Stereospecific palladium(0)-catalyzed reduction of 2-cyclobutylidenepropyl esters. A versatile preparation of diastereomeric monoterpenoids: (±)-fragranol and (±)-grandisol

Article abstract of DOI:10.1016/j.tet.2003.09.074

Mixtures of (E and Z)-2-cyclobutylidenepropyl sulfonates, readily available from α,α-disubstituted cyclobutanones arising from suitable cyclopropane derivatives ring expansion, underwent regioselective and stereospecific reduction by formate anion to offer, through π-1,1- trimethyleneallylpalladium complexes formed upon treatment with palladium(0), a new and convenient entry to the diastereomeric four-membered ring monoterpenoids (±)-fragranol and (±)-grandisol.

Full text of DOI:10.1016/j.tet.2003.09.074

Tetrahedron 59 (2003) 9433–9440
Stereospecific palladium(0)-catalyzed reduction of
2-cyclobutylidenepropyl esters. A versatile preparation of
diastereomeric monoterpenoids: (6)-fragranol and (6)-grandisol
Angela M. Bernard,a Angelo Frongia,a Francesco Secci,a Giovanna Delogu,b Jean Ollivier,c
c
Pier P. Pirasa and Jacques Salau¨n
,
,
*
*
a
`
Dipartimento di Scienze Chimiche, Universita di Cagliari, Complesso Universitario di Monserrato, S.S. 554, Bivio per Sestu, I-09042
Monserrato, Cagliari, Italy
bIstituto di Chimica Biomolecolare, Sez. Sassari, CNR, Traversa La Crucca 3, reg. Baldinca, Li Punti, 07040 Sassari, Italy
c
´ ˆ ´
Laboratoire des Carbocycles (CNRS), UMR 8615, Institut de Chimie Moleculaire d’Orsay, Bat. 420, Universite de Paris-Sud, 91405 Orsay,
France
Received 11 July 2003; revised 5 September 2003; accepted 15 September 2003
Abstract—Mixtures of (E and Z)-2-cyclobutylidenepropyl sulfonates, readily available from a,a-disubstituted cyclobutanones arising from
suitable cyclopropane derivatives ring expansion, underwent regioselective and stereospecific reduction by formate anion to offer, through p-
1,1-trimethyleneallylpalladium complexes formed upon treatment with palladium(0), a new and convenient entry to the diastereomeric four-
membered ring monoterpenoids (^)-fragranol and (^)-grandisol.
q 2003 Elsevier Ltd. All rights reserved.
The monoterpenoid grandisol 1 is the main constituent of
the aggregation male-produced pheromone of the cotton
boll weevil Anthonomous grandis Boheman1 and of the sex
pheromones of other pests responsible for conifer infesta-
tions in North America and Central Europe, like Bark
weevils2 and Bark beetles.3 The diastereomeric monoterpe-
noid fragranol 2 was isolated from the roots of Artemisia
fragrans Willd.4 Due to the potential alternative to classical
pesticides offered by such four-membered ring natural
products involving environmentally friendly use, the total
synthesis of these terpenes is a matter of current
investigation.5
cycloadditions. Although when suitably substituted, cyclo-
propanes provided convenient precursors of cyclobuta-
nones,9 their use as intermediaries for the total synthesis of
grandisol 1 has been scarcely exploited.10
We report herein our investigations to form readily these
natural products from the regioselective and stereospecific
palladium(0) induced reduction of the 2-cyclobutylidene-
propyl esters 3a,b (Y¼O-p-An, CH2OBn),11 easily avail-
able from the cyclobutanones 4a,b, arising from the ring
expansions9 of either the oxaspiropentane 512 or the (1-
phenylthiocyclopropyl)carbinol 6 (Scheme 1).
As a matter of fact, we have previously reported that 1-(1-
alkenyl)cycloalkyl esters (acetate, tosylate, mesylate) 7
(n¼1, 3, 4; R¼H, alkyl, aryl, silyl) underwent palladium(0)
catalyzed hydrogenolysis by sodium formate in the presence
of crown ethers (15-C-5), or by n-butylzinc chloride as
hydride sources, to provide either alkylidenecycloalkanes 9
or (1-alkenyl) cycloalkanes 10, regioselectively.11 This
alternative to the Wittig olefination implied the intermediate
formation of the p-1,1-(polymethylene)allylpalladium com-
plexes 8 which underwent then, nucleophilic hydride
substitution with a regioselectivity monitored by the nature
of the hydride source, by ring strain, silyl substitution and by
the steric effect of phosphorus ligands (Scheme 2).11
In most of the reported syntheses of grandisol 1 and
fragranol 2, formation of the cyclobutane ring arose from
photochemically,6 thermally7 or TiCl4 promoted [2þ2]
8
Keywords: palladium and compounds; stereospecificity; cyclobutanes;
natural products.
*
Corresponding authors. Tel.: þ33-169-157-295; fax: þ33-169-156-278;
e-mail: jasalaun@icmo.u-psud.fr; Fax: þ39-706-754-388;
Our first approach towards the monoterpenoid alcohols 1
e-mail: pppiras@unica.it
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.074

9434
A. M. Bernard et al. / Tetrahedron 59 (2003) 9433–9440
Scheme 1.
Scheme 2.
and 2 involved the reaction of isopropenyl magnesium
bromide with the 2-(p-anisyloxymethyl)-2-methylcyclobu-
tanone 4a, previously obtained from oxaspiropentane 5,12
which furnished in 74% yield, a 70:30 mixture of trans- and
cis-1-isopropenyl-2-(p-anisyloxymethyl)-2-methylcyclobu-
tanols 11. As reported with 1-ethenylcyclopropyl tosylates
and mesylates 7 (n¼1) and 1-ethenylcyclohexyl acetates 7
(n¼4),11 the palladium(0) catalyzed hydride reduction
[Pd(dba)2, P(PPh3)2] by sodium formate of the 1-isoprope-
nylcyclobutylacetates 12 derived from cyclobutanols 11
could be expected to provide analogously the 1-(p-
anisyloxymethyl)-2-isopropenyl-1-methylcyclobutane 13,
a convenient and known precursor of grandisol 1 (Scheme
3).13 However, likely as result of steric hindrance or lability,
the allylic tertiary acetates 12a and the corresponding
sulfonic esters 12b were not obtained.
80% overall yield for these two steps, to an unseparable 20:80
mixture of (E)- and (Z)-allylic tosylates 15 (Scheme 4).
