Enzyme-mediated preparation of enantiomerically pure p-menthan-3,9-diols and their use for the synthesis of natural p-menthane lactones and ethers

Article abstract of DOI:10.1002/1522-2675(200208)85:8<2489::AID-HLCA2489>3.0.CO;2-9

The diastereoselective preparation of the p-menthane-3,9-diols (±)-12, (±)-13a, (±)-13b, and (±)-18 and the study of their enzymic resolution is described (Scheme 1). The corresponding enantiomer-enriched diols obtained by means of the lipase-mediated kinetic acetylation of the racemic diols are suitable synthetic precursors of many relevant p-menthane monoterpenes. Their usefulness is shown in the preparation of different natural products of this class that are interesting for industrial purposes because of their odor qualities, i.e., of the enantiomeric form of 3-hydroxy-p-menthan-9-oic acid lactone 1, of mintlactone 2, of the 3,9-epoxy-p-menth-1,8(10)-diene 10, and of the pheromone vesperal 11 (Schemes 2 and 3).

Full text of DOI:10.1002/1522-2675(200208)85:8<2489::AID-HLCA2489>3.0.CO;2-9

Helvetica Chimica Acta Vol. 85 (2002)
2489
Enzyme-Mediated Preparation of Enantiomerically Pure p-Menthan-
3,9-diols and Their Use for the Synthesis of Natural p-Menthane Lactones
and Ethers
by Stefano Serra* and Claudio Fuganti
C.N.R., Istituto di Chimica del Riconoscimento Molecolare, Sezione −Adolfo Quilico× presso Dipartimento di
Chimica, Materiali ed Ingegneria Chimica −Giulio Natta× del Politecnico, Via Mancinelli 7, I-20133 Milano
The diastereoselective preparation of the p-menthane-3,9-diols (Æ)-12, (Æ)-13a, (Æ)-13b, and (Æ)-18 and
the study of their enzymic resolution is described (Scheme 1). The corresponding enantiomer-enriched diols
obtained by means of the lipase-mediated kinetic acetylation of the racemic diols are suitable synthetic
precursors of many relevant p-menthane monoterpenes. Their usefulness is shown in the preparation of
different natural products of this class that are interesting for industrial purposes because of their odor qualities,
i.e., of the enantiomeric form of 3-hydroxy-p-menthan-9-oic acid lactone 1, of mintlactone 2, of the 3,9-epoxy-p-
menth-1,8(10)-diene 10, and of the pheromone vesperal 11 (Schemes 2 and 3).
1. Introduction.
Among the monoterpenes of the p-menthane family, many
natural products show O-functionalization in both positions 3 and 9 of the p-menthane
framework. Several compounds of different chemical structures belong to this class,
and most of them are well-known as flavoring ingredients. The 3-hydroxy-p-menthan-9-
oic acid lactone 1, (À)-mintlactone ((À)-2), (‡)-isomintlactone (3), (1R)-menthofur-
olactone (4), (1R)-3-hydroxymintlactone 5 as well as (‡)-menthofuran (6) were found
in peppermint oil [1], whilst the isomeric (‡)-mintlactone and (À)-isomintlactone are
key aroma components of the wood of Bursera graveolens [2]. Moreover, the odorants
(À)-wine lactone (7) [3], (‡)-dill ether (8) [4], racemic linden ether (9) [5a], (‡)-3,9-
epoxy-p-mentha-1,8(10)-diene ((‡)-10) [6] together with the structurally related
pheromone (‡)-vesperal ((‡)-11) [7a] have been found in different natural sources.
In this context, p-menthane lactones are very interesting compounds since the most
prominent members of this class, as lactones 1 4, are used as commercial flavoring
ingredients [8]. Moreover, recent studies have highlighted the relevance of the isomeric
wine lactone [3] and of the analogous saturated p-menthane lactones [9] due to the low
threshold and the powerful coumarin-like odor properties, respectively. In addition,
these studies show that either the isomer or the enantiomer composition of these
lactones determined their olfactory features.
In light of these observations, it seemed desirable to develop new synthetic methods
for the stereoselective preparation of this kind of compound. Several enantioselective
synthesis of these natural lactones [3][9][10] and ethers [5b] have been reported, but
the need for expensive enantiomerically pure starting materials is the main obstruction
limiting their large-scale preparation. On the other hand, different isomeric p-
menthane-3,9-diols that are easily prepared in the racemic form from low-cost
industrial products, may be converted to the suitable p-menthane lactones and ethers

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Helvetica Chimica Acta Vol. 85 (2002)
by known and straightforward methods. We envisage that enzymic resolution of these
diols can afford useful chiral building blocks of great utility in the preparation of the
above-mentioned natural compounds. We focused our attention on three kinds of diols:
the p-menthane-3,9-diols, the p-menth-8(10)-ene-3,9-diols, and the p-mentha-1,8(10)-
diene-3,9-diols, which share the same framework but differ in the number of CˆC
bonds observed from the naturally occurring products 1 11. We prepared a set of four
diastereoisomerically pure diols, (Æ)-12, (Æ)-13a, (Æ)-13b, and (Æ)-18, showing the
above-mentioned structural characteristics, and, next, we tested their reactivity toward
the irreversible acetylation catalyzed by three different lipases (lipase PS, CCL, and
PPL). This kind of exploitation was previously applied in the preparation of enan-
tiomerically pure ionone [11] and irone odorants [12] starting from racemic materials.
Accordingly, we extended this acquired enzymic methodology to the preparation of
enantiomerically pure p-menthane odorants. We found that both the kinetics and
enantioselectivity in the acetylation step are strongly affected by the kind of enzyme
used and also by the configurational features of the substrates. By means of this
enzymic selectivity, we obtained the two enantiomeric forms of diols (Æ)-12, (Æ)-13a,
and (Æ)-18, which were then converted by chemical manipulation to both enantiomeric
forms of lactone (Æ)-1, mintlactone (Æ)-2, ether (Æ)-10, and vesperal (Æ)-11.
2. Results. 2.1. Synthesis of Racemic Diols (Æ)-12, (Æ)-13a, (Æ)-13b, and (Æ)-18.
To establish unambiguously both the enantioselectivity and diastereoselectivity in the
lipase-catalyzed acetylation of p-menthane-3,9-diols, we prepared the four diastereo-

Helvetica Chimica Acta Vol. 85 (2002)
2491
isomerically pure diols (Æ)-12, (Æ)-13a, (Æ)-13b, and (Æ)-18 by modification of
reported procedures (Scheme 1).
Diol (Æ)-12 shows the same relative configuration as lactone (Æ)-1, and it was
previously [13] obtained from isopulegol by hydroboration as a key synthetic step.
Since this reaction proceeds with high diastereoselectivity, the availability of the
enantiomeric form of (Æ)-12 and (Æ)-1 [10i] is relegated to the preparation of
enantiomerically pure isopulegol. Accordingly, we treated commercially available
racemic isopulegol with BH3 ¥ Me2S, and subsequent oxidation with NaOH/H2O2 gave a
diastereoisomer mixture of diols. Purification of the latter by crystallization afforded
diol (Æ)-12 in up to 98% diastereoisomer purity.
In the same way, we focused our attention on compounds (Æ)-13a and (Æ)-13b,
which show the same relative configurations at C(1) and C(3) as mintlactone and
isomintlactone, respectively. These two diols are formally obtained by oxidation of the
allylic methyl group of isopulegol and neoisopulegol, which are the main components
of the commercial material. This kind of functionalization was well-studied in the past,
and several procedures to this end have been reported [13 15]. We, therefore, treated
commercially available racemic isopulegol with 3-chloroperbenzoic acid (mClPBA),
and the mixture of epoxides obtained was submitted to a ring-opening rearrangement
by means of lithium diisopropylamide in refluxing THF. The crude diols were then
Scheme 1
i) BH3 ¥ Me2S, THF. ii) H2O2, NaOH. iii) Crystallization from hexane. iv) mClPBA, CH2Cl2. v) lithium
diisopropylanide, THF, reflux. vi) CC, crystallization from hexane/AcOEt. vii) CC, crystallization from Et2O.
viii) 14 ‡ 15, benzene, reflux. ix) Ph3PCH2, THF, reflux. x) KOH, MeOH, reflux. xi) Crystallization from
hexane/AcOE.

