Synthesis of spirovetivane sesquiterpenes from santonin. Synthesis of (+)-anhydro-β-rotunol and all diastereomers of 6,11-spirovetivadiene

Article abstract of DOI:10.1021/jo040189n

The synthesis of the spirovetivane sesquiterpenes (+)-anhydro-β- rotunol and all the diastereomers of 6,11-spirovetivadiene in enantiomerically pure form has been achieved starting from santonin. The key step is the silicon-guided acid-promoted rearrangem

Full text of DOI:10.1021/jo040189n

Syn th esis of Sp ir ovetiva n e Sesqu iter p en es fr om Sa n ton in .
Syn th esis of (+)-An h yd r o-â-r otu n ol a n d All Dia ster eom er s of
6,11-Sp ir ovetiva d ien e
Gonzalo Blay, Luz Cardona, Ana M. Collado, Begon˜a Garc´ıa, Vero´nica Morcillo, and
J ose´ R. Pedro*
Departament de Quı´mica Orga`nica, Facultat de Qu´ımica, Universitat de Vale`ncia,
E-46100-Burjassot (Vale`ncia), Spain
jose.r.pedro@uv.es
Received May 3, 2004
The synthesis of the spirovetivane sesquiterpenes (+)-anhydro-â-rotunol and all the diastereomers
of 6,11-spirovetivadiene in enantiomerically pure form has been achieved starting from santonin.
The key step is the silicon-guided acid-promoted rearrangement of a 1-trimethylsilyl-4,5-epoxy-
eudesmane prepared from santonin in several steps involving lactone reductive opening, conjugate
addition of TMSLi-CuCN, deoxygenation of a carbonyl group, and epoxidation. Rearrangement of
the epoxide gave a spiro[4,5]decanediol which was used as a synthetic intermediate. From this
compound, (+)-anhydro-â-rotunol was prepared after elimination of the primary hydroxyl group
in the side chain, followed by allylic oxidation at C8 and elimination of the tertiary hydroxyl group
in the cyclohexane ring. On the other hand, elimination of the hydroxyl group in the side chain
and reduction of the hydroxyl in the cyclohexane ring gave (-)-premnaspirodiene and (-)-hinesene.
The synthesis of the rest of the diastereomers for these compounds required formal inversion of
the C5 spiro carbon. The synthesis of these compounds showed that the structure of (-)-agarospirene
isolated from Scapania sp. was erroneously assigned, and it has been corrected to be identical to
that of (-)-hinesene.
Spirovetivanes constitute one of the largest groups of
spirocyclic sesquiterpenes. Many of these compounds,
such as hinesol (1)1 or agarospirol (2),2 are fragrant
principles that have been isolated from essential oils from
plants. Others, however, are not produced by healthy
plants, but they are phytoalexins produced as defense
substances after infection by fungi or bacteria. (+)-
Anhydro-â-rotunol (3) and (-)-solavetivone (4) are ex-
amples of natural products produced in this way from
infected potato tubers and tobacco leaves.3 Stereochem-
ical elucidation of compounds of this variety is sometimes
troublesome, and one can find in the literature examples
of structures with undetermined stereochemistry or
contradictory stereochemical data. Furthermore, biologi-
cal activity of 6-spirovetivenes appears to be dependent
on the relative stereochemistry of the methyl group at
C10 and the C1-C5 bond. Thus, trans-spirovetivenes,
characterized by a trans configuration between these
groups, such as solavetivone (4), possess inhibitory
activity against bacteria, while cis-spirovetivenes such
as hinesol (1) and agarospirol (2) are inactive.4 Therefore,
the synthesis of spirovetivenes with known stereochem-
istry is important for structural elucidation as well as
for evaluating structure-activity relationships in these
compounds. These molecules present a synthetic chal-
lenge since they contain several stereogenic centers as
well as a quaternary spiro center in a sterically congested
environment represented by the flanking methyl groups
(Figure 1).
In the past decade, our group has carried out intense
research on the synthesis of sesquiterpenes using san-
tonin (6) as starting material in most of the cases.5 The
availability and functionality of this compound makes it
a suitable starting material for the synthesis of other
sesquiterpenes, especially eudesmanes, guaianes, and
elemanes.6 We recently became interested in the synthe-
sis of spirovetivanes from santonin, a challenge that has
not been achieved so far to the best of our knowledge. In
(4) Marshall, J . A.; Brady, S. F.; Andersen, N. H. Fortsch. Chem.
Org. Naturst. 1974, 31, 283-376.
(5) (a) Bargues, V.; Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J . R.
Tetrahedron 1998, 54, 1845-1852. (b) Bargues, V.; Blay, G.; Cardona,
L.; Collado, A.; Garc´ıa, B.; Mun˜oz, M. C.; Pedro, J . R. J . Org. Chem.
2000, 65, 2138-2144. (c) Blay, G.; Cardona, L.; Garc´ıa, B.; Lahoz, L.;
Pedro, J . R. Eur. J . Org. Chem. 2000, 2145-2151. (d) Blay, G.;
Cardona, L.; Garc´ıa, B.; Lahoz, L.; Monje, B.; Pedro, J . R. Tetrahedron
2000, 56, 6331-6338. (e) Blay, G.; Bargues, V.; Cardona, L.; Garc´ıa,
B.; Pedro, J . R. J . Org. Chem. 2000, 65, 6703-6707. (f) Blay, G.;
Cardona, L.; Garc´ıa, B.; Lahoz, L.; Pedro, J . R. J . Org. Chem. 2001,
66, 7700-7705. (g) Blay, G.; Bargues, V.; Cardona, L.; Garc´ıa, B.;
Pedro, J . R. Tetrahedron 2001, 57, 9719-9725.
* To whom correspondence should be addressed. Tel: +34 963544329.
Fax: +34 96354 4328.
(1) (a) Du, Y.; Lu, X. J . Org. Chem. 2003, 68, 6463-6465. (b) Yosioka,
I.; Kimura, T. Chem. Pharm. Bull. 1965, 13, 1430-1434.
(2) (a) Yoneda, K.; Yamagata, E.; Nakanishi, T.; Nagashima, T.;
Kawasaki, I.; Yoshida, T.; Mori, H.; Miura, I. Phytochemistry 1984,
23, 2068-2069. (b) Varma, K. R.; Maheshwari, M. L.; Bhattacharyya,
S. C. Tetrahedron 1965, 21, 115-138.
(3) (a) Coxon, D. T.; Price, K. R.; Howard, B.; Osman, S. F.; Kalan,
E. B.; Zacharius, R. M. Tetrahedron Lett. 1974, 34, 2921-2924. (b)
Fujimori, T.; Kasuga, R.; Kaneko, H.; Noguchi, M. Phytochemistry
1977, 16, 392-392.
(6) Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J . R. In Studies in
Natural Products Chemistry: Bioactive Natural Products, Part E; Atta-
Ur-Rahman Ed.; Elsevier: Amsterdam, 2000; Vol. 24, pp 53-129.
10.1021/jo040189n CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/23/2004
7294
J . Org. Chem. 2004, 69, 7294-7302

Synthesis of Spirovetivane Sesquiterpenes from Santonin
stereocontrolled base-induced fragmentation of a 1,3-diol
monosulfonate on a [4.4.0]decane framework.
According to a biomimetic approach,4,15 this transfor-
mation should involve the selective migration of the
methylene C9 to C5 (eudesmane numbering) via a
cationic rearrangement promoted by an electron-deficient
center at C5, i.e., a hydroxyl group or an epoxide under
acidic conditions. Although some examples of this trans-
formation have been reported in the literature,16 most of
them were unsuccessful due to one or more of the
following reasons: (a) lack of selectivity of the migrating
group, (b) 1,2-elimination of the hydroxyl group before
rearrangement, and (c) a Grob-type fragmentation of the
1,3-hydroxycarbocations that result after the initial rear-
rangement in the case of epoxides.17 These problems can
be overcome by introducing a trimethylsiliyl (TMS) group
on C1. The TMS group can promote 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 between C1 and C10 (super
proton behavior).18 This strategy has been used by Hwu
in a total synthesis of solavetivone from carvone.9 Fur-
thermore, we have shown that it is possible to achieve
selective migration of the C9 methylene or C14 methyl
groups by properly choosing the disposition between the
TMS group and the epoxide, so selective migration of the
C9 methylene group is observed when they are both in
the same ring.19
According to this strategy, the sequence shown in
Scheme 1 was carried out. The first transformations were
designed to remove the lactone moiety. This was achieved
following the procedure by Piers and Cheng20 in three
steps involving epimerization of C6 by treatment of
santonin (6) with dry DMF containing 5% HCl, followed
by reductive cleavage of the C6-O bond with Zn in
AcOH/MeOH and esterification of the resulting acid with
MeOH-H2SO4 to give ester 7 in 68% overall yield. In the
next step, the TMS group was introduced at C1 by
conjugate addition of a TMS anion to the cross-conjugated
dienone system. A first attempt using TMSLi was unsuc-
cessful probably because this reagent was too reactive
toward the ester group. However, the reaction worked
very well with the mixed cuprate obtained from TMSLi
and CuCN21 to give compound 8 in 85% yield. The
reaction took place regio- and stereoselectively, with the
TMS group being introduced exclusively from the less
hindered R side of the molecule, opposite to the methyl
F IGURE 1. Structures of some spirovetivanes and the
numbering system followed throughout the text.