Palladium(0) [Pd(dba)2, 2PPh3] treatment of the 20:80
mixture of allylic tosylates (E and Z)-15 gave likely the p-
1,1-trimethyleneallylpalladium complex 16,11 which then
underwent nucleophilic addition of formate anion, when
treated by sodium formate in the presence of [15]-crown-5-
ether, to form the s-1,1-trimethyleneallylpalladium formate
complex 17.11 Decarboxylation of the formate ligand and
attack of the resulting hydride, as well as SNi transfer of
hydride to the cyclobutanic allylic end, led to a 20:80
mixture of cis- and trans-1,1,2-trisubstituted cyclobutanes
18 in 77% yield. Finally, cleavage of the O-protective group
by ammonium cerium(IV) nitrate (CAN, CH3CN, H2O)
gave in 74% yield, after chromatography the pure trans-2-
isopropyl-1-methyl cyclobutylcarbinol 19, a reported con-
venient precursor of (^)-fragranol 2 by homologation of the
primary alcohol.8
In order to overcome this failure, we have then prepared the
isomeric allylic tosylates 15. Thus, Wittig–Horner olefina-
tion of cyclobutanone 4a by triethyl 2-phosphonopropionate
(NaH, TDA-1, THF), provided an unseparable 20:80
mixture of (E)- and (Z)-2-[2-(p-anisyloxymethyl)-2-methyl-
cyclobutylidene]propionates 14. Their relative geometries
were assigned on the basis of NOE experiments; effectively
this effect was observed only between the vinylic methyl at
d 1.71 and the cyclobutanic allylic methylene at d 2.76 ppm
of (Z)-14. Then reduction (LiAlH4, THF) of (E and Z)-14,
followed by tosylation (TsCl, DMAP, NEt3, CH2Cl2), led in
The regioselectivity of this Pd(0) catalyzed reduction likely
resulted from the exclusive formation of the s-1,1-
trimethyleneallylpalladium complex 17, where the palla-
dium was positioned exclusively on the primary allylic end,
contrary to the p-1,1-dimethyleneallylpalladium complexes
8 (n¼1) arising from 1-ethenyl-1-tosyloxycyclopropanes
derivatives,14 for which the palladium was shown to be
positioned on the allylic carbon bearing the least
Scheme 3.
Scheme 4.

A. M. Bernard et al. / Tetrahedron 59 (2003) 9433–9440
9435
Scheme 5.
pronounced positive charge, because of the intrinsic three-
membered ring strain (Scheme 5).11,14 The stereospecificity
observed for this reaction, i.e. the formation of a 20:80
mixture of cis- and trans-18 from the 20:80 mixture of
allylic tosylates (E and Z)-15 was also noteworthy.
acid catalyzed ring expansion20 (PTSA, C6H6) to lead to the
cyclobutanone 24 in 98% yield (Scheme 8).
Wittig–Horner reaction of 24 with triethyl 2-phosphono-
propionate (60% NaH in oil, TDA-1, THF, reflux) provided
in 78% yield an unseparable 30:70 mixture of ethyl (E)- and
(Z)-2-[2-(benzyloxyethyl)-2-methyl cyclobutylidene]pro-
pionate 32. Then, successive conjugated double bond (Mg,
MeOH)21 and ester function reductions (LiAlH4, THF) of 32
followed by iodination of the resulting alcohol (I2, PPh3,
imidazole, benzene) gave a diastereomeric mixture of the
2-cyclobutyl-1-iodopropane derivative 33 in 88% overall
yield. Finally, dehydroiodination of 33 by silver fluoride in
pyridine led in 80% yield to a 1:1 diastereomeric mixture of
2-isopropenylcyclobutane derivatives 34 and 35. This lack
With the aim of synthesizing the diastereomeric mono-
terpenoid grandisol 1 with a reduced number of steps, we
have then prepared the 2-(2-benzyloxyethyl)-2-methyl-
cyclobutanone 24. First of all, attempted reaction of the
commercially available 4-benzyloxybutan-2-one 21 with
the cyclopropylidenephosphorane 20 (arising from reaction
of cyclopropyltriphenylphosphonium bromide15 with base)
failed to provide the cyclopropylidene derivative 22,
however potent precursor by peracid epoxidation
(MCPBA)16 of the oxaspiropentane 23, which was expected
to furnish then, by lithium iodide induced ring expansion the
cyclobutanone 24 (Scheme 6).9,16
1
of diastereoselectivity was pointed out from their H NMR
data, in particular by the occurrence of two aliphatic methyl
signals, as well from glc-mass spectroscopy. Furthermore,
after O-deprotection by cleavage of the O-benzyl bond with
Li/NH3 in dry diethyl ether, the mixture exhibited in its 1H
NMR two saturated methyl groups at d 1.17 and 0.92 ppm,
attributed to grandisol 1 and fragranol 2,8 respectively,
which then readily separable by liquid chromatography,
were obtained in 80% yield (Scheme 9).
Formation of methyl vinyl ketone and benzyl alcohol
indicated a competitive base-induced elimination of the
benzyloxy group. Replacement of the O-protective group of
21 by a tetrahydropyranyloxy, led unexpectedly but never-
theless interestingly to the 5-cyclopropylidenepentan-1-ol 29
in 45% yield.17 In fact 25 (prepared from commercially
available 4-hydroxybutan-2-one and THP, PPTs) underwent
likewise, elimination of the tetrahydropyranyloxy by the basic
phosphorane 20, with formation of the methyl vinyl ketone 26
and of the hemiacetal anion 27 in equilibrium with the
5-oxypentan-1-one anion 28, which then underwent Wittig
olefination by the ylide 20 (Scheme 7).18
On the other hand, lithium aluminium hydride reduction of
the unseparable 30:70 mixture of conjugated esters (E and
Z)-32 gave the corresponding allylic alcohols in 98% yield,
which were transformed into the crude tosylates (E and Z)-
36 (TsCl, DMAP, NEt3, CH2Cl2 at rt). Then, palladium(0)
catalyzed reduction of (E and Z)-36 by ammonium formate
in THF, which most probably occurred through the s-1,1-
trimethyleneallylpalladium formate complexes 38, analo-
gous to the s-complexes 17, (see Scheme 5) led in 80%
yield to a 70:30 mixture of cis-34, precursor of grandisol 1,
and of trans-35 precursor of fragranol 2, after O-deprotec-
tion (Li/NH3) and chromatography. Obviously, contrary to
Finally, the expected cyclobutanone 24 was successfully
obtained by reaction of the O-protected b-hydroxyketone 21
with the lithium salt of the cyclopropyl phenyl sulfide 30,19
(n-BuLi, THF, 08C) which furnished the 1-(phenylthio
cyclopropyl)carbinol 31 in 90% yield; then, 31 underwent
Scheme 6.
Scheme 7.

9436
A. M. Bernard et al. / Tetrahedron 59 (2003) 9433–9440
Scheme 8.
Scheme 9.
