New asymmetric synthesis of a pheromone component of the shield bug Cantao Parentum

Article abstract of DOI:10.1134/S1070428014030178

A novel procedure has been developed for the synthesis of (2S,4R,6R,8S)-2,4,8-trimethyl-1,7-dioxaspiro[5.5]undecane, a pheromone component of the shield bug Cantao Parentum, through intermediate cyclopropanol derivatives in the key stages of carbon chain

Full text of DOI:10.1134/S1070428014030178

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 3, pp. 398–405. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © I.V. Mineeva, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 3, pp. 408–417.
New Asymmetric Synthesis of a Pheromone Component
of the Shield Bug Cantao Parentum
I. V. Mineeva
Belarusian State University, pr. Nezavisimosti 4, Minsk, 220030 Belarus
e-mail: i.mineyeva@yandex.ru
Received November 5, 2013
Abstract—A novel procedure has been developed for the synthesis of (2S,4R,6R,8S)-2,4,8-trimethyl-1,7-dioxa-
spiro[5.5]undecane, a pheromone component of the shield bug Cantao Parentum, through intermediate
cyclopropanol derivatives in the key stages of carbon chain construction and introduction of functional groups.
DOI: 10.1134/S1070428014030178
Structurally relatively simple spiro acetals are wide-
spread in nature and are components of higher insect
secretions. It has recently been found that the main
component of the abdominal gland of the shield bug
Cantao Parentum (White) is (2S,4R,6R,8S)-2,4,8-tri-
methyl-1,7-dioxaspiro[5.5]undecane (I), an unusual
representative of methyl-substituted spiro acetals
secreted by insects [1]. The synthesis of compound I
was reported in a few publications [1–3].
was treated with dihydropyran to protect the hydroxy
group. The optical purity of ester V was determined by
Mosher’s method, from the intensity ratio of the
signals of methoxy (δ 3.54 and 3.56 ppm) and methyl
1
protons (δ 1.34 and 1.43 ppm) in the H NMR spec-
trum of the acylation product of V with (S)- and
(R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl
chloride (Mosher’s acid chloride) [8]. Tetrahydropyr-
anyl ether VI was reduced with lithium tetrahydrido-
aluminate, alcohol VII thus obtained was carefully
oxidized with pyridinium dichromate (PDC), and inter-
mediate labile aldehyde was subjected to Wittig
olefination. The overall yield of compound III in five
steps was 41% (Scheme 1).
Key ester II was synthesized from accessible
lactone VIII which was prepared in turn starting from
ethyl 3,3-diethoxypropionate (IX) according to previ-
ously developed procedures [9] (Scheme 2). Cyclopro-
panation of IX, mesylation of X, and oxidation of the
diethyl acetal moiety in XI afforded ethyl 2-(1-meth-
anesulfonyloxycyclopropyl)acetate (XII). Cationic cy-
clopropyl–allyl rearrangement of the latter gave ester
XIII having an allyl bromide fragment, and compound
XIII was converted via mild Barbier allylation [10]
into organotin derivative XIV [11]. Unsaturated
lactone (R)-XV was obtained by modified asymmetric
allylation according to Keck [12]. The high enantio-
meric excess of (R)-XV was determined by Mosher’s
method [8] (from the intensity ratio of the signals of
the methoxy groups, δ 3.41 and 3.57 ppm) after trans-
formation of lactone XV into labile alcohol via succes-
sive reduction to the corresponding diol, ring closure
Me
O
Me
O
O
Me
O
O
OCH2Ph
MeO
O
Me
I
II
O
Me
CH2
III
In the present work the carbon skeleton of molecule
I was built up via reductive cyclopropanation with
ligand exchange between key building block II and
tetrahydropyran-protected alkenol III. Analogous cy-
clopropanol strategy was used previously to synthesize
some bioactive compounds [4].
Compound III was prepared according to the
known scheme of consecutive transformations [5–7]
(Scheme 1). Enzymatic reduction of ethyl acetoacetate
(IV) with baker’s yeast gave hydroxy ester V which
398

NEW ASYMMETRIC SYNTHESIS OF A PHEROMONE COMPONENT
399
Scheme 1.
, CH2Cl2, PPTS
OH
O
O
O
O
O
O
Baker's yeast
O
Me
OEt
Me
OEt
Me
OEt
V, 54%, ee 92%
VI, 98%
IV
(1) PDC, CH2Cl2
(2) MePPh3I, t-BuOK, THF
LiAlH4, Et2O
O
O
O
O
Me
VII, 99%
OH
Me
CH2
III, 78%
of the latter to unsaturated pyran, and removal of the
benzyl protecting group (see the procedure for the
synthesis of the S isomer [9]).
change with alkene III afforded disubstituted cyclo-
propanol XVI as a mixture of diastereoisomers in
a moderate yield (Scheme 3). Oxidative cleavage of
the cyclopropane ring in XVI at the C1−C2 bond by the
action of chromium(VI) oxide in acetone at 0°C [13]
gave hydroxy ketone XVII. The hydroxy group in the
latter was removed via mesylation, and subsequent
reduction of the double C=C bond led to ketone
XVIII. Addition of methanol in the reduction process
improved the solubility and facilitated separation of
products resulting from side reduction of the carbonyl
group.