this paper, we report the transformation of santonin into
the phytoalexin (+)-anhydro-â-rotunol (3) and the prepa-
ration of all diastereomers of spirovetivadiene 5 in
enantiomerically pure form. Structure 5a has been
assigned to (-)-premnaspirodiene, isolated from Premna
latifolia7 and Lepichinia sp.,8 and it is an intermediate
in a reported synthesis of (-)-solavetivone (4).9 Structure
5b has been assigned to (-)-hinesene, a natural product
isolated from Lepidozia reptans,10 Rolanda fructifrosa,11
and Frullania sp.12 Structure 5c has not been described
yet as a natural product, while structure 5d has been
tentatively assigned to (-)-agarospirene, a natural prod-
uct isolated from the Taiwanese liverworts Scapania
robusta and Scapania maxima,13 although the authors
did not exclude a structure enantiomeric to 5a for this
natural product. The most difficult challenge in the
synthesis of spirovetivanes from santonin is the conver-
sion of the eudesmane carbon skeleton into a spiroveti-
vane framework with stereochemical control of the newly
created quaternary spiro carbon. With regard to this
challenge, it is worth mentioning the pioneering work by
Marshall and Brady14 on the synthesis of (()-hinesol
where the spiro[4.5]decane system is generated upon a
(15) Parker, W.; Roberts, J . S.; Ramage, R. Quart. Rev., Chem. Soc.
1967, 21, 331-363.
(7) (a) Rao, C. B.; Krishna, P. G.; Suseela, K. Indian J . Chem. 1985,
24B, 403-407. (b) Rao, C. B.; Suseela, K.; Raju, G. V. S. Indian J .
Chem. 1984, 23B, 177-179. (c) Rao, C.; Raju, G. V. S.; Krishna, P. G.
Indian J . Chem. 1982, 21B, 267-268.
(16) (a) Ceccherelli, P.; Curini, M.; Marcotullio, M. C.; Rosati, O.
Tetrahedron 1989, 45, 3809-3818. (b) Andersen, N. H.; Falcone, M.
S.; Syrdal, D. D. Tetrahedron Lett. 1970, 21, 1759-1762.
(17) (a) Hikino, H.; Kohama, T.; Takemoto, T. Tetrahedron 1969,
25, 1037-1045. (b) Mehta, G.; Chetty, G. L.; Nayak, U. R.; Dev, S.
Tetrahedron 1968, 24, 3775-3786.
(8) (a) Eggers, M. D.; Orsini, G.; Stahl-Biskup, E. J . Essential Oil
Res. 2001, 13, 1-4. (b) Eggers, M. D.; Sinnwell, V.; Stahl-Biskup, E.
J . Phytochemistry 1999, 51, 987-990.
(9) Hwu, J . R. Wetzel, J . M. J . Org. Chem. 1992, 57, 922-928.
(10) Rieck, A.; Buelow, N.; J ung, S.; Saritas, Y, Koenig, W. A.
Phytochemistry 1997, 44, 453-457.
(11) J akupovic, J .; Grenz, M.; Bohlmann, F.; Wasshausen, D. C.;
King, R. M. Phytochemistry 1989, 28, 1937-1941.
(12) Tori, M.; Aoki, M.; Nakashima, K.; Asakawa, Y. Phytochemistry
1995, 39, 99-103.
(18) Colvin, E. W. Silicon Reagents in Organic Synthesis; Academic
Press: London, 1988.
(19) Blay, G.; Cardona, L.; Collado, A. M.; Garc´ıa, B.; Pedro, J . R.
Tetrahedron Lett. 2003, 44, 8117-8119.
(20) (a) Blay, G.; Ferna´ndez, I.; Garc´ıa, B.; Pedro, J . R. Tetrahedron
1989, 45, 5925-5934. (b) Piers, E.; Cheng, K. F. Can. J . Chem. 1968,
46, 377-383.
(13) Wu, C. L. Hattori Bot. Lab. 1984, 56, 221-226. (b) Wu, C. L.;
Lee, T. J . Proc. Natl. Sci. Counc., ROC, B 1983, 428-431.
(14) Marshall, J . A.; Brady, S. F. J . Org. Chem. 1970, 35, 4068-
4077.
(21) (a) Fleming, I.; Newton, T. W. J . Chem. Soc., Perkin Trans. 1
1984, 1805-1808. (b) Ager, D. J .; Fleming, I.; Patel, S. K. J . Chem.
Soc., Perkin Trans. 1 1981, 2520-2526. (c) Still, W. C. J . Org. Chem.
1976, 41, 3063-3064.
J . Org. Chem, Vol. 69, No. 21, 2004 7295

Blay et al.
F IGURE 2. γ Effect in compound 12 and most significant NOES in compounds 21 and 26.
SCHEME 1
group as we will discuss below.22 No products arising
from 1,2- or conjugate addition to C5 were obtained.
Next we undertook the deoxygenation of the carbonyl
group at C3. This was carried out in two steps involving
formation of a thioketal and reductive desulfurization.
Thioketal 9 was obtained in very high yield by treatment
of compound 8 with ethanedithiol in acetic acid contain-
ing BF3‚Et2O. Attempts to carry out desulfuration with
Raney nickel brought about partial migration of the
double bond to the C5-C6 position. To avoid this
inconvenience, desulfurization was carried out with Ca
in liquid ammonia.23 During this treatment, the ester
group was also reduced to give alcohol 11 as the major
product (59%) together with aldehyde 10 (9%). Aldehyde
10 could be conveniently transformed into 11 by reduc-
tion with LAH in THF. NOE experiments were carried
out with compound 11 in order to determine the stereo-
chemistry of C1 in this and all precedent compounds.
Irradiating at the frequency of the H1 double doublet at
δ 0.74 produced enhancement of the singlet at δ 1.07
corresponding to the bridgehead methyl H14. The ob-
served NOE is only possible if both H1 and H14 are to
the same face of the molecule, i.e., the â face. This would
be in good agreement with the preference of the TMS
anion to give axial 1,4 addition in cyclohexenones21b,c and
to approach from the less sterically hindered R face of
the molecule in compound 7. On the other hand, the
coupling constants of the double doublet corresponding
to H1 at δ 0.74 (J ) 10.5, 2.5 Hz) show that H1 is in
axial disposition; this indicates a distorted geometry of
the ring A as a consequence of the bulky TMS group.
Finally epoxidation of 11 with oxone®/acetone24 pro-
vided only one epoxide diastereoselectively. A complete
assignment of the 1H and 13C NMR spectra for compound
1
12 was carried out with the aid of H-13C bidimensional
correlation and decoupling experiments. No NOE effect
was found between H14 (δ 1.13) and H15 (δ 1.32).
NOESY experiments showed some interaction between
H15 and the signal corresponding to H7 at δ 1.44, which
would be in accordance with the R-disposition of methyl
H15. However, because of the partial overlapping of the
signal of H15 with the signals of H2 and the proximity
between the signals of H7 and H6R (δ 1.41) this result
should be considered with caution. Nevertheless, a
marked upfield shift for the 13C NMR signal correspond-
ing to C1 (δ 30.7) was observed with respect to the parent
olefin (δ 37.5). This was attributed to a γ effect which in
polycyclic compounds containing six-membered rings
causes an upfield shift on those carbons in γ position with
respect to the epoxide having an axial hydrogen syn to
the epoxide oxygen (Figure 2).25 According to this effect,
as well as considering the absence of NOEs between H14
and H15 which are normally observed in eudesmanes
(22) Because of the proximity of the signals corresponding to H1
and H14 in the 1H NMR spectrum of 8, lack of selectivity during
irradiation prevented determining the stereochemistry of H1 by NOE
experiments. The stereochemistry of H1 was determined by NOEs in
compound 11.
(23) Hwu, J . R.; Chua, V.; Schroeder, J . E.; Barrans, R. E., J r.;
Khourdary, K. P.; Wang, N.; Wetzel, J . M. J . Org. Chem. 1986, 51,
4731-4733.
(24) Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J . R. J . Nat. Prod. 1993,
56, 1723-1727.
7296 J . Org. Chem., Vol. 69, No. 21, 2004

Synthesis of Spirovetivane Sesquiterpenes from Santonin
SCHEME 2
SCHEME 3
when the epoxide and the methyl H14 are trans,26 we
assigned the â orientation for the epoxide in compound
12. This is also in good agreement with the expected
approach of the epoxidating reagent from the less steri-
cally congested side of the molecule because of the
convexity of the molecule and the presence of the bulky
TMS group to the R side.
With this epoxide available we attempted the acid-
promoted rearrangement of the carbon skeleton. We
expected that a carbocation at C5 should be formed,
which would promote selective migration of methylene
C9 (guided by the TMS group on C1) to give compound
14 with the spirovetivane skeleton (Scheme 2). Ef-
fectively, treatment of compound 12 with BF3‚Et2O in
CH2Cl2 at -40 °C brought about migration of the C9
methylene to C5 with concomitant contraction of the B
ring to give the spiro compound 14 in 64% yield. A diene
13 resulting from opening of the epoxide and dehydration
was also obtained as a byproduct (8%), although no
additional rearranged products were detected in the
hyperconjugation accounts for most of the stabilization
by the â silicon.27 Our results are consistent with those
reported by Lambert and co-workers which have shown
that a anti coplanar alignment of the C-Si bond and the
migrating C-C bond is not a requirement for hypercon-
jugative interaction between the silicon atom and the
developing positive charge, but there is a cosine-squared
dependence on the Si-C-C-C(migrating) dihedral
angle.27,28 Examination of models of cis-4,5-epoxi-10-
methyldecalines indicates that the Si-C-C-C9(meth-
ylene) array is closer to coplanarity than the Si-C-C-
C14(methyl) array, which may account, in the absence
of more precise calculations out of the scope of this paper,
for the preferential migration of C9.