Scheme 10.
the sequence leading from the allylic tosylates (E and Z)-15
to fragranol 2 as major product (80%), as reported on
scheme 5, for the Pd(0)-catalyzed reduction of (E and Z)-36
the more bulky 2-(2-benzyloxyethyl)substituent appeared to
hamper one side of the palladium complexes p-37 and/or
s-38 and to entail the favored formation of the cis-2-
isopropylidenecyclobutane 34 (70%), precursor of (^)-
grandisol 1 after O-deprotection (Scheme 10).
recorded with a GC/MS spectrometer. TLC were carried
out on precoated TLC plates with silica gel 60 F-254. For
liquid chromatography silica gel 60 (230–4000 mesh) was
used. Melting points were determined on a Tottoli apparatus
and are incorrected. Microanalyses were carried out on a
Carlo Erba 1106 Elemental Analyzer. The preparation of
cyclobutanoned 4a has been previously reported.12
1.1.1. trans- and cis-1-Isopropenyl-2-[(4-methoxyphe-
noxy)methyl]-2-methylcyclobutanol 11. To a stirred
solution of cyclobutanone 4a (1 g, 4.5 mmol) in THF
(5 mL) was added at 2208C a solution of isopropenylmag-
nesium bromide [prepared as usual from magnesium
turnings (432 mg, 18 mmol) and 2-bromo propene
(1.6 mL, 18 mmol)] in THF (1 mL). The solution was
allowed to gradually reach room temperature and stirring
was continued for 20 h. The mixture was then quenched
with saturated aqueous NH4Cl and extracted with diethyl
ether. Then the separated organic layer was washed with
brine, dried (Na2SO4) and evaporated to give in 74% yield, a
70:30 mixture of trans- and cis-1-isopropenyl-2-[(4-meth-
oxyphenoxy)methyl]-2-methyl cyclobutanol 11, as exhib-
In conclusion, the palladium(0) catalyzed reduction of 2-
cyclobutylidenepropyl sulfonic esters by sodium formate,
involving p-1,1-trimethyleneallylpalladium complexes,
appeared completely regioselective and stereospecific. It
opened a new and convenient entry to diastereomeric four-
membered ring compounds; thus the allylic tosylates (E and
Z)-15 and (E and Z)-36, which were readily available from
the cyclobutanones 4a and 36, bearing either a 2-p-
anisyloxymethyl- or a 2-(2-benzyloxyethyl) substituents,
and prepared by ring expansion of the oxaspiropentane 512
or of the 2-(phenylthiocyclopropyl)carbinol 31, respect-
ively, afforded the pure (^)-fragranol 2 in 7 steps from 4a
with 25% overall yields and the pure (^)-grandisol 1 in 6
steps from the cyclopropylphenyl sulfide 30, with 42%
overall yields.
1
ited from the H NMR of the crude mixture.
Chromatography on a silica gel (eluent light petroleum/
AcOEt 10:1) allowed to isolate the pure trans-isomer.
Trans-11: IR (neat): 3380 cm21 1H NMR (CDCl3,
;
1. Experimental
1.1. General
300 MHz) d (ppm): 1.34 (3H, s), 1.62–1.82 (3H, m), 1.79
(3H, s), 2.45–2.54 (1H, m), 2.81 (1H, br s) 3.66, 3.71 (2H,
AB q, J¼8.7 Hz), 3.75 (3H, s), 4.91 (2H, s), 6.80 (4H, m);
13C NMR (CDCl3, 62.9 MHz) d (ppm): 18.40, 19.14, 24.96,
29.36, 46.65, 55.68, 73.35, 80.49, 111.32, 114.54, 115.23,
146.54, 153.47, 153.64; Mass spectrum (EI) m/z (rel.
intensity): 262 (3, Mþ), 178 (11), 163 (3), 124 (100), 109
IR spectra were recorded on a Perkin–Elmer 682 spectro-
1
photometer using NaCl plates. H and 13C NMR spectra
were recorded on a 300 MHz spectrometer with tetra-
methylsilane as internal reference. Mass spectra were

A. M. Bernard et al. / Tetrahedron 59 (2003) 9433–9440
9437
(20); Elemental analysis Calcd for C16H22 O3: C, 73.25; H,
8.45. Found: C, 73.32; H, 8.58.
(Z)-Allylic alcohol: IR (neat): 3300 cm21; 1H NMR (CDCl3,
300 MHz) d (ppm): 1.37 (3H, s), 1.61 (3H, s), 1.73–1.80 (1H,
m), 1.86–1.92(1H,m),1.87(1H,brs),2.55(2H,t,J¼8.1 Hz),
3.75 (3H, s), 3.81, 3.88 (2H, AB q, J¼9 Hz), 3.95, 4.17 (2H,
AB q, J¼11.4 Hz), 6.85 (4H, m); 13C (CDCl3, 62.9 MHz) d
(ppm):15.61, 23.36, 24.15, 27.28, 47.03, 55.70, 62.89, 75.10,
114.67, 115.50, 128.89, 141.26, 153.24, 153.97; Mass
spectrum (EI) m/z (rel. intensity): 262 (5, Mþ), 124 (100),
109 (27), 81 (38), 55 (11), 43 (30); Elemental analysis Calcd
for C16H22O3: C, 73.25; H, 8.45. Found: C, 73.18; H, 8.58.
cis-11: IR (neat): 3480 cm21; 1H NMR (CDCl3, 300 MHz)
d (ppm): (data were determined from the diastereomeric
mixture NMR spectra) 1.13 (3H, s), 1.62–2.02 (3H, m),
1.85 (3H, s), 2.45–2.54 (1H, m), 2.81 (br s, 1H), 3.77 (3H,
s), 3.87, 4.15 (2H, AB q, J¼9 Hz), 4.99 (1H, br s) and 5.02
(1H, br s), 6.80 (4H, m); Mass spectrum (EI) m/z (rel.
intensity): 262 (3, Mþ), 178 (11), 163 (3), 124 (100), 109
(20).
(E)-Allylic alcohol: IR (neat): 3300 cm21 1H NMR
;
1.1.2. Ethyl (E)- and (Z)-2-{2-[(4-methoxyphenoxy)-
methyl]2-methylcyclobutylidene}propanoate 14. 2.16 g
of triethyl phosphonopropionate (9 mmol) was rapidly
added to a stirred suspension of pentane-washed NaH
(360 mg, 9 mmol, 60% in oil) in THF (30 mL) under Argon.
After keeping the reaction mixture at 658C for 6 h, a
solution of cyclobutanone 4a (2 g, 9 mmol) and the catalyst
TDA-1 (2.3 mL, 0.9 mmol), was slowly added over about
30 min. The mixture was kept at the same temperature for
16 h. After cooling to room temperature, the solution was
diluted with diethyl ether and washed with brine, dried
(Na2SO4) and evaporated under vacuum to give 2.05 g (75%
yield) of a 20:80 mixture of two (E)- and (Z)-diastereomers,
which were separated by chromatography on silica gel
(eluent light petroleum/diethyl ether, 10:1).
