Natural p-menthene monoterpenes: Synthesis of the enantiomeric forms of wine lactone, epi-wine lactone, dill ether, and epi-dill ether starting from a common intermediate

Article abstract of DOI:10.1002/hlca.200490189

A concise synthesis of the enantiomeric forms of wine lactone (5), epi-wine lactone (14), dill ether (6), and epi-dill ether (15) was accomplished starting from the enantiomeric forms of p-mentha-1,8(10)-diene-3,9-diol (8) (Scheme 3). The latter compounds were previously prepared in high optical purity by means of lipase-mediated kinetic resolution, and they were the common building blocks for this divergent synthesis. The key steps were a number of chemo- and diastereoselective reactions of which the oxidation of 8 to the lactone 7 (see Table 1), the diastereoselective reduction of 7 to the lactones 14 and 5 (see Table 2), and the reduction of enolether 16 to ether 15 were studied comprehensively. The effectiveness of this new synthetic approach allows the preparation of the title p-menthane monoterpenes, which are of considerable interest to the perfume industry, in high yield and in a few simple experimental steps.

Full text of DOI:10.1002/hlca.200490189

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Helvetica Chimica Acta Vol. 87 (2004)
Natural p-Menthene Monoterpenes: Synthesis of the Enantiomeric Forms
of Wine Lactone, Epi-wine Lactone, Dill Ether, and Epi-dill Ether Starting
from a Common Intermediate
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
A concise synthesis of the enantiomeric forms of wine lactone (5), epi-wine lactone (14), dill ether (6), and
epi-dill ether (15) was accomplished starting from the enantiomeric forms of p-mentha-1,8(10)-diene-3,9-diol
(8) (Scheme 3). The latter compounds were previously prepared in high optical purity by means of lipase-
mediated kinetic resolution, and they were the common building blocks for this divergent synthesis. The key
steps were a number of chemo- and diastereoselective reactions of which the oxidation of 8 to the lactone 7 (see
Table 1), the diastereoselective reduction of 7 to the lactones 14 and 5 (see Table 2), and the reduction of enol-
ether 16 to ether 15 were studied comprehensively. The effectiveness of this new synthetic approach allows the
preparation of the title p-menthane monoterpenes, which are of considerable interest to the perfume industry, in
high yield and in a few simple experimental steps.
1. Introduction. The 3,9-dioxygenated p-menthane monoterpenes are well-known
natural products. Recently, we have reported [1] the enzyme-mediated preparation of a
number of enantiomerically pure p-menthan-3,9-diols and their use for the synthesis of
some p-menthane lactones and ethers belonging to this class. By means of this
approach, we obtained both enantiomeric forms of several natural compounds of
different chemical structures such as the 3-hydroxy-p-menthan-10-oic acid lactone (1),
mintlactone (2), (‡)-3,9-epoxy-p-menth-1,8(10)-diene (3), and vesperal (4).
In connection with our continuing interest in the development of synthetic
approaches to enantiomerically pure flavors and fragrances, we extended our studies on
the preparation of p-menth-1-ene lactones and ethers showing cis configuration at the
3,4 position of the p-menthane framework. The latter kind of compound has been
found in Nature, and different researches have demonstrated that both the character
and intensity of their odors are related to relative and absolute configurations [2]. This
¹ 2004 Verlag Helvetica Chimica Acta AG, Z¸rich

Helvetica Chimica Acta Vol. 87 (2004)
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is the case for wine lactone (5), which was first identified as an animal metabolite [3]
then recognized as a key flavor compound of different white wines [4], and, recently, it
was found in orange juice and black pepper [5]. The eight possible isomers of wine
lactone were prepared by Guth [6], and the olfactory evaluation revealed that natural 5
is the most-powerful isomer with an odor threshold < 0.04 pg/l, whereas the weakest
isomers show a threshold > 106 pg/l. These characteristics clearly demonstrate that
odor features are dramatically influenced by the configuration. A similar case is that of
dill ether (6), which is the most-important constituent of dill essential oil from an
organoleptic point of view [7]. Its absolute configuration was elucidated by stereo-
selective synthesis [8], and, only recently, the preparation of its eight isomeric forms
[9a c] allowed to establish that 6 shows a high odor-activity value and is the character-
impact compound of dill-herb flavor. It is noteworthy that 5 and 6 show the same
absolute configuration and a cis relationship at the 3,4 position. Moreover, wine lactone
and dill ether share the difficult accessibility by chemical synthesis, particularly in
enantiomerically pure form.
