Enantioselective synthesis of both enantiomers of γ-ionone, γ-damascone, karahana lactone and karahana ether

Article abstract of DOI:10.1016/S0957-4166(02)00335-X

A straightforward enantioselective synthesis of both enantiomers of the title compounds is described starting from enantiopure methyl (2S,6R)- or (2R,6S)-cis-2-hydroxy-γ-cyclogeraniate. These versatile building blocks are obtained by biomimetic cyclizatio

Full text of DOI:10.1016/S0957-4166(02)00335-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1245–1255
Enantioselective synthesis of both enantiomers of g-ionone,
g-damascone, karahana lactone and karahana ether
Stephen Beszant, Elios Giannini, Giuseppe Zanoni and Giovanni Vidari*
Dipartimento di Chimica Organica, Universita` di Pavia, Via Taramelli 10, 27100 Pavia, Italy
Received 30 April 2002; accepted 25 June 2002
Abstract—A straightforward enantioselective synthesis of both enantiomers of the title compounds is described starting from
enantiopure methyl (2S,6R)- or (2R,6S)-cis-2-hydroxy-g-cyclogeraniate. These versatile building blocks are obtained by
biomimetic cyclization of methyl (6S)- or (6R)-(Z)-6,7-epoxy-7-methyl-3-(trimethylsilyl)methyl-2-octenoate, respectively. The
chiral information was encoded by a highly regioselective Sharpless asymmetric dihydroxylation of the corresponding diene.
© 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
characteristic nuances to the fragrance which can favor-
ably complement other widely used compounds from
the same family.6,7 In this paper we report the first
regio- and enantioselective synthesis of g-ionone not
depending on resolution techniques, a new enantioselec-
tive synthesis of g-damascone as well as a straightfor-
Ionones 1 and damascones 2 are among the most
important fragrance constituents due to their distinctive
fine violet and rose scents.1,2 Both of these C13 norter-
penoids exist in nature as three distinct regioisomers,
which differ only in the position of the double bond,
and are called the a-, b- and g-isomers.
ward synthesis of karahana lactone
5 and the
corresponding ether 6 (Chart 1). Both enantiomers of
these precious aroma components can be readily pre-
pared using the same synthetic strategy but changing
the stereochemistry of the chiral inducer in the asym-
metric step (vide infra). For the sake of conciseness,
herein we describe the synthesis of the enantiomers
(S)-g-ionone (+)-3 and (S)-g-damascone (+)-4. Indeed,
(S)-g-ionone is the most powerful and pleasant odorant
of the isomers6 and (S)-g-damascone is superior to its
enantiomer.7
α
γ
β
O
O
1
2
ionones
damascones
The g-isomers are the more difficult to access syntheti-
cally, especially in enantiomerically pure form. Indeed,
enantiopure g-ionone 3 has been prepared so far only
by means of resolution techniques, either by a classical
resolution of menthyl derivatives3–5 or by an enzymatic
kinetic resolution.6 On the other hand, only one paper
describing the synthesis of enantioenriched g-damas-
cone 4 has appeared in the literature as yet.7 Olfactory
evaluation shows that the regioisomeric purity and the
absolute stereochemistry of these compounds dramati-
cally determines the fragrance properties, sometimes
with amazingly pronounced differences between the
notes and the odor thresholds of the isomers. Further-
more, the exocyclic double bond confers particularly
2. Results and discussion
Years ago, a few seminal papers by Armstrong and
Weiler showed that biomimetic cyclizations of epoxy-
allylsilanes provide elegant stereo- and regiodefined
routes to terpenoid derivatives containing the 1,3-cis-
disubstituted methylenecyclohexane moiety.8,9 Later, we
were among the first to explore a general regio- and
enantioselective approach to these oxirane starting
materials by Sharpless asymmetric dihydroxylation
(AD) of terpenoid polyenes.10,11 In this context we
envisaged that stereodefined g-ionone 3 and g-damas-
cone 4, as well as stereodefined karahana lactone 5 and
* Corresponding author. Fax: +39 0382507323; e-mail: vidari@
chifis.unipv.it
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00335-X

1246
S. Beszant et al. / Tetrahedron: Asymmetry 13 (2002) 1245–1255
5
1
5
1
O
O
(+)-5
O
(+)-6
(1R,5S)-karahana lactone
(1R,5S)-karahana ether
2
6
HO
COOMe
(2S,6R)-(+)-7
O
(+)-3
O
(+)-4
(S)-γ-damascone
(S)-γ-ionone
Chart 1.
TMS
COOMe
TMS
TMS
COOMe
the corresponding ether 6, could be readily obtained
from a common precursor, namely the hydroxy ester 7
which is produced by biomimetic cyclization of the
epoxyallylsilane 8.8,9
a
COOMe
b
OH
OH
9
O
(+)-8
Both enantiomers of compound 8 are easily obtainable
through AD of allylsilane 9 by appropriate choice of
the chiral auxiliary (Scheme 1).
(-)-10
δ−
F
F
B
c
O
SiMe3
CO2Me
HO
CO2Me
F
The absolute stereochemistry of product 7 is therefore
determined by the absolute stereochemistry of epoxide
8, while the cis orientation of the hydroxyl and the ester
groups are dictated by the chairlike conformation of
the transition state of the cyclization (Scheme 1). The
allylsilane moiety serves both to enhance the reactivity
of the substrate and to govern the regioselectivity of the
product giving rise to the desired g isomer.8,9
δ+
(+)-7
t
Scheme 1. Reagents and conditions: (a) AD-mix-b, BuOH/
H2O (1:1), 0°C, 22 h, 91%; (b) MsCl (1.1 equiv.), Et3N (1.1
equiv.), CH2Cl2, −40“−20°C, 1 h, then DBU (3 equiv.), 0°C,
3 h, 74% overall; (c) BF3·Et2O (4 equiv.), CH2Cl2, −78°C, 1 h,
82%.
Compounds 7, 8, and 9 are, indeed, known compounds;
however, 7 and 8 have been described only in a prelim-
inary communication and no experimental or spectro-
scopic data have been reported.12 Given the synthetic
importance of compounds 7 and 8, in Section 4 we
report their data in full, including the specific optical
rotations. In addition, we have markedly speeded up
the synthesis of the allylsilane 98,9 which can conve-
niently be prepared from methyl acetoacetate, 3,3-
dimethylallyl bromide, diethylphosphoryl chloride and
(trimethylsilylmethyl)magnesium chloride in 51% iso-
lated yield according to our new one-pot procedure
(Scheme 2). Multigram amounts of pure diene 9 are
thus available in just 2 days.
O-
O
O
a
b
COOMe
OMe
Me3SiCH2MgCl
TMS
OPO(OEt)2
COOMe
cat. Ni(acac)2
COOMe
c
9
Subsequent dihydroxylation of 9 with AD-mix-b gave
diol (−)-10 in 91% yield and 88% e.e. (Mosher esters)
and epoxide (+)-8 was then obtained in 74% yield
according to the Stork procedure.12 Eventually, BF3-
catalyzed biomimetic cyclization of (+)-8 gave the key
intermediate (+)-7 in 82% isolated yield and 88% e.e.
(enantioselective capillary GC).
Scheme 2. Reagents and conditions: (a) 1. NaH (1.1 equiv.),
THF, 0°C, 15 min; 2. BuLi (1.05 equiv.), 0°C, 15 min; 3.
3,3-dimethylallylbromide (1 equiv.), 0°C“rt, 45 min; (b)
(EtO)2POCl (1.05 equiv.), 0°C“rt, 1.5 h; (c) Me3SiCH2MgCl
1 M in THF (1.8 equiv.), Ni(acac)2 (0.07 equiv.), 0°C, 1 h,
51% (three steps).

S. Beszant et al. / Tetrahedron: Asymmetry 13 (2002) 1245–1255
1247
2.1. Enantioselective synthesis of (1R,5S)-karahana lac-
tone (+)-5 and (1R,5S)-karahana ether (+)-6
Compounds 5 and 6 are monoterpenoid components of
the Japanese hop, Humulus lupulus L.16 In addition,
Monti et al. have recently demonstrated the utility of 5
as an enantiopure building block in the synthesis of
elegansidiol.17
We anticipated that an easy lactonization of 7 to the
furanone derivative 5 would result as a consequence of
the cis-relative configuration of the hydroxyl and carbo-
methoxy substituents on the cyclohexane ring and con-
formational equilibrium to the diaxial conformer
(Scheme 3). In fact, on treatment with NaH the pleas-
antly smelling hydroxy ester (+)-7 was straightfor-
wardly converted into crystalline (+)-karahana lactone
5, identical with the literature data,13,14 in 78% isolated
yield. Purification by recrystallization from hexane
improved the enantiomeric purity of 5 to an e.e. of
96.7% (enantioselective capillary GC). Compound 5 has
already been the subject of two enantioselective synthe-
ses;13,14 however, contrarily to our route, these
approaches were based on biocatalyzed reactions.
