Chemoenzymatic preparation of the p-menth-1,5-dien-9-ol stereoisomers and their use in the enantiospecific synthesis of natural p-menthane monoterpenes

Article abstract of DOI:10.1016/j.tetasy.2011.07.014

A study on the preparation and synthetic exploitation of the isomeric forms of p-menth-1,5-dien-9-ol is reported. The latter alcohols were prepared in high enantiomeric purity from the easily available enantiomers of carvone. Thus, a chemoenzymatic procedure based on lipase-mediated acetylation, allowed the separation of their diastereoisomeric forms. Moreover, the purity of the chiral building blocks obtained was improved by fractional crystallisation of their 3,5-dinitrobenzoyl derivatives. A number of synthetic applications have also been described. The stereospecific cyclisation of the isomerically pure dienic alcohols gave the isomeric forms of the terpenes dill and epi-dill ether, which were hydrogenated diastereoselectively to the corresponding (1R)- or (1S)-derivatives depending on the catalyst used. The oxidation of the latter ethers turned out to be stereoselective, affording either the corresponding p-menthan-9-oic lactone or the keto-acid derivatives depending on the starting isomer used.

Full text of DOI:10.1016/j.tetasy.2011.07.014

Tetrahedron: Asymmetry 22 (2011) 1455–1463
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chemoenzymatic preparation of the p-menth-1,5-dien-9-ol stereoisomers
and their use in the enantiospecific synthesis of natural p-menthane
monoterpenes
Stefano Serra a, , Igor Nobile b
⇑
a C.N.R. Istituto di Chimica del Riconoscimento Molecolare, Via Mancinelli 7, 20131 Milano, Italy
b Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A study on the preparation and synthetic exploitation of the isomeric forms of p-menth-1,5-dien-9-ol is
reported. The latter alcohols were prepared in high enantiomeric purity from the easily available enan-
tiomers of carvone. Thus, a chemoenzymatic procedure based on lipase-mediated acetylation, allowed
the separation of their diastereoisomeric forms. Moreover, the purity of the chiral building blocks
obtained was improved by fractional crystallisation of their 3,5-dinitrobenzoyl derivatives. A number
of synthetic applications have also been described. The stereospecific cyclisation of the isomerically pure
dienic alcohols gave the isomeric forms of the terpenes dill and epi-dill ether, which were hydrogenated
diastereoselectively to the corresponding (1R)- or (1S)-derivatives depending on the catalyst used. The
oxidation of the latter ethers turned out to be stereoselective, affording either the corresponding p-men-
than-9-oic lactone or the keto-acid derivatives depending on the starting isomer used.
Received 7 July 2011
Accepted 15 July 2011
Available online 17 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
rin-like flavour without the toxicological constraints of the
coumarin itself.
The general p-menthane framework 1 (Fig.1) occurs frequently
in the chemical scaffold of a large number of natural terpenes and
sesquiterpenes. These compounds show a great structural variabil-
ity, the presence of one or two unsaturations at C(1) and C(5),
respectively, being common and also oxidation at C(3) by the intro-
duction of an oxygen atom. Furthermore, the latter functional
group allows the formation of bicyclic compounds with the intro-
duction of another stereocentre. Overall, both a large number of
compounds and isomers are possible. Some relevant examples of
All of these compounds, although different from each other,
share the same difficulties in their stereoselective synthesis. In par-
ticular, the most challenging point is the specific preparation of the
two contiguous secondary stereocentres at C(4) and C(8). Since the
products described above show many relevant biological activities
that are definitely related to their absolute configuration, their syn-
thesis requires a very high degree of stereocontrol.
In this context, we have previously reported the stereoselective
preparation of some p-menth-1-en-ols7 and their use as chiral
building blocks in the mono- and sesquiterpene synthesis. The
latter studies face the aforementioned topic by a biocatalytic
approach that allows the introduction of a C(8) stereocentre using
either an enzyme-mediated resolution7a or a baker’s yeast-medi-
ated reduction.7 The starting substrates for the aforementioned
transformations already contain the C(4) asymmetric centre and
were easily prepared from the chiral pool.
Herein, taking advantage of these acquired methodologies, we
selected the isomeric forms of the p-menth-1,5-dien-9-ol 4 as suit-
able chiral building blocks for the synthesis of terpenes of type 2
and 3. In fact, the latter alcohol can be obtained as a mixture of dia-
stereoisomers from carvone enantiomers,8 thus controlling the
C(4) stereocentre. We envisaged that these types of compounds
were good substrates for a lipase-mediated resolution process.
Substituted 2-cyclohexenyl-propanols have been resolved via
PPL7a allowing the separation of the stereoisomers, which show
monocyclic sesquiterpenes of this type include
a-zingiberene and
the -turmerone isomers 2, which can be isolated from a number
a
of essential oils, comprising those of ginger1 and turmeric.2 In addi-
tion, several bicyclic monoterpenes of type 3 are the key compo-
nents of different flavours. It should be noted that dill ether3 is
the most important constituent of the dill herb from an organolep-
tic point of view. Moreover, wine lactone4 is a very powerful odou-
rant, which owes its name to its first isolation source. Further
saturated lactones of type 3 can be found in mint5 and have
attracted great synthetic interest6 for their potential application
in the flavour and fragrance industry. Indeed, some isomers of
these p-menthane lactones, exhibit a strong and suitable couma-
⇑
Corresponding author. Tel.: +39 02 2399 3076; fax: +39 02 2399 3180.
E-mail addresses: stefano.serra@cnr.it, stefano.serra@polimi.it (S. Serra).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.07.014

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S. Serra, I. Nobile / Tetrahedron: Asymmetry 22 (2011) 1455–1463
7
1
2
3
6
5
p-menthane
numbering
4
8
9
G
G = generic substituent
10
1
R=H2 α-zingiberene
R=O α-turmerone
R
2
OH
R=H2, Δ1,2 dill ether
4
R=O, Δ1,2 wine lactone
R=O, 3-hydroxy-p-menthan-9-
O
oic acid lactone
R
3
Figure 1. General structure of the p-menthane framework and structures of some relevant mono and sesquiterpenes having the same skeleton.
different C(8) absolute configurations. The combined use of the lat-
ter findings could afford all the isomeric forms of alcohol 4, which
are obvious precursors of sesquiterpenes of type 2. Moreover, the
high reactivity of the 1,5-dienic system turned out to be a useful
tool in the synthesis of the bicyclic compounds of type 3. Herein
we report the results of these studies, comprising of an effective
chemo-enzymatic protocol for the preparation of the p-menth-
1,5-dien-9-ol stereoisomers and their exploitation as chiral build-
ing blocks in the field of natural product synthesis.
earlier, the reaction conditions employed did not affect the C(4)
stereocentre, thus giving rise to a couple of enantiopure diastereo-
isomers. Their relative configurations were unambiguously as-
signed by chemical correlation with the known isomeric forms of
dill ether (see Section 2.2). Since both enantiomers of carvone
are commercially available in high enantiomeric purity, the de-
scribed pathway was carried out starting from (R)-5 to give,
through the intermediate of (R)-6, alcohols (+)-4b and (+)-4a in a
6:4 ratio, respectively. The diastereoisomeric alcohols are not
separable by chromatography either as acetate or nitrobenzoate
derivatives. The 4:6 couple of diastereoisomers 4a/4b was con-
verted in the corresponding 3,5-dinitrobenzoate ester in order to
study their fractional crystallisation. These experiments again
afforded disappointing results and we observed a significant
increase in the diastereoisomeric ratio only after ten crystallisa-
tions from hexane.
For these reasons, we selected a completely different separation
process based on the lipase-mediated esterification. We have pre-
viously demonstrated that PPL catalyses the irreversible acetyla-
tion of (2S)-substituted-propanol and affords the corresponding
esters with good enantioselectivity.9 When the p-menth-1-en-9-
ol7a stereoisomers were used as substrates, PPL catalysed the enan-
tioselective acetylation of the (8S) enantiomers independent of the
C(4) configuration. The latter good enantioselectivity, coupled with
the lack of diastereoselectivity, allowed the separation of the
diastereoisomers.
