Synthesis and Biological Activity of Point-Fluorinated Pheromone Analogues of Eldana saccharina

Article abstract of DOI:10.1002/ejoc.200300541

Substitution of fluorine atoms on an organic molecule makes it possible to modify the molecular orbital and electron density of the surface without changing its molecular shape. Point-fluorinated analogues of the sex pheromone of the male African sugarcane borer were synthesized in optically active forms and their pheromone activities were investigated using an EAG test. The EAG activity of these point-fluorinated pheromone analogues indicates that the point of fluorination has a critical influence on the pheromone activity. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300541

FULL PAPER
Synthesis and Biological Activity of Point-Fluorinated Pheromone Analogues
of Eldana saccharina
Toshiyuki Itoh,*[a] Kazutoshi Kudo,[b] Kazuhisa Yokota,[b] Naoko Tanaka,[b]
Shuichi Hayase,[a] and Michel Renou*[c]
Keywords: Asymmetric synthesis / Bioorganic chemistry / Fluorine / Pheromones / Radical reaction
Substitution of fluorine atoms on an organic molecule makes
it possible to modify the molecular orbital and electron den-
ated using an EAG test. The EAG activity of these point-flu-
orinated pheromone analogues indicates that the point of flu-
sity of the surface without changing its molecular shape. orination has a critical influence on the pheromone activity.
Point-fluorinated analogues of the sex pheromone of the
male African sugarcane borer were synthesized in optically
active forms and their pheromone activities were investig-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
Therefore, we assumed that 2,2-difluoroeldanolides 2 would
lose their pheromone activity, because α,α-difluoro-γ-lac-
tone was believed to correspond to a cyclic carbonate rather
than to the γ-lactone in vivo.[1] An electroantennogram
(EAG) investigation,[10,11] however, of these pheromone
analogues 2 revealed that both the (ϩ)-2 and (Ϫ)-2 enanti-
omers were as active as the natural eldanolide (ϩ)-1 toward
the insect olfactory receptors.[5] The binding property of a
pheromone molecule with a receptor protein has been dis-
cussed based on its size and electronic interaction with a
specific part of the protein and has been discussed from
the standpoint of hydrogen bonding or coulomb energy; the
docking of an agonist at a receptor site has been evaluated
in terms of, for example, steric repulsion, van der Waals
attraction, electrostatic forces, hydrogen bonds, and metal
complexation.[2,12] Schlosser and co-workers were the first
to synthesize a fluorinated analogue of an insect phero-
mone.[4] They carefully investigated the fluorine-modulated
bioactivity in olfactory response and concluded that it can
be rationalized without steric factors.[3] The origin, how-
ever, of molecular recognition of the olfactory molecule on
the receptor protein is still obscure. Mori established that
there exist many kinds of relationships between the stereo-
chemistry of pheromones and their bioactivity.[13] He
showed that there are at least ten categories of
stereochemistryϪpheromone activity relationships.[13] Al-
though it has been pointed out that this complex relation-
ship may be responsible for the inhibitory action of the
antipode toward a pheromone-catabolizing enzyme,[9a] no
answer to this matter has been proposed so far from the
standpoint of molecular recognition on the pheromone re-
ceptor protein. An electrostatic potential map of natural el-
danolide (ϩ)-1 and 2,2-difluoroeldanolide 2 indicates that
Partly fluorinating analogues of biologically important
compounds causes distinctive modifications in the activities
of these compounds.[1Ϫ3] Fluorine atoms closely mimic the
steric requirements of hydrogen atoms at enzyme receptor
sites, but their strong electronegativity significantly alters
the reactivity of neighboring centers. In addition, fluorine
substitution increases lipid solubility, and enhances the
rates of absorption and transport of the fluorinated deriva-
tives. Therefore, fluorinated derivatives have been a subject
of common interest to many groups, particularly in the field
of pheromone chemistry, because of these special features
of the fluorine atom.[2Ϫ4] Recently, we reported the syn-
thesis of both enantiomers of α ,α-difluorinated analogues
of eldanolide (ϩ)-1,[5,6] which is a sex pheromone of the
male African sugarcane borer, Eldana saccharina,[7] using
a radical cyclization protocol.[5,6,8] It has been shown that
substitutions in the polar group of lepidoptera pheromone
molecules result in reduced recognition by the olfactory re-
ceptors[9] and produce potent inhibitors of the pheromone-
catabolizing enzymes present in the olfactory tissues.[10]
[a]
Department of Materials Science, Faculty of Engineering,
Tottori University,
4Ϫ101 Koyama-minami, Tottori 680Ϫ8552, Japan
Fax: (internat.) ϩ 81-857-31-5259
E-mail: titoh@chem.tottori-u.ac.jp
[b]
Department of Chemistry, Faculty of Education, Okayama
University,
700Ϫ8530, Japan
[c]
NRA, Unite de Phytopharmacie et Mediateurs Chimiques,
Route de Saint Cyr, 78026 Versailles, France
Fax: (internat.) ϩ 33-130-83-3119
E-mail: renou@versailles.inra.fr
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
406
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300541
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Synthesis and Biological Activity of Point-Fluorinated Pheromone Analogues
these isomers look completely dissimilar (Figure 1), while
FULL PAPER
Results and Discussion
the results of computational chemistry suggest that the
shape of the two molecules are quite similar (Figure 1).[15]
Scheme 1 depicts the results of the retrosynthetic analysis
of fluoroeldanolide, (ϩ)-3, from which two key points for
the synthesis were suggested: the first is the synthesis of (S)-
4,4,5-trifluoro-6-methylhepta-1,5-dien-3-ol [(ϩ)-7] in op-
tically pure form and the second is the construction of the
γ-lactone moiety. We planned to synthesize trifluorinated
allylic alcohol 7 by [2,3]-Wittig rearrangement of 1,1,2-tri-
