Synthesis and organoleptic properties of p-menthane lactones

Article abstract of DOI:10.1016/S0040-4020(00)00397-5

The stereoselective synthesis and organoleptic properties of p-menthane lactones 7a-h are described. Apart from correcting the published data concerning these compounds, this work has also allowed an unambiguous identification of 7a, 7b and 7g in Italo Mi

Full text of DOI:10.1016/S0040-4020(00)00397-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4769±4776
Synthesis and Organoleptic Properties of p-Menthane Lactones
*
Jean-Marc Gaudin
Firmenich S.A., Corporate R&D Division, P.O. Box 239, 1211 Geneva 8, Switzerland
Received 19 October 1999; accepted 15 May 2000
AbstractÐThe stereoselective synthesis and organoleptic properties of p-menthane lactones 7a±h are described. Apart from correcting the
published data concerning these compounds, this work has also allowed an unambiguous identi®cation of 7a, 7b and 7g in Italo Mitcham
black peppermint oil (Mentha piperita). In addition, these lactones are of considerable interest to the perfume industry, due to their
exceptional odor intensity and typical coumarin-like note. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Southwell has isolated lactone 5 from the metabolized
essential oil of eucalyptus leaves (Eucalyptus punctata).5
The family of p-menthane lactones is a very interesting
class of compounds for a variety of reasons. For example,
(2)-mintlactone 1a, (1)-isomintlactone 1b and lactones 2,
3 have been identi®ed as minor components from the essen-
tial oil of black peppermint oil (Mentha piperita).1 1a,b are
used as commercial ¯avoring ingredients, and numerous
syntheses of these natural lactones have been reported.2,3
Lactone 4, named wine lactone, has been detected in
several white wines and appears to be an important ¯avor
compound, possessing a sweet coconut odor and a
particularly low threshold (1025 ng/l of air).4 In addition,
Moreover, the isolation of many natural biologically active
mono and sesquiterpenoid a-methylene-g-butyrolactones
has resulted in the synthesis of compounds 6a and 6b6
(Scheme 1).
These lactones, except 3 and 5, are fully characterized in the
literature.
On the other hand, the saturated analogs 7a±h (Scheme 2),
are reported to be insect repellents.7 They have also been
Scheme 1.
Scheme 2.
* Tel.: 141-22-780-34-76; fax: 141-22-780-33-34; e-mail: jean-marc.gaudin@®rmenich.com
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00397-5

4770
J.-M. Gaudin / Tetrahedron 56 (2000) 4769±4776
Scheme 3. (a) mCPBA/CH2Cl2 (88%); (b) LDA/THF (74%); (c) H2/Pd±C (70%); (d) crystallization; (e) KMnO4 (76%); (f) B2H6/NaOH (94%).
used as key intermediates in a synthesis of Pseudopterosins8
and in the synthesis of the promising anti-malaria active
principle 8, isolated from the plant Artemisia annua.9 Five
of these stereoisomers are speci®cally cited in the
literature3,6d,7,8,1,10±14 but are sometimes only partially
characterized, often as a result of synthesis using non stereo-
selective routes.3e,7,10,11 It is evident that, due to the
similarity of their spectral data, unambiguous structural
elucidation of the individual isomers is dif®cult and leads
to errors in stereochemical assignments.
treatment with LDA in THF (2.28 mol equiv.)17 (74%) and
catalytic hydrogenation of the resulting allylic alcohol
(70%) afforded diols 11a/11b. Separation by crystallization
and subsequent oxidation with potassium permanganate16
gave the lactones 7a and 7b.
An alternative and more direct approach was used to synthe-
size 7c and 7d, starting from (1)-neoisopulegol 10. Thus,
hydroboration gave a mixture of diols 11c/11d (20/80) in
94% yield.17 These crude diols were then oxidized with
potassium permanganate to afford 7c/7d (20/80) in 76%
yield. Recrystallization directly afforded pure 7c, whereas
7d was isolated from the mother liquor by preparative GC.
This route was also repeated with 9 as starting material,
allowing a more ef®cient access to 7a/7b.
Our interest in 7a±h results primarily from their powerful
coumarin-like odor properties,15 and we now present the
stereoselective syntheses and full spectral characterization
of all eight stereoisomers, together with a description of
their individual organoleptic properties.