Compound 14 was used as the common intermediate
for the synthesis of the title spirovetivane sesquiterpenes.
The synthesis of (+)-anhydro-â-rotunol (3) was achieved
first (Scheme 3).29 For this purpose, the primary hydroxyl
group in the side chain was eliminated in order to
construct the isopropenyl moiety. In a first approach to
this transformation, the primary alcohol was converted
into an o-nitrophenylselenide;30 however, subsequent
treatment with H2O2 afforded an epoxide 16. Epoxidation
of the double bond may be caused by o-nitrophenylsele-
nenic acid which is produced as byproduct in this reac-
tion, although the fact that it could not be avoided even
in the presence of pyridine may indicate that it arises
via an intramolecular process.31 For this reason, we
changed the strategy for the elimination of this hydroxyl
1
reaction mixture. The H NMR spectrum of compound
14 did not show any signal corresponding to a TMS
group. A signal corresponding to an olefinic proton
appeared at δ 5.17 indicating the existence of a trisub-
stituted double bond that was confirmed in the 13C NMR
spectra by the presence of two signals at δ 119.0 (d) and
at δ 141.4 (s). A signal corresponding to a singlet methyl
group attached to the double bond appeared at δ 1.69
which was assigned to C14. This indicated that, during
the rearrangement, the angular methyl group in com-
pound 12 remains bonded to the former bridgehead
carbon so the double bond is formed by elimination of
the TMS toward a carbocation that is produced upon
migration of the C9 methylene. The new spiro carbon C5
appeared at δ 53.7 (s) while a signal at δ 74.7 (s) was
assigned to the carbon bearing the tertiary alcohol which
results after opening of the epoxide moiety. The results
of this reaction are interpreted in terms of stabilization
of the incipient carbocation at C10 by the silicon atom
at C1 (â effect). Although there is an inductive factor,
(27) Lambert, J . B.; Wang, G. T.; Finzel, R. B.; Teramura, D. H. J .
Am. Chem. Soc. 1987, 109, 7838-7845.
(25) (a) Tori, K.; Komeno, T.; Sangare´, M.; Septe, B.; Delpech, B.;
Ahond, A.; Lukacs, G. Tetrahedron Lett. 1974, 1157-1160. (b) Sangare´,
M.; Septe´, B.; Be´renger, G.; Lukacs, G.; Tori, K.; Komeno, T. Tetra-
hedron Lett. 1977, 699-702. (c) Holland, H. L.; Diakow, P. R. P.; Taylor,
G. J . Can. J . Chem. 1978, 56, 3121-3127. (d) Delmond, D.; Papillaud,
B.; Valade, J .; Petraud, M.; Barbe, B. Org. Magn. Reson. 1979, 12, 209-
211. (e) Garc´ıa-Granados, A.; Mart´ınez, A.; Onorato, M. E.; Santoro,
J . Org. Magn. Reson. Chem. 1981, 24, 853-861.
(26) (a) Su, B.-N.; Takaishi, Y.; Yabuuchi, T.; Kusumi, T.; Tori, M.;
Takaoka, S. Tetrahedron Lett. 2000, 41, 2395-2400. (b) Su, B.-N.;
Takaishi, Y.; Yabuuchi, T.; Kusumi, T.; Tori, M.; Takaoka, S.; Honda,
G.; Ito, M.; Takeda, Y.; Kodzhimatov, O. K.; Ashurmetov, O. J . Nat.
Prod. 2001, 64, 466-471.
(28) Lambert, J . B.; Wang, G. T. J . Phys. Org. Chem. 1988, 1, 169-
178.
(29) For semi-synthesis of (-)-anhydro-â-rotunol see: (a) Hikino, H.;
Kohama, T.; Takemoto, T. Tetrahedron 1971, 27, 4831-4836. (b)
Hikino, H.; Aota, K.; Kuwano, D.; Takemoto, T. Tetrahedron Lett. 1969,
2741-2744. For synthesis of racemic anhydro-â-rotunol see: (c) Marx,
J . N.; Bih, Q. R. J . Org. Chem. 1987, 52, 336-338. (d) Caine, D.; Chu,
C.-Y.; Graham, S. L. J . Org. Chem. 1980, 45, 3790-3797.
(30) Grieco, P. A.; Gilman, S.; Nishizawa, M. J . Org. Chem. 1976,
41, 1485-1486.
(31) Zoretic, P. A.; Chambers, R. J .; Marbury, G. D.; Ribeiro, A. A.
J . Org. Chem. 1985, 50, 2981-2987.
J . Org. Chem, Vol. 69, No. 21, 2004 7297

Blay et al.
SCHEME 4
anhydride, treatment of 19a , 19b, or mixtures of both
compounds with K in tert-butylamine brought about
reduction of the ester to the expected epimeric hydrocar-
bons, which were separated by HPLC. The structure of
the minor compound 5a (38% yield from 17) was deter-
mined by comparison of its NMR data with those reported
in the literature9 for a synthetic product obtained in an
independent synthesis of (-)-solavetivone. The identity
of that compound had been unambiguously established
by chemical synthesis and by its transformation into (-)-
solavetivone.36 Compound 5a also showed spectral data
identical to that of natural (-)-premnaspirodiene.7,8 The
major product (43% yield from 17) was therefore assigned
the epimeric structure at C10 5b and showed spectral
data identical to that of natural (-)-hinesene.10-12
For the synthesis of compounds 5c and 5d the inver-
sion of the spiro carbon was required. This could be
formally achieved by hydrogenation of the double bond
in the cyclohexane ring and elimination of the tertiary
hydroxyl group to form a new double bond. To avoid
possible selectivity problems during the hydrogenation
of the double bond, we started from compound 14 instead
of compound 17 (Scheme 5). Thus, compound 14 was
hydrogenated over Pd/C to give two epimeric compounds
in 52% and 43% yield, respectively. The stereochemistry
of these compounds was assigned by NOE and NOESY
experiments. The major compound 20 was derivatized by
protection of the primary hydroxyl group as a TBS ether
and alkylation of the tertiary hydroxyl group with NaH/
group. Alcohol 14 was treated with mesyl chloride, and
the resulting mesylate was heated with LiBr-Li2CO3 in
DMF to give compound 17 in 70% yield.32 During this
reaction, the corresponding bromide is formed as an
intermediate; it eliminates on prolonged heating in the
basic medium. To complete the synthesis, the cyclohexane
ring of compound 17 was modified in order to create the
cross-conjugated dienone unit characteristic of (+)-an-
hydro-â-rotunol (3). Allylic oxidation was carried out with
CrO3/2,5-dimethylpyrazole (2,5-DMP)33 to give compound
18 in 55% yield. No oxidation of the other allylic positions
was observed under these conditions. Finally, elimination
of the tertiary hydroxyl group in compound 18 with TsOH
at benzene reflux temperature afforded 60% of (+)-
anhydro-â-rotunol (3) whose physical and spectral data
were consistent with those described for the natural
product.3
Next, we undertook the synthesis of all diastereomers
of 6,11-spirovetivadiene. The synthesis of compounds 5a
and 5b could be achieved directly from compound 17 by
deoxygenation of the tertiary alcohol (Scheme 4). The
procedure chosen was the reduction of its acetate ester
by K in tert-butylamine.34 However, treatment of com-
pound 17 with acetic anhydride/pyridine did not yield the
expected acetate; instead, two isomeric compounds in a
ratio of ca. 2:1 were obtained and separated. HRMS gave
a molecular formula C21H30O4, indicating the incorpora-
tion of three acetate units; this was corroborated by the
13C NMR spectra. According to these and other spectral
data the esters contained the 3-acetoxy-2-butenoyl unit.
This moiety presumably resulted from a Claisen acylation
of the initial acetate followed by O-acetylation of the
intermediate dicarbonyl enolate. The stereochemistry
about the double bond was assigned in accord with the
chemical shifts for the allylic methyl group in the 1H
NMR spectra which appeared at δ 2.15 in the major
E-isomer 19a and at δ 1.97 in the minor Z-isomer 19b.35
Although formation of these compounds could not be
prevented even by using equivalent amounts of acetic
1
MeI. Assignment of the key peaks in the H NMR of the
resulting compound 26 was carried out by COSY and
decoupling experiments. Reciprocal NOEs between the
methoxy group at δ 3.16 and a solitary multiplet at δ
1.91 corresponding to the CH in the cyclohexane ring
were observed, clearly indicating the cis disposition
between these groups and, hence, between methyls C14
and C15 in compound 26 as well as in its precursor 20.
On the other hand, irradiation of the singlet methyl
signal (δ 1.14) in the minor compound 21 gave NOE with
the CH in the cyclohexane ring (δ 1.53), indicating the
trans disposition between the C14 and C15 methyl groups
in this product.
