A highly stereocontrolled formal total synthesis of (±)- and of (-)-grandisol by 1,4-conjugated addition of organocopper reagents to cyclobutylidene derivatives

Article abstract of DOI:10.1016/j.tet.2007.03.134

Starting from suitable cyclopropanes, a formal total synthesis of racemic grandisol and of the enantiopure (-)-grandisol is presented. The racemic synthesis of the grandisol precursor was accomplished in five steps. The synthesis of the chiral non-racemic precursor (1S,2S,2′R)-cis of this pheromone was realized in 10 steps, with an overall yield of 45%, using the enantiopure cyclobutanone (R,S), previously obtained by ring expansion of an optically pure oxaspiropentane. The key stereodefining step was the addition of lithium dimethylcuprate to a chiral α,β-unsaturated cyclobutylidene carbonyl derivative.

Full text of DOI:10.1016/j.tet.2007.03.134

Tetrahedron 63 (2007) 4968–4974
A highly stereocontrolled formal total synthesis of ( )- and of
(L)-grandisol by 1,4-conjugated addition of organocopper
reagents to cyclobutylidene derivatives
a,
Angela M. Bernard,a Angelo Frongia,a Jean Ollivier,b, Pier Paolo Piras,
*
*
Francesco Seccia and Marco Spigaa
aDipartimento di Scienze Chimiche, Universitaꢀ degli Studi di Cagliari, 09042 Monserrato (Ca), Italy
b
´
´
Laboratoire de Syntheꢀse Organique et Methodologie, Universite de Paris-sud Ba^t 420, 91405 Orsay cedex, France
Received 19 December 2006; revised 27 February 2007; accepted 22 March 2007
Available online 27 March 2007
Abstract—Starting from suitable cyclopropanes, a formal total synthesis of racemic grandisol and of the enantiopure (ꢀ)-grandisol is pre-
sented. The racemic synthesis of the grandisol precursor was accomplished in five steps. The synthesis of the chiral non-racemic precursor
(1S,2S,20R)-cis of this pheromone was realized in 10 steps, with an overall yield of 45%, using the enantiopure cyclobutanone (R,S), previously
obtained by ring expansion of an optically pure oxaspiropentane. The key stereodefining step was the addition of lithium dimethylcuprate to
a chiral a,b-unsaturated cyclobutylidene carbonyl derivative.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
OAc
Me
OH
Grandisol 1, first isolated in 1967,1 is one of the components
of the male-produced pheromone of the cotton boll weevil
Anthonomus grandis Boheman and of the sex pheromone
of other pests responsible for conifer infestation in North
America and Central Europe.2 This product is present in
nature in the two enantiomeric forms, (+)-1 and (ꢀ)-1, both
showing comparable biological activity.3 One well-known
geometric isomer of grandisol is fragranol 2, a natural prod-
uct isolated from the roots of Artemisia fragrans Willd.4 An-
other interesting natural derivative, structurally related to
grandisol is the pheromone 3 of the Aspidiotus nerii, a pest
that causes damage to lemon and olive trees, and to orna-
mental plants like oleander5 (Fig. 1). Due to their structural
complexity, mainly related to the difficulty of constructing
small-size rings with quaternary carbons, and the possibility
of using 1 and 3 as an alternative to classical pesticides, these
derivatives attracted the attention of many synthetic chem-
ists.6,7 In fact many racemic or enantioselective syntheses
of 1, 2 and 3 have been reported and for most of them the for-
mation of the cyclobutane ring arose from photochemically,
thermally or Lewis acid promoted [2+2] cycloadditions.7
Me
OH Me
OH
(+)-1
2
3
(-)-1
Figure 1. (+)-Grandisol 1, (ꢀ)-grandisol 1, fragranol 2 and the Aspidiotus
nerii pheromone 3.
2. Results and discussion
We have recently reported a new approach to the stereoselec-
tive synthesis of racemic grandisol 1 and fragranol 2, using
the cyclobutanones obtained from suitable substituted cyclo-
propyl derivatives as intermediates.8 Due to the similarity of
the carbon skeleton of 1, 2 and 3 it would be interesting to
find a synthetic approach based on a common intermediate
for all the three compounds. As a possible common ap-
proach, we envisaged the addition of organocopper reagents
to a cyclobutylidene derivative according to the retrosyn-
thetic analysis reported in Scheme 1.
In this paper we report the first results of this new method
used for the synthesis of grandisol, where two goals have
been pursued. First, the improvement of our previously8
obtained stereoselection, in order to reduce the amounts of
fragranol always present as an impurity in the syntheses of
Keywords: Carbocycles; Cuprates; Diastereoselectivity; Pheromones.
* Corresponding authors. Tel.: +39 070 6754410; fax: +39 070 6754388
(P.P.P.); e-mail: pppiras@unica.it
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.134

A. M. Bernard et al. / Tetrahedron 63 (2007) 4968–4974
4969
R
OH
R
OH
O
G
isomers was readily separated by column chromatography
and the stereochemistry of these compounds was confirmed
by NOE experiments assigning the E-configuration to the
major isomer of the mixture (Scheme 3). Despite the low
yields obtained previously in the reaction of methyl cuprate
with ester 5, it was decided to screen a set of Lewis acids as
activators of the a,b-unsaturated ester 10 towards nucleo-
philic attack of the cuprate.
COR'
G
G
R = Me or 4-methyl-4-penten-1-yl-; R' = H, OMe
G = Synthetic equivalent of an isopropenyl group
Scheme 1. Retrosyntheticanalysisforthesynthesisoftheproducts1, 2and3.
grandisol and the reduction of the number of steps; secondly
to carry out a chiral non-racemic synthesis of grandisol.
O
(Me)2CuLi
L.A.
Et2O -78 °C
Me
COOMe
O
COOMe
O
TMPA/NaH
THF refl
88%
H
H
H
O
Our reaction sequence for reaching the first goal is reported
in Scheme 2. The cyclobutanone 49 was prepared initially
and submitted to a Horner–Emmons olefination with tri-
methylphosphonoacetate (TMPA) to give ester 5 as a (50:50)
mixture of E-isomers. Due to the low reactivity of the a,
b-unsaturated esters10 towards organocopper (I) reagents,
the reaction of 5 with (Me)2CuLi did not proceed, while
(Me)2CuLi/BF3-OEt2, (Me)2CuLi/TMSCl and (Me)2CuLi/
TBDMSOTf led to the addition product in very low yields
and stereoselectivity. For this reason we reduced 5 with
DIBAL-H to obtain the allylic alcohol 6, which was readily
oxidized to the corresponding cyclobutylidene aldehyde 7.11
This compound reacted with (Me)2CuLi to give the corre-
sponding addition product 8 as a 90:10 mixture of cis/trans
stereomers.12 After reduction of the carbonyl function, oxi-
dation of the purified alcohol with m-chloroperbenzoic acid
and final reflux in toluene/CaCO3, as reported in the litera-
ture,9 a 90:10 mixture of (ꢁ)-grandisol 1 and (ꢁ)-fragranol
2 was obtained in an overall yield of 42% (Scheme 2).
