Lactones 23: Synthesis of cis-fused bicyclic hydroxy lactones with a p-menthane system

Article abstract of DOI:10.1016/j.tetasy.2005.04.020

Enantiomeric pairs of cis-fused bicyclic hydroxy lactones with a p-menthane system were obtained in a several step synthesis from enantiomerically pure isomers of (+)-(R)- and (-)-(S)-pulegone. One-pot allyl-Claisen rearrangement of cis-pulegols, epoxidation of γ,δ-unsaturated p-nitrophenyl esters and acidic lactonization of epoxy esters are key synthetic steps. The structures of the compounds were confirmed by both spectroscopic and crystallographic methods.

Full text of DOI:10.1016/j.tetasy.2005.04.020

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2087–2097
Lactones 23: Synthesis of cis-fused bicyclic hydroxy lactones
with a p-menthane systemq
b
b
a
Iwona Dams,a, Agata Białonska, Zbigniew Ciunik and Czesław Wawrzenczyk
*
´
´
aDepartment of Chemistry, Agricultural University of Wrocław, Norwida 25, PL-50-375 Wrocław, Poland
bDepartment of Crystallography, Faculty of Chemistry, University of Wrocław, Joliot Curie 14, PL-50-383 Wrocław, Poland
Received 13 March 2005; accepted 21 April 2005
Abstract—Enantiomeric pairs of cis-fused bicyclic hydroxy lactones with a p-menthane system were obtained in a several step syn-
thesis from enantiomerically pure isomers of (+)-(R)- and (ꢀ)-(S)-pulegone. One-pot allyl-Claisen rearrangement of cis-pulegols,
epoxidation of c,d-unsaturated p-nitrophenyl esters and acidic lactonization of epoxy esters are key synthetic steps. The structures
of the compounds were confirmed by both spectroscopic and crystallographic methods.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
mintlactone 9 and wine lactone 10 (Fig. 1).8a,9 The eval-
uation of their odoriferous properties showed that, in
agreement with our expectations, they exhibit interesting
fragrances and can be of considerable interest in the
food or cosmetics industry.8
The p-menthane lactones family is a valuable class of
monoterpenoid compounds mainly for their interesting
odoriferous properties.1–7 Previously we reported the
synthesis of several enantiomeric pairs of bicyclic c-spi-
rolactones 1–6 and optically inactive c-spirolactone 7,
which can be considered as derivatives of three of the
best known p-menthanolides; (ꢀ)-mintlactone 8, (+)-iso-
However, our interest in the synthesis of monoterpenoid
lactones with the p-menthane system was focused
mainly on searching for new synthetic antifeedants of
I
OH
OH
O
O
O
O
O
O
O
O
O
O
O
(+)-(5R,6S,8R)-1a (-)-(5S,8R)-2a
(-)-(5S,6R,8S)-1b (+)-(5R,8S)-2b
(-)-(5S,6R,8R)-4a
(+)-(5R,6S,8S)-4b
(-)-(5R,8R)-5a
(+)-(5S,8S)-5b
(+)-(5R,6S,8R)-3a
(-)-(5S,6R,8S)-3b
O
O
O
O
O
O
O
O
O
O
O
(+)-(5S,8R)-6a
(-)-(5R,8S)-6b
7
8
9
10
Figure 1. Lactones with the p-menthane system.
q See Ref. 9.
*
Corresponding author. Tel.: +48 71 32 05 145; fax: +48 71 32 84 124; e-mail: iwa_dams@ozi.ar.wroc.pl
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.04.020

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I. Dams et al. / Tetrahedron: Asymmetry 16 (2005) 2087–2097
simple structure and availability. The structures of the
natural deterrents found in plants, such as the most po-
tent azadirachtin (Azadirachta indica, Meliaceae)10 and
ajugarin (Ajuga remota, Labiatae),11 are in most cases
too complicated to be synthesized on a large scale.
The agricultural application of natural antifeedants is
also considerably limited by their low concentration in
plants and too expensive isolation to be of much practi-
cal value for plant protection. As many natural deter-
rents incorporate the lactone moiety,11,12 synthetic
monoterpenoid lactones13 of simple structure can be
an alternative option for practical application. Encour-
aged by the high feeding deterrent activity of d-hydroxy-
c-spirolactones 3 and 4 and d-keto-c-spirolactones 5
and 6 towards the Colorado potato beetle (Leptinotarsa
decemlineata Say), the lesser mealworm Alphitobius dia-
perinus Panzer and the peach potato aphid (Myzus Per-
sicae Sulz.),14 we synthesized the enantiomeric pairs of
cis-fused bicyclic hydroxy lactones 22, 25, 30 and 31
(Schemes 2 and 5) to investigate the structure–biological
activity relationship for these compounds. As the con-
figuration of the stereogenic centres is an extremely
important factor for determining biological activity of
chiral pheromones,15 odorants7,16 and drugs,17 hydroxy
lactones 22, 25, 30 and 31 were obtained from enantio-
merically pure isomers of (+)-(R)- and (ꢀ)-(S)-pulegone
11a and 11b via a one-pot allyl-Claisen rearrangement
of (ꢀ)-(1R,5R)- and (+)-(1S,5S)-pulegol, 12a and 12b,
respectively. Herein we report the first use of a one-
pot combination of allylic and Claisen rearrangements
of allylic alcohols in the synthesis of c,d-unsaturated
esters.
rearrangement of cis-pulegols (ꢀ)-(1R,5R)-12a or (+)-
(1S,5S)-12b in the presence of catalytic amounts of
water afforded mixtures of c,d-unsaturated ethyl esters
(+)-(10R,50R)-14a and (10S,50R)-15a or (ꢀ)-(10S,50S)-
14b and (10R,50S)-15b in a ratio of 80:20. Such a course
of the reaction was caused by the allylic rearrangement
of cis-pulegols to more stable tertiary alcohols (40R)-
13a or (40S)-13b, which were then used as substrates
for the Claisen rearrangement.
The orthoacetate modification of the Claisen rearrange-
ment is known to be highly stereoselective; however, in
the case of these tertiary allylic alcohols it led to the dia-
stereoisomeric mixture of ethyl esters 14a and 15a or 14b
and 15b. Apart from the main product—ester 14a or 14b
(80%) with trans-situated methyl and ethoxycarbonyl-
methyl groups—20% of cis-ester 15a or 15b was also ob-
tained. Although the presence of two ethyl esters was
clearly seen by gas chromatography, they were insepara-
ble by means of column and HPLC chromatography. As
phenyl esters possess higher UV activity, and therefore
can be better detected by HPLC, the cis- and trans-ethyl
esters 14a and 15a, or 14b and 15b were transformed
into the corresponding p-nitrophenyl esters (+)-(10R,
50R)-18a and (ꢀ)-(10S,50R)-19a or (ꢀ)-(10S,50S)-18b
and (+)-(10R,50S)-19b. In order to do this, the mix-
tures of ethyl esters 14a and 15a, or 14b and 15b, were
hydrolyzed in KOH/EtOH solution to the correspond-
ing acids (10R,50R)-16a and (10S,50R)-17a, or (10S,50S)-
16b and (10R,50S)-17b, which were subjected to reaction
with PCl5 in anhydrous CCl4 and then esterification of
acid chlorides with sodium p-nitrophenolate (Scheme
1).18 The mixtures of p-nitrophenyl esters 18a and 19a
or 18b and 19b (80:20) were separated by preparative
HPLC chromatography using a mixture of THF and
hexane (99.5:0.5) as eluent. The cis-p-nitrophenyl ester
19a or 19b was eluted first after 21.25 min, whereas the
trans-isomer 18a or 18b had a retention time of
25.27 min. Their enantiomeric purity was confirmed by
GC chromatography on a chiral column (cyclodextrin-
b-2,3,6-m-19).