The transformation of compounds 20 and 21 into the
target molecules required the elimination of both hy-
droxyl groups in the molecule. A first attempt to dehy-
drate the tertiary alcohol by acid in compound 20 resulted
(34) (a) Barret, A. G. M.; Prokopiou, P. A.; Barton, D. H. R.; Boar,
R. B.; McGhie, J . F. J . Chem. Soc., Chem. Commun. 1979, 1173-1174.
(b) Barret, A. G. M.; Prokopiou, P. A.; Barton, D. H. R. J . Chem. Soc.,
Chem. Commun. 1979, 1175-1176.
(35) Pretsch, E.; Clerc, T.; Seibl, J .; Simon, W. Tables of Spectral
Data for Structure Determination of Organic Compounds, 2nd ed.;
Springer-Verlag: Berlin, Heidelberg, New York, 1989.
(36) The structure of solavetivone has been demonstrated through
a number of syntheses: (a) Murai, A.; Sato, S.; Masamune, T. Bull.
Chem. Soc. J pn. 1984, 57, 2282-2285. (b) Iwata, C.; Fusaka, T.;
Fujiwara, T.; Tomita, K.; Yamada, M. J . Chem. Soc., Chem. Commun.
1981, 463-465. (c) Murai, A.; Sato, S.; Masamune, T. Bull. Chem. Soc.
J pn. 1984, 57, 2276-2281. (d) Yamada, K.; Goto, S.; Nagase, H.;
Christensen, A. T. J . Chem. Soc., Chem. Commun. 1977, 554. (e)
Takemoto, Y.; Kuraoka, S.; Ohra, T.; Yonetoku, Y.; Iwata, C. Tetra-
hedron 1997, 53, 603-616. (f) Takemoto, Y.; Kuraoka, S.; Ohra, T.;
Yonetoku, Y.; Iwata, C. Chem. Commun. 1996, 14, 1655-1656. (g)
Iwata, C.; Yamada, M.; Fusaka, T.; Miyashita, K.; Nakamura, A.;
Tanaka, T.; Fujiwara, T.; Tomita, K. Chem. Pharm. Bull. 1987, 35,
544-552. (g) Murai, A.; Sato, S.; Masamune, T. J . Chem, Soc., Chem.
Commun. 1981, 17, 904-905. (h) Murai, A.; Sato, S.; Masamune, T.
Tetrahedron Lett. 1981, 22, 1033-1036.
(32) (a) Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J . R.; Serrano, A.
Tetrahedron 1992, 48, 5265-5272. (b) Corey, E. J .; Hortman, A. G. J .
Am. Chem. Soc. 1965, 87, 5736-5742.
(33) Salmond, W. G.; Barta, M. A., Havens, J . L. J . Org. Chem. 1978,
43, 2057-2059.
7298 J . Org. Chem., Vol. 69, No. 21, 2004

Synthesis of Spirovetivane Sesquiterpenes from Santonin
SCHEME 5
in decomposition. Therefore, we decided first to carry out
the elimination of the primary alcohol in the side chain
by its conversion into an arylselenide: Treatment of
compound 20 with o-nitrophenyl selenocyanate and
n-Bu3P30 gave 80% yield of o-nitrophenylselenide 22
which was transformed into compound 27 after oxidation
with H2O2. However, acidic treatment of this hydroxy-
alkene led again to decomposition. We assumed that
these results were due to the presence of groups sensitive
to acid in the isopropyl side chain. Consequently, elimi-
nation of the tertiary hydroxyl group was carried out on
hydroxyselenide 22. Treatment of this compound with
TsOH under benzene reflux brought about elimination
of the tertiary hydroxyl group to give alkene 23 in almost
quantitative yield (98%). In the last step, oxidation of the
o-nitrophenylselenide with H2O2 followed by elimination
of the resulting selenoxide brought about the formation
of a double bond affording the expected diene 5c in 74%
yield for the last step. No epoxidation of the double bond
in the cyclohexane ring was observed in this case.
Transformation of diol 21 into diene 5d was performed
in a similar way. In this case, elimination of the tertiary
hydroxyl in compound 24 was more troublesome since
prolonged acidic treatment gave rise to decomposition.
A short treatment gave, besides 13% of unreacted start-
ing material, 66% of alkene 25 containing ca. 10% of the
exocyclic double bond isomer which was separated from
diene 5d after oxidative elimination.
was also extensive to optical rotation signs, indicating
that (-)-hinesene and (-)-agarospirene are the same
compound.
In summary, we report here the first synthesis of
spirovetivane sesquiterpenes from commercially available
santonin. The synthetic strategy is based on a regio- and
stereoselective silicon-guided rearrangement of a C4-
C5 eudesmane epoxide. The synthetic utility of this
strategy has been shown by the preparation of (+)-
anhydro-â-rotunol and by the synthesis of all diastereo-
mers of 6,11-spirovetivadiene, three of them being syn-
thesized in enantiomerically pure form for the first time.
As a consequence of this work, the structure of (-)-
agarospirene isolated from Scapania sp. has been estab-
lished to be identical, including absolute stereochemistry,
to (-)-hinesene isolated from L. reptans, R. fructifrosa,
and Frullania sp.
Exp er im en ta l Section
Meth yl (11S)-3-Oxo-1r-tr im eth ylsilyl-7rH-eu d esm -4-
en -12-oa te (8). A solution of hexamethyldisilane (9.2 mL, 45.8
mmol) in HMPA (20 mL) was frozen at -78 °C under argon.
To the frozen solution was added dry THF (50 mL) followed
by 1.6 M MeLi in ethyl ether (25.5 mL, 40.8 mmol). The
reaction flask was introduced in an ice bath and the frozen
solution allowed to melt. After 15 min of stirring at 0 °C, CuCN
(1.7 g, 19.0 mmol) was added, and stirring at this temperature
was continued for 30 min. After this time, the reaction mixture
was cooled at -23 °C, and a solution of compound 7 (5.44 g,
20.7 mmol) in THF (70 mL) was added dropwise over a period
of 20 min. When the addition was complete, the reaction was
quenched with saturated aqueous NH4Cl and extracted with
EtOAc. The organic layer was washed with brine, dried, and
concentrated under reduced pressure. Column chromatogra-
phy eluting with hexanes-EtOAc (8:2) afforded 5.95 g (85%)
Neither compound 5c nor 5d showed spectroscopic data
coincident with those reported for natural (-)-agaro-
spirene isolated from S. robusta and S. maxima,13
indicating that the reported structure for this natural
product needed to be revised. As a matter of fact,
comparison of the 1H and 13C NMR spectra of the natural
product37 with those of our synthetic products showed
that the natural product was identical to 5b; coincidence
of compound 8: oil; [R]25 -53 (c 2.1); IR (NaCl) 1736, 1668
D
cm-1; MS m/e 336 (M+, 39), 321 (100), 261 (52), 231 (90); HRMS
found 336.2117, C19H32O3Si required 336.2121; 1H NMR δ 3.69
(3H, s, MeO), 2.53 (1H, dt, J ) 12.0, 3.0 Hz), 2.5-2.3 (3H, m),
2.04 (1H, t, J ) 12.0 Hz), 1.74 (3H, s), 1.9-1.4 (5H, m), 1.23
(37) We thank professor Chia-Li Wu from Tamkang University for
sending us copies of the NMR spectra for natural (-)-agarospirene.
J . Org. Chem, Vol. 69, No. 21, 2004 7299

Blay et al.
(1H, dd, J ) 10.7, 5.6 Hz), 1.21 (3H, s), 1.16 (3H, d, J ) 7.2
Hz), 0.05 (9H, s); 13C NMR δ 199.7 (s), 176.0 (s), 161.7 (s), 128.1
(s), 51.6 (q), 45.1 (d), 42.0 (d), 40.1 (s), 35.9 (t), 35.7 (t), 34.0
(d), 32.2 (t), 26.2 (q), 24.9 (t), 14.1 (q), 11.1(q), 0.0 (q).
stirred for 1.5 h and extracted with CH2Cl2. The organic layer
was washed with aqueous NaHCO3, 10% Na2S2O3, and aque-
ous NaHCO3 and dried and the solvent evaporated. Column
chromatography eluting with hexanes-EtOAc (9:1) gave 445
mg (91%) of compound 12: oil; [R]24 -126 (c 0.9); IR (NaCl)
D
Met h yl (11S)-1r-Tr im et h ylsilyl-3,3-(1,2-et h a n ed iyl-
d ith io)-7rH-eu d esm -4-en -12-oa te (9). To a solution contain-
ing compound 8 (5.69 g, 16.9 mmol) and 1,2-ethanedithiol (10.5
mL, 124 mmol) in AcOH (50 mL) was added BF3‚Et2O (1.4
mL). The solution was stirred at room temperature for 7 h
and then diluted with water and extracted with EtOAc. The
organic layer was washed with saturated aqueous NaHCO3
and brine and dried. Evaporation of the solvent under reduced
pressure and column chromatography (hexanes-EtOAc, 9:1)
3436 cm-1; MS m/e 310 (M+, 7), 295 (30), 237 (100), 121 (64),
73 (91); HRMS found 310.2315, C18H34O2Si required 310.2328;
1H NMR δ 3.61 (1H, dd, J ) 10.5, 5.9 Hz, H12), 3.48 (1H, dd,
J ) 10.5, 6.6 Hz, H12′), 1.79 (2H, m, H8, H8′), 1.74 (1H, t, J
) 12.5 Hz, H6â), 1.70 (1H, td, J ) 13.0, 4.3 Hz, H9R), 1.65-
1.55 (2H, m, H8R, H11), 1.51 (1H, dt, J ) 13.0, 3.5 Hz, H9â),
1.47 (1H, m, H7), 1.42-1.28 (3H, m, H8â, 2H2), 1.41 (1H, br
d, J ) 12.5 Hz, H6R), 1.32 (3H, s, H15), 1.13 (3H, s, H14),
0.92 (3H, d, J ) 6.8 Hz, H13), 0.82 (1H, dd, J ) 13.0, 2.6 Hz,
H1), 0.01 (9H, s, TMS); 13C NMR δ 69.3 (s), 66.0 (t), 64.5 (s),
40.2 (d), 38.8 (d), 37.5 (s), 33.3 (t), 32.0 (t), 30.8 (d), 30.8 (t),
24.0 (t), 19.3 (t), 22.8 (q), 22.2 (q), 13,4 (q), 0.13 (q).