Since the p-menth-1,5-dien-9-ol isomers are very similar to the
aforementioned alcohols, we tested the PPL-mediated acetylation
of the diastereoisomers 4a and 4b. We first treated a mixture of
(ꢀ)-4a and (ꢀ)-4b with vinyl acetate in the presence of PPL as a
catalyst. The acetate 5a (Scheme 2) obtained turned out to be the
ester of (4S,8S)-p-menth-1,5-dien-9-ol, thus confirming our initial
insight.
Since we required all the isomers in high purity, we performed
the above resolution by means of a two step procedure. A 4:6 mix-
ture of alcohols (ꢀ)-4a and (ꢀ)-4b was acetylated until 55% con-
version. The following chromatographic separation afforded the
unreacted alcohol (ꢀ)-4b and acetate 5a in very good and low dia-
stereoisomerical purity, respectively. Thus, the latter acetate was
treated with NaOH in methanol and the derived alcohol was
2. Results and discussion
2.1. Preparation of the p-menth-1,5-dien-9-ol stereoisomers
As introduced before, p-menth-1,5-dien-9-ol was previously
obtained from carvone8 by a two step process. We followed this
synthetic method, carrying out some modifications in order to
make it suitable for larger scale preparation.
First we submitted the tosylhydrazone of the (S)-carvone 5
(Scheme 1) to the Shapiro reaction, carefully controlling the exper-
imental conditions, especially the temperature (see Section 4) min-
imized the side reactions, thus affording the p-mentha-1,5,8-triene
6 in higher purity. Overheating of the reaction favours the aroma-
tization of 6 to give 1-isopropenyl-4-methyl benzene, which in
turn is converted into 2-(p-tolyl)-propan-1-ol via a hydroboration.
The latter compound is not separable by chromatography and is
itself a good substrate for PPL mediated acetylation.9 Performing
the base addition at low temperature, followed by slow decomposi-
tion of the hydrazone, meant that the overall amount of this side
compound was less than 5% of the alcohol mixture.
In order to make the process less expensive, the regioselective
hydroboration of (S)-6 was performed using the less expensive
disiamylborane instead of 9-BBN. The latter reagent did not show
any diastereoselectivity, whereas disiamylborane afforded, after
oxidation of the intermediated borane with NaOH/H2O2, alcohols
(ꢀ)-4a and (ꢀ)-4b in a 4:6 ratio, respectively. As demonstrated
2-(p-Tolyl)-propan-1-ol 3,5-dinitrobenzoate is separable from p-menth-1,5-
dien-9-ol 3,5-dinitrobenzoate by chromatography.

S. Serra, I. Nobile / Tetrahedron: Asymmetry 22 (2011) 1455–1463
1457
O
iii, iv
59%
i, ii
4 : 6
H
H
H
H
H
H
OH
OH
(S)-5
(S)-6
(-)-4a
(-)-4b
O
i, ii
iii, iv
55%
6 : 4
H
H
H
H
H
H
OH
OH
(R)-6
(+)-4b
(+)-4a
(R)-5
Scheme 1. Synthesis of the p-menth-1,5-dien-9-ol stereoisomers from carvone enantiomers. Reagents and conditions: (i) TsNHNH2, MeOH, HCl cat.; (ii) BuLi, Et2O ꢀ60 °C
then rt; (iii) disiamylborane, THF, 0 °C then rt; (iv) NaOH/H2O then H2O2.
submitted again to the PPL-mediated acetylation until the reaction
reached about 60% conversion. Analysis of the obtained acetate
crystallised from hexane with a concurrent increase in purity. With
these results in hand, we repeated the PPL-mediated separation
protocol starting from a 6:4 mixture of alcohols (+)-4b and (+)-
4a. In this case, with the major (8S)-diastereoisomer, the first acet-
ylation reaction was stopped at the 75% conversion whereas the
second one was interrupted when it reached 60% conversion. The
obtained acetate (+)-5b and alcohol (+)-4a were converted into
their corresponding 3,5-dinitrobenzoyl esters (+)-6b and (+)-6a
whose crystallisations confirmed a further increase in purity.
(ꢀ)-5a showed
a very good diastereoisomeric purity. Both
p-menth-1,5-dien-9-ol isomers were obtained, thus confirming
the overall efficiency of the enzymatic process. In addition, both
the chemical and diastereoisomeric purity of the latter chiral
synthons, as well as their chemical stability, could be increased.
The diastereoenriched alcohols were converted into the corre-
sponding 3,5-dinitrobenzoyl esters (ꢀ)-6a and (ꢀ)-6b which were
2.2. Acid-mediated cyclisation of the p-menth-1,5-dien-9-ol
stereoisomers, synthesis of the dill ether
ii, iii, iv
22%
In accordance with our first aim, we exploited the obtained
chiral building blocks for the synthesis of natural p-menthane
monoterpenes. First, we tested the reactivity of the 1,5-dienic sys-
tem towards the intramolecular addition of the alcohol functional
group. A relevant finding was that either Brønsted acids or Lewis
acids efficiently catalysed the cyclisation of the p-menth-1,
5-dien-9-ol isomers to give the corresponding 3,9-epoxy-p-
menth-1-ene ethers. Moreover, the reaction proceeded with
complete diastereoselectivity and the formation of the new C–O
bond gives rise only to the bicyclic ethers with a cis-configuration
at the 3,4-positions of the p-menthane framework. The experi-
ments, carried out using isomerically pure starting alcohols, affor-
ded the corresponding ethers as a single isomer, thus confirming
H
H
H
H
ii, i
OR
OR
OAc
c=60%
(-)-5a
(-)-6a
i
(-)-4a/(-)-4b
(4 : 6)
c=55%
iii, iv
(-)-4b
34%
H
(-)-6b
H
c = conversion
R = 3,5-dinitrobenzoyl
ii, iii, iv
32%
i
i
(+)-7
ii, i
(-)-8
H
c=60%
H
H
H
80%
74%
OAc
OR
OR
O
O
H
H
H
H
OH
OH
i
(+)-5b
(+)-6b
(+)-4b/(+)-4a
(6 : 4)
(-)-4b
(-)-4a
c=75%
dill ether
epi-dill ether
iii, iv
18%
(+)-4a
i
i
(-)-7
(+)-8
H
H
75%
79%
O
O
H
H
H
H
(+)-6a
OH
OH
(+)-4b
(+)-4a
Scheme 2. Lipase-mediated resolution of the p-menth-1,5-dien-9-ol stereoisomers.
Reagents and conditions: (i) PPL, vinyl acetate, t-BuOMe then chromatography; (ii)
NaOH, MeOH, rt; (iii) 3,5-dinitrobenzoyl chloride, Py, CH2Cl2, rt; (iv) crystallisation
from hexane.
Scheme 3. Acid-catalysed cyclisation of the p-menth-1,5-dien-9-ol stereoisomers.
Reagents and conditions: (i) BF3ꢁOEt2, Et2O, rt.

1458
S. Serra, I. Nobile / Tetrahedron: Asymmetry 22 (2011) 1455–1463
that the pre-existing stereocentres were left unaffected under the
cyclisation conditions (Scheme 3).
deed, the C(1) double bond could be transformed with the intro-
duction of at least one more stereocentre. We focused our
attention on the hydrogenation reaction, since the saturated ethers
obtained by this means have been used11 as starting materials in
the synthesis of p-menthane lactone isomers, which are of interest
in the fields of flavour and fragrance.
The hydrogenation has been roughly investigated in some pre-
vious work,10d,11 which indicate that high diastereoselectivity can
be obtained when PtO2 is employed as catalyst. The use of further
catalysts was not examined leaving the study of this transforma-
tion incomplete. Therefore, we performed the hydrogenation reac-
tion selecting different catalysts and using either dill or epi-dill
isomers as substrates (Table 2 and Scheme 4).
Accordingly, alcohols (ꢀ)- and (+)-4b were treated with
BF3ꢁOEt2 in diethyl ether to give (+)- and (ꢀ)-dill ether 7, respec-
tively. Using the same experimental conditions, the alcohols (ꢀ)-
and (+)-4a afforded (ꢀ)- and (+)-epi-dill ether 8, respectively. We
chose BF3ꢁOEt2 as the catalyst since it gave better results in terms
of higher yields and lower amounts of side products. Other acids
did efficiently catalyse the cyclisation (Table 1).
