Novel rearrangements of sesquiterpenoid panasinsane derivatives under acidic conditions

Article abstract of DOI:10.1021/jo0155557

The sesquiterpenoid panasinsane derivatives 11 and 14-16 have been prepared from caryophyllene oxide (7). The novel rearrangement reactions of compounds 11 and 14 under TCNE-catalyzed solvolysis conditions and the reactions of compounds 15 and 16 under superacid conditions (HSO₃F/Et₂O, -63 °C) have been investigated. The ginsenol derivative 17 is obtained from compounds 11 and 14 under TCNE-catalyzed conditions. The rearrangement of compounds 15 and 16 under superacid conditions leads to the novel sesquiterpene derivatives (1S,4S,7S,10S,11S)-3,3,10,11-tetramethyltricyclo [5.3.1.0^4,10]undecan-1,11-yl sulfate (19) and (1S,4S,5S,8S)-2,2,4,8-tetramethyl tricyclo[3.3.2.1^4,8]undecan-11-one (20). The influence of the secondary hydroxyl group at C-5 of the panasinsane derivatives on the course of these rearrangements is discussed.

Full text of DOI:10.1021/jo0155557

J . Org. Chem. 2001, 66, 4327-4332
4327
Novel Rea r r a n gem en ts of Sesqu iter p en oid P a n a sin sa n e
Der iva tives u n d er Acid ic Con d ition s
Carlos F. D. Amigo,† Isidro G. Collado,*,† J ames R. Hanson,‡ Rosario Herna´ndez-Gala´n,†
Peter B. Hitchcock,‡ Antonio J . Mac´ıas-Sa´nchez,† and Daniel J . Mobbs‡
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Ca´diz, Apartado 40,
11510 Puerto Real, Ca´diz, Spain, and The School of Chemistry, Physics and Environmental Sciences,
University of Sussex, Brighton, BN1 9QJ , Great Britain
isidro.gonzalez@uca.es
Received February 3, 2001
The sesquiterpenoid panasinsane derivatives 11 and 14-16 have been prepared from caryophyllene
oxide (7). The novel rearrangement reactions of compounds 11 and 14 under TCNE-catalyzed
solvolysis conditions and the reactions of compounds 15 and 16 under superacid conditions (HSO3F/
Et2O, -63 °C) have been investigated. The ginsenol derivative 17 is obtained from compounds 11
and 14 under TCNE-catalyzed conditions. The rearrangement of compounds 15 and 16 under
superacid conditions leads to the novel sesquiterpene derivatives (1S,4S,7S,10S,11S)-3,3,10,11-
tetramethyltricyclo[5.3.1.04,10]undecan-1,11-yl sulfate (19) and (1S,4S,5S,8S)-2,2,4,8-tetramethyl
tricyclo[3.3.2.14,8]undecan-11-one (20). The influence of the secondary hydroxyl group at C-5 of the
panasinsane derivatives on the course of these rearrangements is discussed.
In tr od u ction
Panasinsanol A (1), ginsenol (2), and R-neoclovene (3)
are representatives of a group of sesquiterpenoids found
in the roots of Panax ginseng.1 They are derived from
caryophyllene (4) and isocaryophyllene (5) through a
series of cyclizations and rearrangements that interrelate
each class within this group.2
Compounds 1-3 present a structural similarity to the
proposed key intermediate 63 in the biosynthesis4 of the
phytotoxic5 botryane metabolites produced by Botrytis
cinerea. In continuation of our previous studies, deriva-
tives with the same skeleta are suitable candidates as
inhibitors of the biosynthesis of the botryane metabolites.
This is part of a rational approach to the control of the
pathogenicity of the phytopathogenic fungus B. cinerea.
Thus ginsenol (2) has been shown to inhibit the growth
of B. cinerea.6 The detoxification of compound 2 by the
fungus has also been reported.7 Further research requires
the preparation of novel derivatives of ginsenol (2) and
of the related panasinsane and neoclovane skeleta.
This paper deals with the synthesis of the panasinsane
derivatives 11, 14, 15, and 16 and their rearrangements
under TCNE-catalyzed and superacid conditions (HSO3F/
Et2O, -63 °C). The treatment of compounds 15 and 16
under superacid conditions leads to (1S,4S,7S,10S,11S)-
3,3,10,11-tetramethyltricyclo[5.3.1.04,10]undecan-1,11-yl
sulfate (19) and (1S,4S,5S,8S)-2,2,4,8-tetramethyl tricyclo-
[3.3.2.14,8]undecan-11-one (20), which possesses novel
sesquiterpenoid skeleta.
† Universidad de Ca´diz.
‡ University of Sussex.
(1) (a) Iwabuchi, H.; Yoshikura, M.; Ikawa, Y.; Kamisako, W. Chem.
Pharm. Bull. 1987, 35, 1975. (b) Iwabuchi, H.; Yoshikura, M.; Ka-
misako, W. Chem. Pharm. Bull. 1988, 36, 2447.
Resu lts a n d Discu ssion
(2) Collado, I. G.; Hanson, J . R.; Mac´ıas-Sa´nchez, A. J . Nat. Prod.
Rep. 1998, 187.
(3) Collado, I. G.; Herna´ndez-Gala´n, R.; Dura´n-Patro´n, R.; Cantoral,
J . M. Phytochemistry 1995, 38, 647.