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Helvetica Chimica Acta Vol. 85 (2002)
purified by chromatography and crystallization to afford diastereoisomerically pure
(Æ)-13a and (Æ)-13b.
Structural considerations of compounds 7 11 suggested that a third kind of diol
showing at least one unsaturation at C(1) and cis relative configuration at C(3) and
C(4) should be investigated. To this end, we selected the diol (Æ)-18, which was
previously prepared in the synthesis of (‡)-vesperal ((‡)-11) [7a]. According to the
latter method, we built up the cyclohexene ring with the required cis relative
configuration at C(3) and C(4) by Diels-Alder reaction of diene 14 [16] and vinyl
ketone 15 [17]. The resulting ketone (Æ)-16 was obtained in good diastereoselectivity
(95%), and the following Wittig methylenation afforded the diacetate (Æ)-17 showing
the entire p-menthane framework. Subsequent KOH hydrolysis of the acetate moieties
gave crude diol (Æ)-18, which was further purified by crystallization to give (Æ)-18 in
99% diastereoisomer purity.
2.2. Lipase-Catalyzed Acetylation of Diols (Æ)-12, (Æ)-13a, (Æ)-13b, and (Æ)-18.
Each of the four diastereoisomerically pure diols (Æ)-12, (Æ)-13a, (Æ)-13b and (Æ)-18
was treated with vinyl acetate in tBuOMe solution in the presence of lipases (lipase PS,
CCL, and PPL). The reactivity of each substrate toward the irreversible acetylation
was tested by monitoring at regular time intervals the product distribution by GC
analysis. After good conversion (45 100%) of the starting diols, the products were
isolated and fully characterized. The results of this study are collected in the Table and
allow some interesting considerations.
Table. Results of Enzyme-Mediated Acetylation of Diols (Æ)-12, (Æ)-13a, (Æ)-13b, and (Æ)-18
Enzyme Time ee of
ee of
ee of
Enantiomer Conversion
[days] recovered alcohola) monoacetylated diacetylated ratio
producta)b)
producta)
(Æ)-12
PPL
CCL
PS
4
21
21
28
72
17
92
a
a
a
a
a
a
a
6
55
64
c
c
c
c
c
99
c
c
c
1.9
4
15
0.923
0.236
0.59
(Æ)-13a PPL
0, b
0, b
92
0, b
0, b
0, b
0, b
0, b
94
CCL
PS
(Æ)-13b PPL
CCL
662
0.482
PS
(Æ)-18
PPL
CCL
PS
c
c
99
a
a
712
0.487
a) The GC analysis of the reaction mixture showed that none of the compound (a), more than 90% of the
compound (b), and less than 5% of the compound (c) was detected. b) Compounds (Æ)-13a, (Æ)-13b, and (Æ)-
18 were monoacetylated by each lipase in less than 36 h.
All the lipases used mediated the acetylation of the primary alcohol functions, but,
when these groups were allylic (compounds (Æ)-13a, (Æ)-13b, and (Æ)-18), the reaction
was very fast (less then 36 h), and no enantioselectivity was observed in this step.
Otherwise, the saturated diol (Æ)-12 reacted slowly, and, after four days, ca. 50% of the
starting diol was acetylated. The enantioselectivity of this step was dependent on the

Helvetica Chimica Acta Vol. 85 (2002)
2493
kind of lipase used. Lipase PS showed higher selectivity with a preference for the
conversion of the (‡)-isomer. Differently, PPL showed the lowest selectivity, whereas
CCL, though with poor selectivity, converted the (À)-isomer. The monoacetylated
compounds obtained were not further acetylated by the above-mentioned enzymes,
even after long reaction time.
Concerning the acetylation of the secondary-alcohol group, the behaviors of the diols
(Æ)-13a, (Æ)-13b, and (Æ)-18 were again different. Compounds (Æ)-13a and (Æ)-18 were
slowly converted to the enantiomerically pure diacetates (99% ee) and to the enantiomer-
enriched (92 and 94% ee, resp.) monoacetylated derivatives only when lipase PS was
used as a catalyst. Otherwise, (Æ)-13b, which differed from (Æ)-13a only in the cis
relative configuration at C(3) and C(4), was not converted by any of the enzymes used.
2.3. Preparation of Enantiomer-Enriched Diols (‡)- and (À)-12, (‡)- and (À)-13a,
and (‡)- and (À)-18 and Their Conversion to the Natural Products (‡)- and (À)-1, (‡)-
and (À)-2, (‡)- and (À)-10, and (‡)- and (À)-11. Taking advantage of the above-
described enzymic selectivity, we devised a large-scale method for the preparation of all
the enantiomeric forms of diols (Æ)-12, (Æ)-13a, and (Æ)-18 and then to the natural
products (‡)- and (À)-1, (‡)- and (À)-2, (‡)- and (À)-10, and (‡)- and (À)-11. We first
t
treated (Æ)-12 with lipase PS in the presence of vinyl acetate and BuOMe as solvent
allowing the reaction to proceed to >50% conversion (Scheme 2). The unreacted diol
(À)-12 was isolated in satisfactory enantiomer purity (92% ee), whereas acetylated
(‡)-19 showed lower purity (64% ee). To obtain enantiomerically pure (‡)-12, we
exploited the reverse selectivity of CCL toward acetylation of (À)-12. Accordingly,
(‡)-19 was hydrolyzed and the crude diol obtained submitted to CCL-mediated
acetylation forcing again the reaction to >50% of conversion. The isolation procedure
provided, besides (‡)-19 (38% ee), the unreacted diol (‡)-12 in good enantiomer
purity (94% ee). The oxidation of diols (‡)- and (À)-12 was accomplished by means of
KMnO4 /CuSO4 ¥ 5 H2O [10i] in CH2Cl2 solution to afford natural lactone (‡)-1 and its
enantiomer (À)-1, respectively.
On the other hand, the enantiomeric forms of (Æ)-13a and (Æ)-18 were prepared by
a more direct pathway. Treatment of (Æ)-13a with lipase PS in the presence of vinyl
t
acetate and BuOMe as solvent gave diacetate (À)-21 in very high enantiomer purity
(99% ee) and the monoacetylated (‡)-20 also in good enantiomer purity (92% ee)
(Scheme 2). Thus, KOH hydrolysis of the acetate moieties provided (À)- and (‡)-13a,
respectively. The conversion of the latter diols to trans-p-menthene lactones 22 [10a]
[14][15][18] was performed according to the two-step procedure reported by Friedrich
and Bohlmann [14]. The reaction of (À)- and (‡)-13a with MnO2 gave the related
hydroxy-aldehydes, which were directly converted to (‡)- and (À)-22, respectively, by
oxidation with Ag2CO3 on Celite. Moreover, to obtain the enantiomeric form of
mintlactone, we examined the isomerization reaction of the exocyclic CˆC bond of 22.
Although Ogasawara and co-workers [10b] achieved this transformation by means of
RhCl3 ¥ 3 H2O as catalyst, we were unable to achieve satisfactory results using either the
latter salt or [RhCl(Ph3P)3]. On other hand, we found that the more effective
rhodium(I) hydride complex [RhH(Ph3P)4] [19] was an efficient catalyst for this kind
of isomerization. Accordingly, the reaction of (‡)- and (À)-22 with [RhH(Ph3P)4]
(10 mol-%) in refluxing toluene afforded enatiomerically pure (À)-mintlactone ((À)-2)
and (‡)-mintlactone ((‡)-2), respectively, both in good chemical yields.