2.2. Enantioselective synthesis of (S)-g-ionone (+)-3 and
(S)-g-damascone (+)-4
While the integrity of the C(6) stereochemistry of
hydroxy ester 7 was of no concern in its conversion into
lactone 5 due to conformational constraint, it became
our main issue in the synthesis of (S)-g-ionone (+)-3
and (S)-g-damascone (+)-4, from (+)-7. Indeed, we
envisaged the synthesis of both isomeric ketones 3 and
4 by appropriate C3-elongations of g-cyclocitral 13
which, in principle, could be obtained by deoxygenation
at C(2) and reduction of the C(6) ester group of com-
pound 7.
Karahana lactone 5 was previously converted to kara-
hana ether 6 via the cis-diol 11.9,14 We explored an
alternative route, based on a slightly modified Rych-
novsky procedure for the conversion of esters into
ethers,15 which allowed the previously installed furan
ring to be preserved. Thus, reduction of enantioen-
riched (+)-5 with DIBALH (1 equiv.) in toluene at
−78°C and subsequent treatment with DMAP (1.1
equiv.), pyridine (3 equiv.) and Ac2O (4 equiv.) with
slow heating to rt, furnished, after 14 h, an anomeric
mixture of karahana lactol-acetate 12 in 82% isolated
yield. Finally, on exposure to BF3 (2.5 equiv.) and
Et3SiH (5 equiv.) in CH2Cl2 at −78°C compound 12
smoothly afforded the highly volatile (+)-karahana
ether, (+)-6, as a colorless liquid with a pleasant cam-
phor-like odor in 80% yield. The spectral data of 6 were
in complete agreement with those reported in the
literature.13,14
2
6
2
6
COOMe
ImCO
S
COOMe
PhOCO
S
CHO
15
14
13
2
6
CH2OTBDMS
PhOCO
S
CH2OH
17
16
Among the very few procedures described in the litera-
ture for the deoxygenation of hindered secondary alco-
hols structurally related to compound 7, Barton-like
radical deoxygenation reactions18 are by far the most
commonly employed methods.19,20 Rather unexpect-
edly, in our hands, the success of the reaction proved to
be sensitive to the type of substituents at C-2 and C-6
of the dimethylcyclohexane moiety. Thus, either the
phenoxythiocarbonate 14† or the imidazoylthiocarbon-
ate 15‡ on exposure to Bu3SnH and catalytic AIBN in
toluene at reflux, followed by reduction in situ with
LiAlH4, afforded the desired g-cyclogeraniol (+)-16 in
about 30% yield. Similarly, radical deoxygenation of
In conclusion, karahana lactone (+)-5 and the corre-
sponding ether (+)-6 were prepared from readily avail-
able starting materials in only five steps and 22%
overall yield and eight steps and 14% overall yield,
respectively, with excellent diastereomeric purities.
HO
CH2OH
ref. 9
ref. 9
11
OH
a
COOMe
c
b
O
O
O
O
(+)-5
(+)-7
OAc
(+)-6
12
Scheme 3. Reagents and conditions: (a) NaH (1.05 equiv.), THF, 0°C, 2 h; crystallization, 78%; (b) 1. DIBALH (1 equiv.), toluene,
−78°C, 45 min; 2. Py (3 equiv.), DMAP (1.1 equiv.), Ac2O (4 equiv.), −78°C“rt, 14 h, 82%; (c) Et3SiH (5 equiv.), BF3·Et2O (2.5
equiv.), CH2Cl2, −78“−60°C, 1 h, 80%.
† 7, PhOC(S)Cl (2 equiv.), Py (4 equiv.), CH2Cl2, rt, 6 h, yield=95%.
‡ 7, Im2CꢀS (2 equiv.), toluene, reflux, 18 h, yield=91%.

1248
S. Beszant et al. / Tetrahedron: Asymmetry 13 (2002) 1245–1255
phenoxythiocarbonate 17§ followed by silyl ether cleav-
age with Bu4NF, met with limited success, giving alco-
hol 16 in only 40% yield. The carbomethoxy, as well as
the TBDMS group appeared to interfere to some extent
with the radical deoxygenation of compounds 14, 15,
and 17, respectively.
which was expected to occur with allyllithium or mag-
nesium derivatives. After some experimentation the
highest efficiency was achieved with the tin reagent.
Thus, slow addition of BF3 (1 equiv.) to a mixture of
(S)-g-cyclocitral (+)-13 (1 equiv.) and excess allyl-
tributyltin (3 equiv.) smoothly furnished epimeric
adducts 22A and 22B (undetermined stereochemistry at
the carbinol center) as a ca. 56:44 mixture (GC). Subse-
quent oxidation of alcohols 22A–B using the Dess–
Martin periodinane27 gave (+)-23 in 71% overall yield
(2 steps). This ketone was immediately exposed to a
hindered base with the expectation that double-bond
conjugation to (S)-g-damascone (+)-4 would occur
Consequently, with the expectation that a hindered
ester protecting group could be more stable to radical
species, diol 11 was exposed to pivaloyl chloride (1.1
equiv.) in CH2Cl2–pyridine (1:1) at 0°C in order to
prepare the primary pivaloate 18 (Scheme 4). In the
event, a ca. 7:3 (TLC) mixture of monoprotected esters
18 and 19 was formed after 1 h at 0°C, regardless of the
apparently different steric accessibility of the two
hydroxyl groups of compound 11; however, subsequent
in situ intramolecular equilibration at room tempera-
ture slowly enriched the mixture in the thermodynami-
cally more stable pivaloate (−)-18 (Scheme 4).
Chromatographically pure ester 18 was converted into
imidazoylthiocarbonate 20, which was cleanly deoxy-
genated to pivaloate 21 under standard conditions.
Reduction of compound 21 afforded the long sought
(S)-g-cyclogeraniol (+)-16 uneventfully (Scheme 5).
Oxidation of (+)-16 using the Swern protocol21 fur-
nished (S)-g-cyclocitral (+)-13 in 86% isolated yield,
which had identical spectral data to that reported in the
literature.7 C3-elongation of this readily epimerizable,
base sensitive aldehyde to diastereomerically and
regioisomerically pure (GC) (S)-g-ionone (+)-3, [h]2D0=
+30.3 (c 1.1, CH2Cl2), was effected straightforwardly
and cleanly with the barium-hydroxide-promoted
modification22 of the Horner–Wadsworth–Emmons
(HWE) reaction in 81% yield. The spectral data of our
synthetic sample were in complete agreement with the
literature;6 moreover, GC analysis on an enantioselec-
tive capillary column showed an e.e. of 88%, indicating
a completely enantiospecific conversion of (+)-7 into
(+)-3.
b
d
RO
CH2OPiv
18 R = H
CH2OR
21 R = Piv
a
c
20 R = C(S)Im
(+)-16 R = H
e
CHO
O
(+)-3
(+)-13
Scheme 5. Reagents and conditions: (a) Im2CS (2.5 equiv.),
toluene, 110°C, 14 h, 92%; (b) Bu3SnH (5 equiv.), cat. AIBN,
toluene, 110°C, 26 h; (c) LiAlH4 (8 equiv.), 0°C, 1.5 h, 75%
overall; (d) Swern oxidation, 86%; (e) Ba(OH)2·8H2O (0.6
equiv.), (EtO)2P(O)CH2COCH3 (3 equiv.), THF/H2O 40:1, 15
h, 81%.
a
b
CHO
OH
22A, 22B
(+)-13
c
Synthesis of (S)-g-damascone (+)-4 was the last target
of our synthetic plan. To secure this valuable fragrance
constituent we envisioned an alternative elongation of
g-cyclocitral (+)-13 through nucleophilic allylation of
the carbonyl group (Scheme 6). Allylations of aldehyde
13 with allyltrimethylsilane under Sakurai reaction
6
O
O
(+)-23
(+)-4
Scheme 6. Reagents and conditions: (a) Bu3SnCH2CHꢀCH2 (3
equiv.), BF3·Et2O (1 equiv.), CH2Cl2, −78°C, 30 min; (b)
Dess–Martin periodinane27 (1.2 equiv.), CH2Cl2, rt, 1.5 h,
71% (two steps); (c) DBU (0.5 equiv.), CH2Cl2, rt, 7 h, 90%.
conditions23,24
or
with
the
more
reactive
allyltributyltin25,26 were the methods of choice to pre-
vent base-catalyzed enolization of the carbonyl group,
a
+
b
PivO
CH2OH
HO
COOMe
HO
CH2OH HO
CH2OPiv
18
(+)-7
19
(+)-11
Scheme 4. Reagents and conditions: (a) LiAlH4 (2.5 equiv.), THF, 0°C, 2 h, 99%; (b) PivCl (1.1 equiv.), CH2Cl2–Py (1:1),
0°C“25°C, 18 h, 70% 18 from 11.
