Syntheses of cyclobutane derivatives: Total synthesis of (+) and (-) enantiomers of the oleander scale Aspidiotus nerii sex pheromone

Article abstract of DOI:10.1002/(SICI)1099-0690(199905)1999:5<1201::AID-EJOC1201>3.0.CO;2-7

Synthesis of both enantiomers of the Aspidiotus nerii sex pheromone and their diastereomers has been achieved using, as a key step, an intramolecular ester enolate alkylation reaction for the formation of the cyclobutane ring with a good control of the relative configurations of the asymmetric centers. Stereoselective synthesis of a number of other trisubstituted cyclobutane derivatives also proves the versatility of the methodology used for the synthesis of the Aspidiotus nerii sex pheromone.

Full text of DOI:10.1002/(SICI)1099-0690(199905)1999:5<1201::AID-EJOC1201>3.0.CO;2-7

FULL PAPER
Syntheses of Cyclobutane Derivatives: Total Synthesis of (؉) and (–)
Enantiomers of the Oleander Scale Aspidiotus nerii Sex Pheromone
Francois-Didier Boyer*[a] and Paul-Henri Ducrot[a]
¸
Keywords: Pheromones / Aspidiotus nerii / Sex attractant / Cyclobutane / Enantiomeric purity
Synthesis of both enantiomers of the Aspidiotus nerii sex
asymmetric centers. Stereoselective synthesis of a number of
pheromone and their diastereomers has been achieved
other trisubstituted cyclobutane derivatives also proves the
versatility of the methodology used for the synthesis of the
Aspidiotus nerii sex pheromone.
using, as
a key step, an intramolecular ester enolate
alkylation reaction for the formation of the cyclobutane ring
with a good control of the relative configurations of the
Aspidiotus nerii (Homoptera, Diaspididae) is an endemic
pest in southern Europe. This highly polyphagous[1] scale
insect attacks olive, citrus fruits, plum and various other
trees, shrubs, low-growing and ornamental plants such as
oleander. The life cycle of the insect has, in the case of the
adult female, two nymphal instars before molt and, in the
case of the adult male, four. The adult female is immobile,
but the male has two wings and is therefore able to fly. The
damage caused by this piercing and sucking insect consists
of a weakening of the plant, leaf fall, drying of shoots and
deformation of fruits. This scale insect usually has three
generations per year. These consequences have led us to in-
vestigate the structure of the female sex pheromone pro-
duced by this species as it is a potentially decisive factor
in survey and control strategies. The structure of the sex
pheromone of Aspidiotus nerii[2][3] has been elucidated by
1H- and 13C-NMR experiments and mass spectrometry.
However, these spectrometric methods did not allow the
relative and absolute configurations of the two stereogenic
centers of the molecule to be determined. A synthetic
sample of the pheromone with a known absolute configura-
tion would therefore be useful as a reference material in
order to assign the absolute configuration of that occurring
naturally. Accordingly, one must compare the synthetic
sample with the natural pheromone by physical and/or bio-
logical methods. Hence the problem of synthesizing the four
stereomers (1S,2S)- and (1R,2R)-1 and (1R,2S)- and
(1S,2R)-2 (see Figure 1) was addressed. This work presents
the studies required to obtain these four stereomers, involv-
ing stereoselective synthesis of various cyclobutane deriva-
tives. This class of compounds is involved in many organic
transformations,[4Ϫ6] their skeleton constituting the basic
structure of several natural products[7Ϫ9] and the design of
a versatile methodology for their synthesis is of topical
interest.
Figure 1. Four enantiomers of Aspidiotus nerii sex pheromone
resolution and/or sophisticated reactions in order to be able
to scale up the synthesis for biological field assays. An
abundant monoterpene, carvone, commercially available
either as a racemate or enantiomerically pure, was used as
starting material. The initial strategy was based on alky-
lation of cyclobutane A, as K. Mori et al. described for the
total synthesis of (ϩ)-grandisol [(1S,2R)-(ϩ)-2-isopropenyl-
1-methylcyclobutaneethanol];[10] the pheromone compo-
nent of the boll weevil Anthonomus grandis (see Scheme 1)
and some other beetles.[11]
Scheme 1. Strategy based on alkylation of cyclobutane A
The starting ester 3 was synthesized from carvone in four
steps according to a standard procedure[12,13] [34% overall
yield (3 ϫ) in our hands]. Treatment of 3 with PTSA in a
mixture acetone/water gave the formyl ester 4, which was
immediately reduced with sodium tetrahydridoborate to
furnish the hydroxy ester 5 in an overall yield of 64%. Es-
terification of the hydroxy ester 5 under standard con-
ditions led to the tosylate 6. This substrate for the key cycli-
The goal was to design an enantiospecific synthesis of
all these diastereomers without having recourse to optical
[a]
´
´
Unite de Phytopharmacie et Mediateurs Chimiques, I.N.R.A.,
Route de Saint-Cyr, F-78026 Versailles, France.
Fax: (internat.) ϩ 33-1/30833119
E-mail: boyer@versailles.inra.fr
Eur. J. Org. Chem. 1999, 1201Ϫ1211
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0505Ϫ1201 $ 17.50ϩ.50/0
1201

F.-D. Boyer, P.-H. Ducrot
FULL PAPER
zation reaction needed to be carefully purified by flash
However, for the purposes of this study, the alkylation of
chromatography on silica gel in order to afford a high yield ester 3 by treatment with KHMDS and iodide 10 in THF/
in the next step. After a number of attempts, the best yield HMPA (1:1) was performed and afforded the desired ester
for this intramolecular ester enolate alkylation was obtained 11 as a mixture of inseparable diastereomers (73:27) in a
with LiHMDS in THF/HMPA (85:15) at Ϫ10°C with high yield of 30%, in addition to 50% of recovered starting mate-
diastereoselectivity (> 95:5) (see Scheme 2). The observed rial 3. Modification of the experimental procedure did not
high stereoselectivity can be explained by invoking the most increase the yield of alkylation (base, temperature, reaction
stable “1-H-eclipsed” transition-state geometry as depicted time). The same conditions to form 6 from 3 were used to
in Scheme 2.[14][15][16]
furnish the tosylate 14 in a yield of 43%. Intramolecular
ester enolate alkylation was performed on 14 with LiHMDS
in the presence of HMPA to afford the ethyl cyclo-
butanecarboxylate 15 in a yield of 46%. Surprisingly how-
ever, this reaction occurred with a similarly high diastereo-
selectivity as for 7 (> 95:5) in favour of the diastereomer
having the configuration required for the synthesis of 1.
In order to complete the synthesis, compound 15 was
further converted into 1 through a six-step procedure using
a conventional one-carbon homologation protocol.[14] Re-
duction of the ester 15 with lithium aluminium hydride in
THF followed by tosylation in the presence of 4-DMAP
gave the corresponding tosylate 17 in a yield of 70%. Substi-
tution of the tosyloxy group of 15 by sodium cyanide in
aqueous HMPA furnished the cyanide 18 in a yield of 87%.
The crude aldehyde, obtained by DIBAL-H reduction of
the cyanide 18 and careful acidic aqueous hydrolysis of the
resultant imine, was immediately reduced to the alcohol 19
in an overall yield of 44%. Final acetylation of 19
furnished 1.
Scheme 2. (a) PTSA, acetone/water, room temp., 48 h; (b) NaBH4,
EtOH, 0°C; (c) TsCl, pyridine, 0°C, 18 h; (d) LiHMDS, THF/
HMPA, Ϫ10°C to room temp.
However, all attempts to perform the further alkylation
of ethyl cyclobutanecarboxylate 7 with the iodide 10[17][18]
prepared, in our case, from commercially available ethyl le-
vulinate by Wittig reaction involving the ketone function,
reduction of the ester 8 and iodination of the resultant al-
cohol 9 (32% overall yield, see Scheme 3) failed. In all cases,
the substrate 7 was recovered in a quantitative yield. It was
therefore decided to introduce the 4-methyl-4-penten-1-yl
side chain before cyclization into the cyclobutane derivative.
Scheme 3. (a) Ph3PCH3Br, BuLi, THF, Ϫ70°C to room temp., 24 h;
(b) LiAlH4, Et2O, 0°C, 1 h; (c) I2, Ph3P, imidazole, benzene, 1 h,
room temp.
The only problem which should arise from this choice of
strategy would be that of the diastereoselectivity of the ester
enolate alkylation reaction used for the formation of the
cyclobutane ring. Indeed, one could argue that the “1-H-
eclipsed” transition state advocated in the earlier reports in
the literature as the explanation of the diastereoselectivity
of the reaction would be disfavored when the side chain in
the α position to the ester group experiences steric interac-
tions with the isopropenyl substituent in the β position. It
is of note that the only reports in the literature using this
reaction with a substrate bearing an alkyl substituent at this
position were aimed at the synthesis of fragranol[14] or
grandisol,[16] the alkyl chain being a methyl group in both
cases. Increasing the size of the side chain to a 4-methyl-4-
penten-1-yl group should result in a decrease of the dia-
stereoselectivity of the reaction.
Scheme 4. (a) KHMDS, THF, HMPA, 5-iodo-2-methyl-1-pentene
(10), Ϫ20°C to 0°C; (b) PTSA, acetone, water, room temp., 48 h;
(c) NaBH4, EtOH, 0°C; (d) TsCl, pyridine, 0°C, 18 h; (e) LiHMDS,
THF, HMPA, Ϫ10°C; (f) LiAlH4, THF, 0°C to room temp., 3 h;
(g) TsCl, 4-DMAP, CH2Cl2, 0°C, 18 h; (h) NaCN, aq. HMPA; (i)
DIBAL-H, CH2Cl2, Ϫ20°C; (j) NaBH4, EtOH, 0°C; (k) Ac2O, py-
ridine
1202
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Total Synthesis of (ϩ) and (–) Enantiomers of the Oleander Scale Aspidiotus nerii Sex Pheromone
FULL PAPER
On the other hand, it was decided to synthesize 2 by tak-
ing advantage of the high diastereoselectivity observed in
the formation of the cyclobutane ring by the reaction de-
scribed above. It was thus necessary to form the 4-methyl-
4-penten-1-yl chain from the ethoxycarbonyl side chain
while the R group introduced in α position to the ester be-
fore the cyclization reaction was chosen as a good precursor
of the acetoxyethyl moiety (see Scheme 5).
Scheme 5. Strategy based on trisubstituted cyclobutane ester
The first attempt used an alkenyl chain (allyl or 3,3-di-
methylallyl) as a protected hydroxyethyl precursor before
cyclization. Moreover, the use of an allyl bromide as the
alkylating agent should enhance the efficiency of the alky-
lation step. Indeed, alkylation of 3 with 3,3-dimethylallyl
bromide (KHMDS in a mixture THF/HMPA) gave the
ester 20 in a yield of 94%.
Scheme 6. (a) LiHMDS, THF, HMPA, 3,3-dimethylallyl bromide,
Ϫ60°C to 0°C; (b) cat. OsO4, NMO, acetone, water, room temp.,
1 h; (c) NaIO4, acetone/water, NaHCO3, room temp., 1 h; (d)
NaBH4, EtOH, 0°C; (e) TBDPSCl, imidazole, DMF, room temp.,
18 h; f) PTSA, acetone/water, room temp., 72 h; (g) TsCl, pyridine,
0°C, 18 h; (h) LiHMDS,THF/HMPA, 0°C, H2O hydrolysis; (i)
LiHMDS,THF/HMPA, 0°C, aq. NH4Cl hydrolysis
Initially the transformation of this newly introduced alk-
enyl side chain into the desired hydroxyethyl substituent be-
fore cyclization was attempted. The selective osmylation of
the more substituted double bond followed by the oxidative
cleavage of the resultant vicinal diol afforded the aldehyde
21, reduction of which afforded the alcohol 22 which could
be then protected as its tert-butyldiphenylsilyl ether to yield chain did not seem to have any influence on the diastereo-
23. The same sequence as described above furnished the selectivity of the reaction, its increasing size induced a sig-
hydroxy ester 25. Tosylation under standard conditions nificant decrease in the chemical yield of the cyclobutane
gave the tosylate 26. Disappointingly, all attempts to form formation reaction (see Scheme 8). This work shows the
the cyclobutane derivative from this substrate through the versatility of the intramolecular enolate alkylation method
previously optimized procedure failed. The tosylate 26 was developed by D. Kim and co-workers[14Ϫ16] to form various
either recovered untouched or transformed into the chloro cyclobutane derivatives as summarized in Scheme 8. How-
ester 27 upon hydrolysis with saturated aqueous ammonium ever, the inefficiency of this method when performed on a
chloride (see Scheme 6).
substrate bearing a protected hydroxyethyl side chain could
Nevertheless, an alternative route was to keep the alkenyl be explained not only by steric considerations but also by
precursor of the acetoxyethyl side chain unchanged for the an intramolecular chelation of the counterion by the oxygen
cyclization to form the four-membered ring. Therefore, 3 atom of the side chain. It induces a folded conformation of
was transformed into the tosylate 30 (3 steps, yield 30%) the molecule which prevents the cyclization to occur.
