Synthesis of terpenoid lactones with the p-menthane system

Article abstract of DOI:10.1002/ejoc.200300800

Starting from (R)-(+)- and (S)-(-)-pulegone enantiomeric pairs of hydroxy lactones and keto lactones were obtained by Claisen rearrangement of cis-pulegols and lactonization of epoxy esters. The hydroxy lactones were reduced with Li-AlH₄ in ord

Full text of DOI:10.1002/ejoc.200300800

FULL PAPER
Synthesis of Terpenoid Lactones with the p-Menthane System[‡]
[a]
[b]
[b]
[a]
´
´
Iwona Dams,* Agata Białonska, Zbigniew Ciunik, and Czesław Wawrzenczyk
Keywords: Antifeedants / Lactones / Natural products / Pulegone / Terpenoids
Starting from (R)-(+)- and (S)-(−)-pulegone enantiomeric
pairs of hydroxy lactones and keto lactones were obtained
by Claisen rearrangement of cis-pulegols and lactonization
of epoxy esters. The hydroxy lactones were reduced with Li-
The structures of the synthesized compounds were estab-
lished on the basis of spectroscopic and crystallographic
data.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
AlH4 in order to assign the configuration of the chiral centers. Germany, 2004)
Introduction
Terpenoid compounds containing the lactone moiety are
widespread in nature. Lactones isolated from plants,[1]
microorganisms[2] and insects[3] possess interesting and
specific biological properties; the best known is their anti-
fungal,[4] antibacterial[4b][4c,5] and antitumor[4b,6] activity. As
they are common secondary metabolites of plants, lactones
are also found as part of plants’ protective system against
predators.[7] Our research in this area involves the synthesis
of terpenoid lactones and tests of their activity as insect
feeding deterrents. We have synthesized many mono-,[8] bi-
[9]
and tricyclic[10] lactones which were tested for feeding
Figure 1. Biologically active lactones
deterrence against three storage pests — the granary weevil
beetle (Sitophilus granarius L.), the khapra beetle (Trogod-
erma granarium Ev.) and the confused flour beetle (Tribol-
ium confusum Duv.). Some of them (1Ϫ8; Figure 1 exhibit
quite good deterrent activity similar to that of the most
potent antifeedant, azadirachtin.[11]
Enantiomeric lactones with the p-menthane system 5Ϫ8,
synthesized from optically pure isomers of perillyl alcohol
and limonene, appeared to be especially active. Comparison
of the biological activity of the corresponding enantiomers
indicated that, in general, compounds with the 8R configu-
ration are more active than those with the 8S configura-
tion.[12] The lactones synthesized were also tested for feed-
ing deterrence against the peach potato aphid (M. persicae
Sulz.), but only a few of them were significantly active (3,
4, 6b).[11b,13]
Here we present the synthesis of four enantiomeric pairs
of γ-spirolactones with the p-menthane system as potential
insect feeding deterrents. The lactones were obtained from
optically pure isomers of (R)-(ϩ)- and (S)-(Ϫ)-pulegone in
order to estimate the influence of the configuration of the
chiral centers on their biological activity. Studies of the
structure-activity relationship are one of the most import-
ant aspects of research on biologically active compounds,
and such types of study are especially useful in the search
for new synthetic drugs, agrochemicals, food additives, flav-
ours and fragrances.[14]
Results and Discussion
Enantiomeric pairs of δ-hydroxy-γ-lactones (5R,6S,8R)-
[‡]
´
Lactones, 22. Part 21: I. Dams, A. Białonska, Z. Ciunik, C.
(ϩ)-14a,
(5S,6R,8S)-(Ϫ)-14b
and
(5S,6R,8R)-15a,
´
Wawrzenczyk, J. Agric. Food Chem. 2004, 52, 1630Ϫ1634.
[a]
[b]
(5R,6S,8S)-15b were obtained in a four-step synthesis from
optically pure isomers of (R)-(ϩ)- and (S)-(Ϫ)-pulegone (9a
and 9b; Scheme 1). The first step of the synthesis was the
reduction of pulegones with sodium borohydride according
Department of Chemistry, Agricultural University
Norwida 25, 50-375 Wrocław, Poland
E-mail: iwa dams@ozi.ar.wroc.pl
Ϫ
Faculty of Chemistry, University of Wrocław
Joliot-Curie 14, 50-383 Wrocław, Poland
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DOI: 10.1002/ejoc.200300800
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Terpenoid Lactones with the p-Menthane System
FULL PAPER
to the standard procedure.[15] A 5:1 methanol/water mixture cation of the Claisen rearrangement[18] to give the enanti-
as solvent and a small excess of NaBH4 were used to omerically pure (4ЈR)-(ϩ)-11a and (4ЈS)-(Ϫ)-11b isomers of
shorten the time of the reaction. The choice of sodium ethyl 3-methyl-3-(4Ј-methyl-1Ј-cyclohexen-1Ј-yl)butanoate
borohydride as a hydride reducing agent was motivated by were obtained in good yields (86% and 84%, respectively).
its high stereoselectivity in the reduction of α,β-unsaturated Their enantiomeric purity (ee 99%) was confirmed by GC
ketones. The addition of CeCl3 to prevent the formation on a chiral column (cyclodextrin-β-2,3,6-m-19).