In this context, the first preparation of enantiomerically pure wine lactone (5) is due
to Guth [6] who, starting from (‡)- and (À)-limonene, prepared the eight isomers of
wine lactone as a mixture of diastereoisomers and then separated these by
chromatography. Again starting from an enantiomerically pure building block, Chavan
and co-workers [10] described the conversion of (‡)-isolimonene to (À)-wine lactone
and its 8-epimer by means of iodolactonization as the key step. An enantioselective
asymmetric synthesis of the same two compounds was reported by Bergner and
Helmchen [11]. The latter approach is based on a Pd-catalyzed enantioselective allylic
substitution and involved the use of asymmetric ligands and a number of chemical
manipulations.
Dill ether (6) was prepared first by Ohloff and co-workers [12] before its isolation in
Nature. This synthetic pathway started from (À)- and (‡)-limonene and afforded,
besides some 2,9-epoxy-p-menthene isomers, the 3,4-cis-configured stereoisomer of 6
as a couple of enantiomerically pure diastereoisomers. Mosandl and co-workers [9a,b]
reported two synthetic methods for the preparation of 3,4-cis- and 3,4-trans-configured
stereoisomers of 6 starting from the eight isomers of wine lactone, which, in turn, were
obtained by the Guth procedure from (À)- and (‡)-limonene.
Based on these observations, it seemed desirable to develop a new synthetic method
to the enantiomerically pure forms of 5 and 6 by means of a procedure not necessarily
involving troublesome diastereoisomer separation, low-yielding steps, or the use of
expensive catalyst and enantiomerically pure starting materials.
According to our retrosynthetic analysis (Scheme 1), we anticipated that diol 8
could be a useful building block for the preparation of both wine lactone and dill ether.
We have previously prepared the enantiomeric form of 8 in high enantiomeric purity
by lipase-mediated acetylation of the racemic material [1]. This latter was obtained by
diastereoselective DielsÀAlder reaction of the easily available vinyl ketone 10 and
diene 11 followed by Wittig methylenation and hydrolysis. To achieve our synthesis
plan, diol 8 should be chemoselectively oxidized to lactone 7 and then diastereose-
lectively reduced to 5. The latter compound is the direct precursor of 6, which should
be obtained also by chemoselective reduction of ether 3, the latter being again easily
available from 8.

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Scheme 1. Retrosynthetic Analysis
2. Results. 2.1. Oxidation of Diols (‡)- and (À)-8. The preparation of wine
lactone (5) by our synthetic pathway required the preparation of a,b-unsaturated
lactone 7. The chemoselective oxidation of 8 is an intriguing synthesis step since both
OH groups are in an allylic position. Therefore, compounds derived from the oxidation
of the secondary OH group such as keto-aldehyde 4 and lactol 13 and those showing
partial oxidation at C(9) such as lactol 12 are possible products of the reaction
(Scheme 2). To find the best procedure to obtain 7, we tested different oxidants
(Table 1). With transition-metal reagents, the oxidation of 8 afforded a mixture of
lactone 7 and keto-aldehyde 4 without formation of the lactols 12 and 13. Pyridinium
chlorochromate (PCC) gave mainly 4, whilst MnO2 in the same solvent showed reverse
selectivity. Even though the reagent Ag2CO3 on Celite [13] was described as an
Scheme 2

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Table 1. Oxidation of Diol 8
a
b
Oxidant
)
Conditions (solvent, time, temp.) Product distribution [%] )
8
7
12/13
4
unidentified
PCC (2.1 equiv.)
MnO2 (5 equiv.)
Ag2CO3/Celite (5 equiv.)
IBX (5 equiv.)
BAIB (3 equiv.), TEMPO (cat.) CH2Cl2, 4 h, r.t
DMP (2.1 equiv.) CH2Cl2, 5 h, r.t.
CH2Cl2, 2 h, r.t.
0c) 24
0c) 60
0c) 73
0c)
0c)
0c)
54
68
38
25
22
2
8
2
2
6
1
5
CH2Cl2, 4 h, reflux
benzene, 6 h, reflux
DMSO, 6 h, r.t.
16
2
0c) 97
0c)
0c)
0c)
6
89
a) PCC ˆ pyridinium chlorochromate, IBX ˆ 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide; BAIB ˆ bis(ace-
tato-kO)phenyliodine; TEMPO ˆ 2,2,6,6-tetramethylpyridin-1-yloxy; DMP ˆ DeanÀMartin periodinane ˆ
1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one. b) The products distribution was measured after
workup by GC analysis. c) The compound was not detected by GC analysis.
excellent chemoselective oxidant for the preparation of butenolides starting from 1,4
diols [14], we observed that the latter reagent was fairly superior to MnO2.