The tetrahydropyranyl protecting groups were
removed from XVIII by treatment with methanol in
the presence of a catalytic amount of p-toluenesulfonic
acid, and the intermediate cyclic acetal thus formed
was subjected to reductive debenzylation by hydro-
genolysis over Pd/C in methanol. The major diastereo-
Diastereoselective reduction of the prochiral double
bond in lactone XV [9] gave key lactone VIII which
was subjected to column chromatography on silica gel;
as a result, the ratio of the cis and trans isomers of
VIII increased from 10:1 to 20:1. Treatment of VIII
with triethylamine in methanol produced intermediate
hydroxy ester, and the hydroxy group in the latter was
protected by transformation into tetrahydropyranyl
ether (Scheme 2). In this way, the second building
block II was isolated in an overall yield of 20%
(9 steps) starting from readily accessible ethyl 3,3-di-
ethoxypropionate (IX).
Reductive cyclopropanation of II with the use of
cyclohexylmagnesium bromide and an equivalent
amount of titanium tetraisopropoxide and ligand ex-
Scheme 2.
OEt
O
OEt OH
OEt OMs
EtMgBr, Ti(OPr-i)4, THF–H2O
MsCl, Et3N, Et2O
EtO
OEt
EtO
O
EtO
IX
X, 95%
CH2
XI, 98%
Bu3SnCl, Zn
NH4Cl, THF–H2O
O
OMs
O
CH2
HCl, H2O2, EtOH
MgBr2, CHCl3
Br
SnBu3
EtO
EtO
EtO
XII, 68%
XIII, 83%
XIV, 64%
Me
O
Me
PhCH2OCH2CHO, (R)-BINOL
Ti(OPr-i)4, CF3COOH, MePh
NaBH4, NiCl2·6H2O
H3BO3, THF–H2O
OCH2Ph
OCH2Ph
O
O
O
XV, 88%, ee 98%
VIII, 90%, de 91%
(1) Et3N, MeOH
(2)
, CH2Cl2, PPTS
O
II, 74%
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014

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400
Scheme 3.
cyclo-C6H11MgBr
Ti(OPr-i)4, THF
II
+ III
O
O
OH
Me
O
O
OCH2Ph
Me
XVI, 77%
CrO3, NaOAc
Me2CO
O
O
OH
O
Me
O
O
OCH2Ph
Me
XVII, 62%
(1) MsCl, Et3N, CHCl3
(2) NiCl2·6H2O, NaBH4, MeOH, THF
O
O
O
Me
O
O
OCH2Ph
Me
XVIII, 88%
Me
Me
O
O
(1) TsOH, MeOH
(2) H2, Pd/C, MeOH
(1) MsCl, Et3N, Et2O
(2) LiAlH4, Et2O
Me
Me
O
O
OH
Me
XIX, 90%
I, 87%
isomer of XIX was isolated by column chromatog-
raphy, and its spectral characteristics completely coin-
cided with those reported in [3]. Successive mesylation
and exhaustive reduction of the intermediate methane-
sulfonate with lithium tetrahydridoaluminate in diethyl
ether at room temperature afforded target pheromone
component I whose spectral parameters were identical
to those given in [3]. The overall yield of I in the 17-
step synthesis starting from ester IX was 7%.
The described methodology for the synthesis of
a secretion component of the shield bug Cantao
Parentum is advantageous due to high yields, simple
experimental procedures, and the use of cheap and
accessible reagents; it requires no expensive or toxic
catalysts and ensures convenient combination of
complex polyfunctional building blocks into the target
carbon skeleton.
ured on a Bruker Vertex 70 spectrometer. The optical
rotations were determined at room temperature on
an SM-3 polarimeter (scale mark 0.05°). The pure
products were isolated by chromatography on silica gel
(70–230 mesh). All solvents were dried according to
standard methods and distilled before use.
Ethyl (3S)-3-hydroxybutanoate (V). Dry baker’s
yeast, 25 g, was dispersed in 300 mL of water at 30°C,
50 g of saccharose was added, the mixture was vigor-
ously stirred for 10 min to initiate fermentation, and
3 g (23 mmol) of freshly distilled ethyl acetoacetate
(IV) was added. The mixture was vigorously stirred
for 12 h at a bath temperature of 35–38°C, 100 mL of
diethyl ether was added, and the mixture was filtered
through a layer of alumina. The organic phase was
separated, the aqueous phase was extracted with
diethyl ether (3×30 mL), the extracts were combined
with the organic phase, washed with brine (150 mL),
and dried over MgSO4, the solvent was removed under
reduced pressure, and the residue was subjected to
chromatography using petroleum ether–ethyl acetate
(40:1 to 5:1) as eluent. Yield 1.64 g (54%). The spec-
tral parameters of ester V were consistent with those
reported in [7].