(4) (a) Hanson, J . R. Pure Appl. Chem. 1981, 53, 1155. (b) Bradshaw,
A. P. W.; Hanson, J . R.; Nyfeler, R. J . Chem. Soc., Perkin Trans. 1
1981, 1469. (c) Bradshaw, A. P. W.; Hanson, J . R.; Nyfeler, R.; Sadler,
I. H. J . Chem. Soc., Perkin Trans. 1 1982, 2187.
(5) (a) Rebordinos, L.; Cantoral, J . M.; Victoria-Prieto, M.; Hanson,
J . R.; Collado, I. G. Phytochemistry 1996, 42, 383. (b) Collado, I. G.;
Hernandez-Gala´n, R.; Victoria-Prieto, M.; Hanson, J . R.; Rebordinos,
L. Phytochemistry 1996, 41, 513.
Epoxides 11 and 14 and alcohols 15 and 16 were
prepared from caryophyllene oxide (7). Treatment of
compound 7, dissolved in CH2Cl2, with ozone at room
temperature and workup with Me2S, gave kobusone8 (8)
in 52% yield. When kobusone was refluxed with KOH in
MeOH for 3 h, a mixture of the hydroxy norpanasin-
sanone 9 (60%) and (1S,3S,5R,6R,9R)-6-hydroxy-6,10,-
10-trimethyltricyclo[7.2.0.03,5]undecan-2-one9 (10) (14%)
were obtained (Scheme 1).
(6) Collado, I. G.; Aleu, J .; Mac´ıas-Sa´nchez, A. J .; Herna´ndez-Gala´n,
R. J . Nat. Prod. 1994, 57, 738.
(7) Aleu, J .; Hernandez-Gala´n, R.; Hanson, J . R.; Hitchcock, P. B.;
Collado, I. G. J . Chem. Soc., Perkin Trans 1 1999, 722.
(8) Hikino, H.; Aota, K.; Takemata, T. Chem. Pharm. Bull. 1969,
17, 1390.
10.1021/jo0155557 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/23/2001

4328 J . Org. Chem., Vol. 66, No. 12, 2001
Amigo et al.
Sch em e 1
Sch em e 3
Sch em e 2
exclusively compound 14 (74%) (Scheme 2). The 1H NMR
of this compound showed signals at δΗ 2.51 (dd, 1H, J )
3.4, 11.7 Hz), 3.08 (d, 1H, J ) 4.2 Hz), and 2.58 (d, 1H,
J ) 4.2 Hz), which corresponded to a proton geminal to
an hydroxyl group, and to the protons on an exocyclic
epoxy methylene moiety. The structure and stereochem-
istry of the compound were confirmed by 2D COSY and
NOE experiments to be consistent with the representa-
tion of the epoxide as 14.
Compound 9 was also the starting material for the
preparation of alcohols 15 and 16. Treatment of a solution
of compound 9 in dry diethyl ether with 12 equiv of MeLi
at room temperature for 24 h yielded two isomeric
products, 15 and 16 (Scheme 2). Both of them showed
absorption in the IR spectrum corresponding to a hy-
droxyl group (3425-7 cm-1) and fragmentations in their
MS corresponding to the elimination of one and two
molecules of water (220 [M - 18] and 202 [M - 18 -
The Corey-Chaykovsky reaction of ketol 9 with 2
equiv of the sulfur ylide derived from trimethylsulfonium
iodide10 furnished the epoxide 11 in 60% yield. Signals
1
18], respectively). Compound 16 showed signals in its H
1
in its H NMR spectrum at δΗ 2.48 (d, 1H, J ) 4.4 Hz,
NMR at δΗ 3.40 (dd, 1H, J ) 4.6, 11.0 Hz), 2.24 (1H, d,
J ) 6.6 Hz), and 1.12 (s, 3H), corresponding to H-5â,
H-1â, and H-13R, respectively, while compound 15 showed
signals at δΗ 3.36 (dd, 1H, J ) 4.1, 12.0 Hz), 2.04 (1H, d,
J ) 8.0 Hz), and 1.41 (s, 3H), corresponding to H-5â,
H-1â, and H-13â, respectively. The structure and stereo-
chemistry of these products were confirmed by 2D NMR
and NOE experiments. In particular, irradiation of the
methyl group at δΗ 1.41 gave a NOE enhancement of 4%
and 5% to the signals at δΗ 3.36 and 2.04, respectively,
supporting the assigned structure for compound 15.
The tetracyanoethylene (TCNE)-catalyzed alcoholysis
of epoxides leads to ring opening14 and selective re-
arrangement products.15 Therefore, it was a reagent of
choice to study the rearrangement of panasinsane de-
rivatives (epoxides 11 and 14) under mild conditions. The
separate treatment of epoxides 11 and 14 with a catalytic
amount of TCNE in methanol gave, in both cases, the
same product, compound 17 (Scheme 3). Signals in the
1H NMR spectrum at δΗ 3.93 (d, 1H, J ) 11.6 Hz, H-15′),
3.69 (d, 1H, J ) 11.6 Hz, H-15), 3.42 (dd, 1H, J ) 1.8,
4.2 Hz, H-5R), and 3.40 (s, 3H, -OCH3) revealed the
presence of hydroxy methylene, hydroxy methyne, and
H-15) and 2.60 (d, 1H, J ) 4.4 Hz, H-15′) confirmed the
presence of an exocyclic methylene epoxide. Confirmation
of the stereochemistry of the epoxide was demonstrated
by oxidation of the epoxy alcohol 11 to the crystalline
epoxyketone 12 with the Collins reagent.11 Signals in the
1H NMR spectrum at δH 2.57 (d, 1H, J ) 4.7 Hz, H-15)
and 2.61 (d, 1H, J ) 4.7 Hz, H-15′) confirmed the
retention of the epoxide. A quaternary resonance at δC
213.92 (s, C-5) in the 13C NMR spectrum and absorption
at 1704 cm-1 in the IR spectrum verified the successful
oxidation of the alcohol to the ketone. An X-ray12 of this
product confirmed the stereochemistry of the epoxide as
shown in 12 (Scheme 2).