of saturated alcohols was not necessary. The course of the
The epoxidation of esters 11a or 11b with m-chloroper-
reactions and the purity of the products were controlled by benzoic acid in dichloromethane[19] afforded a mixture of
GC on a capillary column (HP-5). The allylic alcohols cis- epoxy ester (1ЈR,2ЈR,4ЈR)-(ϩ)-12a and hydroxy lactone
(1R,5R)-(Ϫ)- and cis-(1S,5S)-(ϩ)-pulegol (10a and 10b) (5R,6S,8R)-(ϩ)-14a or enantiomeric epoxy ester
were the main products of the reductions. The stereochem- (1ЈS,2ЈS,4ЈS)-(Ϫ)-12b and hydroxy lactone (5S,6R,8S)-(Ϫ)-
ical assignment of the cis-pulegols was based on the value 14b respectively. These mixtures were separable by GC on
of their optical rotation.[16] Their structure was also con- a capillary column (HP-5). From integration of the signals
1
firmed by H NMR and IR spectroscopy.[17]
in the GC chromatograms these mixtures were found to
contain 45% of the epoxy ester and 55% of the hydroxy
lactone. The mixture of epoxy ester 12a or 12b and hydroxy
lactone 14a or 14b was separated by column chromatogra-
phy on silica gel. The first fraction, eluted with hexane/ace-
tone (50:1), afforded the epoxy ester 12a or 12b. Unfortu-
nately, these epoxy esters undergo partial decomposition on
silica gel to unidentified and inseparable products, so their
purity after column chromatography was only 86% and
82%, respectively. Their structures were confirmed by the
1H NMR spectra. The presence of the doublet (J ϭ 5.1 Hz)
at δ ϭ 3.07 ppm for H-2Ј indicates that this proton is cou-
pled with only one proton of the CH2-3Ј group. According
to the analysis with a Driding models this is only possible
in the half-chair conformation of the cyclohexane ring with
the C-1Ј, C-2Ј, C-3Ј, C-4Ј and C-6Ј atoms in one plane. In
such a conformation the dihedral angle between H-2Ј and
one proton of the CH2-3Ј group is close to 90°. In consider-
ation of the above facts the doublet at δ ϭ 3.07 ppm (J ϭ
5.1 Hz) was ascribed to the H-2Ј proton of the cis isomer
12a or 12b. The trans-epoxy ester 13a or 13b undergoes lac-
tonization to the hydroxy lactone 14a or 14b under epoxid-
ation conditions. Elution with hexane/acetone (5:1) gave the
pure hydroxy lactone 14a or 14b. The presence of the γ-
lactone moiety in 14a and 14b was confirmed by the ab-
sorption band at 1768 cmϪ1 in the IR spectrum. The shape
1
of the narrow multiplet for H-6 in the H NMR spectrum
of 14a or 14b suggests the equatorial position of this proton
and thereby the axial position of the hydroxy group.
The ease of lactonization of epoxy esters 12a and 12b was
confirmed by their reactions under acidic conditions. The
reaction of the epoxy ester 12a catalyzed by HClO4 in THF/
H2O solution (pH 1.2) after 24 h (when the epoxy ester was
no longer detected by TLC analysis) gave the mixture of
lactones (5R,6S,8R)-(ϩ)-14a (28%) and (5S,6R,8R)-15a
(72%). In spite of many attempts, the mixture of hydroxy
lactones was inseparable by column chromatography. The
structure of 14a was again determined on the basis of spec-
troscopic data of the mixture of hydroxy lactones 14a and
15a and confirmed by the X-ray structure of the triol
(1ЈR,2ЈS,4ЈR)-(ϩ)-18a. This triol is the product of LiALH4
reduction of the hydroxy lactone 14a in anhydrous diethyl
Scheme 1. (i) NaBH4, EtOH, MeOH/H2O,
0 °C, 2 h; (ii)
CH3C(OEt)3, C2H5COOH, 138 °C, 8 h; (iii) m-CPBA, CH2Cl2, 0
°C, 24 h; (iv) THF/HClO4/H2O (pH ϭ 1.2), 24 h; (v) LiAlH4, Et2O,
1 h; (vi) CrO3·2Py, CH2Cl2, 24 h.
The crude pulegols, without further purification (accord- ether. Lactol (5R,6S,8R)-(ϩ)-19a is the minor product of
ing to the GC analysis they had purities of 96% and 97%, this reduction. The crystals of 19a were not suitable for X-
respectively), were subjected to the orthoacetate modifi- ray analysis and the absolute configuration was not as-
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I. Dams, A. Białonska, Z. Ciunik, C. Wawrzenczyk
FULL PAPER
signed to the C-2 atom. The configuration of the chiral cen- ratio of lactones [14a or 14b (28%) and 15a or 15b (72%)]
ters of the triol 18a and, indirectly, of the lactone 14a was in the products of the lactonization of the pure epoxy esters
provided by the X-ray structural analysis of 18a (Figure 2). 12a or 12b.