(CDCl3, 300 MHz) d (ppm): 1.35 (3H, s), 1.71 (3H, s),
1.62–1.80 (1H, m), 1.96–2.08 (1H, m), 2.20 (1H, br s), 2.58
(2H, t, J¼8.4 Hz), 3.73 (3H, s), 3.83, 3.91 (2H, q, J¼9 Hz),
3.90 (2H, s), 6.78–6.86 (4H, m); 13C NMR (CDCl3,
62.9 MHz) d (ppm): 14.51, 22.13, 23.88, 27.34, 46.84,
55.53, 63.29, 74.38, 114.44, 115.44, 127.57, 140.45, 153.54,
153.58; Mass spectrum (EI) identical to (Z)-allylic alcohol;
Elemental analysis Calcd for C16H22O3: C, 73.25; H, 8.45.
Found: C, 73.38; H, 8.32.
To a solution of 412 mg (1.57 mmol) of the 20:80 mixture
of these (E, Z)-allylic alcohols in 10 mL of CH2Cl2 was
added triethylamine (462 mL, 4.71 mmol) at 08C, 19 mg of
DMAP (0.15 mmol) and 598 mg of tosylchloride
(3.14 mmol). The reaction mixture was maintained at 08C
for 6 h and then diluted with CH2Cl2. The organic layer was
washed with brine and then dried (Na2SO4). Evaporation of
the solvent afforded 650 mg (80% yield) of crude (4-
methylbenzene)sulfonate 15, which was used without
further purification in the next step. Spectroscopic data of
the crude mixture of (E,Z)-15: IR (neat): 1150 and
(Z)-14: Colourless oil: IR (neat): 1710 cm21 1H NMR
;
(CDCl3, 300 MHz) d (ppm): 1.25 (3H, t, J¼9 Hz), 1.38 (3H,
s), 1.71 (3H, s), 1.72–1.82 (1H, m), 2.26–2.36 (1H, m),
2.65 (2H, t, J¼8.4 Hz), 3.74 (3H, s), 3.91, 4.20 (2H, AB q,
J¼9 Hz), 4.12 (2H, q, J¼9 Hz), 6.82 (4H, m); 13C NMR
(CDCl3, 62.9 MHz) d (ppm): 14.16, 14.18, 21.28, 26.09,
27.15, 49.06, 55.52, 59.80, 73.13, 114.37, 115.58, 121.11,
153.56, 153.69, 160.80, 166.56; Mass spectrum (EI) m/z
(rel. intensity): 304 (5, Mþ), 259 (3), 181 (48), 153 (18), 135
(24), 124 (100), 109 (22), 91 (12); Elemental analysis Calcd
for C18H24O4: C, 71.03; H, 7.95. Found: C, 71.14; H, 7.79.
1
1200 cm21; H NMR (CDCl3, 300 MHz) d (ppm): 1.37
(3H, s), 1.41 (3H, s), 1.62 (3H, s), 1.63 (3H, s), 1.89–2.08
(4H, m), 2.48 (6H, s), 2.44–2.62 (4H, m), 3.75 (3H, s), 3.83,
3.88 (2H, AB q, J¼8.1 Hz), 4.06, 4.29 (2H, AB q,
J¼10.8 Hz), 3.86–3.94 (2H, m), 4.20–4.25 (2H, m),
6.83–7.93 (8H, m).
(E)-14: Colourless oil: IR (neat): 1710 cm21
;
1H NMR
1.1.4. 2-Isopropenyl-1-methyl-1-(4-methoxyphenoxy)cy-
clobutane 18. A solution of the crude tosylate (E,Z)-15
(650 mg, 1.57 mmol) in 15 mL of dry CH3CN was added to a
stirred solution of 50.63 mg (78.5 mmol, 5 mol%) of Pd(dba)2
and 41.13 mg (157 mmol, 10 mol%) of PPh3 in 15 mL of dry
CH3CN. After 10 min to the mixture was added 320 mg of
sodium formate (4.71 mmol) and 50 mg of [15]-crown-5
(0.4 mmol). The reaction mixture was stirred for 16 h at room
temperatureandthenwaterwasadded.Theaqueousphasewas
extracted with ether and the ether extracts were washed with
brine,driedandevaporated. Chromatographyoftheresidueon
silica gel (eluent pentane/diethyl ether, 9:1) gave 297 mg
(77% yield) of a 80:20 mixture of 18 as a yellow oil.
(CDCl3, 300 MHz) d (ppm): 1.28 (3H, t, J¼6.9 Hz), 1.41
(3H, s), 1.75–1.85 (1H, m), 1.84 (3H, s), 2.08–2.18 (1H,
m), 3.08 (2H, t, J¼9 Hz), 3.76 (3H, s), 3.88, 3.96 (2H, AB q,
J¼9 Hz), 4.16 (2H, q, J¼6.9 Hz), 6.83 (4H, m); 13C NMR
(CDCl3, 62.9 MHz) d (ppm): 13.68, 14.32, 21.56, 28.14,
29.06, 48.35, 55.67, 59.89, 73.76, 114.56, 115.51, 121.16,
153.39, 153.84, 161.56, 168.17; Mass spectrum (EI) m/z
(rel. intensity): 304 (6, Mþ), 259 (2), 180 (8), 151 (11), 135
(10), 124 (100), 109 (20), 91 (10); Elemental analysis Calcd
for C18H24O4: C, 71.03; H, 7.95. Found: C, 71.28; H, 7.72.
1.1.3. 2-(2-[(4-Methoxyphenoxy)methyl]-2-methylcyclo-
butylidene(propyl (4-methylbenzene) sulfonate 15. To a
stirred solution of the diastereomeric mixture of (E,Z)-14
(5.16 g, 0.017 mol) in 50 mL of dry THF at 2208C was
added dropwise a 1.5 M solution of LiAlH4 in THF
(11.34 mL, 0.017 mol). After 2 h the mixture was treated
with wet Na2SO4, then filtered on celite, dried (Na2SO4) and
the solvent evaporated under vacuum. Flash chromatog-
raphy of the residual oil (silica gel, pentane/diethyl ether
1:1) gave 3.74 g (84% yield) of a 20:80 mixture of the
corresponding (E)- and (Z)-allylic alcohols.
1
Major isomer: H NMR (CDCl3, 300 MHz) d (ppm): 1.05
(3H, s), 1.64 (3H, s), 1.70–2.12 (3H, m), 2.90 (2H, t), 3.71
(2H, s), 3.77 (3H, s), 4.67 (1H, s), 4.98 (1H, s), 6.87 (4H, s);
Mass spectrum (EI) m/z (rel. intensity): 246 (1, Mþ), 178
(1), 125 (8), 124 (100), 123 (28), 109 (21), 107 (5), 95 (14),
81 (22), 79 (10), 67 (14), 55 (14), 53 (8).