Epoxide 14 was prepared from panasin-8(15)-en-5R-ol
(13), obtained by oxymercuration of caryophyllene oxide
(7).13 Treatment of the olefin 13 with m-CPBA gives
(9) (a) Hinkley, S. F. R.; Perry, N. B.; Weavers, R. T. Phytochemistry
1994, 35, 1489. (b) Hinkley, S. F. R.; Perry, N. B.; Weavers, R. T.
Tetrahedron 1997, 53, 7035.
(10) Corey, E. J .; Chaykovsky, M. J . Am. Chem. Soc. 1962, 84, 3782.
(11) Collins, J . C.; Hess, W. W.; Frank, F. J . Tetrahedron Lett. 1968,
3363.
(12) Atomic coordinates for compounds 12, 17, and 19 have been
deposited with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
U.K.
(13) Tkachev, A. V.; Mamatyuk, V. I.; Dubovenko, Zh. V. Zh. Org.
Khim. 1987, 23, 526 (J . Org. Chem. USSR (Engl. Trans.) 1987, 23,
475).
(14) (a) Masaki, Y.; Miura, T.; Ochiai, M. Synlett 1993, 847. (b)
Masaki, Y.; Miura, T.; Ochiai, M. Chem. Lett. 1993, 17. (c) Masaki, Y.;
Miura, T.; Ochiai, M. Bull. Chem. Soc. J pn. 1996, 69, 195.
(15) Collado, I. G.; Hanson, J . R.; Mac´ıas-Sa´nchez, A. J . Tetrahedron
1996, 52, 7961.

Rearrangements of Sesquiterpenoid Panasinsane Derivatives
J . Org. Chem., Vol. 66, No. 12, 2001 4329
Sch em e 4
methyl ether moieties. Since compound 17 was crystal-
line, its structure and streochemistry were confirmed by
X-ray crystallography.12 Compound 17 possesses the
same carbon skeleton as that of ginsenol (2). Cleavage
of the epoxide in either 11 or 14 would generate a carbo-
cation at C-8 (A), which Parker et al.16 proposed as a
probable intermediate in the rearrangement of caryo-
phyllene (4) to neoclovene (3). The transposition of the
1,9-σ bond to discharge the C-8 cation leads to the
formation of a ginsenane carbocation B, which must be
sufficiently stable under these conditions not to rearrange
to neoclovene but to be trapped by the solvent and to yield
compound 17 (Scheme 3).
Superacids have provided valuable catalysts for more
deep-seated rearrangements of sesquiterpenes.2 The
separate treatment of alcohols 15 and 16 with HSO3F in
dry Et2O at -63 °C gave, in both cases, a mixture of three
compounds, 18 (10%), 19 (6%), and 20 (5%) (Scheme 4).
Product 18 showed absorption in its IR spectrum at 1710
cm-1 and a resonance in its 13C NMR at δC 214.15 (s,
C-3). These observations are consistent with the presence
of a ketone functionality in the molecule. Study of the
1D and 2D NMR spectra and comparison with literature
data17 support the assignment of the structure of com-
pound 18 as (1R,2R,6S,7S)-2,6,8,8-tetramethyltricyclo-
[5.2.2.01,6]undecan-3-one. This compound possesses the
same carbon skeleton as neoclovene (3).
Compound 19 possessed different spectroscopic char-
acteristics. Absorptions in its IR spectrum at 1365 and
1112 cm-1, two resonances in its 13C NMR at δC 103.14
(s, C-1) and 97.82 (s, C-11), a molecular ion of m/z 300,
together with a fragment of m/z 202 (M - 98), in its mass
spectra, suggested the presence of a cyclic sulfate func-
tionality in the molecule. Since compound 19 was crystal-
line,12 its structure and stereochemistry were finally
established by X-ray crystallography as (1S,4S,7S,10S,-
11S)-3,3,10,11-tetramethyltricyclo[5.3.1.04,10]undecan-1,-
11-yl sulfate. This compound has a novel sesquiterpenoid
skeleton.
Compound 20 showed an absorption in its IR spectrum
at 1708 cm-1 as well as a resonance in its 13C NMR at δC
226.66 (s, C-11), consistent with the presence of an
alicyclic ketone. 2D NMR experiments as well as NOE
experiments led to an assignment of the 1H NMR
spectrum consistent with the stereochemistry shown for
compound 20, (1S,4S,5S,8S)-2,2,4,8-tetramethyltricyclo-
[3.3.2.14,8]undecan-11-one. This compound also has a
novel sesquiterpenoid skeleton.
The rearrangements shown for alcohols 15 and 16 can
be explained by a mechanism in which evolution of
ginsenane carbocation C, under strongly acidic and low-
temperature conditions, leads, on one hand, to further
rearrangement to yield compound 18, with a neoclovane
skeleton (Scheme 4). On the other hand, trapping of the
tertiary carbocation by the hydrogen sulfate anion and
further ionization of the secondary alcohol gives a car-
bocation F , which via a σ bond rearrangement furnishes
the tertiary carbocation G, which undergoes two further
transformations. Intramolecular attack by the sulfate
moiety affords the cyclic sulfate 19, or further rearrange-
ment gives the carbocation H, which on quenching the
reaction generates the ketone 20.