fluoroallylic ether 6 and optical resolution using subsequent
lipase-catalyzed enantioselective reaction.[16Ϫ18] For the se-
cond key reaction to construct the γ-lactone moiety, we em-
ployed our original methodology of intramolecular radical
cyclization.[8]
Synthesis of the racemic alcohol 7 was accomplished by
[2,3]-Wittig rearrangement of the 1,1,2-trifluoroallylic ether
6; allylic ether 6 was treated with lithium tetramethylpiperi-
dine (LTMP) in tetrahydrofuran (THF) at Ϫ78 °C and the
mixture was then warmed to 0 °C with stirring for over
14 h. Racemic 4,4,5-trifluoro-6-methylhepta-1,5-dien-3-ol
[(Ϯ)-7] was obtained in 62% yield.[16,18] Alcohol (Ϯ)-7 was
next converted into the corresponding acetate (Ϯ)-8, which
was subjected to lipase-catalyzed hydrolysis.[16,18] The en-
antiomeric excess of the alcohol produced, (R)-7, was deter-
mined by capillary GC analysis using a chiral-phase column
(Chiraldex G-Ta) as its acetate 8 and its absolute configura-
tion was determined by the modified Mosher method pro-
Figure 1. Electrostatic potential maps of eldanolide and fluorinated
analogues by MO (PM3) calculations
Modification of the electron spin density at a specific
part of a molecule is expected to occur by introduction of
a fluorine atom instead of a hydrogen atom, as is shown in
Figure 1. To gain more detailed insight into the molecular
recognition of a pheromone molecule on the receptor pro-
tein, 5,5,6-trifluoroeldanolide [(ϩ)-3 and (Ϫ)-3] and
2,2,5,5,6-pentafluoroeldanolide [(ϩ)-4 and (Ϫ)-4] were
chosen as the synthetic targets for the present study (Fig-
ure 1). These fluorinated-analogues 3 and 4 have a different
pattern of electron spin density on their molecular surface
from that of natural eldanolide 1 and 2,2-difluoroeldanolide
2. Here, we report the full details of the synthesis of the
partly fluorinated eldanolides 3 and 4[8] in optically active
forms, and the results of EAG tests of these novel phero-
mone analogues.
Scheme 2. Preparation of optically active 4,4,5-trifluoro-6-meth-
ylhepta-1,4-dien-3-ol
Scheme 1. Retrosynthetic analysis of (ϩ)-4 (pentafluoroeldanolide)
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T. Itoh, K. Kudo, K. Yokota, N. Tanaka, S. Hayase, M. Renou
FULL PAPER
posed by Kusumi and Ohtani.[19] Thus, both enantiomers
5,5,6-Trifluoroeldanolide [(ϩ)-4] was synthesized through
of the alcohol, (S)-7 and (R)-7, were prepared successfully another type of radical cyclization protocol: the
(Scheme 2).
UenoϪStork procedure[20] (Scheme 3). Alcohol (S)-7 was
The synthesis of 2,2,5,5,6-pentafluoroeldanolide [(ϩ)-3] converted into the corresponding butyl acetal (S)-11 in 62%
was accomplished using our original radical cyclization pro- yield. The acetal (S)-11 was subjected to radical cyclization
tocol (Scheme 3).[5,6,8] Alcohol (S)-7 was converted into its in the presence of tributylstannyl hydride to give the cyclic
α-bromo-α,α-difluoroacetate, which was then reduced to acetal in 44% yield, which, following Jones oxidation, pro-
the corresponding acetal by diisobutylaluminum hydride vided (ϩ)-4 in 48% yield (99% ee). Using the same protocol,
(DIBAL) in dichloromethane (CH2Cl2) at Ϫ78 °C; sub- the antipode of (Ϫ)-4 was also synthesized.
sequent treatment with trimethylsilyl triflate (TMSOTf) in
The EAG test of these analogues showed that both en-
the presence of pyridine gave the O-TMS-acetal 9 in 94% antiomers of trifluoroeldanolide 3 and pentafluoroeldanol-
yield. A benzene solution of tributyltinhydride (1.5 equiv.) ide 4 were significantly less active relative to the natural
was then slowly added over 5 h to a benzene solution of the pheromone (Figure 2). Thus, we established that the olfac-
acetal 9 and azobisisobutyrylnitrile (AIBN; 10 mol %) un- tory activity of Eldana saccharina by point-fluorinated
der reflux . The reaction mixture was heated under reflux pheromone analogues is determined critically by the fluor-
for an additional 24 h, then cooled to room temperature. ine-substituted part of the molecule.
After evaporation, flash column chromatography on silica
gel using hexane/ethyl acetate (200:1 to 50:1) as eluent gave
the cyclized product 10 (88%). This step occurred regiospec-
ifically to provide only the five-membered lactol; no six-
membered lactol was obtained. The TMS lactol was then
treated with a 1.0  THF solution of tetrabutylammonium
fluoride (TBAF) at room temperature for 12 h to provide
the deprotected lactol, which was then subjected to PDC
oxidation. Although oxidation of this lactol proceeded very
slowly — the reaction of lactol 7 with PDC in CH2Cl2 in
˚
the presence of powdered molecular sieves 4 A at room tem-
perature took 24 h — the subsequent purification using a
flash column of silica gel gave the desired γ-lactone (ϩ)-3
in 74% yield. The optical purity of the final product (ϩ)-3
was confirmed by GC analysis to be 98% ee. Using the
same protocol, the antipode of pentafluoroeldanolide (Ϫ)-
3 was synthesized from (R)-7 having an ee of 91%.
Figure 2. Results of the EAG test using optically active fluori-
nated eldanolide
As mentioned earlier, difluoroeldanolide 2 exhibited the
same biological activity as the natural pheromone, while the
pentafluoro-analogue 3 and the trifluoro-analogue 4 were
inactive; these results seem to suggest that the electrostatic
properties of the 3-methyl-2-butenyl group, which is con-
nected at the 4-position of the γ-lactone ring, may be im-
portant for molecular recognition by the receptor protein,
while those of the γ-position of the lactone ring are inde-
pendent. It is unclear, however, whether or not these fluori-
nated analogues bind with the protein in the same fashion
as does the natural eldanolide. If fluorinated analogues bind
Scheme 3. Synthesis of (ϩ)-3 and (ϩ)-4 by a radical-cyclization
strategy
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Synthesis and Biological Activity of Point-Fluorinated Pheromone Analogues
FULL PAPER
in hexane (13.1 mL, 21.0 mmol) was added dropwise over 10 min
and then the mixture was warmed slowly to Ϫ78 °C with stirring.