1
Minor isomer: H NMR (CDCl3, 300 MHz) d (ppm): 1.34
(3H, s). 1.73 (3H, s), 1.70-2.12 (3H, m), 2.65 (2H, t), 3.68

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A. M. Bernard et al. / Tetrahedron 59 (2003) 9433–9440
(2H, s), 3.75 (3H, s), 4.80 (1H, s), 4.98 (1H, s), 6.80 (4H, s);
Mass spectrum (EI) m/z 246 (1, Mþ), 178 (1), 125 (8), 67
(11), 55 (12), 53 (8).
water-saturated benzene was refluxed for 4 h. After cooling
to room temperature, the benzene solution was washed
twice with saturated aqueous sodium bicarbonate solution
(20 mL) and with brine (20 mL). After drying (Na2SO4) and
concentration in vacuum, chromatography of the residue
(eluent diethyl ether/light petroleum, 1:5) gave 2.91 g (yield
98%) of cyclobutanone 24: IR (neat): 1765 cm21; 1H NMR
(CDCl3, 300 MHz) d (ppm): 1H NMR (CDCl3) 1.86 (3H, s),
1.64–1.79 (2H, m), 1.93–2.01 (2H, m), 2.98 (2H, t,
J¼9.6 Hz), 3.56 (2H, t, J¼6.3 Hz), 4.40–4.46 (2H, AB q,
J¼11.7 Hz), 7.30 (5H, m); 13C NMR (CDCl3, 62.9 MHz) d
(ppm) 21.30, 23.87, 35.32, 42.32, 62.22, 66.66, 72.85,
127.41, 128.22, 138.13, 214.821; Mass spectrum (EI) m/z
(rel. intensity): 218 (0.5, Mþ), 127 (12), 97 (11), 91 (100),
41 (38); Elemental analysis Calcd for C14H18O2: C, 77.03;
H, 8.31. Found: C, 77.24; H, 8.42.
1.1.5. trans-2-Isopropenyl-1-methylcyclobutanemetha-
nol 19. Ammonium cerium(IV) nitrate (169.3 mg,
0.33 mmol) dissolved in 5 mL of water was added to a
cooled (2108C) solution of the 20:80 mixture of 18
(36.8 mg, 015 mmol) in 10 mL of CH3CN. The reaction
mixture was stirred for 2 h and then diluted with CH2Cl2.
The organic phase was washed with saturated aqueous
NaHCO3, dried and evaporated under reduced pressure.
Purification of the residue by liquid chromatography on
silica gel (eluent pentane/ether, 9:1) gave 16 mg (74%
yield) of pure (E)-19: 1H NMR (CDCl3, 300 MHz) d (ppm):
0.95 (3H, s), 1.14–2.20 (5H, m), 1.65 (3H, s), 2.74 (1H, t,
J¼9.2 Hz), 3.49 (2H, br s), 4.67 (1H, br s), 4.85 (1H, br s).22
1.1.9. Ethyl 2-(2-[2-(benzyloxy)ethyl]-2-methylcyclobu-
tylidene(propanoate 32. To a stirred suspension of
pentane-washed NaH (364 mg, 9.1 mmol, 60% in oil) in
THF (30 mL) was rapidly added 2.16 g (9.1 mmol) of
triethylphosphonopropionate and the mixture was stirred
under argon at 658C for 6 h. Then a solution of
cyclobutanone 24 (2 g, 9.1 mmol) and of tris-(3,6-dioxa
heptyl)amine (TDA-1) (290 mL, 0.91 mmol) in THF
(10 mL) was slowly added within 30 min. The mixture
was stirred at the same temperature for 16 h and after
cooling to room temperature, the solution was diluted with
diethyl ether and washed with brine, dried (Na2SO4) and
evaporated under vacuum. Chromatography of the residue
on silica gel (eluent light petroleum/diethyl ether, 10:1)
gave 2.14 g (78% yield) of a 30:70 (E,Z) diastereomeric
mixture of 32.
1.1.6. 5-Cyclopropylidenepentan-1-ol 29. 50.73 g of (3-
bromopropyl)triphenylphosphonium bromide (0.109 mol)
rapidly added to a stirred suspension of pentane washed
NaH (8.72 g, 0.218 mol, 60% in oil) in dry THF (150 mL)
under Argon was stirred at 658C for 6 h. Then a solution
of 4-(tetrahydropyran-2-yloxy)butan-2-one 25 (9.4 g,
0.054 mol) and the catalyst TDA-1 (1.73 mL, 5.4 mmol)
in THF (30 mL) was slowly added. The mixture was kept at
same temperature for 16 h and after cooling to room
temperature the solution was diluted with diethyl ether and
washed with brine, dried (Na2SO4) and evaporated under
vacuum. Chromatography of the residue on silica gel (eluent
light petroleum/diethyl acetate, 1:1) gave 3.10 g (45%
yield) of known 5-cyclopropylidenepentan-1-ol 29, with
spectral data in complete agreement with the literature.17
1.1.7. 4-(Benzyloxy)-2-[1-(phenylthio)cyclopropyl]bu-
A 1.5 M solution of n-BuLi (13 mL,
(Z)-32: (spectroscopic data were worked out from pure (Z)-
32, isolated by chromatography): IR (neat): 1675 cm21; 1H
NMR (CDCl3, 300 MHz) d (ppm): 1.22 (3H, t, J¼6.8 Hz),
1.24 (3H, s), 1.60 (3H, s), 1.63–1.68 (1H, m), 1.85–2.05
(3H, m), 2.42–2.59 (2H, m), 3.40–3.52 (2H, m), 4.08 (2H,
q, J¼6.8 Hz), 4.40 (2H, s), 7.25 (5H, m); 13C NMR (CDCl3,
62.9 MHz) d (ppm) 14.28, 25.01, 25.89, 29.07, 29.70, 37.25,
47.58, 59.91, 67.96, 72.88, 120.16, 127.45, 128.26, 138.67,
138.67, 163.59, 166.89; Mass spectrum (EI) m/z (rel.
intensity): 302 (1.6, Mþ), 256 (13), 216 (10), 168 (28),
153 (16), 139 (25), 91 (100); Elemental analysis Calcd for
C19H26O3: C, 75.46; H, 8.67. Found: C, 75.28; H, 8.52.
tan-2-ol 31.
0.02 mol) in hexane was added to a stirred solution of
cyclopropyl phenyl sulfide (3 g, 0.02 mol) in THF (50 mL)
at 08C. The resulting solution was stirred for 5 h at room
temperature and then 4-(benzyloxy)butan-2-one 21 (3.6 g,
0.02 mol) was added at 08C. The reaction mixture was
allowed to warm to room temperature and stirred for 16 h.