Hypervalent iodine oxidants demonstrated a considerably different behavior over
the previously mentioned reagents. The selective transformation of p-menthan-3,9-
diols [15a] to the corresponding 9-hydroxy-lactols by means of o-iodoxybenzoic acid
( ˆ 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide; IBX) in DMSO [15b] was previ-
ously reported. In our hands, the latter approach proceeded without chemoselective
control affording predominantly a mixture of lactols 12 and 13 besides keto-aldehyde 4,
unreacted 8, and a trace of lactone 7. Further, the use of DessÀMartin periodinane
(ˆ1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one; DMP) [16] gave se-
lectively 4 free of any lactol isomers, besides a small amount of 7. Surprisingly enough,
the use of catalytic TEMPO (ˆ2,2,6,6-tetramethylpiperidin-1-yloxy) and [bis(acetoxy)-
iodo]benzene (ˆ bis(acetato-kO)-phenyliodine; BAIB) [17] as the co-oxidant was the
best methodology for the preparation of lactone 7. The latter approach was previously
used for the selective oxidation of 1,5-diols to d-lactone, and, in the present work, we
describe its usefulness also for the conversion of 1,4-diols 8 to g-lactone 7. Indeed, this
procedure is the most selective and effective of those tested (see Table 1) yielding
enantiomerically pure 7 in up to 97% yield with complete transformation of the starting
diol 8.
2.2. Reduction of Lactone 7. According to our retrosynthetic analysis, we studied the
reduction of 7 to wine lactone (5) and/or its 8-epimer 14. Some problems of regio- and
diastereoselectivity arose since only the C(8)ˆC(10) bond should be reduced giving
two possible isomers. All the reducing agents tested (Table 2) left the C(1)ˆC(2)
unaffected but showed different activities on the conjugated C(8)ˆC(10) bond. In all
cases, the main reduction product was epi-wine lactone (14). The use of Mg turnings in
MeOH [18] was the most effective procedure, since all starting 7 was reduced, and the
smallest amount of unidentified by-products (<1%) was formed. Different results were
obtained with the hydrides as reducing agents. Both NaBH4 in EtOH and in situ formed
copper hydride (Bu3SnH/LiCl/CuI) [19] in THF reduced 7 efficiently showing a slightly
superior diastereoselectivity in the formation of 14 than Mg in MeOH. The reduction
with silicon [20] and tin [21] hydrides afforded, besides the lactones 14 and 5, a

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Helvetica Chimica Acta Vol. 87 (2004)
Table 2. Reduction of Lactone 7
Reducing agent
Conditions (solvent, time, temp.)
Product distribution [%)]a)
7
5
14
unidentified
Mg
NaBH4
MeOH, 3 h, r.t.
EtOH 1.5 h, r.t.
benzene, 4 h, r.t.
THF, 4 h, r.t.
THF, 1 h, À608; then 2 h, 08
0b)
0b)
0b)
5
13
5
4
6
7
86
92
26
51
90
1
3
Et3SiH, [RhCl(PPh3)3] (cat.)
Bu3SnH, [PdCl2(PPh3)2] (cat.)
Bu3SnH/LiCl/CuI
70c)
c
38
2
)
1
a) The product distribution was measured after workup by GC analysis. b) The compound was not detected by
GC analysis. c) GC/MS Analysis showed that more than 95% of the unidentified compounds corresponded to a
single isomer of lactone 7. The isolation procedure afforded an inseparable mixture of lactone 14 and the
unidentified compound; its structure was determined as 3,9-epoxy-p-mentha-1,4(8)-dien-9-one by MS and 1H-
NMR analysis.
considerable amount of 3,9-epoxy-p-mentha-1,4(8)-dien-9-one, which is an isomer of
7. This is probably due to the RhI and PdII catalyst used in association with Et3SiH and
Bu3SnH that allowed both reduction and isomerization of the conjugated CˆC bond.
2.3. Enantiomerically Pure Epi-wine Lactone (14) and Wine Lactone (5). Taking
advantage of the above-described results, we devised a method for the preparation of
all the enantiomeric forms of lactones 14 and 5. The enantiomerically pure (‡)- and
(À)-8 were oxidized with BAIB/TEMPO to afford enantiomerically pure (À)- and (‡)-
7, respectively (Scheme 3). The next step was the reduction of the conjugate CˆC bond
by means of Mg in MeOH. Lactones (À)- and (‡)-7 afforded epi-wine lactones (‡)-
and (À)-14, respectively, besides a small amount of isomeric (À)- and (‡)-5,
respectively. The enantiomers (‡)- and (À)-14 were easily separated from their
epimers (À)- and (‡)-5, respectively, by chromatography, and their optical rotation
values compared favorably with reported data [10][11] thus establishing that our
synthetic pathway does not involve racemization. Furthermore, with the objective to
prepare both enantiomers of wine lactone (5), we experimented with the basic
epimerization of 14. Thus, treatment with tBuOK in tBuOH [22] of either pure 14 or the
mixture 14/5 (> 7:1) obtained as above gave a new mixture 5/14 (>4 :1) where 5 was
the main component. By means of the latter synthetic sequence, natural wine lactone
(À)-5 and lactone (‡)-5 were prepared from (À)- and (‡)-7, respectively, in
enantiomerically pure form and with an overall yield of ca. 55%.