Lactones 7e and 7f were synthesized from (2)-mintlactone
1a (e.e. 97%) as shown in Scheme 4.
Results and Discussion
Synthesis of (7a±h)
Thus, stereoselective catalytic reduction of (2)-mintlactone
1a using Raney nickel under 40 atmospheres of hydrogen
afforded 7f (96%), which underwent ready base-catalyzed
epimerization (MeONa/MeOH) to the thermodynamically
more stable 7e. This equilibration is fully in favor of 7e
(see later). Similarly, reduction of (1)-isomintlactone 1b
gave the already mentioned 7c. It is interesting to note
that the reduction of (2)-mintlactone 1a by magnesium in
methanol19 provided 7e (88%) directly with high diastereo-
selectivity.
Starting from (2)-isopulegol 9 and (1)-neoisopulegol 10
(e.e.$99%), isomers 7a-d were synthesized according to
known procedures16±18 (Scheme 3).
18
Thus, epoxidation of 9 in CH2Cl2 (88%), followed by
In order to synthesize the ®nal two isomers 7g and 7h, it was
necessary to inverse the stereochemistry at the C(7a)
position (Scheme 5).
To carry out this synthetic transformation, we opted for a
Scheme 4. (a) H2/Raney Ni; (b) MeOH; (c) Mg/MeOH.
Scheme 5.

J.-M. Gaudin / Tetrahedron 56 (2000) 4769±4776
4771
Scheme 6. (a) LiAlH4; (b) Ac2O; (d) Jones reagent; (d) Li/liq NH3/Et2O/NH4Cl; (e) KMnO4; (f) MeONa/MeOH.
Scheme 7.
method published by Garcia-Granados et al. to convert 6a-
lactones into 6b-lactones in the eudesmane series.20
position, was achieved by treatment with Li in liquid NH3,
in the presence of NH4Cl as proton donor.21,22 Under these
conditions, the epimeric 11f, possessing an axial hydroxyl
group, was formed in 16% yield (Scheme 7, Entry 1). It
should be noted that treatment of 14 with Na in liquid
NH3, in the presence of MeOH, a weaker proton donor,
was less satisfactory, resulting in a partial isomerization at
C(3a) and a reversal of selectivity (11b/11h 2/1) (Scheme 7,
Entry 2). Not unexpectedly, LiAlH4 reduction of 14
furnished 11f exclusively and only trace amounts of 11h
were detected (Scheme 7, Entry 3). Completion of the
synthesis (Scheme 6) was effected by chemoselective oxida-
tion of the primary hydroxyl group of 11h with KMnO4 and
Accordingly, hydride reduction of 7f (76%) to diol 11f was
followed by chemoselective mono-acetylation to the desired
product 12 (78%), which was separated from the diacetate
13 (8%) by column chromatography (Scheme 6).
Oxidation of 12 with Jones reagent gave quantitatively the
ketone 14.
Stereoselective reduction of 14 to 11h, with the C(7a)
hydroxyl group in the thermodynamically more stable
Table 1. 13C NMR chemical shifts (d [ppm]) of lactones 7a±h in CDCl3
Lactones
C(6)
C(7)
C(7a)
C(3a)
C(4)
C(5)
Me±C(6)
C(3)
C(2)
Me±C(3)
7a
7b
7c
7d
7e
7f
31.3
31.4
26.2
26.0
29.5
25.3
28.2
28.1
38.8
38.2
36.2
36.0
37.8
33.1
35.7
36.1
81.5
82.5
78.2
77.4
77.5
77.9
79.3
78.2
47.2
51.5
39.1
41.3
41.7
38.8
52.5
48.1
23.8
26.7
23.2
27.3
24.0
17.4
23.0
20.2
34.2
34.2
32.1
31.6
28.7
28.9
31.0
31.0
22.0
22.0
22.0
21.5
22.0
19.8
19.2
19.2
38.8
41.4
42.3
44.1
35.3
41.3
41.5
38.9
180.4
179.5
179.8
180.5
179.6
179.7
179.5
180.3
9.6
12.6
9.1
14.1
13.3
9.7
7g
7h
12.5
12.5

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J.-M. Gaudin / Tetrahedron 56 (2000) 4769±4776