This analysis indicated the presence of two symmetrically
independent molecules of 18a in the crystals. The X-ray
structure undoubtedly confirms the axial position of the
hydroxy group at C-2Ј of the triol 18a and, indirectly, the
axial position of this group at C-6 in the hydroxy lactone
14a. The structure of diastereoisomeric hydroxy lactones
Similar results were obtained when the crude mixture of
cis-epoxy esters 12a or 12b and hydroxy lactones 14a or
14b was subjected to lactonization under acidic conditions.
From integration of the signals in the GC chromatograms
it follows that the mixture of products contains 80% of
hydroxy lactone 14a or 14b and 20% of 15a or 15b. This
synthetic path was applied further to avoid decomposition
of epoxy esters on silica gel and gain the keto lactones
(5S,8R)-(ϩ)-20a or (5R,8S)-(Ϫ)-20b and (5R,8R)-(Ϫ)-21a
or (5S,8S)-(ϩ)-21b in good yields. The mixture of hydroxy
lactones 14a and 15a or 14b and 15b was oxidized with
pyridinium dichromate in dichloromethane[21] to give a
mixture of keto lactones 20a and 21a or 20b and 21b (20%
and 80% respectively), which was separable on silica gel.
The first fraction, eluted with hexane/acetone (20:1), af-
forded the pure keto lactone 21a or 21b as colourless crys-
tals. The X-ray analysis indicated two symmetrically inde-
pendent molecules of 21b in the crystals. The crystal struc-
ture of (5S,8S)-(ϩ)-21b (Figure 3) shows a cis relationship
between the CH3-8 group of the chair-like cyclohexane ring
and the C5ϪO1 bond of the lactone moiety. As the same
relative configuration of the corresponding substituents
CH3-4Ј and OH-1Ј was determined for the triol 19a, the
X-ray structure of keto lactone 21b indirectly confirms the
configuration of the chiral centers of the hydroxy lactones
14a and 14b.
1
15a and 15b was determined from the H NMR and IR
spectra of the mixture of hydroxy lactones 14a and 15a or
14b and 15b. The difference in chemical shift (∆δ ϭ
0.2 ppm) of the two methyl groups at C-4 in the spectrum
of 15a indicates the deshielding effect of the hydroxy group
at C-6 on the closer methyl group. Such effective deshield-
ing is only possible when this group is in an equatorial posi-
tion. The spectrum of 14a shows the two methyl groups at
C-4 as a single six-proton singlet at δ ϭ 1.18 ppm. In this
case, as was subsequently confirmed by X-ray analysis of
18a, the hydroxy group at C-6 occupies the axial position.
Figure 2. Molecular structure of (1ЈR,2ЈS,4ЈR)-(ϩ)-18a with crys-
tallographic numbering
It is generally supposed that lactonization of epoxy esters,
induced by Hϩ ions, proceeds via the diols 16a and 16b or
17a and 17b respectively. According to earlier observations
concerning the cleavage of an oxirane ring in the limonene
system 1,2-oxides,[9a,20] a nucleophile should attack the C-
1Ј atom from the opposite side of the oxonium ion that is
formed after Hϩ addition to the oxirane oxygen. In the case
of the trans-epoxides 13a and 13b, this mode of action leads
to the trans-diaxial diols 17a and 17b with the ethoxycar-
bonyl group in the equatorial position; these diols undergo
lactonization to the hydroxy lactones 14a and 14b. This was
confirmed by the X-ray structure of the triol 18a, obtained
by the reduction of hydroxy lactone 14a with LiAlH4. In
Figure 3. Molecular structure of (5S,8S)-(ϩ)-21b with crystallo-
graphic numbering
The second eluted keto lactone was 20a or 20b. In the
the case of the more stable cis-epoxides 12a and 12b, attack case of (5S,8R)-(ϩ)-20a the X-ray analysis also indicates
on C-1Ј leads to the trans-diequatorial diols 16a and 16b the presence of two symmetrically independent molecules in
with the ethoxycarbonyl group in the axial position. As this the crystals. The crystal structure of 20a (Figure 4) afforded
conformation is energetically unfavourable, the attack of a information about the trans-diequatorial orientation of the
nucleophile at C-2Ј of the epoxides 12a and 12b, leading to CH3-8 group and the C5ϪO1 bond, thereby confirming the
the diols 17a and 17b, is also reasonable. Such a pattern of configuration of the chiral centers assigned to the hydroxy
diol (16a and 16b or 17a and 17b) formation explains the lactones 15a and 15b.
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Terpenoid Lactones with the p-Menthane System
FULL PAPER
H3[P(Mo3O10)4] in 10% H2SO4, followed by heating to 120 °C. Pre-
parative column chromatography: silica gel (Kieselgel 60, 40Ϫ63
µm, 230Ϫ400 mesh, Merck), hexane, acetone and diethyl ether in
varying ratios as eluents. X-ray structural analyses: X-ray data were
collected at low temperature using an Oxford Cryosystem device
on a Kuma KM4CCD κ-axis diffractometer with graphite-mon-
˚
ochromated Mo-Kα radiation (λ ϭ 0.71073 A). The crystal was
positioned at 65 mm from the CCD camera. Frames (n ϭ 612)
were measured at 0.75° intervals with a counting time of 15Ϫ20 s.
