(R)-4-menthenone in the synthesis of optically pure sex pheromone of the peach leafminer moth (Lyonetia clerkella)

Article abstract of DOI:10.1023/B:RUCB.0000011889.58249.43

The synthesis of (14S)-methyloctadec-1-ene, sex pheromone of the peach leafminer moth (Lyonetia clerkella), is described to demonstrate a new potential of the synthetic use of (R)-4-menthenone.

Full text of DOI:10.1023/B:RUCB.0000011889.58249.43

Russian Chemical Bulletin, International Edition, Vol. 52, No. 10, pp. 2267—2269, October, 2003
2267
(R)ꢀ4ꢀMenthenone in the synthesis of optically pure sex pheromone
of the peach leafminer moth (Lyonetia clerkella)
b
b
a
a
a
R. Ya. Kharisov,a E. R. Latypova, R. F. Talipov, R. R. Muslukhov, G. Yu. Ishmuratov, and G. A. Tolstikov
ꢀ
aInstitute of Organic Chemistry of the Ufa Scientific Center of the Russian Academy of Sciences,
71, prosp. Oktyabrya, 450054 Ufa, Russian Federation,
Fax: +7 (347 2) 35 6066. Eꢀmail: kharis@anrb.ru
bBashkir State University,
32, ul. Frunze, 450074 Ufa, Russian Federation,
Fax: +7 (347 2) 22 6105. Eꢀmail: TalipovRF@bsu.bashedu.ru
The synthesis of (14S)ꢀmethyloctadecꢀ1ꢀene, sex pheromone of the peach leafminer moth
(Lyonetia clerkella), is described to demonstrate a new potential of the synthetic use of
(R)ꢀ4ꢀmenthenone.
Key words: (–)ꢀmenthol, (R)ꢀ4ꢀmenthenone, (5R,1RS)ꢀ1ꢀethylꢀ2ꢀisopropylꢀ
5ꢀmethylcyclohexꢀ2ꢀenol, (S)ꢀ3ꢀethylꢀ2ꢀisopropylꢀ5ꢀmethylcyclohexꢀ2ꢀenone, methyl
(3S)ꢀmethylꢀ5ꢀoxoheptanoate, (14S)ꢀmethyloctadecꢀ1ꢀene, ozonolysis, CrVI oxidation, insect
pheromones.
Previously,1—3 we reported ozonolytic transformation
of (R)ꢀ4ꢀmenthenone (1) prepared from (–)ꢀmenthol to
give a valuable chiral synthon, namely, methyl (R)ꢀ5,5ꢀdiꢀ
methoxyꢀ3ꢀmethylpentanoate,1,2 and the use of this
product in the synthesis of optically pure juvenoid,
(S)ꢀ(+)ꢀhydroprene.3
In the present study, we report the synthesis of
(14S)ꢀmethyloctadecꢀ1ꢀene (2), the sex pheromone of
the peach leafminer moth (Lyonetia clerkella), as an exꢀ
ample to demonstrate a new potential for the synthetic
use of enone 1 related to the ability of conjugated enones
to undergo selective 1,2ꢀaddition of organometallic reꢀ
agents followed by oxidative rearrangement of the resultꢀ
ing tertiary allylic alcohols upon treatment with CrVI 4,5
.
Previously, syntheses of optically pure biologically acꢀ
tive (S)ꢀisomer 2 have made use of (R)ꢀ3ꢀhydroxyꢀ
2ꢀmethylpropionic acid6 or (R)ꢀ(+)ꢀpulegone;7 fracꢀ
tional crystallization of 2ꢀmethylhexanoic acid was also
used.8 We proposed to use readily available natural
(–)ꢀmenthol as the starting compound.
Scheme 1
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2146—2148, October, 2003.
1066ꢀ5285/03/5210ꢀ2267 $25.00 © 2003 Plenum Publishing Corporation

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Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Kharisov et al.
Na2SO4, and concentrated to give 4.74 g of alcohol 3. IR,
ν/cm–1: 916, 994 (H—C=); 1162 (C—O); 1654 (C=C); 3460
(O—H). This product was used in the next step without purifiꢀ
cation.
Regioselective 1,2ꢀaddition of EtLi to enone 1 and
subsequent treatment of the resulting (5R,1RS)ꢀ1ꢀethylꢀ
2ꢀisopropylꢀ5ꢀmethylcyclohexꢀ2ꢀenol (3) with pyridiꢀ
nium chlorochromate yielded (S)ꢀethylmenthenone (4)
Alcohol 3 (4.70 g, 25.8 mmol) in 5 mL of dry CH2Cl2 was
added to a vigorously stirred suspension of pyridinium chloroꢀ
chromate (11.98 g, 55.7 mmol) in 20 mL of dry CH2Cl2
(5—10 °C, Ar). The reaction mixture was stirred for 2 h at
∼20 °C, Et2O (30 mL) was added, and the mixture was stirred
for an additional 15 min and filtered through a layer of Al2O3.
