Asymmetric synthesis of (+)-(S)-massoia lactone, pheromone of idea leuconoe. formal total synthesis of valilactone and lachnelluloic acid

Article abstract of DOI:10.1134/S1070428013110146

Simple and efficient asymmetric synthesis was developed of the cyclic scaffold of (-)-valilactone, an effective inhibitor of the pancreas lipase, applying the Keck allylation in the key stage of building up the carbon skeleton of the target molecule and of the unnatural (S)-isomer of Massoia lactone, lachnelluloic acid, possessing fungicidal properties, and (5R,7S)- 7-hydroxy-5-dodecanolid, pheromone component of the Large Tree Nymph butterfl y Idea leuconoe. Pleiades Publishing, Ltd., 2013.

Full text of DOI:10.1134/S1070428013110146

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 11, pp. 16471654. Pleiades Publishing, Ltd., 2013.
Original English Text  I.V. Mineeva, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 11, pp. 16651672.
Asymmetric Synthesis of (+)-(S)-Massoia Lactone,
Pheromone of Idea leuconoe. Formal Total Synthesis
of Valilactone and Lachnelluloic Acid
I. V. Mineeva
Belarus State University, Minsk, 220030 Belarus
e-mail: i.mineyeva@yandex.ru
Received May 15, 2013
Abstract—Simple and efficient asymmetric synthesis was developed of the cyclic scaffold of (–)-valilactone, an effective
inhibitor of the pancreas lipase, applying the Keck allylation in the key stage of building up the carbon skeleton of the target
molecule and of the unnatural (S)-isomer of Massoia lactone, lachnelluloic acid, possessing fungicidal properties, and (5R,7S)-
7-hydroxy-5-dodecanolid, pheromone component of the Large Tree Nymph butterfly Idea leuconoe.
DOI: 10.1134/S1070428013110146
Optically active esters of hydroxy-β-ketoacids are
convenient intermediates in the total synthesis of complex
biologically active and natural compounds [1, 2]. The
universal methods of synthesis of this class compounds
do not exist. In the preparation of esters of δ-hydroxy-β-
ketoacids the corresponding esters of β,δ-diketoacids are
subjected to enzymatic reduction [3], an aldol condensation
is performed of optically active esters of β-hydroxacids
[4], esters are reduced of 4,5-epoxy-3-oxoacids [5], or-
ganometallic reagents are added to the esters of oxiranyl-
3-oxobutanoic acid [6], Blaise reaction is carried out
with the optically active β-hydroxynitriles [7], and the
carbonylation of optically active epoxides followed by
the aldol condensation [8].
method from the ratio of the integral intensities of the me-
thoxy group signals (3.47 and 3.49 ppm) in the 1Н NMR
spectrum of the acylation product of compound VI with
(S)- and (R)-2-methoxy-2-phenyl-3,3,3-trifluoropropano-
yl chloride (Mosher’s acid chloride) [13].
Through a series of simple transformations via a
nonselective reduction of a carbonyl group in ketone
I, a lactonization and hydroxy group elimination in the
intermediate hydroxylactone the unnatural (S)-isomer of
Massoia lactone (II) was prepared (Scheme 3) [14–20],
the minor component of the oil of the bay-tree Crypto-
carya massoia bark [21], which is utilized in the food and
perfume industry [22]. The stable interest to the syntheses
of the Massoia lactone (II) isomers is due to the wide
spread of α,β-unsaturated lactones in the nature and to
their versatile biological activity promising for medical
applications [23–26].
In this study methyl ester of δ-hydroxy-β-ketoacid
I was used for building up the target carbon skeleton
of several biologically active compounds, like the (S)-
isomer of Massoia lactone (II), lachnelluloic acid (III),
(5R,7S)-7-hydroxy-5-dodecanolid (IV) , and valilactone
(V) (Scheme 1).
Ketoester I was transformed under basic conditions
into ketolactone VIII which might be converted in one
stage by the procedure [27] into lachnelluloic acid (III).
The latter is produced by Lachnellula fuscosanguinea
and possesses strong fungicidal properties.
Ester I was obtained by ozonolysis of methyl (5S)-
5-hydroxy-3-methylidenedecanoate (VI) (Scheme 2)
easily prepared from methyl-3-[(tributylstannyl)methyl]
but-3-enoate (VII) by the asymmetric allylation [9, 10]
under Keck reaction conditions (Scheme 2) in 82% yield
and >99% enantioselectivity [11, 12]. The enantiomeric
excess in the allylation stage was established by Mosher’s
Further ketoester I was reduced with sodium boro-
hydride in the presence of titanium tetraisopropoxide by
the procedure [28] (Scheme 4). The reduction occurred
with a high selectivity giving predominantly 3R,5R-
diastereomer IX (3R,5R–3S,5R, 20:1), the minor isomer
1647

MINEEVA
1648
Scheme 1.