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Helvetica Chimica Acta Vol. 85 (2002)
Scheme 2
i) Vinyl acetate, tBuOMe, lipase PS. ii) KOH, MeOH, reflux. iii) Vinyl acetate, tBuOMe, CCL. iv) KMnO4/
CuSO4 ¥ 5H2O, CH2Cl2. v) MnO2, CH2Cl2. vi) 10% Ag2CO3/Celite, benzene, reflux. vii) [RhH(Ph3P)4 (cat.),
toluene, reflux.
Finally, as described for compound (Æ)-13a, treatment of (Æ)-18 with lipase PS in
presence of vinyl acetate and tBuOMe as solvent gave the diacetate (À)-17 in very high
enantiomer purity (99% ee) and the monoacetylated (‡)-23 also in good enantiomer
purity (94% ee) (Scheme 3). The subsequent KOH hydrolysis of the acetate moieties
provided (À)- and (‡)-18, respectively. The reaction of the latter diols with a catalytic
amount of 5% aqueous HCl solution in Et2O as solvent smoothly provided the ethers

Helvetica Chimica Acta Vol. 85 (2002)
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Scheme 3
i) Vinyl acetate, tBuOMe, lipase PS. ii) KOH, MeOH, reflux. iii) 5% aq. HCl soln. (cat.), Et2O. iv)
[RhH(Ph3P)4] (cat.), toluene, reflux. v) Dess-Martin reagent, CH2Cl2.
(‡)- and (À)-10, respectively, in very good yields. Confirmatory experiments were
performed, treating the above-mentioned diols with 1 equiv. of p-toluenesulfonyl
chloride in pyridine solution. The ethers obtained by this means were chemically
identical to those prepared by the acidic catalyst and showed comparable optical-
rotation values. These results clearly demonstrate1) that no racemization or double-
bond isomerization occurred during the ring closure in acidic media. Moreover, ether
(‡)-102) showed identical spectroscopic data and a similar optical-rotation value to
those recorded for the natural compound found in Ledum palustre L. [6], which is also
known as wild rosemary or Labrador tea and is used in folk medicine by the native
peoples of North America.
Furthermore, with the aim of preparing both enantiomers of linden ether 9, we tried
the isomerization of (À)- or (‡)-10 by means of the [RhH(Ph3P)4] catalyst. Surprisingly
enough, the ethers (À)- and (‡)-10 were regiospecifically isomerized to the
thermodynamically less-stable enol ethers (À)- and (‡)-24, respectively, in good yields
1
)
Since the reaction of diol (‡)- or (À)-18 with 1 equiv. of p-toluenesulfonyl chloride in a deficiency of base
afforded only the 9-(tosyloxy) derivative, the SN2 process in this ring closure conserves the starting
configuration.
2
)
The (‡)-10 obtained was evaluated by an expert perfumer who described its aroma feature as sweet mint
and spearmint like, suitable for fresh-fruits- and spearmint-aroma formulations.

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Helvetica Chimica Acta Vol. 85 (2002)
and without apparent racemization (Scheme 3). Analysis of the reaction mixtures
showed that linden ether 9 could also not be formed by prolonging the reflux for many
days.
Finally, since the absolute configurations of diols (‡)- and (À)-18 and ether (‡)-
and (À)-10 were not determined before, we correlated these two compounds with the
pheromone vesperal, whose absolute configuration was previously assigned [7a]. Thus,
the oxidation of (‡)- and (À)-18 with Dess-Martin periodinane provided (‡)-(S)-
vesperal ((‡)-11) and (À)-(R)-vesperal ((À)-11), respectively (Scheme 3). Therefore,
the absolute configuration of the natural ether (‡)-10 and of the diol (À)-18 is (3R,4R)
(p-menthane numbering).
3. Conclusions. The lipase-mediated resolution of different p-menthan-3,9-diols is
described in this work. The high-quality results obtained in terms of chemical yields and
enzyme selectivity allows the preparation of the enantiomeric diols (‡)- and (À)-12,
(‡)- and (À)-13a, and (‡)- and (À)-18 in high optical purity. These diols are easily
converted to the enantiomerically pure p-menthane terpenes (À)-and (‡)-1, (‡)- and
(À)-2, (À)- and (‡)-10, and (‡)- and (À)-11, respectively, which are of both industrial
and academic interest. Moreover, the first enantiospecific synthesis of natural ether (‡)
-10 allows us to assign unambiguously its absolute configuration. Since the racemic
starting materials are straightforwardly available from industrial sources, the overall
chemo-enzymatic sequence may be regarded as a general and useful procedure for the
enantioselective preparation of many relevant p-menthane compounds. Studies
devoted to the enantioselective synthesis of the structurally related wine lactone, dill
ether, and linden ether are still in progress and will be reported in due course.
The authors would like to thank COFIN-MURST for partial financial support.
Experimental Part
1. General. Lipase PS from Pseudomonas cepacia (Amano Pharmaceuticals Co., Japan, 30 U mgÀ1),
Candida cylindracea lipase (CCL; Sigma, type VII, 880 U mgÀ1), porcine pancreatic lipase (PPL, Sigma, type II,
147 U mgÀ1) and technical-grade isopulegol (sum of isomers: 96%; isopulegol/neoisopulegol/isoisopulegol/
isoneoisopulegol 66 :30 :3 :1) were employed. TLC: Merck silica gel 60 F254 plates. Column chromatography
(CC): silica gel. GC: DANI-HT-86.10 gas chromatograph; enantiomer and diastereoisomer excesses determined
on a Chirasil DEX-CB column (25 m  0.25 mm; Chrompack) with the following temp. program 1158 (3 min)
À0.58/min À1308 À88/min À1808 (1 min); analysis of (Æ)-(1RS,3RS,4SR,8RS)-p-menthane-3,9-diol diacetate:
tR 17.59, 18.01; analysis of (Æ)-(1RS,3RS,4SR)-p-menth-8(10)-ene-3,9-diol diacetate: tR 17.45, 17.88; analysis of
(Æ)-(1RS,3RS,4RS)-p-mentha-1,8(10)-diene-3,9-diol diacetate: tR 16.42, 16.53; tR in min. Optical rotations: Jasco
1
DIP-181 digital polarimeter. H-NMR Spectra: CDCl3 solns. at r.t.; Bruker AC-250 spectrometer at 250 MHz
(1H); chemical shifts in ppm rel. to internal SiMe4 (ˆ0 ppm), J values in Hz. Mass spectra: Finnigan-Mat TSQ-
70 spectrometer; m/z (rel. %). IR Spectra: Perkin-Elmer 2000-FT-IR spectrometer; films: nÄ in cmÀ1. Micro-
analyses were determined on an analyzer 1106 from Carlo Erba.
2. Racemic Diols (Æ)-12, -13, and -18. The diols (Æ)-12, -13, and -18 were prepared by partial modification
of known procedures.
2.1. (Æ)-(1RS,3RS,4SR,8RS)-p-Menthane-3,9-diol (ˆ(bRS,1SR,2RS,4RS)-2-Hydroxy-b,4-dimethylcyclo-
hexaneethanol; (Æ)-12). Borane ¥ methyl sulfide (57 ml, 0.6 mol) in dry THF (100 ml) was added dropwise to
a cooled (08) soln. of technical-grade isopulegol (80 g, 0.519 mol) in dry THF (400 ml) under N2. The resulting
clear soln. was warmed to r.t. and stirred at r.t. for 2 h. Then, 4n aq. KOH (250 ml) was added slowly, and the
resulting mixture was warmed to 508 for 2 h. After this time, 35% aq. H2O2 soln. (350 ml, 3.6 mol) was added
dropwise keeping the temp. <308 by external cooling (ice bath). After the addition, the mixture was stirred at