2.4. Enantiomerically Pure Dill Ether (6) and Epi-Dill Ether (15). The trans-
formation of lactones 5 and 14 to the dill ether (6) and epi-dill ether (15) [23],
respectively, was achieved by a slight modification of a known procedure [9a,b]. It was
reported that the LiAlH4 reduction of these lactones affords smoothly the correspond-
ing diastereoisomeric diols that could be cyclized to the related ethers by treatment
with an acid catalyst. This ring closure affords stereospecifically the bicyclic ethers with
3,4-cis configuration. Consequently, starting from enantiomerically pure lactones with
these structural features, the overall process affords the corresponding ethers without
any epimerization. Therefore, we submitted the lactone (À)- or (‡)-5 to LiAlH4
reduction, and the reaction mixture was quenched directly with an excess of diluted
aq. HCl solution (Scheme 3). After isolation, the natural dill ether (À)-6, and its

Helvetica Chimica Acta Vol. 87 (2004)
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Scheme 3
t
t
i) BAIB, CH2Cl2, TEMPO (cat.). ii) Mg, MeOH. iii) BuOK, BuOH. iv) 3% aq. HCl soln. v) LiAlH4, Et2O.
vi) 70% aq. HClO4 soln. (cat.), THF/H2O 2 :1. vii) NaBH4.
enantiomer (‡)-6, respectively, were obtained in chemically and isomerically pure form
as confirmed by comparison of their analytical data with those reported [9].
Analogously, the same procedure was applied to (‡)- and (À)-14 to afford pure epi-
dill ether (‡)- and (À)-15, respectively.
Finally, we studied a more-straightforward approach to (‡)- and (À)-15. As
mentioned in our retrosynthetic analysis, ether 3 could be a suitable precursor of dill
ether by chemoselective reduction of the C(8)ˆC(10) bond. Accordingly, we trans-
formed the diols (‡)- and (À)-8 to the ethers (À)- and (‡)-3, respectively, by treatment
with a catalytic amount of HCl. The following isomerization by means of a rhodium
hydride catalyst [1] gave the enol ethers (À)- and (‡)-16, respectively. The activated
C(8)ˆC(9) bond of the latter compounds was selectively reduced by means of a one-
pot procedure that involved hydration, reduction, and cyclization (Scheme 3). Hence,

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Helvetica Chimica Acta Vol. 87 (2004)
(À)- and (‡)-16 were dissolved in a THF/water mixture and treated with a catalytic
amount of HClO4. The starting materials were smoothly converted in the correspond-
ing lactols, which were treated with an excess of NaBH4. The mixtures were quenched
with diluted HCl solution, and the isolation procedure afforded epi-dill ethers (‡)- and
(À)-15, respectively. It is noteworthy that this synthesis path is highly diastereoselective
since the latter compounds were obtained with 93 and 94% de, respectively, without
any chromatographic separation.
3. Conclusions. A new enantiospecific approach to the isomeric forms of natural
wine lactone and dill ether is described in this work. The enantiomeric forms of p-
mentha-1,8(10)-diene-3,9-diol (8) were the common building blocks for this divergent
synthesis. The key steps were a number of chemo- and diastereoselective reactions that
were optimized. The high-quality results obtained in terms of chemical yields and
selectivity allows the preparation of all the enantiomeric forms of wine lactone (5), epi-
wine lactone (14), dill ether (6), and epi-dill ether (15). Since the starting
enantiomerically pure building blocks are straightforwardly prepared by resolution
of the corresponding racemic diol that is easily available by chemical synthesis, the
overall synthetic pathway may be regarded as a useful procedure for the enantiose-
lective preparation of these p-menthene compounds.
The authors would like to thank COFIN-MURST for partial financial support.
Experimental Part
1. General. All moisture-sensitive reactions were carried out under a static atmosphere of N2. All reagents
were of commercial quality, with the exception of Ag2CO3 on Celite, −o-iodoxybenzoic acid× (IBX),
DessÀMartin periodinane (DMP), and hydridotetrakis(triphenylphosphine)rhodium, which were prepared
according to [13], [15b], [16], and [24], respectively. Lipase PS from Pseudomonas cepacia (Amano
Pharmaceuticals Co., Japan, 30 U mgÀ1) was employed in this work. TLC: Merck silica-gel 60 F254 plates.