O
O
O
C7H15
C5H11
OH
O
III
O
O
OH
О
O
OH
O
C5H11
OMe
I
C5H11
C5H11
II
IV
NHCHO
O
O
O
O
C5H11
C6H13
V
Scheme 2.
C5H11CHO,
(1) O3, CH2Cl2
(2) PPh3
OH
O
O
(R)-BINOL, Ti(OPr-i)4, CH2Cl2
SnBu3
I
C5H11
OMe
MeO
82%
96%
VII
VI
Scheme 3.
(1) NaBH4, MeOH
O
(2) п-TsOH, CH2Cl2
(3) MsCl, Et3N, CH2Cl2
78%
[27]
Na2CO3, MeOH
87%
O
II
III
I
C5H11
O
VIII
was removed by the chromatography.
dominal gland of the Large Tree Nymph butterfly Idea
leuconoe (monarch), which possessed the properties of
the pheromone of anxiety and communication [30, 31].
Only two protocols were described for the synthesis of
the components of monarch pheromones [32, 33]. The
overall yield of hydroxylactone IV along the developed
protocol reached 23% calculated with respect to stannane
VII (10 subsequent stages).
Hydroxyester IX was converted in succession into an
acetonide, reduced into alcohol, and then carefully oxidized
into aldehyde X. The Wittig olefination of compound X
by a stabilized ylide (ethoxycarbonylmethylene)triphe-
nylphosphorane in dichloromethane at room temperature
[29] led to the formation of unsaturated ester XI with the
prevalence of the E-isomer (E–Z 10 : 1) (Scheme 4). The
reduction of compound XI, the removal of the aceton-
ide protection, and the subsequent lactonization in acid
conditions afforded (5R,7S)-7-hydroxy-5-dodecanolid
(IV), one of the components of the secretions of the ab-
In its turn diol IX made it possible by the application
of Ghosh procedure used in the preparation of tetrahy-
drolipstatin [34] to carry out the formal synthesis of
valilactone (V) (Scheme 5).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

ASYMMETRIC SYNTHESIS OF (+)-(S)-MASSOIA LACTONE
1649
Scheme 4.
Ti(OPr-i)4, NaBH4,
THF
OH ОH
O
I
C5H11
OMe
70%
IX
(1) (CH3)2C(OCH3)2, (CH3)2CO, PPTS
(2) LiAlH4, Et2O
(3) PDC, CH2Cl2
O
O
O
63%
C5H11
H
X
.
(1) NaBH4, NiCl2 6H2O, H3BO3,
THF_H2O
(2) PPTS, MeOH
Ph3P=CHCO2Et,
CH2Cl2
O
O
O
(3) п-TsOH, CH2Cl2
IV
80%
87%
C5H11
OEt
XI
Scheme 5.
(1) TBSCl, imidazol, CH2Cl2
(2) Et3N, MeOH
О
(3) DHP, PPTS, CH2Cl2
78%
п-TsOH, PhH
O
O
O
OTBSO
IX
82%
C5H11
ОН
C5H11
OMe
XII
XIII
LDA, C6H13Br, THF
77%
O
O
OH
O
Bu4NF, THF
88%
O
O
OH
O
C5H11
OMe
C5H11
OMe
O
C6H13
XIV
XV
O
(1) NaOH, MeOH, H2O
(2) PhSO2Cl, Py
[37]
OH
O
PPTS, MeOH
88%
O
O
O
V
C5H11
86%
C6H13
C5H11
C6H13
XVII
XVI
Valilactone (V) is a metabolite of microbes MG 147-
CF2 similar to the species Streptomyces albolongus, it is
an efficient inhibitor of the pancreas lipase [35] due to the
reaction with the serine residue in the latter. Therewith
the fatty acids are conserved as triglycerides, they are
not consumed by the organism and as a result lead to the
weight loss because of preventing the accumulation of
fat. Therefore the valilactone may be used as a drug for
weight reduction at obesity [36, 37].
Since the discovery of valilactone (V) [38] only
four protocols were developed for the synthesis of this
compound involving the application of modified iron
complexes [36, 39, 40], Mukaiyama reaction [41], and
also the lactonization of an appropriate anti-1,3-diol [37].
To perform the selective protection of hydroxy groups
in diol IX it was subjected to lactonization into hydroxy-
ether XII, and a tert-butyldimethylsilyl protection was
carried out. The opening of the obtained lactone into
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

MINEEVA
1650
an intermediate hydroxyester followed by performing
a tetrahydropyranyl protection resulted in ester XIII
(Scheme 5).
and 1.5 g of activated molecular sieves 4 Å (calcinated
in a vacuum of an oil pump at 125–130°С) in 50 mL of
anhydrous CH2Cl2 was added 2.9 mL of 0.1 M solution
of Ti(OPr-i)4, (294 μmol) and the mixture was boiled
at vigorous stirring for 1 h. To the prepared catalyst
was added at –78°С while stirring 1.76 g (12 mmol) of
hexanal in 10 ml of anhydrous CH2Cl2, and 15 min later
was added 6.15 g (15.6 mmol)of stannane VII [10] in
20 ml of anhydrous CH2Cl2, and the mixture was left
standing without stirring in a freezer at –25°С for 5 days.