Table 2. 1H NMR chemical shifts (d [ppm]) of lactones 7a±h in CDCl3 (360 MHz)
H
Lactones
7a
7b
7c
7d
7e
7f
7g
7h
H±C(6)
H±C(7)
H0 ±C(7)
H±C(7a)
H±C(3a)
H±C(4)
H0 ±C(4)
H±C(5)
H0 ±C(5)
Me±C(6)
H±C(3)
Me±C(3)
1.60
m
1.24
1.63
m
1.22
m
2.22
m
3.76
1.57
m
1.21
m
2.22
m
4.44
m
2.22
m
1.11
m
1.67
m
0.90
m
1.80
m
1.25
m
2.17
dm(14)
4.69
dd(4,4)
1.95
m
1.25
m
1.80
m
0.94
m
1.80
m
1.40
m
0.98
m
2.08
m
1.88
m
1.90
m
1.90
m
4.52
dd(5,5)
2.32
m
1.33
m
1.50
m
1.50
m
1.50
m
2.30
m
2.30
m
1.72
dd(12,5)
2.10
ddd(12,3,3)
4.23
ddd(12,12,4)
1.94
m
1.4±1.7
m
1.4±1.7
m
1.62
m
1.62
m
1.07
d(7)
2.65
dq(7,7)
1.17
d(7)
1.70
dd(12,5)
2.16
ddd(12,3,3)
3.99
ddd(11,9,4)
1.48
m
ddd(11,11,11)
2.25
ddd(11,4,4)
4.00
ddd(11,11,4)
1.93
4.49
ddd(12,7,7)
2.22
m
1.67
m
1.86
dm(14)
0.98
m
1.56
dm(13)
0.96
d(7)
2.48
dq(14,7)
1.21
d(7)
ddd(13,13,4)
1.47
dddd(13,13,13,4)
1.26
m
1.94
ddd(13,5,3)
1.03
m
1.34
m
1.77
m
1.11
m
1.82
m
1.02
d(7)
2.64
dq(7,7)
1.15
d(7)
1.48
m
1.80
m
1.62
m
1.62
m
1.07
d(7)
2.30
m
1.23
d(7)
m
1.82
dm(13)
1.02
d(7)
2.24
m
1.22
1.67
m
0.92
d(7)
2.79
dq(7,7)
1.16
d(7)
0.93
d(7)
2.36
q(7)
1.27
d(7)
1.02
d(7)
2.77
dq(7,7)
1.18
d(7)
d(7)
concomitant lactonization of the intermediate hydroxy acid
to 7h (65%).
MacroModel program (version 5.5)23 and were consistent
with equilibration experiments (MeONa in MeOH or THF)
(Table 3).
Subsequent base-catalyzed epimerization allowed access to
its thermodynamically more stable epimer 7g (60%).
GC separation of (7a±h)
Lactones 7a±h were conveniently separated on a 60 m
Supelcowax capillary column; conditions and retention
times are described in Fig. 1.
Spectral and thermodynamic properties of (7a±h)
1
On the basis of H, 13C and COSY NMR spectra, together
with nOe experiments, all protons and all carbons of 7a±h
were unambiguously assigned. The data are summarized in
Tables 1 and 2.
This separation technique has allowed an unambiguous
identi®cation of 7a, 7b and 7g as components of Italo
Mitcham black peppermint oil (Mentha piperita).1d This is
the ®rst time that stereoisomers of 7 have been found in nature.
The mass spectra of 7a±h have similar fragmentation
patterns, although there is a large difference with regard to
the relative peak intensities. Five of them (7a, 7b, 7e, 7g,
7h) have an identical mass spectrum (base peak at m/z 81),
while 7c, 7d and 7f show a second type of spectrum with a
base peak at m/z 95.
Organoleptic properties of (7a±h)
The odor evaluation has been done by Firmenich's
perfumers using neat compound on smelling stips. Lactones
7a±h possess very interesting olfactive properties (Table 4).
In general, their odors are more coumarin-like and less
lactonic than the odor of mintlactone 1. They have the
typical hay character of coumarin, which is lacking in 1.15
The stereoisomers 7a and 7b are particularly powerful and
exhibit an exceptional tenacity on cloth.
The MM2 energies of 7a±h were calculated using
Table 3. MM2 energies of lactones 7a±h and results of some epimerization
experiments
Lactones
MM2
Energy
(kcal/mol)
Energy
difference
(kcal/mol)
Theoretical
equilibrium
at 300 K
Experimental
equilibrium
at 300 K
Table 4.
