with mesyl chloride
gave the corresponding mesylate, which was treated with sodium
phenylselenolate to afford phenylselenide 11. Oxidation of the
selenide with aqueous H2O2, followed by elimination of the
resulting selenoxide gave alkene 12 in 69% yield. Finally,
hydrogenation of the double bond with diimine28 afforded
epoxide 13 in 78% yield.29
FIGURE 2. Some significant NOEs in compounds 9, 10, and 14.
stereochemistry of H3 in compound 9 was further corroborated
by NOE experiments (Figure 2), which were carried out after
1
the assignment of the key peaks in the H NMR of compound
9 by homodecoupling experiments. The most significant NOEs
were found between the signals of H3 (δ 4.15, m) and the signals
of H2eq (δ 1.90, m) and H1ax (1.33, br t, J ) 12.5 Hz), which
indicates the axial disposition of H3. The stereochemical
outcome of the reaction is also in good agreement with the
expected preferential attack of the hydride from the less-hindered
side of the carbonyl group in compound 4a, opposite to the
C14 methyl group.
Unfortunately, the major alcohol 9 did not have the proper
stereochemistry at C3 to induce epoxidation of the double bond
from the â-side of the molecule, therefore, it was epimerized at
C3 following a Mitsunobu protocol.25 Treatment of compound
9 with benzoic acid, triphenylphosphine, and diethyl azodicar-
boxylate (DEAD) gave a benzoate that was reduced with LiAlH4
to yield alcohol 8 in 64% yield in two steps. With this allyl
alcohol available, we carried out the epoxidation of the double
bond. The reaction of compound 8 with tert-butyl hydroperoxide
in the presence of Ti(i-PrO)4 afforded only the cis-epoxy alcohol
10 in 44% yield,26 part of the allyl alcohol being reoxidized to
enone 4a. For comparative purposes, we also carried out the
epoxidation of compound 8 with m-CPBA, which afforded a
corresponding diastereomeric epoxy alcohol that was given
structure 14 with a trans disposition between the hydroxyl group
and the epoxide. Both epoxy alcohols were studied by NOE
experiments to confirm the expected stereochemistry of the
oxirane ring (Figure 2).
Epoxide 7b30 was synthesized following a similar sequence
to that used in the synthesis of epoxide 7a but starting from
enone 4b, which also can be readily prepared in three steps
from R-(-)-carvone (1), using ethyl vinyl ketone (EVK) in the
Robinson annulation step.
2. Acid-Promoted Rearrangement of 4,5-Epoxy-9-trimeth-
ylsilyldecalines. With the above epoxides available, we studied
their rearrangement in the presence of a Lewis acid. From the
different systems tested, the best results were obtained with BF3‚
Et2O in acetonitrile at low temperature. The results are sum-
marized in Scheme 4.
Treatment of compound 7a with BF3‚Et2O in acetonitrile at
-25 °C afforded 75% yield of an about 8:2 mixture of two
products that could be separated by HPLC. The minor product
was assigned structure 16 on the basis of its NMR spectra. The
1H NMR of this compound did not show any signal correspond-
ing to a TMS group. A signal corresponding to an olefinic proton
appeared at δ 5.38 (m), indicating the existence of a trisubsti-
tuted double bond. A signal corresponding to a singlet methyl
group attached to an aliphatic quaternary carbon appeared at δ
(27) Barton, D. H. R.; Motherwell, R. S. H.; Motherwell, W. B. J. Chem.
Soc., Perkin Trans. 1 1981, 2363-2367.
(28) Catalytic hydrogenation attempts with Pd/C or Wilkinson’s catalyst
resulted in the hydrogenolysis of the allyl C-O bond.
(29) Mori, K.; Ohki, M.; Sato, A.; Matsui, M. Tetrahedron 1972, 28,
3739-3745.
(30) The stereochemistry of epoxide 7b was assigned on the assumption
of a preferential attack of the epoxidating reagent from the R side of the
molecule, opposite to the isopropyl chain, as it was proved in compounds
7a and 20. See also a discussion on the stereochemistry of compound 20 in
the text.
To prepare epoxide 13, removal of the hydroxyl group at C3
in compound 10 was required. Several attempts to cleave the
(25) Marchand, A.; Lioux, T.; Mathe´, T.; Imbach, J.-L.; Gosselin, G. J.
Chem. Soc., Perkin Trans. 1 1999, 2249-2254.
(26) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703-710.
4932 J. Org. Chem., Vol. 71, No. 13, 2006

Rearrangement of 4,5-Epoxy-9-trimethylsilyldecalines
SCHEME 5. Rearrangement of
4,5-Epoxy-9-trimethylsilyldecalines. Mechanistic Pathways
1.00, which was assigned to C14. This indicated that, during
rearrangement, the angular methyl group migrated from C10
to C5. The new quaternary bridgehead carbon C5 appeared at
δ 41.3 (C), while a signal at δ 80.4 (CH) was assigned to the
carbon bearing the secondary alcohol, which results after the
opening of the epoxide moiety. The stereochemistry of this
carbon was assigned according to the coupling constants for
the H4 proton in the 1H NMR (δ 3.24) that appeared as a double
doublet with J ) 4.2 Hz (ax-eq) and 11.5 Hz (ax-ax),
indicating that the OH group was in equatorial disposition and
R-oriented, as expected from the stereochemistry of the epoxide
in compound 7a. The major product 15 showed similar NMR
spectra to compounds 16 and was also assigned a decalin-
derived structure. Most significantly, the CH-O proton appeared
at a lower field (δ 4.03) than in compounds 16 (and 17) as a
triplet (J ) 7.2 Hz), indicating the possible presence of an allyl
alcohol in axial disposition. This fact was confirmed by NOE
between the CH-O (δ 4.03) and the olefinic protons (δ 5.36).