§ (a) 11, TBDMSCl (1.1 equiv.), Im (1.5 equiv.), DMAP (0.3 equiv.), CH2Cl2, rt, 4 h, yield=99%; (b) PhOC(S)Cl (2 equiv.), Py (4 equiv.), CH2Cl2,
rt, 4 h, yield=98%.

S. Beszant et al. / Tetrahedron: Asymmetry 13 (2002) 1245–1255
1249
without concomitant appreciable erosion of the C(6)
stereochemistry. In the event, double bond isomeriza-
tion promoted by catalytic DBU proceeded smoothly at
room temperature, affording (S)-g-damascone (+)-4,
[h]2D0=+230 (c 1.40, CH2Cl2), in 90% yield and with
complete conservation of the optical purity (87.5% e.e.
by enantioselective HPLC). The 1H NMR and GC
analysis of 4 revealed a mixture of E/Z olefins whose
ratio was depending on reaction time and base amount,
changing from 24:1 after 7 h to 50:1 after 18 h with 0.5
equiv. of DBU. The IR and NMR data of the major
diastereomer were fully consistent with those of g-dam-
ascone reported in the literature.28
with a Perkin–Elmer 241 polarimeter. [h]D values are
given in 10−1 deg cm2 g−1. Mass spectra were recorded
with a Finnigan Mat 8222 instrument using the electron
impact ionization technique (70 eV, 0.5 mA). Electro-
spray mass spectrometry was carried out using a
1
Thermo Finnigan LCQ-DECA instrument. H NMR
(300 MHz) and 13C NMR (75.47 MHz) spectra were
recorded in CDCl3 solution with a Bruker CXP 300
spectrometer. Chemical shifts are reported in l units
relative to CHCl3 [lH 7.26, lC (central line of t) 77.0];
the abbreviations s=singlet, d=doublet, t=triplet, q=
quartet, qu=quintuplet, m=multiplet, and br=broad
are used throughout. Coupling constants (J) are given
in Hz. The multiplicity (in parentheses) of each carbon
atom was determined by DEPT experiments. Infra-red
absorption spectra were recorded on FT-IR Perkin–
Elmer Paragon 100 PC spectrophotometer in the range
of 4000–600 cm−1. GC analyses were carried out with a
Hewlett–Packard 5890 II instrument on a HP-5 column
(25 m, 0.25 mm i.d., 0.33 mm f.t., N2 carrier gas: 50
kPa) with the following temperature program: 80°C (3
min)“7°C/min“140°C (0 min)“10°C/min“250°C (0–
10 min). Enantiomeric excesses (e.e.) were determined
with the following techniques: (i) enantioselective GC
analysis on a b-Dex 110 column (30 m, 0.25 mm i.d.,
0.25 mm f.t, He carrier gas) mounted on a Hewlett–
Packard 5890 II chromatograph for compound 7; (ii)
enantioselective GC analysis on a DMePeBETACDX
column (25 m, 0.25 mm i.d., 0.25 mm f.t., ‘EasySep’
purchased from Analytical Technologies; He carrier
gas) mounted on a Hewlett–Packard 5890 II chro-
matograph for g-ionone 3; (iii) enantioselective GC
analysis using a DAcTBuSilBETACDX column (25 m,
0.32 mm i.d., 0.25 mm f.t., ‘EasySep’ purchased from
Analytical Technologies; He carrier gas) mounted on a
Hewlett–Packard 5890 II instrument for karahana lac-
tone 5; (iv) enantioselective HPLC analysis on a Daicel
Chiralcel® OD 4.6×250 mm column mounted on a
Waters HPLC instrument (pump: Waters 515, UV–Vis
detector: Waters 409E (454 nm)) for g-damascone
3. Conclusion
In conclusion, an enantiospecific synthesis of (S)-g-
ionone (+)-3, (S)-g-damascone (+)-4, (1R,5S)-karahana
lactone (+)-5, and (1R,5S)-karahana ether (+)-6 was
accomplished starting from a common precursor,
hydroxy ester (+)-7, which was readily available by
biomimetic cyclization of epoxide (+)-8. This represents
the first enantioselective synthesis of g-ionone not
depending on resolution techniques, the second enan-
tioselective synthesis of g-damascone, and a very conve-
nient route to enantioenriched karahana lactone and
the corresponding ether. Moreover, the opposite series
of enantiomers is easily at hand by using (−)-7 as the
starting material. In fact, this compound is readily
available through AD of diene 9 (Scheme 1) with the
opposite AD mixture, AD-mix-a.
4. Experimental
Tetrahydrofuran, diethyl ether and toluene were dis-
tilled from sodium/benzophenone; pyridine and methyl-
ene chloride were distilled over calcium hydride. All the
solvents were distilled under an argon atmosphere.
Commercially available reagents were used as supplied
without further purification, except for methanesulfonyl
chloride and triethylamine, which were distilled over
calcium hydride under an argon atmosphere prior to
use. All the reactions were performed in glassware that
had been dried in an oven at 140°C for at least 3 h
prior to use and allowed to cool in a desiccator over
self-indicating silica gel pellets. Syringes and needles for
the transfer of reagents were dried at 140°C and
allowed to cool in a desiccator over P2O5 before use.
The reactions were carried out under a slight positive
static pressure of argon. Routine monitoring of reac-
tions was performed using GF-254 Merck (0.25 mm),
aluminum-supported TLC plates. Compounds were
visualized by UV irradiation at a wavelength of 254
nm, or stained by exposure to a 0.5% solution of
vanillin in H2SO4–EtOH followed by charring. Flash
column chromatography was performed using Kieselgel
60 Merck (40–63 mm). Yields are reported for chro-
matographically and spectroscopically pure isolated
compounds. Melting points were carried out on an
Electrothermal Fisher–Johns apparatus and are uncor-
rected. Optical rotation measurements were obtained
4.1. Methyl (Z)-7-methyl-3-(trimethylsilyl)methyl-2,6-
octadienoate, 9
A solution of methyl acetoacetate (9.3 mL, 85.9 mmol)
in dry THF (50 mL) was added dropwise to NaH (60%
dispersion in mineral oil, 3.78 g, 1.1 equiv.) in dry THF
(100 mL) at 0°C. After complete addition, the solution
was stirred at the same temperature for 15 min, then
BuLi (2.5 M solution in hexanes, 36.1 mL, 1.05 equiv.)
was added dropwise and the mixture was stirred at 0°C
for further 15 min. 3,3-Dimethylallylbromide (10 mL,
85.9 mmol, 1 equiv.) was then added and the mixture
was allowed to warm to room temperature (45 min).