(see Scheme 7). Intramolecular ester enolate alkylation per-
The further elaboration of the two side chains of the mo-
formed on 30 gave, in this case, the cyclobutane derivative lecule was then tried. Unfortunately, neither selective os-
31 in a yield of 50%, again with high diastereoselectivity (> mylation on compound 31 or 37, nor alkylation on the tos-
95:5). The stereochemistry of cyclobutane ester derivatives, ylate 33 or the cyanide 34, which would have allowed the
at first assumed from mechanistic considerations, was un- formation of 4-methyl-4-penten-1-yl chain were possible,
ambiguously confirmed by NOE difference experiments probably due to the steric hindrance of this part of the mol-
performed on 31 and 32 (see Figure 2) and was in agree- ecule (see Scheme 7).
ment with the literature.[14Ϫ16] In the same fashion, use of
So, it seemed essential to form the 4-methyl-4-penten-1-
an allyl substituent instead of the 3,3-dimethyl did not af- yl chain before cyclization to the four-membered ring. As
fect the course of the reaction sequence and the cyclobutane the configuration of the target molecule 2 and the stereo-
37 was synthesized from 35 in a good overall yield with the selectivity observed in the four-membered ring formation
same diastereoselectivity. Noteworthy was the fact that, in were incompatible with this experimental feature, we were
all cases, the four-membered ring-formation reaction gave forced to adopt another synthetic strategy. Therefore, we
similar diastereoselection without being influenced by the decided to use compound 18 already obtained for synthesis
nature and the bulkiness of the substituent in α position to of 1. Indeed, the diastereomer 2 was finally synthesized by
the ester group. However, even if the nature of the side epimerization at C-2 of the cyclobutane as described below.
Eur. J. Org. Chem. 1999, 1201Ϫ1211
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F.-D. Boyer, P.-H. Ducrot
FULL PAPER
Scheme 9. (a) OsO4, NMO, acetone/water, 18 h, room temp.; (b)
NaIO4, MeOH/water, 18 h, room temp.; (c) DBU, benzene, 80°C,
18 h; (d) Ph3PϩCH2Ϫ, THF, Ϫ70°C to room temp.; (e) DIBAL-H,
CH2Cl2, Ϫ20°C, then 5% H2SO4, H2O; (f) NaBH4, EtOH, 0°C;
(g) careful separation on silica gel; (h) Ac2O, pyridine
Scheme 7. (a) PTSA, acetone/water, room temp., 72 h; (b) NaBH4,
EtOH, 0°C; (c) TsCl, pyridine, 0°C, 18 h; (d) LiHMDS, THF/
HMPA, 0°C; (e) LiAlH4, Et2O, 0°C; (f ) TsCl, 4-DMAP, CH2Cl2,
0°C; (g) NaCN, aq. HMPA, 60°C
Figure 2. NOE for 31 and 32
Scheme 8. Results of intramolecular ester enolate alkylation
Osmylation of 18 and oxidative cleavage of the resultant
diol gave the diketone 38. Epimerization at C-2 of 38 by
treatment with base (DBU, benzene, 70°C, 18 h) yielded a
40:60 mixture of the diketones 38/39. Double Wittig reac-
tion performed on the diketone mixture 38/39 furnished the
cyanides 18 and 40. The same sequence as described for the
preparation of 1 (see Scheme 9) completed the synthesis
of 2. Using either (S)-(ϩ) or (R)-(Ϫ)-carvone as a starting
material for the synthesis afforded (1R,2R)-(ϩ)-1 and (1R,
2S)-(Ϫ)-2 {[α]D20 ϭ Ϫ2.5 (c ϭ 1.1, n-hexane)} and (1S, 2S)-
Scheme 10. Diaspididae: Aonidiella aurantii (a, b), Aonidiella citrina
(c), Pseudaulacapsis pentagona (d), Quadraspidiotus perniciosus (e,
f, g), Aspidiotus nerii (h), Pseudococcidae: Planococcus citri (i),
Pseudococcus comstocki (j), Margarodidae: Matsucoccus resinosae
(k), Matsucoccus thunbergianae (k), Matsucoccus matsumurae (k),
Matsucoccus feytaudi (l), Matsucoccus josephi (m)
20
(Ϫ)-1 and (1S, 2R)-(ϩ)-2 {[α]D ϭ ϩ2.4 (c ϭ 0.9, n-
hexane)}, respectively.
Comparison of the sprectroscopic data and coinjection
with a sample of the natural pheromone led us to conclude 2 and (Ϫ)-2 allowed unambiguous attribution of the abso-
that the pheromone has the relative configuration of 2. GC lute configuration of the active enantiomeric form of Aspi-
separation of the enantiomers of 2 on chiral stationary diotus nerii pheromone as (1R,2S)-(Ϫ)-2.[2] This confirms
phases failed. However, biological activity in greenhouse the high diversity of structures of known sex pheromones
bioassays and field tests of these synthetic enantiomers (ϩ)- in the Superfamilia Coccoidea[19][20] (see Scheme 10). Insect
1204
Eur. J. Org. Chem. 1999, 1201Ϫ1211

Total Synthesis of (ϩ) and (–) Enantiomers of the Oleander Scale Aspidiotus nerii Sex Pheromone
FULL PAPER
103 (80), 93 (100), 75 (65), 67 (25), 47 (95). Ϫ IR (neat): ν˜ ϭ 3060
pheromones and/or attractants containing a cyclobutane
function are relatively uncommon.[11] The sesquiterpene
skeleton of the pheromone of Aspidiotus nerii is similar to
that of the monoterpenic pheromone grandisol, with an ad-
ditional isoprenic unit branched on the methyl group of
grandisol.
cmϪ1, 2970, 2920, 1735, 1640.
Ethyl 3-Isopropenyl-5-oxopentanoate (4): PTSA (450 mg,
2.36 mmol) was added to a solution of 3 (1.7 g, 6.58 mmol) in ace-
tone/water (2:1, 135 mL). The resultant mixture was stirred for 48 h
at room temp. and acetone was removed by distillation under re-
In connection with the synthesis of this pheromone, we duced pressure. The aqueous phase was extracted with ether (3 ϫ
75 mL) and the combined organic layers were washed with brine,
dried (MgSO4) and concentrated under reduced pressure. The
crude product was purified by flash chromatography (AcOEt/cyclo-
hexane, 10:90) to give 0.96 g (80%, 2 steps) of the product 4 as a
have investigated the scope and the limitations of the ester
enolate alkylation methodology developed for the synthesis
of cyclobutane derivatives. The usefulness of this method-
ology has been proven for the diastereoselective formation
of various cyclobutane derivatives having two adjacent
stereocenters bearing alkyl or alkenyl side chains, with an
almost complete control of the configuration of the quater-
nary center formed in the course of the reaction.
1
colourless liquid. Ϫ H NMR: δ ϭ 9.63 (br. s), 4.77 (br. s, 2 H),
4.05 (q, 2 H, J ϭ 7 Hz), 3.10 (m, 1 H), 2.50Ϫ2.37 (m, 4 H), 1.68
(s, 3 H), 1.19 (t, 3 H, J ϭ 7 Hz). Ϫ 13C NMR: δ ϭ 201.2 (d), 171.7
(s), 145.2 (s), 112.4 (t), 60.5 (t), 46.7 (d), 38.4 (t), 37.6 (t), 19.7 (q),
14.2 (q). Ϫ GC analysis (BPX-5, 0.32 mm i.d. ϫ 30 m, 120°C),
retention time 2.90 min. Ϫ EI MS; m/z (%): 184 (1), 166 (4), 156
(4), 143 (6), 139 (10), 110 (10), 95 (25), 82 (45), 69 (70), 60 (15), 55
(30), 43 (25), 41 (100). Ϫ IR (CCl4): ν˜ ϭ 3049 cmϪ1, 2980, 2921,
2840, 1735, 1715, 1637.
Experimental Section
General: Melting points: Büchi 510, uncorrected values. Ϫ NMR
(1H: 300 MHz; 13C: 75.5 MHz): VARIAN Gemini 300 instrument,
in deuteriochloroform (CDCl3), CHCl3 (CDCl3) as internal refer-
ence: δ ϭ 7.27 for 1H (δ ϭ 77.14 for 13C). Ϫ MS: Nermag
R10Ϫ10C linked to a Varian 3300 GC, ionization obtained either
by electronic impact (EI) or chemical ionization with ammonia (CI,
NH3). Ϫ IR: Perkin Elmer FT 1600 instrument or PerkinϪElmer
397 instrument using either NaCl salt plates (thin film) or NaCl
cell (in the specified solvent). Ϫ Optical rotations: PerkinϪElmer
241 polarimeter in a 1-dm cell. Ϫ All reactions were monitored by
thin layer chromatography (TLC): E. Merck Ref. 5554 precoated
silica-gel 60F 254 plates, visualization accomplished with UV light
then 7Ϫ10% ethanolic phosphomolybdic acid solution or KMnO4
solution followed by heating were used as developing agents. Tetra-
hydrofuran (THF) and diethyl ether (Et2O) were distilled from so-
dium/benzophenone, dichloromethane (CH2Cl2) and dimethyl-
formamide (DMF) from calcium hydride.
Ethyl 5-Hydroxy-3-isopropenylpentanoate (5): NaBH4 (146 mg,
3.66 mmol) was added to a solution of aldehyde 4 (368 mg, 2 mmol,
0°C) in EtOH (18 mL). The reaction mixture was stirred for 10 min
at 0°C, then 0.5  HCl (10 mL) and water (10 mL) added. The
aqueous phase was extracted with ether (3 ϫ 30 mL), the combined
organic layers dried (MgSO4) and concentrated under reduced
pressure. The crude product was purified by flash chromatography
(AcOEt/cyclohexane, 20:80) to give 297 mg (80%) of the product 5
1
as a colourless liquid. Ϫ H NMR: δ ϭ 4.75 (br. s, 2 H), 4.06 (q,
2 H, J ϭ 7 Hz), 3.55 (m, 2 H), 2.71 (m, 1 H), 2.36 (m, 3 H), 2.25
(m, 2 H), 1.65 (s, 3 H), 1.19 (t, 3 H, J ϭ 7 Hz). Ϫ 13C NMR: δ ϭ
172.7 (s), 146.2 (s), 112.3 (t), 60.7 (t), 60.4 (t), 40.5 (d), 39.1 (t),
35.7 (t), 18.7 (q), 14.2 (q). Ϫ GC analysis (BPX-5, 0.32 mm i.d. ϫ
30 m, 120°C), retention time 4.52 min. Ϫ EI MS; m/z (%): 168 (3),
156 (8), 143 (10), 141 (14), 154 (6), 122 (6), 110 (14), 97 (28), 95
(25), 83 (42), 79 (25), 69 (100), 67 (70), 55 (45), 53 (34), 43 (42), 41
(91). Ϫ IR (neat): ν˜ ϭ 3400 cmϪ1, 3050, 2920, 2860, 1720, 1630.
Ethyl 5,5-Diethoxy-3-isopropenylpentanoate (3): Pb(OAc)4 (58.1 g,
262.4 mmol) was added to a solution of a mixture of diastereomeric
trans-diol obtained from carvone[12][13] (12.08 g, 65.6 mmol, 0°C)
in a mixture benzene/ethanol (1:1, 140 mL). The reaction mixture
was stirred for 2 h at room temp. and filtered through Celite. The
solid was washed with ether and the filtrate washed with water,
satd. aqueous sodium bicarbonate solution, brine, dried (MgSO4)
and concentrated under reduced pressure. The crude product was
diluted with EtOH (250 mL) and triethyl orthoformate (37 mL)
and PTSA (0.5 g, 2.6 mmol) were then added to this solution. The
reaction mixture was stirred overnight at room temp. and concen-
trated under reduced pressure. The residue was dissolved in ether
and the solution washed with water, dried (MgSO4) and concen-
trated under reduced pressure. The crude product was purified by
flash chromatography on silica gel (AcOEt/cyclohexane, 30:70) and
distillation (115Ϫ120°C, 0.1 Torr) to give 14.1 g (84%) of 3 as a
Ethyl 3-Isopropenyl-5-(tosyloxy)pentanoate (6): TsCl (2.12 g,
11.1 mmol) was added to a solution of alcohol 5 (1 g, 5.37 mmol,
0°C) in pyridine (8 mL). The reaction mixture was stirred overnight
at 0°C under argon and poured into a mixture of water and ice (40
mL). The aqueous phase was extracted with ether (3 ϫ 40 mL),
the combined organic layers washed with 2  HCl, brine, dried
(MgSO4) and concentrated under reduced pressure. The crude
product was purified by flash chromatography (AcOEt/cyclohex-
ane, 30:70) to give 1.53 g (82%) of the product 6 as a colourless
liquid. Ϫ 1H NMR: δ ϭ 7.65 (d, 2 H, J ϭ 8 Hz), 7.21 (d, 2 H, J ϭ
8 Hz), 4.61 (br. s, 1 H), 4.53 (br. s, 1 H), 3.97Ϫ3.79 (m, 4 H), 2.52
(m, 1 H), 2.32 (s, 3 H), 2.26Ϫ2.14 (m, 2 H), 1.65Ϫ1.53 (m, 2 H),
1.47 (s, 3 H), 1.10 (t, 3 H, J ϭ 7.0 Hz). Ϫ 13C NMR: δ ϭ 171.8
(s), 144.8 (s), 144.2 (s), 133.0 (s), 129.8 (d), 127.9 (d), 113.4 (t), 68.4
(t), 60.5 (t), 40.0 (d), 38.9 (t), 31.6 (t), 21.7 (q), 18.4 (q), 14.3 (q).