Treatment of compound 13 with BF3‚Et2O in acetonitrile at
-25 °C afforded only a major product 17, which only differed
from 16 in the stereochemistry of carbon C4 bearing the
secondary alcohol. The stereochemistry of this carbon was
confirmed by the shape of the H4 signal in the 1H NMR, which
appeared as a broad unresolved dd (δν1/2 ≈ 9.0 Hz), indicating
the R-equatorial orientation of this proton.
Finally, rearrangement of the tetrasubstituted epoxide 7b was
achieved under similar conditions to afford compound 18 in
58% yield. The structure of compound 18 was assigned in a
similar way as described above for compounds 16 and 17. The
stereochemistry of C4 was assigned on the assumption of a
similar behavior between epoxides 7b and 20; see below.
The formation of compounds 16, 17, and 18 can be explained
in terms of a 1,2-shift of the angular methyl from C10 to C5 in
the carbocation (i) that results after the acid-promoted cleavage
of the epoxide to give a C10 carbocation (ii), followed by
elimination of the TMS group with concomitant formation of a
double bond between C9 and C10 (Scheme 5, path a). The
formation of compound 15 is more difficult to explain. A
possible mechanism would involve successive methylene and
methyl migrations, as outlined in Scheme 5 (path b).
Independently of their fate, all these rearrangements start with
the formation of a carbocation at C5, followed by methyl or
methylene migration to form a carbocation at C10. The
formation of the C10 carbocation would be favorable because
of the stabilization of the incipient positive charge at C10 by
the silicon atom at C9 (â effect), which is accounted for by
two different contributions: an inductive effect and hypercon-
jugation.31 While the inductive effect does not depend on the
migrating group, the hyperconjugative interaction between the
silicon atom and the developing positive charge has a cosine-
square dependence with the Si-C-C-C (migrating) dihedral
angle.31,32 An examination of the models of epoxides 7a, 7b,
and 13 indicates that the dihedral angles for the Si-C-C-C1
(methylene) and Si-C-C-C14 (methyl) arrays are similar
within each one of the compounds, and they are far from the
anti-coplanar arrangement, which would be the most favorable
scenario for the hyperconjugative stabilization. Therefore,
hyperconjugation must have little differentiating effect to favor
a mechanistic pathway (path a or path b) in respect to the other,
and the selectivity observed during the rearrangements of
compounds 7a, 7b, and 13 most probably is obedient to other
causes, probably steric. Thus, in the case of compound 7a,
migration of the methylene C1 anti to the epoxide breaking C-O
bond would be preferred with respect to the migration of the
C14 methyl syn to the epoxide ring; therefore, path b is the
major pathway in this reaction. For some reason, elimination
of the TMS group in the resulting spiranic carbocation (iii) is
not fast enough, and this allows further rearrangements until
the final quenching of the carbocation (v) to give compound
15.33 In the case of the rearrangement of epoxide 13, migration
of the C14 methyl anti to the epoxide (path a) would be the
most favorable process leading to compound 17. Finally, in the
case of the tetrasubstituted epoxide 7b migration of the C1
methylene would be hindered by the C15 methyl group, and,
therefore, the reaction would follow path a, with methyl
migration to give compound 18. The influence of the TMS group
in these rearrangements should be remarked (compare with
Scheme 1); and although it is not the only determining factor
in the selectivity of methyl versus methylene migration, it plays
an important role by stabilizing the C10 carbocation, hence,
favoring the reaction pathways (a and b) that occur through this
carbocation with respect to other possible mechanistic pathways.
It also determines the regioselectivity in the formation of the
double bond in the final step of the rearrangements.
3. Synthesis of (-)-Aristolochene. To show a synthetic
application of these rearrangements, we report here the synthesis
of the eremophilane sesquiterpene (-)-aristolochene (24; Scheme
(33) The reasons for the slow elimination of the TMS group in (iii) are
not clear at the moment, but it may be due to a lack of coplanarity between
the involved orbitals of the C-Si bond and the carbocation. This would
permit successive rearrangements from (iii) to (v) that would relieve the
angular strain associated with the spiranic carbon and would lead to a final
carbocation (v) stabilized by the TMS and also by the neighboring alkoxide.
(31) Lambert, J. B.; Wang, G. T.; Finzel, R. B.; Teramura, D. H. J. Am.
Chem. Soc. 1987, 109, 7838-7845.
(32) Lambert, J. B.; Wang, G. T. J. Phys. Org. Chem. 1988, 1, 169-
178.
J. Org. Chem, Vol. 71, No. 13, 2006 4933

Blay et al.