The
mixture
was
then
cooled
to
0°C,
diethylchlorophosphate (12.8 mL, 1.05 equiv.) was
added dropwise, and the resulting enolphosphate was
stirred for 1.5 h while warming to rt. In a separate flask
Me3SiCH2MgCl was prepared from Me3SiCH2Cl (1 M
in THF, 21.6 mL, 1.8 equiv.) and Mg (3.86 g, 1.85
equiv.) in dry THF (160 mL) at 0°C, and to it was
added Ni(acac)2 (1.63 g, 0.07 equiv.), followed after 15
min by the mixture of the enolphosphate. After com-

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S. Beszant et al. / Tetrahedron: Asymmetry 13 (2002) 1245–1255
plete addition (30 min) the mixture was kept for 1 h at
0°C and then poured into a mixture of 1 M aq. HCl
and Et2O at 0°C; the phases were separated and the
organic layer was washed with a further portion of 1
M aq. HCl. The aq. phase was extracted with Et2O
(×3) and the organic layer washed with brine (×3),
dried over Na2SO4 and evaporated. The crude extract
was purified by silica gel chromatography (hexane“
hexane:EtOAc, 98:2) to give ester 99 as a pale yellow
oil (11.1 g, 51% overall yield); IR (neat): w 1714; 1626;
1434; 1248; 1157; 849; 1H NMR: l 0.04 (s, 3×3H,
Me3Si), 1.60 and 1.68 (2s, 2×3H, CMe2), 1.99–2.17 (m,
4H, C(4)H2 and C(5)H2), 2.41 (s, 2H, CH2Si), 3.65 (s,
3H, COOMe), 5.08 (s, 1H, C(2)H), 5.54 (t, J=6.3 Hz,
1H, C(6)H); 13C NMR: l 1.0 (Me3Si), 17.5 and 25.4
(C(7)Me2), 25.9, 26.4 and 40.4 (C(4), C(5) and
CH2TMS), 50.3 (COOMe), 110.8 (C(6)), 122.9 (C(2)),
132.3 (C(7)), 164.2 and 167.5 (C(3) and C(1)); EIMS:
m/z (%) 254 [M+] (9), 239 (46), 223 (40), 211 (5), 195
(6), 186 (12), 171 (22), 150 (35), 135 (21), 122 (12), 121
(11), 107 (78), 89 (21), 82 (51), 73 (100), 69 (26), 59
(11), 45 (23), 41 (38).
−40°C. The solution was kept between −40 and −20°C
for 1.5 h, then warmed to 0°C, and DBU (5.3 mL, 3
equiv.) was added. After 3 h satd aq. NaHCO3 was
added; the aqueous phase was extracted with CH2Cl2
(×3) and the combined organic layers were washed
with satd aq. CuSO4 (×2) and brine, dried (Na2SO4)
and evaporated. The crude residue was purified by
chromatography on silica gel (hexane–EtOAc, 95:5) to
afford epoxide. (+)-8 (2.39 g, 74% yield); [h]2D0=+0.5 (c
2.78, CH2Cl2); IR (neat): w 2955; 1713; 1626; 1434;
1
1378; 1248; 1234; 1189; 1160; 1028; 844; 695; 637; H
NMR:
l 0.06 (s, 3×3H, Me3Si), 1.26 (s, 3H,
MeC(7)Me), 1.30 (s, 3H, MeC(7)Me), 1.68–1.75 (m,
2H, C(5)H2), 2.13–2.30 (m, 2H, C(4)H2), 2.37 and 2.49
(ABq, J=11.2 Hz, 2H, Me3SiCH2), 2.71 (t, J=6.1 Hz,
1H, C(6)H), 3.66 (s, 3H, COOMe), 5.56 (s, 1H,
C(2)H); 13C NMR: l −1.0 (Me3Si), 18.6 and 24.7
(Me2C(7)), 26.1 and 27.4 (C(4) and C(5)), 37.2
(CH2TMS), 50.5 (COOMe), 58.4 (C(7)), 63.4 (C(6)),
111.3 (C(2)), 164.2 (C(3)), 167.4 (C(1)); EIMS: m/z
(%) 270 [M+] (2), 255 (9), 239 (3), 223 (2), 211 (3), 195
(5), 181 (8), 166 (8), 149 (18), 121 (50), 107 (9), 95 (32),
89 (25), 82 (19), 73 (100), 67 (16), 59 (17), 45 (16), 43
(20), 41 (16). Anal. calcd for C14H26O3Si: C, 62.18; H,
9.69; O, 17.75; Si, 10.39. Found: C, 62.25; H, 9.75%.
4.2. Methyl (6R)-(Z)-6,7-dihydroxy-7-methyl-3-
(trimethylsilyl)methyl-2-octenoate, (−)-10
4.4. Methyl (1%R,3%S)-3%-hydroxy-2%,2%-dimethyl-6%-meth-
ylene-1%-cyclohexylcarboxylate (methyl (2S,6R)-(+)-cis-
2-hydroxy-g-cyclogeraniate), (+)-7
AD-mix-b (25g, 2.1 g/mmol) and MeSO2NH2 (1.19,
1.05 equiv.) were added to a mixture of diene 9 (3.04 g,
11.9 mmol) in H2O–tBuOH (1:1, 240 mL) at 0°C, and
the mixture was vigorously stirred at 0°C for 22 h and
then quenched with sodium metabisulfite. The mixture
was stirred at rt for 30 min, diluted with abundant
H2O and CH2Cl2, and the phases were separated. The
aq. layer was extracted with CH2Cl2 (×3) and the
organic layer was washed with brine, dried (Na2SO4),
BF3·Et2O (4 equiv.) was added dropwise to a solution
of epoxide (+)-8 (2.89 g, 10.7 mmol) in dry CH2Cl2
(110 mL) at −78°C and the solution was stirred at
−78°C for 1 h. The reaction was then quenched with
satd aq. NaHCO3 and the mixture was stirred at rt for
30 min. The organic layer was washed with a further
portion of satd aq. NaHCO3 and the aq. phase was
extracted with CH2Cl2 (×3). The combined organic
layers were then washed with brine, dried (Na2SO4)
and evaporated. The crude residue was purified by
chromatography on silica gel (hexane-EtOAc, 95:5“
80:20) to give 1.75 g (82% yield) of ester (+)-7;12 [h]D20=
+109 (c 0.78, CH2Cl2); 88% e.e.{enantioselective GC
on a b-Dex 110 column; temperature program=100°C
(3 min)“5°C/min“190°C (5 min); tR=16.9 min for
(−)-7 and 17.2 min for (+)-7)}; IR (neat): w 3432; 2948;
1741; 1708; 1649; 1437; 1357; 1251; 1211; 1155; 1131;
t
and evaporated. The residue of BuOH was evaporated
as its azeotrope with hexane. The crude extract was
purified by silica gel chromatography (hexane-EtOAc,
8:2“7:3) to give diol (−)-10 as a viscous pale yellow oil
(3.11 g, 91% yield, 88% e.e. determined with Mosher
esters); [h]2D0=−7.50 (c 1.1, CH2Cl2); IR (neat): w 3435;
2955; 2928; 2856; 1713; 1694; 1622; 1435; 1372; 1249;
1
1159; 1077; 1030; 941; 844; 773; 697; 641; H NMR: l
0.04 (s, 3×3H, Me3Si), 1.15 (s, 3H, MeC(7)Me), 1.20
(s, 3H, MeC(7)Me), 1.44–1.73 (m, 2H, C(4)H2), 1.72 (s,
1H, C(7)OH), 2.07–2.17 and 2.34–2.40 (2m, 2×1H,
C(5)H2), 2.16 (d, J=4.4 Hz, 1H, C(6)OH), 2.31 and
2.55 (ABq, J=11.2 Hz, 2H, Me3SiCH2), 3.35 (ddd,
J=2.2, 4.4, 6.6 Hz, 1H, C(6)H), 3.64 (s, 3H, COOMe),
5.55 (s, 1H, C(2)H); 13C NMR: l −0.9 (Me3Si), 23.2
and 25.5 (Me2C(7)), 25.1 and 29.9 (C(4) and C(5)),
37.5 (CH2TMS), 50.5 (COOMe), 73.0 (C(7)), 77.7
(C(6)), 111.1 (C(2)), 164.3 (C(3)), 167.5 (C(1)). Anal.
calcd for C14H28O4Si: C, 58.29; H, 9.78; O, 22.19; Si,
9.74. Found: C, 58.41; H, 9.83%.
1
1073; 1027; 950; 900; 853; 781; 664; H NMR: l 0.96
and 1.07 (2s, 2×3H, Me2C(2%)), 1.79–1.85 (m, 2H,
C(4%)H2), 2.06–2.14 (dt, J=4.8, 14.0 Hz, 1H, HC(5%)H),
2.49–2.60 (m, 1H, HC(5%)H), 2.99 (s, 1H, C(1%)H),
3.36–3.42 (m, 1H, C(3%)H), 3.68 (s, 3H, COOMe), 4.42
(d, J=10.1 Hz, 1H, CHOH), 4.82 and 4.93 (2 br s,
2×1H, ꢀCH2); 13C NMR: l 18.1 and 23.1 (C(2%)Me2),
22.5 and 26.5 (C(4%) and C(5%)), 34.1 (C(2%)), 49.0
(C(1%)), 55.4 (COOMe), 70.2 (C(3%)), 109.0 (ꢀCH2),
138.5 (C(6%)), 175.1 (C(1)); EIMS: m/z (%) 198 [M+]
(21), 181 (20), 180 (13), 165 (5), 155 (3), 139 (10), 138
(11), 137 (8), 121 (100), 105 (20), 95 (36), 93 (18), 91
(16), 81 (18), 79 (28), 77 (16), 67 (31), 59 (8), 55 (15),
43 (29), 41 (23). Anal. calcd for C11H18O3: C, 66.64; H,
9.15; O, 24.21. Found: C, 66.81; H, 9.22%.