Table 1
Results of the acids-mediated cyclisation of the p-menth-1,5-dien-9-ol
Acid
Reaction conditionsa
Yieldsb (%)
As previously described, PtO2 in ethanol diastereoselectively
catalyses the reduction of either (+)-7 or (ꢀ)-8 to give the corre-
sponding (1R)-derivatives as the main products. The distereoselec-
tivity was good, especially for the hydrogenation of the epi-dill
ether. It is noteworthy, that when using PtO2, we obtained a signif-
icant amount of p-menthan-9-ol isomers, likely formed through
the C(3)–O hydrogenolysis process. In addition, a minor amount
of the 3,9-epoxy-p-menthane isomers, conceivably derived by the
metal-catalysed epimerization at C(8), was detected in the reaction
mixtures. Therefore we tried the hydrogenation using rhodium-
based catalysts, which do not usually give hydrogenolysis. As ex-
pected, both Rh/Al2O3 and (Ph3P)3RhCl gave only trace amounts
of the p-menthan-9-ol and afforded the saturated ethers with
low diastereoselectivity.
Moreover, Rh/Al2O3 gave a considerable quantity of isomerisa-
tion-derived compounds whereas the Wilkinson’s catalyst left a
large part of the starting ethers unreacted even after a long reac-
tion time. Worse results were obtained when using palladium on
activated charcoal, which showed a lower selectivity but a high
activity towards the epimerization and hydrogenolysis reactions.
A breakthrough was achieved by mean of Raney Ni. The latter me-
tal showed an opposite diastereoselectivity to that of all the previ-
ously studied catalysts affording (1S) derivatives with very high
selectivity. In addition, the latter reaction did not give hydrogenol-
ysis products and the unwanted isomers were formed in very small
amounts. These results demonstrate that it is possible to prepare
all four isomers 9–12 by using different catalysts. Accordingly, dill
ether and epi-dill were hydrogenated using either PtO2 or Raney-Ni
as catalyst to afford ether (+)-9 or (ꢀ)-10, and ether (ꢀ)-11 or (ꢀ)-
12, respectively (Scheme 4).
HCl aq (37%) 2 equiv
HCl aq (37%) 0.2 equiv
H2SO4 (96%), 1.1 equiv
BF3ꢁOEt2 1.1 equiv
SnCl4 1.1 equiv
Et2O, 17 h
Et2O, 24 h
Et2O, 5 h
Et2O, 15 h
CH2Cl2, 13 h
53
47
81
80
16
a
(ꢀ)-4b was used as the starting alcohol for all the entries.
Yield of (+)-7 after purification and bulb to bulb distillation
b
We observed that concentrated HCl aq converted alcohol 4b
into ether 7 in about 50% yield, using either a catalytic amount of
acid or an excess. Since increasing of the acid catalyst reduced
the reaction time, we settled on the use of a stoichiometric
amount. Accordingly, concentrated sulfuric acid afforded the bicy-
clic ether with the highest yield (81%) and the shortest reaction
time. As described above, Lewis acids are effective catalysts for
the latter cyclisation and both BF3ꢁOEt2 and SnCl4 transformed
alcohol 4b although with very different yields. It is noteworthy
that the relative amount of the side products changed significantly
upon which acid was used. Concentrated sulfuric acid and SnCl4
did not leave unreacted alcohol and afforded a number of degrada-
tion/polymerization products. Otherwise, concentrated HCl and
BF3ꢁOEt2 gave the dill ether and the starting alcohol together with
a minor extent of side products.
Overall, these results represent a new synthetic pathway to dill
ether stereoisomers. Indeed the previously reported enantiospeci-
fic preparations10 of this relevant flavour were performed using a
completely different approach which was based on the cyclisation
of different p-menth-1-en-diols instead of the ring closure trig-
gered by acid activation of the 1,5-dienic system.
The saturated derivatives obtained were further purified by
chromatography in order to increase their diastereoisomeric purity
and make them suitable as starting materials in the next step. For
the sake of completeness, the above described reactions were
2.3. Stereoselective hydrogenation of the dill and epi-dill ethers
Having an effective method for the synthesis of the dill ether
isomers, we turned our attention to their further exploitation. In-
Table 2
Results of the hydrogenation of the dill and epi-dill ethers
3,9-Epoxy-p-menth-1-ene
Catalyst
Conditiona
3,9-Epoxy-p-menthaneb (%)
Unreactedb (%)
p-Menthan- 9-olb,c (%)
(1R,3R,4R,8R)
(+)-9
(1S,3R,4R,8R)
(ꢀ)-10
(1R,3R,4R,8S)
(ꢀ)-11
(1S,3R,4R,8S)
(ꢀ)-12
(3S,4R,8R) (+)-7
PtO2
Rh/Al2O3
Pd/C
(Ph3P)3RhCl
Raney Ni
PtO2
Rh/Al2O3
Pd/C
EtOH, 2 h
EtOH, 2 h
AcOEt, 1 h
EtOH, 48 h
EtOH, 2 h
EtOH, 2 h
EtOH, 2 h
AcOEt, 1 h
EtOH, 48 h
EtOH, 2 h
68
53
36
31
5
2
—
2
10
22
16
10
95
—
17
8
—
—
—
1
—
—
79
67
35
17
7
7
24
35
1
—
4
15
15
4
—
—
—
58
—
—
—
—
78
—
15
1
12
—
—
15
1
40
—
—
(3S,4R,8S) (ꢀ)-8
(Ph3P)3RhCl
Raney Ni
1
—
4
89
a
b
c
The hydrogenation was performed at rt, using H2 at atmospheric pressure.
Yield determined by GC analysis.
As a mixture of isomers.

S. Serra, I. Nobile / Tetrahedron: Asymmetry 22 (2011) 1455–1463
1459
dill ether
epi-dill ether
(+)-7
(-)-8
O
O
i
ii
90%
i
ii
63%
70%
78%
(+)-9
(-)-11
(-)-12
(-)-10
O
O
O
O
Scheme 4. Stereoselective hydrogenation of the dill and epi-dill ethers. Reagents and conditions: (i) PtO2, EtOH, H2/atmospheric pressure, rt; (ii) Raney Ni, EtOH,
H2/atmospheric pressure, rt.
(+)-9
(-)-10
(-)-11
(-)-12
O
O
O
O
i
70%
i
67%
i
58%
i
60%
(+)-13
14a
15a
16a
O
O
O
O
H
H
H
H
COOR
H
H
COOR
COOR
O
ii
ii
ii
a) R=H
b) R=Me
(+)-14b
(+)-15b
(+)-16b
Scheme 5. Oxidation of the 3,9-epoxy-p-menthane isomers 9–12. Reagents and conditions: (i) RuCl3ꢁnH2O cat., CCl4/CH3CN, NaIO4/H2O rt; (ii) CH2N2, Et2O, 0 °C.
repeated starting from (ꢀ)-dill ether and (+)-epi dill ether with al-
13 in good yields. The other diastereoisomers were transformed in
the corresponding keto-acids 14a–16a while only trace amounts of
lactones were detected. In order to control this over-oxidation pro-
cess, we stopped the reactions at early stage but we again obtained
the keto-acids close to the unreacted ethers. Concerning the struc-
ture assignment of 14a–16a, it should be noted that the enantio-
mers of the latter compounds were previously obtained by
photo-oxidation of natural menthofurane.13 Isomer 14a is a crys-
talline compound and its melting point matched that reported14
for the corresponding enantiomer. In addition, the NMR analyses
of the three acids 14a–16a were in rough agreement with those de-
scribed. In spite of these first confirmations the given analytical
characterizations are not adequate enough to unambiguously con-
firm the chemical structures of the aforementioned compounds.
Both the CG and the NMR analyses of the keto acids showed very
broad signals, thus making the purity determination and the struc-
ture assignation difficult. This effect was due to the concurrent
presence of the open keto-acid form and of the bicyclic lactol form,
conceivably existing in a tautomeric equilibrium in solution.