SCHEME 6. Synthesis of (-)-Aristolochenea
corresponding to the geminal C15 methyl and the C14 angular
methyl in axial position, indicating the R orientation of the
hydroxyl group. Finally, the synthesis of (-)-aristolochene
required the deoxygenation of the tertiary alcohol. The procedure
chosen was the reduction of its acetate ester with K in tert-
butylamine. However, treatment of compound 22 with acetic
anhydride/pyridine did not yield the corresponding acetate, but
an about 1:2.4 mixture of diastereomeric 3-acetoxy-2-butenoyl
esters. This moiety presumably results from a Claisen acylation
of the initial acetate, followed by O-acetylation of the intermedi-
ate dicarbonyl enolate, as we have already reported in a similar
transformation.14a
The stereochemistry about the double bond was assigned in
accord with the chemical shifts for the allylic methyl group in
1
the H NMR spectra which appeared at δ 2.15 in the major
E-isomer 23a and at δ 1.97 in the minor Z-isomer 23b.36
Although the formation of these compounds could not be
prevented even by using equivalent amounts of acetic anhydride,
treatment of mixtures of 23a and 23b with K in tert-butylamine
brought about the reduction of the ester to give an almost
quantitative yield of a product that showed spectral data
coincident with those described in the literature for (-)-
aristolochene (24). During the last reaction, inversion of C4 is
produced as a consequence of the preferential protonation from
the less-hindered side of the molecule opposite to the angular
methyl C14.
In summary, we report the acid rearrangement of several 4,5-
epoxy-9-trimethylsilyl eudesmane and 15-nor-eudesmanes hav-
ing different relative stereochemistry and substitution at the
oxirane ring. The presence of the silicon at C9 favors two
different main reaction pathways involving C14-methyl or C1-
methylene migration through the stabilization of a C10 car-
bocation intermediate. Selective 1,2-migration of the bridgehead
methyl group takes place with trisubstituted â-epoxide and
tetrasubstituted R-epoxide, yielding 4-hydroxy- eremophilane
and 15-nor-eremophilane compounds, while the trisubstituted
R-epoxide suffers successive rearrangements to give a 1-hy-
droxy-nor-eremophilane through a pathway inolving the initial
migration of the C1 methylene. The synthetic utility of these
rearrangements is shown by the synthesis of natural (-)-
aristolochene.
a (a) LiAlH4 (4.3 equiv), AlCl3 (12.8 equiv), Et2O, 0 °C, 5 min, then
3b, 0 °C. (b) m-CPBA (1.5 equiv), NaOAc (2.5 equiv), CHCl3, 0 °C. (c)
TiF4 (1.5 equiv), CH3CN, -20 °C. (d) 4-DMAP (0.46 equiv), Ac2O-Pyr
(1:1); 15% starting material recovered. (e) K (2.5 equiv), 18-crown-6 (cat),
t-BuNH2.
6), using the rearrangement of epoxide 20 as the key step in
this synthesis. The synthesis started with compound 3b. To
remove the oxygen at C3 in this compound, we attempted the
same thioketalization-desulfurization procedure that we have
described previously for the preparation of 7b. However, during
formation of the thioketal in the presence of BF3‚Et2O-acetic
acid, migration of the double bond from the isopropilydene chain
toward the cyclohexane ring took place. Therefore, deoxygen-
ation was achieved in one step by reduction with LiAlH4-AlCl3
to give diene 19 in 54% yield.34 Epoxidation of 19 with MCPA
at 0 °C afforded epoxide 20 in 70% yield together with 5% of
diepoxide 21. We assumed that epoxidation of the C4-C5
double bond with MCPA took place from the R side of the
molecule, as in compounds 6a and 6b. This assumption was
confirmed by NOE experiments carried out with alcohol 22,
which results after acid rearrangement of compound 20.
Rearrangement of epoxide 20 was carried out with TiF4 instead
of BF3‚Et2O to avoid migration of the isopropilydene double
bond. In this way, compound 22 was obtained in 45% yield.
The stereochemistry of the carbon bearing the hydroxyl group
and, hence, that of epoxide 20, was confirmed by NOE
experiments carried out in DMSO-d6.35 Using this solvent, it
was possible to induce the selective irradiation of the OH proton,
which caused NOEs with two signals at δ 0.80 and δ 1.05,
Experimental Section37
(6R,7R,9S)-(-)-3,3-(1,2-Ethanediyldithio)-9-isopropyl-6-meth-
yl-7-trimethylsilylbicyclo[4.4.0]dec-1-ene (5a). A solution contain-
ing compound 4a15 (1.28 g, 4.59 mmol), ethanedithiol (1.6 mL,
19.1 mmol), and BF3‚Et2O (0.33 mL) in acetic acid (17 mL) was
stirred under argon at room temperature for 2 h. After this time,
the mixture was diluted with EtOAc, washed with saturated aqueous
NaHCO3 and brine, and dried over Na2SO4. Evaporation of the
solvent under reduced pressure and chromatography, eluting with
hexanes-EtOAc (from 100:0 to 95:5), gave 1.62 g (99%) of
compound 5a: white solid; mp 106-107 °C (hexanes-EtOAc);
[R]20D -123 (c 1.3, CHCl3); EM m/z 354 (M+, 84), 311 (65), 294
(26), 293 (53), 279 (29), 189 (22), 73 (100); HRMS calcd for
C19H34S2Si, 354.1871; found, 354.1862 (M+); IR (KBr) 1458, 1247,
829 cm-1; 1H NMR δ 5.38 (1H, s), 3.39-3.18 (4H, m, SCH2CH2S),
2.27-2.08 (3H, m), 1.83 (1H, dt, J ) 13.5, 3.6 Hz), 1.69-1.57
(34) (a) Brewster, J. H.; Bayer, H. O. J. Org. Chem. 1964, 29, 116-
121. (b) Broome, J.; Brown, B. R.; Roberts, A.; White, A. M. S. J. Chem.