7a
7b
44.34
42.95
Lactones
Odor description
1.39
0.07
2.74
1.32
9/91
54/47
99/1
10/90
57/43
97/3
7a
7b
7c
7d
7e
7f
Lactonic
7c
7d
42.82
42.89
Coumarinic, lactonic, tonka, hay, ¯ouve
Coumarinic, fatty, weak
Coumarinic, lactonic, weak
Weak, without character
Weak, vaguely lactonic
Flouve, coumarinic, sulfury, hay
Coumarinic, ¯ouve
7e
7f
42.14
44.88
7g
7h
44.83
46.15
7g
7h
90/10
75/25

J.-M. Gaudin / Tetrahedron 56 (2000) 4769±4776
4773
Â
Figure 1. Retention times in min and Kovats indices of lactones 7a±h on Supelcowax 10 column (60 m£0.25 nm), 1608C isotherm.
Conclusion
m-chloroperbenzoic acid were added to 40.7 g (264 mmol)
of (2)-isopulegol (Fluka, e.e.$99%) in CH2Cl2 (130 ml).
The reaction mixture was stirred for 4 h at room temperature
and then ®ltered, washed with saturated NaHSO3 solution,
water and brine. The organic layer was dried, concentrated
and the crude product was distilled to give 39.5 g (88%)
of pure epoxide. It should be noted that the method
with H2O2/MeCN18a gave exactly the same yield.
16.15 g (95 mmol) of this epoxide in THF (30 ml)
were slowly added to 295 mmol of LDA in 170 ml of
THF at 08C. Then the reaction was heated for 1 h at
458C and cooled to room temperature. The reaction
mixture was poured on ice and extracted with ether. The
organic layer was washed with brine, dried and concentrated
to give 14 g of crude material. It was recrystallized from
hexane and afforded 11.96 g (74%) of pure diol. 15 g
(88 mmol) of this diol were hydrogenated with 0.15 g of
10% palladium on charcoal in ethyl acetate (150 ml)
under atmospheric pressure of hydrogen. 15.7 g of crude
oil were distilled, which gave 10.6 g (70%) of diols 11a
and 11b. Both diols were separated by crystallization in
hexane.
The stereoselective synthesis of p-menthane lactones 7a±h
has been effected and their individual organoleptic proper-
ties have been investigated. This work has thus clari®ed and
recti®ed the published data concerning some of these
compounds, and also allowed an unambiguous identi®cation
of 7a, 7b and 7g as trace components in Italo Mitcham black
peppermint oil (Mentha piperita).1d These compounds, in
spite of their very low concentration, make an important
contribution to the organoleptic quality of this mint oil. In
addition, they are of considerable interest to the perfume
industry, due to their exceptional odor intensity and typical
coumarinic-note (in particular 7a and 7b).15
Further work on other p-menthane derivatives is in progress
and will be reported in due course.
Experimental
GLC: Hewlett-PackardÐ6890 instrument equipped with a
¯ame-ionization detector.
11a. MS: 172(1, M1z), 154(3), 139(7), 124(18), 112(28),
95(33), 81(100), 71(62), 55(65), 41(35); 13C NMR:
12.0(q), 22.1(q), 29.5(t), 31.5(d), 34.7(t), 38.6(d), 44.6(t),
Flash chromatography (FC)
1
Silica gel 60, Merck, 230±400 mesh. MS: Finnigan 4021 C,
70 eV, m/z, intensities in % relative to the base peak.
HR-MS: GC mate JEOL 230 eV-EI resolution 5000.
48.6(d), 67.0(t), 70.1(d); H NMR: 0.93(d, Jˆ7 Hz, 3H),
0.97(d, Jˆ7 Hz, 3H), 0.8±1.0(m, 2H), 1.24(dddd,
J1ˆ11 Hz, J2ˆ11 Hz, J3ˆ11 Hz, J4ˆ3 Hz, 1H), 1.35(dm,
Jˆ11 Hz, 1H), 1.42(m, 1H), 1.56(dm, Jˆ13 Hz, 1H),
1.64(dm, Jˆ13 Hz, 1H), 1.84(m, 1H), 1.97(dm, Jˆ13 Hz,
1H), 3.44(ddd, J1ˆ10 Hz, J2ˆ10 Hz, J3ˆ4 Hz, 1H),
3.58(dd, J1ˆ11 Hz, J2ˆ3 Hz, 1H), 3.65(dd, J1ˆ11 Hz,
J2ˆ5 Hz, 1H); [a]Dˆ222.58 (cˆ1.2); mp: 100±1018C.