Therefore, we blocked the compounds 14a–16a in their open form
by converting them into the corresponding keto esters by a diazo-
methane treatment. The analytical data of the obtained com-
pounds (+)-14b, (+)-15b and (+)-16b were in good agreement
most identical results.
2.4. Regioselective oxidation of the 3,9-epoxy-p-menthane
stereoisomers
As aforementioned, racemic ethers 9 and 11 were oxidised11 by
RuO4 to give the corresponding lactones, which were further trans-
formed in the mint flavour mintlactone. More recently,6 the stereo-
isomers of the p-menthan-9-oic lactones were comprehensively
studied in order to achieve their olfactory evaluation. Indeed these
compounds turned out to be relevant odourants of potential indus-
trial applications giving a distinctive coumarinic odour note. In
addition, lactone 13 and its C(9) epimer can be found in the essen-
tial oil of Mentha suaveolens5a and are therefore regarded as natu-
ral, although their absolute configurations are still unassigned.
Having both enantiomeric forms of ethers 9–12 in hand, we as-
sessed their oxidation. We submitted ethers (+)-9, (ꢀ)-10, (ꢀ)-11
and (ꢀ)-12 to the RuO4 mediated oxidation process (Scheme 5).
The reactions were performed using a catalytic amount of RuCl3
and a large excess of NaIO4 as oxidant, while a mixture of CCl4 and
CH3CN12 was used as solvent in order to increase the efficiency of
the oxidation. Only ether (+)-9 gave the corresponding lactone (+)-

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S. Serra, I. Nobile / Tetrahedron: Asymmetry 22 (2011) 1455–1463
with the given structures and showed that the oxidation of the
ethers (ꢀ)-10 and (ꢀ)-12 proceeded with complete stereocontrol
to give diastereoisomerically pure (+)-14b and (+)-16b. Conversely,
ether (ꢀ)-11 gave keto derivative (+)-15b impure with (ꢀ)-14b (a
4:1 ratio), clearly demonstrating a partial epimerization at C(4). All
the above described experiments were then repeated starting from
ether (ꢀ)-9, (+)-10, (+)-11 and (+)-12 with comparable results (see
Section 4).
kept at 0 °C for 1 h and then was left to reach room temperature
and stirred for another 2 h. The mixture was then quenched by
addition to crushed ice (1 Kg). The organic layer was separated
and the aqueous phase was extracted with ether (100 mL). The
combined organic phases were washed with water (100 mL) and
brine (100 mL) and dried (Na2SO4). The solvent was removed under
reduced pressure and the residue was used immediately in the
next step. The triene obtained as above was dissolved in dry THF
(100 mL) and then treated at 0 °C under nitrogen with a freshly
prepared solution of disiamylborane (78 mL of 1.2 M solution in
THF). When the addition was complete, the resulting clear solution
was stirred at rt overnight after which sodium hydroxide (80 mL of
an aqueous 4 M solution) was added slowly. The resulting mixture
was treated with an excess of hydrogen peroxide (35% solution in
water, 60 mL, 698 mmol). The reaction was very exothermic and so
the oxidant was added dropwise while keeping the reaction tem-
perature below 30 °C by external cooling (ice bath). When the
addition was complete, the reaction mixture was stirred for a fur-
ther 4 h, then was diluted with water (250 mL) and extracted with
Et2O (3 ꢂ 100 mL). The organic phase was sequentially washed
with 5% aq Na2S2O5 (100 mL) and brine, dried (Na2SO4) and con-
centrated under reduced pressure. The residue was purified by
chromatography eluting with hexane/ether (9:1–3:1) as eluent to
afford pure (4S)-p-menth-1,5-dien-9-ol (8.45 g, yield 59%) as a
4:6 mixture of the (4S,8S)- and (4S,8R)-isomers, respectively (by
NMR analysis).
3. Conclusion
The present study highlights the usefulness of the p-menth-1,
5-dien-9-ol stereoisomers as chiral building blocks in terpene syn-
thesis. Different outcomes were achieved. First, we have developed
a
chemo-enzymatic procedure based on the lipase-mediated
acetylation, which allows the separation of the diastereoisomeric
p-menth-1,5-dien-9-ol isomers. The latter alcohols were in turn
prepared in high enantiomeric purity from the easily available
carvone enantiomers. Moreover, the purity of the chiral building
blocks obtained was improved by fractional crystallisation of their
stable 3,5-dinitrobenzoyl derivatives. As a first synthetic applica-
tion, we have described the acid-mediated cyclisation of the iso-
merically pure dienic alcohols to give the isomeric forms of the
terpenes dill and epi-dill ether. With the aim of preparing odour
active compounds, we hydrogenated the latter ethers and found
two diastereoselective pathways to the 3,9-epoxy-p-menthane iso-
mers. The regioselective oxidation of the saturated ethers afforded
either the enantiomeric forms of the natural lactone 13 or the keto-
acids 14a–16a, depending on the substrate used. Further studies
with the purpose of using p-menth-1,5-dien-9-ol stereoisomers
as chiral building blocks in terpenes and sesquiterpenes synthesis
are currently ongoing and will be reported in due course.
The above procedure was repeated starting from (R)-carvone
tosylhydrazone (30.1 g, 94.6 mmol) to give pure (4R)-p-menth-
1,5-dien-9-ol (7.9 g, 55% yield) as a 6:4 mixture of the (4R,8S)-
and (4R,8R)-isomers, respectively (by NMR analysis).
4.3. General procedure for lipase-mediated acetylation
A solution of p-menth-1,5-dien-9-ol (70 mmol), PPL (8 g), vinyl
acetate (20 mL) and t-BuOMe (80 mL) was stirred at rt and the for-
mation of the acetylated compounds was monitored by TLC analy-
sis. The reaction was stopped at the reported conversion (see
below) by filtration of the enzyme and evaporation of the solvent
at reduced pressure. The residue was then purified by chromatog-
raphy using hexane–diethyl ether (95:5–3:1) as eluent.
4. Experimental
4.1. General
All moisture-sensitive reactions were carried out under a static
atmosphere of nitrogen. All reagents were of commercial quality.
(S)-Carvone (95% ee) and (R)-carvone (98% ee) were purchased
from Fluka and from Aldrich, respectively. Lipase from Porcine
pancreas (PPL) type II, Sigma, 147 units/mg was employed in this
work. TLC: Merk Silica Gel 60 F254 plates. Column chromatography
(CC): silica gel. GC–MS analyses: HP-6890 gas chromatograph
equipped with a 5973 mass detector, using an HP-5MS column
The above general procedure was used in the acetylation of the
4:6 mixture of the (4S,8S)- and (4S,8R)-p-menth-1,5-dien-9-ol iso-
mers, respectively (10.2 g, 67 mmol). The reaction was stopped at
about 55% conversion and the unreacted alcohol (ꢀ)-4b was trea-
ted with pyridine (30 mL) and a solution of 3,5-dinitrobenzoylchlo-
ride (7.6 g, 33 mmol) in CH2Cl2 (40 mL). After complete conversion
of the starting alcohol, the mixture was diluted with water
(300 mL) and extracted with CH2Cl2 (2 ꢂ 200 mL). The combined
organic phases were washed with aq NaHCO3 (5% solution), brine
and then dried (Na2SO4). Concentration at reduced pressure gave
an oil which was purified by chromatography (hexane/Et2O 9:1)
and crystallized twice from hexane to give pure (4S,8R)-p-menth-
1,5-dien-9-ol 3,5-dinitrobenzoate (ꢀ)-6b (7.8 g, 22.5 mmol, 34%
(30 m ꢂ 0.25 mm, 0.25
lm film thickness; Hewlett Packard) with
the following temp programme: 60° (1 min)ꢀ6°/minꢀ150°
(1 min)ꢀ12°/minꢀ280° (5 min); carrier gas, He; constant flow
1 ml/min; split ratio, 1/30; tR given in min: tR(4a) 13.20, tR(4b)
13.27, tR(5a) 15.93, tR(5b) 15.98, tR(6a) 29.31, tR(6b) 29.36, tR(7)
11.24, tR(8) 12.30, tR(9) 10.69, tR(10) 9.86, tR(11) 10.90, tR(12)
10.47, tR(13) 16.52, tR(14b) 17.00, tR(15b) 16.74, tR(16b) 16.50.