Accurate cell parameters were determined and refined by a least-
squares fit of 1800Ϫ2000 of the strongest reflections. The data were
corrected for Lorentz and polarization effects. No absorption cor-
rection was applied. Data reduction and analysis were carried out
with the Oxford Diffraction (Poland) programs. The structures
were solved by direct methods (program SHELXS-97) and refined
by the full-matrix least-squares method on all F2 data using the
SHELXL-97 programs. Non-hydrogen atoms were refined with an-
isotropic displacement parameters; hydrogen atoms were included
from geometry of molecules and ∆ρ maps. They were refined with
isotropic displacement parameters.
Figure 4. Molecular structure of (5S,8R)-(ϩ)-20a with crystallo-
graphic numbering
It is not surprising that esters (4ЈR)-(ϩ)-11a and (4ЈS)-
cis-(1R,5R)-(؊)-Pulegol (10a): A suspension of NaBH4 (0.4 g,
(Ϫ)-11b, containing the p-menthane system, possess inter- 10.57 mmol) in EtOH (21 mL) was added dropwise to an ice-cooled
solution of pulegone (R)-(ϩ)-9a (1.5 g, 9.85 mmol) in MeOH (18
mL) and water (3.6 mL). Stirring was continued for 2 h at room
temperature. When the reaction was complete (TLC, hexane/ace-
tone, 20:1), the mixture was poured into brine and the product was
extracted with hexane. The combined extracts were washed with
water and dried over anhydrous MgSO4. The solvent was evapo-
rated in vacuo and the crude product (1R,5R)-(Ϫ)-10a (1.51 g, ac-
cording to the GC analysis 96% purity) was used for the next step
without further purification. [α]2D5 ϭ Ϫ105.2 (c ϭ 1.9, EtOH), m.p.
30Ϫ31 °C (ref. [α]D ϭ Ϫ104, EtOH/H2O, 95:5; m.p. 29Ϫ30 °C[16]).
esting odors. Their odoriferous properties are slightly influ-
enced by the absolute configuration of the odorant. The
fragrance of ester (4ЈR)-(ϩ)-11a is intense and fruity with a
ripe pear note, whereas its enantiomer (4ЈS)-(Ϫ)-11b has
moderately intense, fruity-pear odor with a woody note.
The lactones synthesized were tested for their deterrent
activity against selected storage pest insects (Sitophilus
granarius L., Tribolium confusum Duv., Trogoderma granar-
ium Ev.), the peach-potato aphid (Myzus persicae Sulz.) and
the Colorado potato beetle (Leptinotarsa decemlineata Say) 1H NMR (300 MHz, [D6]acetone, 25 °C): δ ϭ 1.07 (d, J ϭ 6.8 Hz,
according to the procedures described by Paruch et al.,[12]
3 H, CH3-5), 1.33Ϫ1.42 (m, 1 H, H-5), 1.49Ϫ1.58 (m, 2 H, CH2-
group), 1.62 and 1.74 [two s, 6 H, (CH3)2Cϭ], 1.66Ϫ1.72 (m, 2 H,
Gabrys et al.[13] and Szczepanik et al.,[22] respectively. The
CH2-group), 2.11 and 2.34 (two m, 2 H, CH2-group), 3.25 (br. s, 1
compounds tested showed moderate activity towards all
H, ϪOH), 4.58 (m, 1 H, H-1). IR (nujol): ν˜ ϭ 3300 cmϪ1 (br. s,
mentioned grain pests (total coefficients of deterrence[12]
66Ϫ162) and appeared much more effective antifeedants
OH), 1340 and 1272 (s, CϪOH), 1116 (s, OH).
against the Colorado potato beetle (total coefficients of de- cis-(1S,5S)-(؉)-Pulegol (10b): In the same manner as described for
the preparation of (1R,5R)-(Ϫ)-10a, pulegone (S)-(Ϫ)-9b (1 g,
6.57 mmol) yielded the crude cis-pulegol (1S,5S)-(ϩ)-10b (0.95 g,
according to the GC analysis 97% purity). [α]2D5 ϭ ϩ103.8 (c ϭ 1.6,
EtOH). Its IR and NMR spectra were identical with those of
(1R,5R)-(Ϫ)-10a.
terrence 119Ϫ184). Among all tested compounds only
hydroxy lactones (5R,6S,8R)-(ϩ)-14a and (5S,6R,8S)-(Ϫ)-
14b were active against M. persicae. The details of these
studies will be the subject of a separate publication.
Ethyl (4ЈR)-(؉)-3-Methyl-3-(4Ј-methyl-1Ј-cyclohexen-1Ј-yl)butano-
ate (11a): A mixture of the crude cis-pulegol (1R,5R)-(Ϫ)-10a
(1.51 g, 9.79 mmol), triethyl orthoacetate (15 mL, 80 mmol) and a
catalytic amount of propionic acid (1 drop) was heated at 138 °C
for 8 h under the conditions for distillative removal of ethanol.