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded from
solutions in chloroform-d on a Bruker AC 400 spec-
trometer at 400 and 100 MHz, respectively. The IR
spectra of solutions in carbon tetrachloride were meas-
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NEW ASYMMETRIC SYNTHESIS OF A PHEROMONE COMPONENT
401
Ethyl (3S)-3-(tetrahydro-2H-pyran-2-yloxy)-
butanoate (VI). Hydroxy ester V, 0.70 g (5.3 mmol),
was dissolved in 10 mL of anhydrous methylene
chloride, 0.56 g (6.6 mmol) of 3,4-dihydro-2H-pyran
and a catalytic amount of pyridinium p-toluenesul-
fonate (PPTS) were added, and the mixture was heated
for 2.5 h under reflux. When the reaction was complete
(TLC), the mixture was washed with a saturated solu-
tion of NaHCO3 (100 mL) and dried over MgSO4. The
solvent was removed under reduced pressure to obtain
a compound VI as a colorless oily substance. Yield
1.12 g (98%). The spectral parameters of the product
were consistent with those reported in [14].
(3S)-3-(Tetrahydro-2H-pyran-2-yloxy)butan-1-ol
(VII). A solution of 1.30 g (6.0 mmol) of protected
hydroxy ester VI in 6 mL of anhydrous diethyl ether
was added under stirring to a suspension of 0.12 g
(3 mmol) of LiAlH4 in 6 mL of anhydrous diethyl
ether. The mixture was stirred for 1 h and diluted with
30 mL of diethyl ether, 0.5 mL of water was added, the
mixture was filtered, and the precipitate was washed
with diethyl ether (15 mL). The organic phases were
combined, dried over Na2SO4, and evaporated under
reduced pressure to isolate compound VII as a mixture
of diastereoisomers. Yield 1.03 g (99%). IR spectrum,
ν, cm–1: 3401, 1076, 1023. 1H NMR spectrum, δ, ppm:
1.14 d (3H, CH3, J = 6.1 Hz), 1.26 d (3H, CH3, J =
6.4 Hz), 1.43–1.55 m (8H, CH2CH2CH2CHO,
CH2CH2CH2CHO), 1.58–1.66 m (1H, CH2CH2OH),
1.68–1.81 m (7H, CH2CH2OH, CH2CH2CH2CHO),
2.52 br.s (1H, OH), 3.27 br.s (1H, OH), 3.45–3.51 m
(2H, CH3CHOCH), 3.62–3.71 m (2H, CH2CH2O),
3.73–3.85 m (2H, CH2CH2O), 3.86–3.96 m (3H,
CH2OH), 3.98–4.06 m (1H, CH2OH), 4.54–4.56 m
(1H, OCHO), 4.66–4.68 m (1H, OCHO). 13C NMR
spectrum, δC, ppm: 20.2, 20.3, 21.2, 22.0, 25.4, 25.6,
31.5, 31.6, 39.0, 39.3, 60.0, 60.4, 63.2, 64.6, 70.8,
74.0, 98.1, 99.6. Found, %: C 62.06; H 10.39.
C9H18O3. Calculated, %: C 62.04; H 10.41.
thus obtained (1.21 g) was used in the next step
without additional purification. A suspension of 2.34 g
(5.8 mmol) of methyltriphenylphosphonium iodide in
12 mL of THF was cooled to −78°C, 0.62 g
(5.5 mmol) of potassium tert-butoxide was added, the
mixture was stirred for 1.5 h, a solution of 1.21 g
(5.3 mmol) of the aldehyde in 6 mL of THF was
slowly added over a period of 1 h at −5°C, and the
mixture was stirred for 2 h. The mixture was diluted
with water (30 mL), the aqueous phase was extracted
with chloroform (3×15 mL), the extracts were com-
bined and dried over MgSO4, the solvent was distilled
off under reduced pressure, and the product was
isolated by chromatography on silica gel using petro-
leum ether–ethyl acetate (100:1) as eluent. Yield
0.78 g (78%). IR spectrum, ν, cm–1: 1261, 1021.
1H NMR spectrum, δ, ppm: 1.08 d and 1.19 d (1.5H
each, CH3, J = 6. 1 Hz), 1. 42–1. 84 m (6H,
OCHCH2CH2CH2), 2.11–2.37 m (2H, CH2CH=CH2),
3.43–3.55 m (1H, CH3CHOCH), 3.76–3.95 m (2H,
CH2O), 4.54–4.78 m (1H, OCHO), 4.91–5.07 m (2H,
CH2=), 5.71–5.86 m (1H, CH=). 13C NMR spectrum,
δC, ppm: 19.6, 19.9, 20.5, 21.1, 25.4, 25.5, 30.9, 31.1,
40.7, 41.9 62.3, 62.6, 70.8, 72.6, 97.9, 98.3, 116.6,
116.8, 134.8, 135.3. Found, %: C 70.59; H 10.62.
C10H18O2. Calculated, %: C 70.55; H 10.66.
1-(2,2-Diethoxyethyl)cyclopropanol (X). A solu-
tion of 9.5 g (50 mmol) of ester IX and 2.8 mL
(10 mmol) of Ti(OPr-i)4 in 50 mL of THF–Et2O (1:1)
was cooled to 10°C, a solution of 150 mmol of ethyl-
magnesium bromide in 150 mL of THF−Et2O (1:1)
was added under stirring over a period of 6 h, and the
mixture was stirred for 24 h. The solvent was removed
under reduced pressure, the residue was treated with
200 mL of diethyl ether and 15 mL of a saturated
aqueous solution of ammonium chloride under effi-
cient cooling, the mixture was filtered, the precipitate
was washed with diethyl ether (3×50 mL), and the
organic phase was washed with brine (100 mL) and
dried over Na2SO4. The solvent was removed under
reduced pressure to isolate 8.27 g (95%) of compound
X whose spectral parameters were consistent with
those reported in [15].