2. Results and discussion
Four enantiomeric pairs of cis-fused bicyclic hydroxy
lactones with the p-menthane system 22a,b, 25a,b,
30a,b and 31a,b (Schemes 2 and 5) were obtained in a
several step synthesis from (+)-(R)- and (ꢀ)-(S)-pule-
gone, 11a and 11b, respectively. The first step of the syn-
thesis was the reduction of pulegones with NaBH4 in a
mixture of MeOH/H2O according to the procedure de-
scribed by us (Scheme 1).8a,9 A one-pot allyl-Claisen
The assignment of the structures 18a and 19a or 18b and
19b for the p-nitrophenyl ester isomers was based on the
i
ii
78%
iii
+
96%
98%
O
OH
CO2Et
(+)-(1'R,5'R)-14a
(-)-(1'S,5'S)-14b
CO2Et
(1'S,5'R)-15a
OH
(4'R)-13a
(4'S)-13b
(+)-(R)-11a
(-)-(S)-11b
(-)-(1R,5R) -12a
(+)-(1S,5S) -12b
(1'R,5'S)-15b
iv
87%
+
+
CO2Ph-NO2
CO2Ph-NO2
CO2H
CO2H
(1'R,5'R)-16a
(1'S,5'S)-16b
(1'S,5'R)-17a
(1'R,5'S)-17b
(-)-(1'S,5'R)-19a
(+)-(1'R,5'S)-19b
(+)-(1'R,5'R)-18a
(-)- (1'S,5'S)-18b
Scheme 1. Reagents and conditions: (i) NaBH4, EtOH, MeOH/H2O, 0 ꢁC to rt, 2 h; (ii) CH3C(OEt)3, C2H5COOH, H2O, 3 h at 138 ꢁC,
14a:15a = 80:20; (iii) (a) KOH, EtOH, reflux, 3 h; (b) 0.1 M HCl, 16a:17a = 80:20; (iv) (a) PCl5, CCl4, 12 h at 45 ꢁC; (b) NaO–C6H4–NO2-p, CH2Cl2,
10 h at rt, 18a:19a = 80:20; (c) HPLC, hexane/THF (99.5:0.5).

I. Dams et al. / Tetrahedron: Asymmetry 16 (2005) 2087–2097
2089
1
careful examination of their 300 MHz H NMR spectra
and confirmed by the X-ray structures of c-hydroxy-d-
lactone (+)-(1S,6R,8R)-22a (Fig. 2) and d-hydroxy-c-
lactone (ꢀ)-(1R,4R,6R)-25a (Fig. 3). The H-10 proton
of the trans-p-nitrophenyl ester 18a or 18b can be seen
as a multiplet at a lower field (d = 3.47) compared with
the same proton of the cis-isomer 19a or 19b
(d = 3.23). According to the analysis with a Driding
model, this is only possible in the chair-like conforma-
tion of cyclohexane ring with the aryloxycarbonylmethyl
group at the axial position. In such a conformation the
double bond of isopropylidene group and the equatorial
H-10 proton are situated in the same plane, therefore the
H-10 proton of the trans-ester 18a or 18b is more effec-
tively deshielded by the double bond. The crystal struc-
tures of hydroxy lactones 22a (Fig. 2) and 25a (Fig. 3)
undoubtedly confirmed the trans relationship between
the CH3-8 or CH3-4 methyl group of the cyclohexane
ring and the C5–C6 or C6–C7 bond of the lactone ring.
(ꢀ)-(10S,20S,50S)-20b and (10S,20R,50S)-21b (Scheme 2).
Unfortunately, these mixtures were inseparable by GC
and TLC.
The presence of both diastereoisomers could be only
proven by 1H NMR spectrum. The multiplet at
d = 2.41 was ascribed to the H-10 proton of the isomer
20a or 20b with cis-situated epoxide ring and aryloxycar-
bonylmethyl group, while the multiplet at d = 2.22 to
this proton in the trans-isomer 21a or 21b. From the
integration of these signals, it could be seen that the mix-
ture contained 40% of the cis-epoxy ester 20a or 20b and
60% of the trans-isomer 21a or 21b. In the case of trans-
epoxy ester 21a or 21b, the proton H-10 is seen as a
multiplet at a higher field d = 2.22, which indicates a stron-
ger shielding effect of the oxirane ring on this proton.
This also suggests the equatorial position of the H-10
proton and confirms the trans relationship between the
epoxide ring and the aryloxycarbonylmethyl substituent.
In spite of many attempts, preparative column chroma-
tography afforded only the pure cis-isomer 20a or 20b.
In addition to this epoxy ester, c-hydroxy-d-lactone
22a or 22b was eluted from the column as the result of
the lactonization of the trans-epoxy ester 21a or 21b
on silica gel. The presence of the d-lactone ring was con-
firmed by the IR spectrum (1704 cmꢀ1).
Structures 20a and 20b were assigned to the cis-epoxy es-
ter isomers on the basis of their 300 MHz 1H NMR
spectra. According to the analysis with a Driding model,
the oxirane oxygen situated cis with respect to the meth-
ylene group CH2-2 shows stronger deshielding effect to-
wards these protons compared with the trans-isomer 21a
or 21b. Both protons of the CH2-2 group are seen as an
AB system (dd, J = 14.9 and 7.8 Hz at d = 2.77 and dd,
J = 14.9 and 7.4 Hz at d = 2.87) at a lower field com-
pared with the same protons of the trans-isomer (dd,
J = 15.2 and 11.1 Hz at d = 2.82 and ddd J = 15.2, 4.1
and 0.9 Hz at d = 2.57).
Figure 2. The molecular structure of c-hydroxy-d-lactone (+)-
(1S,6R,8R)-22a with crystallographic numbering.
The established mechanism of acidic lactonization of
epoxy esters, induced by H+ ions, states that the reaction
proceeds through diols 23a and 24a or 23b and 24b
(Schemes 2 and 3).19 Thus, a nucleophile should attack
the C-20 or C-70 atom from the opposite side of the oxo-
nium ion that is formed after H+ addition to the oxirane
oxygen. In the case of trans-epoxy esters 21a and 21b
with p-nitrophenyl group at the axial position, this mode
of action only leads to diols 24a and 24b with trans-diax-
ial situated hydroxyl and aryloxycarbonylmethyl groups
(Scheme 3). This was confirmed by the X-ray structure
of the c-hydroxy-d-lactone 22a (Fig. 2). The crystal
structure of 22a undoubtedly confirms the trans-diaxial
orientation of the hydroxy group at the C-1 atom and
the bond C6–C5 of the lactone ring.
Figure 3. The molecular structure of d-hydroxy-c-lactone (ꢀ)-
(1R,4R,6R)-25a with crystallographic numbering.