Then, brine and diethyl ether were added. The organic layer
was separated and the aqueous layer was extracted with
diethyl ether. The combined organic layers were dried
(Na2SO4), evaporated in vacuum and the crude product was
purified by liquid chromatography on silica gel (eluent
diethyl ether/light petroleum, 1:10) to provide 5.9 g (90%
(E)-32: (spectroscopic data were worked out from spectra of
(E,Z) mixture of 32); IR (neat): 1765 cm21 1H NMR
;
1
yield) of 31 as yellow oil. IR (neat): 3484 cm21; H NMR
(CDCl3, 300 MHz) d (ppm): 0.90 (4H, m), 1.26 (3H, s),
1.96–2.05 (2H, m), 2.26–2.19 (2H, m), 3.78 (1H, br s),
3.61–3.68 (1H, m), 3.74–3.81 (1H, m), 4.46 (2H, s), 7.26–
7.46 (10H, m); 13C NMR (CDCl3, 62.9 MHz) d (ppm):
11.09, 13.15, 26.83, 38.37, 67.92, 73.50, 126.15, 127.81,
127.86, 128.44, 128.53, 129.88, 137.02, 137.31, 178.19;
Mass spectrum (EI) m/z (rel. intensity): 328 (0.5, Mþ), 221
(1), 204 (3), 179 (13) 150 (7), 135 (6), 117 (12), 91 (100);
Elemental analysis Calcd for C20H24O2S: C, 73.13; H, 7.36;
S, 9.76. Found: C, 73.24; H, 7.42; S, 9.62.
(CDCl3, 300 MHz) d (ppm): 1.20 (3H, t, J¼7.6 Hz), 1.22
(3H, s), 1.57–1.66 (1H, m), 1.68 (3H, s), 1.80–1.99 (3H,
m), 2.80–2.89 (2H, m), 3.42–3.54 (2H, m), 4.07 (2H, q,
J¼7.6 Hz), 4.42 (2H, s), 7.25 (m, 5H); Mass spectrum (EI)
m/z (rel. intensity): 302 (1.6, Mþ), 256 (10), 216 (16), 168
(33), 153 (20), 139 (33), 91 (100).
1.1.10. 2-[2-(2-Benzyloxy)ethyl-2-methylcyclobutyl]-1-
iodopropane 33. To a stirred solution of cyclobutylidene
propanoate (E,Z)-32 (1.5 g, 4.9 mmol) in dry methanol
(15 mL) Mg turning (935 mg, 39 mmol) was added. After
stirring for 24 h, the mixture was diluted with diethyl ether,
treated with few drops of acetic acid and washed with
saturated solution of NH4Cl. After evaporation of the
1.1.8. 2-[2-(Benzyloxy)ethyl]-2-methylcyclobutanone 24.
A mixture of cyclopropylcarbinol 31 (4.5 g, 13.6 mmol) and
2.2 g (13.6 mmol) of p-toluensulfonic acid in 80 mL of

A. M. Bernard et al. / Tetrahedron 59 (2003) 9433–9440
9439
solvent in vacuum, the crude oil was purified by flash
chromatography on silica gel (eluent light petroleum/diethyl
ether 5:1) to afford 1.29 g (87% yield) of a diastereomeric
mixture of four corresponding 2-cyclobutylpropanoates: IR
7.31 (5H, m); Mass spectrum (EI) m/z (rel. intensity): 244
(0.5, Mþ), 229 (0.5), 153 (3), 135 (8), 107 (25), 91 (100).
1
trans-35: H NMR (CDCl3, 300 MHz) d (ppm): 0.92 (3H,
1
(neat): 1720 cm21; H NMR (CDCl3, 300 MHz) d (ppm):
s), 1.41–1.96 (6H, m), 1.63 (3H, s), 2.45–2.62 (1H, m),
3.45–3.54 (2H, m), 4.47 (2H, s), 4.60 (1H, br s), 4.81 (1H,
br s), 7.31 (5H, m); Mass spectrum (EI) m/z (rel. intensity):
244 (0.5, Mþ), 229 (0.5), 153 (3), 135 (8), 107 (25), 91
(100).
0.98 (3H, t, J¼7.2 Hz), 1.07, 1.03, 1.05, 1.07 (s, 3H), 1.75–
1.24 (3H, doublets), 1.38–2.52 (6H, m), 3.43–3.63 (2H, m),
4.02 (2H, m), 4.45 (2H, br s), 4.48 (2H, br s), 7.22–7.32
(5H, m); Mass spectrum (EI) m/z (rel. intensity): (first
diastereomer: 43%): 276 (1, Mþ228), 259 (3), 196 (7) 176
(14), 167 (4), 161 (8) 129 (8), 107 (18) 91 (100); (second
diastereomer: 32%): 259 (1, Mþ245), 176 (10), 161 (7),
131 (4), 107 (16), 91 (100); (third diastereomer: 13%) :259
(3, Mþ245), 196 (4), 176 (7), 167 (5), 161 (5), 129 (6), 107
(13), 91 (100); (fourth diastereomer: 12%): 276 (1,
Mþ228), 259 (3), 196 (7) 176 (14), 167 (4), 161 (8) 129
(8), 107 (18) 91 (100).
1.1.12. 2-[2-(2-Benzyloxy)ethyl-2-methylcyclobutylide-
ne]propyl (4-methylbenzene)sulfonate 36. To a solution
of the diastereomeric mixture (E,Z)-32 (1 g, 3.3 mmol) in
dry THF (30 mL) stirred at 2208C, was added dropwise a
1.5 M solution of LiAlH4 (2.2 mL, 3.3 mmol) in THF. After
stirring for 2 h, the mixture was treated with wet Na2SO4,
filtered on celite, dried (Na2SO4) and the solvent evaporated
under vacuum. Flash chromatography of the residual oil on
silica gel (eluent pentane/diethyl ether 5:1) gave 0.84 g
(98% yield) of a 30:70 mixture of the corresponding 2-
cyclobutylidenepropan-1-ols: IR (neat): 3380 cm21; major
isolated isomer: 1H NMR (CDCl3, 300 MHz) d (ppm): 1.22
(3H, s), 1.55 (3H, br s), 1.72–1.98 (4H, m), 2.22 (1H, br s),
2.37–2.52 (2H, m), 3.56 (2H, t, J¼6.9 Hz), 3.81–4.05 (2H,
m), 4.45–4.51 (2H, AB q, J¼11.4 Hz), 7.25–7.36 (5H, m);
13C NMR (CDCl3, 62.9 MHz) d (ppm) 15.08, 23.66, 27.38,
28.52, 38.50, 39.72, 45.21, 62.25, 63.54, 67.69, 73.02,
127.68, 128.26, 138.02, 144.11; Mass spectrum (EI) m/z
(rel. intensity): 260 (0.1, Mþ), 177 (10), 159 (8), 131 (6),
107 (11), 91 (100), 84 (24);); Elemental analysis Calcd for
C17H24O2: C, 78.42; H, 9.29. Found: C, 78.28; H, 9.42:
minor isomer (spectroscopic data worked out from mixture
To a stirred solution of this diastereomeric mixture of
propanoates (5.16 g, 1.7 mmol) in dry THF (50 mL) at
2208C was added dropwise a 1.5 M solution of LiAlH4
(11.34 mL, 0.017 mol) in THF. After 2 h the mixture was
treated with wet Na2SO4, then filtered on celite, dried
(Na2SO4) and the solvent evaporated under vacuum. Flash
chromatography of the residual oil on silica gel, (eluent
pentane/diethyl ether 10:1) gave 3.43 g (77% yield) of a
diastereomeric mixture of 2-cyclobutyl propanols. IR
1
(neat): 3400 cm21; H NMR (CDCl3, 300 MHz) d (ppm):
1.05 (3H, s), 1.07 (3H, s), 0.8–2.00 (6H, m), 3.24–3.59 (3H,
m), 4.47 (4H, s), 4.50 (2H, s), 7.20–7.31 (5H, m); Mass
spectrum (EI) m/z (rel. intensity): 262 (0.5, Mþ), 228 (0.3),
197 (0.7), 176 (15), 161 (18), 153 (3), 131 (5), 113 (2); 107
(17), 91 (100).