1
NMR: Bruker WH-360, Bruker AMX-360; H at 360 and
13C at 90.5 MHz, in CDCl3; chemical shifts d in ppm; tetra-
methylsilane as internal standard, dˆ0.00 ppm; coupling
constants J in Hz.
Optical rotation
11b. MS: 172(1, M1z), 154(3), 139(6), 123(16), 112(16),
95(38), 81(100), 71(63), 55(57), 41(32); 13C NMR:
12.6(q), 22.2(q), 25.3(t), 31.6(d), 34.4(t), 35.6(d), 45.2(t),
Perkin±Elmer 241 Polarimeter, in CHCl3 at 208C, c:
concentration in %. IR: GC-FTIR Hewlett Packard 5890.
Calculations were carried out on a Silicon Graphics Iris
4D/35 computer system with the program MacroModel
(version 5.5).23 The Monte Carlo method was used for
conformational searching from an energy-minimized
(MM2) starting conformation by using the automatic set-
up from the MacroModel program.
1
45.6(d), 66.6(t), 71.7(d); H NMR: 0.85(d, Jˆ7 Hz, 3H);
0.89(m, 1H); 0.92(d, Jˆ6 Hz, 3H); 0.98(m, 2H); 1.35(m,
1H); 1.41(m, 1H); 1.63(m, 2H); 1.99(dm, Jˆ13 Hz, 1H);
2.07(m, 1H); 3.42(ddd, J1ˆ11 Hz, J2ˆ4 Hz, J3ˆ4 Hz,
1H); 3.48(dd, J1ˆ11 Hz, J2ˆ7 Hz, 1H); 3.56(dd,
J1ˆ11 Hz, J2ˆ5 Hz, 1H); [a]Dˆ228.58 (cˆ0.9); mp: 89±
918C.
(1R,3R,4S,8R)-3,9-p-Menthanediol (11a) and (1R,3R,
4S,8S)-3,9-p-menthanediol (11b) 64.5 g (317 mmol) of
(1R,3S,4S,8S)-3,9-p-Menthanediol (11d). 21.3 g (150 mmol)

4774
J.-M. Gaudin / Tetrahedron 56 (2000) 4769±4776
of boron tri¯uoride ethyl etherate were added dropwise,
within 1 h at 210 to 08C, to an ice cooled solution of
30.8 g (200 mmol) of (1)-neoisopulegol 10 (e.e.$99%),
4.18 g (110 mmol) of sodium borohydride in THF (80 ml)
under nitrogen. After complete addition, the reaction was
stirred at 08C for 3 h. Then 30 ml of water were added
slowly (15 min) and the reaction was stirred for 15 min
80 g of a 12% KOH solution in ethanol and after 20 min,
22 g (460 mmol) of hydrogen peroxide (70% solution in
water) were added always at 08C (exothermic). After
complete addition, the reaction was stirred at 208C for 2
additional hours. Then, the THF was removed and the
crude material was extracted with ether and washed with
brine. The organic mixture was dried and concentrated to
afford 32 g (94%) of oily crude material constituted by diols
11c and 11d (20/80), which were used without further
puri®cation. Pure 11d was obtained for analysis from 1 g
of this crude oil by ¯ash chromatography (eluent: pentane/
etherˆ1/2).
(3S,3aS,6R,7aR)-Perhydro-3,6-dimethyl-2-benzo[b]fura-
none (7b). NMR: see Tables 1 and 2; MS: 167(1), 139(1),
124(6), 109(16), 95(27), 81(100), 67(62), 55(18), 41(17);
IR: 2939, 2884, 1809, 1175, 1093, 1006; e.e.$99%;
[a]Dˆ119.58 (cˆ1.25); mp: 54±558C.