After 2 h, to the solution of generated vinyllithium was added a
solution of acetone (0.58 g, 10.0 mmol) in THF (25.0 mL) and then
the mixture was warmed slowly to Ϫ50 °C with stirring for 6 h.
The reaction was quenched with saturated aqueous NH4Cl. The
mixture was diluted with ethyl acetate, washed with water and
brine, dried with anhydrous MgSO4, filtered and concentrated.
Flash column chromatography (hexane/ethyl acetate, 30:1Ϫ5:1)
afforded allyl alcohol 5 (1.07 g, 7.19 mol) as a pale-yellow oil in
with the receptor protein in a manner different from that
of the natural pheromone, or bind with the protein at a
completely different position as a result of the substitution
by the fluorine atoms, the EAG activity will be independent
of the molecular recognition mechanism on the receptor
protein. In addition, the conformation of an organic mol-
ecule may be altered when it attaches to the receptor pro-
tein. Thus, many unsolved questions must still be acknowl-
edged in any discussion that uses the results of EAG tests
and calculations of the electron spin density of the molecu- 92% yield; Rf ϭ 0.37 (hexane/ethyl acetate, 7:1); b.p. 65 °C/135 Torr
(kugelrohr distillation). 1H NMR (200 MHz, CDCl3): δ ϭ 1.47 (dd,
lar surface.
J ϭ 4.6 Hz, 1.8 Hz, 6 H), 2.16 (br. d, J ϭ 6.2 Hz, 1 H, OH) ppm.
13C NMR (50 MHz, CDCl3): δ ϭ 26.86 (t, J ϭ 2.0 Hz), 67.88,
133.52 (ddd, J ϭ 235.9, 43.4, 14.0 Hz), 153.39 (ddd, J ϭ 288.1,
279.7, 48.6 Hz) ppm. 19F NMR (188 MHz, CDCl3, C6F6): δ ϭ
Ϫ18.04 (dd, J ϭ 109.7, 33.6 Hz, 1 F), 46.96 (dd, J ϭ 110.1, 84.1 Hz,
Conclusion
1 F), 59.41 (dd, J ϭ 84.3, 33.7 Hz, 1 F) ppm. IR (neat): ν˜ ϭ 3401,
We have synthesized several types of point-fluorinated
analogues of eldanolide in optically active forms and evalu-
ated their pheromone activities by EAG tests. This test re-
2979, 2873, 1777, 1306, 1269, 1165, 1061 cmϪ1. C5H7F3O (140.1):
calcd. C 42.86, H 5.04; found C 43.18, H 5.19.
vealed that the point of fluorination on the pheromone
molecule influences the olfactory response critically. An
investigation by computational chemistry of the fluorinated
pheromone analogues and the natural pheromone sug-
gested that EAG activity is not responsible for the electro-
static pattern on the molecular surface and that the molecu-
lar orbital of these compounds may be important for recog-
3-Allyloxy-1,1,2-trifluoro-3-methylbut-1-ene (6): A solution of al-
cohol 5 (1.40 g, 9.99 mmol) in THF (11.0 mL) was added dropwise
to sodium hydride (480 mg, 12.0 mmol of a 60% dispersion from
which the oil had been removed using toluene) in THF (11.0 mL)
at 0 °C. The reaction mixture was stirred at 23 °C for 2 h and then
a DMF (11.0 mL) solution of allyl bromide (2.47 g, 19.98 mmol)
was added dropwise. The reaction mixture was stirred at 70 °C for
nition of the pheromone molecule at the olfactory receptor 12 h (overnight). The solution was poured into cold water and the
aqueous layer was extracted with diethyl ether. The organic layer
was washed with water and brine, dried with anhydrous MgSO4,
filtered and concentrated. Purification by flash column chromatog-
raphy (silica gel; hexane/ethyl acetate, 20:1Ϫ5:1) afforded trifluo-
roallylic ether 6 (1.30 g, 7.19 mmol) as a pale-yellow oil in 72%
yield; Rf ϭ 0.77 (hexane/ethyl acetate, 7:1); b.p. 70 °C/18 Torr (kug-
elrohr distillation). 1H NMR (200 MHz, CDCl3): δ ϭ 1.43Ϫ1.49
(m, 6 H), 3.88 (d, J ϭ 5.6 Hz, 2 H), 5.15 (ddd, J ϭ 10.4, 3.2, 1.7 Hz,
1 H), 5.28 (ddd, J ϭ 17.1, 3.4, 1.7 Hz, 1 H), 5.90 (ddt, J ϭ 17.1,
10.3, 5.6 Hz, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 24.30
(t, J ϭ 1.9 Hz), 31.59, 64.71, 116.6, 132.5 (ddd, J ϭ 239.4, 44.1,
site. Further investigations in the field of point-fluorinated
pheromone analogues will provide not only a better knowl-
edge of pheromone chemistry, but also useful insights for
the development of new bioactive molecules.
Experimental Section
General Remarks: Reagents and solvents were purchased from
common commercial sources and were used as received or purified
by distillation from appropriate drying agents. Reactions requiring
anhydrous conditions were carried out under argon using dry,
freshly distilled solvents and magnetic stirring. Diethyl ether and
tetrahydrofuran (THF) were distilled from sodium/benzophenone.