The precipitate was washed with Et2O and the filtrate was conꢀ
centrated. The residue was chromatographed on SiO2 (using
light petroleum as the eluent) to give 2.98 g of compound 4
(63%, based on enone 2) whose chemical purity, according to
GLC, was 97%, Rf 0.62 (light petroleum : ButOMe = 2 : 1),
1
(Scheme 1). The signals for the protons in the H NMR
spectrum of compound 4 were assigned and the spinꢀspin
coupling constants were determined by means of 2D corꢀ
relation (COSYꢀ90°) and double resonance techniques.
Large vicinal coupling constants, 3J4a,5 and 3J6a,5, suggest
an equatorial orientation of the Ме group at C(5).9 The
magnetic nonequivalence of the methyl groups (δ 1.09
and 1.12) in the Pri substituent is apparently due to the
presence of a barrier to the rotation of the Pri group around
the C(2)—C(7) bond.
Subsequent ozonolysis of enone 4 accompanied by
elimination of the CCHMe2 fragment2 followed by
methanolysis yielded keto ester 5. The Huang—Minlon
deoxygenation of keto ester 5 accompanied by saponifiꢀ
cation of the ester group gave rise to (3S)ꢀmethylheptanoic
acid (6), which was converted, using a standard route via
alcohol 7 and tosylate 8, into the target pheromone 2 in
an overall yield of 15.4% starting from enone 1.
21
[α]D +70.9 (c 7.23, CHCl3). IR, ν/cm–1: 1612 (C=C); 1666
3
(C=O). 1H NMR, δ: 1.02 (d, 3 H, H(12), J = 6.0 Hz); 1.08 (t,
3 H, H(11), 3J = 7.6 Hz); 1.09 and 1.12 (both d, each 6 H, H(8),
H(9), 3J = 7.2 Hz); 1.95—2.01 (m, 1 H, Hax(5)); 2.03 (dd, 1 H,
Hax(6), 2J = 10.2 Hz, 3J = 10.6 Hz); 2.31 (dd, 1 H, Heq(6), 2J =
10.2 Hz, 3J = 2.6 Hz); 2.06 (dd, 1 H, Hax(4), 2J = 13.7 Hz, 3J =
12.3 Hz); 2.38 (dd, 1 H, Heq(4), 2J = 13.7 Hz, 3J = 3.3 Hz); 2.23
(q, 2 H, H(10), 3J = 7.6 Hz); 2.83 (sept, 1 H, H(7), 3J = 7.2 Hz).
13C NMR, δ: 12.23 (q, C(11)); 20.48 (q, C(12)); 20.49 and
21.01 (both q, C(8), C(9)); 26.52 (d, C(7)); 27.16 (t, C(10));
29.81 (d, C(5)); 39.13 (t, C(4)); 46.65 (t, C(6)); 137.66 (s, C(2));
158.31 (s, C(3)); 198.08 (s, C(1)). Found (%): C, 79.85; H, 11.12.
C12H10O. Calculated (%): C, 79.94; H, 11.16.
Thus, we demonstrated a new potential for the synꢀ
thetic application of readily available (R)ꢀ4ꢀmenthenone
involving chemoselective transformations leaving the
asymmetric center intact.
Methyl (3S)ꢀmethylꢀ5ꢀoxoheptanoate (5). An O3/O2 mixꢀ
ture (ozonizer productivity 40 mmol of O3 per h) was passed at
5 °C through a solution of enone 4 (2.90 g, 16.1 mmol) in a
mixture of 15 mL of anhydrous МеOH and 15 mL of CH2Cl2
until the starting compound disappeared (TLC). The reaction
mixture was purged with Ar, TsOH (0.14 g) and anhydrous
МеOH (20 mL) were added, the mixture was stirred for 48 h at
∼20 °C, NaHCO3 (1.47 g) was added, and the mixture was
concentrated in vacuo. The residue was diluted with 100 mL of
Et2O, washed with brine to рH 7, dried with Na2SO4, concenꢀ
trated, and chromatographed on SiO2 (light petroleum as the
eluent) to give 2.35 g (85%) of keto ester 5, whose chemical
Experimental
IR spectra were recorded on a Specord Mꢀ82 spectrometer
in thin film. NMR spectra (δ, J/Hz) were recorded on a Bruker
1
AMꢀ300 spectrometer (300.13 МHz for H and 75.47 МHz for
13C) in CDCl3 relative to Me4Si. Gas chromatography was carꢀ
ried out on a Chromꢀ5 instrument (column length 2.4 m;
PEGꢀ6000 (5%) on Inerton AWꢀDMCS (0.125—0.160 mm) as
the stationary phase; working temperature 50—200 °C); helium
was used as the carrier gas. Optical rotation was measured on a
Perkin—Elmer 241ꢀMC polarimeter. Column chromatography
was performed on Lancaster silica gel L (60—200 µm) (UK).
