Stereoselective synthesis of (R)- and (S)-ipsdienols, pheromone components of bark beetles of the Ips family

Article abstract of DOI:10.1134/S1070428012090035

Abstract-(R)- and (S)-Ipsdienols, components of pheromones of bark beetles of the Ips family, were synthesized with high enantiomeric purity (>98%) from 8-chloro-2-methyl-6-methylideneoct-2-en-4-ol prepared from ethyl 3-chloropropionate via cyclopropanati

Full text of DOI:10.1134/S1070428012090035

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 9, pp. 1168–1172. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © V.N. Kovalenko, E.A. Matyushenkov, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 9, pp. 1172–1175.
Stereoselective Synthesis of (R)- and (S)-Ipsdienols, Pheromone
Components of Bark Beetles of the Ips Family
V. N. Kovalenko and E. A. Matyushenkov
Belarusian State University, pr. Nezavisimosti 4, Minsk, 220030 Belarus
e-mail: matiushenkov@tut.by
Received April 9, 2012
Abstract—(R)- and (S)-Ipsdienols, components of pheromones of bark beetles of the Ips family, were synthe-
sized with high enantiomeric purity (>98%) from 8-chloro-2-methyl-6-methylideneoct-2-en-4-ol prepared from
ethyl 3-chloropropionate via cyclopropanation according to Kulinkovich. 8-Chloro-2-methyl-6-methylideneoct-
2-en-4-ol was converted into the corresponding hydrogen phthalate whose stereoisomeric salts with (R)- and
(S)-1-phenylethanamines were separated by crystallization, and subsequent hydrolysis of the latter and dehy-
drohalogenation with potassium tert-butoxide gave targeted (R)- and (S)-ipsdienols.
DOI: 10.1134/S1070428012090035
cationic cyclopropyl–allyl isomerization of cyclopro-
panol II methanesulfonate into 2-chloroethyl-3-bromo-
prop-1-ene [10], and condensation of the latter with
prenal in the presence of zinc (Scheme 1). Alcohol III
thus obtained was converted into ipsdienol (I) by pro-
tection of the hydroxy group and dehydrochlorination.
The developed scheme ensured preparation of racemic
ipsdienol (I) on a multigram level without resorting to
column chromatography. In this work we have mod-
ified the above procedure with a view to obtain pure
enantiomers of I.
Ipsdienol (I) is a monoterpenoid allylic alcohol
which is a component of aggregation pheromones of
several bark beetle species of the Ips family that are
harmful forest pests [1]. In many cases pheromone
compositions produced by these insects contain enan-
tiomerically enriched ipsdienol (I), and its activity is
largely determined by its absolute configuration and
optical purity. For example, (S)-(+)-ipsdienol [(S)-I] is
the main component of I. confusus, I. paraconfusus,
I. acuminatus, I. lecontei, I. cembrae, I. mannsfeldi,
and I. shangrila beetle pheromones [1], whereas its
enantiomer (R)-I constitutes pheromones of I. calli-
graphus, I. avulsus, I. amitinus, I. typorgaphus, and
I. nitidus [2]. The enantiomer ratio in the natural
pheromone of I. pini depends on the geographic region
[1, 3]. Response of I. calligraphus, I. avulses, and
I. pini California to (R)-I is suppressed in the presence
of its (S)-enantiomer. Likewise, (R)-I inhibits the
activity of (S)-I in I. paraconfusus and I. acuminatus
species [1–3]. These findings indicate that both indivi-
dual ipsdienol enantiomers are necessary for efficient
capture of many forest pests. Therefore, optically
active alcohol I was the subject of numerous studies
[4–7], and development of simple and efficient proce-
dures for the preparation of its enantiomers remains an
important problem.
Scheme 1.
OH
CH2 OH
Me
[8, 10]
Cl
Cl
Me
II
III
CH2 OH
Me
[8]
H2C
Me
I
A simple and convenient procedure for the isolation
of pure enantiomers is based on racemate resolution by
transformation into diastereoisomers differing in their
solubility, so that the latter can be separated by crystal-
lization [11, 12]. This technique is used in large-scale
syntheses of optically active medicines, and it ensures
high purity of the products and good reproducibility of
the results. In this work we used the known method for
optical resolution of some racemic secondary alcohols
We previously described [8] an efficient synthesis
of racemic ipsdienol (I) starting from accessible ethyl
3-chloropropionate via titanium-catalyzed cyclopro-
panation according to Kulinkovich [9], subsequent
1168