The reaction mixture was treated at vigorous stirring
with a saturated water solution of NaHCO3 (100 ml).
The organic layer was separated, the reaction product
was extracted from the water layer into CH2Cl2 (3 × 30
ml), the combined organic solutions were washed with
brine (50 ml) and dried with MgSO4. The solvent was
removed at a reduced pressure, the reaction product was
isolated by chromatography (eluent petroleum ether–ethyl
acetate, 40 : 1–5 : 1). Yield 2.10 g (82%), [α]D –3.9°
(c1.6, CHCl3). IR spectrum, cm–1: 3446, 1739, 1245,
1199, 1161. 1Н NMR spectrum, δ, ppm: 0.88 t (3Н, СН3,
J 6.9 Hz), 1.24–1.49 m [8Н, СН3(СН2)4], 2.14 d.d (1Н,
СНСН2С, J1 14.1, J2 9.7 Hz), 2.33 d.d (1Н, СНСН2С,
J1 14.1, J2 2.1 Hz), 3.07 d (1Н, CH2СO, J 15.6 Hz), 3.14
d (1Н, CH2СO, J 15.6 Hz), 3.66–3.72 m (1H, СНOH),
3.69 s (3Н, CH3O), 5.04 s (1Н, CH2=), 5.07 s (1Н, CH2=).
13С NMR spectrum, δ, ppm: 14.0 (СН3), 22.6 (СН2), 25.4
(СН2), 31.8 (СН2), 37.1 (СН2), 41.5 (СН2), 44.7 (СН2),
52.0 (СН3), 69.1 (СН), 117.5 (СН2), 139.3 (С), 172.3(С).
Found, %: C 67.28; H 10.34. C12H22O3. Calculated, %:
С67.26; H 10.35.
By maintaining ester XIII in THF in the presence of
excess tetrabutylammonium fluoride the tert-butyldi-
methylsilyl protection was removed, and the obtained
hydroxyester XIV was alkylated with hexyl bromide
(~15% of the substance did not react) with the predomi-
nant formation of anti-product XV, as was established
from the data of 1Н NMR spectra.
The hydrolysis of ester XV in basic environment
followed by the lactonization [42] resulted in the forma-
tion in a moderate yield of diastereomeric 2-oxetanones
XVI. The removal of the tetrahydropyranyl protection
by boiling in methanol in the presence of pyridinium
p-toluenesulfonate (PPTS) proceeded without complica-
tions and rearrangements furnishing the target product
XVII. The structure of compound was confirmed by
the comparison of its spectral characteristics with the
published data [37], and also by the characteristic of the
coupling constants of the protons of the 2-oxetane ring in
the trans-configuration (4 Hz). The esterification by the
method [37] of lactone XVII may give valilactone (V).
The overall yield of hydroxylactone XVII starting
with stannane VII attained 18.7% calculated for 13
subsequent stages. The approach to the valilactone syn-
thesis described in this article is inferior in the number
of stages to the other schemes [36, 37, 39–41] but it is
distinguished by the simplicity of the experimental pro-
cedures, the availability of the reagents, the absence of
expensive and toxic catalysts, and by the high yields of
the separate stages.
Methyl (5S)-5-hydroxy-3-oxodecanoate (I).
Through the solution of 0.84 g (3.9 mmol) of ester VI
in 25 ml of CH2Cl2 at –78°С was passes a mixture О3/
О2 for 1 h till the appearance of a stable blue color of
the solution, then oxygen was passed to remove the
excess ozone. Then by portions at vigorous stirring was
added 1.03 g (8.7 mmol) of PPh3 , and the mixture was
warmed to room temperature within 3 h. After treating
with Н2O (30 ml) the organic layer was separated, the
reaction product was extracted from the water layer with
CH2Cl2 (2 × 10 ml), the combined organic solutions were
dried with MgSO4. After the solvent was distilled off at
a reduced pressure the reaction product was isolated by
chromatography on silica gel (eluent petroleum ether–
ethyl acetate, 30 : 1). Yield 0.81 g (96%), [α]D +26.0°
(c1.2, CHCl3). IR spectrum, cm–1: 3441, 1746, 1713,
1260, 1130. 1Н NMR spectrum, δ, ppm: 0.88 t (3Н, СН3,
EXPERIMENTAL
1H and 13С NMR spectra were registered on a spec-
trometer Bruker AC-400 at operating frequencies 400
and 100 MHz respectively from solutions of compounds
in deuterochloroform. IR spectra were recorded on a
spectrophotometer Bruker Vertex 70 from solutions
of compounds in tetrachloromethane. Optical rotation
was measured on a polarimeter SM-3 (scale division
0.05°) at room temperature. Chromatographic separa-
tion of individual substances was carried out on silica
gel (70–230 mesh). All solvents before use were dried
by common methods and distilled.