20
pale yellow liquid. (3R)-3 from (R)-carvone, [α]D ϭ ϩ2.7 (c ϭ
20
1.51, CH2Cl2), (3S)-3 from (S)-carvone, [α]D ϭ Ϫ2.5 (c ϭ 2.61,
Ethyl trans-2-Isopropenylcyclobutanecarboxylate (7): A solution of
CH2Cl2). Ϫ 1H NMR: δ ϭ 4.77 (m, 2 H), 4.43 (dd, 1 H, J ϭ 7 Hz, LiHMDS (23.4 mL, 23.4 mmol, 1  solution in THF) was added
J ϭ 4 Hz), 4.08 (q, 2 H, J ϭ 7 Hz), 3.70Ϫ3.40 (m, 4 H), 2.74 (m, dropwise under argon to a solution of tosylate 6 (4.0 g, 11.7 mmol,
1 H), 2.44Ϫ2.34 (m, 2 H), 1.68 (m, 1 H), 1.67 (s, 3 H), 1.24Ϫ1.15 Ϫ10°C) in THF/HMPA (90 mL/15 mL). The reaction mixture was
(m, 9 H). Ϫ 13C NMR: δ ϭ 172.4 (s), 145.9 (s), 112.5 (t), 101.3 (d), stirred for 10 min at Ϫ10°C and for 2 h at 0°C, then quenched with
61.1 (t), 60.3 (t), 40.0 (t), 39.3 (t), 36.9 (t), 18.8 (q), 15.5 (2 C, q), satd. aqueous ammonium chloride solution (100 mL) at 0°C. The
14.3 (q). Ϫ Capillary GC analysis (DB5-MS, 0.32 mm i.d. ϫ 30 m,
aqueous phase was extracted with ether (3 ϫ 150 mL) and the
100Ϫ300°C, 10°C/min), retention time 8.75 min. Ϫ EI MS; m/z combined organic layers washed with water (150 mL), brine (150
(%): 257 (1), 212 (4), 187 (2), 185 (4), 167 (18), 139 (4), 121 (10), mL), dried (MgSO4) and concentrated under reduced pressure. The
Eur. J. Org. Chem. 1999, 1201Ϫ1211
1205

F.-D. Boyer, P.-H. Ducrot
crude product (diastereoselectivity > 95:5) was purified by flash (36 mL 1:1) was added dropwise under argon to a solution of
FULL PAPER
chromatography (AcOEt/cyclohexane, 5:95) to give 1.38 g (70%) of
the product 7 as a colourless oil. Ϫ 1H NMR: δ ϭ 4.75 (br. s, 1
H), 4.71 (br. s, 1 H), 4.12 (q, 2 H, J ϭ 7 Hz), 3.10 (dd, 1 H, J ϭ
KHMDS (54 mL, 27 mmol, 0.5 m solution in toluene, Ϫ20°C) in
THF (16 mL). The reaction mixture was stirred for 1 h at Ϫ20°C,
then added a solution of 10 (5.5 g, 26 mmol) in THF/HMPA (36
9 Hz, J ϭ 18 Hz), 2.94 (dt, 1 H, J ϭ 9 Hz, J ϭ 18 Hz), 2.20Ϫ1.70 mL 1:1), warmed to 0°C, stirred for 3.5 h and quenched with satd.
(m, 4 H), 1.66 (s, 3 H), 1.24 (t, 3 H, J ϭ 7 Hz). Ϫ 13C NMR: δ ϭ aqueous ammonium chloride solution (75 mL). The aqueous phase
174.6 (s), 146.8 (s), 108.9 (t), 60.4 (t), 45.1 (s), 43.4 (d), 23.5 (t),
was extracted with ether (3 ϫ 100 mL) and the combined organic
21.1 (t), 20.2 (q), 14.3 (q). Ϫ Capillary GC analysis (BPX-5-MS,
layers washed with water (50 mL), brine (50 mL), dried (MgSO4)
0.32 mm i.d. ϫ 30 m, 80°C), retention time 6.35 min. Ϫ EI MS; and concentrated under reduced pressure to give the crude product
m/z (%): 168 (5), 140 (5), 165 (1), 111 (5), 95 (40), 79 (20), 68 (100),
67 (80), 55 (50), 53 (30), 41 (40).
11 (2.3 g) which was used in the next step without further purifi-
cation. For pure product, flash chromatography (100 cyclohexane
then AcOEt/cyclohexane, 5:95). Ϫ Major isomer: 1H NMR: δ ϭ
4.87 (br. s, 1 H), 4.83 (br. s, 1 H), 4.68 (br. s, 1 H), 4.63 (br. s, 1
H), 4.37 (dd, 1 H, J ϭ 6.5 Hz, J ϭ 6 Hz), 4.15 (m, 2 H), 3.60 (m,
2 H), 3.44 (m, 2 H), 2.51Ϫ2.20 (m, 2 H), 2.1Ϫ1.3 (m, 8 H), 1.60
(s, 3 H), 1.55 (s, 3 H), 1.25Ϫ1.15 (m, 9 H). Ϫ 13C NMR: δ ϭ 175.7
(s), 145.6 (s), 143.8 (s), 114.9 (t), 110.1 (t), 101.0 (d), 61.5 (t), 60.1
(t), 60.0 (t), 48.8 (d), 46.1 (d), 37.6 (t), 34.0 (t), 30.3 (t), 25.4 (t),
22.4 (q), 18.2 (q), 15.5 (2 C, q), 14.5 (q). Ϫ The ratio of stereomers
was determined by capillary GC analysis (DB5-MS, 0.32 mm i.d.
ϫ 30 m, 140Ϫ300°C, 10°C/min), retention time 7.40 min (73%),
7.56 min (27%). Ϫ EI MS; m/z (%): 340 (1), 295 (2), 249 (2), 203
(3), 175 (12), 116 (24), 103 (100), 75 (36), 47 (41). Ϫ IR (neat): ν˜ ϭ
3073 cmϪ1, 2974, 2931, 1732, 1646, 1373, 1058.
Ethyl 4-Methyl-4-penten-1-oate (8):[17] n-Butyllithium (96 mL,
201.6 mmol, 2.1  solution in hexane) was added dropwise to a
solution of methyltriphenylphosphonium bromide (66 g, 183 mmol,
Ϫ60°C) in THF (250 mL) under argon. The solution of ylide was
stirred for 1 h at 0°C. A solution of ethyl levulinate (20.7 mL,
144 mmol) in THF (150 mL) was added to the solution of ylide
(Ϫ60°C). The resultant reaction mixture was heated at room temp.,
stirred overnight and quenched with water. The aqueous phase was
extracted with cyclohexane (3 ϫ 200 mL). The combined organic
layers were washed with brine, dried (MgSO4) and concentrated
under reduced pressure. The residue was dissolved in pentane and
stirred for 1 h at room temp. The solution was filtered and the
solvent removed under reduced pressure to give 9.2 g of the crude
1
product 8 used in the next step without further purification. Ϫ H
Ethyl 3-Isopropenyl-2-(4Ј-methyl-4Ј-penten-1Ј-yl)-5-oxopentanoate
(12): Prepared from the crude product 11 by the same procedure
as for 4 (20%, 2 steps). Colourless oil. (2RS, 3R)-12 from (3R)-3:
NMR: δ ϭ 4.65 (br. s, 1 H), 4.55 (br. s, 1 H), 4.10 (q, 2 H, J ϭ
7.5 Hz), 2.42 (t, 2 H, J ϭ 8 Hz), 2.33 (t, 2 H, J ϭ 8 Hz), 1.73 (s, 3
H), 1.25 (t, 3 H, J ϭ 7 Hz). Ϫ 13C NMR: δ ϭ 173.3 (s), 144.1 (s),
110.3 (t), 60.3 (t), 32.72 (t), 32.68 (t), 22.5 (q), 14.3 (q). Ϫ GC
analysis (BPX-5, 0.32 mm i.d. ϫ 30 m, 100°C), retention time
0.60 min. Ϫ EI MS; m/z (%): 142 (10), 96 (18), 97 (19), 81 (4), 69
(100), 55 (12), 53 (14), 41 (36). Ϫ IR (neat): ν˜ ϭ 3090 cmϪ1, 3000,
2940, 2880, 1740, 1650.
20
[α]D ϭ Ϫ33.0 (c ϭ 1.47, CH2Cl2), (2RS, 3S)-12 from (3S)-3:
20
[α]D ϭ ϩ30.0 (c ϭ 2.55, CH2Cl2). Ϫ Major isomer: 1H NMR:
δ ϭ 9.53 (dd, 1 H, J ϭ 3 Hz, J ϭ 1.5 Hz), 4.85 (br. s, 1 H), 4.83
(br. s, 1 H), 4.65 (br. s, 1 H), 4.60 (br. s, 1 H), 4.11 (q, 2 H, J ϭ
7 Hz), 2.88 (m, 1 H), 2.50Ϫ2.30 (m, 3 H), 2.00Ϫ1.90 (m, 2 H), 1.65
(s, 3 H), 1.61 (s, 3 H), 1.60Ϫ1.20 (m, 4 H), 1.23 (t, 3 H, J ϭ 7 Hz).
13C NMR: δ ϭ 201.2 (d), 175.0 (s), 145.2 (s), 143.4 (s), 115.0 (t),
110.2 (t), 60.5 (t), 48.1 (d), 45.1 (t), 44.2 (d), 37.4 (t), 30.2 (t), 25.1
(t), 22.2 (q), 18.6 (q), 14.3 (q). Ϫ The ratio of stereomers was deter-
mined by capillary GC analysis (BPX-5, 0.32 mm i.d. ϫ 30 m,
140Ϫ300°C, 10°C/min), retention time 7.33 min (73%), 7.45 min
(27%). Ϫ EI MS; m/z (%): 223 (2), 205 (2), 197 (8), 175 (6), 169
(6), 156 (8), 133 (4), 123 (6), 110 (10), 101 (16), 95 (40), 82 (42), 69
(50), 55 (56), 41 (100). Ϫ IR (neat): ν˜ ϭ 3050 cmϪ1, 2960, 2920,
2840, 2820, 2705, 1715, 1635. Ϫ HRMS; C16H27O3 [MHϩ]: calcd.
267.1950; found 267.1958.
4-Methyl-4-penten-1-ol (9):[17] A solution of the crude product 8
(9.2 g) in THF (150 mL) was added to a solution of LiAlH4 (8.0 g,
216 mmol, 0°C) in THF (200 mL). The reaction mixture was
stirred at 0°C for 1 h, quenched with water (8 mL), NaOH (15%) (8
mL), water (24 mL) and stirred for 1 h at room temp. The resultant
mixture was filtered and solvent removed under reduced pressure.
The residue was purified by distillation (78Ϫ79°C, 20 Torr) to give
1
6.8 g (46%) of 9 as a colourless liquid. Ϫ H NMR: δ ϭ 4.77 (br.
s, 2 H), 3.65 (t, 2 H, J ϭ 7.5 Hz), 2.50Ϫ1.60 (m, 5 H), 1.75 (s, 3
H). Ϫ 13C NMR: δ ϭ 145.5 (s), 110.2 (t), 62.6 (t), 34.1 (t), 30.5
(t), 22.4 (q). Ϫ GC analysis (BPX-5, 0.32 mm i.d. ϫ 30 m, 80°C),
retention time 0.98 min. Ϫ EI MS; m/z (%): 100 (2), 81 (10), 72
(15), 67 (100), 56 (70), 41 (90). Ϫ IR (neat): ν˜ ϭ 3350 cmϪ1, 3090,
3000, 2940, 2880, 1655.
Ethyl
5-Hydroxy-3-isopropenyl-2-(4Ј-methyl-4Ј-penten-1Ј-yl)pen-
tanoate (13): Prepared from 12 by the same procedure as for 5
20
(84%). Colourless oil. (2RS, 3R)-13 from (2RS, 3R)-12: [α]D
ϭ
Ϫ10.3 (c ϭ 1.18, CH2Cl2), (2RS, 3S)-13 from (2RS, 3S)-12:
20
[α]D ϭ ϩ11.6 (c ϭ 1.29, CH2Cl2). Ϫ Major isomer: 1H NMR:
5-Iodo-2-methyl-1-pentene (10):[18] Triphenylphosphane (22.2 g,
84.2 mmol), imidazole (11.1 g, 163.5 mmol) and I2 (20.1 g,
79.7 mmol) were added to a solution of 9 (5.8 g, 58 mmol, 0°C) in
benzene (330 mL). The reaction mixture was stirred for 1 h at room
temp. and filtered. The solid was washed with pentane and the
filtrate concentrated under reduced pressure. The residue was puri-
fied by flash chromatography on silica gel (pentane) to give 8.46 g
δ ϭ 4.85 (br. s, 1 H), 4.80 (br. s, 1 H), 4.70 (br. s, 1 H), 4.60 (br. s,
1 H), 4.20 (m, 2 H), 3.50 (m, 2 H), 2.50Ϫ2.30 (m, 2 H), 2.10Ϫ1.90
(m, 3 H), 1.61 (s, 3 H), 1.55 (s, 3 H), 1.4 (m, 6 H), 1.20 (t, 3 H,
J ϭ 7.5 Hz). Ϫ 13C NMR: δ ϭ 176.0 (s), 145.5 (s), 144.2 (s), 114.8
(t), 110.0 (t), 61.1 (t), 60.4 (t), 48.6 (d), 47.0 (d), 37.4 (t), 33.8 (t),
30.5 (t), 25.2 (t), 22.3 (q), 17.7 (q), 14.4 (q). Ϫ The ratio of stereo-
mers was determined by capillary GC analysis (BPX-5, 0.32 mm
i.d. ϫ 30 m, 140Ϫ300°C, 10°C/min), retention time 8.25 min
(73%), 8.35 min (27%). Ϫ EI MS; m/z (%): 223 (4), 198 (6), 181 (2),
169 (4), 154 (6), 142 (10), 121 (4), 107 (8), 95 (30), 81 (24), 69 (30),
55 (34), 41 (100). Ϫ IR (neat): ν˜ ϭ 3420 cmϪ1, 3080, 2980, 2940,
1730, 1645.