Helvetica Chimica Acta Vol. 85 (2002)
2497
r.t. overnight. The main part of THF was evaporated, the aq. mixture extracted with Et2O (3 Â 250 ml), the org.
phase successively washed with 5% aq. Na2S2O5 soln. (100 ml) and brine, dried (Na2SO4), and evaporated, and
the residue (90 g) dissolved in hexane (250 ml) and stored at À108 for 3 days. The crystalline precipitate was
further purified by a second crystallization: (Æ)-12 (44 g, 49%). M.p. 82 848. Chemical purity 99% (GC of the
corresponding diacetate), de 98% (GC). IR: 3270, 2953, 2921, 2871, 1457, 1375, 1216, 1106, 1024, 668. 1H-NMR:
4.36 (s, OHÀC(3), OHÀC(9)); 3.64 (dd, J ˆ 10.8, 5.1, HÀC(9)); 3.56 (dd, J ˆ 10.8, 3.4, HÀC(9)); 3.43
(ddd, J ˆ 10, 10, 4.2, HÀC(3)); 1.96 (dm, J ˆ 12, 1 H); 1.89 1.75 (m, 1 H); 1.63 (dm, J ˆ 12, 1 H); 1.56 (dm, J ˆ
12, 1 H); 1.50 1.13 (m, 3 H); 1.04 0.80 (m, 2 H) (HÀC(1), HÀC(4), HÀC(8), CH2(5), CH2(6), CH2(2)); 0.95
‡
‡
(d, J ˆ 7.3, Me(10)); 0.91 (d, J ˆ 6.5, Me(7)). MS: 173 (53, [M ‡ 1] ), 172 (30, M ), 155 (4), 139 (5), 124 (17),
123 (9), 112 (22), 97 (29), 95 (34), 81 (100), 71 (68), 67 (50), 55 (45), 41 (19). Anal. calc. for C10H20O2: C 69.72,
H 11.70; found: C 69.63, H 11.68.
2.2. (Æ)-(1RS,3SR,4SR)- and (Æ)-(1RS,3SR,4SR)-p-Menth-8(10)-ene-3,9-diol (ˆ(1RS,2RS,4SR)- and
(1RS,2RS,4RS)-2-Hydroxy-4-methyl-b-methylenecyclohexaneethanol; (Æ)-13a and (Æ)-13b, resp.). At 08, 3-
chloroperbenzoic acid (100 g of a 75% wet acid, 0.435 mol) was added portionwise to a soln. of technical-grade
isopulegol (60 g, 0.389 mol) in CH2Cl2 (300 ml). The mixture was stirred for 2 h, and then the 3-chlorobenzoic
acid formed was filtered off over a Celite pad. The clear soln. obtained was washed with 5% aq. Na2SO3 soln.
(100 ml) and sat. aq. NaHCO3 soln. (100 ml), dried (Na2SO4), and evaporated. The residue, dissolved in dry
THF (100 ml), was added dropwise to a stirred 3m lithium diisopropylamide soln. in THF (400 ml, 1.2 mol)
under N2. The resulting mixture was heated under reflux for 2 h and then poured into ice, acidified with 5% HCl
soln. (900 ml), and extracted with AcOEt (3 Â 250 ml). The org. phase was dried (Na2SO4) and evaporated and
the residue submitted to CC (hexane/AcOEt 7:3). The 1st eluted fraction was further purified by crystallization
from Et2O: pure (Æ)-13b (7.12 g, 11%). M.p. 1108. Chemical purity 99%, de 97% (GC of the corresponding
diacetate). IR: 3379, 2923, 1649, 1456, 1385, 1263, 1121, 1075, 1048, 952, 911. 1H-NMR: 5.81 (br. d, J ˆ 1.1,
HÀC(10)); 5.00 (br. s, HÀC(10)); 4.13 (br. d, J ˆ 12.7, HÀC(9)); 4.05 (br. d, J ˆ 12.7, HÀC(9)); 3.97
(m, HÀC(3)); 2.56 (br. s, OHÀC(3), OHÀC(9)); 2.19 (br. d, J ˆ 12.5, HÀC(4)); 1.98 1.70 (m, 4 H); 1.51
1.39 (m, 1 H), 1.18 (ddd, J ˆ 12.5, 11.4, 2.4, 1 H), 1.09 0.91 (m, 1 H) (CH2(2), CH2(6), CH2(5), HÀC(1)); 0.89
‡
‡
(d, J ˆ 6.3, Me(7)). MS: 171 (60, [M ‡ 1] ), 170 (23, M ), 167 (30), 152 (16), 137 (9), 123 (24), 109 (42), 108
(41), 95 (52), 93 (100), 81 (73), 79 (72), 69 (59), 67 (75), 57 (26), 55 (51), 41 (53). Anal. calc. for C10H18O2:
C 70.55, H 11.66; found: C 70.65, H 11.65.
The 2nd eluted fraction was further purified by crystallization from hexane/AcOEt 4 :1: pure (Æ)-13a
(39.2 g, 59%). M.p. 102 1038. Chemical purity 99%, de 98% (GC of the corresponding diacetate). IR: 3319,
2951, 2920, 2854, 1651, 1458, 1377, 1126, 1097, 1044, 897. 1H-NMR: 5.19 (br. d, J ˆ 1.1, HÀC(10)); 5.04
(s, HÀC(10)); 4.12 (br. d, J ˆ 12.7, HÀC(9)); 4.05 (br. d, J ˆ 12.7, HÀC(9)); 3.53 (ddd, J ˆ 10.4, 10.4, 4.2,
HÀC(3)); 2.93 (br. s, OHÀC(3), OHÀC(9)); 2.08 1.86 (m, 2 H), 1.78 1.60 (m, 2 H), 1.62 1.42 (m, 1 H),
1.43 1.24 (m, 1 H), 1.10 0.84 (m, 2 H) (HÀC(4), CH2(2), CH2(6), CH2(5), HÀC(1)); 0.95 (d, J ˆ 6.4, Me(7)).
‡
‡
MS: 171 (20, [M ‡ 1] ), 170 (7, M ), 167 (3), 153 (5), 152 (17), 137 (9), 123 (24), 109 (43), 108 (41), 95 (57), 93
(100), 81 (92), 79 (76), 69 (56), 67 (75), 55 (48). Anal. calc. for C10H18O2: C 70.55, H 11.66; found: C 70.68,
H 11.68.
2.3. (Æ)-(3RS,4RS)-p-Mentha-1,8(10)-diene-3,9-diol (ˆ(1RS,2RS)-2-Hydroxy-4-methyl-b-methylenecyclo-
hex-3-eneethanol; (Æ)-18). A mixture of diene 14 (56 g, 444 mmol) and ketone 15 (45 g, 352 mmol) in dry
benzene (300 ml) was heated for 12 h under reflux and a static atmosphere of N2. The mixture was cooled and
evaporated. The residue was purified by CC (hexane/AcOEt 9 :1): pure 6-[(acetyloxy)acetyl]-3-methylcyclohex-
2-en-1-yl acetate (ˆ2-(acetyloxy)-1-[2-(acetyloxy)-4-methylcyclohex-3-en-1-yl]ethanone; (Æ)-16; 72.8 g, 81%) as
a diastereoisomer mixture (cis/trans 95 :5 by GC). IR: 2940, 2835, 1732, 1672, 1431, 1371, 1239, 1079, 1063, 1045,
1
1020, 956, 905. H-NMR: 5.62 (m, HÀC(2)); 5.56 (m, HÀC(1)); 4.84 (d, J ˆ 16.7, 1 H, AcOCH2); 4.72 (d, J ˆ
16.7, 1 H, AcOCH2); 2.79 2.68 (m, HÀC(6)); 2.20 1.86 (m, CH2(4), CH2(5)); 2.16 (s, MeCOO); 2.01
‡
(s, MeCOO); 1.75 (s, MeÀC(3)). MS: 211 (3, [M À MeCO] ), 194 (8), 169 (4), 152 (39), 151 (30), 139 (20), 134
(46), 121 (66), 110 (25), 101 (22), 93 (100), 91 (53), 77 (38).
A sample of the obtained (Æ)-16 (50 g, 197 mmol), dissolved in dry THF (100 ml), was added to 1m
(triphenylphosphonio)methanide (250 ml) previously prepared by reaction of (Ph3PMe)Br (89.2 g, 252 mmol)
in THF with 10m BuLi in hexane (25.1 ml). The resulting mixture was heated under reflux for 4 h, cooled to r.t.
and then poured into cool (08) H2O (500 ml). The quenched mixture was extracted twice with Et2O (2 Â
300 ml), and the org. phase was successively washed with sat. NH4Cl soln. and brine, dried (Na2SO4), and
evaporated. The residue was dissolved in hexane/Et2O 3 :1 (100 ml), and the triphenylphosphine oxide was
eliminated by crystallization (ice-bath cooling). The liquid phase was evaporated and purified by CC: pure p-
mentha-1,8(10)-diene-3,9-diol diacetate (ˆ2-(acetyloxy)-4-methyl-b-methylenecyclohex-3-eneethanol acetate;