Methyl (5S)-5-hydroxy-3-methylydenedecanoate
(VI). To a mixture of 168 mg (588 μmol) of (R)-BINOL
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

ASYMMETRIC SYNTHESIS OF (+)-(S)-MASSOIA LACTONE
1651
J 6.9 Hz), 1.23–1.53 m [8Н, СН3(СН2)4], 2.63 d.d (1Н,
СН2СНОН, J1 17.4, J2 9.0 Hz), 2.72 d.d (1Н, СН2СНОН,
J1 17.4, J2 3.1 Hz), 3.49 s (2Н, CH2СО), 3.73 s (3Н,
CH3O), 4.02–4.09 m (1H, СНOH). 13С NMR spectrum,
δ, ppm: 14.0 (СН3), 22.5 (СН2), 25.1 (СН2), 31.6 (СН2),
36.4 (СН2), 49.6 (2 СН2), 52.4 (СН3), 67.5 (СН), 167.4
(С), 203.6 (С). Found, %: С61.15; H 9.27. C11H20O4.
Calculated, %: С61.09; H 9.32.
СН2СНОСО, J1 18.2, J2 2.6 Hz), 3.43 d (1Н, CH2СО,
J 18.9 Hz), 3.57 d (1Н, CH2СО, J 18.9 Hz), 4.59–4.66 m
(1H, СНOСО). 13С NMR spectrum, δ, ppm: 13.9 (СН3),
22.5 (СН2), 24.4 (СН2), 31.3 (СН2), 34.5 (СН2), 43.5
(СН2), 47.0 (СН2), 75.6 (СН), 170.4 (С), 200.3 (С).
Found, %: С65.22; H 8.71. C10H16O3. Calculated, %:
С65.19; H 8.75.
Methyl (3S,5S)-3,5-dihydroxydecanoate (IX). At
–78°С to a solution of 0.43 g (2 mmol) of ketone I in
20 ml of THF was added 0.58 ml (2 mmol) of Ti(OPr-i)4.
After 30 min was added in one portion 0.38 g (10 mmol)
of NaBH4 and the mixture was vigorously stirred for 1.5 h.
After adding 40 ml of saturated water solution of NH4Cl
the reaction mixture was warmed to the room tempera-
ture. The reaction product was extracted into Et2O (3 ×
30 ml), the combined organic solvents were dried with
MgSO4. After the solvent was distilled off at a reduced
pressure the reaction product was isolated by chroma-
tography on silica gel as a mixture of two diastereomers
(3S,5S–3R,5S, 20 : 1) (eluent petroleum ether–ethyl
acetate, 15 : 1). Yield 0.31 g (70%), [α]D +18.0° (c 1.9,
CHCl3). IR spectrum, cm–1: 3446, 1739, 1417, 1338,
1200, 1156. 1Н NMR spectrum, δ, ppm: 0.82 t (3Н, СН3,
J 6.4 Hz), 1.17–1.53 m [9Н, СН2СНОН, СН3(СН2)4],
1.90 d.t (1Н, СН2СНОН, J1 13.8, J2 2.6 Hz), 2.40 d.d
(1Н, СН2СО, J1 15.6, J2 5.9 Hz), 2.56 d.d (1Н, СН2СО,
J1 15.6, J2 7.2 Hz), 3.05 s (1Н, ОН), 3.45 s (1Н, OН),
3.64 s (3Н, СН3О), 3.91–3.99 m [1H, СН3(СН2)4СНOH],
4.36–4.43 m (1Н, СН2СНОН). 13С NMR spectrum, δ,
ppm: 14.0 (СН3), 22.6 (СН2), 25.4 (СН2), 31.8 (СН2),
37.2 (СН2), 41.1 (СН2), 43.6 (СН2), 51.1 (СН3), 67.6
(СН), 68.1 (СН), 172.3 (С). Found, %: С60.56; H 10.11.
C11H22O4. Calculated, %: С60.52; H 10.16.