O
O
O
(R,S)-9
10
(E/Z) = 80:20
(cis/trans)-11
Scheme 3. Conjugated addition of (Me)2CuLi-L.A. to the ester 10.
As listed in Table 1, the reaction afforded the cyclobutyl
esters 11 in good to high yields and varying cis/trans ratios.
The best result was obtained using TBDMSOTf as Lewis
acid, which afforded the addition product 11 in quantitative
yield and with a cis/trans ratio of 95:5, determined by NOE
experiments (Fig. 2). The stereoselectivity of the addition is
clearly controlled by the steric effects of the activating Lewis
acid and does not depend on the stereochemistry of the
Table 1. Conjugated addition of (Me)2CuLi-L.A. to the ester 10
Entry (E/Z)-10 Lewis acid
(cis/trans)-11 Ratioa % Yieldb
1
2
3
4
5
6
7
8
80:20
80:20
80:20
80:20
100:0
0:100
80:20
100:0
—
—
—
70:30
80:20
80:20
80:20
0
0
57
98
97
98
>99
>99
Since the synthesis of grandisol through this route appeared
efficient, particularly the high stereoselectivity and the re-
duced number of steps, we decided to use this approach
for the enantioselective formal total synthesis of grandisol
using the enantiopure cyclobutanone 9, which we have
previously reported.13
BF3-OEt2
TMSCl
TMSOTf
TMSOTf
TMSOTf
TBDMSOTf 95:5
TBDMSOTf 95:5
Cis/trans ratios were determined by GC and 1H NMR analysis of the crude
reactions.
Yields were calculated after chromatography purification.
a
The cyclobutanone 9 was transformed into the a,b-unsatu-
rated methyl ester 10. The E/Z (80:20) mixture of geometric
b
MeOOC
HO
O
PCC
CHO
DIBAL-H
THF -78 °C
90%
TMPA/NaH
THF refl.
88%
CH2Cl2 0 °C
Me
Me
Me
Me
90%
SPh
SPh
SPh
SPh
5
6
7
4
(E-isomers)
50:50 mixture of
diastereomers
(Me)2CuLi
Et2O -78 °C
98%
Me
OH
Me
Me
Me
OH
Lit. 9
Three steps
75%
CHO
CHO
Me
+
+
H
H
Me
SPh
SPh
2
8
1
(cis/trans) = 90:10
Scheme 2. Stereoselective synthesis of (ꢁ)-grandisol 1 through the 1,4-conjugated addition of (Me)2CuLi to the cyclobutylidene aldehyde 7.
(cis/trans) = 90:10

4970
A. M. Bernard et al. / Tetrahedron 63 (2007) 4968–4974
O
3. Conclusions
R
Me
H
H
H
In summary, we have reported two different approaches for
a formal total synthesis of racemic grandisol and of the enan-
tiopure (ꢀ)-grandisol 1 through the intermediary of cyclobu-
tylidene derivatives. Moreover, as the other diastereoisomer
of 9 has been prepared enantiomerically enriched,13 both
isomers of grandisol can be prepared using this synthetic
approach. Research is now in progress to apply this method
to the synthesis of fragranol and to the pheromone of the
A. nerii.
NOE
NOE
O
H
O
11 R = OMe
14 R = H
Figure 2. NOE experiments for the (cis)-ester 11 and the (cis)-aldehyde 14.
double bond of the starting material. Thus, by avoiding the
transformation of the ester function into the corresponding
aldehyde, two reaction steps were gained in the synthetic
plan.
4. Experimental
4.1. General
In order to evaluate the possibility of further increasing the
stereoselectivity of the organocopper addition, a sequence
analogous to that reported in Scheme 2 was followed.
1H NMR spectra were recorded at 300 and 400 MHz VAR-
IAN spectrometer at ambient temperature with CDCl3 as
solvent and TMS as internal standard. 13C NMR spectra
were recorded at 75 or 100 MHz at ambient temperature
with CDCl3 as solvent unless otherwise stated. NMR data
are reported as follows: chemical shifts, integration, multi-
plicity and coupling constants.
Thus the ester 10 was converted into the corresponding
allylic alcohol 12 and subsequently oxidized to give the
a,b-unsaturated cyclobutylidene aldehyde 13.
We were pleased to find that in the reaction of this aldehyde
with (Me)2CuLi, the only detectable product was the diaster-
eomerically pure cis-14; the stereochemistry was assigned
by NOE experiments (Fig. 2).
Infrared spectra were recorded on a Nicolet Nexus 670 FTIR
spectrophotometer. Mass spectra analyses were recorded on
Agilent 5973N (Cpsil 32m) and Nermag R10-10 (quartz-
Cpsil 5.25m). (EI 70 eV; CI NH3). The high-resolution
mass analysis spectra were recorded on a electrospray
Finningan MAT-95 (precision 5/1000).
This excellent stereoselectivity could very likely be attrib-
uted to the increased steric requirement of the oxadiolane
ring in 13, in comparison with the phenylthiopropyl group
in 7 (Schemes 2 and 4).
The optical rotation values were measured at 25 ꢂC with
a Perkin–Elmer 241 and PolAAr 32. Analytical thin layer
chromatography was performed using 0.25 mm silica gel
60-F plates. Flash chromatography was performed using
200–400 mesh silica gel (Merk KGaA). Yields refer to chro-
matography and spectroscopically pure materials, unless
otherwise stated. Diisopropylamine and triethylamine were
distilled from calcium hydride and stored under argon. Meth-
ylene chloride and acetonitrile were freshly distilled from
calcium hydride or P2O5. THF and diethyl ether were freshly
distilled from sodium/benzophenone. Ethanol was dried over
Reduction of the derivative 14 afforded the alcohol 15,
whose hydroxyl group was protected to give the benzoyl
ester 16. Hydrolysis of the dioxolane group of 16 led to
the cyclobutyldiol 17. After purification, the diol was treated
with DIAD/P(Ph)3 in refluxing benzene to afford the epoxide
18, which was treated with DIBAL-H to give the optically
pure diol 19, [a]2D7 ꢀ27.83 (c 1.60, CH2Cl2) (Scheme 4).