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Helvetica Chimica Acta Vol. 85 (2002)
(Æ)-17; 35.2 g, 71%). Colorless oil (cis/trans 95 :5 by GC). IR: 2938, 1740, 1653, 1436, 1372, 1241, 1022, 958, 911.
1H-NMR: 5.64 5.55 (m, HÀC(2)); 5.38 5.28 (m, HÀC(3)); 5.17 (s, HÀC(10)); 5.01 (s, HÀC(10)); 4.65
(d, J ˆ 13.2, HÀC(9)); 4.52 (d, J ˆ 13.2, HÀC(9)); 2.34 (dm, J ˆ 12.5, HÀC(4)); 2.15 1.79 (m, 3 H), 1.76 1.62
‡
(m, 1 H), (CH2(6), CH2(5)); 2.08 (s, MeCOO); 1.97 (s, MeCOO); 1.74 (s, Me(7)). MS: 209 (6, [M À MeCO] ),
192 (11), 177 (1), 150 (34), 135 (29), 132 (100), 117 (59), 105 (22), 92 (70), 91 (58), 84 (87), 79 (21), 77 (20).
A sample of (Æ)-17 (30 g, 119 mmol) was treated with KOH (28.1 g, 500 mmol) in MeOH (200 ml) under
reflux for 2 h. The mixture was poured in ice and extracted with Et2O (3 Â 200 ml). The dried (Na2SO4) org.
phase was evaporated and the residue purified by CC (hexane/AcOEt 7:3) and crystallization (hexane/AcOEt
3 :1): pure (Æ)-18 (17.2 g, 86%). M.p. 58 608. Chemical purity 98% and de 99% (GC of the corresponding
diacetate). IR: 3403, 2931, 2907, 1679, 1653, 1442, 1385, 1297, 1274, 1156, 1108, 1065, 1051, 1025, 958, 896.
1H-NMR: 5.64 (m, HÀC(2)); 5.24 (s, HÀC(10)); 5.02 (s, HÀC(10)); 4.19 4.03 (m, HÀC(3), CH2(9)); 2.70
(br. s, OHÀC(3), OHÀC(9)); 2.29 (dm, J ˆ 12.5, HÀC(4)); 2.12 1.93 (m, 2 H), 1.92 1.75 (m, 1 H), 1.66 1.53
‡
‡
(m, 1 H) (CH2(6), CH2(5)); 1.72 (s, Me(7)). MS: 169 (3, [M ‡ 1] ), 168 (23, M ), 153 (2), 150 (7), 135 (18), 133
(15), 122 (9), 105 (7), 94 (10), 91 (22), 84 (100), 83 (82), 79 (29), 61 (23), 56 (24), 55 (20). Anal. calc. for
C10H16O2: C 71.39, H 9.59; found: C 71.30, H 9.60.
3. Lipase-Mediated Acetylation of Diols (Æ)-12, (Æ)-13, and (Æ)-18. 3.1. General Procedure (GP). A
t
mixture of the suitable (Æ)-diol (50 mmol), lipase (see Table), and vinyl acetate (30 ml) in BuOMe (100 ml)
was stirred at r.t. and the conversion to acetate monitored by TLC. The reaction was stopped by filtration of the
enzyme and evaporation of the filtrate. The residue was purified by CC (hexane/AcOEt): unreacted diol,
monoacetylated diol, and diacetylated diol. The enantiomer composition of the products was determined by
chiral GC analysis of the corresponding diacetate (see Table).
3.2. (À)-(1R,3R,4S,8R)- and (‡)-(1S,3S,4R,8S)-p-Menthane-3,9-diol (ˆ(bR,1S,2R,4R)- and (bS,1R,2S,4S)-
2-Hydroxy-b,4-dimethylcyclohexaneethanol; (À)-12 and (‡)-12, resp.). According to the GP, lipase-PS-
mediated acetylation of (Æ)-12 (16 g, 93 mmol) gave the less-polar monoacetate (‡)-19 (10.1 g, 51%) and
unreacted (À)-12 (7.1 g, 44%).
Data of (‡)-(1S,3S,4R,8S)-p-Menthane-3,9-diol 9-Acetate (ˆ(bS,1R,2S,4S)-2-Hydroxy-b,4-dimethylcyclo-
hexaneethanol a-Acetate; ( ‡ )-19): [a]2D0 ˆ ‡32.6 (c ˆ 2, CHCl3). Chiral GC: ee 64%, chemical purity 97%. IR:
1
3440, 2952, 2922, 2870, 1740, 1457, 1394, 1370, 1243, 1039, 983, 923. H-NMR: 4.23 (dd, J ˆ 10.7, 5.7, HÀC(9));
3.86 (dd, J ˆ 10.7, 7.7, HÀC(9)); 3.51 (ddd, J ˆ 10.5, 10.5, 4.2, HÀC(3)); 2.31 2.15 (sym. m, 1 H), 2.01 1.91
(m, 1 H), 1.72 1.60 (m, 2 H), 1.54 1.32 (m, 1 H), 1.33 1.19 (m, 1 H), 1.17 0.8 (m, 3 H) (HÀC(8), HÀC(4),
HÀC(1), CH2(5), CH2(6), CH2(2)); 2.06 (s, MeCOO); 1.95 (s, OHÀC(3)); 0.99 (d, J ˆ 7, Me(10)); 0.92 (d, J ˆ
‡
6.4, Me(7)). MS: 214 (1, M ), 196 (1), 171 (2), 154 (19), 139 (25), 136 (24), 121 (28), 112 (100), 97 (54), 95 (37),
81 (62), 69 (42), 55 (38). Anal. calc. for C12H22O3: C 67.26, H 10.35; found: C 67.40, H 10.20.
Data of (À)-12: M.p. 102 1048. [a]2D0 ˆ À18.5 (c ˆ 1.9, CHCl3). Chiral GC: ee 92%, chemical purity 98%.
1
IR, H-NMR, MS: in accordance with that of (Æ)-12.
A sample of the monoacetate (‡)-19 (12.8 g, 60 mmol) was treated with KOH (5.05 g, 90 mmol) in MeOH
(70 ml) under reflux for 2 h. The mixture was poured in ice and extracted with Et2O (3 Â 100 ml). The dried
(Na2SO4) org. phase was evaporated and the crude diol obtained submitted to CCL-mediated acetylation
according to the GP. Purification by CC gave the less-polar monoacetate (‡)-19 (8.1 g, 63%) and unreacted
(‡)-12 (2.9 g, 28%).
Data of (‡)-19: [a]2D0 ˆ ‡19.5 (c ˆ 2, CHCl3). Chiral GC: ee 38%, chemical purity 97%. IR, 1H-NMR, MS:
in accordance with that of starting (‡)-19.
Data of (‡)-12: M.p. 103 1048. [a]2D0 ˆ ‡19.2 (c ˆ 1.9, CHCl3). Chiral GC: ee 94%, chemical purity 98%.
1
IR, H-NMR, MS: in accordance with that of (Æ)-12.
3.3. (À)-(1R,3R,4S)- and (‡)-(1S,3S,4R)-p-Menth-8(10)-ene-3,9-diol (ˆ(1S,2R,4R)- and (1R,2S,4S)-2-
Hydroxy-4-methyl-b-methylenecyclohexaneethanol; (À)-13a and (‡)-13a, resp.). According to the GP, lipase-
PS-mediated acetylation of (Æ)-13a (10 g, 59 mmol) gave the less-polar diacetate (À)-21 (6 g, 40%) and
monoacetate (‡)-20 (5.9 g, 47%).
Data of (À)-(1R,3R,4S)-p-Menth-8(10)-ene-3,9-diol Diacetate (ˆ(1S,2R,4R)-2-(Acetyloxy)-4-methyl-b-
methylenecyclohexaneethanol Acetate; (À)-21): [a]2D0 ˆ À43.4 (c ˆ 2, CHCl3). Chiral GC: ee 99%, chemical
purity 98%. IR: 2930, 2871, 1737, 1655, 1456, 1373, 1245, 1130, 1089, 1028, 984, 906, 842. 1H-NMR: 5.08 (d, J ˆ
1.1, HÀC(10)); 5.01 (s, HÀC(10)); 4.78 (ddd, J ˆ 10.7, 10.7, 4.4, HÀC(3)); 4.57 (d, J ˆ 13.5, HÀC(9)); 4.49
(d, J ˆ 13.5, HÀC(9)); 2.17 1.95 (m, 2 H), 1.90 1.77 (dm, J ˆ 13.4, 1 H), 1.76 1.63 (dm, J ˆ 14, 1 H), 1.65
1.48 (m, 1 H), 1.47 1.28 (dq, J ˆ 13, 3.4, 1 H), 1.08 0.85 (m, 2 H) (HÀC(4), HÀC(1), CH2(2), CH2(5),
CH2(6)); 2.09 (s, MeCOO); 1.98 (s, MeCOO); 0.93 (d, J ˆ 6.4, Me(7)). MS: 212 (1), 194 (12), 179 (3), 161 (7),