(3R,3aR,6R,7aR)-Perhydro-3,6-dimethyl-2-benzo[b]fur-
anone (7e). 1.70 g (70 mmol) of magnesium were added by
portions to a solution of 0.83 g (5 mmol) of (2)-mintlactone
1a (e.e. 97%) in THF (50 ml). The exothermic reaction was
maintained near room temperature with a water bath and
stirred overnight. Then the reaction mixture was hydrolyzed
by a 10% HCl solution and extracted with ether. The organic
layer was washed with brine, dried and evaporated. The
residue was puri®ed by ¯ash chromatography, which gave
743 mg (88%) of product 7e.
7e. NMR: see Tables 1 and 2; MS: 169(1), 139(1), 124(3),
109(19), 95(44), 81(100), 67(65), 55(27), 41(32); IR: 2939,
1802, 1169, 1007; e.e.97%; e.e. 97%; [a]Dˆ145.78
(cˆ0.9); mp: 55±568C.
11d. MS: 172(2, M1z), 154(8), 139(13), 123(25), 112(40),
95(63), 81(100), 71(78), 55(88), 41(67); 13C NMR: 15.9(q),
22.4(q), 25.5(t), 26.2(d), 35.4(t), 38.2(d), 42.4(t), 46.0(d),
(3S,3aR,6R,7aR)-Perhydro-3,6-dimethyl-2-benzo[b]fur-
anone (7f). 10 g (60 mmol) of (2)-mintlactone 1a in metha-
nol (40 ml) was hydrogenated with 3 g of Raney nickel
under 50 atm. of hydrogen during 3 days at room tempera-
ture. An extraction with ether furnished 9.7 g (96%) of
lactone 7f, which was used without further puri®cation.
1
66.1(t), 66.6(d); H NMR: 0.88(d, Jˆ7 Hz, 3H); 1.00(d,
Jˆ7 Hz, 3H); 1.13(m, 1H); 1.23(m, 1H); 1.47(m, 1H);
1.57(m, 1H); 1.65(m, 1H); 1.7±1.9(m, 4H); 3.55(m, 1H);
3.70(dd, J1ˆ11 Hz, J2ˆ3 Hz, 1H); 4.34(m, 1H); [a]Dˆ
119.88 (cˆ1.20).
(3R,3aS,6R,7aS)-Perhydro-3,6-dimethyl-2-benzo[b]fura-
none (7c) and (3S,3aS,6R,7aS)-perhydro-3,6-dimethyl-2-
benzo[b]furanone (7d). 6.88 g (40 mmol) of crude diols
11c and 11d in solution with 20 ml of ethyl acetate were
added dropwise within 10 min to 15.15 g (96 mmol) of
potassium permanganate in 50 ml of ethyl acetate. The
reaction mixture was stirred at room temperature
overnight, then hydrolyzed by addition of saturated
sodium bisul®te solution, until complete fading. The
white precipitate was ®ltered, the organic layer was washed
with brine until pH 7, dried and concentrated to afford
6.34 g of a 20/80 mixture of lactones 7c and 7d, from
which lactone 7c was recrystallized in hexane. The lactone
7d was isolated in pure form from the mother liquor by
preparative GC.
7f. Oil NMR: see Tables 1 and 2; MS: 167(1), 139(1),
124(10), 109(21), 95(100), 81(55), 67(76), 55(35), 41(44);
EI-HR-MS (30 eV): 139.0831 (M1229; C8H11O2; calc
139.0759); IR: 2943, 1803, 1156, 972; e.e. 97%; [a]Dˆ
19.28 (cˆ1.1).
(1R,3R,4R,8S)-3,9-p-Menthanediol (11f). 9.7 g (57.7 mmol)
of lactone 7f were added slowly to a cold (08C) magnetically
stirred suspension of 2.2 g (57 mmol) of lithium aluminum
hydride in ether (200 ml). The exothermic reaction was
maintained near 08C with an ice bath. When the reaction
was ®nished, it was diluted with ether and hydrolyzed by a
small quantity of brine solution. Then the white granular
solid was removed by ®ltration and rinsed with ether. The
organic layer was ®ltered and evaporated to furnish 7.5 g
(76%) of p-menthanediol 11f.
7c. NMR: see Tables 1 and 2; MS: 167(1), 139(1), 124(12),
109(18), 95(100), 81(38), 67(70), 55(27), 41(35); IR: 2938,
1806, 1158, 962; e.e.$99%; [a]Dˆ731.38 (cˆ0.95); mp:
47±488C.