STEREOSELECTIVE SYNTHESIS OF (R)- AND (S)-IPSDIENOLS
1169
Scheme 2.
C(O)R
O Me
(1) (R)-PhCH(NH2)Me
Me2CO
CH2
o-C6H4(CO)2O
Et3N
(2) Three crystallizations
(R)-IV·(R)-PhCH(NH2)Me
+ mother liquor
III
Cl
Me
IV
(1) H2SO4, H2O
(2) t-BuOK, t-BuOH
R = C6H4COOH-o
(R)-(–)-I
(1) H2SO4, H2O
(2) (R)-PhCH(NH2)Me
Me2CO
(1) H2SO4, H2O
(2) t-BuOK, t-BuOH
(3) Three crystallizations
Mother liquor
(S)-IV·(S)-PhCH(NH2)Me
(S)-(+)-I
via their transformations into phthalic acid monoesters
and subsequent crystallization of their salts with
(R)- and (S)-1-phenylethanamines [12].
(R)-1-phenylethylammonium salt considerably en-
riched in the (R)-enantiomer of IV. To enhance its dia-
stereoisomeric purity, the salt was recrystallized from
acetone two times more (see table). The mother liquors
were combined and evaporated under reduced pres-
sure, and the residue was treated with dilute sulfuric
acid to isolate hydrogen phthalate IV enriched in the
(S)-enantiomer. Likewise, (S)-enriched hydrogen
phthalate salt with (S)-1-phenylethanamine was recrys-
tallized thrice from acetone. As a result, we obtained
both enantiomeric salts with opposite optical rotations:
(R)-IV·(R)-PhCH(Me)NH2, [α]D = –29.3° (c = 0.8,
MeOH); (S)-IV ·(S)-PhCH(Me)NH2, [α]D = +29.0°
(c = 1.1, MeOH).
First of all, this approach was tested directly for
racemic ipsdienol (I). By treatment of its solution in
benzene with phthalic anhydride in the presence of
triethylamine on heating under reflux we synthesized
the corresponding hydrogen phthalate in quantitative
yield. However, an attempt to obtain its readily crys-
tallizable salt with (R)-1-phenylethanamine was unsuc-
cessful, for the resulting salt was readily soluble in
methanol, ethanol, acetone, ethyl acetate, and diethyl
ether, and it failed to separate from these solvents as
crystals. Only addition of petroleum ether to its solu-
tion induced precipitation of a solid, poorly crystalliz-
able material which was a mixture of diastereoisomers.
After unsuccessful experiments with ipsdienol (I),
we focused on its synthetic precursor, racemic alcohol
III (Scheme 2). Following the above procedure, com-
pound III was converted into hydrogen phthalate IV
by treatment with phthalic anhydride. Crude hydrogen
phthalate IV was dissolved in acetone (~1 M solution),
an equimolar amount of (R)-1-phenylethanamine was
added, the mixture was cooled to –15°C, and crystals
precipitated and were filtered off. We thus isolated
The next step in the synthetic sequence implied
formation of the ipsdienol diene fragment. The reac-
tion of (R)-IV and (S)-IV with excess potassium tert-
butoxide in boiling tert-butyl alcohol resulted in de-
hydrochlorination with simultaneous removal of the
phthalate fragment. In such a way, the target (R)- and
(S)-enantiomers of ipsdienol (I) were obtained in
a moderate yield in one preparative step. The ee values
of (R)-I and (S)-I were determined on the basis of
1
the H NMR spectra of their esters with (S)-Mosher’s
acid according to [7]; after triple recrystallization of
Yields of salts (R)-IV·(R)-PhCH(Me)NH2 and (S)-IV·(S)-PhCH(Me)NH2 and enantiomeric purity of ipsdienol obtained
therefrom
(R)-IV·(R)-PhCH(Me)NH2
yield,a % (R)-I, ee,b %
40 92
(S)-IV·(S)-PhCH(Me)NH2
yield,a % (S)-I, ee,b %
41 93
Number of
crystallizations
1
2
3
33
31
98
34
32
98
>98>
>98>
a
Calculated on racemic alcohol III.
b
1
Determined by H NMR spectroscopy after transformation of the salts into ipsdienol (I) enantiomers and subsequent conversion of the
latter into (S)-Mosher’s acid esters.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 9 2012