Dichloromethane was distilled from calcium hydride. Benzene was
distilled and stored over sodium. All reactions were monitored by
thin-layer chromatography using silica gel plates. Flash chromatog-
raphy was performed with the indicated solvents and silica gel
13.7 Hz), 134.71, 154.41 (ddd, J ϭ 289.9, 280.7, 48.5 Hz) ppm. 19
F
NMR (188 MHz, CDCl3, C6F6): δ ϭ Ϫ17.16 (ddd, J ϭ 216.7,
111.6, 33.6 Hz, 1 F), 47.14 (ddd, J ϭ 183.1, 112.2, 85.5 Hz, 1 F),
60.47 (ddd, J ϭ 571.7, 85.1, 33.5 Hz, 1 F) ppm. IR (neat): ν˜ ϭ
2993, 1772, 1311, 1277, 1161, 1060 cmϪ1. C8H11F3O (180.17):
calcd. C 53.33, H 6.15; found C 53.21, H 6.32.
4,4,5-Trifluoro-6-methylhepta-1,5-dien-3-ol (7): A solution of n-bu-
tyllithium in hexane (12.5 mL, 20.0 mmol) was added dropwise to
a solution of tetramethylpiperidine (2.97 g, 21.0 mmol) in THF
(50.0 mL) at Ϫ20 °C. The solution was warmed to 0 °C for 30 min
to ensure complete formation of lithium tetramethylpiperidine
(LTMP) and was subsequently re-cooled to Ϫ100 °C. A solution
of the appropriate allylic ether 6 (2.42 g, 10.0 mmol) in tetrahydro-
furan (50.0 mL) was added dropwise over 50 min. After the solu-
tion was stirred at Ϫ100 °C for 6 h, the solution was warmed slowly
to room temperature over 18 h. The reaction was quenched with
saturated aqueous NH4Cl, diluted with ethyl acetate, extracted with
the same solvent, dried with anhydrous MgSO4, filtered and con-
centrated. Flash column chromatography (SiO2; hexane/ethyl acet-
ate, 30:1 to 5:1) afforded allylic alcohol 7 (1.14 g, 6.32 mmol) as a
1
(Wako gel C-300E). H, 19F, and 13C NMR spectra were recorded
with Varian VXR-200 (200 MHz) and JNM-270 (270 MHz) spec-
trometers; chemical shifts are expressed in ppm downfield from
tetramethylsilane (TMS) as the internal reference in CDCl3 or
hexafluorobenzene (C6F6). IR spectra were obtained with a JASCO
FTIR-230 spectrometer. Optical rotation was measured using a JA-
SCO DIP-370 digital polarimeter. The stereoselectivity was deter-
mined by capillary gas chromatography (MS, ϕ 0.25 mm ϫ 25 m,
100Ϫ250 °C, N2). The optically purity was determined by capillary
gas chromatography (Chiraldex G-Ta, ϕ 0.25 mm ϫ 20 m,
100Ϫ150 °C, He).
3,4,4-Trifluoro-2-methylbut-3-en-2-ol (5): A solution of 1,1,1,2,2-
pentafluoroethane in THF (11.98 mmol, 5.21 mL) was diluted with pale-yellow oil in 63% yield; Rf ϭ 0.26 (hexane/ethyl acetate, 7:1);
THF (25.0 mL) and cooled to Ϫ100 °C. A solution of butyllithium
b.p. 85 °C/15 Torr (kugelrohr distillation). 1H NMR (200 MHz,
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T. Itoh, K. Kudo, K. Yokota, N. Tanaka, S. Hayase, M. Renou
FULL PAPER
CDCl3): δ ϭ 1.74Ϫ1.82 (m, 6 H), 2.05Ϫ2.28 (br. s, 1 H, OH), (3S)-[2-Bromo-2,2-difluoro-1-(2,2,3-trifluoro-4-methyl-1-vinylpent-
4.41Ϫ4.58 (m, 1 H), 5.40 (d, J ϭ 10.4 Hz, 1 H), 5.51(dt, J ϭ 17.2, 3-enyloxy)ethoxy]trimethylsilane (9): A suspension of lithium brom-
1.6 Hz, 1 H), 5.86Ϫ6.03 (m, 1 H) ppm. 13C NMR (50 MHz, odifluoroacetate (3.62 g, 20.0 mmol) in diethyl ether (20.0 mL) was
CDCl3): δ ϭ 16.39 (q, J ϭ 4.4 Hz), 17.54 (d, J ϭ 9.7 Hz), 73.15
(dd, J ϭ 28.5, 28.6 Hz), 118.25 (dt, J ϭ 247.4, 39.8 Hz), 119.58 (d, 20.0 mmol) in diethyl ether (3.0 mL) was added dropwise slowly.
J ϭ 12.2 Hz), 119.78, 131.80 (t, J ϭ 3.1 Hz), 145.46 (dt, J ϭ 239.6, The mixture was stirred for 2 h at 23 °C. To the mixture were added
31.2 Hz) ppm. 19F NMR (188 MHz, CDCl3, C6F6): δ ϭ 34.08 (s, a solution of alcohol (S)-7 (1.80 g, 10.0 mmol) and triethylamine
1 F), 52.22 (dd, J ϭ 506.8, 266.2 Hz, 2 F) ppm. IR (neat): ν˜ ϭ (4.18 mL, 30.0 mmol) in diethyl ether (10.0 mL), and the mixture
3410, 2930, 2195, 1642, 1385, 1135, 1065 cmϪ1. C8H11F3O (180.17): was stirred for 2 h at 23 °C. The reaction mixture was filtered
cooled to 0 °C and then a solution of oxalyl chloride (2.54 g,
calcd. C 53.33, H 6.15; found C 53.25, H 5.93.
through short column of silica gel (eluted with ether) and concen-
trated to give 2,2,3-trifluoro-4-methyl-1-vinylpent-3-enyl bromodi-
fluoroacetate (3.38 g) as a colorless oil, which was used for the next
reaction without further purification. To a solution of bromodi-
fluoroacetate (3.37 g, 10.0 mmol) in CH2Cl2 (25.0 mL) was added
DIBAL-H in toluene (7.35 mL, 11.0 mmol) at Ϫ78 °C over 10 min
and the mixture was stirred at Ϫ78 °C for 1.5 h. To the mixture
were added pyridine (2.45 mL, 30.0 mmol) and a solution of
TMSOTf (3.33 g, 15.0 mmol) in CH2Cl2 (8.0 mL), and then it was
slowly warmed up to room temp. with stirring for 7 h. The reaction
was quenched by the addition of powdered KF (2.10 g) and water
(1.0 mL), and then the mixture was stirred for an additional 15 min
open to the atmosphere. The mixture was filtered through a short
column of Florisil (eluted with CH2Cl2) and was then concentrated.