2-[(2S)-Pent-4-en-2-yloxy]tetrahydro-2H-pyran
(III). A solution of 1.03 g (5.9 mmol) of alcohol VII in
10 mL of anhydrous methylene chloride was added in
one portion to a suspension of 3.22 g (8.8 mmol) of
pyridinium dichromate in 15 mL of anhydrous methy-
lene chloride, and the mixture was stirred for 10 h until
the reaction was complete. The mixture was filtered
through a layer of silica gel, and the filtrate was
evaporated under reduced pressure. The residue was
dissolved in 50 mL of diethyl ether, the solution was
filtered through a layer of silica gel, and the solvent
was removed under reduced pressure. The aldehyde
1-(2,2-Diethoxyethyl)cyclopropyl methanesul-
fonate (XI). A solution of 5.38 g (31 mmol) of com-
pound X in 40 mL of anhydrous diethyl ether was
cooled to 0°C, 8.6 mL (62 mmol) of triethylamine was
added under stirring, and a solution of 3.6 mL
(37 mmol) of methanesulfonyl chloride in 40 mL of
anhydrous diethyl ether was added dropwise. The mix-
ture was stirred for 2 h and treated with a saturated
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aqueous solution of NaHCO3 (100 mL), the organic
layer was separated, the aqueous layer was extracted
with diethyl ether (3×25 mL), and the extracts were
combined with the organic phase, washed with brine
(50 mL), and dried over Na2SO4. Removal of the
solvent gave methanesulfonate XI which was brought
into the next step without additional purification. Yield
7.66 g (98%). IR spectrum, ν, cm–1: 1331, 1171, 1145.
1H NMR spectrum, δ, ppm: 0.78–0.82 m (2H, CH2,
cyclopropyl), 1.19 t (6H, CH3CH2O, J = 7.0 Hz), 1.21–
1.25 m (2H, CH2, cyclopropyl), 2.13 d (2H, CHCH2C,
J = 5.4 Hz), 3.00 s (3H, CH3SO2), 3.49–3.57 m (2H,
CH3CH2O), 3.62–3.70 m (2H, CH3CH2O), 4.78 t (1H,
OCHO, J = 5.4 Hz). 13C NMR spectrum, δC, ppm: 11.6
(2C), 15.2 (2C), 39.8, 40.3, 62.1, 63.8 (2C), 100.9.
Found, %: C 47.66; H 7.94. C10H20O5S. Calculated, %:
C 47.60; H 7.99.
Ethyl [1-(methanesulfonyloxy)cyclopropyl]-
acetate (XII). A solution of 20.92 g (83.0 mmol) of
methanesulfonate XI in 130 mL of ethanol was cooled
to 0°C, 10.6 mL of concentrated aqueous HCl and
14.5 mL of 33% hydrogen peroxide were added in
succession, and the mixture was stirred for 1 h and
kept for 5 h at 50–55°C. The mixture was cooled to
0°C, 7.1 mL of concentrated aqueous HCl and 9.7 mL
of 33% hydrogen peroxide were added, and the mix-
ture was heated again for 5 h at 50–55°C. The main
part of the solvent was removed under reduced
pressure, the residue was diluted with ethyl acetate
(100 mL), the mixture was neutralized with an aqueous
solution of NaHCO3 (400 mL), the organic phase was
separated, and the aqueous phase was extracted with
ethyl acetate (3×50 mL). The extracts were combined
with the organic phase and dried over Na2SO4, and the
solvent was distilled off under reduced pressure to
isolate compound XII which was used in the next step
without additional purification. Yield 12.53 g (68%).
IR spectrum, ν, cm–1: 1740, 1358, 1175, 1037.
1H NMR spectrum, δ, ppm: 0.88–0.91 m (2H, CH2,
cyclopropyl), 1.27 t (3H, CH3CH2O, J = 7.2 Hz), 1.36–
1.40 m (2H, CH2, cyclopropyl), 2.84 br.s (2H,
CH2CO), 3.03 s (3H, CH3SO2), 4.18 q (2H, CH3CH2O,
J = 7.2 Hz). 13C NMR spectrum, δC, ppm: 12.0 (2C),
14.1, 39.7, 41.1, 60.8, 62.2, 169.9. Found, %: C 43.27;
H 6.30. C8H14O5S. Calculated, %: C 43.23; H 6.35.
completely. About 180 mL of diethyl ether was
distilled off from the resulting solution of MgBr2 to
obtain a colorless viscous mixture, a solution of
37.30 g (168 mmol) of methanesulfonate XII in
200 mL of chloroform was added under stirring, and
the mixture was heated for 8 h under reflux. The
mixture was treated with 200 mL of water, the organic
phase was separated, the aqueous phase was extracted
with chloroform (3×75 mL), the extracts were com-
bined with the organic phase and dried over MgSO4,
the solvent was distilled off under reduced pressure,
and the product was isolated by chromatography on
silica gel using petroleum ether–ethyl acetate (100:1)
as eluent. Yield 16.23 g (83%). IR spectrum:
1
ν 1740 cm–1. H NMR spectrum, δ, ppm: 1.26 t (3H,
CH3CH2O, J = 7.2 Hz), 3.25 br.s (2H, CH2CO),
4.11 br.s (2H, CH2Br), 4.15 q (2H, CH3CH2O, J =
7.2 Hz), 5.11 br.s and 5.34 br.s (1H each, CH2=).
13C NMR spectrum, δC, ppm: 14.1, 36.1, 38.8, 60.9,
119.3, 138.7, 170.7. Found, %: C 40.64; H 5.33.