When the reaction was complete (GC, TLC), the mixture was con-
centrated in vacuo to remove unchanged orthoacetate. The residue
Experimental Section
General: (R)-(ϩ)-Pulegone, (S)-(Ϫ)-pulegone, triethyl orthoacetate
and m-chloroperbenzoic acid were purchased from Aldrich or
Fluka. 1H NMR: Bruker Avance DRX 300 (300 MHz), TMS as
internal standard, for solutions (CDCl3 or [D6]acetone). IR: Spe-
cord M 80 spectrophotometer (Carl Zeiss Jena). Melting points: was chromatographed on silica gel. Elution with hexane/diethyl
Boetius Apparatus. Optical rotation: Autopol IV automatic polar-
imeter (Rudolph), in acetone or ethanol, concentrations denoted in
g/100 mL. GC analyses: Varian CP-3380 instrument (FID, carrier
ether (80:1) gave the pure ester (4ЈR)-(ϩ)-11a (1.89 g, 86% yield).
[α]2D5 ϭ ϩ44.1 (c ϭ 5.63, acetone), n2D0ϭ 1.4630. 1H NMR
(300 MHz, CDCl3, 25 °C): δ ϭ 0.91 (d, J ϭ 6.1 Hz, 3 H, CH3-4Ј),
gas H2), using the following capillary columns: HP-1 (crosslinked 1.10 and 1.13 [two s, 6 H, (CH3)2CϽ], 1.20 (t, J ϭ 7.1 Hz, 3 H,
methyl siloxane) 25 m ϫ 0.32 mm ϫ 0.52 µm; HP-5 (crosslinked ϪOCH2CH3), 1.44Ϫ1.66 (m, 4 H, CH2-groups), 1.96Ϫ2.10 (m, 3
5% phenyl methyl siloxane) 25 m ϫ 0.32 mm ϫ 0.52 µm; CP-Cyclo-
H, CH2-group and H-4Ј), 2.29 and 2.32 (AB system, J ϭ 13.2 Hz,
dextrin-β-2,3,6-m-19, 25 m ϫ 0.25 mm ϫ 0.25 µm. Analytical TLC: 2 H, CH2-2), 4.04 (q, J ϭ 7.1 Hz, 2 H, ϪOCH2CH3), 5.41 (m, 1
Silicagel DC-Alufolien Kieselgel 60 F254 (Merck), hexane, acetone
and diethyl ether in various ratios as developing systems, com-
pounds detected by spraying the plates with 1% Ce(SO4)2/2%
H, H-2Ј). IR (film): ν˜ ϭ 1748 cmϪ1 (s, CϭO), 1392 and 1372 [s,
(CH3)2CϽ], 1232 and 1120 (s, CϪOϪC). C14H24O2 (224.3): calcd.
C 74.97, H 10.78; found C 74.75, H 10.86.
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Ethyl (4ЈS)-(؊)-3-Methyl-3-(4Ј-methyl-1Ј-cyclohexen-1Ј-yl)butano-
ate (11b): According to the procedure described for the preparation
analysis 72:28) was chromatographed on silica gel. Elution with
various solvent systems (hexane/acetone, 5:1 or hexane/ethyl acet-
(4ЈR)-(ϩ)-11a, the crude cis-pulegol (1S,5S)-(ϩ)-2b (1.6 g, ate, 3:1) gave the pure mixture of the hydroxy lactones (5S,6R,8R)-
10.37 mmol) yielded the unsaturated ester (4ЈS)-(Ϫ)-11b (1.95 g,
84%): [α]2D5 ϭ Ϫ44.4 (c ϭ 3.87, acetone). Its IR and NMR spectra
were identical with those of (4ЈR)-(ϩ)-11a.
15a and (5R,6S,8R)-(ϩ)-14a (0.33 g, 94% total reaction yield).
Spectral data for the hydroxy lactone (5S,6R,8R)-15a. 1H NMR
(300 MHz, CDCl3, 25 °C): δ ϭ 0.97 (d, J ϭ 6.4 Hz, 3 H, CH3-8),
1.09 and 1.29 [two s, 6 H, (CH3)2CϽ], 2.36 and 2.61 (AB system,
J ϭ 17.1 Hz, 2 H, CH2-3), 3.95 (m, 1 H, H-6). IR (film): ν˜ ϭ 3488
cmϪ1 (m, br., OH), 1768 (s, CϭO), 1256 (s, CϪOϪC), 1164 (s,
CϪOH), 1052 (s, CϪOϪC).