gave 6.83 g (98%) of compound 9: oil; [R]23 -89 (c 1.8); IR
D
(NaCl) 1736 cm-1; H NMR δ 3.66 (3H, s), 3.5-3.1 (4H, m),
1
2.31 (1H, q, J ) 7.0 Hz), 2.28 (1H, dt, J ) 12.0, 3.0 Hz), 2.03
(1H, d, J ) 2.2 Hz), 2.00 (1H, s), 1.87 (1H, t, J ) 11.5 Hz),
1.83 (3H, s), 1.7-1.4 (5H, m), 1.30 (1H, dd, J ) 6.9, 8.9 Hz),
1.11 (3H, d, J ) 7.0 Hz), 1.04 (3H, s), 0.01 (9H, s); 13C NMR δ
176.5 (s), 143.4 (s), 125.6 (s), 73.6 (s), 51.4 (q), 45.2 (d), 42.2
(d), 39.3 (t), 38.6 (s), 35.8 (d), 35.7 (t), 31.3 (t), 26.5 (q), 25.3
(t), 16.5 (q), 13.9 (q), -0.2 (q).
(2R,5R,10S,11S)-6-Sp ir ovetiven e-10,12-d iol (14). A solu-
tion of BF3‚Et2O (195 µL, 0.72 mmol) in CH2Cl2 (11 mL) was
added dropwise to a solution of epoxide 12 (225 mg, 0.72 mmol)
in CH2Cl2 (11 mL) at -40 °C. The reaction mixture was stirred
at this temperature for 2 h. Saturated aqueous NaHCO3 was
added, and the temperature was allowed to reach room
temperature until the frozen mixture melted. The mixture was
extracted with EtOAc, washed with brine, and dried. Column
chromatography (9:1 to 5:5 hexanes-EtOAc) eluted in this
order 17 mg of compound 13 (8%) and 112 mg (64%) of
compound 14.
(11S)-1r-Tr im eth ylsilyl-7rH-eu desm -4-en -12-al (10) an d
(11S)-1r-Tr im eth ylsilyl-7rH-eu d esm -4-en -12-ol (11). Cal-
cium metal (430 mg, 10.7 mmol) was dissolved in liquid
ammonia (50 mL) at -78 °C under argon in a flask equipped
with a dry ice-acetone cooled condenser. To the blue solution
was added dry ethyl ether (20 mL) and a solution of compound
9 (880 mg, 2.13 mmol) in dry diethyl ether (2 mL). The cooling
bath was removed, and the solution was kept at reflux for 5
h. Solid NH4Cl was added cautiously, followed by ether (25
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
saturated aqueous NH4Cl, 10% aqueous NaOH, and brine,
dried, filtered, and concentrated under reduced pressure.
Column chromatography of the residue eluting with hexanes-
EtOAc (9:1) gave 59 mg (9%) of compound 10 (containing ca.
20% of its epimer at C11) and 370 mg (59%) of compound 11.
Compound 13: oil; MS m/e 292 (M+, 3), 277 (1), 233 (5), 159
(34), 73 (100); HRMS found 292.2238, C18H32OSi required
292.2222; 1H NMR δ 5.52 (1H, br d, J ) 6.0 Hz), 5.33 (1H, s),
3.66 (1H, dd, J ) 10.5, 6.8 Hz), 3.59 (1H, dd, J ) 10.5, 6.7
Hz), 2.54 (2H, m), 2.16 (1H, dd, J ) 18.6, 6.0 Hz), 1.85 (2H,
m), 1.76 (3H, br s), 1.7-1.5 (3H, m), 1.46 (1H, dt, J ) 12.0,
3.4 Hz), 1.10 (3H, s), 0.90 (3H, d, J ) 7.0 Hz), 0.84 (1H, d, J
) 6.2 Hz), -0.03 (9H, s).
Compound 14: mp 90-93 °C; [R]24 -86 (c 1.0); IR (NaCl)
D
3350 cm-1; MS m/e 238 (M+, 18), 220 (13), 180 (49), 161 (40),
121 (100); HRMS found 238.1934, C15H26O2 required 238.1933;
1H NMR δ 5.17 (1H, s), 3.61 (1H, dd, J ) 10.5, 4.0 Hz), 3.52
(1H, dd, J ) 10.5, 6.0 Hz), 2.09 (1H, ddd, J ) 12.5, 7.5, 1.2
Hz), 2.05 (2H, m), 2.04-1.4 (8H, m), 1.64 (1H, dd, J ) 12.5,
6.6 Hz), 1.4-1.1 (2H, m), 1.69 (3H, d, J ) 1.3 Hz), 1.14 (3H,
s), 0.99 (3H, d, J ) 6.8 Hz); 13C NMR δ 141.4 (s), 119.0 (d),
74.7 (s), 67.0 (t), 53.7 (s), 43.6 (d), 41.5 (d), 41.3 (t), 34.3 (t),
33.6 (t), 30.8 (t), 24.2 (t), 22.6 (q), 19.6 (q), 15.8 (q).
Compound 10 had the following features: oil; [R]25 -17 (c
D
0.8); IR (NaCl) 2697, 1726 cm-1; MS m/e 292 (M+, 10), 277
(63), 234 (10), 187 (28), 160 (23), 145 (45), 73 (100); HRMS
found 292.2214, C18H32OSi required 292.2222; 1H NMR δ 9.64
(1H, s), 2.43 (1H, dd, J ) 1.5, 12.0 Hz), 2.26 (1H, m), 2.0-1.7
(4H, m), 1.7-1.3 (6H, m), 1.57 (3H, s), 1.37 (3H, s), 1.09 (3H,
s), 0.75 (1H, dd, J ) 2.8, 10.5 Hz), 0.04 (9H, s); 13C NMR δ
295.5 (d), 135.8 (s), 125.2 (s), 51.7 (d), 39.8 (d), 38.4 (s), 37.6
(t), 37.4 (d), 34.0 (t),30.1 (t), 26.5 (q), 25.2 (t), 21.7 (t), 19.7 (q),
10.1 (q), 0.3 (q). Compound 11 had the following features: oil;
(2R,5R,10S)-6,11-Sp ir ovetiva d ien -10-ol (17). To a solu-
tion of compound 14 (400 mg, 1.68 mmol) in pyridine (8 mL)
at 0 °C was added MsCl (325 µL, 4.2 mmol). The reaction
mixture was stirred for 0.5 h, and then it was diluted with
EtOAc (150 mL), washed twice with 2 M HCl, saturated
aqueous NaHCO3, and brine until neutrality, and dried.
Evaporation of the solvent under reduced pressure afforded
525 mg (99%) of an oil which mainly consisted of the mesylate
of 14: 1H NMR δ 5.13 (1H, br s), 4.15 (1H, dd, J ) 3.8, 9.6
Hz), 4.03 (1H, dd, J ) 6.6, 9.6 Hz), 2.98 (3H, s), 2.05 (1H, dd,
J ) 12.0, 6.0 Hz), 2.01 (2H, m), 2.0-1.6 (7H, m), 1.64 (3H, d,
J ) 1.5), 1.49 (1H, dt, J ) 12.0, 4.5 Hz), 1.4-1.1 (2H, m), 1.07
(3H, s), 0.99 (3H, d, J ) 6.4 Hz); 13C NMR δ 140.8 (s), 119.6
(d), 74.3 (s), 74.2 (t), 53.7 (s), 43.6 (d), 40.8 (t, broad), 38.8 (d),
37.3 (q), 34.5 (t), 33.2 (t), 30.9 (t, broad), 24.1 (t), 22.9 (q), 19.8
(q), 15.6 (q).