Flash column chromatography (SiO2; hexane/ethyl acetate,
100:1Ϫ30:1) gave silyl acetal 9 (3.50 g, 8.51 mmol) in 85% yield
(two steps); Rf ϭ 0.72 (hexane/ethyl acetate, 7:1); b.p. 135 °C/2 Torr
2,2,3-Trifluoro-4-methyl-1-vinylpent-3-enyl Acetate (8): A solution
of acetyl chloride (1.18 g, 15.0 mmol) in dichloromethane
(13.0 mL) was added dropwise to a solution of allylic alcohol (Ϯ)-
7 (1.80 g, 10.0 mmol) and pyridine (2.43 mL, 15.0 mmol) in di-
chloromethane (20.0 mL) at 0 °C. The solution was warmed to
room temperature over 6 h. The reaction was quenched with
crushed ice, diluted with ethyl acetate, extracted with the same sol-
vent, dried with anhydrous MgSO4, filtered and concentrated.
Flash column chromatography (SiO2; hexane/ethyl acetate,
60:1Ϫ5:1) afforded acetate 8 (2.12 g, 9.52 mmol) as a pale-yellow
oil in 95% yield; Rf ϭ 0.72 (hexane/ethyl acetate, 7:1); b.p. 125 °C/
1
8 Torr (kugelrohr distillation). H NMR (200 MHz, CDCl3): δ ϭ
1.72Ϫ1.81 (m, 6 H), 2.12 (s, 3 H), 5.43 (d, J ϭ 10.3 Hz, 1 H), 5.47
(d, J ϭ 17.1 Hz, 1 H), 5.68Ϫ5.85 (m, 2 H) ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 16.24 (q, J ϭ 4.3 Hz), 17.39 (d, J ϭ 9.3 Hz),
20.63, 73.39 (dd, J ϭ 30.8, 28.1 Hz), 116.89 (dt, J ϭ 248.2,
39.5 Hz), 119.72 (d, J ϭ 13.9 Hz), 121.93, 128.25 (t, J ϭ 2.7 Hz),
144.90 (dt, J ϭ 241.2 Hz, 30.5 Hz), 169.00 ppm. IR (neat): ν˜ ϭ
2936, 1758, 1376, 1225, 1050 cmϪ1. C10H13F3O2 (222.20): calcd. C
54.05, H 5.90; found C 53.85, H 5.77.
1
(kugelrohr distillation). H NMR (200 MHz, CDCl3, diastereoiso-
meric mixture): δ ϭ 0.21 (s, 9 H), 1.70Ϫ1.82 (m, 6 H), 4.35Ϫ4.46
(m, 1 H), 4.76Ϫ4.86 (m, 1 H), 5.45Ϫ5.62 (m, 2 H), 5.75Ϫ6.00 (m,
1 H) ppm. 13C NMR (50 MHz, CDCl3, diastereoisomeric mixture):
δ ϭ 0.09, 16.27Ϫ16.45 (m), 17.54 (d, J ϭ 9.4 Hz), 77.27 (dt, J ϭ
77.9, 33.8 Hz), 94.44 (dt, J ϭ 114.5, 31.2 Hz), 116.70 (ddt, J ϭ
247.6, 39.5, 14.5 Hz), 119.05 (t, J ϭ 14.2 Hz), 121.71 (dd, J ϭ
309.6, 15.5 Hz), 122.76 (d, J ϭ 71.9 Hz), 129.49 (d, J ϭ 26.5 Hz),
143.77 (dt, J ϭ 239.2, 31.9 Hz) ppm. 19F NMR (188 MHz, CDCl3,
C6F6, diastereoisomeric mixture): δ ϭ 33.31 (d, J ϭ 112.9 Hz, 1
F), 49.02Ϫ50.71 (m, 1 F), 56.56 (d, J ϭ 268.6 Hz, 1 F),
98.20Ϫ100.76 (m, 2 F) ppm. IR (neat): ν˜ ϭ 2959, 1375, 1260, 1203,
1139 cmϪ1. C13H20BrF5O2Si (411.28): calcd. C 37.96, H 4.90;
found C 38.52, H 4.84.