Column chromatography (CC): silica gel. GC: HP-6890 gas chromatograph; diastereoisomer excesses (de)
determined with a HP-5 column (30 m  0.32 mm; Hewlett-Packard) with the following temp. program 608
(1 min) 68/min 1508 (1 min) 128/min 2808 (5 min); tR in min racemic 7, 5, 14, 6, and 15: tR 17.50, 16.75, 17.76,
10.78, and 11.77, resp. M.p.: Reichert apparatus, equipped with a Reichert microscope; uncorrected. Optical
rotations: Jasco DIP-181 digital polarimeter. IR Spectra: Perkin-Elmer 2000-FT-IR spectrometer; films; nÄ in
cmÀ1. 1H- and 13C-NMR Spectra: CDCl3 solns. at r.t.; Bruker-AC-250 spectrometer at 250 MHz; chemical shifts
d in ppm rel. to internal SiMe4 (ˆ0 ppm), J values in Hz. Mass Spectra: Finnigan-Mat-TSQ-70 spectrometer; m/z
(rel. %). Microanalyses: analyzer 1106 from Carlo-Erba.
2. Enantiomerically Pure Starting Materials. 2.1. (‡)-(3S,4S)- and (À)-(3R,4R)-p-Mentha-1,8(10)-diene-3,9-
diol (ˆ(1S,2S)- and (1R,2R)-2-Hydroxy-4-methyl-b-methylenecyclohex-3-ene-1-ethanol; (‡) and (À)-8, resp.).
The resolution procedure was performed according to [1] with lipase PS as catalyst, vinyl acetate as acetyl donor,
t
and BuOMe as solvent.
Data of (‡)-8: M.p. 728. [a]2D0 ˆ ‡207.2 (c ˆ 2, CHCl3). Chiral GC: ee 95%, chemical purity (GC) 97%.
Data of (À)-8: M.p. 738. [a]2D0 ˆ À220 (c ˆ 2, CHCl3). Chiral GC: ee 99%, chemical purity (GC) 98%.
2.2. (À)-(3S,4S)- and (‡)-(3R,4R)-3,9-Epoxy-p-mentha-1,8(9)-diene (ˆ(3aS,7aS)- and (3aR,7aR)-
3a,4,5,7a-Tetrahydro-3,6-dimethylbenzofuran; (À)- and (‡)-16, resp.). According to [1], from (‡)- and (À)-8,
resp.
Data of (À)-16: [a]2D0 ˆ À132.2 (c ˆ 2, CHCl3). Chemical purity (GC) 97%.
Data of (‡)-16: [a]2D0 ˆ ‡146.5 (c ˆ 2, CHCl3). Chemical purity (GC) 97%.
3. Oxidation of Diol 8. 3.1. Keto-aldehyde 4 and Lactols 12 and 13. The product distribution after oxidation
of 8 was analyzed by GC and GC/MS. The keto-aldehyde 4 (tR 16.55) was obtained as described previously [1].
Lactol 12 was obtained by DIBAH reduction [25] of lactone 7. Compound 12 was unstable and rapidly

Helvetica Chimica Acta Vol. 87 (2004)
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decomposed after workup to give a diastereoisomer mixture of dimeric compounds. For this reason, the lactols
obtained on oxidation of 8 were not isolated and were characterized only by GC/MS.
‡
Data of 12: tR 15.05 (br.). MS: 166 (4, M ), 148 (18), 137 (16), 119 (13), 105 (24), 91 (39), 84 (100), 83 (65),
‡
79 (28), 77 (26), 65 (11), 55 (21), 39 (23). Data of 13: (tR 15.29, br.). MS: 166 (5, M ), 148 (14), 137 (18), 119 (8),
108 (14), 105 (16), 91 (26), 84 (100), 83 (64), 77 (16), 65 (9), 55 (16), 39 (18).
3.2. (‡)-(3R,4R)- and (À)-(3S,4S)-3,9-Epoxy-p-mentha-1,8(10)-dien-9-one (ˆ(3aR,7aR)- and (3aS,7aS)-
3a,4,5,7a-Tetrahydro-6-methyl-3-methylenebenzofuran-2(3H)-one; (‡)- and (À)-7, resp.). A soln. of (À)-8
(2.2 g, 13.1 mmol) in CH2Cl2 (60 ml) was treated with [bis(acetoxy)iodo]benzene (BAIB, 12.8 g, 39.7 mmol) and
2,2,6,6-tetramethylpiperidin-1-yloxy (TEMPO; 0.3 g, 1.9 mmol) and stirred at r.t. until no more (À)-8 was
detected by TLC (4 h). The mixture was then poured in ice (100 g), treated with sat. aq. Na2S2O3 soln. (100 ml)
and extracted with Et2O (2 Â 150 ml). The combined org. phase was washed with sat. aq. NaHCO3 soln. (80 ml)
and brine (100 ml), dried (Na2SO4), and evaporated and the residue purified by CC (hexane/AcOEt 9 :1): pure
(‡)-7 (1.96 g, 91%).