(6S)-6-Pentyl-5,6-dihydro-2Н-pyran-2-one (Mas-
soia lactone) (II). To a solution of 1 g (4.6 mmol) of
ester I in 25 ml of methanol cooled to 0°С was added by
portions at vigorous stirring 0.35 g (9.2 mmol) of NaBH4,
and the mixture was stirred for 1 h. After treating with a
saturated solution of NH4Cl (50 ml) the reaction product
was extracted from the reaction mixture with CH2Cl2
(3 × 20 ml), the combined organic solutions were washed
with a saturated water solution of NaHCO3 (50 ml) and
dried with MgSO4. After the solvent was distilled off at
a reduced pressure the residue was dissolved in 15 ml
of CH2Cl2 and at room temperature 0.1 g (0.6 mmol) of
p-TsOH·2Н2О was added. After 12 h into the reaction
mixture was added 2 ml (14.4 mmol) of Et3N and 0.3 ml
(4.5 mmol) of MsCl in 1 ml of СН2Cl2. After stirring
for 2 h the reaction mixture was treated with a saturated
water solution of NaHCO3 (25 ml). The organic layer was
separated, the water layer was extracted with СНCl3 (3 ×
10 ml), the combined organic solutions were dried with
Na2SO4. After the solvent was distilled off at a reduced
pressure the reaction product was isolated by chromatog-
raphy (eluent petroleum ether–ethyl acetate, 20 : 1). Yield
0.57 g (74%), [α]D +91.0° (c 1.8, CHCl3). The spectral
characteristics of the compound obtained were in agree-
ment with those published in [43].
(6S)-6-Pentyldihydro-2Н-pyran-2,4(3Н)-dione
(VIII). To a solution of 0.86 g (4 mmol) of compound
I in 25 ml of MeOH was added 1.07 g (10.0 mmol) of
Na2CO3, and the mixture was stirred for 8 h.After treating
with water (50 ml) the reaction product was extracted into
CHCl3 (3 × 20 ml), the combined organic solutions were
dried with MgSO4. After the solvent was distilled off at
a reduced pressure the reaction product was isolated by
chromatography on silica gel (eluent petroleum ether–
ethyl acetate, 3 : 1). Yield 0.64 g (87%), mp 86–88°С,
[α]D +42.0° (c 1.1, CHCl3). IR spectrum, cm–1: 1740,
1730, 1264. 1Н NMR spectrum, δ, ppm: 0.90 t (3Н, СН3,
J 6.9 Hz), 1.25–1.50 m [6Н, СН3(СН2)3], 1.65–1.73 m
(1Н, СН2СНОС), 1.79–1.88 m (1Н, СН2СНОС), 2.47 d.d
(1Н, СН2СНОСО, J1 18.2, J2 11.4 Hz), 2.71 d.d (1Н,
[(4S,6S)-2,2-Dimethyl-6-pentyl-1,3-dioxan-4-yl]
acetaldehyde (X). To a solution of 2.18 g(10 mmol) of
diol IX in 50 ml of anhydrous acetone was added 0.87 g
(12 mmol) of dimethoxypropane and 0.16 g (0.6 mmol) of
pyridinium p-toluenesulfonate, and the mixture was main-
tained for 12 h till the completion of the reaction. After
adding several drops of Et3N acetone was evaporated at
a reduced pressure, the residue was dissolved in 50 ml
of Et2O, and the solution was passed through a bed of
silica gel. After the solvent was distilled off at a reduced
pressure we obtained 2.01 g (78%) of the ester which
without additional purification was dissolved in 10 ml of
anhydrous Et2O and added to a slurry of 0.19 g (5 mmol)
of LiAlH4 in 10 ml of anhydrous Et2O, and the reaction
mixture was vigorously stirred for 2 h. The mixture was
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

MINEEVA
1652
diluted with 20 ml of Et2O and at cooling 0.5 ml of H2O
was added. The reaction mixture was filtered through a
thin bed of silica gel, the solvent was removed at a reduced
pressure. We obtained 1.79 g (98%) of colorless oily
substance that was used without further purification. To
a slurry of 4.28 g (11.7 mmol) of pyridinium dichromate
in 25 ml of anhydrous CH2Cl2 was added in one portion
1.79 g (7.8 mmol) of the previously obtained alcohol in
10 ml of anhydrous CH2Cl2, and the mixture was stirred
for 10 h till the completion of the reaction. The reaction
mixture was filtered through a thin bed of silica gel, the
solvent was removed at a reduced pressure. The residue
was dissolved in 50 ml of ethyl ether and was again fil-
tered through a bed of silica gel. The solvent was removed
at a reduced pressure, the reaction product was isolated
by chromatography (eluent petroleum ether–ethyl acetate,
90 : 1). Yield 1.43 g (83%, 63% calculated with respect
to 3 stages), [α]D +154.0° (c1.1, CHCl3). The spectra of
compound obtained are in agreement with the published
data [44].