1
(69%) of product 10 as a colourless liquid. Ϫ H NMR: δ ϭ 4.77,
4.73 (2 br. s, 2 H), 3.19 (t, 2 H, J ϭ 7 Hz), 2.13 (t, 2 H, J ϭ 7 Hz),
1.97 (m, 2 H), 1.73 (s, 3 H). Ϫ 13C NMR: δ ϭ 143.8 (s), 111.2 (t),
38.4 (t), 31.4 (t), 22.4 (q), 6.5 (t). Ϫ GC analysis (BPX-5, 0.32 mm
i.d. ϫ 30 m, 100°C), retention time 1.41 min. Ϫ EI MS; m/z (%):
210 (5), 182 (3), 155 (2), 127 (2), 83 (36), 67 (7), 55 (100), 41 (26).
Ethyl 5,5-Diethoxy-3-isopropenyl-2-(4Ј-methyl-4Ј-penten-1Ј-yl)pen-
tanoate (11): A solution of 3 (3.34 g, 12.9 mmol) in THF/HMPA
Ethyl 3-Isopropenyl-2-(4Ј-methyl-4Ј-penten-1Ј-yl)-5-(tosyloxy)pen-
tanoate (14): Prepared from 13 by the same procedure as for 6
1206
Eur. J. Org. Chem. 1999, 1201Ϫ1211

Total Synthesis of (ϩ) and (–) Enantiomers of the Oleander Scale Aspidiotus nerii Sex Pheromone
FULL PAPER
1
(79%). Colourless oil. Ϫ Major isomer: H NMR: δ ϭ 7.76 (d, 2
(138 mg, 1.13 mmol) were added to a solution of crude alcohol 16
H, J ϭ 8 Hz), 7.33 (d, 2 H, J ϭ 8 Hz), 4.80 (br. s, 1 H), 4.67 (br. (120 mg, 0.57 mmol, 0°C) in CH2Cl2 (1.2 mL) The reaction mix-
s, 2 H), 4.62 (br. s, 1 H), 4.16Ϫ3.80 (m, 4 H), 2.45 (s, 3 H), 2.35 ture was stirred overnight at 0°C under argon, and then poured
(m, 2 H), 2.00Ϫ1.90 (m, 9 H), 1.66 (s, 3 H), 1.40 (s, 3 H), 1.26 (t,
into a mixture of water and ice (20 mL). The aqueous phase was
3 H, J ϭ 7.1 Hz). Ϫ 13C NMR: δ ϭ 175.3 (s), 145.4 (s), 144.7 (s), extracted with ether (3 ϫ 15 mL), the combined organic layers
133.2 (s), 129.8 (d), 128.0 (d), 115.0 (t), 110.2 (t), 68.6 (t), 60.5 (t), washed with brine (10 mL), dried (MgSO4) and concentrated under
48.5 (d), 46.3 (d), 37.5 (t), 30.5 (t), 29.8 (t), 25.2 (t), 22.4 (q), 21.7 reduced pressure. The crude product was purified by flash chroma-
(q), 17.6 (q), 14.4 (q). Ϫ IR (neat): ν˜ ϭ 3074 cmϪ1, 2918, 2854,
1716, 1645, 1598, 1363, 1174.
tography (AcOEt/cyclohexane, 10:90) to give 168 mg (81%) of the
1
product 17 as a colourless oil. Ϫ H NMR: δ ϭ 7.75 (d, 2 H, J ϭ
7.5 Hz), 7.35 (d, 2 H, J ϭ 7.5 Hz), 4.84 (br. s, 1 H), 4.64 (br. s, 2
H), 4.56 (br. s, 1 H), 3.88 (AB, 2 H, J ϭ 11 Hz), 2.72 (br. t, 1 H,
J ϭ 9 Hz), 2.43 (s, 3 H), 2.00Ϫ1.10 (m, 10 H), 1.63 (s, 3 H), 1.57
(s, 3 H). Ϫ 13C NMR: δ ϭ 145.6 (s), 144.8 (s), 144.1 (s), 132.9 (s),
129.9 (d), 128.0 (d), 110.9 (t), 109.9 (t), 75.4 (t), 46.9 (d), 44.7 (s),
38.3 (t), 29.3 (t), 23.8 (t), 21.3 (t), 19.1 (t), 23.5 (q), 22.5 (q), 21.7
(q).
Ethyl trans-2-Isopropenyl-1-(4Ј-methyl-4Ј-penten-1Ј-yl)cyclobutane-
carboxylate (15): A solution of LiHMDS (6.6 mL, 6.6 mmol, 1 
solution in THF) was added dropwise under argon to a solution
of tosylate 14 (920 mg, 2.18 mmol, Ϫ10°C) in THF/HMPA (17
mL:3.2 mL). The reaction mixture was stirred for 15 min at Ϫ10°C
and for 1 h at room temp., then quenched with satd. aqueous am-
monium chloride solution (15 mL) at 0°C. The aqueous phase was
extracted with ether (3 ϫ 30 mL) and the combined organic layers
washed with water (30 mL), brine (30 mL), dried (MgSO4) and
concentrated under reduced pressure. The crude product (dia-
stereoselectivity > 95:5) was purified by flash chromatography (Ac-
OEt/cyclohexane, 5:95) to give 255 mg (46%) of the product 15 as
trans-2-Isopropenyl-1-(4Ј-methyl-4Ј-penten-1Ј-yl)cyclobutane-
acetonitrile (18): Three drops of water and NaCN (34 mg,
0.69 mmol) were added to a solution of tosylate 17 (168 mg,
0.46 mmol) in HMPA (1 mL). The reaction mixture was stirred for
3 h at 80Ϫ90°C, cooled to room temp. and diluted in a mixture of
AcOEt/cyclohexane (5:95). The organic layer was washed with
water (10 mL), brine (2 ϫ 10 mL), dried (MgSO4) and concentrated
under reduced pressure. The crude product was purified by flash
chromatography (cyclohexane to AcOEt/cyclohexane, 10:90) to
give 87 mg (87%) of the product 18 as a colourless oil. (1S, 2S)-18
20
a colourless oil. (1R, 2S)-15 from (2RS, 3R)-13: [α]D ϭ Ϫ13.4
(c ϭ 2.07, CH2Cl2), (1S, 2R)-15 from (2RS, 3S)-13: [α]D20 ϭ ϩ13.5
1
(c ϭ 2.34, CH2Cl2). Ϫ H NMR: δ ϭ 4.93 (br. s, 1 H), 4.71 (br. s,
1 H), 4.67 (br. s, 1 H), 4.64 (br. s, 1 H), 4.15 (q, 2 H, J ϭ 7 Hz),
3.04 (br. t, 1 H, J ϭ 9 Hz), 2.41 (ddd, 1 H, J ϭ 20 Hz, J ϭ 10 Hz,
J ϭ 1 Hz), 2.05Ϫ1.30 (m, 9 H), 1.73 (s, 3 H), 1.67 (s, 3 H), 1.26 (t,
3 H, J ϭ 7 Hz). Ϫ 13C NMR: δ ϭ 176.7 (s), 145.7 (s), 144.0 (s),
111.6 (t), 109.9 (t), 60.3 (t), 51.0 (s), 48.1 (d), 38.2 (t), 30.3 (t), 24.6
(t), 23.0 (q), 22.4 (t), 22.4 (q), 19.3 (t), 14.3 (q). Ϫ Capillary GC
analysis (DB5-MS, 0.32 mm i.d. ϫ 30 m), retention time 4.40 min.
Ϫ EI MS; m/z (%): 250 (0.5), 235 (2), 222 (2), 177 (8), 168 (10),
139 (8), 121 (25), 109 (25), 93 (25), 91 (10), 81 (25), 69 (80), 68
20
from (1R, 2S)-16: [α]D ϭ Ϫ2.6 (c ϭ 1.17, CH2Cl2), (1R, 2R)-18
20
1
from (1S, 2R)-16: [α]D ϭ ϩ3.0 (c ϭ 5.01, CH2Cl2). Ϫ H NMR:
δ ϭ 4.92 (br. s, 1 H), 4.71 (br. s, 2 H), 4.67 (br. s, 1 H), 2.87 (br. t,
1 H, 9.5 Hz), 2.48 (AB, 2 H, J ϭ 17 Hz), 2.10Ϫ1.26 (m, 10 H),
1.72, 1.71 (2s, 6 H). Ϫ 13C NMR: δ ϭ 145.5 (s), 143.5 (s), 118.6
(s), 111.4 (t), 110.2 (t), 49.2 (d), 43.0 (d), 38.3 (t), 32.0 (t), 28.6 (t),
26.7 (t), 21.7 (t), 19.3 (t), 23.6 (q), 22.5 (q). Ϫ Capillary GC analysis
(BPX-70-MS, 0.32 mm i.d. ϫ 30 m, 125Ϫ275°C, 10°C/min), reten-
tion time 5.25 min. Ϫ EI MS; m/z (%): 217 (0.1), 216 (1), 202 (3),
177 (5), 161 (1), 146 (2), 134 (3), 121 (10), 109 (15), 93 (12), 79
(14), 69 (15), 68 (100), 67 (50), 56 (13), 53 (17), 41 (41). Ϫ IR (neat):
ν˜ ϭ 3085 cmϪ1, 2840, 2760, 2250, 1650, 1450, 1360, 890. Ϫ HRMS;
C15H24N [MHϩ]: calcd. 218.1903; found 218.1909.
(100), 67 (60), 55 (30), 53 (25), 41 (60). IR (neat): ν˜ ϭ 3060 cmϪ1
,
2960, 2920, 2840, 1715, 1635. Ϫ HRMS; C16H27O2 [MHϩ]: calcd.
251.2004; found 251.2019.
trans-2-Isopropenyl-1-(4Ј-methyl-4Ј-penten-1Ј-yl)cyclobutane-
methanol (16): A solution of ester 15 (250 mg, 1 mmol) in THF (4.5
mL) was added under argon to a suspension of LiAlH4 (46 mg,
1.2 mmol, 0°C) in THF (4.5 mL). The reaction mixture was stirred
for 3 h at room temp., then diluted with ether (20 mL) and
quenched with 6 drops of water at 0°C. The organic phase was
washed with water (5 mL), the aqueous phase reextracted with
ether (2 ϫ 20 mL) and the combined organic layers dried (MgSO4)
and concentrated under reduced pressure. The crude product
(180 mg, 86%) 16 was used in the next step without further purifi-
trans-2-Isopropenyl-1-(4Ј-methyl-4Ј-penten-1Ј-yl)cyclobutaneethanol
(19): Diisobutylaluminium hydride (0.1 mL, 0.1 mmol, 1  solution
in toluene) was added dropwise under argon to a solution of 18
(13 mg, 0.059 mmol, Ϫ20°C) in CH2Cl2 (0.5 mL). The reaction
mixture was stirred for 2 h at Ϫ20°C and 0.5 h at room temp. then
water (0.1 mL) and 5% H2SO4 (0.3 mL) added. The mixture was
stirred for 1 h at 0°C, the aqueous phase was separated and ex-
tracted with Et2O (2 ϫ 10 mL). The combined organic layers were
washed with satd. aqueous sodium bicarbonate solution (5 mL),
brine (5 mL), dried (MgSO4) and concentrated under reduced
pressure to give the aldehyde used in the next step without further
purification. NaBH4 (5 mg, 0.13 mmol) was added to a solution of
this aldehyde in EtOH (0.5 mL, 0°C). The reaction mixture was
stirred for 15 min at 0°C and hydrolyzed with 9 drops of acetone.