The pure cis-epoxy esters 20a and 20b were subjected to
acidic lactonization catalyzed by HClO4 in THF/H2O
solution (Scheme 2). The reaction mixture after 24 h
(when the epoxy ester was no longer detected by TLC
analysis) contained two isomeric hydroxy lactones 22a
and 25a or 22b and 25b (2.5:97.5), which were then sep-
arated by column chromatography. The first fraction
The epoxidation of pure trans-p-nitrophenyl esters
18a or 18b with m-chloroperbenzoic acid (m-CPBA)
afforded the diastereoisomeric mixture of epoxy
esters (+)-(10R,20R,50R)-20a and (10R,20S,50R)-21a or

2090
I. Dams et al. / Tetrahedron: Asymmetry 16 (2005) 2087–2097
i
+
O
O
CO2Ph-NO2
CO2Ph-NO2
CO2Ph-NO2
(+)-(1'R,5'R)-18a
(-)-(1'S,5'S)-18b
(1'R,2'S,5'R)-21a
(1'S,2'S,5'S)-21b
(+)-(1'R,2'R,5'R)-20a
(-)-(1'S,2'S,5'S)-20b
ii
88%
5'
6'
8
4'
3'
9
7
6
+
OH
1
1'
2
10
5
4
2'
O
CO2Ph-NO2
2
O
O
7'
3
(+)-(1'R,2'R,5'R)-20a
(-)-(1'S,2'S,5'S)-20b
(+)-(1S,6R,8R)-22a
(-)-(1R,6S,8S)-22b
iii
attack on C-2'
attack on C-7'
OH
OH
+
H
H
HO
OH
O2N-PhO2C
O2N-PhO2C
23a
23b
24a
24b
92%
4
3
5
6
OH
+
2
1
7
8
9
O
OH
O
O
O
(-)-(1R,4R,6R)-25a
(+)-(1S,4S,6S)-25b
(+)-(1S,6R,8R)-22a
(-)-(1R,6S,8S)-22b
Scheme 2. Reagents and conditions: (i) m-CPBA, CH2Cl2, 0 ꢁC to rt, 24 h; (ii) silica gel; (iii) THF, HClO4, H2O, 24 h at rt, 22a:25a = 2.5%:97.5%.
OH
H
HO
23a
23b
attack on C-2'
O2N-PhO2C
5'
4'
3'
6'
1'
H+, H2O
2'
O
OH
CO2Ph-NO2
7'
attack on C-7'
OH
H
(1'R,2'S,5'R)-21a
(1'S,2'R,5'S)-21b
OH
O2N-PhO2C
O
O
24a
24b
(+)-(1S,6R,8R)-22a
(-)-(1R,6S,8S)-22b
Scheme 3. Acidic lactonization of trans-epoxy esters (10R,20S,50R)-21a and (10S,20R,50S)-21b.
eluted with hexane/ethyl acetate (3:1) afforded the pure
d-hydroxy-c-lactone 22a or 22b (Rf = 0.21), whereas
the second one afforded a small amount of a mixture
of hydroxy lactones 22a and 25a or 22b and 25b. The

I. Dams et al. / Tetrahedron: Asymmetry 16 (2005) 2087–2097
2091
structure of d-hydroxy-c-lactones 25a and 25b was
established on the basis of spectroscopic and crystallo-
graphic methods. The presence of the c-lactone ring
was confirmed by the IR spectrum (1764 cmꢀ1). The ra-
tio of lactones obtained 22a and 25a (2.5:97.5) indicates
that in the case of cis-epoxy ester 20a or 20b with p-
nitrophenyl group in the axial position the attack of a
nucleophile on the C-70 atom, leading to the diols 23a
or 23b with trans-diaxial situated hydroxyisoporopyl
and aryloxycarbonylmethyl groups, is favourable
(Scheme 2). The X-ray structure of the d-hydroxy-c-lac-
tone 25a undoubtedly confirmed the axial position of
the hydroxyisopropyl group at the C-1 atom and the ax-
ial orientation of the C6–C7 bond (Fig. 3).
(1R,6S,8R)-30a and (1S,4R,6S)-31a or (1S,6R,8S)-30b
and (1R 4S,6R)-31b in a ratio of 24:76.
Similar results were obtained from the pure trans-epoxy
ester 27a or 27b—23% of c-hydroxy-d-lactone 30a or
30b and 77% of d-hydroxy-c-lactone 31a or 31b.
Although the presence of both hydroxy lactone isomers
30a and 31a or 30b and 31b was very clearly seen by GC,
they were inseparable by means of preparative column
and HPLC chromatography. However, the ratio of hy-
droxy lactones obtained, indicates that in the case of
cis-epoxy ester 26a or 26b with the equatorial aryloxy-
carbonylmethyl group, the attack of a nucleophile on
the C-20 or C-70 atom leads to diols 28a and 29a or
28b and 29b, respectively. As the same was observed
for the pure trans-epoxy ester 27a or 27b, it can be sup-
posed that the equatorial orientation of aryloxycarbon-
ylmethyl group allows it to form diols 29 with the
hydroxyisopropyl group at the equatorial position as
the main intermediates of the acidic lactonization of
epoxy esters 26 and 27.
Two other enantiomeric pairs of cis-fused bicyclic c-hy-
droxy-d-lactones 30a and 30b and d-hydroxy-c-lactones
31a and 31b were obtained from the pure p-nitrophenyl
esters 19a and 19b with cis-situated methyl and aryloxy-
carbonylmethyl groups (Scheme 4). The epoxidation
of cis-ester 19a or 19b with m-CPBA afforded a dia-
stereoisomeric mixture of cis- and trans-epoxy esters
(ꢀ)-(10S,20S,50R)-26a and (ꢀ)-(10S,20R,50R)-27a or (+)-
(10R,20R,50S)-26b and (+)-(10R,20S,50S)-27b in the ratio
of 44:56.
Pure cis-fused bicyclic c-hydroxy-d-lactones 22a and 22b
and d-hydroxy-c-lactones 25a and 25b were tested for
antifeedant activity against selected storage pest insects
(Sitophilus granarius L., Trogoderma granarium Ev.,
Tribolium confusum Duv.), the lesser mealworm (Alphito-
bius diaperinus Panzer), the Colorado potato beetle
(Leptinotarsa decemlineata Say) and the peach potato
aphid (Myzus persicae Sulz). Biological tests were car-
Fortunately, these epoxy esters were easily separable by
column chromatography. The first fraction eluted with
hexane/acetone (10:1, Rf = 0.43) gave the pure epoxy ester
26a or 26b with a cis-situated epoxide ring and aryloxy-
carbonylmethyl group, whereas the second fraction gave
trans-isomer 27a or 27b (Rf = 0.39). The structures of
epoxy esters 26 and 27 were established on the basis of
ried out according to the procedures described by Par-
13d
uch et al.13c Szczepanik et al.13a and Gabrys et al.,
´
respectively. The lactones synthesized showed moderate
activity against all mentioned storage pest insects (total
coefficients of deterrence13c ꢀ44 to 171).14d A strong
relationship between biological activity and the configu-
ration of the stereogenic centres was seen for cis-fused
bicyclic d-hydroxy-c-lactones 25a and 25b. Lactone
25a with a (1R,4R,6R)-configuration was a quite good
antifeedant against Tribolium confusum beetles (total
coefficient of deterrence 114), whereas its enantiomer
(1S,4S,6S)-25b slightly stimulated feeding in these in-
sects (total coefficient of deterrence ꢀ44). Hydroxy lac-
tones 22a and 22b and 25a and 25b appeared to be
more effective antifeedants against the Colorado potato
beetle, Leptinotarsa decemlineata Say, (total coefficients
of deterrence 116–175) and the lesser mealworm Alphito-
bius diaperinus Panzer (total coefficients of deterrence
123–184).14a,d,20 Only c-hydroxy-d-lactone 22a with a
(1S,6R,8R)-configuration was active against M. persi-
cae. Sulz.14d The details of these studies will be the sub-
ject of separate publications.