TLC was carried out using Silufol plates (Czechia); light petroꢀ
leum with b.p. 40—70 °C was used for chromatography.
The solvents were dried by standard procedures;10 THF and
Et2O were distilled over DIBAH prior to the reaction. The folꢀ
lowing commercial reagents were used: TsCl ("pure" grade, proꢀ
duced at the Shostka chemical plant) was recrystallized from
CHC13; N2H4•H2SO4 ("pure" grade, Reakhim); and LiAlH4
(USSR). Li2CuCl4 was prepared by a procedure described preꢀ
viously.11
purity was 98%, according to GLC, Rf 0.3 (light petroleum :
21
ButOMe = 2 : 1), [α]D +2.8 (c 5.76, C2H5OH). IR, ν/cm–1
:
1114, 1258 (C—O—C); 1714, 1738 (C=O). 1H NMR, δ: 0.89
(d, 3 H, H3CC(3), 3J = 6.3 Hz); 0.97 (t, 3 H, H(7), 3J = 7.3 Hz);
2.14 (dd, 1 H, H(2), J = 14.9 Hz, J = 6.8 Hz); 2.42 (dd, 1 H,
H´(2), 2J = 14.9 Hz, 3J = 6.8 Hz); 2.26 (dd, 1 H, H(4), 2J =
13.2 Hz, 3J = 7.0 Hz); 2.39 (dd, 1 H, H´(4), J = 13.2 Hz, 3J =
2
3
2
7.0 Hz); 2.25—2.33 (m, 1 H, H(3)); 2.37 (q, 2 H, H(6), 3J =
7.3 Hz); 3.59 (s, 3 H, H3CO). 13C NMR, δ: 7.57 (q, C(7)); 19.90
(q, H3CC(3),); 26.22 (d, C(3)); 36.19 (t, C(6)); 40.57 (t, C(2));
48.40 (t, C(4)); 51.29 (q, H3CO); 172.81 (s, C(1)); 210.29
(s, C(5)). Found (%): C, 62.59; H, 9.31. C9H16O3. Calcuꢀ
lated (%): C, 62.77; H, 9.36.
(3S)ꢀMethylheptanoic acid (6). Keto ester 5 (0.60 g,
3.5 mmol) and diethylene glycol (3.5 mL) were added dropwise
with stirring at 15 °C to a solution of N2H4•H2SO4 (1.36 g,
10.5 mmol) in 13 mL of 10% aqueous КOH. The mixture was
stirred at this temperature for 2.5 h and allowed to stand for
16 h. Potassium hydroxide (1.00 g, 17.4 mmol) was added, the
mixture was refluxed for 2 h, and water and excess hydrazine
hydrate were distilled off until the reaction temperature reached
(S)ꢀ3ꢀEthylꢀ2ꢀisopropylꢀ5ꢀmethylcyclohexꢀ2ꢀenone (4).
A 1.75 М solution of EtLi (45 mL) in anhydrous THF was added
dropwise to a stirred solution of menthenone 12,3 (4.00 g,
26.3 mmol) in 30 mL of anhydrous Et2O (–78 °C, Ar).12 The
reaction mixture was stirred for 1 h, the temperature being graduꢀ
ally raised to ∼20 °C. Then the mixture was stirred for an addiꢀ
tional 2 h and cooled to 5 °C, a saturated solution of NH4Cl
(40 mL) was added, and the mixture was extracted with Et2O
(3×30 mL). The extract was washed with brine, dried with

Synthesis of pheromones
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2269
18
195 °C. The mixture was heated for an additional 4 h at 195 °C,
cooled, diluted with 4 mL of water, and extracted with CH2Cl2
(3×20 mL). The aqueous layer was acidified with 10% H2SO4
and extracted with CH2Cl2 (3×20 mL). The extract was dried
with MgSO4 and concentrated. The residue was chromatoꢀ
graphed on SiO2 (CHCl3 as the eluent) to give 0.31 g (61%)
of acid 6, Rf 0.67 (light petroleum : ethyl acetate = 2 : 1),
(63%) of olefin 1, [α]D +1.18 (c 5.1, CHCl3) (cf. Ref. 7).