(1.1 mmol) of NiCl2·6H2O, 0.12 г (2 mmol) of H3BO3,
and at stirring was added by portions within 5 min 0.08 g
(2.2 mmol) of NaBH4. The reaction mixture was stirred
at cooling for 0.5 h more, then 1 g of NaCl was added
at room temperature, and the product was extracted with
Et2O (4 × 5 ml). The combined organic solvents were
dried with Na2SO4. The solvent was removed at a reduced
pressure, the residue was dissolved in 5 ml of MeOH, 0.05
g (0.2 mmol) of pyridinium p-toluenesulfonate was added,
and the mixture was boiled for 1 h. After adding several
drops of Et3N MeOH was evaporated at a reduced pres-
sure, the residue was dissolved in 10 ml of Et2O, and the
resulting solution was passed through a bed of silica gel.
The solvent was removed at a reduced pressure to give
0.24 g (91%) of colorless oily liquid that was dissolved
in 5 ml of CH2Cl2, 0.05 g (0.3 mmol) of p-TsOH·2Н2О
was added, and the mixture was stirred for 24 h. After
adding several drops of Et3N the reaction mixture was
evaporated. The reaction product was isolated by chro-
matography (eluent petroleum ether–ethyl acetate, 3 :
1–1 : 1). Yield 0.17 g (80% with respect to 3 stages), [α]
D +4.0° (c 0.9, CHCl3). IR spectrum, cm–1: 3440, 1733,
Ethyl (2Е)-4-[(4R,6S)-2,2-dimethyl-6-pentyl-1,3-
dioxan-4-yl]but-2-enoate (XI). To a solution of 0.46 g
(2 mmol) of aldehyde X in 20 ml of anhydrous CH2Cl2
was added in one portion 1.39 g (4 mmol) of (ethoxy-
carbonylmethylene)triphenylphosphorane, and the
mixture was stirred for 24 h at room temperature. The
solvent was removed at a reduced pressure, the reaction
product was isolated by chromatography (eluent petro-
leum ether–ethyl acetate, 100 : 1). Yield 0.52 g (87%),
[α]D +19.1° (c0.9, CHCl3). IR spectrum, cm–1: 1723,
1379, 1266, 1170. 1Н NMR spectrum, δ, ppm: 0.86 t [3Н,
СН3(СН2)4, J 6.4 Hz], 1.36 s (3Н, СН3СО), 1.42 s (3Н,
СН3СО), 1.20–1.51 m [12Н, CH3(CH2)4, CH3(CH2)3СН2,
CH3(CH2)3СН2, ОСНСН2СНО], 1.56–1.61 m (1Н,
ОСНСН2СНО), 2.25–2.45 m (2Н, CH2СН=СНСО2),
3.72–3.79 m [1Н, ОСН(СН2)4СН3], 3.87–3.97 m (1Н,
ОСНСН2СН=), 4.15–4.20 q (2Н, СН3СН2О, J 7.2 Hz),
5.87 d (1Н, СН=СНСО2), 6.88–6.97 m (1Н, СН=СНСО2).
13С NMR spectrum, δ, ppm: 14.0 (СН3), 14.2 (СН3),
19.6 (СН3), 22.6 (СН2), 24.8 (СН2), 29.9 (СН3), 31.8
(СН2), 35.9 (СН2), 38.3 (СН2), 38.4 (СН2), 60.2 (СН2),
65.4 (СН), 66.5 (СН), 98.2 (С), 123.3 (СН), 144.8 (СН),
166.4(С). Found, %: С68.45; H 10.12. C17H30O4. Calcu-
lated, %: С68.42; H 10.13.
1
1248, 1046. Н NMR spectrum, δ, ppm: 0.89 t (3Н,
СН3, J 6.7 Hz), 1.22–1.60 m [11Н, СН3(СН2)4СНОН,
СН2СН2С=О, НОСНСН2СНОСО], 1.66–1.90 m (3Н,
СН2СН2СНОС, НОСНСН2СНОСО), 2.37–2.47 m
(1Н, СН2СНОС), 2.53–2.61 (1Н, СН2СНОС), 3.78 br.s
(1Н, ОН), 3.85–3.90 m (1H, СНOН), 4.56–4.62 m (1Н,
CHОН). 13С NMR spectrum, δ, ppm: 14.0 (СН3), 18.4
(СН2), 22.5 (СН2), 25.4 (СН2), 28.3 (СН2), 29.2 (СН2),
31.7 (СН2), 37.9 (СН2), 43.2 (СН2), 69.2 (СН), 79.6
(СН), 172.1 (С). Found, %: С67.28; H 10.33. C12H20O2.
Calculated, %: С67.26; H 10.35.
(4S,6S)-4-Hydroxy-6-pentyltetrahydro-2Н-pyran-
2-one (XII). To a solution of 0.22 g (1 mmol) of ester
IX in 4 ml of benzene was added 50 mg (0.3 mmol) of
p-TsOH·2Н2О, and the mixture was left standing for 24 h.