Soc. 1960, 1406-1408.
(35) DMSO-d6 slows down the exchange of the hydroxyl proton so it
gives a defined signal that can be irradiated in NOE experiments: Sanders,
J. K. M.; Hunter, B. K. Modern NMR Spectroscopy; Oxford University:
Oxford, 1989.
(36) Pretsch, E.; Clerc, T.; Seibl, J.; Simon, W. Tables of Spectral Data
for Structure Determination of Organic Compounds, 2nd edition; Springer-
Verlag: Berlin, Heidelberg, New York, 1989.
(37) For a description of the general experimental methods, see Sup-
porting Information.
4934 J. Org. Chem., Vol. 71, No. 13, 2006

Rearrangement of 4,5-Epoxy-9-trimethylsilyldecalines
(5H, m), 1.28 (1H, m), 1.11 (3H, s), 0.88 (3H, d, J ) 6.6 Hz), 0.79
(3H, d, J ) 6.6 Hz), 0.77 (1H, dd, J ) 11.4, 6.0 Hz, overlapped),
0.03 (9H, s, (CH3)3Si); 13C NMR δ 144.9 (C), 124.9 (CH2), 65.8
(C), 43.1 (CH), 40.0 (CH2), 39.7, 39.4 (2CH2, SCH2CH2S), 38.1
(CH2), 37.2 (C), 35.6 (CH2), 33.6 (CH), 26.8 (CH2), 25.1 (CH),
22.0 (CH3), 21.0 (CH3), 20.6 (CH3), 0.3 (3CH3, (CH3)3Si).
(CH2), 33.4 (CH), 27.7 (CH2), 26.7 (CH2), 25.1 (CH), 21.4 (CH3),
21.0 (CH3), 20.5 (CH3), 0.4 (3CH3, (CH3)3Si).
9: white solid, mp 123-124 °C (hexanes-EtOAc); [R]23D -58
(c 1.3, CHCl3); EM m/z 263 (M+ - OH, 10), 262 (38), 219 (38),
146 (12), 145 (100), 73 (12); HRMS calcd for C17H31Si, 263.2195;
found, 263.2119 (M+ - OH); IR (KBr) 3154, 1461, 1381, 1248,
1
870 cm-1; H NMR (400 MHz) δ 5.16 (1H, d, J ) 1.2 Hz), 4.15
(6R,7R,9S)-(-)-9-Isopropyl-6-methyl-7-trimethylsilylbicyclo-
[4.4.0]dec-1-ene (6a). In a flask equipped with a dry ice-acetone
condenser, calcium metal (0.92 g, 23.0 mmol) was dissolved in
liquid ammonia (ca. 110 mL) at -78 °C under argon. To the
resulting blue solution was added dry diethyl ether (30 mL) and a
solution of compound 5a (1.62 g, 4.57 mmol) in dry diethyl ether
(19 mL). The cooling bath was removed, and the solution was kept
at reflux for 6 h. After this time, solid NH4Cl was cautiously added,
followed by diethyl ether (40 mL), and ammonia was allowed to
evaporate overnight. Saturated aqueous NH4Cl was added, and the
aqueous phase was extracted with ether. The organic layer was
washed with aqueous NH4Cl, 10% aqueous NaOH, and brine, dried,
filtered, and concentrated under reduced pressure. Column chro-
matography (hexanes) gave 1.08 g (89%) of compound 6a: oil;
(1H, br m, δν1/2 ≈ 20 Hz), 2.27 (1H, m), 2.09 (1H, m), 1.90 (1H,
m), 1.80-1.57 (4H, m), 1.50-1.40 (1H, m), 1.34 (1H, t, J ) 12.5
Hz), 1.25 (1H, m), 1.14 (3H, s), 0.86 (3H, d, J ) 6.4 Hz), 0.79
(3H, d, J ) 6.8 Hz), 0.73 (1H, dd, J ) 4.0, 12.8 Hz), 0,02 (9H, s,
(CH3)3Si); 13C NMR δ 145.5 (C), 124.5 (CH), 67.8 (CH), 43.1
(CH), 38.0 (C), 37.9 (CH2), 35.6 (CH2), 33.9 (CH), 29.4 (CH2),
26.8 (CH2), 25.0 (CH), 22.3 (CH3), 20.9 (CH3), 20.5 (CH3), 0.3
(3CH3, (CH3)3Si).
Compound 8 from 9. A solution of 9 (309 mg, 1.11 mmol),
triphenylphosphine (870 mg, 3.32 mmol), and benzoic acid (405
mg, 3.32 mmol) in dry THF (13 mL) at 0 °C under argon was
treated with a solution of DEAD (430 µL, 1.95 mmol) in THF (13
mL). After 30 min, the solvent was removed under reduced pressure.
The crude was then dissolved in dry THF (20 mL) and cooled at
0 °C, and LiAlH4 was added in portions at intervals of 20 min
(4 × 42 mg, 1.11 mmol). After 1.5 h, the excess reagent was
destroyed by the addition of water. The mixture was diluted with
EtOAc, washed with brine, and dried over Na2SO4. After filtration,
the solvent was removed under reduced pressure, and the residue
was chromatographed on silica gel (hexanes-EtOAc, 90:10) to give
198 mg (64%) of alcohol 8.