The resultant solution was stirred for 30 min at room temp. and
concentrated under reduced pressure. The residue was purified by
flash chromatography (AcOEt/cyclohexane, 10:90) to give 7 mg
20
cation. (1R, 2S)-16 from (1R, 2S)-15: [α]D ϭ ϩ13.6 (c ϭ 0.85,
20
CH2Cl2), (1S, 2R)-16 from (1S, 2R)-15: [α]D ϭ Ϫ14.4 (c ϭ 2.71,
1
CH2Cl2). Ϫ H NMR: δ ϭ 4.87 (br. s, 1 H), 4.69 (br. s, 2 H), 4.65
(br. s, 1 H), 3.54 (AB, 2 H, J ϭ 11 Hz), 2.82 (br. t, 1 H, J ϭ 9 Hz),
2.05Ϫ1.30 (m, 11 H), 1.70 (s, 6 H). Ϫ 13C NMR: δ ϭ 146.1 (s),
145.2 (s), 110.3 (t), 109.8 (t), 68.9 (t), 47.1 (s), 46.3 (d), 38.7 (t),
29.8 (t), 23.5 (t), 21.8 (t), 19.2 (t), 23.7 (q), 22.6 (q). Ϫ Capillary
GC analysis (DB5-MS, 0.32 mm i.d. ϫ 30 m, 140Ϫ240°C, 10°C/
min), retention time 5.03 min. Ϫ EI MS; m/z (%): 193 (0.5), 177
(11), 165 (1), 147 (6), 134 (6), 121 (51), 109 (40), 108 (12), 107 (41),
95 (38), 93 (52), 91 (23), 82 (37), 81 (36), 79 (43), 70 (43), 69 (60),
68 (96), 67 (100), 55 (67), 53 (37), 43 (33), 41 (88). Ϫ IR (neat):
ν˜ ϭ 3350 cmϪ1, 3070, 2970, 2930, 2860, 1640, 1445, 1360. Ϫ
HRMS C14H25O (MHϩ): calcd. 209.1899; found 209.1901. Ϫ
HRMS; C14H23 [MHϩ Ϫ H2O]: calcd. 191.1794; found 191.1798.
1
(44%) of 19 as a colourless oil. Ϫ H NMR: δ ϭ 4.88 (br. s, 1 H),
4.72 (br. s, 2 H), 4.69 (br. s, 1 H), 3.61 (m, 2 H), 2.64 (br. t, 1 H,
J ϭ 9 Hz), 2.05Ϫ1.25 (m, 12 H), 1.72 (s, 3 H), 1.70 (s, 3 H). Ϫ 13C
NMR: δ ϭ 145.9 (s), 145.5 (s), 110.5 (t), 110.1 (t), 59.7 (t), 49.3
(d), 44.8 (s), 40.1 (t), 38.5 (t), 36.2 (t), 28.0 (t), 24.0 (q), 22.6 (t),
trans-2-Isopropenyl-1-(4Ј-methyl-4Ј-penten-1Ј-yl)cyclobutanemethyl 22.5 (q), 19.5 (t). Ϫ Capillary GC analysis (DB5-MS, 0.32 mm i.d.
p-Toluenesulfonate (17): TsCl (120 mg, 0.57 mmol) and 4-DMAP
ϫ 30 m, 150Ϫ225°C, 10°C/min), retention time 6.46 min. Ϫ EI
Eur. J. Org. Chem. 1999, 1201Ϫ1211
1207

F.-D. Boyer, P.-H. Ducrot
FULL PAPER
MS; m/z (%): 208 (1), 191 (1), 177 (5), 149 (3), 139 (22), 135 (5),
(500 mg) and NaIO4 (3.45 g, 16 mmol) were added to a solution of
121 (20), 119 (16), 109 (16), 107 (18), 95 (23), 93 (35), 81 (45), 79 the residue in acetone/water (1:1, 30 mL) and the resultant mixture
(30 ), 77 (13), 69 (66), 68 (100), 67 (70), 55 (38), 53 (30), 43 (11), stirred for 1.5 h at room temp. Acetone was removed under reduced
41 (71), 40 (15). Ϫ IR (CCl4): ν˜ ϭ 3632 cmϪ1, 3078, 2931, 2853,
1645, 1449, 1373, 1226, 1042.
pressure and the aqueous phase extracted with dichloromethane
(30 mL). The organic layer was washed with water (10 mL), brine
(10 mL), dried (MgSO4) and concentrated under reduced pressure
to give the aldehyde 21 (850 mg, 94%) as a crude product. To a
solution of the aldehyde 21 (850 mg, 0°C) in ethanol (25 mL) was
added NaBH4 (175 mg, 4.6 mmol). The reaction mixture was
stirred for 10 min at 0°C and quenched with 0.5  HCl (5 mL),
water (5 mL). The aqueous phase was extracted with ether (3 ϫ 30
mL), the combined organic layers dried (MgSO4) and concentrated
under reduced pressure. The crude product was purified by flash
chromatography (AcOEt/cyclohexane, 50:50) to give 320 mg (35%)
of the product 22. Ϫ Major isomer: 1H NMR: δ ϭ 4.89 (br. s, 1
H), 4.84 (br. s, 1 H), 4.38 (dd, 1 H, J ϭ 7.5 Hz, J ϭ 7 Hz), 4.17
(m, 2 H), 3.60 (m, 4 H), 3.44 (m, 2 H), 2.48 (m, 2 H), 1.70 (m, 2
H), 1.62 (s, 3 H), 1.27 (t, 3 H, J ϭ 7 Hz), 1.19 (m, 6 H). Ϫ 13C
NMR: δ ϭ 175.8 (s), 143.6 (s), 115.4 (t), 101.0 (d), 61.5 (t), 61.1
(t), 60.7 (t), 60.1 (t), 45.8 (d), 34.6 (t), 33.7 (t), 18.2 (q), 15.5 (2 C,
q), 14.4 (q). Ϫ The ratio of stereomers was determined by capillary
GC analysis (DB5-MS, 0.32 mm i.d. ϫ 30 m, 140Ϫ280°C, 10°C/
min), retention time 8.55 min (71%), 8.72 min (29%). Ϫ IR (neat):
ν˜ ϭ 3450 cmϪ1, 3050, 2960, 2910, 2860, 1720, 1635.
trans-2-Isopropenyl-1-(4Ј-methyl-4Ј-penten-1Ј-yl)cyclobutaneethanol
Acetate (1): A solution of alcohol 19 (5 mg, 0.22 mmol) in pyridine
(0.15 mL) with Ac2O (0.05 mL) was stirred overnight at room temp.
The reaction mixture was concentrated under reduced pressure and
the residue purified by flash chromatography (AcOEt/cyclohexane,
10:90) to give 4 mg (70%) of 1 as colourless oil. (1S, 2S)-1 from
20
(1S, 2S)-18: [α]D ϭ Ϫ3.1 (c ϭ 0.6, n-hexane), (1R, 2R)-1 from
20
1
(1R, 2R)-18: [α]D ϭ ϩ2.9 (c ϭ 1.0, CH2Cl2). Ϫ H NMR: δ ϭ
4.86 (br. s, 1 H), 4.70 (br. s, 2 H), 4.66 (br. s, 1 H), 4.13 (m, 2 H),
2.66 (br. t, 1 H, J ϭ 8 Hz), 2.2Ϫ1.2 (m, 12 H), 2.04 (s, 3 H), 1.70
(s, 6 H). Ϫ 13C NMR: δ ϭ 171.2 (s), 146.1 (s), 145.2 (s), 110.6 (t),
109.9 (t), 62.0 (t), 49.5 (d), 44.5 (s), 38.8 (t), 38.2 (t), 33.1 (t), 23.9
(t), 22.0 (t), 19.8 (t), 22.5 (q), 22.3 (q), 21.2 (q). Ϫ Capillary GC
analysis (DB5-MS, 0.32 mm i.d. ϫ 30 m, 120Ϫ300°C, 10°C/min),
retention time 9.66 min. Ϫ EI MS; m/z (%): 204 (1), 189 (6), 175
(5), 161 (12), 148 (7), 133 (12), 121 (43), 119 (14), 107 (27), 105
(15), 93 (63), 91 (20), 81 (33), 79 (42), 77 (13), 69 (58), 68 (74), 67
(43), 55 (22), 53 (20), 43 (100), 41 (64). Ϫ CI/NH3 MS; m/z (%):
282 (100), 265 (8), 205 (67), 183 (3), 149 (30), 135 (13), 123 (13),
121 (18), 109 (18), 95 (18), 81 (10). Ϫ IR (CCl4): ν˜ ϭ 3079 cmϪ1
,
Ethyl 2-{2Ј-[(tert-Butyldiphenylsilyl)oxy]ethyl}-3-isopropenyl-5-oxo-
pentanoate (24): Imidazole (100 mg, 1.5 mmol) and TBDPSCl
(0.305 mL, 1.16 mmol) were added to a solution of the alcohol 22
(320 mg, 1 mmol) in DMF (1 mL). The reaction mixture was
stirred overnight at room temp. and diluted with dichloromethane
(50 mL), washed with water (20 mL), HCl (0.5 , 20 mL), water
(20 mL), brine (20 mL), dried (MgSO4) and concentrated under
reduced pressure to give the crude product 23 (660 mg). The crude
product 23 was diluted in acetone/water (6.5 mL:3.5 mL) and
PTSA (84 mg, 0.44 mmol) added to the resultant mixture. The reac-
tion mixture was stirred for 72 h at room temp. The aqueous phase
was extracted with ether (3 ϫ 30 mL) and the combined organic
layers were washed with brine, dried (MgSO4) and concentrated
under reduced pressure. The crude product was purified by flash
chromatography (AcOEt/cyclohexane, 20:80) to give 302 mg (64%)
of the product 24 as a colourless oil. The ratio of stereomers was
determined by capillary GC analysis (DB5-MS, 0.32 mm i.d. ϫ
30 m, 160Ϫ300°C, 10°C/min), retention time 15.35 min (71%),
15.64 min (29%). Ϫ EI MS; m/z 466, 421, 421, 409, 363, 335, 227,
2933, 2856, 1741, 1647, 1453, 1365, 1238. Ϫ HRMS; C17H29O2
[MHϩ]: calcd. 265.2160; found 265.2178. Ϫ HRMS; C15H25 [MHϩ
Ϫ AcOH]: calcd. 205.1950; found 205.1939.
Ethyl 5,5-Diethoxy-2-(3Ј,3Ј-dimethylallyl)-3-isopropenylpentanoate
(20): A solution of 3 (1.0 g, 3.87 mmol) in THF/HMPA (1:1, 12
mL) was added dropwise under argon to a solution of LiHMDS
(11.6 mL, 11.6 mmol, 1  solution in THF, Ϫ60°C) in THF (6
mL). The reaction mixture was stirred for 45 min at Ϫ60°C, then
a solution of 4-bromo-2-methyl-2-butene (2.2 mL, 19.35 mmol) in
HMPA (6 mL) was added. It was then stirred for 1 h at Ϫ40°C,
warmed to 0°C and quenched with satd. aqueous ammonium chlo-
ride solution (15 mL) at Ϫ20°C. The aqueous phase was extracted
with ether (3 ϫ 60 mL) and the combined organic layers were
washed with water (60 mL), brine (60 mL), dried (MgSO4) and
concentrated under reduced pressure. The crude product was puri-
fied by flash chromatography (AcOEt/cyclohexane, 5:95) to give
1.19 g (94%) of the product 20 as a colourless oil. Ϫ Two isomers:
13C NMR: δ ϭ 175.3 (s), 174.6 (s), 144.8 (s), 143.7 (s), 135.5 (s),
133.4 (s), 121.1 (d), 115.0 (t), 114.0 (t), 101.4 (d), 101.0 (d), 61.4
(t), 61.3 (t), 60.2 (t), 60.1 (t), 59.9 (t), 59.8 (t), 49.9 (d), 49.3 (d),
45.7 (d), 34.6 (t), 33.8 (t), 29.7 (t), 28.6 (t), 25.8 (d), 18.9 (q), 18.1
(q), 18.0 (q), 17.8 (q), 17.7 (q), 15.5 (q), 14.4 (q), 14.3 (q). Ϫ The
ratio of stereomers was determined by capillary GC analysis (DB5-
MS, 0.32 mm i.d. ϫ 30 m, 140Ϫ300°C, 10°C/min), retention time
12.30 min (73%), 12.36 min (27%). Ϫ EI MS; m/z (%): 326 (0.03),
280 (2), 265 (0.5), 234 (14), 161 (18), 139 (15), 125 (19), 103 (100),
75 (77), 69 (49), 55 (18), 47 (69), 43 (28), 41 (42). Ϫ IR (neat): ν˜ ϭ
3080 cmϪ1, 2980, 2940, 1735, 1645.
199, 183, 165, 139, 105, 77, 55, 41. Ϫ IR (neat): ν˜ ϭ 3480 cmϪ1
,
3060, 3040, 2950, 2920, 2890, 2850, 2730, 1730, 1710, 1640, 1580.