Comparison of the optical rotation of 19 with the value
reported by Narasaka for (+)-cis 19,14 [a]D24 +27.3 (c 1.59,
CH2Cl2) confirmed that the absolute configuration of the
(ꢀ)-cis 19 diol, a direct precursor of (ꢀ)-1, was (1S,2S,20R).
˚
2 A molecular sieves. Methanol was dried on magnesium
powder. Reactions requiring anhydrous conditions were
performed in oven-dried glassware under argon atmosphere.
OH
Me
Me
OH
CHO
O
COOMe
(Me)2CuLi
CHO
O
NaBH4
DIBAL-H
Oxidation
88%
H
H
H
H
H
THF
-78 °C
88%
Et2O
-78 °C
97%
MeOH/THF 1:1
0 °C
O
O
O
O
O
94%
O
O
O
(Z and/or E)-13
15
(Z and/or E)-12
14
(Z and/or E)-10
Me
Me
Me
Me
Me
OBz
OBz
OBz
OH
Ref. 14
OH
DIAD/P(Ph)3
BzCl/DMAP
Et3N/CH2Cl2
94%
TFA
DIBAL-H
H
H
O
H
H
H
C6H6
91%
MeOH/H2O
r.t.
THF
-78 °C
94%
O
OH
OH
Me
Me
(-)-1
91%
O
OH
16
Scheme 4. Formal total synthesis of (ꢀ)-grandisol 1.
17
18
(1S,2S,2'R )-(cis)-19

A. M. Bernard et al. / Tetrahedron 63 (2007) 4968–4974
4971
4.1.1. Methyl 2-(2-(1-(phenylthio)propan-2-yl)cyclobutyl-
idene)acetate (5). To a stirred suspension of pentane-
washed NaH (364 mg, 9.1 mmol, 60% mineral oil dispersion)
in THF (30 mL), trimethylphosphonoacetate (2.16 g,
9.1 mmol) was rapidly added and the mixture was stirred
for 6 h under argon at 65 ꢂC. Then a solution of cyclobuta-
none 4 (2 g, 9.1 mmol) and TDA-1 (290 mL, 0.91 mmol)
in THF (10 mL) was slowly added within 30 min. The mix-
ture was stirred at the same temperature for 16 h. After cool-
ing, the solution was diluted with diethyl ether and washed
with brine, dried on Na2SO4 and evaporated under vacuum.
Chromatography of the residue on silica gel (light petro-
leum/diethyl ether 10:1) gave an inseparable 50:50 dia-
stereomeric mixture of the (E)-derivatives 5, 88% yield
(2.41 g).
temperature, the solvent was evaporated and the residue
was diluted in diethyl ether and filtered on Celite. The filtrate
was washed twice with brine and the organic phase was
dried on Na2SO4. After concentration, the resultant
crude oil was used in the next step without further puri-
fication; 80:20 mixture of (E/Z)-isomers.11 Colourless oil.
IR (neat): 3000, 1680, 1120 cmꢀ1 1H NMR (CDCl3,
.
300 MHz): d 1.04 (d, 3H, J¼6.6 Hz), 1.12 (d, 3H,
J¼6.6 Hz), 1.84–2.29 (m, 8H), 2.69 (dd, 1H, J¼8.7,
12.6 Hz), 2.81 (dd, 1H, J¼6.9, 12.6 Hz), 2.94 (dd, 1H,
J¼5.7, 12.6 Hz), 3.01–3.08 (m, 3H), 3.17–3.27 (m, 1H),
3.38–3.47 (m, 1H), 5.85 (m, 2H), 7.15–7.63 (m, 10H),
9.56 (dd, 1H, J¼3.0, 5.4 Hz), 9.65 (dd, 1H, J¼1.8,
7.8 Hz). MS (same for all isomers) m/z: 246 (M+ (18)),
217 (9), 176 (10), 150 (38), 135 (7), 123 (100), 118 (20),
95 (37), 81 (22), 77 (22), 65 (20), 55 (11), 45 (41). Anal.
Calcd for C15H18OS: C, 73.13; H, 7.36; S, 13.01. Found:
C, 73.21; H, 7.38; S, 13.11.
1
Yellow oil. First isomer: IR (neat): 3000, 1730 cmꢀ1. H
NMR (CDCl3, 300 MHz): d 1.03 (d, 3H, J¼6.6 Hz), 1.77–
1.95 (m, 2H), 1.97–2.18 (m, 2H), 2.78 (dd, 1H, J¼7.5,
12.6 Hz), 2.97–3.02 (m, 2H), 3.26–3.29 (m, 1H), 3.69 (s,
3H), 5.63 (q, 1H, J¼2.4 Hz), 7.12–7.36 (m, 5H). MS m/z:
276 (M+ (30)), 248 (43), 234 (15), 216 (12), 199 (12), 167
(40), 150 (28), 135 (72), 123 (100), 121 (54), 109 (41),
107 (76), 93 (58), 79 (54), 77 (66), 65 (54), 45 (97).