Ethyl (1ЈR,2ЈR,4ЈR)-(؉)-3-Methyl-3-(1Ј,2Ј-epoxy-4Ј-methylcyclo-
hex-1Ј-yl)butanoate (12a) and (5R,6S,8R)-(؉)-6-Hydroxy-4,4,8-tri-
methyl-1-oxaspiro[4.5]decan-2-one (14a): A solution of m-chlorop-
erbenzoic acid (1.46 g, 8.45 mmol) in CH2Cl2 (20 mL) was added
dropwise to an ice-cooled and stirred solution of the ester (4ЈR)-
(ϩ)-11a (1.58 g, 7.04 mmol) in CH2Cl2 (40 mL). The reaction tem-
perature was gradually raised to room temperature and the mixture
was stirred for 24 h. When the reaction was complete (GC, TLC),
the excess of m-chloroperbenzoic acid was destroyed with saturated
Na2S2O3 solution. The separated organic layer was washed with
10% Na2CO3 solution and brine, dried over anhydrous MgSO4 and
concentrated in vacuo. The crude mixture of the epoxy ester
(1ЈR,2ЈR,4ЈR)-(ϩ)-12a and the hydroxy lactone (5R,6S,8R)-(ϩ)-
14a (according to the GC analysis 45:55) was chromatographed on
silica gel. The first fraction, eluted with hexane/acetone (50:1), gave
the epoxy ester (1ЈR,2ЈR,4ЈR)-(ϩ)-12a (0.79 g, according to the GC
(5R,6S,8S)-6-Hydroxy-4,4,8-trimethyl-1-oxaspiro[4.5]decan-2-one
(15b) and (5S,6R,8S)-(؊)-6-Hydroxy-4,4,8-trimethyl-1-oxaspiro-
[4.5]decan-2-one (14b): In the same manner as described for the
preparation of (5S,6R,8R)-15a and (5R,6S,8R)-(ϩ)-14a, the epoxy
ester (1ЈS, 2ЈS, 4ЈS)-(Ϫ)-12b (0.39 g, according to the GC analysis
82% purity, 1.33 mmol) yielded the mixture of hydroxy lactones
(5R,6S,8S)-15b and (5S,6R,8S)-(Ϫ)-14b (according to the GC
analysis 72:28, 0.26 g, 93% total reaction yield). Spectral data for
the hydroxy lactone (5R,6S,8S)-15b were identical with those of
(5S,6R,8R)-15a.
(1ЈR,2ЈS,4ЈR)-(؉)-3-Methyl-3-(1Ј,2Ј-dihydroxy-4Ј-methylcyclohex-
1Ј-yl)butan-1-ol (18a) and (5R,6S,8R)-(؉)-4,4,8-Trimethyl-1-oxaspi-
ro[4.5]decane-2,6-diol (19a): A solution of the hydroxy lactone
(5R,6S,8R)-(ϩ)-14a (0.31 g, 1.46 mmol) in anhydrous Et2O (20
mL) was added dropwise to a solution of LiAlH4 (0.055 g,
1.46 mmol) in Et2O (20 mL). The reaction mixture was stirred for
1 h at room temperature and then poured into saturated potassium
hydrogen tartrate solution. The separated ethereal solution was
washed with brine, dried over MgSO4 and the solvents evaporated
in vacuo. The crude mixture of (1ЈR,2ЈS,4ЈR)-(ϩ)-18a and
(5R,6S,8R)-(ϩ)-19a (according to the GC analysis 80:20) was chro-
matographed on silica gel. The first fraction, eluted with hexane/
acetone (5:1), gave the pure lactol (5R,6S,8R)-(ϩ)-19a (0.069 g) as
a white solid. [α]2D6 ϭ ϩ12.7 (c ϭ 1.11, acetone), m.p. 114Ϫ115 °C.
1H NMR (300 MHz, [D6]acetone, 0 °C): δ ϭ 0.79 (d, J ϭ 6.6 Hz,
3 H, CH3-8), 0.84 and 1.06 [two s, 6 H, (CH3)2CϽ], 1.21Ϫ1.91 (m,
10 H, H-8, four CH2-groups and OH-6), 3.67 (m, 1 H, H-6), 4.97
(m, 1 H, H-2), 5.37 (d, J ϭ 6.5 Hz, 1 H, OH-2). IR (nujol): ν˜ ϭ
3260 cmϪ1 (m, br., OH), 1468 and 1380 [s, (CH3)2CϽ], 1072 (s,
CϪOH) and 1032 (s, CϪOϪC). C12H22O3 (214.3): calcd. C 67.26,
H 10.35; found C 67.16, H 10.34. The second fraction, eluted with
hexane/acetone (5:1), gave the crystalline triol (1ЈR,2ЈS,4ЈR)-(ϩ)-
18a (0.24 g). [α]2D7 ϭ ϩ21.9 (c ϭ 1.65, acetone), m.p. 127Ϫ128 °C.
1H NMR (300 MHz, [D6]acetone, 0 °C): δ ϭ 0.80 (d, J ϭ 6.3 Hz,
3 H, CH3-4Ј), 0.96 and 1.05 [two s, 6 H, (CH3)2CϽ], 1.22Ϫ1.83
(m, 9 H, H-4Ј, four CH2-groups), 3.51 (d, J ϭ 4.4 Hz, 1 H, OH-
2Ј), 3.63 (m, 2 H, CH2-1), 3.84 (s, 1 H, OH-1Ј), 3.95 (m, 1 H, OH-
1), 4.13 (m, 1 H, H-2Ј). IR (nujol): ν˜ ϭ 3256 cmϪ1 (s, br., OH),
1468 and 1392 [s, (CH3)2CϽ], 1264 and 1080 (s, CHϪOH), 1172
(s, CϪOH), 1036 (s, CH2ϪOH). C12H24O3 (216.3): calcd. C 66.63,
H 11.18; found C 66.51, H 11.27. Total reaction yield was 97%.