Ethyl 2-{2Ј-[(tert-Butyldiphenylsilyl)oxy]ethyl}-5-hydroxy-3-isopro-
penylpentanoate (25): NaBH4 (30 mg, 0.79 mmol) was added to a
solution of the aldehyde 24 (302 mg, 0.65 mmol, 0°C) in EtOH (6
mL). The reaction mixture was stirred for 10 min at 0°C, then 0.5 
HCl (4 mL) and water (4 mL) added. The aqueous phase was ex-
tracted with ether (3 ϫ 10 mL), the combined organic layers were
dried (MgSO4) and concentrated under reduced pressure. The
crude product was purified by flash chromatography (AcOEt/cyclo-
hexane, 50:50) to give 163 mg (53%) of the product 25 as a colour-
1
Ethyl
5,5-Diethoxy-2-(2Ј-hydroxyethyl)-3-isopropenylpentanoate
less oil. Ϫ H NMR: δ ϭ 7.60 (m, 5 H), 7.39 (m, 5 H), 4.90 (br. s,
(22): N-methylmorpholine N-oxide (385 mg, 3.0 mmol) and a solu-
tion of OsO4 (1 mL, 2.5% solution in 2-methyl-2-propanol) was
added to a solution of 20 (1.0 g, 3.0 mmol, 0°C) in acetone/water
1 H), 4.85 (br. s, 1 H), 4.11 (m, 2 H), 3.58 (m, 4 H), 2.64 (dt, 1 H,
J ϭ 11 Hz, J ϭ 4 Hz), 2.46 (dt, 1 H, J ϭ 11 Hz, J ϭ 4 Hz), 1.8Ϫ1.4
(m, 5 H), 1.64 (s, 3 H), 1.22 (t, 3 H, J ϭ 7 Hz), 1.05 (s, 9 H). Ϫ
(9:1, 2.5 mL). This was then stirred for 1 h at 0°C, treated with 13C NMR: δ ϭ 175.8 (s), 144.6 (s), 135.7 (d), 133.9 (s), 129.7 (d),
Na2S2O3 (2.3 g, 14.5 mmol) for 2 h at room temp. and diluted with
dichloromethane (50 mL). The mixture was filtered through Celite,
the solid washed with AcOEt and the combined organic layers
127.7 (d), 115.0 (t), 62.0 (t), 61.4 (t), 60.4 (t), 47.2 (d), 45.5 (d), 33.9
(2 C, t), 27.0 (q), 19.3 (s), 17.9 (q), 14.4 (q). Ϫ GC analysis (DB5-
MS, 0.32 mm i.d. ϫ 30 m, 160Ϫ300°C, 10°C/min), retention time
dried (MgSO4) and concentrated under reduced pressure. NaHCO3 16.87 min. Ϫ EI MS; m/z (%): 366 (20), 365 (69), 287 (4), 251 (5),
1208 Eur. J. Org. Chem. 1999, 1201Ϫ1211

Total Synthesis of (ϩ) and (–) Enantiomers of the Oleander Scale Aspidiotus nerii Sex Pheromone
FULL PAPER
225 (6), 199 (100), 183 (28), 135 (30), 121 (27),105 (41), 91 (34), 77 time 6.77 min. Ϫ EI MS; m/z (%): 249 (1), 208 (2), 180 (2), 165 (1),
(49), 67 (44), 55 (30), 41 (39). Ϫ IR (neat): ν˜ ϭ 3450 cmϪ1, 3050, 140 (8), 126 (8), 125 (8), 111 (18), 82 (69), 81 (40), 67 (100), 55 (15),
2960, 2910, 2860, 1720, 1635.
41 (52). Ϫ IR (neat): ν˜ ϭ 3400 cmϪ1, 3040, 2940, 2900, 1710, 1630.
Ethyl 2-{2Ј-[(tert-Butyldiphenylsilyl)oxy]ethyl}-3-isopropenyl-5-(tos-
Ethyl 2-(3Ј,3Ј-Dimethylallyl)-3-isopropenyl-5-(tosyloxy)pentanoate
yloxy)pentanoate (26): Prepared from 25 by the same procedure as (30): Prepared from 29 by the same procedure as for 6 (70%).
1
for 6 (93%). Colourless oil. Ϫ 1H NMR: δ ϭ 7.77 (d, 2 H, J ϭ
Colourless oil. Ϫ H NMR: δ ϭ 7.75 (d, 2 H, J ϭ 8 Hz), 7.32 (d,
8 Hz), 7.65 (m, 5 H), 7.40 (m, 7 H), 4.83 (br. s, 1 H), 4.69 (br. s, 1 2 H, J ϭ 8 Hz), 4.95 (t, 1 H, J ϭ 7 Hz), 4.82 (br. s, 1 H), 4.70 (br.
H), 4.08 (q, 2 H, J ϭ 7 Hz), 4.05Ϫ3.88 (m, 2 H), 3.59 (m, 2 H), s, 1 H), 4.17Ϫ3.80 (m, 4 H), 2.44 (s, 3 H), 2.40Ϫ2.14 (m, 2 H),
2.60 (m, 1 H), 2.45 (s, 3 H), 2.35 (m, 1 H), 1.71 (m, 3 H), 1.61 (s, 2.14Ϫ2.00 (m, 4 H), 1.63 (s, 3 H), 1.6Ϫ1.7 (m, 2 H), 1.53 (s, 6 H),
3 H), 1.21 (t, 3 H, J ϭ 7 Hz), 1.08 (m, 9 H). Ϫ 13C NMR: δ ϭ 1.22 (t, 3 H, J ϭ 7 Hz). Ϫ 13C NMR: δ ϭ 174.9 (s), 144.7 (s), 142.3
175.2 (s), 144.7 (s), 144.4 (s), 135.6 (d), 133.6 (s), 129.8 (d), 129.7
(s), 138.0 (s), 133.1 (s), 129.8 (d), 128.0 (d), 120.7 (d), 115.9 (t),
(d), 127.9 (d), 127.7 (d), 116.0 (t), 68.6 (t), 61.7 (t), 60.5 (t), 46.3 68.6 (t), 60.4 (t), 49.0 (d), 45.9 (d), 29.76 (t), 29.71 (t), 25.8 (q), 21.7
(d), 45.4 (d), 33.8 (t), 29.6 (t), 26.8 (q), 21.7 (q), 19.1 (s), 17.5 (q), (q), 17.77 (q), 17.63 (q), 14.4 (q).
14.5 (q).
Ethyl trans-1-(3Ј,3Ј-Dimethylallyl)-2-isopropenylcyclobutanecarbox-
Ethyl 2-{2Ј-[(tert-Butyldiphenylsilyl)oxy]ethyl}-5-chloro-3-isopropen-
ylpentanoate (27): A solution of LiHMDS (1 mL, 1 mmol, 1  solu-
tion in THF) was added dropwise under argon to a solution of the
ylate (31): A solution of LiHMDS (1.41 mL, 1.41 mmol, 1  solu-
tion in THF) was added dropwise under argon to a solution of
tosylate 30 (194 mg, 2.05 mmol, Ϫ20°C) in THF/HMPA (3.7
tosylate 26 (189 mg, 0.31 mmol, Ϫ20°C) in THF/HMPA (5:1, 6 mL:0.6 mL). The reaction mixture was stirred for 1 h at 0°C and
mL). The reaction mixture was stirred for 1 h at 0°C and for 1 h for 1 h at room temp., then quenched with satd. aqueous am-
at room temp., then quenched with satd. aqueous ammonium chlo-
monium chloride solution (10 mL) at 0°C. The aqueous phase was
ride solution (10 mL) at 0°C. The aqueous phase was extracted extracted with ether (3 ϫ 15 mL) and the combined organic layers
with ether (3 ϫ 15 mL) and the combined organic layers were were washed with water (10 mL), brine (10 mL), dried (MgSO4)
washed with water (10 mL), brine (10 mL), dried (MgSO4) and
concentrated under reduced pressure. The crude product was puri-
fied by flash chromatography (AcOEt/cyclohexane, 10:90) to give
and concentrated under reduced pressure. The crude product
{diastereoselectivity > 95:5; the ratio of stereomers was determined
by capillary GC analysis [DB5-MS, 0.32 mm i.d.
ϫ 30 m,
120 mg (80%) of the product 27 as a colourless oil. Ϫ Major iso-
mer: H NMR: δ ϭ 7.60 (m, 5 H), 7.39 (m, 5 H), 4.95 (br. s, 1 H), 95%)} was purified by flash chromatography (AcOEt/cyclohexane,
4.88 (br. s, 1 H), 4.13 (q, 2 H, J ϭ 7 Hz), 3.67Ϫ3.20 (m, 4 H), 2.66 5:95) to give 58 mg (50%) of the product 31 as a colourless oil. Ϫ
140Ϫ300°C, 10°C/min), retention time 4.40 min (< 5%), 4.51 (>
1
(m, 1 H), 2.55 (dt, 1 H, J ϭ 11 Hz, J ϭ 3.5 Hz), 1.8Ϫ1.6 (m, 4 H),
1H NMR: δ ϭ 4.98 (t, 1 H, J ϭ 5 Hz), 4.95 (br. s, 1 H), 4.74 (br.
1.62 (s, 3 H), 1.22 (t, 3 H, J ϭ 7 Hz), 1.05 (s, 9 H). Ϫ 13C NMR: s, 1 H), 4.14 (m, 2 H), 3.06 (t, 1 H, J ϭ 9 Hz), 2.40Ϫ1.74 (m, 6 H),
δ ϭ 175.4 (s), 142.6 (s), 135.6 (d), 133,7 (s), 129.7 (d), 127.7 (d), 1.74 (s, 3 H), 1.65 (s, 3 H), 1.60 (s, 3 H), 1.25 (t, 3 H, J ϭ 7 Hz).
116.1 (t), 61.8 (t), 60.5 (t), 47.5 (d), 45.2 (d), 42.8 (t), 33.8 (t), 33.6
(t), 26.9 (q), 19.3 (s), 17.6 (q), 14.4 (q). Ϫ GC analysis (DB5-MS, 60.4 (t), 50.9 (s), 47.9 (d), 28.9 (t), 26.0 (q), 24.1 (t), 22.9 (q), 19.2
0.32 mm i.d. ϫ 30 m, 160Ϫ300°C, 10°C/min), retention time (t), 18.1 (q), 14.3 (q). Ϫ EI MS; m/z (%): 221 (1), 208 (1), 207 (1),
Ϫ
13C NMR: δ ϭ 176.5 (s), 144.2 (s), 133.9 (s), 119.6 (d), 111.6 (t),
16.20 min. Ϫ CI/NH3 MS; m/z (%): 489 (60), 488 (50), 487 (100), 191 (5), 190 (2), 180 (2), 175 (2), 153 (26), 139 (9), 125 (32), 111
429 (20), 409 (25), 371 (15). Ϫ IR (neat): ν˜ ϭ 3070 cmϪ1, 3020, (18), 107 (39), 95 (96), 94 (58), 93 (100), 81 (32), 79 (67), 77 (40),
2960, 2910, 2860, 1725, 1640.
67 (45), 55 (41), 55 (67), 53 (41), 43 (37), 41 (95).
Ethyl 2-(3Ј,3Ј-Dimethylallyl)-3-isopropenyl-5-oxopentanoate (28):
trans-1-(3Ј,3Ј-Dimethylallyl)-2-isopropenylcyclobutanemethanol
(32): A solution of ester 31 (195 mg, 0.82 mmol) in Et2O (6 mL)
Prepared from 20 by the same procedure as for 4 (60%). Colourless
1
oil. Ϫ H NMR: δ ϭ 9.54 (dd, 1 H, J ϭ 3 Hz, J ϭ 2 Hz), 4.99 (tt, was added under argon to a suspension of LiAlH4 (40 mg,
1 H, J ϭ 7.5 Hz, J ϭ 1.5 Hz), 4.87 (t, 1 H, J ϭ 1.5 Hz), 4.85 (br. 1.0 mmol, 0°C) in Et2O (6 mL). The reaction mixture was stirred
s, 1 H), 4.08 (m, 2 H), 2.92 (dt, 1 H, J ϭ 10 Hz, J ϭ 5 Hz),
for 1 h at 0°C, then quenched at 0°C with water (0.04 mL), 15%
2.50Ϫ2.13 (m, 4 H), 1.63 (s, 6 H), 1.54 (s, 3 H), 1.21 (t, 3 H, J ϭ NaOH (0.12 mL), water (0.04 mL) and stirred for 30 min at room
7 Hz). Ϫ 13C NMR: δ ϭ 201.3 (s), 174.6 (s), 143.3 (s), 133.9 (s), temp. The resultant mixture was filtered, the solid washed with
120.4 (d), 115.0 (t), 60.5 (t), 48.5 (d), 45.0 (t), 43.8 (d), 29.4 (t), 25.8 and the combined organic layers were concentrated under reduced
(q), 18.6 (q), 17.7 (2 C, q), 14.3 (q). Ϫ Capillary GC analysis (BPX-
5, 0.32 mm i.d. ϫ 30 m, 120Ϫ300°C, 10°C/min), retention time next step without further purification. Ϫ H NMR: δ ϭ 5.13 (td,
7.89 min. Ϫ EI MS; m/z (%): 237 (1), 234 (1), 209 (3), 208 (9), 206 1 H, J ϭ 7 Hz, J ϭ 1 Hz), 4.89 (br. s, 1 H), 4.71 (br. s, 1 H), 3.53
pressure to give the crude product 32 (150 mg, 94%) used in the
1
(8), 191 (1), 179 (5), 169 (9), 155 (9), 139 (17), 135 (14), 111 (15), (AB, 2 H, J ϭ 11 Hz), 2.81 (t, 1 H, J ϭ 7 Hz), 2.20Ϫ1.50 (m, 6
109 (40), 107 (11), 95 (16), 93 (34), 91 (12), 81 (79), 80 (22), 69 (52), H), 1.71 (s, 3 H), 1.69 (s, 3 H), 1.63 (s, 3 H). Ϫ 13C NMR: δ ϭ
67 (23), 55 (21), 53 (19), 43 (29), 41 (100). Ϫ IR (neat): ν˜ ϭ 3070 145.3 (s), 133.7 (s), 120.5 (d), 110.4 (t), 69.8 (t), 47.7 (s), 46.5 (d),
cmϪ1, 2970, 2920, 2720, 1725, 1640.