[R]22 -88 (c 1.2, CHCl3); EM m/z 264 (M+, 46), 191 (19), 190
D
(94), 175 (53), 147 (84), 91 (20), 73 (100); HRMS calcd for C17H32-
Si, 264.2273; found, 264.2282 (M+); IR (NaCl) 1458, 1248, 858,
1
833 cm-1; H NMR δ 5.19 (1H, m), 2.29 (1H, m), 2.08 (1H, dt,
J ) 13.5, 2.1 Hz), 1.95-1.86 (2H, m), 1.79 (1H, dt, J ) 12.9, 3.5
Hz), 1.71-1.62 (2H, m), 1.61-1.51 (2H, m), 1.34-1.19 (2H, m),
1.12 (3H, s), 0.88 (3H, d, J ) 6.3 Hz), 0.82 (3H, d, J ) 6.6 Hz),
0.05 (9H, s, (CH3)3Si); 13C NMR δ 142.7 (C), 120.2 (CH), 43.1
(CH), 40.2 (CH2), 37.9 (C), 36.0 (CH2), 33.7 (CH), 26.9 (CH2),
25.7 (CH2), 25.1 (CH), 23.0 (CH3), 21.1 (CH3), 20.6 (CH3), 19.3
(CH2), 0.5 (3CH3, (CH3)3Si).
(1R,2S,3S,6R,7R,9S)-(-)-1,2-Epoxy-9-isopropyl-6-methyl-7-
(trimethylsilyl)bicyclo[4.4.0]decan-3-ol (10). Alcohol 8 (141 mg,
0.50 mmol) and Ti(i-PrO)4 (0.75 mL, 2.51 mmol) were dissolved
in benzene (2 mL) and stirred under argon for 5 min. Then, an
80% solution of t-BuOOH in di-tert-butylperoxide (100 µL, 1.0
mmol) was added. Additional Ti(i-PrO)4 and t-BuOOH were added
after 1 h (0.3 mL and 50 µL, respectively) and after 2 h (0.5 mL
and 100 µL, respectively). After an overall reaction time of 3 h,
saturated aqueous NaHCO3 was added, and the solution was
extracted with EtOAc. After drying and removal of the solvent
under reduced pressure, column chromatography, eluting with
hexanes-EtOAc (95:5 to 80:20), gave 39.4 mg (14%) of enone 4a
and 64.8 mg (44%) of epoxy alcohol 10: white solid; mp 61-62
(1S,2R,6R,7R,9S)-(+)-1,2-Epoxy-9-isopropyl-6-methyl-7-tri-
methylsilylbicyclo[4.4.0]decane (7a). To a solution of compound
6a (215 mg, 0.81 mmol) and NaOAc (167 mg, 2.04 mmol) in
chloroform (17 mL) at 0 °C was added m-CPBA (210 mg, 1.22
mmol). After 20 min, saturated aqueous NaHCO3 was added, and
the solution was extracted with EtOAc and dried. After filtration
and removal of the solvent under reduced pressure, column
chromatography afforded 203 mg (89%) of epoxide 7a: oil; [R]24
D
+2 (c 1.0, CHCl3); EM m/z 280 (16), 237 (19), 207 (28), 147 (24),
145 (22), 129 (21), 105 (22), 73 (100); HRMS calcd for C17H32-
OSi, 280.2222; found, 280.2233 (M+); IR (NaCl) 1460, 1246, 860,
°C (hexanes-EtOAc); [R]29 -114 (c 1.1, CHCl3); EM m/z 296
D
(M+, 3), 226 (80), 145 (39), 119 (18), 107 (39), 105 (28), 95 (17),
94 (42), 93 (26), 73 (100); HRMS calcd for C17H32O2Si, 296.2172;
1
831 cm-1; H NMR δ 2.93 (1H, br t, J ) 2.6 Hz), 2.05 (1H, dd,
J ) 13.5, 4.8 Hz), 1.87-1.83 (2H, m), 1.75-1.62 (3H, m), 1.45-
1.16 (6H, m), 1.08 (3H, s), 0.89 (3H, d, J ) 6.6 Hz), 0.86 (3H, d,
J ) 6.6 Hz), 0.05 (9H, s, (CH3)3Si); 13C NMR δ 63.0 (C), 62.2
(CH), 42.5 (CH), 36.5 (C), 34.4 (CH2), 34.1 (CH2), 27.2 (CH),
26.6 (CH), 26.0 (CH2), 24.2 (CH2), 21.6 (2CH3), 20.7 (CH3), 16.1
(CH2), 0.4 (3CH3, (CH3)3Si).
1
found, 296.2167 (M+); IR (KBr) 3375, 1249, 861, 832 cm-1; H
NMR (400 MHz) δ 3.98 (1H, br s), 3.00 (1H, d, J ) 4.0 Hz), 2.04
(1H, dd, J ) 14.0, 6.4 Hz), 2.00 (1H, m), 1.82 (1H, ddd, J ) 14.8,
13.4, 2.4 Hz), 1.71 (1H, td, J ) 23.6, 5.2 Hz), 1.51 (1H, td, J )
14.5, 4.0 Hz), 1.49 (1H, m), 1.35 (1H, m), 1.25 (1H, d, J ) 14.5
Hz), 1.17 (1H, m), 1.07 (3H, s), 1.02 (1H, dd, J ) 2.8, 13.6 Hz),
0.86 (3H, d, J ) 6.4 Hz), 0.84 (3H, d, J ) 6.4 Hz), 0.02 (9H, s,
(CH3)3Si); 13C NMR δ 68.9 (C), 63.4 (CH), 61.6 (CH), 42.2 (CH),
36.2 (C), 31.2 (CH2), 30.6 (CH2), 29.4 (CH), 27.1 (CH2), 26.9 (CH),
25.5 (CH2), 21.7 (CH3), 21.5 (CH3), 20.0 (CH3), 0.4 (3CH3, (CH3)3-
Si).