To support the proposed mechanism and to clarify the
role of the secondary alcohol in the previously described
rearrangements, diol 16 was oxidized with PCC to yield
the hydroxy ketone 21. Treatment of this compound with
HSO3F in dry Et2O at -63 °C gave a major product 22
and two minor products (23 and 24) (Scheme 5). Com-
pound 22 showed absorption in its IR spectrum at 3371
cm-1, as well as resonances in its 13C NMR at δC 86.50
(s, C-1) and 213.10 (s, C-8), which are consistent with
the presence of hydroxyl and carbonyl group in the
(16) (a) Parker, W.; Raphael, R. A.; Roberts, J . S. Tetrahedron Lett.
1965, 2313. (b) McKillop, T. F. W.; Martin, J .; Parker, W.; Roberts, J .
S. J . Chem. Soc. Chem. Commun. 1967, 162. (c) Parker, W.; Roberts,
J . S. J . Chem. Soc. C 1969, 2634.
(17) Khomenko, T. M.; Korchagina, D. V.; Gatilov, Yu. V.; Bagry-
anskaya, I. Yu.; Barkhash, V. A. Zh. Org. Khim. 1991, 27, 559 (J . Org.
Chem. USSR (Engl. Trans.) 1991, 27, 516).

4330 J . Org. Chem., Vol. 66, No. 12, 2001
Amigo et al.
Sch em e 5
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. TLC
was performed on Merck Kieselgel 60 F254, 0.2 mm thick. Silica
gel (Merck) was used for column chromatography. Purification
by HPLC was accomplished using a silica gel column (Hibar
60, 7 µm, 1 cm wide, 25 cm long).
4â,5â-Ep oxy-15-n or ca r yop h yllen -8-on e (Kobu son e, 8).
Epoxy ketone 8 was synthesized by ozonolysis (1.15 bar of
ozonized oxygen, for 45 min) of caryophyllene 4â,5R-oxide (7)
(10.8 g) in anhydrous CH2Cl2 (30 mL) at room temperature,
followed by treatment with Me2S (3.4 mL) for 30 min.
Evaporation of the solvent under reduced pressure, followed
by column chromatography with increasing gradients of ethyl
acetate in petroleum ether, gave 5.9 g (52%) of kobusone (8).
The physical data for compound 8 were identical to the
literature.9a
5r-Hyd r oxyn or p a n a sin sa n -8-on e (9) a n d (1S,3S,5R,-
6R,9R)-6-Hyd r oxy-6,10,10-tr im eth yltr icyclo[7.2.0.03,5]u n -
d eca n -2-on e (10). A solution of KOH (8.44 g) in MeOH (18
mL) and H2O (2 mL) was added dropwise to a solution of
kobusone (8) (1.42 g) in MeOH (10 mL) and heated to reflux
for 3 h with stirring. The mixture was then allowed to cool to
room temperature, H2O (25 mL) was added, and the solution
was carefully brought to neutral pH with 2 N HCl. The mixture
was extracted with diethyl ether, the combined organic layers
were dried (Na2SO4), and the solvent was evaporated under
reduced pressure. The crude reaction product was purified by
column chromatography on silica gel, with increasing gradients
of ethyl acetate in petroleum ether, to give 9 (941 mg) (66%)
and 10 (202 mg) (14%). The physical data for compounds 9
and 10 were identical with those described in the literature.9a,b
8â,15-Ep oxyp a n a sin sa n -5r-ol (11). A solution of sodium
hydride (180 mg, 60% dispersion in mineral oil, washed three
times with anhydrous hexane and dried in vacuo) in anhydrous
dimethyl sulfoxide (DMSO) (30 mL) was stirred for 20 min at
room temperature. Anhydrous tetrahydrofuran (THF) (50 L)
was then added, and the solution was cooled in an ice bath.
At this point, a solution of trimethyl sulfonium iodide (930 mg)
in DMSO (15 mL) was added and the resulting solution was
stirred for 10 min in the ice bath. Compound 9 (500 mg),
dissolved in anhydrous DMSO (20 mL), was then added to this
solution, and the mixture was stirred in the ice bath for 30
min. The ice bath was then removed, and the reaction was
allowed to warm to room temperature and allowed to stir for
12 h. The solution was carefully poured into ice/water (200
mL) and extracted with ethyl acetate. The combined organic
layers were washed with brine and dried (Na2SO4), and the
solvent was evaporated under reduced pressure. The crude
reaction product was purified by column chromatography on
silica gel. Elution with ethyl acetate/petroleum ether (1:3) gave
molecule. Analysis of their 1D and 2D NMR spectra and
comparison with previously published data7 leads to the
assignment of the structure to compound 22 as 8-oxo-
ginsenol.
Compounds 23 and 24 showed common features in
their spectra. Both showed IR absorption and resonances
in their 13C NMR spectra consistent with the presence
of two carbonyl groups. 2D COSY, and NOE analysis led
to their identification as (1S,5S,8S)-1,5,9,9-tetramethyl-
bicyclo[6.3.0]undecane-4,11-dione (23) and (1S,5R,8S)-
1,5,9,9-tetramethylbicyclo[6.3.0]undecane-4,11-dione (24).
Both compounds possess a novel sesquiterpenoid skel-
eton.