1
spectroscopic methods. Similar to the H NMR spectra
of epoxy esters 20 and 21 with the axial aryloxycarbon-
ylmethyl group, the oxirane oxygen situated cis with re-
spect to the equatorial methyl group CH2-2 in epoxy
esters 26a and 26b shows a stronger deshielding effect to-
wards these protons (dd, J = 15.1 and 6.7 Hz at d = 2.63
and dd, J = 15.1 and 8.2 Hz at d = 2.91) compared with
the same protons of trans-isomer 27a or 27b (d,
J = 10.4 Hz at d = 2.74 and t, J = 10.4 Hz at d = 2.53).
One proton of the CH2-2 group in the 1H NMR spectrum
of trans-epoxy esters 27a or 27b should be seen as a mul-
tiplet dd, but similar coupling constants mean that it gives
the triplet at a higher field d = 2.53 (J = 10.4 Hz) covering
with the multiplet from the proton H-10.
The pure cis-epoxy esters 26a and 26b were subjected to
the acidic lactonization catalyzed with HClO4 in a mix-
ture of THF/H2O (Scheme 5). After 24 h, the product
mixture contained two isomeric hydroxy lactones
m-CPBA, CH2Cl2, 0 oC, 24 h
+
86%
O
O
CO2Ph-NO2
CO2Ph-NO2
CO2Ph-NO2
44%
56%
(-)-(1'S,5'R)-19a
(+)-(1'R,5'S)-19b
(-)-(1'S,2'S,5'R)-26a
(+)-(1'R,2'R,5'S)-26b
(-)-(1'S,2'R,5'R)-27a
(+)-(1'R,2'S,5'S)-27b
Scheme 4. Epoxidation of p-nitrophenyl esters (ꢀ)-(10S,50R)-19a and (+)-(10S,50R)-19b.

2092
I. Dams et al. / Tetrahedron: Asymmetry 16 (2005) 2087–2097
5'
6'
1'
4'
3'
2'
2
O
CO2Ph-NO2
7'
(-)-(1'S,2'S,5'R)-26a
(+)-(1'R,2'R,5'S)-26b
i
92%
attack on C-2'
attack on C-7'
OH
OH
4
4
5
6
3
2
3
2
5
6
CO2Ph-NO2
CO2Ph-NO2
OH
+
+
1
7
8
7
8
1
HO
9
O
OH
10
H
H
O
O
OH
9
O
29a
29b
28a
28b
(1R,6S,8R)-30a
(1S,6R,8S)-30b
(1S,4R,6S)-31a
(1R,4S,6R)-31b
attack on C-7'
attack on C-2'
ii
90%
5'
6'
1'
4'
3'
2'
2
O
CO2Ph-NO2
7'
(-)-(1'S,2'R,5'R)-27a
(+)-(1'R,2'S,5'S)-27b
Scheme 5. Reagents and conditions: (i) THF, H2O, HClO4, 24 h at rt, 30a:31a = 24%:76%; (ii) THF, H2O, HClO4, 24 h at rt, 30a:31a = 23%:77%.
3. Conclusion
dium p-nitrophenolate (70–80%) were purchased from
Aldrich or Fluka (Poland). H NMR spectra: Bruker
1
Enantiomeric pairs of cis-fused bicyclic c-hydroxy-d-lac-
tones 22a and 22b, 30a and 30b as well as d-hydroxy-c-
lactones 25a and 25b, 31a and 31b with the p-menthane
system were obtained in a few step synthesis from enan-
tiomerically pure isomers of (+)-(R)- and (ꢀ)-(S)-pule-
gone. The synthetic methodology involved a one-pot
combination of allylic and Claisen rearrangements of
cis-pulegols, transesterification of ethyl esters to p-nitro-
phenyl esters through acid chlorides, epoxidation of c,d-
unsaturated p-nitrophenyl esters and acidic lactoniza-
tion of epoxy esters to the corresponding hydroxy lac-
tones. The structures of compounds were established
on the basis of spectroscopic and crystallographic meth-
ods. Hydroxy lactones 22a and 22b and 25a and 25b
proved to be very active antifeedants against the Colo-
rado potato beetle (Leptinotarsa decemlineata Say) and
the lesser mealworm Alphitobius diaperinus Panzer. Bio-
logical tests for antifeedant activity indicated the strong
relationship between biological activity and the configu-
ration of stereogenic centres.
Avance DRX 300 (300 MHz) spectrometer, TMS as
internal standard, for CDCl3 or CD2Cl2 solutions. IR
spectra: Specord M 80 spectrophotometer (Carl Zeiss
Jena). Melting points: Boetius apparatus (uncorrected).
Optical rotations: Autopol IV automatic polarimeter
(Rudolph), in acetone or ethanol solutions, concen-
trations denoted in g/100 ml. GC analyses: Varian
CP-3380 instrument (FID, carrier gas H2), using the follow-
ing capillary columns: HP-5 (crosslinked 5% phenyl
methyl siloxane) 25 m · 0.32 mm · 0.52 lm and CP-
Cyclodextrin-b-2,3,6-m-19, 25 m · 0.25 mm · 0.25 lm.
HPLC analyses: Waters 2690 Separations Module Alli-
ance and Waters 600 Controller instruments, Waters
996 Detector (Photodiode Array Detector UV), using
the following columns: Waters Spherisorbꢂ 5 lm silica
analytical column (4.6 mm · 250 mm) and Nova-Packꢂ
silica 6 lm preparative column (19 mm · 300 mm), with
a mixture of THF and hexane (99.5%:0.5%) as eluent.
Analytical TLC: Silicagel DC-Alufolien Kieselgel 60
F254 (Merck), hexane, acetone and diethyl ether in vari-
ous ratios as developing systems, compounds detected
by spraying the plates with 1% Ce(SO4)2/2% H3
[P(Mo3O10)4] in 10% H2SO4. Column chromatography:
silica gel (Kieselgel 60, 40–63 lm, 230–400 mesh,
Merck), hexane, acetone and diethyl ether in varying ra-
tios as eluents. X-ray structural analyses: X-ray data
were collected at low temperature using an Oxford
Cryosystem device on a Kuma KM4CCD j-axis
4. Experimental
4.1. General methods
Reagents: (+)-(R)-pulegone, (ꢀ)-(S)-pulegone, triethyl
orthoacetate, m-chloroperbenzoic acid (77%) and so-

I. Dams et al. / Tetrahedron: Asymmetry 16 (2005) 2087–2097
2093
diffractometer with graphite-monochromated MoKa
radiation (k = 0.71073 A). The crystal was positioned
4.3. Preparation of ethyl esters (ꢀ)-(10S,50S)-14b and
(10R,50S)-15b
˚
at 65 mm from the CCD camera. Frames (n = 612) were
measured at 0.75ꢁ intervals with a counting time of 15–
20 s. Accurate cell parameters were determined and re-
fined by a least-squares fit of 1800–2000 of the strongest
reflections. The data were corrected for Lorentz and
polarization effects. No absorption correction was ap-
plied. Data reduction and analysis were carried out with
the CrysAlice ÔREDÕ program.21 Space groups were
determined using the XPREP program. The structures
were solved by direct methods using the XS program
and refined on all F2 data with the XL program.22
Non-hydrogen atoms were refined with anisotropic dis-
placement parameters; hydrogen atoms were included
from geometry of molecules and Dq maps. These were
refined with isotropic displacement parameters. Crystal-
lographic data for the structures reported in this paper
(excluding structure factors) have been deposited with
the Cambridge Crystallographic Data Centre. Copies
of this information may be obtained free of charge from
the Director, CCDC, 12 UNION Road, Cambridge
1EZ, UK (fax: +44-1223-336033; e-mail: deposit@ccdc.
cam.ac.uk or http://www.ccdc.cam.ac.uk).