After adding 0.25 ml (1.8 mmol) of Et3N the reaction mix-
ture was evaporated. The reaction product was isolated by
chromatography (eluent petroleum ether–ethyl acetate, 3 :
1–1 : 1). Yield 0.15 g (82%), [α]D –26.9° (c 1.1, CHCl3).
The spectra of compound obtained are in agreement with
the published data [45].
Methyl (3S,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-
5-(tetrahydro-2Н-pyran-2-yloxy)decanoate (XIII).
To a solution of 0.37 g (2 mmol) of compound XII in
10 ml of anhydrous CH2Cl2 was added 0.3 g (3.5 mmol)
of imidazole, 0.45 g (3 mmol) of tert-butyldimethylsilyl
(6R)-6-[(2S)-2-Hydroxyheptyl]tetrahydro-2Н-
pyran-2-one [(5R,7S)-7-hydroxy-5-dodecanolid] (IV).
To an emulsion of 0.3 g (1 mmol) of compound XI in 5 ml
of THF and 5 ml of water cooled to 0°С was added 0.26 g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

ASYMMETRIC SYNTHESIS OF (+)-(S)-MASSOIA LACTONE
1653
chloride, and the mixture was stirred for 12 h.After treat-
ing with H2O (30 ml) the organic layer was separated,
the reaction product was extracted from the water layer
with CH2Cl2 (3 × 10 ml), the combined organic solvents
were dried with MgSO4. The solvent was removed at a
reduced pressure, the residue was dissolved in 10 ml of
MeOH, 5 ml of Et3N was added, and the mixture was
maintained for 24 h. The mixture of MeOH and Et3N
was removed at a reduced pressure, the residue was di-
luted with 5 ml of anhydrous CH2Cl2, 0.25 g (3 mmol)
of dihydropyran was added and a catalytic quantity of
pyridinium p-toluenesulfonate, and the mixture was main-
tained for 12 h at room temperature.After adding several
drops of Et3N the reaction mixture was evaporated at a
reduced pressure. The reaction product was isolated by
chromatography (eluent petroleum ether–ethyl acetate,
100:1). Yield 0.65 g (78% with respect to 3 stages). IR
spectrum, cm–1: 1741, 1258, 1078, 1023. 1H NMR spec-
trum, δ, ppm: 0.03 s [1.5Н, (CH3)2SiC(CH3)3], 0.05 s
[3Н, (CH3)2SiC(CH3)3], 0.06 с [1.5Н, (CH3)2SiC(CH3)3],
0.83–0.90 m [12Н, (CH3)2SiC(CH3)3, CH3(CH2)4], 1.24–
1.82 m [16Н, ОСН(CH2)3, SiОСНСН2СНО–tetrahydro-
pyran, CH3(CH2)4], 2.40–2.65 m (2Н, СН2СО2СН3),
3.42–3.54 m (1.5Н, СН2ОСНО, СНО–tetrahydropy-
ran), 3.63 br.s (1.5Н, CH3О), 3.64 br.s (1.5Н, CH3О),
3.82–3.94 m (1.5Н, СН2ОСНО, СНО–tetrahydropyran),
4.12–4.35 m (0.5Н, СНОSi), 4.54–4.65 m (1Н, ОСНО,
СНОSi), 4.92–4.94 m (0.5Н, ОСНО). Found, %: С 63.45;
Н 10.61. C22H44O5Si. Calculated, %: С 63.42; Н 10.64.
4.51–4.53 m (0.5Н, ОСНО), 4.62–4.66 m (0.5Н, ОСНО).
Found, %: С 63.60; Н 9.97. C16H30O5. Calculated, %: С
63.55; Н 10.00.
Methyl (2S,3S,5S)-2-hexyl-3-hydroxy-5-
(tetrahydro-2Н-pyran-2-yloxy)decanoate (XV). To 2.5
mmol of a solution of lithium diisopropylamide (LDA)
prepared from 2.7 ml of 1.6 M BuLi solution in hexane
and 0.6 ml (2.5 mmol) of (i-Pr)2NН in 2 ml of THF at
–50°С was added a solution of 0.51 g (1.7 mmol) of es-
ter XIV in 3 ml of THF. After 1 h to the mixture 1.16 g
(7.0 mmol) of hexyl bromide was added, the mixture
was kept for another hour at low temperature and within
2 h was warmed to 0°С. After treating with the saturated
NH4Cl solution (20 ml) the reaction product was extracted
with Et2О (3×10 ml), the combined organic solutions
were dried with MgSO4. The solvent was removed at a
reduced pressure, the reaction product was isolated by
chromatography (eluent petroleum ether–ethyl acetate,
35:1). Yield 0.51 g (77%), [α]D –3.4° (c1.4, CHCl3). IR
spectrum, cm–1: 3463, 1738, 1200, 1024. 1Н NMR spec-
trum, δ, ppm: 0.87–0.90 m [6Н, CH3(CH2)5, CH3(CH2)4],
1.16–1.86 m [26Н, CH3(CH2)4, CH3(CH2)5, CH2СНОH,
ОCH2(CH2)3], 2.41–2.53 m (1Н, СН2СНСО2CH3),
3.42–3.53 m (3Н, СН2ОCH, ОН), 3.71 br.s (3Н, СН3О),
3.83–4.10 m (2Н, СНО–tetrahydropyran, СНОН), 4.55–
4.78 m (1Н, СНОCH2). Found, %: С 68.39; H 10.92.