KOVALENKO, MATYUSHENKOV
1170
the corresponding salts, the ee values were higher
than 98%.
7.1 Hz), 4.22 q (1H, CHCH3, J = 6.7 Hz), 4.85 s and
4.91 s (1H each, =CH2), 5.20 d (1H, =CH, J = 8.7 Hz),
5.75 d.t (1H, CHO, J = 8.7, 6.6 Hz), 7.13–7.31 m (8H,
To conclude, we have developed an efficient proce-
dure for the synthesis of (R)- and (S)-ipsdienols I with
high optical purity (ee >98%) starting from racemic
8-chloro-2-methyl-6-methylideneoct-2-en-4-ol (III).
H
arom), 7.60–7.63 m (1H, Harom), 8.00 br.s (3H, NH3+).
13C NMR spectrum, δC, ppm: 18.1 (CH3), 21.3 (CH3),
25.6 (CH3), 39.1 (CH2), 41.1 (CH2), 42.5 (CH2), 51.0
(CH), 70.5 (CH), 115.1 (CH2), 123.5 (CH), 126.6 (2C,
CH), 127.8 (2C, CH), 128.1 (CH), 128.3 (CH), 128.7
(2C, CH), 130.1 (C), 130.9 (CH), 137.2 (C), 140.1 (C),
140.2 (C), 141.2 (C), 167.2 (C), 174.4 (C). Found, %:
C 68.10; H 7.09. C26H32ClNO4. Calculated, %:
C 68.18; H 7.04.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded from
solutions in chloroform-d on a Bruker Avance 400
spectrometer at 400 and 100 MHz, respectively. The
IR spectra were measured on a Bruker Vertex 70 spec-
trometer. The optical rotations were determined on
a SM-3 polarimeter at 20±2°C. Silica gel 60 (70–
230 mesh, Merck) was used for column chromatog-
raphy. The solvents used were dried according to
standard procedures and distilled.
(S)-1-Phenylethanaminium 2-[(4S)-8-chloro-
2-methyl-6-methylideneoct-2-en-4-yloxycarbonyl]-
benzoate (S)-IV·(S)-PhCH(Me)NH2. The mother
liquors obtained after crystallization of (R)-IV·(R)-(+)-
PhCH(Me)NH2 were combined and evaporated under
reduced pressure, 200 ml of methylene chloride and
200 ml of 10% H2SO4 were added to the residue, the
organic and aqueous phases were thoroughly stirred,
the organic phase was separated, and the aqueous phase
was extracted with methylene chloride (2×100 ml).
The extracts were combined with the organic phase,
washed with 10% H2SO4 and a saturated solution of
sodium chloride, dried over MgSO4, and evaporated
under reduced pressure to isolate 24.5 g of crude
hydrogen phthalate IV enriched in the (S)-isomer
(a viscous oily substance). The product was dissolved
in 250 ml of hot acetone, 9.1 g (75 mmol) of (S)-(–)-
1-phenylethanamine was added, and the mixture was
cooled to –15°C and kept for 12 h at that temperature.
The precipitate was filtered off, washed with cold
acetone [yield 18.6 g (41%)], and recrystallized twice
from boiling acetone. Yield of (S)-IV · (S)-(–)-
PhCH(Me)NH2 15.0 g (34%) after first crystallization
and 14.5 g (32%) after second crystallization. Color-
less crystals, mp 134–135°C, [α]D = +29.0° (c = 1.1,
MeOH). The spectral parameters of the product were
the same as those given above for (R)-IV·(R)-(+)-
PhCH(Me)NH2.
(R)-1-Phenylethanaminium 2-[(4R)-8-chloro-
2-methyl-6-methylideneoct-2-en-4-yloxycarbonyl]-
benzoate (R)-IV·(R)-PhCH(Me)NH2. 8-Chloro-2-
methyl-6-methylideneoct-2-en-4-ol (III) [8], 18.7 g
(99.2 mmol), was dissolved in 100 ml of benzene,
20.9 ml (150 mmol) of triethylamine and 16.2 g
(109 mmol) of phthalic anhydride were added, and the
mixture was heated for 45 min under reflux in an argon
atmosphere, cooled, and treated with 200 ml of
10% H2SO4. The organic layer was separated, the
aqueous layer was extracted with 100 ml of benzene,
the extract was combined with the organic phase,
washed with a saturated solution of sodium chloride,
dried over MgSO4, and evaporated under reduced
pressure to isolate 34.5 g of crude hydrogen phthalate
IV as a viscous oily substance. A solution of 34.5 g of
IV in 110 ml of acetone was heated to the boiling
point, 12.0 g (99.0 mmol) of (R)-(+)-1-phenylethan-
amine was added, and the mixture was cooled to
–15°C and kept for 12 h at that temperature. The
precipitate was filtered off, washed with cold acetone
(2×100 ml) [yield 18.1 g (40%)] and recrystallized
twice from boiling acetone. Yield of (R)-IV·(R)-(+)-
PhCH(Me)NH2 14.5 g (33%) after first crystallization
and 14.1 g (31%) after second crystallization. Color-
less crystals, mp 133–135°C, [α]D = –29.3° (c = 0.8,
MeOH). IR spectrum (KBr), ν, cm–1: 3433 (NH3+),
1718 (C=O), 1546 (CO2–).1H NMR spectrum, δ, ppm:
1.48 d (3H, CHCH3, J = 6.7 Hz), 1.64 s and 1.65 s [3H
each, C(CH3)2], 2.28 d.d (1H, CHCH2, J = 14.1,
6.6 Hz), 2.45 t (2H, CH2CH2Cl, J = 7.1 Hz), 2.53 d.d
(1H, CHCH2, = J 14.1, 6.6 Hz), 3.53 t (2H, CH2Cl, J =
2-[(4R)-8-Chloro-2-methyl-6-methylidene-oct-2-
en-4-yloxycarbonyl]benzoic acid (R)-(IV). Hydrogen
phthalate salt (R)-IV·(R)-(+)-PhCH(Me)NH2, 14.0 g
(30.6 mmol), was treated with 100 ml of 10% H2SO4,
and acid (R)-IV was extracted into methylene chloride
(3×100 ml). The combined extracts were washed with
a saturated solution of sodium chloride, dried over
MgSO4, and evaporated under reduced pressure. Yield
10.3 g (100%), viscous oily substance, [α]D = –56.0°
(c = 1.3, benzene). IR spectrum (CCl4), ν, cm–1: 3500
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 9 2012