(1R,2R,3R,6R,7R,9S)-1,2-Epoxy-3-phenylselenenyl-9-isopro-
pyl-6-methyl-7-trimethylsilylbicyclo[4.4.0]decane (11). Mesyl
chloride (70 µL, 0.90 mmol) was added to a solution of epoxy
alcohol 10 (58 mg, 0.20 mmol) and triethylamine (165 µL, 1.2
mmol) in CH2Cl2 (1.2 mL) at -10 °C under argon. After 30 min,
the reaction mixture was diluted with EtOAc, washed with 1 M
HCl, saturated aqueous NaHCO3, and brine, and dried over Na2-
SO4. After filtration, the solvent was removed under reduced
pressure. A solution of sodium phenylselenolate was prepared by
adding NaBH4 (31 mg, 0.82 mmol) to a solution of PhSeSePh (204
mg, 0.65 mmol) in DMF (2 mL) under argon, followed by the
addition of acetic acid (22 µL) after 5 min. To the resulting solution
was added via syringe a solution of the crude mesylate in DMF
(2.7 mL). The mixture was stirred under argon for 24 h, quenched
(3S,6R,7R,9S)-(-)-9-Isopropyl-6-methyl-7-trimethylsilylbicyclo-
[4.4.0]dec-1-en-3-ol (8) and (3R,6R,7R,9S)-(-)-9-Isopropyl-6-
methyl-7-trimethylsilylbicyclo[4.4.0]dec-1-en-3-ol (9). To a so-
lution of compound 4a (739 mg, 2.66 mmol) in MeOH was added
NaBH4 in four portions at intervals of 15 min (4 × 100 mg, 2.66
mmol) at 0 °C. After 1 h, the reaction was quenched with saturated
aqueous NH4Cl and extracted with EtOAc. The organic layer was
washed with brine until neutrality and dried. Column chromatog-
raphy eluting with hexanes-EtOAc (from 95:5 to 80:20) gave 27
mg (4%) of alcohol 8 and 675 mg (91%) of alcohol 9.
8: oil, [R]25 -128 (c 1.2, CHCl3); EM m/z 280 (M+, 2), 262
D
(25), 219 (30), 131 (12), 145 (100), 73 (99); HRMS calcd for
C17H32OSi, 280.2222; found, 280.2229 (M+); IR (NaCl) 3520-
1
3300, 1250, 830 cm-1; H NMR (400 MHz) δ 5.36 (1H, d, J )
5.2 Hz), 3.98 (1H, br m, δν1/2 ≈ 10.8 Hz), 2.28 (1H, dd, J ) 13.6,
3.6 Hz), 2.10 (1H, t, J ) 12.0 Hz), 1.8-1.5 (8H, m), 1.28 (1H, m),
1.06 (3H, s), 0.86 (3H, d, J ) 6.4 Hz), 0.78 (3H, d, J ) 6.8 Hz,
overlapped with 1H, dd), 0.03 (9H, s, (CH3)3Si); 13C NMR δ 148.4
(C), 121.9 (CH), 64.0 (CH), 42.8 (CH), 38.2 (C), 35.7 (CH2), 34.0
J. Org. Chem, Vol. 71, No. 13, 2006 4935

Blay et al.
with water, extracted with EtOAc, washed with brine, and dried.
Evaporation of the solvent and column chromatography (hexanes-
EtOAc, 95:5) gave 60.4 mg (71%) of phenylselenide 11: 1H NMR
(300 MHz) δ 7.55 (2H, m), 7.25 (3H, m), 3.50 (1H, t, J ) 9.5 Hz),
3.05 (1H, s), 1.99 (1H, dd, J ) 14.3, 5.5 Hz), 1.70 (1H, dd, J )
13.0, 4.3 Hz), 1.01 (1H, dd, J ) 13.0, 3.3 Hz), 0.92 (3H, s), 0.83
(3H, d, J ) 6.8 Hz), 0.81 (3H, d, J ) 6.8 Hz), 0.00 (9H, s, (CH3)3-
Si).
and 4-(dimethylamino)pyridine (4-DMAP; 90 mg, 0.75 mmol), and
the mixture was stirred at room temperature. Additional loads of
pyridine (4 × 2 mL) and acetic anhydride (4 × 2 mL) were added
at intervals of 1.5 h. After a total of 8 h, the reaction mixture was
diluted with EtOAc, washed with 2 M HCl, saturated aqueous
NaHCO3, and brine, and dried. Filtration and solvent evaporation
under reduced pressure, followed by column chromatography
(hexanes-EtOAc 100:0 to 90:10), afforded 252 mg (47%) of 23a,
105 mg (20%) of 23b, and 52.4 mg (15%) of unreacted starting
material 22.