The same method was applied to (‡)-8 (1.8 g, 10.7 mmol): (À)-7 (1.65 g, 94%).
Data of (‡)-7: M.p. 538. [a]2D0 ˆ ‡75.3 (c ˆ 2, CHCl3). Chemical purity (GC) 97%. IR: 1756, 1744, 1668,
1450, 1441, 1383, 1319, 1246, 1194, 1114, 959, 946, 816, 651. 1H-NMR: 6.24 (d, J ˆ 2.4, 1HÀC(10)); 5.60 (d, J ˆ 2.4,
1HÀC(10)); 5.59 (m, HÀC(2)); 4.90 (m, HÀC(3)); 3.11 (m, HÀC(4)); 2.12 1.84 (m, 3 H), 1.84 1.66 (m, 1 H)
(CH2(6), CH2(5)); 1.75 (s, Me(7)). 13C-NMR: 170.3; 142.2; 138.9; 120.9; 118.2; 74.7; 37.2; 26.5; 24.3; 23.7. MS:
‡
‡
165 (3, [M ‡ 1] ), 164 (25, M ), 150 (9), 149 (100), 136 (31), 121 (16), 117 (5), 105 (32), 93 (17), 91 (33), 79
(24), 77 (20), 65 (8), 53 (19). Anal. calc. for C10H12O2: C 73.15, H 7.37; found: C 73.20, H 7.35.
Data of (À)-7: M.p. 52 538. [a]2D0 ˆ À71.6 (c ˆ 2, CHCl3). Chemical purity (GC) 97%. IR, 1H-NMR, MS:
in accordance with that of (‡)-7.
4. Epi-wine Lactone (14) and Wine Lactone (5). 4.1. Reduction of Lactone 7: (‡)-(3R,4S,8R)- and (À)-
(3S,4R,8S)-3,9-Epoxy-p-menth-1-en-9-one (ˆ(3R,3aS,7aR)- and (3S,3aR,7aS)-3a,4,5,7a-Tetrahydro-3,6-dime-
thylbenzofuran-2(3H)-one; (‡)- and (À)-14, resp.). A soln. of (À)-7 (0.5 g, 3 mmol) in MeOH (30 ml) was
treated with Mg turnings (0.3 g, 12.5 mmol) under stirring at r.t. until no more (À)-7 was detected by TLC (3 h).
The mixture was then poured into a cooled (08) 3% aq. HCl soln. (150 ml) and extracted with Et2O (3 Â 100 ml).
The combined org. phase was washed with brine (150 ml), dried (Na2SO4), and evaporated, and the residue
purified by CC (hexane/AcOEt 9 :1): pure (‡)-14 (350 mg, 70%) and (‡)-14/(À)-5 55 :45 (by GC; 120 mg,
24%).
The same method was applied to the reduction of (‡)-7 (0.5 g, 3 mmol): (À)-14 (365 mg, 73%) and (À)-14/
(‡)-5 51:49 (by GC; 100 mg, 20%).
Data of (‡)-14: M.p. 58 598. [a]2D0 ˆ ‡121.2 (c ˆ 1, CHCl3). Chemical purity 98%, d.e. 99% (GC). IR:
1752, 1670, 1449, 1384, 1352, 1203, 1172, 943, 887. 1H-NMR: 5.68 (m, HÀC(2)); 4.64 (m, HÀC(3)); 2.91 (dq, J ˆ
7.3, 7.2, HÀC(8)); 2.36 (dm, J ˆ 13.5, HÀC(4)); 2.11 1.89 (m, CH2(6)); 1.79 (s, Me(7)); 1.76 1.63 (m,
1
1HÀC(5)); 1.29 1.09 (m, HÀC(5)); 1.20 (d, J ˆ 7.2, Me(10)). 13C-NMR: 178.8; 144.0; 116.9; 74.6; 40.2; 37.8;
‡
‡
28.8; 23.7; 19.6; 9.2. MS: 167 (2, [M ‡ 1] ), 166 (31, M ), 152 (9), 151 (100), 138 (9), 123 (13), 122 (18), 107
(42), 95 (21), 93 (92), 91 (44), 79 (41), 77 (28), 69 (9), 67 (11), 65 (8), 55 (25). Anal. calc. for C10H14O2: C 72.26,
H 8.49; found: C 72.20, H 8.45.
Data of (À)-14: M.p. 59 608. [a]2D0 ˆ À124.1 (c ˆ 1, CHCl3). Chemical purity 97%, d.e. > 99% (GC). IR,
1H-NMR, MS: in accordance with that of (‡)-14.