4.3. Methyl (6S)-(Z)-6,7-epoxy-7-methyl-3-(trimethyl-
silyl)methyl-2-octenoate, (+)-8
Et3N (1.8 mL, 1.1 equiv.), followed by MsCl (1 mL,
1.1 equiv.), was added dropwise to a solution of diol
(−)-10 (3.437 g, 11.9 mmol) in dry CH2Cl2 (120 mL) at

S. Beszant et al. / Tetrahedron: Asymmetry 13 (2002) 1245–1255
1251
4.5. (1R,5S)-8,8-Dimethyl-2-methylene-6-oxabicyclo-
[3.2.1]octan-7-one ((1R,5S)-(+)-karahana lactone), (+)-5
was stirred for an additional 30 min while warming to
−60°C. The reaction was quenched with satd aq.
NaHCO3 and stirred at rt for 15 min. After phase
separation, the aq. phase was extracted with CH2Cl2
(×3) and the organic layer was washed with brine, dried
over Na2SO4, and evaporated at room pressure. The
residue was purified by chromatography on silica gel
(petroleum ether–Et2O, 95:5) and the fractions were
carefully evaporated at reduced pressure (0°C, from 120
to 80 torr) to give (+)-karahana ether (+)-6 as a color-
less liquid (128 mg, 80% yield); [h]2D0=+76.6 (c 0.88,
CH2Cl2), [lit. [h]D=−70.3 (c 1.02, pentane)13 and [h]D25=
−68.0 (c 1.0, pentane)14 for (−)-6]; IR (neat): w 3071,
2983, 2939, 2877, 1647, 1494, 1454, 1388, 1368, 1286,
1226, 1174, 1148, 1066, 1035, 1018, 979, 937, 924, 911,
888, 799, 775, 738; 1H NMR: l 0.97 and 1.10 (2s,
2×3H, C(8)Me2), 1.61–1.81 (m, 2H, C(4)H2), 2.13 (dd,
J=6.6, 15.4 Hz, 1H, HC(3)H), 2.33 (d, J=4.6 Hz, 1H,
C(1)H), 2.35–2.50 (m, 1H, HC(3)H), 3.77 (d, J=3.7
Hz, 1H, C(5)H), 3.82 (1H, d, J=8.1 Hz, 1H, HC(7)H),
4.04 (dd, J=4.6, 8.1 Hz, 1H, HC(7)H), 4.57 and 4.66
(2×1H, 2 br s, ꢀCH2); 13C NMR: l 20.8 and 25.4
(Me2C(8)), 25.7 and 28.5 (C(3) and C(4)), 42.2 (C(8)),
53.9 (C(1)), 71.1 (C(7)), 82.3 (C(5)), 107.4 (ꢀCH2),
148.9 (C(2)); EIMS: m/z (%) 152 [M+] (8), 135 (8), 122
(25), 121 (51), 120 (28), 107 (100), 105 (15), 95 (21), 93
(29), 91 (41), 81 (28), 79 (68), 77 (21), 67 (32), 53 (12),
43 (18), 41 (31).
NaH (60% dispersion in mineral oil, 28.6 mg, 1.05
equiv.) was added in small portions over 5 min to a
solution of (+)-7 (135 mg, 0.681 mmol) in dry THF (7
mL) at 0°C. The mixture was stirred at 0°C for 2 h,
then the reaction was quenched with satd aq. NH4Cl.
After dilution with Et2O and separation of the phases,
the aq. phase was extracted with Et2O (×3); the organic
layer was then washed with satd aq. NaHCO3 and
brine, dried over Na2SO4, and evaporated. The crude
residue was recrystallized from hexane (0.5 mL) by
progressive cooling (rt, 0°C, −20°C) to give (+)-kara-
hana lactone (+)-5 as colorless needles (87.8 mg, 78%
yield); mp 38–41°C; 96.7% e.e. {enantioselective GC on
a DAcTBuSilBETACDX column; He gas carrier, 1.27
mL/min; split ratio=1:36; temperature program=
120°C (1 min), 1°C/min“135°C (0 min), 5°C/min“
150°C (0 min); tR=15.0 min for (+)-5 and 15.8 min for
(−)-5); [h]2D0=+260.5 (c 0.90, CH2Cl2), [lit. [h]D=−236.0
(c 0.83, CHCl3)13 and [h]D25=−295.0 (c 1.0, CHCl3)14 for
(−)-5]; IR (KBr): w 2963, 1772, 1648, 1395, 1373, 1341,
1293, 1252, 1199, 1139, 1059, 1033, 991, 943, 915, 875,
1
666; H NMR: l 1.01 and 1.19 (2s, 2×3H, C(8)Me2),
1.77–1.89 and 1.96–2.06 (2 m, 2H, C(4)H2), 2.29–2.44
(m, 2H, C(3)H2), 2.77 (s, 1H, C(1)H), 4.35 (br d, J=4.0
Hz, 1H, C(5)H), 4.85 and 4.92 (2br s, 2×1H, ꢀCH2);
13C NMR: l 20.5 and 25.9 (C(8)Me2), 24.9 and 25.6
(C(3) and C(4)), 42.6 (C(8)), 59.7 (C(1)), 85.6 (C(5)),
113.1 (ꢀCH2), 140.1 (C(2)), 177.2 (C(7)); EIMS: m/z
(%) 167 [M+] (22), 122 (22), 121 (19), 107 (100), 105
(18), 93 (21), 91 (46), 79 (58), 77 (19), 67 (12), 65 (10),
53 (8), 41 (15).
4.7. (1%R,3%S)-cis-(3%-Hydroxy-2%,2%-dimethyl-6%-methyl-
ene-1%-cyclohexyl)methanol ((2S,6R)-(+)-cis-2-hydroxy-
g-cyclogeraniol), (+)-11
A solution of LiAlH4 in THF (1 M, 8.33 mL, 2.5
equiv.) was added to a solution of (+)-7 (660 mg, 3.33
mmol) in dry THF (30 mL) at 0°C and the mixture was
stirred at 0°C for 2 h. The reaction was then quenched
by cautious and sequential addition of H2O (315
mL),15% aq. NaOH (475 mL) and again H2O (315 mL)
while vigorously stirring at 0°C for 5 min after each
addition. The mixture was filtered on a glass Buchner
funnel and the solid was abundantly washed with Et2O;
the resulting solution was then dried over Na2SO4 and
evaporated. Filtration of the residue through a pad of
silica gel with hexane–EtOAc, 1:2, gave diol (+)-11 as a
colorless solid (560 mg, 99% yield), mp 71–74°C; [h]2D0=
+46.6 (c 1.02, CH2Cl2), [lit.14 [h]D=−54.0 (c 1.0,
CHCl3) for (−)-11]; IR (KBr): w 3315, 2936, 2876, 1651,
1482, 1455, 1363, 1291, 1256, 1200, 1134, 1097, 1029,
4.6. (1R,5S)-8,8-Dimethyl-2-methylene-6-oxabicyclo-
[3.2.1]octane ((1R,5S)-(+)-karahana ether), (+)-6
DIBALH (1 M in hexane, 2.62 mL, 1 equiv.) was added
to a solution of (+)-5 (435.7 mg, 2.62 mmol) in toluene
(13 mL) at −78°C. After stirring for 45 min at −78°C,
freshly distilled pyridine (630 mL, 3 equiv.), followed by
a solution of DMAP (350 mg, 1.1 equiv.) in toluene–
CH2Cl2, 4:1 (7.5 mL) and freshly distilled Ac2O (990
mL, 4 equiv.) were sequentially added. The mixture was
stirred for 14 h allowing it to warm to rt. The reaction
was then quenched with a 1:1 mixture of satd aq.
NH4Cl and satd aq. sodium–potassium tartrate and the
mixture was stirred at rt for 15 min. After phase
separation the aq. layer was extracted with Et2O (×3).