(1R,2S,6R,7R,9S)-(-)-1,2-Epoxy-9-isopropyl-6-methyl-7-tri-
methylsilylbicyclo[4.4.0]dec-3-ene (12). A solution of phenyl-
selenide 11 (49 mg, 0.11 mmol) in CH2Cl2 (1.2 mL) at 0 °C was
treated with 30% aq H2O2 (27 µL, 0.24 mmol). The mixture was
stirred at room temperature for 30 min. After this time, the mixture
was diluted with EtOAc, washed with brine, and dried. After
removal of the solvent under reduced pressure, the residue was
chromatographed (hexanes-EtOAc, 98:2) to give 22 mg (69%) of
23a: oil; [R]18 -63 (c 1.3, CHCl3); EM m/z 346 (M+, 5), 202
D
(62), 201 (16), 161 (23), 159 (35), 147 (43), 145 (15), 119 (18),
105 (18), 85 (100); HRMS calcd for C21H30O4, 346.2144; found,
346.2131 (M+); IR (NaCl) 2937, 1766, 1717, 1667, 1439, 1372,
1
1343, 1206, 1117, 1022, 899 cm-1; H NMR (400 MHz) δ 5.60
(1H, d, J ) 1.2 Hz), 5.45 (1H, dt, J ) 6.3, 2.0 Hz), 4.71, (1H, d,
J ) 1.8 Hz), 4.69 (1H, br s), 2.59 (1H, br d, J ) 12.6 Hz), 2.30
(3H, s), 2.15 (3H, s), 1.72 (3H, s), 1.54 (3H, s), 1.23 (3H, s); 13C
NMR δ 168.4 (C), 165.2 (C), 162.8 (C), 150.0 (C), 140.4 (C), 122.4
(CH), 111.7 (CH), 108.5 (CH2), 87.3 (C), 45.2 (C), 37.8 (CH), 35.8
(CH2), 31.7 (CH2), 30.9 (CH2), 30.6 (CH2), 22.7 (CH2), 22.2 (CH3),
21.1 (CH3), 21.0 (CH3), 20.9 (CH3), 17.8 (CH3).
compound 12: white solid; mp 50-51 °C (hexanes-EtOAc); [R]29
D
-132 (c 1.1, CHCl3); EM m/z 278 (M+, 5), 145 (36), 143 (20),
135 (31), 129 (23), 93 (30), 73 (100), 57 (28); HRMS calcd for
C17H30OSi, 278.2066; found, 278.2077 (M+); IR (KBr) 1461, 1249,
833 cm-1; 1H NMR δ 5.85 (1H, ddd, J ) 10.0, 4.0, 3.5 Hz), 5.72
(1H, m), 2.85 (1H, dd, J ) 4.0, 1.9 Hz), 2.17 (1H, dd, J ) 14.3,
4.9 Hz), 1.67 (1H, td, J ) 14.0, 4.1 Hz), 1.07 (1H, dd, J ) 13.6,
2.6 Hz), 0.98 (3H, s), 0.88 (3H, d, J ) 6.4 Hz), 0.83 (3H, d, J )
6.6 Hz), 0.04 (9H, s, (CH3)3Si); 13C NMR δ 131.3 (CH), 123.3
(CH), 67.0 (C), 54.1 (CH), 41.8 (CH), 38.4 (CH2), 35.7 (C), 31.7
(CH2), 29.6 (CH), 26.4 (CH), 26.1 (CH2), 21.8 (CH3), 21.3 (C),
19.5 (CH3), 0.4 (3CH3, (CH3)3Si).
23b: oil; [R]18 -35 (c 1.2, CHCl3); EM m/z 346 (M+, 5), 203
D
(34), 202 (53), 201 (15), 161 (28), 159 (33), 147 (42), 145 (15),
119 (23), 105 (29), 85 (100); HRMS calcd for C21H30O4, 346.2144;
found, 346.2129 (M+); IR (NaCl) 2927, 1763, 1715, 1672, 1644,
885, 830 cm-1; 1H NMR δ 5.53 (1H, t, J ) 1.5 Hz), 5.44 (1H, br
d), 4.71 (1H, d, J ) 1.5 Hz), 4.70 (1H, br s), 2.55 (1H, br d, J )
13.0 Hz), 2.22 (3H, s), 1.97 (3H, s), 1.73 (3H, s), 1.50 (3H, s),
1.22 (3H, s); 13C NMR δ 168.1 (C), 162.9 (C), 158.8 (C), 150.0
(C), 140.5 (C), 122.4 (CH), 109.6 (CH), 108.5 (CH2), 87.1 (C),
45.2 (C), 37.8 (CH), 35.8 (CH2), 31.7 (CH2), 31.0 (CH2), 30.6
(CH2), 22.7 (CH2), 22.1 (CH3), 21.5 (CH3), 21.1 (CH3), 21.0 (CH3),
20.9 (CH3).
(1R,2S,6R,7R,9S)-(-)-1,2-Epoxy-9-isopropyl-6-methyl-7-tri-
methylsilylbicyclo[4.4.0]decane (13). A solution of compound 12
(12 mg, 0.04 mmol) and N2H4‚H2O (42 µL, 0.86 mmol) in absolute
EtOH (0.2 mL) at 0 °C was treated with 30% aq H2O2 (48 µL,
0.42 mmol) under argon, and the reaction mixture was stirred at
room temperature for 21 h. The reaction mixture was diluted with
EtOAc and washed with brine. Chromatography, eluting with
hexanes-EtOAc (99:1), gave 9.1 mg (78%) of epoxide 13 and 2.0
mg (17%) of unreacted starting material 12.