28.7 (t), 26.1 (q), 23.7 (q), 23.4 (t), 19.1 (t), 18.0 (q). Ϫ GC analysis
(DB5-MS, 0.32 mm i.d. ϫ 30 m, 120Ϫ300°C, 10°C/min), retention
time 5.92 min. Ϫ EI MS; m/z (%): 179 (1), 163 (6), 147 (1), 138 (1),
133 (4), 125 (4), 123 (4), 111 (5), 108 (26), 107 (20), 105 (10), 97
(6), 95 (29), 93 (98), 91 (21), 81 (16), 79 (24), 71 (16), 69 (53), 67
(37), 65 (8), 57 (19), 55 (41), 53 (27), 43 (39), 41 (100).
Ethyl
2-(3Ј,3Ј-Dimethylallyl)-5-hydroxy-3-isopropenylpentanoate
(29): Prepared from 28 by the same procedure as for 5 (80%).
1
Colourless oil. Ϫ H NMR: δ ϭ 5.00 (t, 1 H, J ϭ 7 Hz), 4.88 (br.
s, 1 H), 4.86 (br. s, 1 H), 4.12 (m, 2 H), 3.52 (m, 2 H), 2.46 (dt, 1
H, J ϭ 11 Hz, J ϭ 4 Hz), 2.33 (ddd, 1 H, J ϭ 11 Hz, J ϭ 9 Hz,
J ϭ 5.5 Hz), 2.10 (m, 2 H), 1.64 (s, 3 H), 1.62 (s, 3 H), 1.54 (s, 3
trans-1-(3Ј,3Ј-Dimethylallyl)-2-isopropenylcyclobutanemethyl
p-
H), 1.23 (t, 3 H, J ϭ 7 Hz). Ϫ 13C NMR: δ ϭ 175.6 (s), 144.3 (s), Toluenesulfonate (33): 4-DMAP (117 mg, 0.96 mmol) and TsCl
140.9 (s), 133.5 (s), 120.9 (d), 115.0 (t), 61.2 (t), 60.3 (t), 49.2 (d), (95 mg, 0.66 mmol) were added to a solution of crude alcohol 32
46.8 (d), 33.8 (t), 29.8 (t), 25.8 (q), 17.7 (q), 14.4 (q). Ϫ GC analysis
(93 mg, 0.47 mmol, 0°C) in dichloromethane (1 mL) . The reaction
(DB5-MS, 0.32 mm i.d. ϫ 30 m, 140Ϫ300°C, 10°C/min), retention mixture was stirred for 36 h at 0°C under argon, poured into water
Eur. J. Org. Chem. 1999, 1201Ϫ1211
1209

F.-D. Boyer, P.-H. Ducrot
FULL PAPER
and ice (5 mL). The aqueous phase was extracted with ether (3 ϫ 5
mL), the combined organic layers were washed with satd. aqueous
copper(II) sulfate solution (3 ϫ 5 mL), water (5 mL), brine (10
mL), dried (MgSO4) and concentrated under reduced pressure. The
crude product 33 (160 mg, 100%) was used in the next step without
further purification. Ϫ 1H NMR: δ ϭ 7.79 (d, 2 H, J ϭ 8 Hz), 7.35
(d, 2 H, J ϭ 8 Hz), 4.88 (br. s, 1 H), 4.86 (m, 1 H), 4.68 (br. s, 1
H), 3.86 (AB, 2 H, J ϭ 9.5 Hz), 2.77 (br. t, 1 H, J ϭ 9 Hz), 2.45
(s, 3 H), 2.2Ϫ1.5 (m, 6 H), 1.62 (s, 3 H), 1.60 (s, 3 H), 1.55 (s, 3
H). Ϫ 13C NMR: δ ϭ 144.7 (s), 144.3 (s), 134.5 (s), 133.1 (s), 129.8
(d), 128.0 (d), 118.8 (d), 109.9 (t), 75.3 (t), 46.4 (d), 45.3 (s), 27.8
(t), 26.0 (q), 23.5 (q), 23.4 (t), 21.7 (q), 19.0 (t), 18.1 (q).
H, J ϭ 7 Hz). Ϫ 13C NMR: δ ϭ 174.4 (s), 144.7 (s), 142.2 (s), 135.0
(d), 133.3 (s), 129.8 (d), 127.9 (d), 116.8 (t), 116.0 (t), 68.5 (t), 60.4
(t), 48.5 (d), 45.9 (d), 35.2 (t), 29.8 (t), 21.6 (q), 17.6 (q), 14.4 (q).
Ethyl trans-1-Allyl-2-isopropenylcyclobutanecarboxylate (37): Pre-
pared from 36 by the same procedure as for 15 (52%), colourless
oil. Diastereoselectivity > 95:5 Ϫ 1H NMR: δ ϭ 5.66 (m, 1 H),
5.07Ϫ4.94 (m, 3 H), 4.74 (s, 1 H), 4.15 (q, 2 H, J ϭ 7 Hz), 3.09 (t,
1 H, J ϭ 9 Hz), 2.41Ϫ2.34 (m, 2 H), 2.21 (ddd, 1 H, J ϭ 14 Hz,
J ϭ 6.5 Hz, J ϭ 1 Hz), 2.05 (m, 1 H), 1.85 (m, 1 H), 1.73 (s, 3 H),
1.67 (m, 1 H), 1.27 (t, 3 H, J ϭ 7 Hz). Ϫ 13C NMR: δ ϭ 176.2 (s),
143.8 (s), 134.1 (d), 117.7 (t), 111.8 (t), 60.5 (t), 50.3 (s), 47.9 (d),
34.9 (t), 23.8 (t), 19.0 (t), 22.9 (q), 14.4 (q). Ϫ The ratio of stereo-
mers was determined by capillary GC analysis of the crude product
trans-1-(3Ј,3Ј-Dimethylallyl)-2-isopropenylcyclobutaneacetonitrile
(34): NaCN (34 mg, 0.7 mmol) was added to a solution of crude (DB5-MS, 0.32 mm i.d. ϫ 30 m, 140Ϫ300°C, 10°C/min), retention
tosylate 33 (160 mg, 0.47 mmol) in HMPA (1 mL) with 3 drops of
water. The reaction mixture was warmed at 60°C overnight, cooled
to room temp., diluted with AcOEt/cyclohexane (5:95, 40 mL),
time 3.28 min (< 5%), 3.43 (> 95%). Ϫ EI MS; m/z (%): 193 (0.5),
177 (11), 165 (1), 147 (6), 134 (6), 121 (51), 109 (40), 108 (12), 107
(41), 95 (38), 93 (52), 91 (23), 82 (37), 81 (36), 79 (43), 70 (43), 69
washed with water (10 mL), brine (2 ϫ 10 mL), dried (MgSO4) (60), 68 (96), 67 (100), 55 (67), 53 (37), 43 (33), 41 (88). Ϫ IR
and concentrated under reduced pressure. The crude product was
purified by flash chromatography (AcOEt/cyclohexane, 5:95) to
give 73 mg (76%) of the product 34 as a colourless oil. Ϫ 1H NMR:
δ ϭ 5.03 (br. t, 1 H, J ϭ 5 Hz), 4.92 (br. s, 1 H), 4.73 (br. s, 1 H),
2.91 (br. t, 1 H, J ϭ 8 Hz), 2.43 (AB, 2 H, J ϭ 17 Hz), 2.25 (dd, 1
H, J ϭ 6.5 Hz, J ϭ 15 Hz), 2.10Ϫ1.75 (m, 5 H), 1.73, 1.71 (2s, 6
H), 1.62 (s, 3 H). Ϫ 13C NMR: δ ϭ 143.6 (s), 135.4 (s), 118.8 (s),
118.7 (d), 111.4 (t), 48.6 (d), 43.7 (s), 30.6 (t), 28.3 (t), 26.3 (t), 26.1
(q), 23.5 (q), 19.2 (t), 18.1 (q). Ϫ GC analysis (DB5-MS, 0.32 mm
i.d. ϫ 30 m, 140Ϫ300°C, 10°C/min), retention time 4.95 min. Ϫ EI
MS; m/z (%): 203 (3), 188 (3), 160 (7), 148 (3), 134 (21), 120 (40),
107 (14), 105 (14), 95 (60), 93 (60), 69 (62), 68 (100), 67 (70), 53
(40), 41 (80). Ϫ IR (neat): ν˜ ϭ 3080 cmϪ1, 2916, 2848, 2244, 1646,
1462, 1377.
(CCl4): ν˜ ϭ 3080 cmϪ1, 2927, 2855, 1726, 1641.
trans-2-(1Ј-Oxoethyl)-1-(4Ј-oxopent-1Ј-yl)cyclobutaneacetonitrile
(38): 4-Methylmorpholine N-oxide (344 mg, 2.9 mmol) and a solu-
tion of OsO4 (0.75 mL, 2.5% in 2-methyl-2-propanol) were added
dropwise under argon to
a solution of nitrile 18 (290 mg,
1.33 mmol) in an acetone/water mixture (9:1). The reaction mixture
was stirred at room temp. for 15 h, then Na2S2O3 (1.6 g,
10.1 mmol) was added . The resultant mixture was stirred for 1 h,
diluted with CH2Cl2 (20 mL) filtered through Celite and concen-
trated under reduced pressure to give the crude product as an or-
ange oil. To a solution of this crude product in a mixture of MeOH/
water (1:1, 12 mL) was added NaHCO3 (480 mg) and NaIO4
(1.25 g, 5.85 mmol). The resultant white suspension was stirred for
18 h at room temp. and concentrated under reduced pressure. The
residue was diluted with CH2Cl2 (40 mL) and the organic layer
Ethyl 2-Allyl-5,5-diethoxy-3-isopropenylpentanoate (35): A solution
of 3 (410 mg, 1.57 mmol) in THF/HMPA (1:1, 4 mL) was added washed with water (10 mL), brine (10 mL) dried (MgSO4) and
dropwise under argon to a solution of LiHMDS (4.7 mL, concentrated under reduced pressure. The crude product was puri-
4.7 mmol, 1  solution in THF, Ϫ60°C) in THF (2 mL). The reac- fied by flash chromatography (AcOEt/cyclohexane, 40:60) to give
tion mixture was stirred for 1 h at Ϫ60°C, then added a solution 190 mg (64%) of the product 38 as a colourless oil. (1S, 2R)-38
20
of freshly distilled allyl bromide (2 mL, 23.5 mmol) in HMPA (2 from (1S, 2S)-18: [α]D ϭ Ϫ33.7 (c ϭ 2.1, CH2Cl2), (1R, 2S)-38
20
1
mL), warmed to room temp. and quenched with satd. aqueous am-
from (1R, 2R)-18: [α]D ϭ ϩ30.3 (c ϭ 2.7, CH2Cl2). Ϫ H NMR:
monium chloride solution (15 mL) at Ϫ20°C. The aqueous phase δ ϭ 3.27 (t, 1 H, J ϭ 8 Hz), 2.61 (AB, 2 H, J ϭ 17 Hz), 2.5Ϫ1.4
was extracted with ether (3 ϫ 20 mL) and the combined organic
layers were washed with water (20 mL), brine (20 mL), dried
(MgSO4) and concentrated under reduced pressure. The crude
product was purified by flash chromatography (AcOEt/cyclohex-
(m, 10 H), 2.15, 2.12 (2s, 6 H). Ϫ 13C NMR: δ ϭ 207.9 (s), 207.4
(s), 118.0 (s), 53.1 (d), 43.9 (s), 43.3 (t), 32.5 (t), 30.9 (q), 30.1 (q),
28.1 (t), 27.0 (t), 17.4 (t), 16.7 (t). Ϫ Capillary GC analysis (BPX-
70-MS, 0.32 mm i.d. ϫ 30 m, 125Ϫ270°C, 10°C/min), retention
time 14.13 min. Ϫ EI MS; m/z (%): 178 (4), 164 (4), 151 (12), 136
ane, 5:95) to give 447 mg (90%) of the product 35 as a colourless
1
oil. Ϫ Major isomer: H NMR: δ ϭ 5.69 (m, 1 H), 5.04Ϫ4.75 (m, (5), 133 (7), 120 (5), 108 (30), 94 (12), 91 (6), 79 (8), 71 (77), 58
3 H), 4.38 (dd, 1 H, J ϭ 7.5 Hz, J ϭ 4 Hz), 4.13 (m, 2 H), 3.60 (m, (38), 55 (14), 43 (100). Ϫ IR (CCl4): ν˜ ϭ 2958 cmϪ1, 1719, 1708,
2 H), 3.44 (m, 2 H), 2.51Ϫ2.13 (m, 5 H), 1.63 (m, 1 H), 1.62 (s, 3 1359, 1260, 1163, 1097.
H), 1.25Ϫ1.15 (m, 9 H). Ϫ 13C NMR: δ ϭ 174.9 (s), 143.5 (s),
135.5 (d), 116.7 (t), 115.3 (t), 101.0 (d), 61.5 (t), 60.4 (t), 60.0 (t),
cis-2-(1Ј-Oxoethyl)-1-(4Ј-oxopent-1Ј-yl)cyclobutaneacetonitrile (39):
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.43 mL, 2.57 mmol) was ad-
48.8 (d), 45.8 (d), 35.4 (t), 34.7 (t), 18.2 (q), 15.5 (2 C, q), 14.4 (q).
ded to a solution of ketone 38 (190 mg, 0.85 mmol) in benzene (9
Ϫ The ratio of stereomers was determined by capillary GC analysis
mL). The resultant mixture was stirred overnight at 80°C then
(DB5-MS, 0.32 mm i.d. ϫ 30 m, 140Ϫ300°C, 10°C/min), retention
cooled to room temp., and diluted with Et2O (30 mL). The mixture
was washed with HCl (0.5 , 10 mL), brine (10 mL), dried
time 7.40 min (73%), 7.56 min (27%). Ϫ EI MS; m/z (%): 269 (1),
253 (2), 180 (4), 133 (30), 116 (28), 103 (100), 89 (28), 75 (88), 55
(15), 47 (68), 43 (30), 41 (30).