4.1.4. 2-(1-Methyl-2-(1-(phenylthio)propan-2-yl)cyclo-
butyl)acetaldehyde (8). To a stirred suspension of CuI
(570 mg, 3.04 mmol) in dry diethyl ether (7 mL) under ar-
gon, cooled at ꢀ10 ꢂC, a 1.6 M solution of methyllithium
in THF (3.8 mL, 6.09 mmol) was added dropwise until the
formation of a colourless solution. The reaction mixture
was cooled at ꢀ78 ꢂC and the aldehyde 7 (250 mg,
1.01 mmol) in diethyl ether (5 mL) was added in one
portion. The reaction mixture was stirred for 15 min,
quenched with some drops of acetic acid and warmed to
room temperature. The mixture was diluted with diethyl
ether and washed with a saturated solution of NH4Cl. The
separated organic layer was dried on Na2SO4 and con-
centrated under reduced pressure. The residual oil was puri-
fied by chromatography (light petroleum/diethyl ether 5:1)
to provide a 90:10 mixture of the cis/trans derivatives
8; 98% yield (253 mg). Colourless oil. IR (neat): 2730,
1715, 1579, 1475 cmꢀ1. cis-Isomer: 1H NMR (CDCl3,
300 MHz): d 0.91 (d, 3H, J¼6.6 Hz), 0.97 (d, 3H, J¼
6.3 Hz), 1.23 (s, 3H), 1.24 (s, 3H), 1.56–1.77 (m, 6H),
1.82–1.97 (m, 6H), 2.25 (dd, 1H, J¼3.0, 15.3 Hz), 2.27
(dd, 1H, J¼3.0, 15.3 Hz), 2.43–2.64 (m, 4H), 2.96 (dd,
2H, J¼3.6, 12.6 Hz), 7.15–7.36 (m, 10H), 9.78 (t, 1H,
J¼3.0 Hz), 9.81 (t, 1H, J¼3.0 Hz). MS m/z (same for the
two cis-isomers): 262 (M+(33)), 219 (5), 178 (35), 150
(5), 123 (100), 110 (25), 95 (10), 77 (10), 69 (25), 55 (33),
45 (35), 41 (45). Minor trans-isomer: MS m/z: 262 (M+
(40)), 219 (5), 178 (42), 150 (7), 123 (100), 110 (30), 95
(8), 77 (10), 69 (25), 55 (35), 45 (37), 41 (50). Anal. Calcd
for C16H22OS: C, 73.23; H, 8.45; S, 12.22. Found: C,
73.31; H, 8.49; S, 12.20.
Second isomer: IR (neat): 3000, 1730 cmꢀ1 1H NMR
.
(CDCl3, 300 MHz): d 1.10 (d, 3H, J¼6.6 Hz), 1.77–1.95
(m, 2H), 1.97–2.18 (m, 2H), 2.67 (dd, 1H, J¼1.0,
12.6 Hz), 2.92–3.10 (m, 3H), 3.68 (s, 3H), 5.64 (q, 1H,
J¼2.4 Hz), 7.12–7.36 (m, 5H). MS m/z: 276 (M+ (30)),
248 (43), 234 (15), 216 (12), 199 (12), 167 (40), 150 (28),
135 (72), 123 (100), 121 (54), 109 (41), 107 (76), 93 (58),
79 (54), 77 (66), 65 (54), 45 (97). Anal. Calcd for
C16H20O2S: C, 69.53; H, 7.29; S, 11.60. Found: C, 69.58;
H, 7.35; S, 11.70.
4.1.2. 2-(2-(1-(Phenylthio)propan-2-yl)cyclobutylide-
ne)ethanol (6). To a stirred solution of the diastereomeric
mixture of 5 (300 mg, 1.2 mmol) in dry THF (30 mL),
cooled at ꢀ78 ꢂC, a 1.0 M solution of DIBAL-H (2.4 mL,
2.4 mmol) in toluene was added dropwise. After 8 h, the re-
action mixture was treated with methanol (5 mL) and con-
centrated under reduced pressure. The residue was purified
by flash chromatography (pentane/diethyl ether 5:1) to
afford an inseparable 50:50 mixture of the alcohols 6
in 90% yield (267 mg). Colourless oil. IR (neat): 3437,
3000, 1615, 1201 cmꢀ1 1H NMR (CDCl3, 300 MHz):
.
d 1.02 (d, 3H, J¼6.9 Hz), 1.10 (d, 3H, J¼6.9 Hz), 1.22
(br s, 1H), 1.25 (br s, 1H), 1.32–2.11 (m, 7H), 2.54–2.61
(m, 4H), 2.66 (dd, 1H, J¼7.8, 12.6 Hz), 2.90–3.04 (m,
4H), 3.92 (d, 4H, J¼6.3 Hz), 5.26–5.34 (m, 2H), 7.03–
7.26 (m, 10H). MS (same for all isomers) m/z: 248 (M+
(30)), 234 (15), 216 (12), 199 (12), 167 (40), 150 (28), 135
(72), 123 (100), 121 (54), 109 (41), 107 (76), 93 (58), 79
(54), 77 (66), 65 (54), 45 (97). Anal. Calcd for C15H20OS:
C, 72.54; H, 8.12; S, 12.91. Found: C, 72.67; H, 8.14; S,
13.01.
4.1.5. cis and trans-2-(1-Methyl-2-(prop-1-en-2-yl)cyclo-
butyl)ethanol (1) and (2). Derivative 8 was first reduced
to the corresponding alcohol and then oxidized to the corre-
sponding sulfoxides according to the literature.9
To a stirred solution of these sulfoxides (267 mg,
0.95 mmol) in dry toluene, CaCO3 (190 mg, 1.90 mmol)
was added and the mixture was refluxed for 4 h. After filtra-
tion and concentration under reduced pressure, the crude
90:10 mixture of (ꢁ)-1 and (ꢁ)-2 was easily separated by
flash chromatography (light petroleum/diethyl ether
90:10). Overall yield 75% (113 mg).
4.1.3. 2-(2-(1-(Phenylthio)propan-2-yl)cyclobutylide-
ne)acetaldehyde (7). To a stirred suspension of PCC
(300 mg, 1.2 mmol) in CH2Cl2 at 0 ꢂC, a solution of the
alcohol 6 in dichloromethane was added dropwise. The
mixture was stirred for 6 h and after warming at room

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A. M. Bernard et al. / Tetrahedron 63 (2007) 4968–4974
4.1.5.1. ( )-Grandisol (1). Yellow oil. 1H NMR (CDCl3,
6 h, the reaction mixture was quenched with some drops of
a saturated solution of NaHCO3 and warmed to room
temperature. The 95:5 diastereomeric mixture was diluted
with diethyl ether (7 mL) and washed with a saturated
solution of NH4Cl. The organic layer was dried on
Na2SO4 and concentrated under reduced pressure. The resid-
ual oil was purified by chromatography (light petroleum/
diethyl ether 5:1) to provide 11 in 99% yield (253 mg).