Optical rotations: Jasco-DIP-181 digital polarimeter. 1H and 13C
Spectra: CDCl3 solutions at rt; Bruker-AC-400 spectrometer at
400 and 100 MHz, respectively; chemical shifts in ppm rel to
internal SiMe4 (=0 ppm), J values in Hz. Melting points were
measured on a Reichert apparatus, equipped with a Reichert
microscope, and are uncorrected.
yield); mp 68–69 °C, ½a D20
¼ ꢀ104:5 (c 2.1, CHCl3), 99% chemical
ꢃ
purity by GC, 97% diastereoisomeric purity. 1H NMR (400 MHz,
CDCl3) d 1.07 (d, J = 6.9 Hz, 3H), 1.73 (m, 3H), 2.09-2.29 (m, 3H),
2.35–2.46 (m, 1H), 4.33 (dd, J = 7.0, 11.0 Hz, 1H), 4.47 (dd, J = 5.9,
11.0 Hz, 1H), 5.44–5.51 (m, 1H), 5.73 (dd, J = 3.7, 9.7 Hz, 1H), 5.88
(dt, J = 9.7, 1.8 Hz, 1H), 9.14 (br d, J = 2.1 Hz, 2H), 9.22 (br t,
J = 2.1 Hz, 1H). 13C NMR (100 MHz) d 14.6, 20.9, 25.1, 35.1, 36.0,
69.7, 119.8, 122.2, 128.3, 129.0, 129.3, 131.3, 134.0, 148.7, 162.5.
GC–MS m/z (rel intensity) 346 (M+, 2), 281 (1), 207 (2), 195 (11),
149 (12), 132 (100), 119 (71), 105 (20), 93 (41), 77 (15), 65 (4).
The acetate was then dissolved in methanol (10 mL) and treated
with NaOH (5 g, 125 mmol) in methanol (20 mL) with stirring at rt
until no more starting material was detected by TLC analysis. The
4.2. Preparation of p-menth-1,5-dien-9-ol isomers
At first, BuLi (28.3 mL of a 10 M solution in hexane) was added
dropwise under nitrogen to a stirred and cooled (–60 °C) suspen-
sion of (S)-carvone tosylhydrazone (30 g, 94.3 mmol) in dry diethyl
ether (300 mL). After the addition was complete, the reaction was

S. Serra, I. Nobile / Tetrahedron: Asymmetry 22 (2011) 1455–1463
1461
mixture was diluted with water (80 mL) and extracted with diethyl
ether (3 ꢂ 80 mL). The organic phase was washed with brine, dried
(Na2SO4) and concentrated in vacuo. The residue was submitted
again to the lipase-mediated acetylation and the reaction was
stopped at 60% conversion. The obtained (4S,8S)-p-menth-1,5-
1H NMR (400 MHz, CDCl3) d 0.96 (d, J = 7.0 Hz, 3H), 1.49 (br s,
1H), 1.65–1.81 (m, 1H), 1.72 (m, 3H), 1.99–2.21 (m, 2H), 2.31–
2.42 (m, 1H), 3.48 (dd, J = 6.6, 10.8 Hz, 1H), 3.64 (dd, J = 6.0,
10.8 Hz, 1H), 5.43–5.49 (m, 1H), 5.71 (dd, J = 3.6, 9.8 Hz, 1H), 5.82
(dt, J = 9.8, 1.8 Hz, 1H). 13C NMR (100 MHz) d 14.1, 21.0, 26.2,
35.2, 39.1, 65.8, 120.3, 128.5, 128.8, 131.3. GC–MS m/z (rel inten-
sity) 152 (M+, 10), 137 (36), 119 (35), 105 (25), 93 (97), 91 (100),
77 (50), 65 (11), 40 (34).
dien-9-ol acetate (ꢀ)-5a (4.1 g, 21.1 mmol) showed
½
a 2D0
ꢃ
¼
ꢀ129:3 (c 2, CHCl3), 91% chemical purity by GC, 91% diastereoiso-
meric purity. 1H NMR (400 MHz, CDCl3) d 0.96 (d, J = 6.9 Hz, 3H),
1.71 (m, 3H), 1.80–1.92 (m, 1H), 1.98–2.21 (m, 2H), 2.04 (s, 3H),
2.28–2.39 (m, 1H), 3.92 (dd, J = 7.0, 10.9 Hz, 1H), 4.07 (dd, J = 6.0,
10.9 Hz, 1H), 5.42–5.48 (m, 1H), 5.69 (dd, J = 9.7, 3.6 Hz, 1H), 5.82
(dt, J = 9.7, 1.8 Hz, 1H). 13C NMR (100 MHz) d14.2, 20.8, 20.9,
26.2, 35.2, 35.8, 67.1, 120.1, 128.0, 128.7, 131.2, 171.0. GC-MS m/
z (rel intensity) 194 (M+, 1), 134 (59), 119 (51), 105 (44), 92
(100), 77 (30), 61 (8), 43 (25).
(4S,8R)-p-Menth-1,5-dien-9-ol (ꢀ)-4b;
½
a 2D0
ꢃ
¼ ꢀ213:9 (c 2,
CHCl3), 99% chemical purity by GC, 97% diastereoisomeric purity.
1H NMR (400 MHz, CDCl3)d 0.93 (d, J = 6.9 Hz, 3H), 1.38 (br s,
1H), 1.71 (m, 3H), 1.73–1.83 (m, 1H), 2.00–2.20 (m, 2H), 2.30–
2.41 (m, 1H), 3.50 (dd, J = 6.4, 10.8 Hz, 1H), 3.61 (dd, J = 6.1,
10.8 Hz, 1H), 5.42–5.47 (m, 1H), 5.70 (dd, J = 3.7, 9.7 Hz, 1H), 5.81
(dt, J = 9.7, 1.8 Hz, 1H). 13C NMR (100 MHz) d 14.1, 21.0, 25.1,
34.9, 39.4, 66.0, 120.1, 128.4, 129.7, 131.2. GC–MS m/z (rel inten-
sity) 152 (M+, 12), 137 (35), 119 (19), 109 (10), 105 (23), 93
(100), 91 (93), 77 (50), 65 (11), 39 (10).
The above acetate was hydrolysed with NaOH in methanol.
After work-up, the crude alcohol was converted into the corre-
sponding 3,5-dinitrobenzoate ester and crystallized twice from
hexane to give (4S,8S)-p-menth-1,5-dien-9-ol 3,5-dinitrobenzoate
(4R,8R)-p-Menth-1,5-dien-9-ol (+)-4a; ½a D20
¼ þ218:4 (c 1, CHCl3),
ꢃ
(ꢀ)-6a (5.2 g, 22% yield), mp 67–68 °C, ½a D20
ꢃ
¼ ꢀ97:1 (c 2, CHCl3),
99%chemical purityby GC, 96% diastereoisomeric purity. 1H NMR, 13
C
99% chemical purity by GC, 96% diastereoisomeric purity. 1H
NMR (400 MHz, CDCl3) d 1.09 (d, J = 6.9 Hz, 3H), 1.73 (m, 3H),
2.06–2.18 (m, 2H), 2.18-2.29 (m, 1H), 2.36–2.47 (m, 1H), 4.33
(dd, J = 7.1, 11.0 Hz, 1H), 4.45 (dd, J = 6.0, 11.0 Hz, 1H), 5.45–5.52
(m, 1H), 5.75 (dd, J = 3.7, 9.7 Hz, 1H), 5.88 (dt, J = 9.7, 1.8 Hz, 1H),
9.14 (br d, J = 2.1 Hz, 2H), 9.22 (br t, J = 2.1 Hz, 1H). 13C NMR
(100 MHz) d 14.6, 21.0, 25.8, 35.6, 36.0, 69.5, 120.0, 122.3, 127.9,
129.1, 129.3, 131.4, 134.1, 148.7, 162.5. GC–MS m/z (rel intensity)
346 (M+, 3), 281 (6), 207 (12), 195 (11), 149 (13), 134 (76), 119
(69), 105 (35), 93 (100), 91 (66), 77 (34), 65 (7).