(MgSO4) and concentrated under reduced pressure to give 190 mg
of unseparable 39/38 (60:40) as crude product. Ϫ 39: 1H NMR:
2-Allyl-3-isopropenyl-5-(tosyloxy)pentanoate (36): Prepared from 35
δ ϭ 3.15 (t, 1 H, J ϭ 9 Hz), 2.59 (AB, 2 H, J ϭ 17 Hz), 2.5Ϫ1.4
by the same procedure as for 14 (76%), colourless oil. Ϫ Major (m, 10 H), 2.15, 2.14 (2s, 6 H). Ϫ 13C NMR: δ ϭ 208.5 (s), 208.2
1
isomer: H NMR: δ ϭ 7.74 (d, 2 H, J ϭ 8 Hz), 7.31 (d, 2 H, J ϭ
(s), 118.2 (s), 51.8 (d), 44.4 (s), 43.2 (t), 39.5 (t), 30.2 (2 C, q), 28.3
8 Hz), 5.66 (m, 1 H), 4.97 (m, 2 H), 4.81 (br. s, 1 H), 4.68 (br. s, 1 (t), 22.7 (t), 18.3 (t), 18.2 (t). Capillary GC analysis (BPX-70-MS,
H), 4.13Ϫ3.81 (m, 4 H), 2.43 (s, 3 H), 2.37Ϫ2.14 (m, 2 H), 0.32 mm i.d. ϫ 30 m, 125Ϫ270°C, 10°C/min), retention time
2.14Ϫ2.11 (m, 2 H), 1.67Ϫ1.60 (m, 2 H), 1.51 (s, 3 H), 1.22 (t, 3 13.84 min. Ϫ EI MS; m/z (%): 203 (1), 178 (7), 164 (5), 151 (10),
1210
Eur. J. Org. Chem. 1999, 1201Ϫ1211

Total Synthesis of (ϩ) and (–) Enantiomers of the Oleander Scale Aspidiotus nerii Sex Pheromone
FULL PAPER
136 (7), 133 (4), 120 (5), 108 (15), 94 (10), 91 (5), 79 (8), 71 (60), (35), 81 (45), 79 (30 ), 77 (13), 69 (66), 68 (100), 67 (70), 55 (38),
58 (30), 55 (12), 43 (100).
53 (30), 43 (11), 41 (71), 40 (15). Ϫ IR (CCl4): ν˜ ϭ 3632 cmϪ1
,
3078, 2931, 2853, 1645, 1449, 1373, 1226, 1042.
cis-2-Isopropenyl-1-(4Ј-methyl-4Ј-penten-1Ј-yl)cyclobutane-
acetonitrile (40): n-Butyllithium (2.1 mL, 3.36 mmol, 1.6  solution
in hexane) was added dropwise under argon to a solution of meth-
yltriphenylphosphonium bromide (1.2 g, 3.4 mmol, Ϫ60°C) in
THF (17 mL). The ylide solution was stirred for 1 h to 0°C. A
solution of a mixture of the crude diastereomers 38 and 39 (190 mg,
0.85 mmol) in THF (17 mL) was added to the ylide solution
(Ϫ60°C). The resultant reaction mixture was warmed at room
temp. overnight and quenched with water. The aqueous phase was
extracted with cyclohexane (3 ϫ 20 mL). The combined organic
layers were washed with brine (10 mL), dried (MgSO4) and concen-
trated under reduced pressure. The residue was dissolved in pentane
(50 mL) and stirred for 1 h at room temp. The solution was filtered
and the solvent removed under reduced pressure. The residue was
purified by flash chromatography (AcOEt/cyclohexane, 5:95) to
give 140 mg (75%) of a mixture of unseparable diastereomers 18
cis-2-Isopropenyl-1-(4Ј-methyl-4Ј-penten-1Ј-yl)cyclobutaneethanol
Acetate (2): A solution of alcohol 41 (12 mg, 0.54 mmol) in pyri-
dine (0.3 mL) with Ac2O (0.1 mL) was stirred overnight at room
temp. The reaction mixture was concentrated under reduced press-
ure and the residue purified by flash chromatography (AcOEt/
cyclohexane, 10:90) to give 9.3 mg (70%) of 2 as colourless oil. (1S,
20
2R)-2 from (1S, 2R)-41: [α]D ϭ ϩ2.4 (c ϭ 0.9, n-hexane), (1R,
20
2S)-2 from (1R, 2S)-41: [α]D ϭ Ϫ2.5 (c ϭ 1.1, n-hexane). 1H-,
13C-NMR spectra and mass data are identical to those of the natu-
ral sample.[2]
Acknowledgments
The authors wish to thank C. Malosse and L. Kerhoas (I. N. R.
A. Versailles) for mass spectra and GC analysis and P. Toullec for
technical assistance.
1
and 40 as a colourless oil. Ϫ 40: H NMR: δ ϭ 4.98 (br. s, 1 H),
4.76 (br. s, 1 H), 4.74 (br. s, 1 H), 4.72 (1 br. s, 1 H), 2.75 (br. t, 1
H, J ϭ 7 Hz), 2.37 (AB, 2 H, J ϭ 17 Hz), 2.10Ϫ1.26 (m, 10 H),
1.72, 1.71 (2s, 6 H). Ϫ 13C NMR: δ ϭ 145.4 (s), 143.9 (s), 118.9
(s), 111.9 (t), 110.4 (t), 48.3 (d), 44.5 (s), 39.9 (t), 38.1 (t), 27.5 (t),
23.9 (q), 22.6 (t), 22.5 (q), 22.4 (t), 18.9 (t). Ϫ GC analysis (BPX-70-
MS, 0.32 mm i.d. ϫ 30 m, 125Ϫ275°C, 10°C/min), retention time
5.42 min. Ϫ EI MS; m/z (%): 217 (0.1), 216 (1), 202 (3), 177 (5),
161 (1), 146 (2), 134 (3), 121 (10), 109 (15), 93 (12), 79 (14), 69
(15), 68 (100), 67 (50), 56 (13), 53 (17), 41 (41).
[1]
´
J. W. Beardsley, R. H. Gonzalez, Annu. Rev. Entomol. 1975, 20,
47Ϫ73 .
[2]
J. Einhorn, A. Guerrero, P. H. Ducrot, F. D. Boyer, M. Giesel-
mann, W. Roelofs, Proc. Natl. Acad. Sci. USA 1998, 95,
9867Ϫ9872.
[3]
[4]
F. D. Boyer, P. H. Ducrot, C. R. Acad. Sci., Sect. IIc 1999,
29Ϫ33 .
D. Bellus, B. Ernst, Angew. Chem. Int. Ed. Eng. 1988, 27,
797Ϫ827.
[5]
[6]
[7]
W. Oppolzer, Acc. Chem. Res. 1982, 15, 135Ϫ141.
B. M. Trost, Top. Curr. Chem. 1986; 133, 3Ϫ82.
cis-2-Isopropenyl-1-(4Ј-methyl-4Ј-penten-1Ј-yl)cyclobutaneethanol
(41): Diisobutylaluminium hydride (0.425 mL, 0.425 mmol, 1 
solution in toluene) was added dropwise under argon to a solution
of diastereomers 18 and 40 (40 mg, 0.18 mmol, Ϫ20°C) in CH2Cl2
(1.6 mL) The reaction mixture was stirred for 2 h at Ϫ20°C, then
water (0.3 mL) and 5% H2SO4 (0.9 mL) were added. The mixture
was stirred for 1 h at 0°C, the aqueous phase was separated and
extracted with Et2O (2 ϫ 25 mL). The combined organic layers
were washed with satd. aqueous sodium bicarbonate solution (10
mL), brine (10 mL), dried (MgSO4) and concentrated under re-
duced pressure to give a mixture of aldehydes used in the next step
without further purification. NaBH4 (15 mg, 0.39 mmol) was ad-
ded to a solution of these aldehydes in EtOH (1.5 mL, 0°C) The
reaction mixture was stirred for 15 min at 0°C and quenched with
9 drops of acetone. The resultant solution was stirred for 30 min at
room temp. and concentrated under reduced pressure. The residue
was purified by flash chromatography (AcOEt/cyclohexane, 10:90)
to give 13 mg (32%) of 41 and 4 mg of 19 (10%) as colourless oils.
`
A. F. Thomas,Y. Bessiere, The Synthesis of Monoterpenes,
1980Ϫ1986 in The Total Synthesis of Natural Products (Ed.: J.
ApSimon), John Wiley & Sons, New York, 1988, vol. 7, pp.
328Ϫ336.
[8]
[9]
S. J. Bloor, Tetrahedron Lett. 1993, 34, 5617Ϫ5620.
S. F. R. Hinkley, N. B. Perry, R. T. Weavers, Tetrahedron Lett.
1994, 35, 3775Ϫ3776.
[10]
[11]
K. Mori, K. Fukamatsu, Liebigs Ann. Chem. 1992, 489Ϫ493.
K. Mori, The Synthesis of Insect Pheromones, 1979Ϫ1989 in
The Total Synthesis of Natural Products (Ed.: J. ApSimon), John
Wiley & Sons, New York, 1992, vol. 9, pp. 303Ϫ334.
[12]
´
W. Roelofs, M. Gieselmann, A. Carde, H. Tashiro, D. S. Mo-
reno, C. A. Hennick, R. J. Anderson, J. Chem. Ecol. 1978, 4,
211Ϫ224.
[13]
[14]
K. Tanida, K. Mori, Nippon Kagaku Kaishi (J. Chem. Soc.
Jpn.) 1981, 635Ϫ637.
D. Kim, Y. K. Lee, Y. M. Jang, I. O. Kim, W. P. Sang, J. Chem.
Soc., Perkin Trans. 1 1990, 3221Ϫ3224.
[15]
[16]
D. Kim, Y. K. Lee, Tetrahedron Lett. 1991, 47, 6885Ϫ6886.
D. Kim, Y. S. Kwak, K. J. Shin, Tetrahedron Lett. 1994, 49,
9211Ϫ9212.
[17]
1
P. H. Mazzocchi, P. Wilson, F. Khachik, L. Klinger, S. Minami-
kawa, J. Org. Chem. 1983, 48, 2981Ϫ2989.
E. A. Mash, J. A. Fryling, J. Org. Chem. 1991, 56, 1094Ϫ1098.
M. J. Gieselmann, Armored Scale Insects; their Biology Natural
Enemies and Control in World Crop Pests, Elsevier, Amsterdam,
New York, 1990, vol. B (Ed.: D. Rosen), pp. 225Ϫ231.
B. S. Fletcher, T. E. Bellas, in CRC Handbook of Natural Pesti-
cides, 1988, vol. IV-B, pp. 207Ϫ215.
Ϫ 41: H NMR: δ ϭ 4.85 (br. s, 1 H), 4.69 (br. s, 2 H), 4.66 (br. s,
1 H), 3.74 (m, 2 H), 2.67 (br. t, 1 H, J ϭ 9 Hz), 2.05Ϫ1.25 (m, 12
H), 1.71 (s, 6 H). Ϫ 13C NMR: δ ϭ 146.2 (s), 145.4 (s), 110.4 (t),
109.8 (t), 60.1 (t), 49.5 (d), 44.4 (s), 42.7 (t), 38.8 (t), 33.0 (t), 28.1
(t), 24.0 (q), 22.6 (q), 21.9 (t), 19.8 (t). Ϫ Capillary GC analysis
(DB5-MS, 0.32 mm i.d. ϫ 30 m, 150Ϫ225°C, 10°C/min), retention
time 6.31 min. Ϫ EI MS; m/z (%): 208 (1), 191 (1), 177 (5), 149 (3),
139 (22), 135 (5), 121 (20), 119 (16), 109 (16), 107 (18), 95 (23), 93
[18]
[19]
[20]
Received November 16, 1998
[O98515]
Eur. J. Org. Chem. 1999, 1201Ϫ1211
1211