Major cis-isomer: colourless oil. [a]2D7 ꢀ16.5 (c 0.6225,
CHCl3). IR (neat): 2730, 1715, 1579, 1475 cmꢀ1. 1H NMR
(CDCl3, 400 MHz): d 1.21 (s, 3H), 1.28 (s, 3H), 1.34
(s, 3H), 1.37–1.50 (m, 1H), 1.63–1.79 (m, 1H), 1.81–1.89
(m, 1H), 2.02–2.12 (m, 2H), 2.55 (ABq, 2H, J¼19.2 Hz),
3.40 (dd, 1H, J¼8.8, 10.4 Hz), 3.62 (s, 3H), 3.94 (dd,
1H, J¼10.4, 8.8 Hz), 4.08 (dt, 1H, J¼8.4, 13.2 Hz). 13C
NMR (CDCl3): d 17.95, 25.68, 27.12, 30.05, 39.23, 40.09,
48.31, 51.17, 68.08, 76.64, 107.08, 173.13. MS m/z: 227
(M+ꢀ15 (18)), 211 (13), 207 (9), 184 (3), 167 (7), 152 (4),
135 (9), 125 (7), 113 (16), 107 (34), 101 (10), 93 (26), 83
(21), 79 (25), 72 (26), 59 (44), 55 (24), 43 (100), 31 (12).
Anal. Calcd for C13H22O4: C, 64.44; H, 9.15. Found: C,
64.43; H, 9.17. trans-Isomer (traces): MS m/z: 227
(M+ꢀ15 (18)), 211 (13), 207 (12), 184 (3), 167 (9), 152
(4), 135 (12), 125 (7), 113 (18), 107 (32), 101 (10), 93
(26), 83 (21), 79 (25), 72 (21), 59 (44), 55 (24), 43 (100),
31 (14).
300 MHz): d 1.17 (s, 3H), 1.45 (m, 1H), 1.58 (br s, 1H), 1.67
(s, 3H), 1.75–2.04 (m, 4H), 2.54–2.59 (m, 1H), 3.66–3.73
(m, 2H), 4.65 (s, 1H), 4.84 (s, 1H). MS m/z: 154 (M+
(0.2)), 139 (2), 121 (4), 109 (21), 93 (11), 91 (6), 79 (12),
68 (100), 67 (80).
4.1.5.2. ( )-Fragranol (2). Yellow oil. 1H NMR (CDCl3,
300 MHz): d 0.93 (s, 3H), 1.42 (m, 1H), 1.65 (s, 1H), 1.58 (br
s, 1H), 1.75–2.04 (m, 4H), 2.56–2.59 (m, 1H), 3.66–3.73 (m,
2H), 4.62 (s, 1H), 4.83 (q, 1H, J¼1.5 Hz). MS m/z: 154 (M+
(0.2)), 139 (2), 121 (3), 109 (17), 93 (11), 91 (6), 79 (12), 68
(100), 67 (82).
4.1.6. (Z and E)-Methyl 2-((S)-2-((S)-2,2-dimethyl-1,3-di-
oxolan-4-yl)cyclobutylidene)acetate (10). To a stirred sus-
pension of pentane-washed NaH (360 mg, 9.0 mmol, 60% in
mineral oil dispersion) in THF (30 mL) under argon, trime-
thylphosphonoacetate (2.16 g, 8.9 mmol) was rapidly added.
After keeping the reaction mixture at 65 ꢂC for 6 h, a solution
of the cyclobutanone 911 (1.51 g, 8.9 mmol) and TDA-1
(2.76 mL, 0.9 mmol) was slowly added over about 30 min.
The mixture was kept at the same temperature for 16 h. After
cooling, the solution was diluted with diethyl ether and
washed with brine. The separated organic phase was dried
on Na2SO4 and evaporated under reduced pressure to
give 2 g of a 80:20 mixture of two (E)- and (Z)-diastereo-
mers, which were separated by chromatography on silica
gel (eluent light petroleum/diethyl ether 5:1). Global yield
88% (1.77 g). (E)-isomer: IR (neat): 1713 cmꢀ1. [a]D26
+130.7 (c, 0.3672, CHCl3). Colourless oil. 1H NMR
(CDCl3, 300 MHz): d 1.36 (s, 3H), 1.40 (s, 3H), 2.04–2.12
(m, 1H), 2.14–2.25 (m, 1H), 2.64–2.85 (m, 2H), 3.68 (s,
3H), 3.74 (t, 1H, J¼7.5 Hz), 3.78–3.81 (m, 1H), 3.97 (dd,
1H, J¼7.8, 6.9 Hz), 4.73 (q, 1H, J¼6.9 Hz), 5.66 (s, 1H).
13C NMR (CDCl3): d 18.9, 25.2, 26.3, 31.1, 46.4, 50.8,
65.9, 74.9, 108.4, 114.1, 164.8, 165.9. MS m/z: 211
(M+ꢀ15 (7)), 195 (2), 169 (1), 151 (9), 137 (4), 125 (2),
119 (1), 107 (6), 101 (48), 91 (14), 77 (16), 65 (11), 59
(23), 43 (100). Anal. Calcd for C12H18O4: C, 63.70; H,
8.02. Found: C, 63.58; H, 8.15. (Z)-isomer: IR (neat):
1715 cmꢀ1. [a]D24.6 ꢀ31.4 (c, 0.6994, CHCl3). 1H NMR
(CDCl3, 300 MHz): d 1.31 (s, 3H), 1.40 (s, 3H), 1.75–1.86
(m, 1H), 2.10–2.22 (m, 1H), 3.02–3.10 (m, 2H), 3.20–3.25
(m, 1H), 3.62 (dd, 1H, J¼6.0, 8.1 Hz), 3.68 (s, 3H), 4.02
(dd, 1H, J¼6.0, 8.1 Hz), 4.18 (dd, 1H, J¼8.1, 6.0 Hz),
5.85 (q, 1H, J¼2.4 Hz). 13C NMR (CDCl3): d 19.7, 25.3,
26.7, 30.9, 46.9, 50.7, 67.1, 77.2, 109.2, 112.9, 166.3,
166.5. MS m/z: 211 (M+ꢀ15 (15)), 195 (2), 168 (4),
151 (16), 137 (11), 125 (4), 119 (9), 107 (13), 101 (35),
91 (18), 77 (18), 65 (14), 59 (26), 43 (100). Anal.
Calcd for C12H18O4: C, 63.70; H, 8.02. Found: C, 63.58;
H, 8.04.
4.1.8. (Z and E)-2-((S)-2-((S)-2,2-Dimethyl-1,3-dioxolan-
4-yl)cyclobutylidene)ethanol (12). To a stirred solution of
the diastereomeric mixture of the cyclobutylidene acetate
10 (1.4 g, 6.2 mmol) in dry THF (50 mL) at ꢀ78 ꢂC,
DIBAL-H (1 M in THF, 12 mL, 12 mmol) was added drop-
wise. The mixture was stirred at the same temperature for
2 h, diluted with diethyl ether and washed with a saturated
NaHCO3 solution. The organic layer was dried on Na2SO4
and the solvent removed under reduced pressure. Flash chro-
matography of the residual oil on silica gel (eluent pentane/
diethyl ether 1:1) gave a 80:20 diastereomeric mixture of 12.