1
spectra): H NMR (CDCl3, 300 MHz) d (ppm): 1.24, (3H,
s), 1.63 (3H, br s), 1.71–1.98 (4H, m), 2.22 (1H, br s), 2.37–
2.52 (2H, m), 3.56 (2H, t, J¼6.9 Hz), 3.81–4.05 (2H, m),
4.49 (3H, s), 7.25–7.36 (5H, m); Mass spectrum (EI) m/z
(rel. intensity): 260 (0.1, Mþ), 177 (10), 159 (8), 131 (6),
107 (11), 91 (100), 84 (24).
To a stirred solution of triphenylphosphine (1.99 g,
7.6 mmol) in benzene (50 mL), were added imidazole
(1.15 g, 17 mmol), the previously obtained 2-cyclobutyl
propanol (1 g, 3.8 mmol) and iodine (0.96 g, 7.6 mmol); the
mixture was stirred at room temperature for 1 h. Then, it
was diluted with pentane and quenched with an aqueous
solution of 2.5% sodium thiosulfate (20 mL). The organic
layer was separated, dried and concentrated under vacuum
to provide 1.34 g [in 88% yield from (E,Z)-32] of a mixture
of cis- and trans-crude iodopropanes 33, which were used
without further purification in the next step.
To a solution of these 2-cyclobutylidenepropan-1-ols
(290 mg, 1.1 mmol) in dichloromethane (10 mL) were
added at 08C triethylamine (462 mL, 3.34 mmol), DMAP
(13 mg, 0.1 mmol) and tosylchloride (212 mg, 1.1 mmol).
The reaction mixture was maintained at 08C for 6 h and then
diluted with dichloromethane. The separated organic layer
was washed with brine and then dried (Na2SO4). Evapor-
ation of the solvent in vacuum afforded 455 mg of the crude
tosylate 36 which was used without further purification in
the next step.
1.1.11. cis- and trans-1-(2-Benzyloxyethyl)-2-isoprope-
nyl-1-methylcyclobutanes 34 and 35 from iodides 33. To
a stirred solution of 1.4 g (3.8 mmol) of crude iodopropanes
cis- and trans-33 (3.8 mmol) in dry pyridine (10 mL) was
added under argon silver fluoride (0.96 g, 7.6 mmol). The
reaction mixture was stirred at room temperature for 12 h,
and then diluted with diethyl ether. The separated organic
layer was successively washed with a saturated solution of
CuSO4, with brine, then dried (Na2SO4) and concentrated
under vacuum. Chromatography of the residual oil on silica
gel (eluent pentane/diethyl ether 10:1) gave 700 mg (80%
yield) of an unseparable 1:1 mixture of cyclobutanes cis-34
and trans-35 as a colourless oil.
1.1.13. cis- and trans-1-(2-Benzyloxyethyl)-2-isoprope-
nyl-1-methylcyclobutanes 34 and 35 from tosylate 36. A
solution of tosylate 36 (455 mg, 1.1 mmol) in dry CH3CN
(15 mL) was added to a stirred solution of Pd(dba)2
(45.5 mg, mmol,) and of PPh3 (43.6 mg, 173 mmol) in dry
CH3CN (7 mL). After 10 min the mixture had turned orange
and was added to ammonium formate (205 mg, 3.3 mmol).
The reaction mixture was stirred for 16 h at room
temperature and then diethyl ether (20 mL) was added.
The separated organic solution was washed with brine, dried
(Na2SO4) and the solvent evaporated in vacuum. Chroma-
tography of the residue on silica gel (eluent pentane/ether
9:1) gave 215 mg (80% yield) of a 70:30 mixture of
cis-34: 1H NMR (CDCl3, 300 MHz) d (ppm): 1.15 (3H, s),
1.41–1.96 (6H, m), 1.65 (3H, s), 2.45–2.62 (1H, m), 3.45–
3.54 (2H, m), 4.48 (2H, s), 4.63 (1H, br s), 4.81 (1H, br s),

9440
A. M. Bernard et al. / Tetrahedron 59 (2003) 9433–9440
Tuck, K. L. J. Org. Chem. 2000, 65, 7839. Monteiro, H. J.;
Stefani, H. A. Eur. J. Org. Chem. 2001, 14, 2659.
6. Alibes, R.; Bourdelande, J. L.; Font, J.; Parella, T. Tetra-
hedron 1996, 1279.
cyclobutanes cis-34 and trans-35, as a colourless oil, with
spectral data analogous to the data reported above for cis-34
and trans-35, obtained from iodide 33.
7. Hamon, D. P. G.; Tuck, K. L. Tetrahedron Lett. 1999, 40,
7569.
1.1.14. cis-2-(2-Isopropenyl-1-methylcyclobutyl)ethan-1-
ol or grandisol 1 and trans-2-(2-isopropenyl-1-methylcy-
clobutyl)ethan-1-ol or fragranol 2. To a dark blue solution
of Li (33 mg, 4.8 mmol) in liquid NH3 (ca. 40 mL) at
2788C was added under argon a 1:1 mixture of cis-34 and
trans-35 (300 mg, 1.2 mmol) in dry ether (3 mL) all at once.
The mixture was stirred for 10 min and quenched rapidly
with methanol (10 mL). The solution was warmed to room
temperature, treated with saturated aqueous NH4Cl and
extracted with diethyl ether. The extract dried (Na2SO4) and
concentrated in vacuum afforded 200 mg (78%) of a 1:1
mixture of grandisol 1 and fragranol 2 which were isolated
by chromatography on silica gel (eluent hexane/ethyl
acetate, 7:3). Analogously, treatment of a 70:30 mixture
of cis-34 and trans-35 led to a 70:30 mixture of grandisol 1
and fragranol 2.
¨
8. Knolker, H.-J.; Baum, G.; Schmitt, O.; Wanzl, G. J. Chem.
Soc., Chem. Commun. 1999, 1737.
9. Salau¨n, J. In Rearrangements Involving the Cyclopropyl
Group. The Chemistry of the Cyclopropyl Group; Rappoport,
Z., Ed.; Wiley: New York, 1987; p 809. Trost, B. M. Top.