According to the procedure described for the prepara-
tion of (+)-(10R,50R)-14a and (10S,50R)-15a, the crude
cis-pulegol (+)-(1S,5S)-12b (0.90 g, 5.83 mmol) yielded
a mixture of unsaturated esters (ꢀ)-(10S,50S)-14b and
(10R,50S)-15b (according to the GC analysis 80:20,
1.03 g, 79% yield). Their IR and NMR spectra were iden-
tical with those of (+)-(10R,50R)-14a and (10S,50R)-15a.
4.4. Preparation of acids (10R,50R)-16a and (10S,50R)-17a
A mixture of unsaturated esters (+)-(10R,50R)-14a and
(10S,50R)-15a (80:20, 0.80 g, 3.57 mmol) was refluxed
for 3 h in 2.5% KOH/EtOH solution (14 ml). After cool-
ing and evaporating the solvent, the residual solid was
dissolved in water and washed with diethyl ether to re-
move organic impurities. The water layer was acidified
with 0.1 M HCl solution, and the products extracted
with diethyl ether. The combined ethereal solution was
washed with brine, dried over MgSO4 and evaporated
in vacuo to give the crude mixture of acids (10R,50R)-
16a and (10S,50R)-17a (according to the GC analysis
80%:20%, 0.69 g, 98% yield).
4.2. Preparation of ethyl esters (+)-(10R,50R)-14a and
(10S,50R)-15a
4.4.1. (10R,50R)-(20-Isoporopyliden-50-methylcyclohex-10-
yl)acetic acid 16a and (10S,50R)-(20-isopropyliden-50-
methylcyclohex-10-yl)acetic acid 17a. IR (film):
m = 3000 cmꢀ1 (m, br, OH), 1724 (s, C@O), 1364 and
1380 (s, (CH)3C<). The spectral data for the acids
(10R,50R)-16a and (10S,50R)-17a were found from the
1H NMR spectrum (CDCl3, 25 ꢁC) of the mixture of
16a and 17a: (10R,50R)-16a: d = 0.83 (d, J = 6.1 Hz,
3H, CH3-50), 1.62 (s, 3H, @C–CH3), 1.65 (d,
J = 1.8 Hz, 3H, @C–CH3), 3.33 (m, 1H, H-10), 11.0 (br
s, 1H, –COOH). (10S,50R)-17a: d = 0.91 (d, J = 6.7 Hz,
3H, CH3-50), 1.64 and 1.65 (two s, 6H, @C(CH3)2),
3.08 (m, 1H, H-10), 11.0 (br s, 1H, –COOH).
A mixture of the crude cis-pulegol (ꢀ)-(1R,5R)-12a
(0.97 g, 6.29 mmol), triethyl orthoacetate (9.5 ml,
50.32 mmol), propionic acid (two drops) and a catalytic
amount of water was heated at 138 ꢁC for 3 h under the
conditions for the distillative removal of ethanol. When
the reaction was completed (GC, TLC), the mixture was
concentrated in vacuo to remove unreacted orthoace-
tate. The residue was chromatographed on silica gel.
The first fraction, eluted with hexane/diethyl ether
(80:1), gave a small amount of ester (+)-(10R,50R)-14a
(7.4 mg). The second fraction afforded an inseparable
mixture of esters (+)-(10R,50R)-14a and (10S,50R)-15a
(according to the GC analysis 80%:20%, 1.1 g, 78%
yield).
4.5. Preparation of acids (10S,50S)-16b and (10R,50S)-17b
Treatment of the mixture of ethyl esters (ꢀ)-(10S,50S)-
14b and (10R,50S)-15b (80:20, 0.90 g, 4.01 mmol) simi-
lar to the hydrolysis of (+)-(10R,50R)-14a and
(10S,50R)-15a afforded the crude mixture of acids
(10S,50S)-16b and (10R,50S)-17b (according to the GC
analysis 80%:20%, 0.77 g, 98% yield). Their IR and
NMR spectra were identical with those of (10R,50R)-
16a and (10S,50R)-17a.
4.2.1. Ethyl (+)-(10R,50R)-(20-isoporopyliden-50-methyl-
25
cyclohex-10-yl)acetate: 14a. ½aꢁ ¼ þ30.5ꢀ(1c 3.16, ace-
tone); n2D0 ¼ 1.4781; IR (film): mD= 1748 cm (s, C@O),
1376 (m, (CH3)2C<), 1264 (m, C–O–C); 1H NMR
(CDCl3, 25 ꢁC): d = 0.82 (d, J = 6.1 Hz, 3H, CH3-50),
1.11 (m, 1H, one of the CH2-60 group), 1.20 (t,
J = 7.1 Hz, 3H, –OCH2CH3), 1.56–1.71 (m, 4H,
CH2-40, one of the CH2-60 group and H-50), 1.61 (d,
J = 1.2, 3 Hz, @C–CH3), 1.66 (d, J = 2.0 Hz, 3H, @C–
CH3), 1.83 (m, 1H, one of the CH2-30 group), 2.39 (m,
2H, CH2-2), 2.50 (m, 1H, one of the CH2-30 group),
3.31 (m, 1H, H-10), 4.06 (m, 2H, –OCH2CH3).
4.6. Preparation of p-nitrophenyl esters (+)-(10R,50R)-18a
and (ꢀ)-(10S,50R)-19a
PCl5 (0.92 g, 4.43 mmol) was added in one portion to a
stirred mixture of acids (10R,50R)-16a and (10S,50R)-17a
(80:20, 0.87 g, 4.43 mmol) in dry CCl4 (10 ml). Stirring
was continued for 12 h at 45 ꢁC. The solvent was evapo-
rated and the resulting mixture of chlorides dried in vacuo
(1 mmHg, 60 ꢁC) for 45 min. The syrup was then dis-
solved in dry CH2Cl2 (30 ml) and anhydrous sodium p-
nitrophenolate (0.78 g, 4.87 mmol) added in one
portion. The mixture was stirred for a further 10 h at
4.2.2. Ethyl (10S,50R)-(20-isopropyliden-50-methylcyclo-
hex-10-yl)acetate: 15a. Spectral data for the ethyl ester
1
(10S,50R)-15a were found from the H NMR spectrum
(CDCl3, 25 ꢁC) of the mixture of 14a and 15a: d = 0.9
(d, J = 6.7 Hz, 3H, CH3-50), 3.04 (m, 1H, H-10), 4.06
(m, 2H, –OCH2CH3).

2094
I. Dams et al. / Tetrahedron: Asymmetry 16 (2005) 2087–2097
room temperature. When the reaction was completed
(TLC, hexane/Et2O 30:1), the insoluble salt was filtered
and the solvent evaporated in vacuo. The crude mixture
of p-nitrophenyl esters (+)-(10R,50R)-18a and (ꢀ)-
(10S,50R)-19a (according to the GC analysis 80%:20%)
was purified and separated by HPLC (Nova-Packꢂ Silica
6 lm preparative column, 19 mm · 300 mm). The first
fraction, eluted with hexane/THF (99.5:0.5), gave the
pure p-nitrophenyl ester (ꢀ)-(10S,50R)-19a (retention
time 21.25 min, 0.25 g). The second fraction afforded
the pure p-nitrophenyl ester (+)-(10R,50R)-18a (retention
time 25.27 min, 0.97 g). Total reaction yield was 87%.