Colourless oil. Global yield 91% (1.11 g).
(E)-isomer: IR (neat): 3425 cmꢀ1. [a]D17 +23.2 (c, 0.1577,
MeOH). H NMR (CDCl3, 300 MHz): d 1.37 (s, 3H), 1.46
1
(s, 3H), 2.14–2.24 (m, 2H), 2.50–2.62 (m, 1H), 273–2.82
(m, 1H), 3.12–3.18 (m, 1H), 3.62 (t, 1H, J¼6.6 Hz), 3.92–
4.09 (m, 3H), 4.14 (t, 1H, J¼7.8 Hz), 4.19–4.26 (m, 1H),
5.51–5.56 (m, 1H). 13C NMR (CDCl3): d 19.5, 25.3, 26.4,
28.6, 45.7, 58.7, 68.1, 77.8, 109.6, 122.9, 143.6. MS m/z:
183 (M+ꢀ15 (3)), 129 (3), 123 (3), 109 (5), 101 (84), 95
(23), 77 (14), 67 (17), 59 (15), 53 (15), 43 (100). Anal. Calcd
for C11H18O3: C, 66.64; H, 9.15. Found: C, 66.63; H, 9.19.
(Z)-isomer: IR (neat): 3430 cmꢀ1. [a]D17 +14.7 (c 0.065,
MeOH).
1H NMR (CDCl3, 300 MHz): d 1.35 (s, 3H), 1.41 (s, 3H),
1.66–1.78 (m, 2H), 1.98–2.37 (m, 3H), 2.65 (t, 1H,
J¼7.8 Hz), 3.13 (q, 1H, J¼7.5 Hz), 3.63 (dd, 1H, J¼6.6,
8.1 Hz), 4.02 (dd, 2H, J¼1.2, 6.9 Hz), 4.07–4.10 (q, 1H,
J¼6.3 Hz), 5.52–5.58 (m, 1H). 13C NMR (CDCl3): d 19.1,
25.4, 26.6, 26.8, 45.6, 59.1, 66.9, 77.8, 109.0, 120.7, 144.1.
MS m/z: 183 (M+ꢀ15 (4)), 138 (3), 123 (3), 109 (2), 101
(72), 95 (14), 77 (14), 67 (15), 59 (10), 53 (14), 43 (100).
Anal. Calcd for C11H18O3: C, 66.64; H, 9.15. Found: C,
66.59; H, 9.18.
4.1.7. Methyl 2-((1S,2S)-1-methyl-2-((S)-2,2-dimethyl-
1,3-dioxolan-4-yl)cyclobutyl)acetate (11). To a stirred sus-
pension of CuI (570 mg, 3.04 mmol) in dry diethyl ether
(7 mL) at ꢀ10 ꢂC, a 1.6 M solution of methyllithium in
THF (3.8 mL, 6.09 mmol) was added dropwise until the
formation of a colourless solution. The ester 10 (250 mg,
1.01 mmol), stirred at 0 ꢂC with TBDMSOTf (1.01 mmol)
in diethyl ether (5 mL) for 2 h, was added in one portion
to the solution of (Me)2CuLi at ꢀ78 ꢂC under argon. After

A. M. Bernard et al. / Tetrahedron 63 (2007) 4968–4974
4973
4.1.9. (Z and E)-2-((S)-2-((S)-2,2-Dimethyl-1,3-dioxolan-
4-yl)cyclobutylidene)acetaldehyde (13). To a stirred solu-
tion of 12 (594 mg, 3.0 mmol) in 40 mL of methylene
chloride at 0 ꢂC, pyridinium chlorochromate (0.711 mg,
3.3 mmol) was added. The reaction mixture was stirred for
1 h, filtered on Celite and concentrated under reduced pres-
sure. The residue was diluted with diethyl ether and filtered
again on Celite. The obtained solution was washed twice
with solutions of 2 M NaOH and saturated NH4Cl. The or-
ganic phase was dried on Na2SO4 and concentrated under
reduced pressure to give an oil, which was chromatographed
with diethyl ether/light petroleum (1:1) to afford the alde-
hydes 13 in 88% yield (517 mg).
ꢀ20 ꢂC, NaBH4 (62 mg, 1.4 mmol) was added. After 2 h,
the reaction mixture was filtered and evaporated. The residue
was diluted with diethyl ether and washed twice with brine.
After flash chromatography (light petroleum/ethyl acetate
5:1), the alcohol 15 was obtained with 94% yield (331 mg).
[a]2D5 +13.92 (c 0.43, CHCl3). IR (neat): 3485, 2987,
1
1364 cmꢀ1. H NMR (CDCl3, 300 MHz): d 1.19 (s, 3H),
1.34–1.44 (m, 2H), 1.35 (s, 3H), 1.38 (s, 3H), 1.57–1.69 (m,
2H), 1.72–1.78 (m, 1H), 1.91–2.06 (m, 3H), 3.45 (dd, 1H, J¼
8.1, 6.9 Hz), 3.57–3.75 (m, 2H), 4.03 (dd, 1H, J¼8.1, 6.0 Hz),
4.25–4.33 (m, 1H). 13C NMR (CDCl3): d 18.51, 25.73, 26.65,
26.95, 30.65, 31.38, 38.55, 48.44, 59.64, 68.37,
76.56, 109.29. MS m/z: 214 (M+ (1)), 199 (9), 169 (2), 139
(5), 129 (12), 113 (10), 93 (19), 79 (21), 67 (24), 59 (24),
43 (100). Anal. Calcd for C12H22O3: C, 67.26; H, 10.35.
Found: C, 67.28; H, 10.33.
(E)-isomer: IR (neat) 1660 cmꢀ1. [a]D17 +31.4 (c 0.315,
CHCl3). 1H NMR (CDCl3, 300 MHz): d 1.34 (s, 3H), 1.41 (s,
3H), 1.85–1.94 (m, 1H), 2.20–2.32 (m, 2H), 3.03–3.34 (m,
2H), 3.58–3.73 (m, 1H), 4.01–4.06 (m, 1H), 4.08–4.25 (m,
1H), 6.07 (dd, 1H, J¼2.1, 7.8 Hz), 9.66 (d, 1H, J¼7.8 Hz).