The organic layer was washed with satd aq. NaHCO3
and brine, dried over Na2SO4 and evaporated, toluene
being removed as its azeotrope with MeOH. Chromato-
graphic purification (hexane-EtOAc, 95:5“90:10) of
the residue afforded lactol–acetate 12 (425.3 mg, 82%
yield); IR: w 1720;.1H NMR: l 2.10), which was imme-
diately submitted to the following step. Et3SiH (415 mL,
2.5 equiv.) followed by BF3·Et2O (160 mL, 1.2 equiv.)
was added to a solution of 12 (208.2 mg, 1.05 mmol) in
dry CH2Cl2 (10 mL) at −78°C, and the solution was
stirred for 30 min at the same temperature. Then, a
further portion of reactants was added and the solution
1
1010, 987, 958, 925, 883, 859, 782, 675; H NMR: l
0.97 and 1.02 (2s, 2×3H, Me2C(2%)), 1.60–1.71 and
1.82–1.94 (2m, 2×1H, C(4%)H2), 2.01 (dd, J=7.3, 3.3
Hz, 1H, C(1%)H), 2.05–2.15 (m, 1H, C(5%)H), 2.45–2.58
(m, 3H, C(5%)H% and 2×OH), 3.45–3.49 (m, 1H,
C(3%)H), 3.71 (dd, A part of an ABX system, J=10.8,
3.3, 1H, HC(1)HOH), 3.94 (dd, B part of an ABX
system, J=10.8, 7.3, 1H, HC(1)HOH); 4.76 and 4.95
(2s, 2×1H, ꢀCH2); 13C NMR: l 21.3 and 27.7
(Me2C(2%)), 29.2 and 30.6 (C(4%) and C(5%)), 38.7
(C(2%)), 54.7 (C(1%)), 62.7 (C(1)), 74.1 (C(3%)), 110.3
(ꢀCH2), 148.0 (C(6%)); EIMS: m/z (%) 152 [M+-H2O]
(5), 135 (4), 122 (50), 121 (40), 107 (100), 95 (21), 93
(32), 91 (37), 81 (42), 79 (70), 67 (50), 55 (20), 43 (43),

1252
S. Beszant et al. / Tetrahedron: Asymmetry 13 (2002) 1245–1255
41 (38).). Anal. calcd for C9H18O2: C, 70.55; H, 10.66;
O,18.88. Found: C, 70.87; H, 10.43%.
equiv.) was added to a solution of pivaloate (−)-18
(532.6 mg, 2.09 mmol) in dry toluene (20 mL) and the
mixture was heated under reflux for 14 h. Then H2O
was added and the aq. phase was extracted with hexane
(×3); the combined organic layers were washed with
brine, dried (MgSO4) and evaporated. Silica gel chro-
matography of the residue (hexane–EtOAc, 8:2“6:4)
gave ester 20 as an oil (702.0 mg, 92% yield); IR (neat):
w 3080, 2971, 2871, 1725, 1652, 1479, 1385, 1320, 1283,
4.8. (1%R,3%S)-cis-(3%-Hydroxy-2%,2%-dimethyl-6%-methyl-
ene-1%-cyclohexyl)methyl 2,2-dimethylpropionate
((2S,6R)-(−)-cis-2-hydroxy-g-cyclogeranil pivaloate),
(−)-18
DMAP (38.6 mg, 0.1 equiv.), followed by PivCl (421
mg, 1.1 equiv.) were added to a solution of (+)-11 (538
mg, 3.16 mmol) in a 1:1 mixture of CH2Cl2–pyridine
(30 mL) at 0°C and the mixture was stirred for 1 h at
this temperature. TLC analysis of the mixture revealed
the presence of compounds 18 and 19 in a ratio of ca.
7:3. The solution was then allowed to warm to 25°C
and kept at this temperature for an additional 18 h. The
reaction was then quenched with a few drops of MeOH
and the solution was washed with satd aq. NaHCO3.
The aq. phase was extracted with CH2Cl2 (×2) and the
combined organic layers were sequentially washed with
satd aq. NaHSO4 (×3), satd aq. NaHCO3 (×2) and
brine, dried over Na2SO4 and evaporated. Chromato-
graphic purification of the residue on silica gel (hexane–
EtOAc, 95:5“80:20) gave, in order of elution, 90 mg of
dipavaloate of diol 11 (1H NMR: l 0.95 and 1.05 (2s,
2×3H, Me2C(2%)), 1.20 and 1.27 (2s, 2×9H, 2tBu), 1.61–
1.72 and 1.77–1.90 (2m, 2×1H, C(4%)H2), 2.05–2.16 (m,
1H, C(5%)H), 2.25 (dd, J=10, 3.5 Hz, 1H, C(1%)H),
2.30–2.45 (m, 1H, C(5%)H%), 4.25 (dd, J=10, 3.5 Hz,
1H, C(1)H), 4.50 (t, J=10 Hz, 1H, C(1)H%), 4.70 (m,
1H, C(3%)H), 4.68 and 4.90 (2br s, 2×1H, ꢀCH2), 15.6
mg of ester 19 (1H NMR: l 0.91 and 1.02 (2s, 2×3H,
Me2C(2%)), 1.43 (dd, J=10, 2.5 Hz, 1H, OH), 1.25 (s,
1
1231, 1155, 1103, 1035, 1011, 979, 961, 901, 833. H
NMR: l 1.05 and 1.16 (2s, 2×3H, Me2C(2%)), 1.20 (s,
t
9H, Bu), 1.80–1.92 (m, 1H, C(4%)H), 2.06–2.26 (m, 2H,
C(4%)H% and C(5%)H), 2.35 (dd, J=4.2, 9.3 Hz, 1H,
C(1%)H), 2.39–2.49 (1H, m, C(5%)H%), 4.34 (dd, J=4.2,
11.1 Hz, 1H, C(1)H), 4.44 (dd, J=9.3, 11.1 Hz, 1H,
C(1)H%), 4.76 and 5.00 (2s, 2×1H, ꢀCH2), 5.50 (dd,
J=7.9, 3.8 Hz, 1H, C(3%)H), 7.09, 7.67, 8.41 (3s, 3×1H,
Im); ESI-MS: m/z (%) 751 [2M+Na+] (93), 729 [2M+H+
] (14), 387 [M+Na+] (100), 365 [M+H+] (46), 259 (6),
203 (9), 161 (9), 135 (21). Anal. calcd for C19H28N2O3S:
C, 62.61; H, 7.74; N, 7.69; O, 13.17; S, 8.80. Found: C,
62.55; H, 7.81; N, 7.59%.
4.10. (S)-(2%,2%-Dimethyl-6%-methylene-1%-cyclohexyl)-
methanol ((S)-(+)-g-cyclogeraniol), (+)-16
Bu3SnH (1.3 mL, 3 equiv.) and catalytic AIBN were
added to a solution of thiocarbonate 20 (602 mg, 1.65
mmol) in oxygen free dry toluene (17 mL) and the
mixture was heated under reflux for 8 h; then, two
additional equivalents of Bu3SnH and more catalytic
AIBN were added and the mixture was refluxed for
further 18 h. The mixture was then cooled to 0°C and
excess LiAlH4 (1 M in THF) was added. After 1.5 h at
0°C satd aq. NH4Cl was added; the mixture was diluted
with Et2O and 1 M HCl was added until two clear
phases were obtained. They were separated, the aq.
phase was extracted with Et2O (×3), and the organic
layer was washed with satd aq. NaHCO3 and brine.
Excess DBU and a solution of I2 in Et2O were then
added up to persistence of a pale yellow color in order
to allow precipitation of tin salts.29 The mixture was
filtered through a silica pad and washed with Et2O.