Parameters of the IR and NMR spectra were almost identical to
those reported previously.17
References
18
[α]D –4.15 (c 3.99, benzene) (cf. Ref. 13). The parameters of
1. R. Ya. Kharisov, O. V. Botsman, R. R. Gazetdinov, G. Yu.
Ishmuratov, and G. A. Tolstikov, Izv. Akad. Nauk, Ser.
Khim., 2001, 1067 [Russ. Chem. Bull., Int. Ed., 2001,
50, 1117].
2. R. Ya. Kharisov, O. V. Botsman, R. R. Gazetdinov, G. Yu.
Ishmuratov, and G. A. Tolstikov, Zh. Org. Khim., 2002, 38,
1047 [Russ. J. Org. Chem., 2002, 38 (Engl. Transl.)].
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G. A. Tolstikov, Khimiya Prirod. Soedinen., 2002, 122 [Chem.
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the IR spectrum were virtually identical to those reported previꢀ
3
ously:14 1H NMR, δ: 0.89 (t, 3 H, H(7), J = 6.5 Hz); 0.97 (d,
3 H, H3CC(3), 3J = 6.6 Hz); 1.15—1.44 (m, 6 H, H(4)—H(6));
2
1.88—2.05 (m, 1 H, H(3)); 2.15 (dd, 1 H, H(2), J = 14.9 Hz,
2
3
3J = 8.2 Hz); 2.36 (dd, 1 H, H´(2), J = 14.9 Hz, J = 5.9 Hz);
11.15 (br.s, H—O). (cf. Ref. 14).
(3S)ꢀMethylheptanꢀ1ꢀol (7). A solution of acid 6 (0.30,
2.1 mmol) in 2 mL of anhydrous Et2O was added (0 °C, Ar) to a
stirred suspension of LiAlH4 (0.16 g, 4.2 mmol) in 4 mL of
anhydrous Et2O. Then the reaction mixture was heated to ∼20 °C,
stirred for 2 h, and cooled to 0 °C, and 0.3 mL of water and
0.12 mL of a 15% solution of NaOH were added successively
with stirring. The reaction mixture was stirred for 2 h, the orꢀ
ganic layer was separated, and the aqueous layer was extracted
with Et2O (3×15 mL). The extracts were combined with the
organic layer, washed with brine (to pH 7), dried with Na2SO4,
and concentrated to give 0.23 g (75%) of alcohol 7, [α]D18 –2.73
(c 2.96, CHCl3) (cf. Ref. 15). Parameters of the IR and 1H NMR
spectra were almost identical to those reported previously.16
(3S)ꢀMethylꢀ1ꢀtosyloxyheptane (8). Tosyl chloride (0.28 g,
1.5 mmol) was added in small portions to a solution of alcohol 7
(0.20 g, 1.4 mmol) in 4.5 mL of anhydrous pyridine at 0 °C and
the mixture was left for 16 h in a refrigerator. Then the mixture
was dissolved in 20 mL of Et2O, washed successively with brine,
saturated solutions of CuSO4 and NaHCO3, and brine, dried
with Na2SO4, and concentrated to give 0.39 g of tosylate 8. IR,
ν/cm–1: 1180, 1350 (S=O); 1600 (Ar). The product was used in
the next step without further purification.
(14S)ꢀMethyloctadecꢀ1ꢀene (2). A solution of tosylate 8
(0.39 g, 1.4 mmol) in 10 mL of anhydrous THF was added
dropwise (–75 °C, Ar) to a stirred solution of the Grignard
reagent prepared from undecꢀ10ꢀenyl bromide17 (0.36 g,
1.5 mmol) and Mg (0.04 g, 1.7 mmol) in 5 mL of anhydrous
THF. A 0.2 М solution of Li2CuCl4 (0.40 mL) in anhydrous
THF was added. The reaction mixture was stirred for 1 h at
–70 °C, for 2 h at –10 °C, and for 2 h at 25 °C, poured into a
cooled saturated solution of NH4Cl, and extracted with Et2O
(3×20 mL). The combined extract was washed successively with
brine, a saturated solution of NaHCO3, and brine, dried with
MgSO4, and concentrated. The residue was chromatographed
on SiO2 (using light petroleum as the eluent) to give 0.23 g
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1992, 714 [Chem. Nat. Comp., 1992 (Engl. Transl.)].
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Received May 6, 2003;
in revised form July 25, 2003