NMR, MS spectra were in accordance with those of (ꢀ)-4a.
(4R,8S)-p-Menth-1,5-dien-9-ol (+)-4b; ½a D20
¼ þ229:3 (c 2, CHCl3),
ꢃ
99%chemical purityby GC, 99% diastereoisomeric purity. 1H NMR, 13
C
NMR, MS spectra were in accordance with those of (ꢀ)-4b.
4.4. General procedure for the cyclisation of p-menth-1,5-dien-
9-ol isomers
A suitable acid catalyst (see Table 1) was added dropwise to a
solution of the p-menth-1,5-dien-9-ol isomer (6 mmol) in dry
ether (40 mL). After stirring at rt for 5–24 h (see Table 1), the mix-
ture was quenched by the addition of aq NaHCO3 (5% solution,
100 mL) and extracted with ether (2 ꢂ 50 mL). The combined or-
ganic phases were washed with brine and then dried (Na2SO4).
Concentration by distillation of the solvent through a vigreux col-
umn gave an oil, which was purified by chromatography eluting
with hexane/ether (95:5–9:1) as eluent to afford pure ether
7 or 8.
The above general procedure used a 6:4 mixture of the (4R,8S)-
and (4R,8R)-p-menth-1,5-dien-9-ol isomers, respectively (9.8 g,
64.5 mmol). The PPL-catalysed acetylation was stopped at about
75% conversion and the unreacted alcohol (+)-4a was converted
into the corresponding 3,5-dinitrobenzoate and crystallized twice
from hexane to give pure (4R,8R)-p-menth-1,5-dien-9-ol 3,5-dini-
trobenzoate (+)-6a (4.1 g, 18% yield), mp 61–62 °C, ½a D20
¼ þ101:7
ꢃ
(c 2, CHCl3), 99% chemical purity by GC, 96% diastereoisomeric pur-
ity, 1H NMR, 13C NMR, MS spectra were in accordance with those of
(ꢀ)-6a.
The cyclisation of alcohol (ꢀ)-4b (BF3ꢁOEt2) afforded (3S,4R,8R)-
3,9-epoxy-p-menth-1-ene (+)-7 (dill ether) in 80% yield;
The acetate was hydrolysed and the resulting alcohol was sub-
mitted again to the lipase-mediated acetylation. The reaction was
stopped at 60% conversion. The obtained (4R,8S)-p-menth-1,5-
½
a 2D0
ꢃ
¼ þ3:3 (c 2, CHCl3), 99% chemical purity by GC, 99% diastereo-
isomeric purity, Lit.10a
½
a 2D0
ꢃ
¼ þ8:1 (c 1, CHCl3). 1H NMR (400 MHz,
CDCl3) d 1.05 (d, J = 6.8 Hz, 3H), 1.45–1.56 (m, 1H), 1.65–1.77 (m,
5H), 1.80–1.97 (m, 2H), 1.97–2.09 (m, 1H), 3.30 (dd, J = 6.9,
8.3 Hz, 1H), 4.06 (dd, J = 7.3, 8.3 Hz, 1H), 4.21–4.27 (m, 1H), 5.50–
5.53 (m, 1H). 13C NMR (100 MHz) d 17.5, 23.6, 24.1, 28.1, 37.9,
43.9, 73.9, 75.0, 121.0, 138.6. GC–MS m/z (rel intensity) 152 (M+,
5), 151 (6), 138 (11), 137 (100), 124 (6), 109 (33), 107 (5), 95
(12), 93 (14), 91 (16), 79 (15), 69 (24), 55 (9), 41 (10).
dien-9-ol acetate (+)-5b (5.3 g, 27.3 mmol) showed
½
a 2D0
ꢃ
¼
þ169:0 (c 1.7, CHCl3), 91% chemical purity by GC, 95% diastereoiso-
meric purity. 1H NMR (400 MHz, CDCl3) d 0.93 (d, J = 6.9 Hz, 3H),
1.71 (m, 3H), 1.89–1.98 (m, 1H), 2.02–2.17 (m, 2H), 2.04 (s, 3H),
2.27–2.39 (m, 1H), 3.94 (dd, J = 7.0, 10.9 Hz, 1H), 4.05 (dd, J = 6.0,
10.9 Hz, 1H), 5.41–5.47 (m, 1H), 5.65 (dd, J = 9.7, 3.6 Hz, 1H), 5.81
(dt, J = 9.7, 1.8 Hz, 1H). 13C NMR (100 MHz) d 14.2, 20.9, 20.9,
24.7, 35.0, 35.9, 67.3, 120.0, 128.6, 129.2, 131.2, 171.1. GC–MS m/
z (rel intensity) 194 (M+, <1), 134 (52), 119 (31), 105 (41), 92
(100), 77 (30), 61 (7), 43 (22).
The cyclisation of alcohol (ꢀ)-4a (BF3ꢁOEt2) afforded (3S,4R,8S)-
3,9-epoxy-p-menth-1-ene (ꢀ)-8 (epi-dill ether) in 74% yield;
½
a 2D0
ꢃ
¼ ꢀ129:3 (c 2, CHCl3), 99% chemical purity by GC, 96% diaste-
reoisomeric purity, Lit.10a
½
a 2D0
ꢃ
¼ ꢀ133:4 (c 1, CHCl3). 1H NMR
The above acetate was hydrolysed with NaOH in methanol.
After work-up, the crude alcohol was converted into the corre-
sponding 3,5-dinitrobenzoate ester and crystallized from hexane
to give (4R,8S)-p-menth-1,5-dien-9-ol 3,5-dinitrobenzoate (+)-6b
(400 MHz, CDCl3) dd 1.00 (d, J = 6.9 Hz, 3H), 1.20–1.33 (m, 1H),
1.58 (dm, J = 12.8 Hz, 1H), 1.73 (s, 3H), 1.85–2.03 (m, 3H), 2.49–
2.63 (m, 1H), 3.45 (dd, J = 7.9, 9.8 Hz, 1H), 3.93 (dd, J = 7.9, 8.1 Hz,
1H), 4.15–4.19 (m, 1H), 5.58–5.62 (m, 1H). 13C NMR (100 MHz) d
11.6, 19.1, 23.5, 29.7, 37.0, 40.1, 72.3, 76.1, 120.2, 140.0. GC–MS
m/z (rel intensity) 152 (M+, 4), 151 (4), 138 (9), 137 (100), 124
(4), 109 (26), 107 (6), 95 (10), 93 (14), 91 (15), 79 (14), 69 (21),
55 (8), 41 (10).
(7.1 g, 32% yield), mp 68–69 °C, ½a D20
¼ þ103:5 (c 2, CHCl3), 99%
ꢃ
chemical purity by GC, 99% diastereoisomeric purity, 1H NMR,
13C NMR, MS spectra were in accordance with those of (ꢀ)-6b.
The hydrolysis of dinitrobenzoates 6a and 6b was performed
with NaOH in methanol as described for the hydrolysis of acetates
5a and 5b. Accordingly, the reaction was almost quantitative and
the following alcohols were obtained:
The cyclisation of alcohol (+)-4b (BF3ꢁOEt2) afforded (3R,4S,8S)-
3,9-epoxy-p-menth-1-ene (ꢀ)-7 in 75% yield; ½a D20
¼ ꢀ3:4 (c 2,
ꢃ
CHCl3), 99% chemical purity by GC, 98% diastereoisomeric purity,
(4S,8S)-p-Menth-1,5-dien-9-ol (ꢀ)-4a;
½
a 2D0
ꢃ
¼ ꢀ209:1 (c 2,
Lit.10a
½
a 2D0
ꢃ
¼ ꢀ7:3 (c 1, CHCl3), 1H NMR, 13C NMR, MS spectra were
CHCl3), 99% chemical purity by GC, 96% diastereoisomeric purity.
in accordance with those of (+)-7.