Finally, the filtrate was washed in the order with satd
aq. Na2S2O3, satd aq. CuSO4, and brine, dried (MgSO4)
and evaporated at room pressure. Silica gel chromatog-
raphy of the residue (hexane–Et2O, 98:2“90:10 for
(+)-16 and then 7:3“50:50 for (+)-11) and evaporation
of the fractions at room temperature afforded 36.5 mg
(13% yield) of diol (+)-11 (S)-g-cyclogeraniol (+)-16 as
colorless oil (190.8 mg, 75% yield); [h]2D0=+24.9 (c=
0.73, CH2Cl2), [lit. [h]2D0=+24.5 (c 0.03, CHCl3)7 and
[h]2D1=+23.7 (c 0.31, CHCl3)30]; IR (neat): w 3385, 3070,
2931, 2867, 1647, 1479, 1385, 1365, 1159, 1067, 1029,
975, 945, 888, 848. 1H NMR: l 0.89 and 0.97 (2s,
2×3H, Me2C(2%)), 1.24–1.65 (m, 5H, C(3%)H2, C(4%)H2,
OH), 2.06 (dd, J=10.8, 4.9 Hz, 1H, C(1%)H), 2.13 (t,
J=6.4 Hz, 2H, C(5%)H2), 3.60–3.77 (m, 2H, C(1)H2),
4.78 and 4.98 (2 br s, 2×1H, ꢀCH2); 13C NMR: l 26.4
and 28.4 (Me2C(2%)), 23.0, 28.4, and 36.3 (C(3%), C(4%)
and C(5%)), 33.8 (C(2%)), 56.3 (C(1%)), 59.5 (C(1)), 111.5
(ꢀCH2), 147.4 (C(6%)); EIMS: m/z (%) 154 [M+] (4), 136
t
3H, Bu), 1.64–1.76 and 1.80–1.92 (2m, 2×1H, C(4%)H2),
2.05–2.18 (m, 2H, C(1%)H and C(5%)H), 2.31–2.41 (m,
1H, C(5%)H%), 3.75 (td, J=10, 3.7 Hz, 1H, C(1)H), 3.88
(td, J=10, 2.5 Hz, 1H, C(1)H%), 4.71 (m, 1H, C(3%)H),
4.83 and 5.03 (2br s, 2×1H, ꢀCH2), and 562 mg (70%
yield) of pivaloate (−)-18 as a colorless oil; [h]2D0=−7.2
(c 0.91, CH2Cl2); IR (neat): w 3504, 3071, 2975, 2939,
2872, 1727, 1709, 1648, 1481, 1459, 1398, 1365, 1289,
1163, 1117, 1077, 1027, 1010, 997, 955, 891, 857, 772;
1H NMR: l 0.88 and 1.09 (2s, 2×3H, Me2C(2%)), 1.18 (s,
t
9H, Bu), 1.51–1.64 and 1.82–1.93 (2m, 2×1H, C(4%)H2),
2.02–2.18 (m, 2H, C(1%)H and C(5%)H), 2.30 (br s, 1H,
OH), 2.37–2.47 (m, 1H, C(5%)H%), 3.48 (dd, J=8.4, 3.9
Hz, 1H, C(3%)H), 4.34–4.38 (m, 2H, C(1)H2), 4.63 and
4.90 (2s, 2×1H, ꢀCH2); 13C NMR: l 17.4 and 25.9
(Me2C(2%)), 27.0 (Me3C)), 30.9 and 31.3 (C(4%) and
C(5%)), 38.6 and 39.2 (C(2%) and Me3C), 50.6 (C(1%)),
62.4 (C(1)), 76.0 (C(3%)), 109.6 (ꢀCH2), 145.4.0 (C(6%)),
178.6 (tBuCO2); EIMS: m/z (%) 254 [M+] (1), 163 (1),
152 (18), 137 (18), 134 (38), 121 (22), 119 (62), 110 (26),
109 (23), 107 (30), 95 (18), 93 (23), 91 (21), 81 (21), 79
(33), 67 (28), 57 (100), 43 (24), 41 (72). HRMS calcd for
C13H26O3 254.1882, found 254.1885.
4.9. (1%R,3%S)-cis-(3%-Imidazoylthiocarbonyloxy-2%,2%-
dimethyl-6%-methylene-1%-cyclohexyl)methyl 2,2-
dimethylpropionate ((2S,6R)-cis-2-imidazoylthio-
carbonyloxy-g-cyclogeranil pivaloate), 20
1,1%-Thiocarbonyldiimidazole (90% purity, 910 mg, 2.2

S. Beszant et al. / Tetrahedron: Asymmetry 13 (2002) 1245–1255
1253
(30), 123 (39), 121 (61), 109 (32), 107 (25), 95 (38), 93
(97), 91 (36), 81 (100), 79 (65), 77 (30), 69 (89), 67
(68), 55 (22), 41 (77).
1364, 1253, 1231, 1177, 991, 890; 1H NMR: l 0.86
and 0.91 (2s, 2×3H, Me2C(2%)), 1.29–1.41 and 1.45–
1.65 (2m, 1H and 3H, C(3%)H2 and C(4%)H2), 2.00–2.12
and 2.19–2.33 (2m, 2×1H, C(5%)H2), 2.27 (3H, s,
C(1)H3), 2.58 (d, J=10.0 Hz, 1H, C(1%)H), 4.54 and
4.79 (2s, 2×1H, ꢀCH2), 6.09 (d, J=15.8 Hz, 1H,
C(3)H), 6.93 (dd, J=15.8, 10.0 Hz, 1H, C(4)H); 13C
NMR: l 24.3 and 27.6 (Me2C(2%)), 29.6 (C(1)), 23.5,
34.5, and 39.0 (C(3%), C(4%), and C(5%)), 35.9 (C(2%)),
57.9 (C(1%)), 110.0 (ꢀCH2), 133.1 (C(3)), 133. 1 (C(4)),
148.7 (C(6%)), 198.6 (C(2)); EIMS: m/z (%) 192 [M+]
(9), 177 (12), 164 (11), 159 (11), 149 (100), 135 (12),
131 (11), 121 (53), 109 (45), 107 (21), 93 (28), 91 (36),
81 (43), 79 (35), 77 (31), 69 (41), 67 (21), 65 (20), 53
(11), 43 (78), 41 (43).
4.11. (S)-2%,2%-Dimethyl-6%-methylene-1%-cyclohexylcar-
baldehyde ((S)-(+)-g-cyclocitral), (+)-13
A solution of DMSO (92 mL, 2.5 equiv.) in dry
CH2Cl2 (2.5 mL) was added to a solution of freshly
distilled (COCl)2 (68 ml, 1.5 equiv.) in dry CH2Cl2 (6
mL) at −78°C. After 15 min at −78°C, a solution of
g-cyclogeraniol (+)-16 (80.0 mg, 0.518 mmol, 1 equiv.)
in dry CH2Cl2 (4 mL) was added. After 30 min at
−78°C, freshly distilled Et3N (325 mL, 4.5 equiv.) was
added and the mixture was stirred for 3 h while warm-
ing to room temperature. The reaction was then
quenched with H2O; after extraction with CH2Cl2 (×
3), the combined organic layers were washed with
brine, dried (Na2SO4) and evaporated. Chromatogra-
phy of the residue on silica gel (pentane–Et2O, 95:5)
and careful evaporation of the fractions at room tem-
perature afforded of the readily epimerizable aldehyde
(+)-13, as a colorless oil (64.0 mg, 86%), which was
immediately submitted to the following step; IR (neat):
w 3077, 2935, 2870, 2722, 1722, 1688, 1644, 1454, 1388,
4.13. (1%S,1RS)-1-(2%,2%-Dimethyl-6%-methylene-1%-cyclo-
hexyl)-but-3-en-1-ol, 22A–B
Allyltributyltin (480 mL, 3 equiv.) was added to a
solution of aldehyde (+)-13 (78.7 mg, 0.517 mmol) in
dry CH2Cl2 (7 mL) at −78°C; after 2 min, BF3·Et2O
(65 mL, 1 equiv.) was added dropwise over 3 min and
the mixture was stirred at −78°C for 30 min. The
reaction was then quenched with satd aq. NaHCO3
and the aq. phase was extracted with CH2Cl2 (×3).
The combined organic layers were washed with brine,
dried (Na2SO4) and evaporated. Chromatography of
the residue on silica gel (pentane–ether, 98:2“95:5)
furnished 22A (47 mg), contaminated by tin residues,
followed by adduct 22B (38 mg); 22A:22B=56:44 by
GC. Adduct 22A (undetermined stereochemistry at C-
1
1367, 1211, 1159, 988, 896; H NMR: l 0.98 and 1.09
(2×3H, 2s, Me2C(2%)), 1.36–1.45 and 1.58–1.73 (2m,
1H, 3H, C(3%)H2 and C(4%)H2), 2.17–2.26 (m, 2H,
C(5%)H2), 2.69 (d, J=4 Hz, 1H, C(1%)H), 4.72 and 4.97
(2s, 2×1H, ꢀCH2), 9.87 (d, 1H, J=4 Hz, C(1)H); 13C
NMR: l 25.9 and 28.0 (Me2C(2%)), 22.7, 33.3, and 37.4
(C(3%), C(4%), and C(5%)), 34.8 (C(2%)), 66.4 (C(1%)),
112.3 (ꢀCH2), 143.4 (C(6%)), 203.1 (C(1)); EIMS: m/z
(%) 152 [M+] (3), 137 (18), 123 (41), 121 (17), 109 (73),
107 (15), 95 (43), 94 (35), 93 (21), 91 (21), 81 (100), 79
(45), 77 (20), 69 (39), 67 (58), 53 (16), 41 (51).