4.7.2. p-Nitrophenyl (+)-(10R,50S)-(20-isopropyliden-50-
25
D
0.96, acetone). The IR and NMR spectra were identical
methylcyclohex-10-yl)acetate 19b. ½aꢁ ¼ þ74.8 (c
with those of (ꢀ)-(10S,50R)-19a.
4.8. Epoxidation of p-nitrophenyl ester (+)-(10R,50R)-18a
A
solution of m-chloroperbenzoic acid (0.59 g,
2.65 mmol) in CH2Cl2 (15 ml) was added dropwise to
an ice-cooled and stirred solution of the p-nitrophenyl
ester (+)-(10R,50R)-18a (0.7 g, 2.21 mmol) in CH2Cl2
(20 ml). The reaction temperature was gradually in-
creased to room temperature and the mixture was stir-
red for a further 24 h. When the reaction was
completed (GC, TLC) the excess of m-chloroperbenzoic
acid was reduced 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
esters (+)-(10R,20R,50R)-20a and (10R,20S,50R)-21a was
chromatographed on silica gel. During purification
and separation by column chromatography, compound
(10R,20S,50R)-21a underwent lactonization to the c-hy-
droxy-d-lactone (+)-(1S,6R,8R)-22a with only the epoxy
ester (+)-(10R,20R,50R)-20a separated. The first fraction,
eluted with hexane/ethyl acetate (10:1), gave the pure
epoxy ester (+)-(10R,20R,50R)-20a (0.26 g). The second
fraction, eluted with hexane/ethyl acetate (3:1), afforded
the pure c-hydroxy-d-lactone (+)-(1S,6R,8R)-22a
(0.25 g). Total reaction yield was 88%.
4.6.1. p-Nitrophenyl (+)-(10R,50R)-(20-isoporopyliden-50-
25
methylcyclohex-10-yl)acetate 18a. ½aꢁ ¼ þ14.3 (c 3.45,
D
acetone); n2D0 ¼ 1.5338; IR (film): 1772 cmꢀ1 (s, C@O),
1532 and 1352 (s, C–NO2), 1496 and 1108 (s, C–C of
the p-nitrophenyl ring), 1208 (s, C–O–C), 876 (m, C–H
1
of the p-nitrophenyl ring); H NMR (CD2Cl2, 25 ꢁC):
d = 0.88 (d, J = 6.1 Hz, 3H, CH3-50), 1.22 (m, 1H, one
of the CH2-60 group), 1.68 (d, J = 1.4 Hz, 3H, @C–
CH3), 1.69 (s, 3H, @C–CH3), 1.68–1.76 (m, 4H, CH2-
40, one of the CH2-60 group and H-50), 1.96 (m, 1H,
one of the CH2-30 group), 2.60 (m, 1H, one of the
CH2-30 group), 2.69 (dd, J = 14.1 and 7.3 Hz, 1H,
CH2-2), 2.78 (dd, J = 14.0 and 8.7 Hz, 1H, CH2-2),
3.47 (m, 1H, H-10), 7.22 and 8.24 (AA0BB0 system,
4H, –C6H4–); C18H23NO4 (317.16): calcd C 68.12, H
7.30, N 4.41, O 20.16; found C 68.14, H 7.34, N 4.40,
O 20.19.
4.6.2. p-Nitrophenyl (ꢀ)-(10S,50R)-(20-isopropyliden-50-
4.8.1. p-Nitrophenyl (+)-(10R,20R,50R)-(20,70-epoxy-20-
25
D
25
methylcyclohex-10-yl)acetate 19a. ½aꢁ ¼ ꢀ73.9 (c
isoporopyl-50-methylcyclohex-10-yl)acetate 20a. ½aꢁ
¼
D
1.29, acetone); nD20 ¼1.5338; IR (film): 1776 cmꢀ1 (s,
C@O), 1536 and 1352 (s, C–NO2), 1496 and 1164 (s,
C–C of the p-nitrophenyl ring), 1212 (s, C–O–C), 872
þ37.5 (c 3.11, acetone); n2D0 ¼ 1.5149; IR (film):
m = 1764 cmꢀ1 (s, C@O), 1524 and 1347 (s, C–NO2),
1490 and 1111 (s, C–C of the p-nitrophenyl ring), 1212
(s, C–O–C), 869 (m, C–H of the p-nitrophenyl ring);
1H NMR (CD2Cl2, 25 ꢁC): d = 0.93 (d, J = 6.3 Hz, 3H,
CH3-50), 1.03 and 1.30 (two m, 2H, CH2-60), 1.36 and
1.39 (two s, 6H, >C(CH3)2), 1.45 (m, 1H, one of the
CH2-30), 1.64–1.88 (m, 3H, CH2-40 and H-50), 1.90 (m,
1H, one of the CH2-30 group), 2.41 (m, 1H, H-10),
2.77 (dd, J = 14.9 and 7.8 Hz, 1H, one of the CH2-2
group), 2.87 (dd, J = 14.9 and 7.4 Hz, 1H, one of the
CH2-2 group), 7.33 and 8.24 (AA0BB0 system, 4H,
–C6H4–).
1
(m, C–H of the p-nitrophenyl ring); H NMR (CD2Cl2,
25 ꢁC): d = 0.98 (d, J = 6.7 Hz, 3H, CH3-50), 1.20–1.31
(m, 2H, CH2-60), 1.53–1.83 (m, 3H, CH2-40, H-50),
1.68 (s, 3H, @C–CH3), 1.70 (d, J = 1.8 Hz, 3H, @C–
CH3), 2.04 (m, 1H, one of the CH2-30 group), 2.43 (m,
1H, one of the CH2-30 group), 2.57 (dd, J = 14.5 and
9.3 Hz, 1H, CH2-2), 2.68 (dd, J = 14.5 and 6.0 Hz, 1H,
CH2-2), 3.23 (m, 1H, H-10), 7.27 and 8.26 (AA0BB0 sys-
tem, 4H, –C6H4–); C18H23NO4 (317.16): calcd C 68.12,
H 7.30, N 4.41, O 20.16; found C 68.10, H 7.29, N
4.42, O 20.17.
4.8.2. p-Nitrophenyl (10R,20S,50R)-(20,70-epoxy-20-isopro-
pyl-50-methylcyclohex-10-yl)acetate 21a. Spectral data
for the epoxy ester (10R,20S,50R)-21a were found from
4.7. Preparation of p-nitrophenyl esters (ꢀ)-(10S,50S)-18b
and (+)-(10R,50S)-19b
1
the H NMR spectrum (CD2Cl2, 25 ꢁC) of the crude
In the same manner as described for the preparation of
(+)-(10R,50R)-18a and (ꢀ)-(10S,50R)-19a, the mixture of
acids (10S,50S)-16b and (10R,50S)-17b (80%:20%, 0.96 g,
4.89 mmol) yielded the pure p-nitrophenyl esters (ꢀ)-
(10S,50S)-18b (1.08 g) and (+)-(10R,50S)-19b (0.28 g). To-
tal reaction yield was 88% (according to the GC analysis
80% of 18b and 20% of 19b).
mixture of 20a and 21a: d = 0.94 (d, J = 6.0 Hz, 3H,
CH3-50), 1.30 and 1.35 (two s, 6H, >C(CH3)2), 2.22
(m, 1H, H-10), 2.57 (ddd, J = 15.2, 4.1 and 0.9 Hz, 1H,
one of the CH2-2 group), 2.82 (dd, J = 15.2 and
11.1 Hz, 1H, one of the CH2-2 group), 7.31 and 8.25
(AA0BB0 system, 4H, –C6H4–).