A blue solution of potassium was generated by stirring potassium
metal (ca. 50 mg, 1.3 mmol) and 18-crown-6 (10 mg) in dry tert-
butylamine (2 mL) under argon. To this solution was added a
mixture of compounds 23a and 23b (170 mg, 0.49 mmol) dissolved
in tert-butylamine (8 mL), and the reaction mixture was stirred at
room temperature for 30 min. The excess of potassium was
destroyed by the careful addition of tert-butyl alcohol. Water was
added, and the mixture was extracted with pentane and washed
with brine. After careful evaporation of the solvent, the resulting
oil was chromatographed, eluting with pentane to give compound
13: white solid; mp 70-71 °C (hexanes-EtOAc); [R]28 -90
D
(c 1.1, CHCl3); EM m/z 280 (M+, 21), 237 (17), 207 (30), 145
(17), 105 (18), 73 (100); HRMS calcd for C17H32OSi, 280.2222;
found, 280.2224 (M+); IR (KBr) 1462, 1248, 832 cm-1; 1H NMR
δ 2.72 (1H, unresolved dd), 1.46 (1H, d, J ) 8.5 Hz), 1.11 (3H, s),
1.06 (1H, dd, J ) 3.6, 12.8 Hz), 0.85 (3H, d, J ) 6.6 Hz), 0.83
(3H, d, J ) 7.0 Hz), 0.01 (9H, s, (CH3)3Si); 13C NMR δ 65.6 (C),
58.9 (CH), 42.5 (CH), 36.5 (C), 33.5 (CH2), 31.7 (CH2), 29.3 (CH),
26.9 (CH), 25.6 (CH2), 21.7 (CH2), 21.8 (CH3), 21.5 (CH3), 20.0
(CH3), 15.6 (CH2), 0.5 (3CH3, (CH3)3Si).
24 (96 mg, 96%): volatile oil; [R]20 -79 (c 1.1, CHCl3) [lit.16
D
[R]D -76.47°]; EM m/z 204 (M+, 9), 189 (56), 121 (21), 107 (25),
105 (57), 91 (36), 80 (39), 55 (100), 53 (50); HRMS calcd for
C15H24, 204.1878; found, 204.1869 (M+); IR (NaCl) 2922, 1644,
1445, 1373, 887 cm-1; 1H NMR (400 MHz) δ 5.30 (1H, m), 4.69
(2H, s), 2.3-2.1 (2H, m), 1.72 (3H, s), 2.1-1.6 (6H, m), 1.5-1.2
(3H, m), 1.15 (1H, t, J ) 12.4 Hz), 0.95 (3H, s), 0.83 (3H, d, J )
6.8 Hz); 13C NMR δ 150.7 (C), 144.5 (C), 118.7 (CH), 108.3 (CH2),
44.1 (CH), 43.2 (CH2), 38.7 (C), 37.7 (CH), 32.5 (CH2), 31.6 (CH2),
31.3 (CH2), 27.8 (CH2), 20.9 (CH3), 18.1 (CH3), 15.7 (CH3).
Rearrangement of Compound 13: (1R,2S,9R)-(-)-9-Isopro-
pyl-1-methylbicyclo[4.4.0]dec-6-en-2-ol (17). A solution of BF3‚
Et2O (6.0 µL, 0.045 mmol) in dry CH3CN (0.6 mL) was added
dropwise to a solution of epoxide 13 (10 mg, 0.036 mmol) in dry
CH3CN (0.6 mL) cooled at -25 °C under argon. After 15 min, the
reaction was quenched with saturated aqueous NaHCO3 and
extracted with EtOAc, washed with brine, and dried. Column
chromatography (hexanes-EtOAc, 98:2) gave 4.3 mg (58%) of
Acknowledgment. Financial support from the European
Commission (FAIR CT 96-1781) is gratefully acknowledged.
A.M.C. thanks the E.C. for a pre-doctoral grant. We thank Dr.
Luis R. Domingo for valuable discussions on mechanistic
aspects.
compound 17: oil; [R]25 -42 (c 0.7, CHCl3); EM m/z 208 (M+,
D
13), 190 (32), 147 (100), 105 (17), 95 (32); HRMS calcd for
C14H24O, 208.1827; found, 208.1823 (M+); IR (NaCl) 3401, 1249,
1
1041, 832 cm-1; H NMR (300 MHz) δ 5.55 (1H, m), 3.45 (1H,
unresolved m, δν1/2 ≈ 9.0 Hz), 2.18 (1H, m), 2.01-1.84 (3H, m),
1.72-1.63 (3H, m), 1.59-1.52 (4H, m), 1.07 (3H, s), 0.87 (3H, d,
J ) 6.6 Hz), 0.86 (3H, d, J ) 6.6 Hz); 13C NMR δ 139.0 (C),
124.2 (CH), 75.3 (CH), 41.2 (C), 36.4 (CH), 36.2 (CH2), 32.4 (CH),
30.9 (CH2), 29.5 (CH2), 28.4 (CH2), 24.1 (CH3), 20.8 (CH2), 20.0
(CH3), 19.6 (CH3).
Supporting Information Available: Experimental procedures
and characterization data for compounds 3b-7b, 14-16, and 18-
22. 1H and 13C NMR spectra of compounds 5a-7a, 3b-7b, 8-10,
and 12-24. This material is available free of charge via the Internet
at http://pubs.acs.org.
(-)-Aristolochene (24). To a solution of compound 22 (343 mg,
1.6 mmol) in pyridine (4 mL) was added acetic anhydride (4 mL)
JO060643I
4936 J. Org. Chem., Vol. 71, No. 13, 2006