11f. MS: 172(1, M1z), 154(4), 139(8), 123(28), 112(32),
95(69), 81(100), 71(80), 55(73), 41(44); 13C NMR:
17.3(t); 17.6(q); 21.4(q); 27.4(d); 32.1(t); 38.5(d); 39.1(t);
1
46.4(d); 64.7(t); 71.3(d); H NMR: 0.89(m, 2H); 0.95(d,
7d. NMR: see Tables 1 and 2; MS: 167(1), 139(1), 124(13),
109(19), 95(100), 81(55), 67(72), 55(30), 41(38); IR: 2937,
1804, 1161, 969; e.e.$99%; [a]Dˆ267.98 (cˆ1.07); mp:
52±538C.
Jˆ7 Hz, 3H); 1.15(d, Jˆ7 Hz, 3H); 1.30(ddd, J1ˆ13 Hz,
J2ˆ9 Hz, J3ˆ4 Hz, 1H); 1.44(m, 1H); 1.53(m, 1H);
1.68(m, 2H); 1.85(m, 2H); 3.40(dd, J1ˆ8 Hz, J2ˆ4 Hz,
1H); 3.50(dd, J1ˆ11 Hz, J2ˆ8 Hz, 1H); 3.94(m, 1H).
The same method was applied on p-menthanediol 11a to give
the lactone 7a and on the diol 11b to give the lactone 7b.
(1R,3R,4R,8S)-3-Hydroxy-9-p-menthanyl acetate (12)
and (1R,3R,4R,8S)-3,9-p-menthanediyl diacetate (13)
4.8 g of acetic anhydride were added at 258C to a solution
of 8 g (46.7 mmol) of diol 11f in pyridine (50 ml). The
reaction was then stirred overnight at room temperature.
Ether was added and the ethereal solution was washed
successively with a 10% HCl solution, water and brine,
dried over magnesium sulfate and evaporated. The ¯ash
(3R,3aS,6R,7aR)-Perhydro-3,6-dimethyl-2-benzo[b]fur-
anone (7a). Oil NMR: see Tables 1 and 2; MS: 167(1),
139(1), 124(4), 109(18), 95(27), 81(100), 67(73), 55(24),
41(30); IR: 2940, 2883, 1808, 1158, 962; e.e.$99%;
[a]Dˆ1121.08 (cˆ0.7).

J.-M. Gaudin / Tetrahedron 56 (2000) 4769±4776
4775
chromatography (eluent: pentane/etherˆ5/1) of the mixture
(3S,3aR,6R,7aS)-Perhydro-3,6-dimethyl-2-benzo[b]fura-
none (7h). 3.09 g (18 mmol) of diol 11h in solution in 8 ml
of ethyl acetate were added to 6.92 g (44 mmol) of potas-
sium permanganate in 25 ml of ethyl acetate. The reaction
mixture was stirred at room temperature overnight, then
hydrolyzed by addition of saturated sodium bisul®te solu-
tion, until complete fading. The white precipitate was
®ltered and the organic layer was washed with brine until
pH 7, dried and concentrated to afford 1.97 g of lactone 7h.
gave 7.8 g (78%) of acetate 12 and 0.9 g (8%) of diacetate
13.
12. MS: 171(1), 154(9), 136(15), 121(13), 112(58), 97(52),
81(57), 69(58), 55(53), 43(100); EI-HR-MS (30 eV):
171.1412 (M1243; C10H19O2; calc 171.1385); 13C
NMR:16.5(q), 21.0(q), 21.2(t), 21.4(q), 28.0(d), 31.1(t),
33.0(d), 39.2(t), 43.3(d), 68.3(t), 70.2(d), 171.5(s); 1H
NMR: 1.27(d, Jˆ7 Hz, 3H), 1.30(d, Jˆ7 Hz, 3H), 1.40(m,
3H), 1.50(m, 1H), 1.55±1.75(m, 3H), 1.82(m, 1H), 1.91(m,
1H), 2.07(s, 3H), 3.94(dd, J1ˆ11 Hz, J2ˆ7 Hz, 1H), 4.03(m,
1H), 4.20(dd, J1ˆ11 Hz, J2ˆ4 Hz, 1H).