4.8.3. (+)-(1S,6R,8R)-1-Hydroxy-2,2,8-trimethyl-3-oxa-
25
D
4.7.1. p-Nitrophenyl (ꢀ)-(10S,50S)-(20-isoporopyliden-50-
bicyclo[4.4.0]decan-4-one: 22a. ½aꢁ ¼ þ43.8 (c 1.46,
25
methylcyclohex-10-yl)acetate 18b. ½aꢁ ¼ ꢀ15.2 (c 2.62,
acetone); mp = 147–149 ꢁC; IR (Nujol): 3432 cmꢀ1 (s,
OH), 1704 (s, C@O), 1380 and 1372 (m, (CH3)2C<),
1308 (s, C–OH), 1244 (s, C–O–C) 1120 (s, O–H); H
D
acetone). The IR and NMR spectra were identical with
1
those of (+)-(10R,50R)-18a.

I. Dams et al. / Tetrahedron: Asymmetry 16 (2005) 2087–2097
2095
NMR (CDCl3, 25 ꢁC): d = 0.9 (d, J = 5.7 Hz, 3H, CH3-
8), 1.15–1.34 (m, 2H, CH2-7), 1.32 and 1.44 (two s, 6H,
>C(CH3)2), 1.43–1.74 (m, 5H, CH2-9, CH2-10 and H-8),
2.37 (m, 1H, H-6), 2.57 (dd, J = 19.4 and 9.7 Hz, 1H,
one of the CH2-5 group), 2.68 (dd, 19.4 and 9.3 Hz,
1H, one of the CH2-5 group); C12H20O3 (212.29): calcd
C 67.89, H 9.49; found C 67.91, H 9.52. Crystal data for
(1S,6R,8R)-(+)-22a: C12H20O3, M = 212.28, colourless
block, crystal dimensions 0.35 · 0.35 · 0.35, monoclinic,
(m, 1H, one of the CH2-2 group), 2.47 (dd, J = 18.1
and 8.5 Hz, 1H, one of the CH2-7 group), 2.70 (dd,
J = 18.1 and 10.1 Hz, 1H, one of the CH2-7 group),
2.93 (m, 1H, H-6). C12H20O3 (212.29): calcd C 67.89,
H 9.49; found C 67.76, H 9.39.
Crystal data for (ꢀ)-(1R,4R,6R)-25a: C12H20O3,
M = 212.28, colourless block, crystal dimensions 0.30 ·
0.30 · 0.30 mm, orthorhombic, space group P212121,
˚
space group P21, a = 9.1494(16), b = 7.4407(11), c =
a = 6.2914(7), b = 8.3463(7), c = 21.5950(17) A, V =
3
3
9.5183(13) A, b = 118.509(16), V = 569.41(15) A , Z = 2,
1133.95(18) A , Z = 4, Dc = 1.243 Mg mꢀ3, T = 100 K,
˚
˚
˚
Dc = 1.238 Mg mꢀ3
,
T = 100 K, R = 0.0406, Rw =
R = 0.0453, Rw = 0.0819 (2678 reflections, all data) for
216 variables. CCDC 252295.
0.0885 (1974 reflections, all data) for 216 variables.
CCDC 252296.
4.11. Acidic lactonization of epoxy ester (ꢀ)-(10S,20S,50S)-
4.9. Epoxidation of p-nitrophenyl ester (ꢀ)-(10S,50S)-18b
20b
According to the procedure described for the prepara-
tion of (+)-(10R,20R,50R)-20a and (+)-(1S,6R,8R)-22a,
the p-nitrophenyl ester (ꢀ)-(10S,50S)-18b (0.85 g,
2.68 mmol) yielded the pure epoxy ester (ꢀ)-
(10S,20S,50S)-20b (0.32 g) and c-hydroxy-d-lactone (ꢀ)-
(1R,6S,8S)-22b (0.30 g). Total reaction yield was 89%.
Treatment of the epoxy ester (ꢀ)-(10S,20S,50S)-20b
(0.4 g, 1.2 mmol) similar to the lactonization of (+)-
(10R,20R,50R)-20a afforded pure d-hydroxy-c-lactone
(+)-(1S,4S,6S)-25b (0.2 g) and an inseparable mixture
of hydroxy lactones 25b and 22b (0.03 g).
4.11.1. (+)-(1S,4S,6S)-1-(10-Hydroxy-10-methylethyl)-4-
25
D
4.9.1. p-Nitrophenyl (ꢀ)-(10S,20S,50S)-(20,70-epoxy-20-
methyl-9-oxabicyclo[4.3.0]nonan-8-one
þ22.3 (c 1.68, acetone). Its IR and NMR spectra were
25b. ½aꢁ ¼
25
D
isoporopyl-50-methylcyclohex-10-yl)acetate 20b. ½aꢁ
¼
ꢀ38.9 (c 2.46, acetone). Its IR and NMR spectra were
identical with those of (+)-(10R,20R,50R)-20a.
identical with those of (ꢀ)-(1R,4R,6R)-25a.
4.12. Epoxidation of p-nitrophenyl ester (ꢀ)-(10S,50R)-
4.9.2. (ꢀ)-(1R,6S,8S)-1-Hydroxy-2,2,8-trimethyl-3-oxa-
19a
25
bicyclo[4.4.0]decan-4-one 22b. ½aꢁ ¼ ꢀ42.1 (c 1.3, ace-
D
tone). Its IR and NMR spectra were identical with those
of (+)-(1S,6R,8R)-22a.
As described for the preparation of epoxides 20 and 21,
the p-nitrophenyl ester (ꢀ)-(10S,50R)-19a (0.22 g,
0.69 mmol) was treated with m-CPBA (0.2 g,
0.83 mmol) to give a crude mixture of epoxy esters
4.10. Acidic lactonization of epoxy ester (+)-(10R,20R,50R)-
20a
(ꢀ)-(10S,20S,50R)-26a
and
(ꢀ)-(10S,20R,50R)-27a
(according to the GC analysis 44:56), which was then
chromatographed on silica gel. The first fraction, eluted
with hexane/acetone (10:1), gave the pure epoxy ester
(ꢀ)-(10S,20S,50R)-26a (Rf = 0.43, 0.087 g). The second
fraction afforded pure epoxy ester (ꢀ)-(10S,20R,50R)-
27a (Rf = 0.39, 0.11 g). Total reaction yield was 86%.
Perchloric acid (60%, 0.25 ml) was added to a solution
of the epoxy ester (+)-(10R,20R,50R)-20a (0.5 g,
1.5 mmol) in THF (12 ml) and water (6 ml). The mixture
was stirred for 24 h at room temperature and the prod-
ucts extracted with diethyl ether. The combined ethereal
extracts were washed with saturated NaHCO3 solution
and brine, dried over anhydrous MgSO4 and the sol-
vents evaporated in vacuo. The crude mixture of hydro-
xy lactones (ꢀ)-(1R,4R,6R)-25a and (+)-(1S,6R,8R)-22a
(according to the GC analysis 97.5:2.5) was chromato-
graphed on silica gel. The first fraction, eluted with hex-
ane/ethyl acetate (3:1) gave pure d-hydroxy-c-lactone
(ꢀ)-(1R,4R,6R)-25a (Rf = 0.21, 0.25 g). The second frac-
tion afforded a small amount of inseparable mixture of
hydroxy lactones 25a and 22a (0.042 g). Total reaction
yield was 92%.