Helvetica Chimica Acta Vol. 85 (2002)
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152 (100), 134 (68), 123 (21), 119 (36), 109 (28), 108 (31), 95 (27), 93 (49), 81 (34), 79 (26), 67 (15), 55 (13).
Anal. calc. for C14H22O4: C 66.12, H 8.72; found: C 65.95, H 8.70.
Data of (‡)-(1S,3S,4R)-p-Menth-8(10)-ene-3,9-diol 9-Acetate (ˆ(1R,2S,4S)-2-Hydroxy-4-methyl-b-meth-
ylenecyclohexaneethanol a-Acetate; (‡)-20): M.p. 58 598. [a]2D0 ˆ ‡38.9 (c ˆ 2, CHCl3). Chiral GC: ee 92%,
chemicl purity 98%. IR: 3367, 2938, 2921, 2860, 1734, 1652, 1447, 1391, 1371, 1242, 1096, 1049, 1024, 901, 847, 756.
1H-NMR: 5.21 5.16 (m, HÀC(10)); 5.13 5.09 (m, HÀC(10)); 4.57 (s, CH2(9)); 3.55 (ddd, J ˆ 10.5, 10, 4.2,
HÀC(3)); 2.20 (br. s, OHÀC(3)); 2.10 (s, MeCOO); 2.10 1.98 (dm, J ˆ 12.5, 1 H), 1.92 (ddd, J ˆ 12.5, 10, 3.4,
1 H), 1.81 1.62 (m, 2 H), 1.61 1.41 (m, 1 H), 1.41 1.21 (dq, J ˆ 13, 3.4, 1 H), 1.09 0.83 (m, 2 H) (HÀC(4),
‡
HÀC(1), CH2(2), CH2(5), CH2(6)); 0.95 (d, J ˆ 6.4, Me(7)). MS: 194 (1, [M À H2O] ), 179 (1), 170 (2), 161 (1),
152 (29), 137 (22), 123 (53), 109 (75), 108 (89), 95 (57), 93 (100), 81 (53), 79 (50), 69 (33), 67 (36), 55 (25).
Anal. calc. for C12H20O3: C 67.89, H 9.50; found: C 68.00, H 9.55.
Treatment of the diacetate (À)-21 and monoacetate (‡)-20 with KOH/MeOH under the conditions
described above gave the diols (À)-13a (95%) and (‡)-13a (93%), respectively.
Data of (À)-13a: M.p. 102 1038. [a]2D0 ˆ À52.1 (c ˆ 1, EtOH). Chiral GC: ee 99%, chemical purity 99%.
1
IR, H-NMR, MS: in accordance with that of (Æ)-13a.
Data of (‡)-13a: M.p. 102 1038. [a]2D0 ˆ ‡47.6 (c ˆ 1, EtOH). Chiral GC: ee 92%, chemical purity 99%.
1
IR, H-NMR, MS: in accordance with that of (Æ)-13a.
3.4. (À)-(3R,4R)- and (‡)-(3S,4S)-p-Mentha-1,8(10)-diene-3,9-diol (ˆ(1R,2R)- and (1S,2S)-2-Hydroxy-4-
methyl-b-methylenecyclohex-3-eneethanol; (À)-18 and (‡)-18, resp.). According to the GP, lipase-PS-mediated
acetylation of (Æ)-18 (7.1 g, 42.3 mmol) gave the less-polar diacetate (À)-17 (4.9 g, 46%) and monoacetate (‡)-
23 (4.4 g, 49%).
Data of (3R,4R)-p-Mentha-1,8(10)-diene-3,9-diol Diacetate (ˆ(1R,2R)-2-(Acetyloxy)-4-methyl-b-methyl-
enecyclohex-3-eneethanol Acetate; (À)-17): [a]2D0 ˆ À279.4 (c ˆ 2, CHCl3). Chiral GC: ee 99%, chemical purity
99%. IR, 1H-NMR, MS: in accordance with that of (Æ)-17. Anal. calc. for C14H20O4: C 66.65, H 7.99; found:
C 66.80, H 8.00.
Data of (3S,4S)-p-Mentha-1,8(10)-diene-3,9-diol 9-Acetate (ˆ(1S,2S)-2-Hydroxy-4-methyl-b-methylenecy-
clohex-3-eneethanol a-Acetate; (‡)-23): [a]D20 ˆ ‡169.9 (c ˆ 2, CHCl3). Chiral GC: ee 94%, chemical purity
97%. IR: 3460, 2935, 2832, 1737, 1673, 1652, 1449, 1376, 1235, 1155, 1110, 1067, 1027, 957, 907, 848, 817. 1H-NMR:
5.70 5.62 (m, HÀC(2)); 5.25 (s, HÀC(10)); 5.07 (s, HÀC(10)); 4.69 4.54 (m, CH2(9)); 4.20 4.12
(m, HÀC(3)); 2.22 (dm, J ˆ 12.5, 1 H), 2.16 1.93 (m, 3 H), 1.93 1.76 (m, 1 H), 1.67 1.54 (m, 1 H)
‡
(HÀC(4), OHÀC(3), CH2(5), CH2(6)); 2.11 (s, MeCOO); 1.73 (s, Me(7)). MS: 192 (2, [M À H2O] ), 177
(1), 167 (1), 150 (20), 135 (37), 132 (18), 122 (15), 117 (19), 107 (10), 91 (24), 84 (100), 83 (34), 79 (14), 67 (19),
55 (8). Anal. calc. for C12H18O3: C 68.54, H 8.63; found: C 68.70, H 8.55.
Treatment of the diacetate (À)-17 and monoacetate (‡)-23 with KOH/MeOH under the conditions
described above gave the diols (À)-18 (96%) and (‡)-18 (93%), respectively.
Data of (À)-18: M.p. 72 738. [a]2D0 ˆ À219.6 (c ˆ 2, CHCl3). Chiral GC: ee 99%, chemical purity 98%. IR,
1H-NMR, MS: in accordance with that of (Æ)-18.
Data of (‡)-18: M.p. 71 728. [a]2D0 ˆ ‡204.8 (c ˆ 2, CHCl3). Chiral GC: ee 94%, chemical purity 97%. IR,
1H-NMR, MS: in accordance with that of (Æ)-18.
4. Lactones 1, 22, and 2. 4.1. (‡)-(1R,3R,4S,8R)- and (À)-(1S,3S,4R,8S)-3-Hydroxy-p-menthan-9-oic Acid
Lactone (ˆ(3R,3aS,6R,7aR)- and (3S,3aR,6S,7aS)-Hexahydro-3,6-dimethylbenzofuran-2(3H)-one; (‡)-1 and
(À)-1, resp.). A soln. of diol (À)-12 (1.9 g, 11 mmol) in CH2Cl2 (40 ml) was treated with KMnO4/CuSO4 ¥ 5 H2O
according to [10i]. The obtained heterogeneous mixture was stirred at r.t. for 10 h. Then workup afforded crude
lactone, which was purified by CC (hexane/AcOEt 9 :1): pure (‡)-1 (0.95 g, 51%).
The same method was applied to the oxidation of diol (‡)-12 (1.5 g, 8.7 mmol): (À)-1 (0.8 g, 55%).
Data of (‡)-1: [a]D20 ˆ ‡104.2 (c ˆ 1.2, CHCl3). Chemical purity 97% (GC). IR: 2933, 2871, 1781, 1457,
1379, 1293, 1200, 1101, 1044, 993, 964, 849, 798. 1H-NMR: 4.00 (ddd, J ˆ 11.1, 11.1, 3.8, HÀC(3)); 2.64
(quint., J ˆ 7.6, HÀC(8)); 2.25 (ddd, J ˆ 11.1, 3.7, 3.7, HÀC(2)); 2.01 1.87 (m, 1 H), 1.87 1.71 (m, 2 H), 1.69
1.48 (m, 1 H), 1.43 1.19 (m, 1 H), 1.17 0.98 (m, 1 H) (HÀC(4), HÀC(6), HÀC(5), HÀC(1), HÀC(5),
HÀC(6)); 1.24 (ddd, J ˆ 11.1, 11.1, 11.1, HÀC(2)); 1.15 (d, J ˆ 7.6, Me(10)); 1.02 (d, J ˆ 6.6, Me(7)). MS: 167 (1,
‡
[M À 1] ), 139 (1), 124 (7), 109 (23), 95 (26), 82 (21), 81 (100), 68 (20), 67 (48), 55 (17), 41 (16). Anal. calc. for
C10H16O2: C 71,39, H 9.59; found: C 71.45, H 9.55.
Data of (À)-1: [a]2D0 ˆ À106.7 (c ˆ 1.2, CHCl3). Chemical purity 98% (GC). IR, 1H-NMR, MS: in
accordance with that of (‡)-1.
4.2. (‡)-(1R,3R,4S)- and (À)-(1S,3S,4R)-3,9-Epoxy-p-menth-8(10)-en-9-one (ˆ(3aS,6R,7aR)- and (3aR,6-
S,7aS)-Hexahydro-6-methyl-3-methylenebenzofuran-2(3H)-one; (‡)-22 and (À)-22, resp.). Diol (À)-13a (2.4 g,