4.2. Isomerization of 14/5: (À)-(3R,4S,8S)- and (‡)-(3S,4R,8R)-3,9-Epoxy-p-menth-1-en-9-one (ˆ(3S,3a-
S,7aR)- and (3R,3aR,7aS)-3a,4,5,7a-Tetrahydro-3,6-dimethyl-benzofuran-2(3H)-one; (À)- and (‡)-5, resp.). A
sample of (‡)14/(À)-5 87:13 (350 mg, 2.1 mmol) in tBuOH (20 ml) was treated with tBuOK (360 mg,
3.2 mmol). The resulting mixture was stirred at r.t. for 3 h and then poured in a cooled (08) 3% aq. HCl soln.
(100 ml) and extracted with Et2O (3 Â 60 ml). The combined org. phase was washed with brine (80 ml), dried
(Na2SO4), and evaporated and the residue (350 mg) purified by CC (hexane/AcOEt 9 :1): pure (À)-5 (220 mg,
63%) and (‡)-14/(À)-5 56 :44 (by GC; 105 mg, 30%).
The same method was applied to (À)14/(‡)-5 88 :12 (400 mg, 2.4 mmol): (‡)-5 (270 mg, 67%) and (À)-14/
(‡)-5 58 :42 (by GC; 100 mg, 25%).
Data of (À)-5: M.p. 50 518. [a]2D0 ˆ À13.1 (c ˆ 1, CHCl3). Chemical purity 98%, d.e. 99% (GC). IR: 1766,
1673, 1450, 1383, 1323, 1211, 1173, 1149, 973, 950, 899, 712. 1H-NMR: 5.51 (m, HÀC(2)); 4.90 (dm, J ˆ 5,
HÀC(3)); 2.43 (dq, J ˆ 7.3, 7.2, HÀC(8)); 2.33 2.20 (m, HÀC(4)); 2.12 1.93 (m, CH2(6)); 1.92 1.66 (m,
CH2(5)); 1.74 (s, Me(7)); 1.26 (d, J ˆ 7.2, Me(10)). 13C-NMR: 179.8; 140.8; 118.8; 75.5; 40.3; 37.6; 25.9; 23.7;
‡
‡
22.3; 14.0. MS: 167 (2, [M ‡ 1] ), 166 (22, M ), 152 (9), 151 (100), 138 (10), 123 (13), 122 (6), 107 (24), 95 (17),

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Helvetica Chimica Acta Vol. 87 (2004)
93 (51), 91 (28), 79 (27), 77 (18), 69 (9), 67 (8), 65 (5), 55 (18). Anal. calc. for C10H14O2: C 72.26, H 8.49; found:
C 72.20, H 8.50.
Data of (‡)-5: M.p. 49 518. [a]2D0 ˆ ‡16.4 (c ˆ 1, CHCl3). Chemical purity 98%, d.e. 99% (GC). IR,
1H-NMR, MS: in accordance with that of (À)-5.
5. Dill Ether (6) and Epi-dill Ether (15). 5.1. Reduction of Lactone 5 and 14: (À)-(3R,4S,8S)- and (‡)-
(3S,4R,8R)-3,9-Epoxy-p-menth-1-ene (ˆ(3S,3aS,7aR)- and (3R,3aR,7aS)-2,3,3a,4,5,7a-Hexahydro-3,6-dime-
thylbenzofuran; (À)- and (‡)-6, resp.) and (‡)-(3R,4S,8R)- and (À)-(3S,4R,8S)-3,9-Epoxy-p-menth-1-ene
(ˆ(3R,3aS,7aR)- and (3S,3aR,7aS)-2,3,3a,4,5,7a-Hexahydro-3,6-dimethylbenzofuran; (‡)- and (À)-15, resp.).
A soln. of (À)-5 (100 mg, 0.6 mmol) in dry Et2O (10 ml) was added dropwise to a suspension of LiAlH4 (50 mg,
1.3 mmol) in dry Et2O (10 ml). After stirring for 1 h at r.t., the mixture was cautiously treated with an excess of
3% aq. HCl soln. (50 ml) and further stirred for 1 h. The mixture was then diluted with Et2O (20 ml), the aq.
phase extracted with Et2O (20 ml), the combined org. phase washed with brine (50 ml), dried (Na2SO4), and
evaporated, and the residue purified by bulb-to-bulb distillation (oven temp. 95 1008/25 Torr): pure (À)-6
(75 mg, 82%).
The same method was applied to (‡)-5 (80 mg, 0.48 mmol), to (‡)-14 (130 mg, 0.78 mmol), and to (À)-14
(120 mg, 0.72 mmol): (‡)-6 (55 mg, 75%), (‡)-15 (100 mg, 84%), and (À)-15 (90 mg, 82%), resp.