Formation of compounds 23 and 24 can be explained
via a retro-aldol reaction on 8-oxoginsenol (22), which
would lead to an enol intermediate. The tautomeric
equilibrium of this enol would lead to either of the
ketones (23 and 24), as protonation can occur, in prin-
ciple, on either face of the enol. The higher yield of ketone
23 would reflect a hindered approach for protons on the
double bond of the enol. This hindrance can be attributed
to a preferential conformation of enol intermediate K,
consistent with the cis-fused nature of the bicycle K.
11 (321 mg) (60%): colorless oil; [R]25 -37.8 (c 1.1 CHCl3);
D
1H NMR (CDCl3, 300 MHz) δ 3.50 (1H, dd, J ) 3.9, 11.8 Hz;
H-5â), 2.60 (1H, d, J ) 4.4 Hz; H-15), 2.48 (1H, d, J ) 4.4 Hz;
H-15′), 1.15 (3H, s), 0.86 (3H, s), 0.80 (3H,s); IR (film) νmax 3433,
919 cm-1; EIMS m/z (rel intensity) 236 (20) [M+], 221 (26)
[M+ - 15], 205 (18) [M+ - 31], 41 (100); HREIMS 236.1786
[M+] (C15H24O2 requires 236.1776).
8â,15-Ep oxyp a n a sin sa n -5-on e (12). Chromium trioxide
flakes (165 mg) were added cautiously in portions to anhydrous
pyridine (260 mg) in anhydrous dichloromethane (20 mL) in
an ice bath. When the chromium trioxide had completely
dissolved, the ice bath was removed and the solution was
stirred at room temperature for 20 min. 8â,15-Epoxypanasin-
san-5R-ol (10) (380 mg) in anhydrous dichloromethane (20 mL)
was added with cooling (ice bath). The mixture was then
allowed to warm to room temperature, and it was stirred for
24 h. Then, the solvent was decanted and the solid residue
was washed thoroughly with diethyl ether. The combined
organic layers were washed with 1% aqueous sodium hydrox-
ide solution, saturated aqueous copper sulfate solution, water,
and brine and then dried (Na2SO4). The solvent was evapo-
rated under reduced pressure. The crude reaction product was
purified by column chromatography on silica gel. Elution with
ethyl acetate/petroleum ether (1:19) gave 12 (279 mg) (74%).
In conclusion, we have explored the reactivity of C-5,
C-8 dioxygenated panasinsane derivatives, which enabled
us either the selective preparation of compounds with
ginsenane skeleton or the preparation of compounds with
(1S,4S,5S,8S)-2,2,4,8-tetramethyltricyclo[3.3.2.14,8]undec-
ane (20) and (1S,4S,7S,10S,11S)-3,3,10,11-tetramethyl-
tricyclo[5.3.1.04,10]undecane (19) skeleta, via the succes-
sive generation and trapping of carbocations derived from
alcohols at C-5 and C-8 in panasinsane derivatives. When
the hydroxyl group at C-5 is transformed into a ketone
(compound 21), the genesis of compounds 19 and 20 is
inhibited and 8-oxoginsenol (22) is formed. Nevertheless,
compound 22 can suffer, under these conditions, a retro-
aldol reaction, yielding diketones 23 and 24, which also
possess a novel carbon skeleton.

Rearrangements of Sesquiterpenoid Panasinsane Derivatives
Recrystallization from petroleum ether (60/80) gave colorless
J . Org. Chem., Vol. 66, No. 12, 2001 4331
removed in vacuo to give a dark oil, which was purified by
column chromatography on silica gel. Elution with ethyl
acetate/petroleum ether (7:13) yielded 11 (297 mg) and 17 (145
crystals suitable for single X-ray analysis: mp 99-100 °C;
1
[R]25 -31.5 (c 1.5 CHCl3); H NMR (CDCl3, 500 MHz) δ 2.61
D
(1H, dd, J ) 2.0, 4.7 Hz; H-15), 2.57 (1H, d, J ) 4.7 Hz; H-15′),
1.04 (3H, s), 0.84 (3H, s), 0.72 (3H,s); IR (film) νmax 1704, 900
mg) (38%). Compound 17: colorless plates; mp 197-199 °C;
1
[R]25 +6.2 (c 1.4 CHCl3); H NMR (400 MHz, CDCl3) δ 3.93
D
cm-1; EIMS m/z (rel intensity) 234 (25) [M+], 19 (33) [M+
-
(1H, d, J ) 11.6 Hz, H-15), 3.69 (1H, d, J ) 11.6 Hz, H-15′),
3.42 (1H, dd, J ) 1.8, 4.2 Hz, H-8R), 3.40 (3H, s; -OMe), 2.14
(1H, ddd, J ) 8.0, 12.9, 13.9 Hz, H-10â), 2.12 (1H, dd, J ) 0.9,
4.2 Hz, H-2â), 1.91 (1H, d, J ) 4.2 Hz, H-2R), 1.73 (1H, t, J )
3.0 Hz, H-4â), 1.56 (1H, ddd, J ) 2.6, 7.8, 14.5 Hz, H-5R), 1.48
(1H, ddd, J ) 7.9, 11.7, 15.0 Hz, H-6R), 1.28 (3H, s), 1.16 (3H,
s), 1.12 (1H, q, J ) 7.8 Hz, H-6â), 1.08 (3H, s); IR νmax 3354
cm-1; EIMS m/z (rel intensity) 268 (8) [M+], 253 (95)
[M+ - 15], 237 (100) [M+ + 1 - 32], 219 (36) [M+ + 1 - 32 -
18]; HREIMS 238.1963 [M+ - 18] (C15H26O2 requires 238.1932).