STEREOSELECTIVE SYNTHESIS OF (R)- AND (S)-IPSDIENOLS
(OH), 1742 (C=O), 1717 (C=O). 1H NMR spectrum, δ,
1171
REFERENCES
ppm: 1.75 s and 1.80 s [3H each, C(CH3)2], 2.33 d.d
(1H, CHCH2, J = 14.2, 6.3 Hz), 2.51–2.50 m (3H,
CHCH2, CH2CH2Cl), 3.63 t (2H, CH2Cl, J = 7.2 Hz),
4.92 s and 4.97 s (1H each, =CH2), 5.22 d (1H, =CH,
J = 9.0 Hz), 5.89 d.t (1H, CHO, J = 9.0, 6.3 Hz), 7.52–
7.66 m (3H, Harom), 7.90–7.92 m (1H, Harom), 10.90 br.s
(1H, CO2H). 13C NMR spectrum, δC, ppm: 18.6 (CH3),
25.7 (CH3), 39.0 (CH2), 41.1 (CH2), 42.5 (CH2), 71.5
(CH), 115.2 (CH2), 122.5 (CH), 128.8 (CH), 129.8 (C),
129.9 (CH), 130.7 (CH), 132.1 (CH), 133.7 (C), 138.7
(C), 141.1 (C), 167.3 (C), 172.2 (C). Found, %:
C 64.30; H 6.23. C18H21ClO4. Calculated, %: C 64.19;
H 6.28.
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(R)-IV in 10 ml of anhydrous tert-butyl alcohol was
added to a boiling solution of potassium tert-butoxide
in tert-butyl alcohol prepared by dissolution of 6.0 g
(154 mmol) of metallic potassium in 200 ml of anhy-
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light yellow liquid, [α]D = –16.8° (c = 1.8, MeOH);
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MeOH); published data [4]: [α]D24 = +15.7° (c = 0.99,
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The authors thank leading researcher N.V. Masalov
(Belarusian State University) for his help in perform-
ing the present study.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 9 2012

KOVALENKO, MATYUSHENKOV
1172
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 9 2012