Curr. Chem. 1986, 133, 3. Salau¨n, J. J. Top. Curr. Chem. 1988,
144, 1. Nemoto, H.; Ishibashi, H.; Nagamochi, M.; Fukumoto,
K. J. Org. Chem. 1992, 57, 1707. Nemoto, H.; Shiraki, M.;
Fukumoto, K. Tetrahedron 1994, 50, 10391. Nemoto, H.;
Miyata, J.; Fukumoto, K. Heterocycles 1996, 42, 165. Nemoto,
H.; Miyata, J.; Yoshida, M.; Raku, N.; Fukumoto, K. J. Org.
Chem. 1997, 62, 7850. Chevtchouk, T.; Ollivier, J.; Salau¨n, J.
Tetrahedron: Asymmetry 1997, 8, 1011. Cho, S. Y.; Cha, J. K.
Organic Lett. 2000, 9, 1337.
10. Trost, B. M. J. Org. Chem. 1975, 407, 2013. Trost, B. M.;
Keeley, D. E.; Arndt, H. C.; Bogdanowicz, M. J. J. Am. Chem.
Soc. 1977, 99, 3088. Wenkert, E.; Berges, D. A.; Golob, N. F.
J. Am. Chem. Soc. 1978, 100, 1263. Sonawane, H. R.;
Nanjundiah, B. S.; Kumar, M. U. Tetrahedron Lett. 1984, 25,
2245. Sonawane, H. R.; Vishwaniyant, G. N.; Nanjundiah,
B. S.; Virendra, G. S.; Pramod, C. P.; Kumar, M. U.
Tetrahedron 1991, 47, 8259.
1
Grandisol 1: Yellow oil: H NMR (CDCl3, 300 MHz) d
(ppm): 1.17 (3H, s), 1.45 (1H, m), 1.58 (1H, br s),1.67 (3H,
s), 1.75–2.04 (4H, m), 2.54–2.59 (1H, m), 3.66–3.73 (2H,
m), 4.65 (1H, s), 4.84 (1H, s); Mass spectrum (EI) m/z (rel.
intensity): 154 (0.2, Mþ), 139 (2), 121 (4), 109 (21), 93 (11),
91 (6), 79 (12), 68 (100), 67 (80); in accordance with
reported spectral data.5
11. Ollivier, J.; Dorizon, P.; Piras, P. P.; de Meijere, A.; Salau¨n, J.
Inorg. Chim. Acta 1994, 222, 37. Ollivier, J.; Piras, P. P.;
Stolle, A.; Aufranc, P.; de Meijere, A.; Salau¨n, J. Tetrahedron
Lett. 1992, 33, 3307.
1
Fragranol 2: Yellow oil: H NMR (CDCl3, 300 MHz) d
(ppm): 0.93 (3H, s), 1.42 (1H, m), 1.65 (3H, s),1.58 (1H, br
s), 1.75–2.04 (4H, m), 2.56 (1H, m), 3.66–3.73 (2H, m),
4.62 (1H, s), 4.83 (1H, q, J¼1.5 Hz); Mass spectrum (EI) m/
z (rel. intensity): 154 (0.2, Mþ), 139 (2), 121 (3), 109 (17),
93 (11), 91 (6), 79 (12), 68 (100), 67 (80); in accordance
with reported spectral data.8
12. Bernard, A. M.; Floris, C.; Frongia, A.; Piras, P. P. Tetra-
hedron 2000, 56, 4555.
13. Meyers, A. I.; Fleming, S. A. J. Am. Chem. Soc. 1986, 108,
306.
14. Stolle, A.; Ollivier, J.; Piras, P. P.; Salau¨n, J.; de Meijere, A.
J. Am. Chem. Soc. 1992, 114, 4051.
15. Sisido, K.; Utimoto, K. Tetrahedron Lett. 1966, 3267.
Utimoto, K.; Tamura, M.; Sisido, K. Tetrahedron 1973, 29,
1169. Schweizer, E. E.; Berninger, C. J.; Thompson, J. G.
J. Org. Chem. 1968, 33, 336.
Acknowledgements
This work was financially supported by the CNR (Italy) and
the CNRS (France) within a French–Italian Cooperation
Program (Project 2002–2003, No 11389).
16. Crandall, J. K.; Paulson, D. R. J. Org. Chem. 1968, 33, 991.
see also p 3291. Salau¨n, J.; Conia, J. M. J. Chem. Soc., Chem.
Commun. 1971, 1579.
17. Cordero, F. M.; Brandi, A. Tetrahedron Lett. 1995, 1343.
18. Steinbeck, K.; Osterwinter, B. Tetrahedron Lett. 1980, 21,
1515. Bernard, M.; Leandri, G.; Meou, A. Tetrahedron 1981,
37, 1703.
References
1. Hedin, P. A. Chemtech 1976, 444.
2. Booth, D. C.; Phillips, T. W.; Claesson, A.; Silverstein, R. M.;
Lanier, G. N.; West, J. R. J. Chem. Ecol. 1983, 9, 1. Phillips,
T. W.; West, J. R.; Foltz, J. L.; Silverstein, R. M.; Lanier, G. N.
J. Chem. Ecol. 1984, 10, 1417.
19. Truce, W. E.; Hollister, K. R.; Lindy, L. B.; Parr, T. E. J. Org.
Chem. 1968, 33, 43.
20. Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1971, 93,
3773.
3. Francke, W.; Pan, M. L.; Koenig, W. A.; Mori, K.;
Puapoomchaeron, P.; Heuer, H.; Vite, J. P. Naturwissench-
aften 1987, 74, 343.
21. For some previous uses of Me/MeOH for a,b-unsaturated
esters and nitriles reduction see: Ainscow, R. B.; Brettle, R.;
Shibib, S. M. J. Chem. Soc., Perkin Trans. 1 1985, 1781.
Walkup, R. D.; Park, G. Tetrahedron Lett. 1988, 29, 5505.
Walkup, R. D.; Park, G. J. Am. Chem. Soc. 1990, 112, 1597.
Chen, Y.-J.; De Clercq, P.; Vandewalle, M. Tetrahedron Lett.
1996, 37, 9361.
4. Bohlmann, F.; Zdero, C.; Faass, U. Chem. Ber. 1973, 106,
2904.
5. Hamon, D. P. G.; Tuck, K. L. Tetrahedron Lett. 1999, 40,
7569. March, P.; de Figueredo, M.; Font, J.; Raya, J. Org. Lett.
2000, 2, 163. Petschen, I.; Bosch, M. P.; Guerrero, A.
Tetrahedron: Asymmetry 2000, 11, 1691. Hamon, D. P. G.;
22. Kim, D.; Lee, Y. K.; Mi Jang, Y.; Kim, O.; Park, S. W.; Eds.;
J. Chem. Soc., Perkin Trans. 1 1990, 3221.