The resulting oil, Li2CO3 (330 mg, 4.45 mmol), and LiBr (450
mg, 5.2 mmol) in DMF (7.5 mL) were heated at 140 °C. Li2-
CO3 (330 mg) was added after 5 h, and the reaction mixture
was heated for an additional 5 h. After this time, water was
added and the mixture extracted with pentane. The usual
procedure followed by chromatography (9:1 hexanes-EtOAc)
gave 259 mg (70%) of compound 17: mp 41-42 °C; [R]24D -92
(c 0.8); IR (KBr) 3350, 1643 cm-1; MS m/e 220 (M+, 47), 202
[R]25 -32 (c 0.9); IR (NaCl) 3362 cm-1; MS m/e 294 (M+, 24),
D
280 (23), 279 (100), 220 (30), 131 (70), 73 (70); HRMS found
1
294.2368, C18H34OSi required 294.2378; H NMR δ 3.62 (1H,
dd, J ) 10.5, 5.8 Hz), 3.47 (1H, dd, J ) 10.5, 6.8 Hz), 2.40
(1H, dd, J ) 13.0, 1.8 Hz), 1.87 (2H, t,), 1.79 (1H, brt, J )
13.0 Hz), 1.58 (3H, s), 1.7-1.1 (7H, m), 1.07 (3H, s, H14), 0.90
(3H, d, J ) 7.0 Hz), 0.74 (1H, dd, J ) 10.5, 2.5 Hz, H1), 0.02
(9H, s); 13C NMR δ 136.8 (s), 124.3 (s), 66.5 (t), 40.8 (d), 40.7
(d), 38.6 (s), 37.9 (t), 37.5(d), 34.1 (t), 29.9 (t), 26.6 (q), 24.5 (t),
21.8 (t), 19.8 (q), 13.2 (q), 0.3 (q).
A solution of aldehyde 10 (121 mg, 0.41 mmol) in THF (7
mL) was treated with LiAlH4 (16 mg, 0.41 mmol) at 0 °C for
10 min. The excess LiAlH4 was destroyed by careful addition
of water. The solution was diluted with diethyl ether, stirred,
and dried over MgSO4. Solvent removal followed by chroma-
tography eluting with 9:1 hexanes-EtOAc gave 99 mg (82%)
of compound 11.
(11S)-4â,5â-E p oxy-1r-t r im et h ylsilyl-7rH -eu d esm -12-
ol (12). A solution containing compound 10 (460 mg, 1.58
mmol), NaHCO3 (2.1 g, 25.3 mmol), 18-crown-6 (35 mg), H2O
(20 mL), acetone (20 mL), and CH2Cl2 (20 mL) was cooled at
0 °C. To this solution was added Oxone (2.6 g, 4.2 mmol)
carefully in several portions. The mixture was vigorously
(14), 162 (76), 119 (100); HRMS found 220.1823, C15H24
required 220.1827; H NMR δ 5.15 (1H, s), 4.68 (1H, d, J )
O
1
7300 J . Org. Chem., Vol. 69, No. 21, 2004

Synthesis of Spirovetivane Sesquiterpenes from Santonin
0.8 Hz), 4.65 (1H, d, J ) 0.8 Hz), 2.44 (1H, m), 2.03 (3H, m),
1.95-1.55 (4H, m), 1.5-1.1 (3H, m), 1.72 (3H, s), 1.68 (3H, q,
13.0, 6.5, 1.1 Hz), 2.05-1.92 (2H, m), 1.97 (3H, d, J ) 1.0 Hz),
1.9-1.7 (3H, m), 1.7-1.4 (2H, m), 1.74 (3H, s), 1.67 (3H, br d,
J ) 1.5 Hz), 1.39 (1H, dd, J ) 13.5, 12.0 Hz), 1.12 (3H, s); 13
C
J ) 1.5 Hz), 1.46 (3H, s), 1.37 (1H, dd, J ) 13.1, 12.1 Hz); 13
C
NMR δ 148.2 (s), 141.2 (s), 119.3 (d), 108.2 (t), 74.5 (s), 53.4
(s), 48.3 (d), 40.4 (t), 34.5 (t), 33.5 (t), 31.5 (t), 24.1 (t), 23.0 (q),
21.4 (q), 19.9 (q).
NMR δ 168.1 (s), 163.0 (s), 159.1 (s), 139.9 (s), 119.8 (d), 109.5
(d), 108.3 (t), 87.2 (s), 53.9 (s), 48.1 (d), 33.4 (t), 28.9 (t), 23.8
(t), 21.6 (q), 21.6 (q), 21.5 (q), 21.0 (q), 19.7 (q), 19.3 (q).
A blue solution of potassium was generated by stirring
potassium (ca. 50 mg) and 18-crown-6 (10 mg) in dry tert-
butylamine under argon. To this solution was added the
mixture of compounds 19a and 19b dissolved in tert-butyl-
amine (2.2 mL), and the reaction mixture was stirred at room
temperature for 30 min. The excess of potassium was destroyed
by careful addition of tert-butyl alcohol. Water was added and
the mixture extracted with pentane and washed with brine.
After careful evaporation of the solvent, the resulting mixture
was separated by HPLC (normal phase, hexanes) to afford in
order of elution 21.2 mg (38%) of compound 5a and 23.6 mg
(43%) of compound 5b.
(2R,5R,10S)-10-Hydr oxy-6,11-spir ovetivadien -8-on e (18).
Dimethylpyrazole (245 mg, 2.5 mmol) was added to a suspen-
sion of anhydrous CrO3 (256 mg, 2.5 mmol) in CH2Cl2 (1.3 mL)
at -25 °C under argon and stirred for 30 min. Then the
temperature was raised to 0 °C, and compound 17 (28 mg, 0.13
mmol) dissolved in CH2Cl2 (1.3 mL) was added. After 30 min,
the reaction was filtered through a short pad of Celite and
the chromium salts extensively washed with EtOAc. After
solvent removal, column chromatography eluting with hex-
anes-EtOAc (7:3) allowed us to obtain 16.5 mg (55%) of
compound 18: oil; [R]24 -130 (c 1.7); IR (NaCl) 3350, 1696,
D
1643 cm-1; MS m/e 234 (M+, 4), 216 (36), 176 (100); HRMS
1
(-)-P r em n a sp ir od ien e (5a ): oil; [R]24 -85 (c 0.6) (lit.8b
found 234.1625, C15H22O2 required 234.1620; H NMR δ 5.71
D
[R]D -88); IR (NaCl) 3085, 3040, 1645 cm-1; MS m/e 204 (M+,
28), 189 (28), 175 (20), 161 (61), 147 (62), 107 (100); HRMS
found 204.1873, C15H24 required 204.1878; 1H NMR δ 5.25 (1H,
br s), 4.69 (1H, s), 4.65 (1H, s), 2.40 (1H, m), 1.97 (2H, m),
1.9-1.2 (9H, m), 1.72 (3H, s), 1.64 (3H, s), 0.87 (3H, d, J ) 6.8
Hz); 13C NMR δ 148.7 (s), 139.3 (s), 120.9 (d), 108.1 (t), 48.4
(s), 46.7 (d), 43.7 (t), 37.7 (d), 34.0 (t), 32.8 (t), 27.0 (t), 21.9 (t),
21.2 (q), 20.1 (q), 14.8 (q).
(1H, s), 4.71 (2H, s), 2.74 (1H, br d, J ) 16.4 Hz), 2.57 (1H,
m), 2.5-2.4 (2H, m), 2.1-1.3 (5H, m), 1.99 (3H, d, J ) 1.3 Hz),
1.73 (3H, s), 1.22 (3H, s); 13C NMR δ 198.3 (s), 168.4 (s), 147.2
(s), 124.8 (d), 108.9 (t), 75.6 (s), 55.2 (s), 47.4 (d), 40.7 (t), 33.4
(t), 24.5 (q), 21.4 (q).
(+)-An h yd r o-â-r otu n ol (3). A solution containing com-
pound 18 (18.2 mg, 0.077 mmol) and a catalytic amount of
TsOH in benzene (1.5 mL) was heated at reflux temperature
for 1 h. The reaction mixture was diluted with EtOAc and
washed with saturated aqueous NaHCO3 and brine. Column
chromatography over silica gel eluting with hexanes-EtOAc
(8:2) gave 10.0 mg (60%) of compound 3 and 1.8 mg (10%) of
unreacted starting material. Compound 3: mp 43-44 °C (lit.3
mp 44-44.5 °C); [R]24 +52 (c 0.7) (lit.3 [R]24 +57); IR (KBr)
(-)-Hin esen e (5b): oil; [R]24 -40 (c 0.2) (lit.11 [R]24 -44);
D
D
IR (NaCl) 3080, 3042, 1645 cm-1; MS m/e 204 (M+, 27), 189
(40), 175 (26), 161 (64), 147 (62), 133 (68), 107 (100); HRMS
found 204.1876, C15H24 required 204.1878; 1H NMR δ 5.29 (1H,
br s), 4.69 (1H, s), 4.65 (1H, s), 2.42 (1H, m), 1.93 (2H, m),
1.9-1.2 (8H, m), 1.72 (3H, s), 1.66 (3H, d, J ) 1.5 Hz), 1.36
(1H, t, J ) 12.5 Hz), 0.92 (3H, d, J ) 6.8 Hz); 13C NMR δ 148.7
(s), 140.3 (s), 121.6 (d), 108.0 (t), 48.7 (s), 47.6 (d), 37.5 (d),
37.1 (t), 35.8 (t), 32.2 (t), 28.2 (t), 24.5 (t), 21.3 (q), 19.8 (q),
16.4 (q).