Anal. Calcd for C16H28O3: C, 71.6; H, 10.5. Found: C, 71.2; H,
10.7.
15], 203 (13) [M+ - 31], 151 (100). Anal. Calcd for C14H24O:
C, 76.9; H, 9.5. Found: C, 76.7; H, 9.4.
P a n a sin s-8(15)-en -5r-ol (13). Caryophyllene 4â,5R-oxide
(7) (2.20 g) and mercury(II) acetate (6.40 g) were dissolved in
glacial acetic acid (20 mL) and stirred at room temperature
for 7 days. The acetic acid was removed in vacuo, and
consecutively, tetrahydrofuran (30 mL), 3 N sodium hydroxide
solution (40 mL), and sodium borohydride (500 mg) were
added. The solution was stirred at room temperature for 1 h,
and then the aqueous layer was saturated with sodium
chloride, and after 30 min, the solution was extracted with
diethyl ether. The combined organic layers were washed with
brine and dried (Na2SO4), and the solvent was evaporated
under reduced pressure. The crude reaction product was
purified by column chromatography on silica gel. Elution with
ethyl acetate/petroleum ether (7:93) gave 13 (398 mg) (18%).
Recrystallization from acetonitrile gave 13 as white needles.
The physical data for compound 13 were identical to litera-
ture.13
Rea r r a n gem en t of Com p ou n d 14. 9-Meth oxygin sen e-
8â,15-d iol (17). Tetracyanoethylene (32 mg) was added to a
solution of 8R,15-epoxypanasinsan-5R-ol (14) (300 mg) in
anhydrous methanol (10 mL). The reaction mixture was stirred
at room temperature for 2 days. Then, the solvent was removed
in vacuo to give a dark oil, which was purified by column
chromatography on silica gel. Elution with ethyl acetate/
petroleum ether (7:18) gave 17 (73 mg) (21%).
8â,15-Ep oxyp a n a sin sa n -5r-ol (14). m-CPBA (295 mg)
was added slowly and in portions with stirring to a solution
of panasins-8(15)-en-5R-ol (13) (368 mg) in chloroform (100
mL), cooled in an ice bath. The reaction mixture was left to
warm to room temperature, and stirring was continued for 3
h. Then, the solution was washed with saturated sodium
sulfite solution, water, and brine and then dried (Na2SO4). The
solvent was evaporated under reduced pressure, and the crude
reaction product was purified by column chromatography on
silica gel. Elution with ethyl acetate/petroleum ether (1:4) gave
14 (316 mg) (80%) as a colorless oil: [R]25D -30.2 (c 0.7 CHCl3);
1H NMR (CDCl3, 500 MHz) δ 3.51 (1H, dd, J ) 3.4, 11.7 Hz;
H-5â), 3.08 (1H, d, J ) 4.2 Hz; H-15), 2.58 (1H, d, J ) 4.2 Hz;
H-15′), 2.08 (1H, dd, J ) 3.1, 11.7 Hz; H-1â), 1.09 (3H, s), 0.90
(3H, s), 0.88 (3H,s); IR (film) νmax 3433, 919 cm-1; EIMS m/z
(rel intensity) 236 (26) [M+], 221 (29) [M+ - 15], 205 (15)
[M+ - 31], 41 (100); HREIMS 236.1775 [M+] (C15H24O2
requires 236.1776).
P a n a sin sa n e-5r,8r-d iol (15) a n d P a n a sin sa n e-5r,8â-
d iol (16). A solution of 5R-hydroxypanasinsan-8-one (9) (40
mg) in anhydrous diethyl ether (5 mL) was added dropwise to
a solution of MeLi (1.35 mL of 1.6 M solution in diethyl ether)
in anhydrous diethyl ether (2 mL). The reaction was allowed
to stir at room temperature for 24 h. Then, excess MeLi was
carefully quenched with water (50 mL), and the reaction was
extracted with diethyl ether. The combined organic layer was
washed with brine and dried (Na2SO4). The solvent was
evaporated under reduced pressure, and the crude reaction
product was purified in HPLC on silica gel. Elution with ethyl
acetate/petroleum ether (7:18) gave 15 (7 mg) (18%) and 16
(14 mg) (35%).
Rear r an gem en t of Com pou n d 16. (1R,2R,6S,7S)-2,6,8,8-
Tetr am eth yltr icyclo[5.2.2.01,6]u n decan -3-on e (18), (1S,4S,-
7S,10S,11S)-3,3,10,11-Tetr a m eth yltr icyclo[5.3.1.04,10]u n -
d eca n -1,11-yl Su lfa t e (19), a n d (1S,4S,5S,8S)-2,2,4,8-
Tetr a m eth yltr icyclo[3.3.2.14,8]u n d eca n -11-on e (20). Pana-
sinsane-5R,8â-diol (16) (182 mg) was added to a solution of
HFSO3 (5 mL) in anhydrous diethyl ether (1 mL) at -63 °C
and allowed to stir at this temperature for 1 h. Then, a mixture
of acetone (5 mL) and water (1 mL) was added carefully, and
the mixture was left stirring for 5 min. At this point, the
reaction mixture was directly purified by column chromatog-
raphy on silica gel. Elution with ethyl acetate/petroleum ether
(1:49) gave 18 (18 mg) (10%), 19 (10 mg) (6%), and 20 (9 mg)
(5%).