Optical Resolution of Allylic Alcohol (؎)-7 by a Lipase-Catalyzed
Reaction: A mixture of acetate (Ϯ)-8 (3.18 g, 14.3 mmol) and lipase
PS (1.59 g, Amano Enzyme Ltd.) in 0.1 m phosphate buffer (pH
7.2, 30 mL) was stirredat 35 °C for 4.5 h and then the mixture was
filtered through a celite pad in a sintered glass filter and washed
with diethyl ether. The filtrate was extracted with ethyl acetate, the
combined organic layers were dried (MgSO4) and then the solvents
were evaporated. Flash column chromatography (SiO2; hexane/
ethyl acetate, 50:1Ϫ10:1) gave alcohol (R)-7 (775 mg, 4.30 mmol)
in 30% yield and unchanged acetate (S)-8 (2.00 g, 9.03 mmol) in (4R,5S)-[3,3-Difluoro-4-methyl-5-(1,1,2-trifluoro-3-methylbut-2-
63% yield. The enantiomeric excesses of (R)-7 (98% ee) and (S)-8
(68% ee) were determined by capillary GC analysis using a chiral
phase (Chiraldex G-Ta). Because the optical purity of (S)-8 was
too poor for further use, the sample was again subjected to lipase-
catalyzed hydrolysisat 35 °C for 9.5 h . Optically pure (Ͼ 99% ee)
(S)-8 (1.20 g, 5.42 mmol) was obtained in 38% overall yield (two
steps). To a solution of acetate (S)-8 (2.67 g, 12.0 mmol) in THF
enyl)tetrahydrofuran-2-yloxy]trimethylsilane (10):
(110.0 mL) solution of tributyltin hydride (3.00 mL, 10.50 mmol)
was added dropwise over 8 h with stirring to a refluxing solution
A
benzene
of silyl acetal
9 (2.87 g, 7.00 mmol) and AIBN (58.0 mg,
0.35 mmol) in benzene (30.0 mL), and then the mixture was stirred
for additional 2 h under reflux. After being cooled to room temp.,
to the mixture was added saturated aqueous KF (140 mL) and then
(24.0 mL) were added a solution of lithium hydroxide monohydrate the mixture was stirred for 10 min before being extracted with di-
(1.01 g, 24.0 mmol) in water (8.0 mL) and methanol (2.0 mL) at 0
°C, and the mixture was stirred at room temperature for 24 h. After
ethyl ether. The combined organic layers were dried with anhydrous
MgSO4 and flash column chromatography (SiO2; hexane/ethyl
quenching the reaction with 2 n HCl, the aqueous phase was ex- acetate, 1:0Ϫ30:1) gave (4S,5S)-10 (2.05 g, 6.16 mmol) in 88% yield;
tracted with diethyl ether and the organic layers were dried with
anhydrous MgSO4, filtered and concentrated. Flash column chro-
matography (SiO2; hexane/ethyl acetate, 20:1Ϫ10:1) afforded al-
cohol (S)-7 (1.99 g, 11.1 mmol) as a colorless oil in 92% yield. In-
itially we hoped to obtain optically active alcohol (Ϯ)-7 by lipase-
Rf ϭ 0.72 (hexane/ethyl acetate, 7:1); b.p. 75 °C/2.5 Torr (kugelrohr
distillation). 1H NMR (200 MHz, CDCl3, diastereoisomeric mix-
ture): δ ϭ 1.75Ϫ1.83 (m, 9 H), 1.18Ϫ1.25 (m, 3 H), 1.75Ϫ1.83 (m,
6 H), 2.66Ϫ2.94 (m, 1 H), 3.99Ϫ4.34 (m, 1 H) ppm. 13C NMR
(50 MHz, CDCl3, diastereoisomeric mixture): δ ϭ Ϫ0.03, 0.10, 7.57
catalyzed acylation, but because of the poor nucleophilicity of 7, (d, J ϭ 6.4 Hz), 11.81 (d, J ϭ 7.7 Hz), 17.94, 25.74, 32.66, 33.88,
resulting from the effect of the neighboring difluoromethylene
group, it required long reaction time (Ͼ 2 days), we employed li-
39.83 (t, J ϭ 21.1 Hz), 43.14 (t, J ϭ 22.6 Hz), 82.68 (d, J ϭ 8.0 Hz),
83.79 (t, J ϭ 3.8 Hz), 95.53 (dd, J ϭ 40.3, 26.7 Hz), 97.12 (dd, J ϭ
43.5, 24.2 Hz), 118.61, 119.11, 125.75 (dd, J ϭ 261.4, 248.3 Hz),
pase-catalyzed hydrolysis reaction of (Ϯ)-8 for this step istead. (S)-
24
7 (Ͼ 99% ee): [α]D ϭ Ϫ13.0 (c ϭ 1.12, CHCl3); (R)-7 (98% ee): 126.28 (dd, J ϭ 266.1, 247.0 Hz), 134.25, 134.63 ppm. 19F NMR
24
[α]D ϭ ϩ13.2 (c ϭ 1.00, CHCl3).
(188 MHz, CDCl3, C6F6, diastereoisomeric mixture): δ ϭ 37.04
www.eurjoc.org Eur. J. Org. Chem. 2004, 406Ϫ412
410
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis and Biological Activity of Point-Fluorinated Pheromone Analogues
FULL PAPER
(ddd, J ϭ 229.6, 23.0, 6.8 Hz, 0.5 F), 38.71 (d, J ϭ 229.2 Hz, 0.5
F), 38.85 (dd, J ϭ 229.2, 9.8 Hz, 0.5 F), 61.15 (ddd, J ϭ 232.4,
(4R,5S)-5-Ethoxy-3-methyl-2-(1,1,2-trifluoro-3-methylbut-2-enyl)-
tetrahydrofuran (12): A solution of tributyltin hydride (3.45 mL,
24.4, 6.1 Hz, 0.5 F) ppm. IR (neat): ν˜ ϭ 2956, 1259, 1206, 1129, 12.0 mmol) in benzene (130 mL) was added dropwise over 9 h with
1042 cmϪ1. C13H21 F5O2Si (332.38): calcd. C 46.98, H 6.37; found
C 46.45, H 6.84.