1462
S. Serra, I. Nobile / Tetrahedron: Asymmetry 22 (2011) 1455–1463
The cyclisation of alcohol (+)-4a (BF3ꢁOEt2) afforded (3R,4S,8R)-
Hydrogenation of ether (ꢀ)-7 with PtO2 as catalyst gave
3,9-epoxy-p-menth-1-ene (+)-8 in 79% yield; ½a D20
ꢃ
¼ þ143:0 (c 2,
(1S,3S,4S,8S)-3,9-epoxy-p-menthane (ꢀ)-9 in 65% yield; ½a D20
¼
ꢃ
CHCl3), 99% chemical purity by GC, 99% diastereoisomeric purity,
ꢀ89:1 (c 2, CHCl3), 98% chemical purity by GC, 97% diastereoiso-
meric purity, 1H NMR, 13C NMR, MS spectra were in accordance
with those of (+)-9.
Lit.10a
½
a 2D0
ꢃ
¼ þ127:9 (c 1, CHCl3), 1H NMR, 13C NMR, MS spectra
were in accordance with those of (ꢀ)-8.
Hydrogenation of ether (ꢀ)-7 with Ni-Raney as catalyst gave
4.5. General procedure for the hydrogenation of the dill/epi-dill
ether isomers
(1R,3S,4S,8S)-3,9-epoxy-p-menthane (+)-10 in 86% yield;
½
a 2D0
ꢃ
¼ þ17:1 (c 2, CHCl3), 99% chemical purity by GC, 98% diaste-
reoisomeric purity, 1H NMR, 13C NMR, MS spectra were in accor-
dance with those of (ꢀ)-10.
A solution of the unsaturated ether (6 mmol) in absolute
ethanol (30 mL) was treated with the appropriate catalyst (see
Table 2) and was hydrogenated at rt and at atmospheric pressure.
After consumption of the stoichiometric amount of hydrogen, the
catalyst was removed by filtration and the solution was diluted
with water (150 mL). The mixture was extracted with ether
(2 ꢂ 70 mL) and the combined organic phases were washed with
brine and dried (Na2SO4). The solvent was distilled off through a
vigreux column and the residue was purified by chromatography
eluting with hexane/ether (95:5–9:1) as eluent to afford the 3,9-
epoxy-p-menthane isomer.
Hydrogenation of ether (+)-8 with PtO2 as catalyst gave
(1S,3S,4S,8R)-3,9-epoxy-p-menthane (+)-11 in 70% yield;
½
a 2D0
ꢃ
¼ þ52:2 (c 2, CHCl3), 99% chemical purity by GC, 96% diaste-
reoisomeric purity, 1H NMR, 13C NMR, MS spectra were in accor-
dance with those of (ꢀ)-11.
Hydrogenation of ether (+)-8 with Raney-Ni as catalyst gave
(1R,3S,4S,8R)-3,9-epoxy-p-menthane (+)-12 in 80% yield, ½a D20
¼
ꢃ
þ47:6 (c 2, CHCl3), 99% chemical purity by GC, 95% diastereoiso-
meric purity, 1H NMR, 13C NMR, MS spectra were in accordance
with those of (ꢀ)-12.
Hydrogenation of ether (+)-7 with PtO2 as catalyst gave
(1R,3R,4R,8R)-3,9-epoxy-p-menthane (+)-9 in
¼ þ88:5 (c 2, CHCl3), 98% chemical purity by GC, 97%
diastereoisomeric purity, Lit.10d
63% yield;
4.6. General procedure for the oxidation of the ether isomers
9–12
½ ꢃ
a 2D0
½
a 2D0
ꢃ
¼ ꢀ69:5 (for the opposite
enantiomer). 1H NMR (400 MHz, CDCl3) d 0.90 (d, J = 6.6 Hz, 3H),
0.86–1.02 (m, 2H), 0.98 (d, J = 6.5 Hz, 3H), 1.25–1.39 (m, 1H),
1.38–1.47 (m, 1H), 1.55–1.68 (m, 1H), 1.68–1.83 (m, 3H), 2.11–
2.26 (m, 1H), 3.35 (t, J = 8.5 Hz, 1H), 4.04 (dt, J = 6.4, 10.5 Hz, 1H),
4.08 (t, J = 8.3 Hz, 1H). 13C NMR (100 MHz) d 15.9, 22.3, 23.5,
29.5, 29.9, 33.9, 38.4, 44.7, 74.1, 78.7. GC–MS m/z (rel intensity)
154 (M+, 39), 139 (13), 123 (5), 109 (8), 97 (100), 83 (47), 69
(30), 55 (17), 41 (22).
A solution of ether 9–12 (3 mmol) and ruthenium trichloride
hydrate (20 mg) in CCl4/CH3CN (1:1, 20 mL) was treated with a
suspension of NaIO4 (4 g, 18.7 mmol) in water (20 mL). The heter-
ogeneous mixture was stirred vigorously at rt until the starting
ether was no longer detectable by TLC analysis (1–20 h). The reac-
tion was then diluted with water (80 mL) and extracted with
CH2Cl2 (3 ꢂ 50 mL). The combined organic phases were washed
in turn with 5% aq Na2SO3 (80 ml) and brine, dried (Na2SO4) and
concentrated under reduced pressure. The residue was purified
by chromatography eluting with hexane/ether (9:1–3:1) as eluent
to afford compound 13, 14a–16a. Keto acids 14a–16a were further
characterized by analysis of the corresponding methyl ester deriv-
atives 14b–16b. Accordingly, a small sample (100 mg, 0.54 mmol)
of the acids was treated with an excess of diazomethane (2 mL of a
1 M solution in diethyl ether) at 0 °C. The reaction was kept for 1 h
at this temperature. Thus, the solvent was removed in vacuo and
the residue was analysed.
Hydrogenation of ether (+)-7 with Raney-Ni as catalyst gave
(1S,3R,4R,8R)-3,9-epoxy-p-menthane (ꢀ)-10 in 90% yield;
½
a 2D0
ꢃ
¼ ꢀ17:0 (c 2, CHCl3), 99% chemical purity by GC, 99% diaste-
reoisomeric purity, Lit.10d
½
a 2D0
ꢃ
¼ þ11:2 (for the opposite enantio-
mer). 1H NMR (400 MHz, CDCl3) d 0.78–0.89 (m, 1H), 0.87 (d,
J = 6.6 Hz, 3H), 1.02 (d, J = 7.2 Hz, 3H), 1.10–1.23 (m, 2H), 1.47–
1.67 (m, 4H), 1.92–2.05 (m, 2H), 3.33 (dd, J = 3.5, 8.5 Hz, 1H),
3.95–3.99 (m, 1H), 4.14 (dd, J = 7.4, 8.5 Hz, 1H). 13C NMR
(100 MHz) d 19.8, 22.2, 26.5, 28.3, 33.4, 36.8, 39.7, 44.9, 73.9,
75.8. GC–MS m/z (rel intensity) 154 (M+, 23), 139 (15), 121 (8),
109 (9), 97 (100), 83 (43), 69 (31), 55 (18), 41 (24).