13C NMR (CDCl3): d 15.16, 19.86, 26.80, 28.53, 29.60,
48.00, 65.73, 67.12, 109.52, 171.87, 190.21. MS m/z: 181
(M+ꢀ15 (21)), 139 (5), 121 (18), 109 (12), 101 (18), 93
(20), 91 (17), 77 (23), 73 (21), 59 (20), 43 (100), 39 (40).
Anal. Calcd for C11H16O3: C, 67.32; H, 8.22. Found: C,
67.54; H, 8.16.
4.1.12. 2-((1S,2S)-1-Methyl-2-((S)-2,2-dimethyl-1,3-dioxo-
lan-4-yl)cyclobutyl)ethyl benzoate (16). To a stirred solu-
tion of the alcohol 15 (160 mg, 0.74 mmol) in CH2Cl2
(5 mL) at 0 ꢂC, triethylamine (104 mL, 0.82 mmol), DMAP
(100 mg, 0.82 mmol) and benzoylchloride (114 mg,
0.82 mmol) were added dropwise. The reaction mixture
was kept at 0 ꢂC for 6 h and then diluted with CH2Cl2.
The organic layer was washed with brine and then dried
on Na2SO4. Evaporation of the solvent afforded 184 mg of
a crude oil, which was purified by flash chromatography
(light petroleum/ethyl acetate 5:1) to afford the benzoyl
derivative 16; 94% yield (221 mg). Colourless oil. [a]2D7 ꢀ15.5
(c 0.5314, CHCl3). IR (neat) 3018, 2989, 1715, 1648, 1612,
(Z)-isomer: Spectral data were worked out from the E/Z mix-
ture of the aldehydes 13. 1H NMR (CDCl3, 300 MHz):
d 1.33 (s, 3H), 1.37 (s, 3H), 1.68–179 (m, 1H), 2.15–2.30
(m, 2H), 2.93–3.00 (m, 1H), 3.47–3.56 (m, 1H), 4.07–4.13
(m, 1H), 4.14–4.32 (m, 1H), 4.25–4.32 (m, 1H), 5.87 (dd,
1H, J¼2.1, 8.1 Hz), 9.66 (d, 1H, J¼8.1 Hz). MS m/z: 181
(M+ꢀ15 (23)), 139 (6), 121 (17), 109 (11), 101 (19), 93
(20), 91 (17), 77 (23), 73 (21), 43 (100), 39 (42).
1
1548, 1220 cmꢀ1. H NMR (CDCl3, 300 MHz): d 1.22 (s,
3H), 1.33 (s, 3H), 1.39 (s, 3H), 1.43–1.55 (m, 1H), 1.61–
1.73 (m, 1H), 1.82–1.91 (m, 2H), 2.03–2.18 (m, 3H), 3.45
(dd, 1H, J¼5.3, 8.1 Hz), 3.98 (dd, 1H, J¼6, 8.1 Hz), 4.15–
4.25 (m, 1H), 4.31–4.50 (m, 2H), 7.41–7.58 (m, 3H), 8.04
(d, 2H, J¼8.7 Hz). 13C NMR (CDCl3): d 18.04, 25.75,
27.17, 27.58, 30.46, 34.00, 39.12, 45.45, 48.60, 62.49,
68.04, 76.57, 109.08, 128.26, 129.47, 132.73, 166.64.
MS m/z: 318 (M+ (1)), 303 (10), 290 (1), 260 (2), 243
(2), 231 (1), 190 (4), 181 (4), 153 (3), 138 (15), 121 (31),
105 (100), 93 (36), 77 (78), 68 (66), 55 (21), 43 (52).
Anal. Calcd for C19H26O4: C, 71.67; H, 8.23. Found: C,
71.71; H, 8.24.
4.1.10. 2-((1S,2S)-1-Methyl-2-((S)-2,2-dimethyl-1,3-dioxo-
lan-4-yl)cyclobutyl)acetaldehyde (14). Copper(I) iodide
(1.07 g, 5.6 mmol) in dry diethyl ether (4 mL) was treated
dropwise at 0 ꢂC with methyllithium (5.87 mL, 9.4 mmol,
1.6 M in diethyl ether) and stirred for 1 h. Then, the formed
(Me)2CuLi solution was cooled at ꢀ78 ꢂC and the aldehyde
13 (370 mg, 1.88 mmol) dissolved in dry THF (4 mL) was
injected in one portion. The resulting reaction mixture was
stirred for 2 h, diluted with diethyl ether (15 mL) and
quenched with a saturated NH4Cl solution. The organic layer
was dried on Na2SO4 and concentrated under reduced pres-
sure to afford the aldehyde 14, which was purified by flash
chromatography (pentane/diethyl ether 5:1); 97% yield
(387 mg). Colourless oil. [a]1D7 +44.3 (c 0.3613, MeOH).
4.1.13. 2-((1S,2S)-2-((S)-1,2-Dihydroxyethyl)-1-methyl-
cyclobutyl)ethyl benzoate (17). To a stirred solution of 16
(160 mg, 0.74 mmol) in MeOH (5 mL) and H2O (5 mL), tri-
fluoroacetic acid (104 mL, 0.82 mmol) was added dropwise.
The reaction mixture was stirred overnight at room temper-
ature. After concentration under reduced pressure, the resi-
due was purified by chromatography (hexane/EtOAc 1:1)
to give the diol 17; 91% yield (127 mg). Colourless oil.
[a]2D7 ꢀ9.45 (c 0.501, CHCl3). IR (neat) 3445, 2989, 1715,
1658, 1612, 1548, 1220 cmꢀ1. 1H NMR (CDCl3, 300 MHz):
d 1.21 (s, 3H), 1.55–1.70 (m, 2H), 1.73–1.93 (m, 3H), 2.07 (t,
2H, J¼7.5 Hz), 3.22 (br s, 2H exchange with D2O), 3.33 (dd,
1H, J¼6.9, 11.1 Hz), 3.60 (dd, 1H, J¼2.1, 11.1 Hz), 3.77–
3.83 (m, 1H), 4.36 (t, 1H, J¼7.5 Hz), 4.46–4.54 (m, 1H),
7.41–7.55 (m, 3H), 8.03 (d, 2H, J¼8.1 Hz). 13C NMR
(CDCl3): d 18.67, 28.08, 30.41, 33.36, 39.33, 47.37, 62.62,
64.61, 74.93, 128.32, 129.51, 130.27, 132.91, 166.98. MS
m/z: 278 (M+ (3)), 215 (3), 202 (2), 188 (4), 175 (14), 167
(3), 157 (11), 145 (27), 132 (100), 117 (83), 105 (31), 91
1
IR (neat) 1700 cmꢀ1. H NMR (CDCl3, 300 MHz): d 1.31
(s, 6H), 1.37 (s, 3H), 1.50–1.82 (m, 2H), 1.89–1.99 (m,
2H), 2.11–2.19 (m, 1H), 2.60 (dq, 1H, J¼2.7, 15.6 Hz),
3.45 (t, 1H, J¼7.5 Hz), 4.00 (dd, 1H, J¼7.8, 6.2 Hz),
4.11–4.18 (m, 1H), 9.83 (t, 1H, J¼2.7 Hz). 13C NMR
(CDCl3): d 18.2, 25.7, 27.1, 28.1, 30.8, 38.7, 48.3, 49.6,
68.1, 76.6, 109.3, 203.7. MS m/z: 197 (M+ꢀ15 (18)), 136
(2), 119 (8), 109 (16), 93 (23), 81 (15), 67 (25), 59 (23), 43
(100). Anal. Calcd for C12H20O3: C, 67.89; H, 9.50. Found:
C, 67.91; H, 9.49.