C7H11BrO2. Calculated, %: C 40.60; H 5.35.
Ethyl 3-[(tributylstannyl)methyl]but-3-enoate
(XIV). Tributylstannyl chloride, 7 g (22 mmol), was
dissolved in 10 mL of THF, 150 mL of a saturated
aqueous solution of ammonium chloride and 1.68 g
(26 mmol) of zinc were added under vigorous stirring,
a solution of 5.38 g (26 mmol) of compound XIII in
26 mL of THF was added over a period of 20 min,
30 mL of a saturated aqueous solution of ammonium
chloride and 1.68 g (26 mmol) of zinc were addition-
ally added, and the mixture was vigorously stirred for
1 h and extracted with diethyl ether (3×75 mL). The
combined extracts were dried over MgSO4, the solvent
was distilled off under reduced pressure, and the prod-
uct was isolated by chromatography on silica gel using
petroleum ether–ethyl acetate (120:1) as eluent. Yield
6.07 g (64%). The spectral parameters of the product
were in agreement with those given in [11].
(6R)-6-(Benzyloxymethyl)-4-methyl-3,6-dihydro-
2H-pyran-2-one (XV). A 0.1 M solution of Ti(OPr-i)4,
5.8 mL (0.6 mmol), and 0.2 mL (20 μmol) of a 0.1 M
solution of trifluoroacetic acid were added to a mixture
of 0.34 g (1.2 mmol) of (R)-BINOL and 2.5 g of 4-Å
molecular sieves (preliminarily calcined at 125–130°C
in an oil-pump vacuum) in 20 mL of anhydrous
toluene, and the mixture was stirred for 2.5 h at room
temperature. The mixture was cooled to –30°C,
a mixture of 7.76 g (18.0 mmol) of compound XIV
and 1.76 g (12.0 mmol) of benzyloxyacetaldehyde [16]
in 10 mL of anhydrous toluene was added, and the
mixture was left to stand for 7 days in a refrigerator at
Ethyl 3-(bromomethyl)but-3-enoate (XIII). A so-
lution of 29.7 mL (344 mmol) of 1,2-dibromoethane in
200 mL of anhydrous diethyl ether was slowly added
dropwise to 8.06 g (336 mmol) of magnesium turnings
in 100 mL of anhydrous diethyl ether, and the mixture
was heated under reflux until magnesium dissolved
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NEW ASYMMETRIC SYNTHESIS OF A PHEROMONE COMPONENT
403
–15°C without stirring. The mixture was then treated
under vigorous stirring with a saturated aqueous solu-
tion of NaHCO3 (100 mL), the organic phase was
separated, the aqueous phase was extracted with
chloroform (3×30 mL), and the extracts were com-
bined with the organic phase and dried over MgSO4.
The solvent was distilled off under reduced pressure,
and the product was isolated by chromatography using
petroleum ether–ethyl acetate (100:1 to 5:1) as eluent.
Yield 1.22 g (88%), [α]D = –120.7° (c = 1.2, CHCl3).
IR spectrum: ν 1731 cm–1. 1H NMR spectrum, δ, ppm:
1.98 s (3H, CH3), 2.26 d.d (1H, CH2CHO, J = 17.9,
4 Hz), 2.55 d.d (1H, CH2CHO, J = 17.9, 11.7 Hz),
3.63–3.71 m (2H, CHCH2OCH2Ph), 4.53–4.57 m (1H,
CH2CHO), 4.59 br.s (2H, CH2Ph), 5.80 br.s (1H,
CHCO), 7.28–7.40 m (5H, Ph). 13C NMR spectrum,
δC, ppm: 23.0, 31.3, 70.7, 73.6, 75.9, 116.2, 128.0
(2C), 128.3 (2C), 128.4, 131.6, 157.1, 164.5. Found,
%: C 72.42; H 6.91. C14H16O3. Calculated, %: C 72.39;
H 6.94.