analysis 86% purity). [α]2D6 ϭ ϩ46.9 (c ϭ 4.21, acetone), n2D0
1.4652. H NMR (300 MHz, CDCl3, 25 °C): δ ϭ 0.81 (d, J ϭ
6.0 Hz, 3 H, CH3-4Ј), 0.96 and 1.01 [two s, 6 H, (CH3)2CϽ], 1.23
(t, J ϭ 7.2 Hz, 3 H, ϪOCH2CH3), 2.24 and 2.35 (AB system, J ϭ
ϭ
1
13.7 Hz, 2 H, ϪCH2ϪCO2), 3.07 (d, JH-2Ј,
ϭ 5.1 Hz, H-2Ј),
H-3Ј
4.08 (q, J ϭ 7.2 Hz, ϪOCH2CH3). IR (film): ν˜ ϭ 1740 cmϪ1 (s,
CϭO), 1232 and 1040 (s, CϪOϪC). The second fraction, eluted
with hexane/acetone (5:1), afforded the pure hydroxy lactone
(5R,6S,8R)-(ϩ)-14a (0.73 g). [α]2D6 ϭ ϩ22.2 (c ϭ 3.45, acetone),
n2D0 ϭ 1.4865. 1H NMR (300 MHz, CDCl3, 25 °C): δ ϭ 0.88 (d,
J ϭ 6.3 Hz, 3 H, CH3-8), 1.18 [s, 6 H, (CH3)2CϽ], 1.21Ϫ1.34 (m,
2 H, CH2-group), 1.53Ϫ1.96 (m, 6 H, ϪOH, H-8 and two CH2-
groups), 2.17 and 2.55 (AB system, J ϭ 17.2 Hz, 2 H, CH2-3), 4.00
(m, 1 H, H-6). IR (film): ν˜ ϭ 3492 cmϪ1 (m, br., OH), 1768 (s,
CϭO), 1252 (s, CϪOϪC), 1164 (s, CϪOϪH), 1040 (s, CϪOϪC).
C12H20O3 (212.3): calcd. C 67.89, H 9.49; found C 67.67, H 9.24.
Total reaction yield was 89%.
Ethyl (1ЈS,2ЈS,4ЈS)-(؊)-3-Methyl-3-(1Ј,2Ј-epoxy-4Ј-methylcyclohex-
1Ј-yl)butanoate (12b) and (5S,6R,8S)-(؊)-6-Hydroxy-4,4,8-tri-
methyl-1-oxaspiro[4.5]decan-2-one (14b): According to the pro-
cedure described for the preparation of (1ЈR,2ЈR,4ЈR)-(ϩ)-12a and
(5R,6S,8R)-(ϩ)-14a, the unsaturated ester (4ЈS)-(Ϫ)-11b (1.73 g,
7.71 mmol) yielded the epoxy ester (1ЈS,2ЈS,4ЈS)-(Ϫ)-12b (0.89 g,
according to the GC analysis 82% purity): [α]2D6 ϭ Ϫ48.3 (c ϭ 3.24,
acetone) and the pure hydroxy lactone (5S,6R,8S)-(Ϫ)-14b (0.79 g):
[α]2D6 ϭ Ϫ21.9 (c ϭ 3.19, acetone). Their IR and NMR spectra were
identical with those of (1ЈR,2ЈR,4ЈR)-(ϩ)-12a and (5R,6S,8R)-(ϩ)-
14a. Total reaction yield was 87% (according to the GC analysis
45% of 12b and 55% of 14b).
(5S,6R,8R)-6-Hydroxy-4,4,8-trimethyl-1-oxaspiro[4.5]decan-2-one
(15a) and (5R,6S,8R)-(؉)-6-Hydroxy-4,4,8-trimethyl-1-oxaspiro[4.5]-
decan-2-one (14a): Perchloric acid (60%, 0.5 mL) was added to a
solution of the epoxy ester (1ЈS,2ЈR,4ЈR)-(ϩ)-12a (0.46 g, according
to the GC analysis 86% purity, 1.65 mmol) in THF (24 mL) and
water (12 mL). The mixture was stirred for 24 h at room tempera-
ture and the products were extracted with diethyl ether. The com-
bined ethereal extracts were washed with saturated NaHCO3 solu-
tion and brine, dried over anhydrous MgSO4 and the solvents eva-
Crystal Data for (1ЈR,2ЈS,4ЈR)-(؉)-18a: C12H24O3, M ϭ 216.31,
colourless needle, crystal dimensions 0.30 ϫ 0.25 ϫ 0.20 mm,
monoclinic, space group P21, a ϭ 6.9809(11), b ϭ 10.6061(14), c ϭ
3
˚
˚
17.174(2) A, β ϭ 99.331(13)°, V ϭ 1254.7(3) A , Z ϭ 4, Dc ϭ 1.145
Mg·mϪ3, T ϭ 100 K, R ϭ 0.0844, Rw ϭ 0.1247 (5631 reflections,
all data) for 463 variables.