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Helvetica Chimica Acta Vol. 85 (2002)
14.1 mmol) in CH2Cl2 (100 ml) was stirred with MnO2 (6 g, 69 mmol) at r.t. for 3 h. Filtration and evaporation
afforded the crude hydroxy-aldehyde, which was dissolved in dry benzene (100 ml) and stirred with 10%
Ag2CO3 on Celite (45 g, 16.3 mmol). The mixture was heated under reflux for 12 h, then cooled, and filtered.
The filtrate was evaporated and the residue purified by CC (hexane/AcOEt 9 :1). Bulb-to-bulb distillation of
the product (oven temp. 105 1108/0.2 Torr) afforded pure (‡)-22 (1.95 g, 83%).
The same method was applied to the oxidation of diol (‡)-13a (2.2 g, 12.9 mmol): (À)-22 (1.85 g, 86%).
Data of (‡)-22: M.p. 40 418. [a]2D0 ˆ ‡69.6 (c ˆ 2, CHCl3). Chemical purity 99% (GC). IR: 2945, 2925,
2862, 1771, 1678, 1455, 1403, 1354,1250, 1230, 1180, 1123, 994, 944, 842, 819, 697. 1H-NMR: 6.06 (d, J ˆ 3.1,
HÀC(10)); 5.39 (d, J ˆ 3.1, HÀC(10)); 3.73 (ddd, J ˆ 11.0, 11.0, 3.6, HÀC(3)); 2.36 (tq, J ˆ 11.0, 3.1, HÀC(4));
2.12 (dq, J ˆ 12.5, 3.1, HÀC(5)); 2.27 (dm, J ˆ 11.8, 1 H), 1.85 (dm, J ˆ 13.4, 1 H), 1.75 1.53 (m, 1 H), 1.45
1.25 (m, 2 H) (HÀC(6), HÀC(5), HÀC(1), CH2(2)); 1.14 (ddd, J ˆ 12.5, 12.2, 3.9, HÀC(6)); 1.04 (d, J ˆ 6.5,
‡
‡
HÀC(7)). MS: 167 (1, [M ‡ 1] ), 166 (11, M ), 165 (6), 151 (4), 138 (85), 133 (5), 123 (25), 120 (23), 110 (31),
109 (44), 95 (58), 94 (100), 81 (60), 79 (55), 67 (46), 55 (38), 41 (29). Anal. calc. for C10H14O2: C 72.26, H 8.49;
found: C 72.35, H 8.45.
Data of (À)-22: M.p. 40 418. [a]2D0 ˆ À62.1 (c ˆ 1.6, CHCl3). Chemical purity 98% (GC). IR, 1H-NMR,
MS: in accordance with that of (‡)-22.
4.3. (À)-(1R,3R)- and (‡)-(1S,3S)-3,9-Epoxy-p-menth-4(8)-en-9-one (ˆ(À)- and (‡)-Mintlactone
(ˆ(6R,7aR)- and (6S,7aS)-5,6,7,7a-Tetrahydro-3,6-dimethylbenzofuran-2(4H)-one; (À)-2 and (‡)-2, resp. A
soln. of lactone (‡)-22 (0.8 g, 4.8 mmol) in dry toluene (40 ml) was heated under reflux and N2 with a cat.
amount of [RhH(Ph3P)4] (10 mol-%) until no more (‡)-22 was detected by GC (20 h). The mixture was then
cooled and the solvent evaporated. The residue was purified by CC (hexane/AcOEt 8 :2) and bulb-to-bulb
distillation (oven temp. 105 1108/0.2 Torr): pure (À)-2. Colorless oil (0.73 g, 91%).
The same method was applied to the isomerization of lactone (À)-22 (0.5 g, 3 mmol): (‡)-2 (0.46 g, 92%).
Data of (À)-2: [a]2D0 ˆÀ 61.3 (c ˆ 2, EtOH). Chemical purity 99% (GC). IR: 2954, 2930, 2872, 1756, 1688,
1
1456, 1330, 1300, 1099, 1075, 1031, 998, 858, 767, 753, 685. H-NMR: 4.63 (br. dd, J ˆ 11.2, 6.0, HÀC(3)); 2.80
(ddd, J ˆ 14.0, 4.4, 2.0, 1 H), 2.20 (br. ddd, J ˆ 14, 14, 5.5, 1 H) (CH2(5)); 2.48 2.36 (m, 1 H), 2.01 1.88
(m, 1 H), 1.81 1.61 (m, 1 H), 1.12 0.92 (m, 2 H) (CH2(6), CH2(2), HÀC(1)); 1.81 (t, J ˆ 1.6, Me(10)); 1.01
‡
‡
(d, J ˆ 6.6, Me(7)). MS: 167 (10, [M ‡ 1] ), 166 (100, M ), 151 (2), 138 (28), 137 (57), 123 (18), 110 (22), 109
(36), 95 (34), 81 (38), 67 (34). Anal. calc. for C10H14O2: C 72.26, H 8.49; found: C 72.15, H 8.50.
Data of (‡)-2: [a]D20 ˆ ‡56.2 (c ˆ 2, EtOH). Chemical purity 99% (GC). IR, 1H-NMR, MS: in accordance
with that of (À)-2.
5. p-Menthane Ether 10 and 24. 5.1. (‡)-(3R,4R)- and (‡)-(3S,4S)-3,9-Epoxy-p-mentha-1,8(10)-diene
(ˆ(3aR,7aR)- and (3aS,7aS)-2,3,3a,4,5,7a-Hexahydro-6-methyl-3-methylenebenzofuran; (‡)-10 and (À)-10,
resp.). To a soln. of diol (À)-18 (2.1 g, 12.5 mmol) in Et2O (200 ml), 5% aq. HCl soln. (2 ml) was added. The
mixture was stirred at r.t. for 1 h an then washed with H2O (50 ml) and brine (100 ml). The org. layer was
separated, dried (Na2SO4), and concentrated atmospheric pressure by distillation of the solvent through a short
Vigreux column. The crude product was purified by CC (hexane, hexane/Et2O 9 :1). The fractions containing
(‡)-10 were concentrated again at atmospheric pressure. Further purification by bulb-to-bulb distillation (oven
temp. 90 958/20 Torr) gave pure (‡)-10 (1.73 g, 92%). Colorless oil.
The same procedure was applied to diol (‡)-18 (2.5 g, 14.9 mmol): (À)-10 (2.1 g, 94%).
Data of (‡)-10: [a]D20 ˆ ‡42.5 (c ˆ 1.2, CHCl3). Chemical purity 98% (GC). IR: 2927, 2834, 1672, 1449,
1381, 1058, 1033, 942, 927, 906, 884. 1H-NMR: 5.56 5.50 (m, HÀC(2)); 4.97 (q, J ˆ 2.2, HÀC(10)); 4.93 (q, J ˆ
2.2, HÀC(10)); 4.46 4.36 (m, 1 H), 4.35 4.23 (m, 2 H) (HÀC(3), CH2(9)); 2.62 (m, HÀC(4)); 2.18 1.81
‡
(m, 2 H), 1.80 1.54 (m, 2 H) (CH2(6), CH2(5)); 1.73 (s, Me(7)). MS: 150 (9, M ), 136 (9), 135 (100), 122 (32),
117 (4), 107 (7), 105 (6), 93 (11), 91 (21), 79 (38), 77 (13). Anal. calc. for C10H14O: C 79.96, H 9.39; found:
C 80.15, H 9.40.
Data of (À)-10. [a]2D0 ˆ À37.8 (c ˆ 2, CHCl3). Chemical purity 96% (GC). IR, 1H-NMR, MS: in accordance
with that of (‡)-10.
5.2. (‡)-(3R,4R)- and (À)-(3S,4S)-3,9-Epoxy-p-mentha-1,8(9)-diene (ˆ(3aR,7aR)- and (3aS,7aS)-
3a,4,5,7a-Tetrahydro-3,6-dimethylbenzofuran; (‡)-24 and (À)-24, resp.). A soln. of (‡)-10 (0.9 g, 6 mmol) in
dry toluene (40 ml) was heated under reflux and N2 in the presence of a cat. amount of [RhH(Ph3P)4] (10 mol-
%) until no more (‡)-10 was detected by GC (36 h). The mixture was then cooled, and both the solvent and the
catalyst were removed by CC (hexane; hexane/Et2O 9 :1). The fractions containing (‡)-24 were concentrated at
atmospheric pressure by distillation of the solvent through a short Vigreux column. The residue was further
purified by bulb-to-bulb distillation (oven temp. 95 1008/20 Torr): pure (‡)-24 (0.75 g, 83%). Colorless oil.
The same method was applied to the isomerization of ether (À)-10 (0.6 g, 4 mmol): (À)-24 (0.47 g, 78%).