1.80 g (7.7 mmol) of lactone VIII in 30 mL of metha-
nol, and the mixture was kept for 48 h. Excess metha-
nol and triethylamine were removed under reduced
pressure, the residue was diluted with 20 mL of anhy-
drous methylene chloride, 1.33 g (16 mmol) of 3,4-di-
hydro-2H-pyran and a catalytic amount of pyridinium
p-toluenesulfonate were added, and the mixture was
heated for 4 h under reflux. When the reaction was
complete (TLC), a catalytic amount of triethylamine
was added, the solvent was distilled off under reduced
pressure, and the product was isolated by chromatog-
raphy on silica gel using petroleum ether–ethyl acetate
(100:1) as eluent. Yield 1.99 g (74%). IR spectrum, ν,
1
cm–1: 1738, 1077, 1026. H NMR spectrum, δ, ppm:
0.83–0.90 m (4H, OCHCH2CH2), 0.95 d (3H, CHCH3,
J = 6.1 Hz), 0.98 d (3H, CHCH3, J = 6.4 Hz), 1.10–
1.86 m (14H, CHCH3, CHCH2CHO, OCH2CH2CH2),
2.12–2.19 m (2H, CH2CO), 2.33–2.41 m (2H,
CH2CO), 3.41–3.51 m (4H, CH2OCH2Ph), 3.66 s (6H,
OCH3), 3.63–3.67 m (1H, CHOCHCH2), 3.77–3.84 m
(1H, CHOCHCH2), 3.86–3.98 m (4H, CH2OCH),
4.52 d (2H, CH2Ph, J = 2.1 Hz), 4.55 d (2H, CH2Ph,
J = 2.3 Hz), 4.63–4.66 m (1H, OCHO), 4.80–4.83 m
(4R,6R)-6-(Benzyloxymethyl)-4-methyltetrahy-
dro-2H-pyran-2-one (VIII). An emulsion of 2.32 g
(10 mmol) of compound XV in a mixture of 50 mL of
THF and 50 mL of water was cooled to 0°C, 2.60 g
(11 mmol) of NiCl2·6H2O and 2.34 g (40 mmol) of
H3BO3 were added, and 0.84 g (22 mmol) of NaBH4
was added in portions under stirring over a period of
10 min. The mixture was stirred for 0.5 h on cooling,
15 g of sodium chloride was added at room tempera-
ture, and the mixture was extracted with diethyl ether
(4×25 mL). The combined extracts were dried over
Na2SO4, the solvent was distilled off under reduced
pressure, and the major (4R,6R)-diastereoisomer of
VIII was isolated by chromatography using petroleum
ether–ethyl acetate (40:1) as eluent. Yield 2.11 g
(90%), [α]D = –12.8° (c = 1.4, CHCl3). IR spectrum, ν,
13
(1H, OCHO), 7.28–7.36 m (10H, Ph). C NMR spec-
trum, δC, ppm: 19.4, 19.8, 22.6, 22.8, 25.4, 25.5, 26.9,
27.0, 31.0, 31.1, 39.3, 39.5, 42.0, 42.1, 51.3, 51.5,
62.5, 62.7, 72.4, 72.6, 73.0, 73.2, 75.2, 75.5, 94.6,
94.9, 127.5 (3C), 127.6 (3C), 128.2 (2C), 128.3 (2C),
138.3, 138.5, 173.4, 173.5. Found, %: C 68.59; H 8.60.
C20H30O5. Calculated, %: C 68.54; H 8.63.
1-[(2R,4R)-5-Benzyloxy-2-methyl-4-(tetrahydro-
2H-pyran-2-yloxy)pentyl]-2-[(2S)-2-(tetrahydro-
2H-pyran-2-yloxy)propyl]cyclopropan-1-ol (XVI). A
solution of 45.0 mmol of cyclohexylmagnesium
bromide in 45 mL of THF was added under stirring
over a period of 4 h to a solution of 1.70 g (10.0 mmol)
of compound III, 2.8 mL (10.0 mmol) of Ti(OPr-i)4,
and 2.45 g (7.0 mmol) of ester II in 10 mL of THF, and
the mixture was stirred for 12 h. The solvent was
evaporated under reduced pressure, the viscous residue
was dissolved in 80 mL of diethyl ether, and 5 mL of
water was added on cooling. The mixture was filtered,
the precipitate was washed with diethyl ether (3×
30 mL), and the organic extracts were combined,
washed with saturated aqueous solutions of NaHCO3
(50 mL) and NaCl (50 mL), and dried over Na2SO4.
The solvent was distilled off under reduced pressure,
and the product was isolated by chromatography using
petroleum ether–ethyl acetate (30:1) as eluent. Yield
2.64 g (77%). IR spectrum, ν, cm–1: 3390, 1076, 1024.
1H NMR spectrum, δ, ppm: 0.07–0.18 m (1H, CH,
1
cm–1: 1743, 1435, 1161. H NMR spectrum, δ, ppm:
1.04 d (3H, CH3CH, J = 6.4 Hz), 1.35–1.45 m (1H,
CH3CH), 1.93–1.98 m (1H, CCH2CHO), 2.01–2.09 m
(2H, CCH2CHO, CH2CO), 2.68 d.d.d (1H, CH2CO,
J = 12.6, 11.0, 2.1 Hz), 3.61 d.d.d (2H, CHCH2OCH2Ph,
J = 14.9, 10.2, 4.6 Hz), 4.43–4.49 m (1H, CH2CHO),
4.58 br.s (2H, CH2Ph), 7.29–7.38 m (5H, Ph). 13C NMR
spectrum, δC, ppm: 21.6, 26.6, 33.6, 38.2, 72.0, 73.6,
79.2, 127.7 (2C), 127.8, 128.4 (2C), 137.8, 170.8.
Found, %: C 71.80; H 7.72. C14H18O3. Calculated, %:
C 71.77; H 7.74.