(5S,6R,8R)-6-Hydroxy-4,4,8-trimethyl-1-oxaspiro[4.5]decan-2-one
(15a) and (5R,6S,8R)-(؉)-6-Hydroxy-4,4,8-trimethyl-1-oxaspiro[4.5]-
porated in vacuo. The crude mixture of the hydroxy lactones decan-2-one (14a): Perchloric acid (60%, 0.75 mL) was added to
(5S,6R,8R)-15a and (5R,6S,8R)-(ϩ)-14a (according to the GC the crude mixture of the epoxy ester (1ЈS,2ЈR,4ЈR)-(ϩ)-12a and the
2666
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2662Ϫ2668

Terpenoid Lactones with the p-Menthane System
hydroxy lactone (5R,6S,8R)-(ϩ)-14a (1.72 g, according to the GC (21b): In the same manner as described for the preparation of
FULL PAPER
analysis 45:55) in THF (36 mL) and water (18 mL). The reaction
mixture was stirred for 24 h at room temperature and the products
(5S,8R)-(ϩ)-20a and (5R,8R)-(Ϫ)-21a, the mixture of hydroxy lac-
tones (5R, 6S, 8S)-15b and (5S,6R,8S)-(Ϫ)-14b (1.67 g, 7.87 mmol,
were extracted with diethyl ether. The combined ethereal extracts according to the GC analysis 20%:80%) yielded the crystalline keto
were washed with saturated NaHCO3 solution and brine, dried
(MgSO4) and the solvents evaporated in vacuo. The crude mixture
lactones (5S,8S)-(ϩ)-21b (1.23 g). [α]2D5 ϭ ϩ105.0 (c ϭ 2.98, ace-
tone), m.p. 44Ϫ45 °C and (5R,8S)-(Ϫ)-20b (0.31 g). [α]2D5 ϭ Ϫ162.8
of products (5S,6R,8R)-15a and (5R,6S,8R)-(ϩ)-14a (according to (c ϭ 3.18, acetone). Their IR and NMR spectra were identical with
the GC analysis 20:80) was chromatographed on silica gel with hex-
ane/acetone (5:1) to afford the pure mixture of the hydroxy lactones
(5S,6R,8R)-15a and (5R,6S,8R)-(ϩ)-14a (1.57 g, 96% yield).
those of (5S,8R)-(ϩ)-20a and (5R,8R)-(Ϫ)-21a. Total reaction yield
was 93% (according to the GC analysis 20% of 20b and 80% of
21b).
(5R,6S,8S)-6-Hydroxy-4,4,8-trimethyl-1-oxaspiro[4.5]decan-2-one
(15b) and (5S,6R,8S)-(؊)-6-Hydroxy-4,4,8-trimethyl-1-oxaspiro-
[4.5]decan-2-one (14b): according to the procedure described for the
preparation of (5S,6R,8R)-15a and (5R,6S,8R)-(ϩ)-14a, the crude
mixture of the epoxy ester (1ЈR,2ЈS,4ЈS)-(Ϫ)-12b and the hydroxy
lactone (5S,6R,8S)-(Ϫ)-14b (1.80 g, according to the GC analysis
45%:55%) yielded the mixture of the hydroxy lactones (5R,6S,8S)-
15b and (5S,6R,8S)-(Ϫ)-14b (according to the GC analysis 20:80,
1.60 g, 94% yield). Their IR and NMR spectra were identical with
those of (5S,6R,8R)-15a and (5R,6S,8R)-(ϩ)-14a.
Crystal Data for (5S,8S)-(؉)-21b: C12H18O3, M ϭ 210.26, colour-
less block, crystal dimensions 0.25 ϫ 0.25 ϫ 0.20, monoclinic,
˚
space group P21, a ϭ 8.7763(5), b ϭ 12.2135(7), c ϭ 11.3811(8) A,
3
Ϫ3
˚
β ϭ 112.548(6)°, V ϭ 1126.68(12) A , Z ϭ 4, Dc ϭ 1.240 Mg·m
,
T ϭ 100 K, R ϭ 0.0537, Rw ϭ 0.0804 (4805 reflections, all data)
for 415 variables.
CCDC-226233 (for 18a), -226235 (for 20a), -226234 (for 21b) con-
tain the supplementary crystallographic data for this paper. These
data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html [or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: (internat.)
ϩ 44-1223-336-033; E-mail: deposit@ccdc.cam.ac.uk].
(5S,8R)-(؉)-4,4,8-Trimethyl-1-oxaspiro[4.5]decane-2,6-dione (20a)
and
(5R,8R)-(؊)-4,4,8-Trimethyl-1-oxaspiro[4.5]decane-2,6-dione
(21a): A mixture of the hydroxy lactones (5S,6R,8R)-15a and
(5R,6S,8R)-(ϩ)-14a (according to the GC analysis 20:80, 1.57 g,
7.40 mmol) was added in one portion to a suspension of pyridin-
ium dichromate (3.97 g, 10.55 mmol) in CH2Cl2 (20 mL). The mix-
ture was stirred for 24 h at room temperature. The solvent was then
distilled off and the residue was extracted with hexane. The hexane
solution was filtered through Florisil and the solvents evaporated
in vacuo. The crude mixture of (5S,8R)-(ϩ)-20a and (5R,8R)-(Ϫ)-
21a (according to the GC analysis 20:80) was chromatographed on
silica gel. The first fraction, eluted with hexane/acetone (5:1), gave
Acknowledgments
This work was supported by the State Committee for Scientific
Research (KBN), Grant No. PBZ-KBN-060/T09/2001.
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Eur. J. Org. Chem. 2004, 2662Ϫ2668