Oxidation of ether (+)-9 gave (1R,3R,4R,8R)-3,9-epoxy-p-men-
than-9-one (+)-13 in 70% yield, mp 62 °C (hexane), ½a D20
¼ þ48:7
ꢃ
Hydrogenation of ether (ꢀ)-8 with PtO2 as catalyst gave
(c 1, CHCl3), 99% chemical purity by GC, 99% diastereoisomeric pur-
(1R,3R,4R,8S)-3,9-epoxy-p-menthane (ꢀ)-11 in 70% yield;
ity, Lit.6a
½
a 2D0
ꢃ
¼ þ45:7 (c 0.9, CHCl3), mp 55–56 °C. 1H NMR
½
a 2D0
ꢃ
¼ ꢀ51:9 (c 2, CHCl3), 99% chemical purity by GC, 95% diaste-
(400 MHz, CDCl3) d 0.92–1.07 (m, 2H), 0.96 (d, J = 6.6 Hz, 3H),
1.20 (d, J = 6.9 Hz, 3H), 1.31–1.46 (m, 1H), 1.55 (dm, J = 13.5 Hz,
1H), 1.60–1.72 (m, 1H), 1.85 (dm, J = 14.6 Hz, 1H), 2.04–2.12 (m,
1H), 2.16–2.25 (m, 1H), 2.41–2.52 (m, 1H), 4.48 (dt, J = 11.0,
6.8 Hz, 1H). 13C NMR (100 MHz) d 13.2, 22.0, 24.0, 28.6, 29.4,
35.3, 37.8, 41.7, 77.4, 179.5. GC–MS m/z (rel intensity) 168 (M+,
<1), 139 (2), 124 (6), 109 (26), 95 (44), 81 (100), 67 (47), 55 (23),
41 (23).
reoisomeric purity, Lit.10d
½
a 2D0
ꢃ
¼ þ46:5 (for the opposite enantio-
mer). 1H NMR (400 MHz, CDCl3) d 0.95 (d, J = 7.0 Hz, 3H), 1.01 (d,
J = 7.2 Hz, 3H), 1.29–1.51 (m, 4H), 1.54–1.64 (m, 1H), 1.65–1.79
(m, 2H), 1.82–1.92 (m, 1H), 2.32–2.45 (m, 1H), 3.42 (dd, J = 8.4,
8.9 Hz, 1H), 3.86 (t, J = 8.4 Hz, 1H), 3.96–4.02 (m, 1H). 13C NMR
(100 MHz) d 12.4, 17.1, 20.3, 25.9, 30.0, 34.5, 37.6, 40.8, 72.3,
78.7. GC–MS m/z (rel intensity) 154 (M+, 45), 139 (16), 123 (9),
107 (8), 97 (100), 83 (38), 69 (29), 55 (17), 41 (25).
Oxidation of ether (ꢀ)-10 gave (1S,4R,8R)-3-oxo-p-menthan-9-
oic acid 14a in 67% yield, mp 93–96 °C, lit.14 mp 95 °C (for the
opposite enantiomer); the (1S,4R,8R)-3-oxo-p-menthan-9-oic acid
methyl ester (+)-14b was obtained as a colourless oil showing
Hydrogenation of ether (ꢀ)-8 with Raney Ni as catalyst gave
(1S,3R,4R,8S)-3,9-epoxy-p-menthane (ꢀ)-12 in 78% yield,
½
a 2D0
ꢃ
¼ ꢀ46:4 (c 2, CHCl3), 99% chemical purity by GC, 93% diastereo-
isomeric purity, Lit.10d
½
a 2D0
ꢃ
¼ þ39:2 (for the opposite enantiomer).
the following analytical data: ½a D20
¼ þ21:1 (c 1.7, CHCl3), 99%
ꢃ
1H NMR (400 MHz, CDCl3) d 0.77–0.91 (m, 1H), 0.87 (d, J = 6.6 Hz,
3H), 0.95 (d, J = 6.9 Hz, 3H), 1.07–1.21 (m, 2H), 1.44–1.53 (m, 1H),
1.53–1.62 (m, 1H), 1.62–1.70 (m, 1H), 1.70–1.79 (m, 1H), 1.97 (dm,
J = 14.5 Hz, 1H), 2.37–2.54 (m, 1H), 3.44 (dd, J = 7.9, 10.2 Hz, 1H),
3.92 (dd, J = 7.9, 8.3 Hz, 1H), 3.96–4.01 (m, 1H). 13C NMR
(100 MHz) d 11.6, 22.1, 22.2, 26.7, 33.4, 37.6, 37.8, 41.1, 72.3, 79.3.
GC–MS m/z (rel intensity) 154 (M+, 24), 139 (13), 136 (18), 123
(11), 109 (11), 97 (100), 83 (39), 69 (30), 55 (18), 41 (26).
chemical purity by GC, 99% diastereoisomeric purity. 1H NMR
(400 MHz, CDCl3) d 1.03 (d, J = 6.5 Hz, 3H), 1.12 (d, J = 7.0 Hz, 3H),
1.28–1.48 (m, 2H), 1.74–1.90 (m, 1H), 1.88–1.96 (m, 1H), 2.00–
2.16 (m, 2H), 2.37 (ddd, J = 2.3, 3.9, 13.2 Hz, 1H), 2.63–2.78 (m,
2H), 3.68 (s, 3H). 13C NMR (100 MHz) d 14.1, 22.3, 29.0, 33.8,
35.3, 38.5, 50.1, 51.6, 51.9, 176.8, 210.5.GC–MS m/z (rel intensity)
198 (M+, 7), 166 (46), 151 (12), 139 (24), 111 (100), 95 (39), 88
(37), 69 (90), 55 (45), 41 (28).

S. Serra, I. Nobile / Tetrahedron: Asymmetry 22 (2011) 1455–1463
1463
Oxidation of ether (ꢀ)-11 gave (1R,4R,8S)-3-oxo-p-menthan-
9-oic acid 15a (thick oil) in 58% yield; the (1R,4R,8S)-3-oxo-p-men-
than-9-oic acid methyl ester (+)-15b was obtained as a colourless
GC, 98% diastereoisomeric purity, 1H NMR, 13C NMR, MS spectra
were in accordance with those of (+)-14b.
(1S,4S,8R)-3-Oxo-p-menthan-9-oic acid methyl ester (ꢀ)-15b,
oil showing the following analytical data: ½a D20
ꢃ
¼ þ51:9 (c 2,
colourless oil, ½a D20
¼ ꢀ47:9 (c 2, CHCl3), 98% chemical purity by
ꢃ
CHCl3), 98% chemical purity by GC, 75% diastereoisomeric purity.
1H NMR (400 MHz, CDCl3)d 0.98 (d, J = 6.9 Hz, 3H), 1.15 (d,
J = 7.0 Hz, 3H), 1.53–1.67 (m, 1H), 1.79–1.89 (m, 3H), 2.08–2.16
(m, 1H), 2.17–2.29 (m, 1H), 2.44 (dd, J = 5.1, 13.5 Hz, 1H), 2.52–
2.60 (m, 1H), 2.80–2.89 (m, 1H), 3.68 (s, 3H). 13C NMR (100 MHz)
d 15.0, 19.8, 26.8, 30.1, 32.7, 39.2, 48.1, 51.5, 52.7, 175.4, 210.9.
GC–MS m/z (rel intensity) 198 (M+, 13), 166 (66), 151 (14), 139
(28), 111 (100), 95 (44), 88 (40), 69 (97), 55 (50), 41 (31).
GC, 70% diastereoisomeric purity, 1H NMR, 13C NMR, MS spectra
were in accordance with those of (+)-15b.
(1R,4S,8R)-3-Oxo-p-menthan-9-oic acid methyl ester (ꢀ)-16b,
colourless oil, ½a D20
¼ ꢀ22:6 (c 2, CHCl3), 96% chemical purity by
ꢃ
GC, 98% diastereoisomeric purity, 1H NMR, 13C NMR, MS spectra
were in accordance with those of (+)-16b.
References
Oxidation of ether (ꢀ)-12 gave (1S,4R,8S)-3-oxo-p-menthan-
9-oic acid 16a (thick oil) in 60% yield; the (1S,4R,8S)-3-oxo-p-men-
than-9-oic acid methyl ester (+)-16b was obtained as a colourless
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The above oxidation procedure was repeated starting from
ethers (ꢀ)-9, (+)-10, (+)-11 and (+)-12 to give compounds (ꢀ)-13,
(ꢀ)-14b, (ꢀ)-15b, and (ꢀ)-16b, respectively showing the following
analytical data:
(1S,3S,4S,8S)-3,9-Epoxy-p-menthan-9-one (ꢀ)-13 in 65% yield,
mp 62 °C (hexane), ½a D20
¼ ꢀ48:5 (c 1, CHCl3), 99% chemical purity
ꢃ
by GC, 99% diastereoisomeric purity, 1H NMR, 13C NMR, MS spectra
were in accordance with those of (+)-13.
(1R,4S,8S)-3-Oxo-p-menthan-9-oic acid methyl ester (ꢀ)-14b,
colourless oil, ½a D20
¼ ꢀ21:0 (c 2, CHCl3), 98% chemical purity by
ꢃ