1
1): H NMR: l 0.96 and 1.06 (2s, 2×3H, Me2C(2%)),
1.16–1.76 (m, 4H, C(3%)H2 and C(4%)H2), 1.88 (td, J=
13.1, 4.7 Hz, 1H, HC(5%)H); 2.11–2.21 and 2.22–2.33
(2m, 2H and 2H, C(1%)H, HC(5%)H, C(2)H2), 3.91–3.99
(m, 1H, C(1)H), 4.60 and 4.91 (2s, 2×1H, ꢀCH2), 5.10
(A part of an ABX system, 1H, C(4)HH), 5.15 (B part
of an ABX system, 1H, C(4)HH), 5.78–5.92 (X part of
an ABX system, 1H, C(3)H); EIMS: m/z (%) 194 [M+]
(1), 176 (12), 161 (6), 153 (4), 135 (11), 125 (15), 124
(12), 123 (11), 109 (100), 95 (22), 93 (7), 91 (6), 81
(19), 79 (9), 77 (4), 69 (16), 67 (21), 55 (4), 53 (4), 43
(10), 41 (20).
4.12. (S)-(E)-4-(2%,2%-Dimethyl-6%-methylene-1%-cyclo-
hexyl)-but-3-en-2-one ((S)-(+)-g-ionone), (+)-3
Diethyl (2-oxopropyl)phosphonate (225 mL, 1.12
mmol, 3 equiv.) was added to a suspension of finely
pulverized Ba(OH)2·8H2O (71 mg, 0.224 mmol, 0.6
equiv.) in THF (3.6 mL) at room temperature and the
mixture was stirred for 30 min; a solution of (+)-13
(57.0 mg, 0.374 mmol) in THF–H2O 40:1 (3.6 mL)
was then added and stirring was continued at room
temperature for an additional 15 h. After dilution with
CH2Cl2, the mixture was washed with H2O; the aq.
phase was extracted with CH2Cl2 (×3) and the com-
bined organic layers were washed with satd aq.
NaHCO3 and brine, dried (Na2SO4) and evaporated.
Chromatography of the residue on silica gel (pentane-
Et2O, 98:2“90:10) gave 59.6 mg (83% yield, GC
purity=98.3%) of (S)-g-ionone (+)-3 as a colorless oil
with a fine and distinct violet scent; [h]2D0=+30.3 (c
1.1, CH2Cl2), [lit.6 [h]D20=+36.2 (c 1, CHCl3) and
[h]2D0=+30.2 (c 0.5, EtOH)]; 88% e.e. (enantioselective
GC on a DAcTBuSilBETACDX column; He gas car-
rier, 1 mL/min; split ratio=1:50; temperature pro-
gram=80°C(0 min)“2°C/min“150°C; tR=32.7 min
for (−)-3, tR=33.1 min for (+)-3);. IR (neat): w 3078,
2931, 2867, 1697, 1675, 1644, 1625, 1460, 1438, 1386,
Adduct 22B (undetermined stereochemistry at C-1): IR
(neat): w 3444, 3071, 2976, 2931, 2868, 1645, 1462,
1443, 1387, 1365, 1343, 1281, 1205, 1161, 1116, 1066,
1034, 995, 987, 911, 891, 867, 67; 1H NMR: l 0.94
and 1.11 (2s, 2×3H, Me2C(2%)), 1.23–1.82 (m, 5H,
C(3%)H2, C(4%)H2, 1 allylic H), 1.88 (d, J=8.1 Hz, 1H,
allylic H), 1.94–2.07 (m, 1H, allylic H), 2.12–2.30 (2m,
2H, C(1%)H, HC(5%)H), 3.83–3.91 (m, 1H, C(1)H), 4.67
and 4.81 (2s, 2×1H, ꢀCH2), 5.15 (A part of an ABX
system, 1H, C(4)HH), 5.18 (B part of an ABX system,
1H, C(4)HH), 5.81–5.95 (X part of an ABX system,
1H, C(3)H); EIMS: m/z (%) 194 [M+] (1), 176 (9), 161
(6), 153 (3), 135 (7), 125 (12), 124 (14), 123 (11), 109
(100), 95 (15), 93 (8), 91 (8), 81 (23), 79 (9), 77 (5), 69
(15), 67 (22), 55 (6), 43 (12), 41 (23). HRMS calcd. for
C13H22O 194.1671, found 194.1668.

1254
S. Beszant et al. / Tetrahedron: Asymmetry 13 (2002) 1245–1255
4.14. (S)-1-(2%,2%-Dimethyl-6%-methylene-1%-cyclohexyl)-
but-3-en-1-one, (+)-23
J=15.5, 1.8 Hz, 1H, C(2)H), 6.86 (dq, J=15.5, 6.9 Hz,
1H, C(3)H); 13C NMR: l 29.6 (C(4)), 26.6 and 27.7
(Me2C(2%)), 22.8, 31.9, and 35.7 (C(3%), C(4%), and
C(5%)), 34.9 (C(2%)), 63.7 (C(1%)), 111.7 (ꢀCH2), 132.7
(C(2)), 141.5 (C(3)), 145.2 (C(6%)), 199.4 (C(1));. EIMS:
m/z (%) 192 [M+] (12), 177 (5), 159 (2), 149 (5), 136 (4),
135 (5), 123 (8), 122 (12), 121 (10), 109 (8), 107 (7), 93
(8), 91 (9), 81 (16), 79 (11), 77 (8), 69 (100), 67 (10), 43
(8), 41 (38).
Dess–Martin periodinane27 (265 mg, 1.2 equiv.) was
added to a solution of adducts 22A and 22B (100.2 mg,
0.51 mmol) in CH2Cl2 (14 mL) at room temperature
and the mixture was stirred for 1.5 h. Then, a 1:1
mixture of satd aq. NaHCO3 and satd aq. Na2S2O3 was
added and stirring was continued until a clear mixture
was obtained (10 min). The aq. phase was extracted
with CH2Cl2 (×3) and the combined organic layers were
washed with brine, dried (Na2SO4) and evaporated.
Chromatography of the semisolid residue on silica gel
(pentane–Et2O, 25:1) afforded product (+)-23 as color-
less and odorless oil (70.8 mg, 71% overall yield from
aldehyde 13); [h]2D0=+290 (c 1.1, CH2Cl2); IR (neat): w
3075, 2945, 2868, 1713, 1642, 1439, 1387, 1365, 1345,
1234, 1156, 1131, 1068, 1043, 992, 918, 894, 861, 765,
Acknowledgements
We thank the Italian CNR, MURST (funds COFIN),
and the University of Pavia (funds FAR) for financial
support, and Professor Mariella Mella and Professor
Giorgio Mellerio for NMR and MS spectra,
respectively.
1
733; H NMR: l 0.89 and 0.95 (2s, 2×3H, Me2C(2%)),
1.13–1.23, 1.44–1.57 and 1.58–1.69 (3m, 3×1H, C(3%)H2
and C(4%)HH), 1.98 (td, J=12.4, 4.4 Hz, 1H, C(4%)HH),
2.08 (dt, J=13.4, 4.4 Hz, 1H, C(5%)HH), 2.22 (td,
J=13.4, 5.2 Hz, 1H, C(5%)HH), 3.11 (s, 1H, C(1%)H),
3.11–3.33 (m, 2H, C(2)H2), 4.73 and 4.88 (2s, 2×1H,
ꢀCH2), 5.10 (A part of an ABX system, 1H, C(4)HH),
5.17 (B part of an ABX system, 1H, C(4)HH), 5.81–
5.96 (X part of an ABX system, 1H, C(3)H); 13C
NMR: l 27.2 and 27.5 (Me2C(2%)), 22.8, 31.5, and 35.2
(C(3%), C(4%), and C(5%)), 34.9 (C(2%)), 48.8 (C(2)), 65.5
(C(1%)), 112.0 (ꢀCH2), 118.5 (C(4)), 130.7 (C(3)), 145.2
(C(6%)), 208.1 (C(1)); EIMS: m/z (%) 192 [M+] (3), 149
(2), 135 (3), 123 (100), 109 (4), 95 (6), 93 (3), 91 (3), 82
(11), 81 (38), 79 (11), 67 (12), 55 (3), 53 (3), 41 (19).
HRMS calcd for C13H20O 192.1514, found 192.1511.
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