D
D
1667, 1625, 1609 cm-1; MS m/e 216 (M+, 47), 201 8349, 173
(57), 160 (72), 135 (100); HRMS found 216.1515, C15H20
O
1
required 216.1514; H NMR δ 6.01 (2H, s), 4.76 (2H, dd, J )
1.0 Hz), 2.82 (1H, m), 2.1-1.9 (2H, m), 2.07 (3H, d, J ) 0.8
Hz), 2.03 (3H, d, J ) 0.8 Hz), 1.9-1.6 (4H, m), 1.77 (3H, s);
13C NMR δ 186.5 (s), 164.6 (s), 164.4 (s), 146.2 (s), 126.0 (d),
125.9 (d), 109.7 (t), 52.8 (s), 49.3 (d), 41.3 (t), 36.4 (t), 33.5 (5),
21.4 (q), 20.8 (two signals, q).
(2R,5R,6S,10S,11S)-6,12-Sp ir ovet iva n ed iol (20) a n d
(2R,5R,6S,10R,11S)-6,12-Sp ir ovet iva n ed iol (21). Com-
pound 14 (274 mg, 1.15 mmol) dissolved in absolute EtOH (12
mL) was hydrogenated over 5% palladium adsorbed onto
carbon (120 mg) for 2 h. After this time, the mixture was
filtered through a short pad of silica gel and concentrated.
Chromatography of the residue (7:3 hexanes-EtOAc) succes-
sively eluted 143 mg (52%) of compound 20 and 115 mg (43%)
of compound 21.
(-)-P r em n a sp ir od ien e (5a ) a n d (-)-Hin esen e (5b). To
a solution of compound 17 (60 mg, 0.26 mmol) in pyridine (0.7
mL) were added acetic anhydride (0.68 mL, 7.3 mmol) and
4-DMAP (30 mg, 0.25 mmol) at room temperature. After 2 h,
additional Ac2O (0.68 mL) and 4-DMAP (30 mg) were added,
and stirring was continued at room temperature for 3 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
afforded 93 mg (99%) of an oil which was composed of a ca.
2:1 mixture of two compounds. Analytical samples of both
compounds were obtained after chromatography over silica gel
(99:1 hexanes-EtOAc) in an independent run.
Compound 20: mp 123-125 °C; [R]22D +63 (c 1.4); IR (KBr)
3374 cm-1; MS m/e 240 (M+, 1.1), 222 (51), 163 (100); HRMS
1
found 240.2080, C15H28O2 required 240.2089; H NMR δ 3.63
(1H, dd, J ) 10.5, 4.0 Hz), 3.37 (1H, dd, J ) 10.5, 7.1 Hz),
1.96 (1H, br dd, J ) 13.7, 5.8 Hz), 1.84-1.70 (2H, m, H10),
1.68-1.56 (3H, m), 1.52-1.38 (6H, m), 1.26-1.04 (4H, m), 1.10
(3H, s), 0.92 (3H, d, J ) 6.6 Hz), 0.78 (3H, d, J ) 6.6 Hz); 13
C
NMR δ 75.1 (s), 67.5 (t), 52.9 (s), 43.8 (d), 41.6 (d), 36.7 (t),
36.1 (t), 35.1 (d), 33.0 (t), 31.3 (t), 28.4 (t), 26.4 (q), 20.8 (t),
17.7 (q), 15.6 (q).
Compound 19a (major compound): oil; [R]24 -78 (c 0.5);
D
IR (NaCl) 3440, 1767, 1720, 1665 cm-1; MS m/e 346 (M+, 7),
Compound 21: oil; [R]22 -3 (c 1.3); IR (NaCl) 3350 cm-1
;
303 (21), 287 (33), 219 (61), 202 (100); HRMS found 346.2144,
D
1
MS m/e 240 (M+, 1), 222 (50), 163 (100); HRMS found 240.2094,
C
21H30O4 required 346.2144; H NMR δ 5.55 (1H, d, J ) 0.9
15H28O2 required 240.2089; 1H NMR δ 3.58 (1H, dd, J ) 10.9,
Hz), 5.17 (1H, br s), 4.68 (1H, d, J ) 0.6 Hz), 4.66 (1H, d, J )
0.6 Hz), 2.7-2-4 (2H, m), 2.30 (3H, d, J ) 0.9 Hz), 2.15 (3H,
s), 2.1-1.9 (3H, m), 1.9-1.7 (3H, m), 1.72 (3H, s), 1.7-1.4 (2H),
1.67 (3H, br d, J ) 1.5 Hz), 1.50 (3H, s), 1.38 (1H, t, J ) 12.0
Hz); 13C NMR δ 168.3 (s), 165.3 (s), 163.1 (s), 148.3 (s), 139.9
(s), 119.7 (d), 111.5 (d), 108.2 (t), 87.5 (s), 53.9 (s), 48.0 (d),
33.3 (t), 29.0 (t), 23.8 (t), 21.5 (q), 21.1 (q), 19.7 (q), 19.4 (q),
17.8 (q).
C
4.9 Hz), 3.51 (1H, dd, J ) 10.9, 3.8 Hz), 3.21 (2H, br s, 2 OH),
1.85 (1H, dd, J ) 7.0, 1.7 Hz), 1.8-1.6 (4H, m), 1.6-1.4 (3H,
m), 1.4-1.2 (4H, m), 1.14 (3H, s), 1.1-0.9 (3H, m), 0.91 (3H,
d, J ) 6.8 Hz), 0.76 (3H, d, J ) 6.6 Hz); 13C NMR δ 76.2 (s),
67.1 (t), 53.6 (s), 43.5 (d), 41.5 (d), 38.9 (d), 38.0 (t), 32.9 (t),
32.5 (t), 32.4 (t), 31.0 (t), 23.3 (t), 22.3 (q), 17.3 (q), 15.8 (q).
(2R,5R,6S,10S,11S)-12-(ter t-Bu tyld im eth ylsilyloxy)-6-
m eth oxysp ir ovetiva n e (26). A solution of compound 20 (32.0
mg, 0.14 mmol), imidazole (35.4 mg, 0.52 mmol), and TBSCl
(44.9 mg, 0.29 mmol) in DMF (1 mL) was stirred at room
temperature for 2 h. After this time, the reaction mixture was
diluted with EtOAc, washed with water and brine, and dried
with anhydrous Na2SO4. After filtration, the solvent was
Compound 19b (minor compound): oil; [R]24 -71 (c 0.8);
D
IR (NaCl) 3423, 1770, 1720, 1669 cm-1; MS m/e 346 (M+, 2),
303 (4), 287 (6), 219 (20), 202 (75); HRMS found 346.2145,
1
C
21H30O4 required 346.2144; H NMR δ 5.49 (1H, dd, J ) 1.0
Hz), 5.16 (1H, br s), 4.70 (1H, d, J ) 0.7 Hz), 4.68 (1H, d, J )
0.7 Hz), 2.7-2.4 (2H, m), 2.22 (3H, s), 2.08 (1H, dddd, J )
J . Org. Chem, Vol. 69, No. 21, 2004 7301

Blay et al.
removed under reduced pressure and chromatographed with
hexanes-EtOAc (8:2). The resulting oil (30 mg) was dissolved
under argon in THF (1 mL) containing HMPA (0.1 mL) and
treated with a 60% dispersion of NaH in mineral oil (14 mg,
0.35 mmol) and MeI (55 µL, 8.9 mmol). The reaction mixture
was stirred for 48 h and, after this time, quenched with
aqueous NH4Cl and extracted with EtOAc. After the usual
procedure column chromatography eluting with hexane-
diethyl ether (9:1) afforded 29.1 mg (89%) of compound 26:
3040, 1645 cm-1; MS m/e 204 (M+, 71), 189 (61), 175 (21), 161
(86), 147 (45), 107 (100); HRMS found 204.1870, C15H24
required 204.1878; 1H NMR δ 5.28 (1H, br s), 4.70 (1H, s), 4.66
(1H, s), 2.53 (1H, m), 1.92 (2H, m), 1.9-1.2 (9H), 1.73 (3H, s),
1.69 (3H, d, J ) 1.3 Hz), 0.91 (3H, d, J ) 6.8 Hz); 13C NMR δ
148.9 (s), 141.1 (s), 121.6 (d), 108.3 (t), 48.8 (s), 48.7 (d), 41.6
(t), 39.1 (d), 33.0 (t), 32.4 (t), 28.6 (t), 25.3 (t), 21.6 (q), 20.2
(q), 17.0 (q).