4.12.1. p-Nitrophenyl (ꢀ)-(10S,20S,50R)-(20,70-epoxy-20-
27
D
isoporopyl-50-methylcyclohex-10-yl)acetate 26a. ½aꢁ
¼
ꢀ44.1 (c 1.42, acetone); n2D0 ¼1.5152; IR (film):
m = 1765 cmꢀ1 (s, C@O), 1524 and 1346 (s, C–NO2),
1490 and 1111 (s, C–C of the p-nitrophenyl ring),
1210 (s, C–O–C), 689 (m, C–H of the p-nitrophenyl
ring); 1H NMR (CD2Cl2, 25 ꢁC): d = 1.05 (d,
J = 6.8 Hz, 3H, CH3-50); 1.32–1.49 (m, 3H, CH2-60
and one of the CH2-30 group), 1.35 and 1.36 (two s,
6H, >C(CH3)2), 1.68–1.90 (m, 3H, CH2-40 and H-5),
2.03 (m, 1H, one of the CH2-30 group), 2.48 (m, 1H,
H-10), 2.63 (dd, J = 15.1 and 6.7 Hz, 1H, one of the
CH2-2 group), 2.91 (dd, J = 15.1 and 8.2 Hz, 1H, one
of the CH2-2 group), 7.31 and 8.24 (AA0BB0 system,
4H, –C6H4–).
4.10.1. (ꢀ)-(1R,4R,6R)-1-(10-Hydroxy-10-methylethyl)-4-
25
D
methyl-9-oxabicyclo[4.3.0]nonan-8-one
25a. ½aꢁ ¼
ꢀ21.0 (c 1.52, acetone); mp = 85–86 ꢁC; IR (Nujol):
m = 3508 cmꢀ1 (s, OH), 1764 (s, C@O), 1468 and 1380
(m, >C(CH3)2), 1300 (s, C–OH), 1244 (s, C–O–C),
1140 (s, O–H); H NMR (CDCl3, 25 ꢁC): d = 0.93 (d,
J = 6.4 Hz, CH3-4), 1.08 and 1.29 (two m, 2H, CH2-5),
1.24 and 1.31 (two s, 6H, >C(CH3)2), 1.58–1.77 (m,
4H, one of the CH2-2 group, CH2-3 and H-4), 1.97
1
4.12.2. p-Nitrophenyl (ꢀ)-(10S,20R,50R)-(20,70-epoxy-20-
27
isopropyl-50-methylcyclohex-10-yl)acetate 27a. ½aꢁ
¼
D
ꢀ14.3 (c 0.97, acetone), mp = 85–86 ꢁC; IR (Nujol):
m = 1764 cmꢀ1 (s, C@O), 1536 and 1356 (s, C–NO2),

2096
I. Dams et al. / Tetrahedron: Asymmetry 16 (2005) 2087–2097
1500 and 1144 (s, C–C of the p-nitrophenyl ring), 1216
(s, C–O–C), 860 (m, C–H of the p-nitrophenyl ring);
1H NMR (CD2Cl2, 25 ꢁC); 1.02 (d, J = 6.6 Hz, 3H,
CH3-50), 1.18–1.31 (m, 2H, CH2-60), 1.34 and 1.42
(two s, 6H, >C(CH3)2), 1.62 (m, 1H, one of the CH2-
30 group), 1.74–1.92 (m, 3H, CH2-40 and H-50), 1.98
(m, 1H, one of the CH2-30 group), 2.48 (m, 1H, H-10),
2.53 (t, J = 10.4 Hz, 1H, one of the CH2-2 group), 2.74
(d, J = 10.4 Hz, 1H, one of the CH2-2 group), 7.30
and 8.26 (AA0BB0 system, 4H, –C6H4–).
and 3.7 Hz, 1H, one of the CH2-7 group), 2.61 (m,
1H, H-6), 3.20 (dd, J = 17.3 and 8.1 Hz, 1H, one of
the CH2-7 group).
4.15. Acidic lactonization of epoxy ester (+)-(10R,20R,50S)-
26b
According to the procedure described for the prepara-
tion of (1R,6S,8R)-30a and (1S,4R,6S)-31a, epoxy ester
(+)-(10R,20R,50S)-26b (0.095 g, 0.28 mmol) yielded a
mixture of c-hydroxy-d-lactone (1S,6R,8S)-30b and d-
hydroxy-c-lactone (1R,4S,6R)-27b (according to the
GC analysis 24:76, 0.054 g, 90% total reaction yield).
Their IR and NMR spectra were identical with those
of (1R,6S,8R)-30a and (1S,4R,6S)-31a.
4.13. Epoxidation of p-nitrophenyl ester (+)-(10R,50S)-
19b
In the same manner as described for the preparation of
(ꢀ)-(10S,20S,50R)-26a and (ꢀ)-(10S,20R,50R)-27a, p-
nitrophenyl ester (+)-(10R,50S)-19b (0.26 g, 0.82 mmol)
yielded the pure epoxy esters (+)-(10R,20R,50S)-26b
(0.106 g) and (+)-(10R,20S,50S)-27b (0.135 g). Total reac-
tion yield was 88%.
4.16. Acidic lactonization of epoxy ester (ꢀ)-(10S,20R,50R)-
27a
Treatment of epoxy ester (ꢀ)-(10S,20R,50R)-27a (0.09 g,
0.27 mmol) similar to the lactonization of (ꢀ)-
(10S,20S,50R)-26a afforded a mixture of c-hydroxy-d-lac-
4.13.1. p-Nitrophenyl (+)-(10R,20R,50S)-(20,70-epoxy-20-
27
D
isoporopyl-50-methylcyclohex-10-yl)acetate 26b. ½aꢁ
identical with those of (ꢀ)-(10S,20S,50R)-26a.
¼
tone
(1R,6S,8R)-30a
and
d-hydroxy-c-lactone
(1S,4R,6S)-31a (according to the GC analysis 23:77,
þ45.0 (c 0.96, acetone). The IR and NMR spectra were
0.051 g, 90% total reaction yield).
4.13.2. p-Nitrophenyl (+)-(10R,20S,50S)-(20,70-epoxy-20-
4.17. Acidic lactonization of epoxy ester (+)-(10R,20S,50S)-
27b
27
D
isopropyl-50-methylcyclohex-10-yl)acetate 27b. ½aꢁ
¼
þ15.4 (c 1.23, acetone). The IR and NMR spectra were
identical with those of (ꢀ)-(10S,20R,50R)-27a.
Treatment of epoxy ester (+)-(10R,20S,50S)-27b (0.083 g,
0.25 mmol) similar to the lactonization of (+)-
(10R,20R,50S)-26b afforded a mixture of c-hydroxy-d-lac-
4.14. Acidic lactonization of epoxy ester (ꢀ)-(10S,20S,50R)-
26a
tone
(1R,4S,6R)-31b (according to the GC analysis 23:77,
(1S,6R,8S)-30b
and
d-hydroxy-c-lactone
As described for the preparation of hydroxy lactones 22
and 25, the acidic lactonization of the epoxy ester (ꢀ)-
(10S,20S,50R)-26a (0.08 g, 0.24 mmol) gave the crude
mixture of c-hydroxy-d-lactone (1R,6S,8R)-30a and d-
hydroxy-c-lactone (1S,4R,6S)-31a (according to the
GC analysis 24:76), which was then chromatographed
on silica gel. In spite of many attempts, elution with var-
ious solvent systems (hexane/acetone 5:1 or hexane/ethyl
acetate 3:1) gave an inseparable mixture of hydroxy lac-
tones (1R,6S,8R)-30a and (1S,4R,6S)-31a (0.047 g, 92%
total reaction yield).
0.047 g, 88% total reaction yield).
Acknowledgements
This work was supported by the State Committee for
Scientific Research (KBN), Grant No. PBZ-KBN-060/
T09/2001.
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