Helvetica Chimica Acta Vol. 85 (2002)
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Data of (‡)-24: [a]D20 ˆ ‡146.7 (c ˆ 1.5, CHCl3). Chemical purity 95% (GC). IR: 2962, 2925, 2882, 2857,
1
1667, 1448, 1434, 1380, 1257, 1091, 915, 891, 839. H-NMR: 6.04 (t, J ˆ 1.4, HÀC(9)); 5.63 5.57 (m, HÀC(2));
4.71 (dm, J ˆ 8.8, HÀC(3)); 2.59 (td, J ˆ 8.8, 4.4, HÀC(4)); 2.06 1.72 (m, 3 H), 1.45 1.26 (m, 1 H) (CH2(6),
‡
‡
CH2(5)); 1.77 (s, Me(7)); 1.65 (t, J ˆ 1.4, Me(10)). MS: 151 (11, [M ‡ 1] ), 150 (100, M ), 135 (21), 121 (41), 117
(16), 115 (9), 107 (16), 105 (18), 93 (40), 91 (50), 82 (19), 79 (30), 77 (28), 65 (7). Anal. calc. for C10H14O:
C 79.96, H 9.39; found: C 79.85, H 9.35.
Data of (À)-24: [a]2D0 ˆ À129.2 (c ˆ 2, CHCl3). Chemical purity 95% (GC). IR, 1H-NMR, MS: in
accordance with that of (‡)-24.
6. (À)-(R)- and (‡)-(S)-Vesperal (ˆ(1S)- and (1R)-4-Methyl-a-methylene-2-oxocyclohex-3-eneacetalde-
hyde; (‡)-11). Triacetoxy-periodinane (0.6 g, 1.4 mmol) was added portionwise to a cooled (08) soln. of (À)-18
(0.2 g, 1.2 mmol) in CH2Cl2 (40 ml) under N2. The mixture was stirred for 1 h at 08 and then allowed to warm to
r.t. After 24 h, the mixture was treated with sat. Na2S2O3 soln. (30 ml) and sat. NaHCO3 soln. (30 ml). The aq.
layer was extracted with CH2Cl2 (2 Â 40 ml), the combined org. phase dried (Na2SO4) and evaporated, and the
residue purified by CC (hexane/AcOEt 8 :2): pure (À)-11 (140 mg, 71%). White solid.
The same procedure was applied to oxidize (‡)-18 (0.3 g, 1.8 mmol): (‡)-11 (215 mg, 73%).
Data of (À)-11: M.p. 528. [a]2D0 ˆ À50.6 (c ˆ 1.1, CH2Cl2). Chemical purity 97% (GC). IR: 3057, 2940, 1695,
1668, 1640, 1426, 1380, 1318, 1215, 952, 880. 1H-NMR: 9.57 (s, CH(9)ˆO); 6.30 (s, HÀC(10)); 6.21
(s, HÀC(10)); 5.96 (s, HÀC(2)); 3.46 (dd, J ˆ 12.1, 4.9, HÀC(4)); 2.55 2.38 (m, 1 H), 2.37 2.23 (m, 1 H),
‡
2.21 2.00 (m, 2 H) (CH2(6), CH2(5)); 1.99 (s, Me(7)). MS: 164 (10, M ), 162 (14), 149 (19), 145 (14), 136 (20),
135 (28), 121 (6), 108 (7), 105 (10), 91 (17), 82 (100), 77 (9), 65 (5), 54 (15). Anal. calc. for C10H12O2: C 73.15,
H 7.37; found: C 73.05, H 7.45.
Data of (‡)-11: M.p. 508. [a]2D0 ˆ ‡46.2 (c ˆ 1, CH2Cl2). IR, 1H-NMR, MS: in accordance with those of
(À)-11.
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Received March 27, 2002