Methyl (3R,5R)-6-benzyloxy-3-methyl-5-(tetra-
hydro-2H-pyran-2-yloxy)hexanoate (II). Triethyl-
amine, 7 mL (50.5 mmol), was added to a solution of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014

MINEEVA
404
cyclopropyl), 0.82–0.98 m [20H, CH2 in cyclopropyl,
CHCH3, CHOCHCH3, OCH(CH2)3], 0.99–1.90 m
(7H, CHCH3, CHCH2CHO, CH2S, CH3CHCH2),
3.43–4.00 m (9H, OH, CH2CH2O, CH2OCH2Ph,
CHOCHCH2), 4.61–4.83 m (4H, OCHO, CH2Ph),
7.24–7.37 m (5H, Ph). Found, %: C 80.04; H 9.41.
C29H46O6. Calculated, %: C 70.99; H 9.45.
(1.9 mmol) of NiCl2·6H2O was added, and 0.28 g
(2.2 mmol) of NaBH4 was added in portions under stir-
ring over a period of 5 min. The mixture was stirred
for 1 h on cooling, diluted with 30 mL of water at
room temperature, and extracted with diethyl ether
(4×10 mL). The extracts were combined and dried
over Na2SO4, the solvent was distilled off under
reduced pressure, and the product was isolated by
chromatography using petroleum ether–ethyl acetate
(100:1) as eluent. Yield 1.60 g (88%). IR spectrum, ν,
(2R,4R,2S)-1-Benzyloxy-8-hydroxy-4-methyl-
2,10-bis(tetrahydro-2H-pyran-2-yloxy)undecan-6-
one (XVII). A solution of 2.45 g (5 mmol) of com-
pound XVI in 10 mL of acetone was added dropwise
under stirring at –15°C to a solution of 1.5 g
(15 mmol) of CrO3 and 0.41 g (3.0 mmol) of NaOAc·
3H2O in a mixture of 8 mL of acetone and 0.3 mL of
water. The mixture was stirred for 1 h, treated with
2.12 g (21 mmol) of triethylamine, and diluted with
60 mL of diethyl ether. The resulting suspension was
filtered through a fine filter, and the precipitate was
thoroughly washed with diethyl ether (3×10 mL). The
inorganic material was dissolved in water (20 mL), and
the aqueous phase was thoroughly extracted with
diethyl ether (4×30 mL). The filtrates and organic
extracts were combined, washed with brine (10 mL),
and dried over Na2SO4. The solvent was distilled off
under reduced pressure, and the product was isolated
by chromatography using petroleum ether–ethyl ace-
tate (45:1) as eluent. Yield 1.57 g (62%). IR spectrum,
ν, cm–1: 3474, 1710, 1373, 1119, 1076, 1014. 1H NMR
spectrum, δ, ppm: 0.90–1.82 m (23H, CHCH3,
CHCH3, CH2CHOCH, CHOCHCH3, OCHCH2CH2CH2,
CH2CHOH), 2.18–2.67 m (5H, CH2CO, OH), 3.38–
4.40 m (9H, CHOCHCH2, CH2CH2O, CH2OCH2Ph,
CHOH), 4.52–4.55 m (2H, CH2Ph), 4.64–4.82 m (2H,
OCHO), 7.24–7.36 m (5H, Ph). Found, %: C 68.77;
H 9.12. C29H46O7. Calculated, %: C 68.74; H 9.15.
(2R,4R,2S)-1-Benzyloxy-4-methyl-2,10-bis(tetra-
hydro-2H-pyran-2-yloxy)undecan-6-one (XVIII).
A solution of 1.87 g (3.7 mmol) of alcohol XVII in
25 mL of anhydrous chloroform was cooled to 0°C,
1.1 mL (9.5 mmol) of triethylamine and 0.4 mL
(5.5 mmol) of methanesulfonyl chloride in 3 mL of
chloroform were added under stirring, and the mixture
was stirred for 2 h and treated with a saturated aqueous
solution of NaHCO3 (25 mL). The organic phase was
separated, the aqueous phase was extracted with chloro-
form (3×15 mL), the extracts were combined with the
organic phase and dried over MgSO4, and the solvent
was distilled off under reduced pressure. The residue
was dissolved in a mixture of 30 mL of methanol and
10 mL of THF, the solution was cooled to 0°C, 0.43 g
1
cm–1: 1712, 1371, 1118, 1077, 1023. H NMR spec-
trum, δ, ppm: 0.89 d and 0.93 d (1.5H each, CHCH3,
J = 6.4 Hz), 1.10 d and 1.22 d (1.5H each, CH3CHO,
J = 6.14 Hz), 1.39–1.89 m [19H, CHCH3, CH2CH-
OCH, OCH(CH2)3, (CH2)2CH2CO], 2.12–2.53 m (4H,
CH2CO), 3.41–3.95 m (8H, CHOCHCH2, CH2CH2O,
CH2OCH2Ph), 4.51–4.55 m (2H, CH2Ph), 4.61–4.82 m
(2H, OCHO), 7.24–7.37 m (5H, Ph). Found, %:
C 80.03; H 9.42. C29H46O6. Calculated, %: C 70.99;
H 9.45.