(1R,2R,6S,7S)-2,6,8,8-Tetr a m eth yltr icyclo[5.2.2.01,6]u n -
d eca n -3-on e (18): yellow oil; [R]25 -77.7 (c 1.80, CHCl3); 1H
D
NMR (400 MHz, CDCl3) δ 2.53 (1H, dddd, J ) 15.1, 13.2, 7.5,
0.9 Hz; H-4â), 2.39 (1H, qd, J ) 6.6, 0.9 Hz, H-2), 2.25 (1H,
ddd, J ) 15.2, 5.4, 1.6 Hz, H-4R), 2.08 (1H, dddd, J ) 13.4,
13.3, 5.5, 1.0 Hz, H-5R), 1.37 (3H, d, J ) 1.09 Hz, H-13), 1.23
(3H, s, H-15), 1.14 (1H, d, J ) 12.0 Hz, H-9R), 1.01 (3H, s,
H-14), 0.88 (3H, d, J ) 6.6 Hz, H-12); IR νmax 1710 cm-1; EIMS
m/z (rel intensity) 220 (59) [M+], 205(23) [M+ - 15], 69 (100);
HREIMS 220.1829 [M+] (C15H24O requires 238.1827).
(1S,4S,7S,10S,11S)-3,3,10,11-Tetr a m eth yltr icyclo[5.3.-
1.04,10]u n d eca n -1,11-yl su lfa te (19): mp 108-110 °C; [R]25
D
-119.3 (c 0.20, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.41 (1H,
d, J ) 16.0 Hz, H-2â), 2.25 (1H, m, H-7), 2.18 (1H, d, J ) 16.0
Hz, H-2R), 2.08 (1H, m, H-8â), 1.92 (1H, m, H-9â), 1.74 (3H,
s, H-15), 1.33 (3H, s, H-14), 1.28 (3H, s, H-13), 1.06 (3H, s,
H-12); IR νmax 1365, 1112 cm-1; EIMS m/z (rel intensity) 300
(6) [M+], 202 (84) [M+ - 98], 187(86) [M+ - 98 - 15], 85 (100);
HREIMS 300.1388 [M+] (C15H24O4S requires 300.1395).
(1S,4S,5S,8S)-2,2,4,8-Tetr a m eth yltr icyclo[3.3.2.14,8]u n -
P a n a sin sa n e-5r,8r-d iol (15): mp 99-101 °C; [R]25D -32.8
(c 0.60 CHCl3); 1H RMN (400 MHz, CDCl3) δ 3.36 (1H, dd,
J ) 4.1, 12.0 Hz, H-5â), 2.04 (1H, d, J ) 8.0 Hz, H-1â), 1.41
(3H, s, H-13â), 1.16 (3H, s, H-15â), 0.99 (3H, s, H-12R), 0.95
(3H, s, H-14R); IR νmax 3427 cm-1; EIMS m/z (rel intensity)
220 (6) [M+ - 18], 202 (2) [M+ - 18 - 18], 164 (100); HREIMS
220.1829 [M+ - 18] (C15H24O requires 220.1827).
d eca n -11-on e (20): mp 54-56 °C; [R]25 +170.2 (c 1.07,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.32 (1H, ddd, J ) 13.6,
9.7, 9.7 Hz, H-7â), 2.16 (2H, m, H-9R, Η-10â), 2.07 (1H, d, J )
13.8 Hz, H-3â), 1.88 (1H, m, H-9â), 1.78 (1H, m, H-5), 1.60
(2H, m, H-6, H-10R), 1.52 (1H, m, H-6), 1.46 (1H, m, H-1), 1.39
(1H, ddd, J ) 13.6, 10.0, 1.0 Hz, H-7R), 1.30 (1H, d, J ) 13.8
Hz, H-3R), 1.09 (3H, s, H-15), 0.99 (3H, s, H-12), 0.98 (3H, s,
H-14), 0.91 (3H, s, H-13); IR νmax 1708 cm-1; EIMS m/z (rel
intensity) 220 (100) [M+], 205 (16) [M+ - 15]; HREIMS
220.1815 [M+] (C15H24O requires 300.1395).
P a n a sin sa n e-5r,8â-d iol (16): mp 102-104 °C; [R]25
D
-44.0 (c 1.75 CHCl3); 1H NMR (400 MHz, CDCl3) δ 3.40 (1H,
dd, J ) 4.6, 11.0 Hz, H-5â), 2.24 (1H, d, J ) 6.6 Hz, H-1â),
1.19 (3H, s, H-15â), 1.12 (3H, s, H-13â), 0.90 (3H, s, H-14R),
0.84 (3H, s, H-12R); IR νmax 3425 cm-1; EIMS m/z (rel intensity)
238 (2) [M+], 220 (21) [M+ - 18], 202 (6) [M+ - 18 - 18], 43
(100); HREIMS 238.1963 [M+] (C15H26O2 requires 238.1932).