7h. Oil NMR: see Tables 1 and 2; MS: 167(1), 124(3),
109(15), 95(22), 81(100), 67(57), 55(20), 41(15); IR:
2943, 1807, 1186, 989; e.e. 97%; [a]Dˆ71.78 (cˆ0.8).
13. MS: 213(,1), 153(12), 136(48), 121(40), 107(75),
93(72), 79(61), 67(27), 55(28), 43(100); 13C NMR:
15.9(q), 20.6(q), 20.9(q), 21.4(q), 21.6(t), 27.5(d), 30.7(t),
33.1(d), 35.4(t), 41.6(d), 67.8(t), 72.3(d), 170.6(s), 171.3(s);
1H NMR: 0.97(d, Jˆ7 Hz, 3H), 1.02(d, Jˆ7 Hz, 3H), 1.42±
1.56(m, 4H), 1.65(m, 2H), 1.7±1.9(m, 3H), 2.04(s, 3H),
2.07(s, 3H), 3.94(dd, J1ˆ11 Hz, J2ˆ6 Hz, 1H), 4.15(dd,
J1ˆ11 Hz, J2ˆ4 Hz, 1H), 5.18(m, 1H).
(3R,3aR,6R,7aS)-Perhydro-3,6-dimethyl-2-benzo[b]fur-
anone (7g). A solution of 0.33 g (2 mmol) of lactone 7h,
0.064 g (1.2 mmol) of anhydrous sodium methylate in THF
(6 ml) was stirred for 4 h at room temperature, then
quenched with a 10% HCl solution and extracted with
ether. The organic layer was washed with brine, dried and
concentrated to afford a 75/25 mixture of lactones 7g and 7h
in 60% yield. Lactone 7g was obtained in pure form by
preparative GC. This reaction was realized only one time,
so the thermodynamic equilibrium between lactones 7g and
7h might be slightly different.
(1R,4R,8S)-3-Oxo-9-p-menthanyl acetate (14). Jones'
reagent was added dropwise to a solution of 7.44 g
(34.8 mmol) of acetate 12 in acetone (100 ml), until the
end of the oxidation (the reaction was followed by TLC).
Then the reaction mixture was ®ltered on celite and evapo-
rated. Ether was added and the solution was washed 3 times
with water. Evaporation of ether gave 7.29 g (99%) of pure
ketone 14.
7g. NMR: see Tables 1 and 2; MS: 147(1), 140(2), 133(1),
124(3), 109(12), 95(22), 81(100), 67(52), 55(23), 41(18);
EI-HR-MS (30 eV): 124.1266 (M1244; C9H16; calc
124.1252); IR: 2940, 1809, 1171, 999; e.e. 97%;
[a]Dˆ29.88 (cˆ0.92).
14. MS: 212(1, M1z), 169(1), 152(6), 137(11), 123(8),
112(100), 97(17), 69(29), 43(33); 13C NMR: 15.5(q);
20.6(q), 20.9(q), 26.3(t), 29.9(t), 31.6(d), 33.4(d), 48.3(t),
Acknowledgements
1
52.7(d), 66.8(t), 171.1(s), 212.6(s); H NMR (benzene):
We wish to thank Mr W. Thommen and Mr R. Brauchli for
NMR analysis; Mr C. Morel and Miss N. Busset for their
technical assistance, and Dr P.-A. Blanc for the evaluation
of olfactive properties. Dr R. L. Snowden is also thanked for
his help in the redaction of the manuscript.
0.70(d, Jˆ7 Hz, 3H), 0.87(d, Jˆ7 Hz, 3H), 1.15(m, 1H),
1.31(m, 1H), 1.43(m, 1H), 1.54(m, 1H), 1.72(m, 1H),
1.72(s, 3H), 1.87(dd, J1ˆ13 Hz, J2ˆ8 Hz, 1H), 2.03(m,
2H), 2.11(dd, J1ˆ13 Hz, J2ˆ5 Hz, 1H), 3.93(dd,
J1ˆ10 Hz, J2ˆ5 Hz, 1H), 4.02(dd, J1ˆ10 Hz, J2ˆ4 Hz,
1H).
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16/84 ratio. The separation of both stereoisomers could be
conveniently achieved by a ¯ash chromatography (eluent
pentane/etherˆ1/2) in 87% combined yield.
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