4.1.11. 2-((1S,2S)-1-Methyl-2-((S)-2,2-dimethyl-1,3-dioxo-
lan-4-yl)cyclobutyl)ethanol (15). To a stirred solution of
14 (350 mg, 1.65 mmol) in MeOH/THF (20 mL, 1:1) at

4974
A. M. Bernard et al. / Tetrahedron 63 (2007) 4968–4974
(37), 77 (18), 66 (7), 55 (17). Anal. Calcd for C16H22O4: C,
69.04; H, 7.97. Found: C, 69.03; H, 8.00.
References and notes
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J. R.; Foltz, J. L.; Silverstein, R. M.; Lanier, G. N. J. Chem.
Ecol. 1984, 10, 1417.
4.1.14. 2-((1S,2S)-2-((S)-1-Hydroxyethyl)-1-methylcyclo-
butyl)ethanol (19). To a stirred solution of the diol 17
(120 mg, 0.43 mmol) in dry benzene (7 mL) under argon,
triphenylphosphine (123 mg, 0.47 mmol) was added. After
reaching the complete solubilization, DIAD (94 mg,
0.47 mmol) was injected dropwise. The reaction mixture
was stirred overnight and then concentrated under reduced
pressure. The crude benzoyloxirane 18, obtained as an oil,
was filtered on Celite and used for the next step without fur-
ther purification. IR (neat) 2987, 1794, 1728, 1457,
1250 cmꢀ1. MS m/z: 260 (M+ (1)), 259 (2), 244 (3), 233
(2), 215 (4), 198 (2), 191 (7), 173 (25), 158 (12), 149 (24),
131 (32), 113 (7), 105 (12), 88 (15), 70 (12), 59 (10), 43
(100), 31 (4).
3. Francke, W.; Pan, M. L.; Koenig, W. A.; Mori, K.;
H.;
Puapoomchaeron,
Naturwissenschaften 1987, 74, 343.
P.;
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(b) Alibes, R.; Bourdelande, J. L.; Font, J.; Parella, T.
Tetrahedron 1996, 1279; (c) Knolker, H. J.; Baum, G.;
Schmitt, O.; Wanzl, G. Chem. Commun. 1999, 1737; Sarkar,
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A stirred solution of the crude benzoyloxirane 18 (120 mg,
0.46 mmol) was diluted with dry THF (20 mL) and cooled
at ꢀ78 ꢂC under argon. To this solution, DIBAL-H (1 M in
THF, 1.38 mL, 1.2 mmol) was added dropwise. The mixture
was stirred for 14 h, diluted with diethyl ether and washed
with a saturated NaHCO3 solution. The organic layer was
dried on Na2SO4 and concentrated under reduced pressure.
The product was purified by chromatography (hexane/
EtOAc 1:1) to give the diol 19 as a colourless oil. Over-
all yield 94% (67.9 mg). [a]2D7 ꢀ27.83 (c 0.7314, CH2Cl2).
8. Bernard, A. M.; Frongia, A.; Secci, F.; Delogu, G.; Ollivier, J.;
€
Piras, P. P.; Salaun, J. Tetrahedron 2003, 59, 9433.
1
IR (neat) 3450, 2986, 1220, 1120 cmꢀ1. H NMR (CDCl3,
9. (a) Trost, B. M.; Keeley, D. E. J. Org. Chem. 1975, 40, 2013;
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11. During the oxidation reaction of the alcohols 6 and 12 we
observed an acid-promoted isomerization of the aldehydes
(E and Z)-7 and -13. This process occurs without loss of
optical purity of the obtained products in the case of the alde-
hyde 13.
12. (a) Magnin, D. R.; Robl, J. A.; Sulsky, R. B.; Augeri, D. J.;
Huang, Y.; Simpkins, L. M.; Taunk, P. C.; Betebenner, D. A.;
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J. Org. Chem. 2001, 14, 2659.
300 MHz): d 1.05 (s, 3H), 1.06 (d, 3H, J¼4.5 Hz),
1.41–1.53 (m, 1H), 1.56–1.68 (m, 2H), 1.71–1.80 (m, 1H),
1.86 (t, 1H, J¼6 Hz), 1.90–1.94 (m, 2H), 2.56 (br s, 2H),
3.62–3.70 (m, 2H), 3.76–3.82 (m, 1H). 13C NMR (CDCl3):
d 19.12, 22.68, 27.85, 29.95, 37.16, 46.20, 53.08,
59.77, 68.29. MS m/z: 158 (M+ (1)), 141 (2), 124 (4),
113 (5), 109 (4), 99 (24), 95 (11), 81 (74), 77 (12),
67 (77), 57 (71), 53 (68), 41 (89), 39 (100), 31 (22). Anal.
Calcd for C9H18O2: C, 68.31; H, 11.47. Found: C, 68.29;
H, 11.44.
Acknowledgements
Financial support from the MIUR, Rome, and by the Univer-
sity of Cagliari (National Project ‘Stereoselezione in Sintesi
Organica Metodologie ed applicazioni’) and from CINMPIS
is gratefully acknowledged.
13. Bernard, A. M.; Frongia, A.; Piras, P. P.; Secci, F. Org. Lett.
2003, 5, 2923.
14. Narasaka, K.; Kusama, H.; Hayashi, Y. Bull. Chem. Soc. Jpn.
1991, 64, 1471.