(2R ,5R ,6S ,10R ,11S )-12-(o-Nit r op h e n ylse le n e n yl)-6-
sp ir ovetiva n ol (24). By the same procedure used in the
synthesis of compound 22, from compound 21 (38 mg, 0.342
mmol) was obtained 58.9 mg (86%) of compound 24: yellow
oil; [R]24 +53 (c 1.3); MS m/e 368 (M+, 0.1), 311 (5), 279 (12),
D
236 (40), 205 (52), 81 (100); HRMS found 368.3180, C22H44
-
1
SiO2 required 368.3110; H NMR δ 3.64 (1H, dd, J ) 9.6, 3.9
Hz), 3.34 (1H, dd, J ) 9.6, 7.3 Hz), 3.16 (3H, s), 2.05 (1H, br
dd, J ) 13.5, 7.9 Hz), 1.91 (1H, ddq, J ) 11.5, 3.5, 6.9 Hz,
H10), 1.77 (1H, dt, J ) 11.5, 5.9 Hz), 1.73-1.51 (3H, m), 1.50-
1.22 (4H, m), 1.21-1.04 (5H, m), 1.02 (3H, s), 0.92 (3H, d, J )
6.7 Hz), 0.90 (9H, s), 0.78 (3H, d, J ) 6.9 Hz), 0.05 (3H, s),
0.04 (3H, s); 13C NMR δ 79.2 (s), 67.5 (t), 53.6 (s), 48.2 (q),
43.7 (d), 41.9 (d), 36.4 (t), 34.4 (t), 32.8 (t), 31.8 (t), 29.8 (t),
28.6 (t), 25.9 (q), 20.9 (t), 18.9 (q), 18.3 (s), 17.7 (q), 15.9 (q),
-5.35 (q).
oil; IR (NaCl) 3578, 3480, 1513, 1332, 730 cm-1 1H NMR δ
;
8.22 (1H, d, J ) 8.1 Hz), 7.50 (2H, m), 7.25 (1H, td, J ) 8.1,
1.5 Hz), 3.14 (1H, dd, J ) 10.9, 3.2 Hz), 2.68 (1H, dd, J ) 10.9,
9.4 Hz), 1.9-0.9 (15H, m), 1.17 (3H, s), 1.06 (3H, d, J ) 6.6
Hz), 0.80 (1H, m), 0.78 (3H, d, J ) 6.8 Hz); 13C NMR δ 146.9
(s), 133.3 (s), 129.3 (d), 126.3 (d), 125.1 (d), 75.7 (s), 53.5 (s),
47.9 (d), 38.9 (d), 38.3 (t), 38.1 (d), 33.7 (t), 33.0 (t), 32.5 (t),
32.0 (t), 31.0 (t), 23.2 (t), 22.6 (q), 18.9 (q), 17.4 (q).
(2R,5R,10R,11S)-12-(o-Nitr op h en ylselen en yl)-6-sp ir o-
vetiven e (25). By the same procedure used in the synthesis
of compound 23, from compound 24 (29.3 mg, 0.069 mmol) was
obtained 18.6 mg (66%) of compound 25 containing ca. 9% of
the exomethylene isomer and 4.2 mg (13%) of starting mater-
(2R ,5R ,6S ,10S ,11S )-12-(o-Nit r op h e n ylse le n e n yl)-6-
sp ir ovetiva n ol (22). To a solution of diol 20 (50 mg, 0.21
mmol) and o-nitrophenylseleno cyanate (80 mg, 0.35 mmol)
in 3:1 THF-pyridine (2 mL) was added via syringe n-Bu3P
(0.124 mL, 0.49 mmol) under argon. After 18 h, the reaction
mixture was diluted with EtOAc, washed with 2 M HCl and
brine, and dried with MgSO4. After filtration and evaporation
of the solvent under reduced pressure, the residue was
chromatographed (8:2 hexanes-EtOAc) to give 70 mg (80%)
of compound 22: yellow oil; IR (NaCl) 3578, 3480, 1513, 1332,
730 cm-1; 1H NMR δ 8.24 (1H, dd, J ) 8.2, 1.3 Hz), 7.50 (2H,
m), 7.27 (1H, td, J ) 8.2, 1.3 Hz), 3.14 (1H, dd, J ) 10.9, 3.5
Hz), 2.73 (1H, dd, J ) 10.9, 8.7 Hz), 2.14 (1H, ddq, J ) 13.3,
6.8, 1.1 Hz), 1.9-1.0 (15H, m), 1.15 (3H, s), 1.08 (3H, d, J )
6.2 Hz), 0.81 (3H, d, J ) 6.8 Hz); 13C NMR δ 146.9 (s), 134.0
(s), 133.4 (d), 129.3 (d), 126.3 (d), 125.1 (d), 75.0 (s), 52.3 (s),
47.6 (d), 38.5 (d), 36.9 (t), 36.1 (t), 35.1 (d), 33.7 (t), 33.2 (t),
31.3 (t), 28.6 (t), 26.4 (q), 20.8 (t), 19.2 (q), 17.7 (q).
ial. Compound 25: yellow oil; IR (NaCl) 1515, 1335, 730 cm-1
;
1H NMR (major peaks) δ 8.25 (1H, d, J ) 8.3 Hz), 7.50 (2H,
m), 7.25 (1H, td, J ) 8.3, 1.2 Hz), 5.23 (1H, br s), 3.11 (1H, dd,
J ) 10.9, 3.4 Hz), 2.73 (1H, dd, J ) 10.9, 8.9 Hz), 2.2-1.0
(13H), 1.66 (3H, q, J ) 1.3 Hz), 1.10 (3H, d, J ) 6.6 Hz), 0.87
(3H, d, J ) 6.8 Hz); 13C NMR δ 147.1 (s), 139.8 (s), 134.1 (s),
133.4 (d), 129.3 (d), 126.4 (d), 125.2 (d), 120.6 (d), 48.6 (d), 48.5
(s), 40.3 (t), 39.1 (d), 38.5 (d), 38.5 (t, overlapped), 33.7 (t), 31.5
(t), 27.2 (t), 22.4 (t), 20.5 (q), 19.2 (q), 15.3 (q);1H NMR (minor
peaks) 4.78 (s), 4.64 (s), 3.04 (dd, J ) 10.5, 3.5 Hz), 2.66 (dd,
J ) 11.0, 8.5 Hz), 0.83 (d, J ) 6.6 Hz).
(2R,5R,10R)-6,11-Spir ovetivadien e (5d), P r oposed Str u c-
tu r e for (-)-Aga r osp ir en e. By the same procedure used in
the synthesis of compound 5c, from compound 25 (17.9 mg,
0.044 mmol) was obtained 5.3 mg (59%, 65% based on
(2R ,5R ,10S ,11S )-12-(o-N i t r o p h e n y ls e le n e n y l)-6-
sp ir ovetiven e (23). A solution containing compound 22 (35
mg, 0.080 mmol) and TsOH (4 mg) in benzene (2.5 mL) was
heated at reflux temperature for 45 min under argon. After
this time, the reaction mixture was diluted with CH2Cl2,
washed with saturated aqueous NaHCO3 and brine, and dried.
Evaporation of the solvents gave 32.7 mg (98%) of compound
23: yellow oil; IR (NaCl) 1515, 1337, 730 cm-1; 1H NMR δ 8.25
(1H, dd, J ) 8.3, 1.2 Hz), 7.50 (2H, m), 7.26 (1H, td, J ) 8.3,
1.2 Hz), 5.28 (1H, br s), 3.11 (1H, dd, J ) 10.9, 3.4 Hz), 2.73
(1H, dd, J ) 10.9, 8.9 Hz), 2.0-0.8 (13 H, m), 1.68 (3H, q, J )
consumed starting material) of compound 5d : oil; [R]22 -11
D
(c 0.3); IR (NaCl) 3080, 3040, 1645 cm-1; MS m/e 204 (M+, 97),
189 (72), 175 (32), 161 (98), 119 (100), 107 (89); HRMS found
1
204.1868, C15H24 required 204.1878; H NMR δ 5.78 (1H, br
s), 5.24 (1H, s), 5.18 (1H, s), 2.51 (1H, m), 1.75 (3H, s), 2.1-
1.5 (6H, m), 1.69 (3H, d, J ) 1.3 Hz), 1.5-1.0 (4H, m), 0.92
(3H, d, J ) 6.8 Hz), 0.85 (1H, m); 13C NMR δ 148.8 (s), 139.8
(s), 120.5 (d), 107.9 (t), 49.0 (d), 48.1 (s), 40.1 (t), 39.1 (d), 38.7
(t), 31.6 (t), 27.2 (t), 22.2 (t), 21.5 (q), 20.3 (q), 15.0 (q).
1.5 Hz), 1.10 (3H, d, J ) 6.6 Hz), 0.89 (3H, d, J ) 6.8 Hz); 13
C
Ack n ow led gm en t . Financial support from the
European Commission (FAIR CT 96-1781) is gratefully
acknowledged. A.M.C. thanks the E.C. for a predoctoral
grant.
NMR δ 147.1 (s), 140.5 (s), 134.0 (s), 133.3 (d), 129.3 (d), 126.4
(d), 125.2 (d), 121.5 (d), 48.8 (s), 47.9 (d), 41.9 (t), 38.8 (d), 38.5
(d), 33.8 (t), 32.5 (t), 32.0 (t), 28.1 (t), 24.8 (t), 20.0 (q), 19.2
(q), 16.6 (q).
(2R,5R,10S)-6,11-Sp ir ovetiva d ien e (5c). To a solution of
compound 23 (30 mg, 0.073 mmol) in THF (0.6 mL) cooled to
0 °C was added 30% H2O2 (15 µL, 0.15 mmol). The mixture
was stirred at room temperature for 3.5 h, diluted with
pentane, and washed with 8% aqueous Na2S2O3 and brine. The
usual procedure and chromatography (hexane) gave 11.2 mg
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal methods. Preparation of compounds 7, 15, and 16. 1H NMR
spectra of compounds 3, 5a -d , 7-14, and 17-26. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(74%) of compound 5c: oil; [R]22 -3 (c 0.6); IR (NaCl) 3080,
J O040189N
D
7302 J . Org. Chem., Vol. 69, No. 21, 2004