Data of (À)-6: [a]D20 ˆ À7.3 (c ˆ 1, CHCl3). Chemical purity 99%, d.e. 99% (GC). IR: 1673, 1449, 1380,
1081, 1028, 991, 956, 925, 897, 836. 1H-NMR: 5.52 (m, HÀC(2)); 4.24 (br. s, HÀC(3)); 4.06 (dd, J ˆ 8.3, 7.5,
1HÀC(9)); 3.30 (dd, J ˆ 8.3, 7, 1HÀC(9)); 2.08 1.97 (m, HÀC(8)); 1.97 1.80 (m, CH2(6)); 1.77 1.66 (m,
HÀC(4), 1HÀC(5)); 1.70 (s, Me(7)); 1.56 1.45 (m, 1HÀC(5)); 1.05 (d, J ˆ 6.9, Me(10)). 13C-NMR: 138.8;
‡
‡
121.1; 75.1; 74.1; 44.0; 38.0; 28.2; 24.2; 23.7; 17.7. MS: 152 (5, M ), 151 (6, [M À 1] ), 138 (11), 137 (100), 124 (6),
119 (1), 109 (33), 107 (5), 95 (12), 93 (14), 91 (16), 79 (15), 77 (12), 69 (24), 67 (11), 55 (10). Anal. calc. for
C10H16O: C 78.90, H 10.59; found: C 78.85, H 10.55.
1
Data of (‡)-6: [a]D20 ˆ ‡8.1 (c ˆ 1, CHCl3). Chemical purity 99%, d.e. 99% (GC). IR, H-NMR, MS: in
accordance with that of (À)-6.
Data of (‡)-15: [a]D20 ˆ ‡127.9 (c ˆ 1, CHCl3). Chemical purity 99%, d.e. 99% (GC). IR: 1673, 1592, 1449,
1380, 1083, 1052, 1025, 995, 930, 899. 1H-NMR: 5.61 (m, HÀC(2)); 4.18 (br. s, HÀC(3)); 3.94 (t, J ˆ 8.2,
1HÀC(9)); 3.46 (dd, J ˆ 10, 8.2, 1HÀC(9)); 2.68 2.44 (m, HÀC(8)); 2.07 1.83 (m, HÀC(4), CH2(6)); 1.74 (s,
Me(7)); 1.66 1.52 (m, 1HÀC(5)); 1.37 1.15 (m, 1HÀC(5)); 1.00 (d, J ˆ 7.2, Me(10)). 13C-NMR: 140.2; 120.0;
‡
‡
76.1; 72.3; 40.1; 37.0; 29.7; 23.6; 19.0; 11.6. MS: 152 (4, M ), 151 (4, [M À 1] ), 138 (9), 137 (100), 124 (4), 119
(2), 109 (26), 107 (6), 105 (3), 95 (10), 93 (14), 91 (14), 79 (13), 77 (11), 69 (21), 67 (8), 55 (8). Anal. calc. for
C10H16O: C 78.90, H 10.59; found: C 78.80, H 10.60.
Data of (À)-15: [a]2D0 ˆ À133.4 (c ˆ 1, CHCl3). Chemical purity 99%, d.e. 99% (GC). IR, 1H-NMR, MS: in
accordance with that of (‡)-15.
5.2. Reduction of Enol Ether 16. A soln. of (À)-16 (250 mg, 1.67 mmol) in THF (50 ml) was treated with
H2O (20 ml) and 70% aq. HClO4 soln. (0.2 ml, 2.3 mmol). The mixture was stirred at r.t. until no more (À)-16
was detected by TLC (36 h) and then treated with an excess of NaBH4 (320 mg, 8.46 mmol). The mixture was
set aside for 1 h, quenched with 3% aq. HCl soln. (100 ml), and further stirred for 1 h. After dilution with Et2O
(40 ml), the aq. phase was extracted with Et2O (40 ml), the combined org. phase washed with brine (50 ml),
dried (Na2SO4), and evaporated, and the residue purified by bulb-to-bulb distillation (oven temp. 95 1008/25
Torr): (‡)-15 (185 mg, 73%).
The same method was applied to (‡)-16 (200 mg, 1.33 mmol): (À)-15 (135 mg, 67%).
Data of (‡)-15: [a]2D0 ˆ ‡125.4 (c ˆ 1, CHCl3). Chemical purity 98%, d.e. 93% (GC). IR, 1H-NMR, MS: in
accordance with that of (‡)-15.
Data of (À)-15: [a]2D0 ˆ À129.4 (c ˆ 1, CHCl3). Chemical purity 98%, d.e. 94% (GC). IR, 1H-NMR, MS: in
accordance with that of (‡)-15.
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Received March 17, 2004