Rea r r a n gem en t of Com p ou n d 11. 9-Meth oxygin sen e-
8â,15-d iol (17). Tetracyanoethylene (175 mg) was added to a
solution of 8â,15-epoxypanasinsan-5R-ol (11) (630 mg) in
anhydrous methanol (20 mL). The reaction mixture was stirred
at room temperature for 21 days. Then, the solvent was
8â-Hyd r oxyp a n a sin sa n -5-on e (21). PCC on alumina (1.1
g) was added to a solution of compound 16 (300 mg) in CH2-
Cl2 (30 mL). The slurry was stirred for 4 h and then filtered
through a pad of silica gel. The solvent was removed under
reduced pressure, and the resulting oil was dissolved in diethyl
ether (100 mL). The solution was washed with NaHCO3 and

4332 J . Org. Chem., Vol. 66, No. 12, 2001
Amigo et al.
brine and dried (Na2SO4). Then, the solvent was removed
under reduced pressure to give a crude product that was
purified by column chromatography on silica gel, in ethyl
acetate/petroleum ether (3:17), to yield 21 (276 mg) (92%): mp
m, H-7R); IR νmax 1727 cm-1; EIMS m/z (rel intensity) 236(43)
[M+], 221(41) [M+ - 15], 110 (100); HREIMS 236.1781 [M+]
(C15H24O2 requires 236.1776).
(1S,5R,8S)-1,5,9,9-Tetr a m eth ylbicyclo[6.3.0]u n d eca n e-
90-93 °C; [R]25 -33.9 (c 0.66 CHCl3); 1H NMR (400 MHz,
4,11-d ion e (24): mp 42-44 °C; [R]25 -114.6 (c 0.67 CHCl3);
D
D
CDCl3) δ 2.54 (2H, m, H-6R, H-4â), 2.34 (2H, m, H-6â, H-2R),
1.97 (1H, dd, J ) 12.9, 2.1 Hz, H-1â), 1.83 (2H, m, H-7R, H-7â),
1.33 (3H, s, H-12), 1.20 (3H, s, H-9), 1.19 (1H, m, H-3â), 1.05
(3H, s, H-11), 0.94 (3H, s, H-10); IR νmax 3464, 1683 cm-1; EIMS
m/z (rel intensity) 236(4) [M+], 221(16) [M+ - 15], 107 (100);
HREIMS 236.1749 [M+] (C15H24O2 requires 236.1776).
Rea r r a n gem en t of Com p ou n d 21. 8-Oxogin sen ol (22),
(1S,5S,8S)-1,5,9,9-Tetr a m eth ylbicyclo[6.3.0]u n d eca n e-4,-
11-dion e (23), (1S,5R,8S)-1,5,9,9-Tetr am eth ylbicyclo[6.3.0]-
u n d eca n e-4,11-d ion e (24). 8â-Hydroxypanasinsan-5-one (21)
(238 mg) was added to a solution of HFSO3 (5 mL) in
anhydrous diethyl ether (1 mL) at -63 °C and allowed to stir
at this temperature for 1 h. Then, a mixture of acetone (5 mL)
and water (1 mL) was added carefully, and the mixture was
allowed to stir for 5 min. At this point, the reaction mixture
was directly purified by column chromatography on silica gel.
Elution with increasing gradients of ethyl acetate in petroleum
ether gave 227 (60 mg) (25%), 23 (16 mg) (6%), and 24 (7 mg)
(3%).
1H NMR (400 MHz, CDCl3) δ 2.71 (1H, dd, J ) 12.8, 11.2 Hz,
H-3â), 2.54 (1H, m, H-5R), 2.42 (1H, dd, J ) 16.1, 0.91 Hz,
H-10â), 2.20 (2H, m, H-2â, H-3R), 2.01 (1H, d, J ) 16.2 Hz,
H-10R), 1.88 (2H, m, H-7â, H-6R), 1.76 (1H, dd, J ) 12.8, 2.9
Hz, H-8), 1.65 (1H, m, H-2R), 1.41 (1H, m, H-6â), 1.20 (3H, s,
H-12), 1.12 (3H, s, H-14), 1.07 (3H, d, J ) 6.9 Hz, H-13), 1.03
(1H, m, H-7R), 0.70 (3H, s, H-15); IR νmax 1737, 1704 cm-1
;
EIMS m/z (rel intensity) 236 (16) [M+], 221 (14) [M+ - 15],
110 (100); HREIMS 236.1788 [M+] (C15H24O2 requires 236.1776).
Ack n ow led gm en t. This research was supported by
grants from CICYT 1FD97-0668-C06-01 and European
Commission FAIR-5-PL97-3351. We thank Dr. F. Lafont
(University of Cordoba, Spain) for the HREIMS results.
C.F.D.A. thanks the European Commission for a stu-
dentship (FAIR-5-PL97-3351). D.J .M. thanks the EPR-
SC for a studentship.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
(1S,5S,8S)-1,5,9,9-Tetr a m eth ylbicyclo[6.3.0]u n d eca n e-
and 13C NMR spectra for compounds 15, 16, 18-21, 23, and
24. Tables of 13C NMR data for compounds 11, 12, 14-21, 23,
and 24. ORTEP drawings for compounds 12, 17, and 19. This
material is available free of charge via the Internet at
http://pubs.acs.org.
4,11-d ion e (23): mp 74-76 °C; [R]25 -101.1 (c 1.58 CHCl3);
D
1H NMR (400 MHz, CDCl3) δ 0.66 (3H, s, H-15), 2.80 (1H, m,
H-5â), 2.64 (1H, ddd, J ) 12.0, 11.7, 2.2 Hz, H-3â), 2.45 (1H,
d, J ) 15.9 Hz, H-10â), 2.22 (2H, m, H-2â, H-3R), 2.00 (1H, d,
J ) 15.9 Hz, H-10R), 1.51 (1H, m, H-2R), 1.29 (3H, s, H-12),
1.11 (3H, s, H-14), 1.03 (3H, d, J ) 6.6 Hz, H-13), 0.95 (1H,
J O0155557