stirring to a solution of acetal 11 (2.65 g, 8.00 mmol) and AIBN
(67.0 mg, 0.40 mmol) in benzene under reflux (30.0 mL), and then
the mixture was stirred for an additional 2 h. The mixture was co-
oled to room temp. and then saturated aqueous KF (150 mL) was
added and the flask was left open to the atmosphere. After being
stirred for 10 min, the mixture was extracted with diethyl ether and
dried with anhydrous MgSO4, and then the solvents were evapo-
rated to dryness. Flash column chromatography (SiO2; hexane/ethyl
acetate, 1:0Ϫ30:1) afforded lactol (4S, 5S)-12 (1.37 g, 5.43 mmol)
in 68% yield as a colorless oil; Rf ϭ 0.68 (hexane/ethyl acetate,
10:1); b.p. 75 °C/2.5 Torr (kugelrohr distillation). 1H NMR
(200 MHz, CDCl3, diastereoisomeric mixture): δ ϭ 0.10 (s, 4.5 H),
0.11 (s, 4.5 H), 0.98 (d, J ϭ 6.9 Hz, 1.5 H), 1.00 (dd, J ϭ 7.2 Hz,
2.2 Hz, 1.5 H), 1.55 (s, 3 H), 1.64 (s, 3 H), 1.84Ϫ2.19 (m, 1 H),
2.24 (t, J ϭ 6.2 Hz, 2 H), 3.59 (dt, J ϭ 9.3, 6.0 Hz, 0.5 H), 3.85
(dt, J ϭ 6.3, 6.4 Hz, 0.5 H), 4.97 (d, J ϭ 6.7 Hz, 0.5 H), 5.03Ϫ5.14
(m, 1 H), 5.13 (d, J ϭ 6.0 Hz, 0.5 H) ppm. 13C NMR (50 MHz,
CDCl3, diastereoisomeric mixture): δ ϭ Ϫ0.03, 0.10, 7.57 (d, J ϭ
6.4 Hz), 11.81 (d, J ϭ 7.7 Hz), 17.94, 25.74, 32.66, 33.88, 39.83 (t,
J ϭ 21.1 Hz), 43.14 (t, J ϭ 22.6 Hz), 82.68 (d, J ϭ 8.0 Hz), 83.79
(t, J ϭ 3.8 Hz), 95.53 (dd, J ϭ 40.3, 26.7 Hz), 97.12 (dd, J ϭ 43.5,
24.2 Hz), 118.61, 119.11, 125.75 (dd, J ϭ 261.4, 248.3 Hz), 126.28
(4R,5S)-3,3-Difluoro-4-methyl-5-(1,1,2-trifluoro-3-methylbut-2-
enyl)dihydrofuran-2-one (3): Tetrabutylammonium fluoride in THF
(5.20 mL, 5.20 mmol) was added to a THF (22.0 mL) solution of
silyl lactol (4S,5S)-10 (1.33 g, 4.00 mmol) and then the mixture was
stirred at room temperature for 24 h. The mixture was diluted with
diethyl ether and then the organic layer was washed with water and
brine, and dried with anhydrous MgSO4. Evaporation of the sol-
vent gave the corresponding lactol (1.05 g), which was used for the
˚
next reaction without purification. Powdered MS 4A (2.90 g) and
PDC (5.36 g, 14.00 mmol) were added to a dichloromethane
(25.0 mL) solution of lactol (1.05 g) and then the mixture was
stirred for 42 h at room temp. The mixture was filtered through a
short column of silica gel (eluted with ether) and concentrated to
dryness. Flash column chromatography (SiO2; hexane/ethyl acetate,
40:1) gave lactone (ϩ)-(4R,5S)-3 (455 mg, 1.76 mmol) as a colorless
oil in 44% yield (2 steps). The optical purity of this compound
(98% ee) was determined by capillary GC analysis using a chiral
column (Chiraldex G-Ta); Rf ϭ 0.46 (hexane/ethyl acetate, 7:1); b.p.
22
75 °C/2.2 Torr (kugelrohr distillation). [α]D ϭ ϩ39.1 (c ϭ 1.01,
1
CHCl3). H NMR (200 MHz, CDCl3): δ ϭ 1.36 (d, J ϭ 7.3 Hz, 3
(dd,
J ϭ
266.1, 247.0 Hz), 134.25, 134.63 ppm. 19F NMR
H), 1.77Ϫ1.85 (m, 6 H), 2.78Ϫ3.08 (m, 1 H), 4.46Ϫ4.59 (m, 1 H)
ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 9.25 (d, J ϭ 7.5 Hz), 20.95,
22.17 (d, J ϭ 9.2 Hz), 36.80 (t, J ϭ 21.1 Hz), 65.85, 77.20 (t, J ϭ
10.7 Hz), 79.05 (ddd, J ϭ 37.1, 28.6, 7.7 Hz), 114.81 (dt, J ϭ 251.3,
22.4 Hz), 115.74 (dd, J ϭ 260.3, 250.4 Hz), 123.45, 144.10 (dt, J ϭ
240.1, 30.2 Hz), 160.20 (t, J ϭ 33.5 Hz) ppm. 19F NMR (188 MHz,
CDCl3, C6F6): δ ϭ 30.35 (d, J ϭ 12.6 Hz, 1 F), 44.60 (dd, J ϭ
278.1, 18.3 Hz, 1 F), 46.95 (dd, J ϭ 277.7, 13.9 Hz, 1 F), 48.77 (dd,
J ϭ 277.7, 13.9 Hz, 1 F), 55.36 (dd, J ϭ 276.7, 12.2 Hz, 1 F) ppm.
IR (neat): ν˜ ϭ 2930, 1831, 1458, 1202, 1138, 1033 cmϪ1. C10H11
F5O2 (258.19): calcd. C 46.52, H 4.29; found C 45.10, H 4.44.
(188 MHz, CDCl3, C6F6, diastereoisomeric mixture): δ ϭ 37.04
(ddd, J ϭ 229.6, 23.0, 6.8 Hz, 0.5 F), 38.71 (d, J ϭ 229.2 Hz, 0.5
F), 38.85 (dd, J ϭ 229.2, 9.8 Hz, 0.5 F), 61.15 (ddd, J ϭ 232.4,
24.4, 6.1 Hz, 0.5 F) ppm. IR (neat): ν˜ ϭ 2962, 1461, 1370, 1253,
1109 cmϪ1. C12H19F3O2 (252.27): calcd. C 57.13, H 7.59; found C
57.93, H 7.41.