[(2S,4R,6R,8S)-2,4,8-Trimethyl-1,7-dioxaspiro-
[5.5]undec-2-yl]methanol (XIX). A catalytic amount
of p-toluenesulfonic acid was added to a solution of
0.98 g (2 mmol) of ketone XVIII in 6 mL of methanol,
and the mixture was heated for 2 h at 50°C. A few
drops of triethylamine were added, the mixture was
evaporated under reduced pressure, the residue was
dissolved in 50 mL of diethyl ether, and the solution
was filtered through a layer of silica gel. The filtrate
was evaporated under reduced pressure, the residue
was dissolved in 10 mL of methanol, 0.03 g of
5% Pd(OH)2/C was added, and the mixture was vigor-
ously stirred for 4 h under a hydrogen atmosphere. The
mixture was diluted with 30 mL of methylene chloride,
the catalyst was filtered off and washed with 30 mL of
methylene chloride, the solvent was removed under
reduced pressure, and the target diastereoisomer was
isolated by chromatography on silica gel using petro-
leum ether–ethyl acetate (35:1) as eluent. Yield 0.36 g
(90%). The spectral parameters and specific optical
rotation of the product were consistent with those
reported in [3].
(2S,4R,6R,8S)-2,4,8-Trimethyl-1,7-dioxaspiro-
[5.5]undecane (I). A solution of 0.84 g (4.2 mmol) of
compound XIX in 4 mL of anhydrous diethyl ether
was cooled to 0°C, 0.9 mL (6.3 mmol) of triethylamine
and 0.5 mL (5.0 mmol) of methanesulfonyl chloride in
1 mL of anhydrous diethyl ether were added in succes-
sion, and the mixture was stirred for 2 h and treated
with a saturated aqueous solution of NaHCO3 (10 mL).
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NEW ASYMMETRIC SYNTHESIS OF A PHEROMONE COMPONENT
405
2. Tu, Y.Q., Moore, C.J., and Kitching, W., Tetrahedron:
Asymmetry, 1995, vol. 6, p. 397.
3. Tu, Y.Q., Hübener, A., Zhang, H., Moore, C.J.,
Fletcher, M.T., Hayes, P., Dettner, K., Francke, W.,
McErlean, C.S.P., and Kitching, W., Synthesis, 2000,
p. 1956.
The organic phase was separated, the aqueous phase
was extracted with diethyl ether Et2O (3×10 mL), the
extracts were combined with the organic phase,
washed with brine (15 mL), and dried over Na2SO4,
and the solvent was removed under reduced pressure.
The residue was dissolved in 3 ml of anhydrous diethyl
ether, the solution was added under stirring to a sus-
pension of 0.16 g (4.2 mmol) of LiAlH4 in 4 mL of an-
hydrous diethyl ether, and the mixture was stirred for
12 h. The mixture was diluted with 30 mL of diethyl
ether, 1 mL of water was added on cooling, and the
organic phase was separated and dried over Na2SO4.
The solvent was removed under reduced pressure, and
compound I was isolated by chromatography on silica
gel using petroleum ether–ethyl acetate (100:1) as
eluent. Yield 0.67 g (87%). The spectral parameters of
the product were consistent with published data [3].
This study was performed under financial support
by the Belarusian Republican Foundation for Funda-
mental Research (project no. Kh13M-039 2013–2015
“Enantioselective Synthesis of Insect Pheromones with
Methyl-Branched Carbon Skeleton on the Basis of
trans-2,2-Dichloro-3-methylcyclopropane-1-carbox-
ylic and 3-Bromomethylbut-3-enoic Acid Esters,” state
reg. no. 20131542).
4. Haym, I. and Brimble, M.A., Org. Biomol. Chem., 2012,
vol. 10, p. 7649.
5. Mori, K. and Tanida, K., Tetrahedron, 1981, vol. 37,
p. 3221.
6. Mori, K. and Tanida, K., Heterocycles, 1981, vol. 15,
p. 1171.
7. Mori, K. and Watanabe, H., Tetrahedron, 1986, vol. 42,
p. 295.
8. Dale, J.A., Dull, D.L., and Mosher, H.S., J. Org. Chem.,
1969, vol. 34, p. 2543.
9. Mineyeva, I.V. and Kulinkovich, O.G., Tetrahedron
Lett., 2010, vol. 51, p. 1836.
10. Mineeva, I.V. and Kulinkovich, O.G., Russ. J. Org.
Chem., 2008, vol. 44, p. 1261.
11. Keck, G.E. and Yu, T., Org. Lett., 1999, vol. 1, p. 289.
12. Kurosu, M. and Lorca, M., Synlett, 2005, p. 1109.
13. Prokhorevich, K.N., Cand. Sci. (Chem.) Dissertation,
Minsk, 2007.
14. Vakhidov, R.R., Shakhmaev, R.N., Ishmuratov, P.Yu.,
and Zorin, V.V., Russ. J. Org. Chem., 2000, vol. 36,
p. 771.
REFERENCES
15. Limbach, M., Dalai, S., and de Meijere, A., Adv. Synth.
Catal., 2004, vol. 346, p. 760.
1. Moore, C.J., Hübener, A., Tu, Y.Q., Kitching, W.,
Aldrich, J.R., Waite, G.K., Schulz, S., and Francke, W.,
J. Org. Chem., 1994, vol. 59, p. 6136.
16. de Fátima, A. and Pilli, R.A., Arkivoc, 2003, part (x),
p. 118.
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