(4S,5S)-4-Methyl-5-(1,1,2-trifluoro-3-methylbut-2-enyl)-
dihydrofuran-2-one (4): Jones reagent (8 N, 5.2 mL) was added to
an acetone (3.0 mL) solution of (4S, 5S)-12 (757 mg, 3.00 mmol)
and then the mixture was stirred at room temp. for 24 h open to the
atmosphere. The mixture was quenched by the addition of aqueous
NaHSO4 and NaCO3 solutions. The mixture was diluted with di-
ethyl ether and the organic layers were dried with anhydrous
MgSO4 and then the solvents were evaporated to dryness. Flash
column chromatography (SiO2; hexane/ethyl acetate, 50:1Ϫ20:1)
gave (4S,5S)-(ϩ)-4 (393 mg, 1.77 mmol, 99% ee) in 59% yield: Rf ϭ
0.68 (hexane/ethyl acetate, 7:1); b.p. 75 °C/2.2 Torr (kugelrohr dis-
Using (R)-7 (92% ee) as the starting material gave the unnatural-
type eldanolide analogue, (Ϫ)-(4S,5R)-3 (91% ee) in 45% overall
22
yield. [α]D ϭ Ϫ34.3 (c ϭ 1.38, CHCl3).
(3S)-3-(2-Bromo-1-ethoxyethoxy)-4,4,5-trifluoro-6-methylhepta-1,5-
diene (11): To
a solution of N-bromosuccinimide (2.14 g,
12.0 mmol) and (S)-7 (1.80 g, 10.0 mmol) in dichloromethane
(23.0 mL) was added dropwise a solution of ethyl vinyl ether
(1.44 g, 20.0 mmol) in dichloromethane (10.0 mL) at Ϫ20 °C and
then the mixture was stirred for 10 h at Ϫ78 °C. The solution was
slowly warmed up to room temp. with stirring for 2 h and then the
reaction mixture was quenched by the addition of saturated aque-
ous NaHCO3. The mixture was extracted with diethyl ether and
then the combined organic layers were dried with anhydrous
MgSO4 and the solvents were evaporated to dryness. Flash column
chromatography (SiO2; hexane/ethyl acetate, 50:1) gave acetal 11
(2.60 g, 7.88 mmol) as a colorless oil in 79% yield; Rf ϭ 0.70 (hex-
ane/ethyl acetate, 10:1); b.p. 65 °C/3.0 Torr. [α]D22 ϭ ϩ9.6 (c ϭ 1.3,
CHCl3). 1H NMR (200 MHz, CDCl3): δ ϭ 1.62 (s, 3 H), 1.70 (s, 3
H), 2.34Ϫ2.56 (m, 2 H), 5.02Ϫ5.12 (m, 1 H), 5.25Ϫ5.40 (m, 3 H),
5.84 (ddd, J ϭ 17.5, 10.4, 6.2 Hz, 1 H) ppm. 13C NMR (50 MHz,
CDCl3): δ ϭ 17.91, 25.76, 32.81, 79.27, 108.89 (t, J ϭ 314.6 Hz),
117.20, 118.71, 134.01, 136.07, 158.80 (t, J ϭ 31.1 Hz) ppm. 19F
NMR (188 MHz, CDCl3, C6F6): δ ϭ 101.05 (s, 2 F) ppm. IR
22
1
tillation). [α]D ϭ ϩ26.7 (c ϭ 1.18, CHCl3). H NMR (200 MHz,
CDCl3): δ ϭ 1.23 (d, J ϭ 6.8 Hz, 3 H), 1.27Ϫ1.80 (m, 6 H),
2.01Ϫ2.24 (m, 1 H), 2.72Ϫ2.87 (m, 2 H), 4.30Ϫ4.44 (m, 1 H) ppm.
13C NMR (50 MHz, CDCl3): δ ϭ 16.00Ϫ16.19 (m), 17.42 (d, J ϭ
9.3 Hz), 19.89, 29.01, 35.46, 83.49 (dd, J ϭ 34.9, 27.4 Hz), 116.50
(dt, J ϭ 244.3, 41.2 Hz), 120.16 (dd, J ϭ 13.7, 2.9 Hz), 143.47 (dt,
J ϭ 238.6, 29.4 Hz), 175.26 ppm. 19F NMR (188 MHz, CDCl3,
C6F6): δ ϭ 33.06 (s, 1 F), 48.79 (dd, J ϭ 274.7, 14.3 Hz, 1 F), 54.49
(d, J ϭ 274.7 Hz, 1 F) ppm. IR (neat): ν˜ ϭ 2973, 1796, 1455, 1385,
1206 cmϪ1. C10H13F3O2 (222.20): calcd. C 54.05, H 5.90; found C
53.85, H 5.72. Using (R)-7 (98% ee) as the starting material, the
unnatural-type eldanolide analogue, (4R,5R)-(Ϫ)-4, was synthe-
sized in 27% overall yield by following the procedure described
22
above: [α]D ϭ Ϫ25.8 (c ϭ 1.00, CHCl3), 97% ee.
EAG Tests of the Pheromone Analogues: Electroantennograms were
recorded from male moths restrained in a styrofoam block. The
apex of one antenna was cut off and its tip was inserted into the
(neat): ν˜
ϭ .
2927, 1775, 1451, 1297, 1169, 1131 cmϪ1
C12H18BrF3O2 (331.17): calcd. C 43.52, H 5.48; found C 43.10, recording electrode. The neck of the insect was impaled with the
H 5.65.
reference electrode. Glass microelectrodes were filled with the in-
Eur. J. Org. Chem. 2004, 406Ϫ412
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
411

T. Itoh, K. Kudo, K. Yokota, N. Tanaka, S. Hayase, M. Renou
FULL PAPER
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sect’s Ringer. Both electrodes were connected to a Neurolog NL
102 preamplifier through chloridized silver wires. The signal was
filtered (DC to 1 kHz) and fed into an oscilloscope. Compounds
were diluted in hexane at the appropriate concentrations. A volume
of each solution was deposited on a filter paper inserted into a
Pasteur pipette. A purge stream of humidified pure air (1.0 L/min;
100% RH) was blown continuously on the antenna. Stimulations
were achieved by blowing a puff of air (0.5 sec, 0.5 L/min) through
the pipette into the purge air stream. the stimuli were presented in
the order of increasing doses. The EAG responses were recorded
on twelve different insects.
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The authors are grateful to Professor Ryoichi Akaba of Gunma
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Received August 28, 2003
412
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 406Ϫ412