C22H42O5. Calculated, %: С 68.35; H 10.95.
(3S,4S)-3-Hexyl-4-[(2S)-2-(tetrahydro-2Н-pyran-
2-yloxy)heptyl]oxetan-2-one (XVI). To a solution of
0.42 g (1 mmol) of hydroxyester XV in 2.5 ml of MeOH
was added 2.5 ml of 1 M water solution of NaOH, and
the mixture was boiled for 2 h. On cooling the reac-
tion mixture was neutralized with 2.5 ml of 1 M water
solution of НСl. After adding 5 ml of H2O the reaction
product was extracted from the reaction mixture with
Et2O (3 × 5 ml), the combined organic solutions were
dried with MgSO4. On removing the solvent the residue
was dissolved in 10 ml of pyridine, cooled to 0°С, and
0.46 g (2.6 mmol) of benzenesulfonyl chloride was
added in one portion. The mixture was stirred at room
temperature for 24 h. After treating with Н2O (30 ml)
the reaction product was extracted from the water layer
with Et2O (3 × 10 ml), the combined organic solutions
were dried with MgSO4. The solvent was removed at a
reduced pressure, the target compound was isolated as a
mixture of diastereomers by chromatography on silica
gel (eluent petroleum ether–ethyl аcetаte, 100 : 1). Yield
0.30 g (86%). IR spectrum, cm–1: 1822, 1186, 1121,
Methyl (3S,5S)-3-hydroxy-5-(tetrahydro-2Н-
pyran-2-yloxy)decanoate (XIV). To a solution of 0.21
g (0.5 mmol) of ester XIII in 2.5 ml of THF was added
in one portion at room temperature 2.5 ml (2.5 mmol)
of 1 M solution of Bu4NF in THF, and the mixture was
left standing for 8 h. After treating the reaction mixture
with a saturated solution of NH4Cl (10 ml) the reac-
tion product was extracted with Et2О (3 × 5 ml), the
combined organic solutions were dried with MgSO4.
The solvent was removed at a reduced pressure, the
reaction product was isolated by chromatography (elu-
ent petroleum ether–ethyl acetate, 25 : 1). Yield 0.13 g
(88%), [α]D –23.4° (c 1.4, CHCl3). IR spectrum, cm–1:
3462, 1739, 1200, 1165, 1076, 1024. 1H NMR spectrum,
δ, ppm: 0.80–0.84 m [3Н, CH3(CH2)4], 1.17–1.35 m
[16Н, ОСН(CH2)3, НОСНСН2СНО–tetrahydropyran,
CH3(CH2)4], 2.25–2.51 m (2Н, СН2СО2СН3), 3.36–
3.45 m (1Н, СН2ОСНО), 3.73–3.91 m (2Н, СН2ОСНО,
СНО–tetrahydropyran), 3.63 br.s (1.5Н, CH3О),
3.64 br.s (1.5Н, CH3О), 4.04–4.32 m (2Н, СНОН, ОН),
1
1014. Н NMR spectrum, δ, ppm: 0.87–0.92 m [6Н,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

MINEEVA
1654
1993, vol. 4, p. 1017.
18. Minami, T., Moriyama,A., and Hanaoka, M., Synlett, 1995,
p. 663.
19. Pais, G.C.G., Fernandes, R.A., and Kumar, P., Tetrahedron,
1999, vol. 55, p. 13445.
20. Gupta, P., Naidis, V., and Kumar, P., Tetrahedron Lett.,
2004, vol. 45, p. 849.
CH3(CH2)5, CH3(CH2)4], 1.21–1.99 m [26Н, CH3(CH2)4,
CH3(CH2)5, CH2СНОСО, ОCH2(CH2)3], 3.17–3.34 m
(1Н, СН2СНСО2), 3.39–3.58 m (2Н, СН2ОCH),
3.73–3.97 m (1Н, СНО–tetrahydropyran), 4.49–4.63 m
(2Н, СНОCH2, СНOСО). Found, %: С71.18; H 10.77
C21H38O4. Calculated, %: С71.14; H 10.80.
.
(3S,4S)-3-Hexyl-4-[(2S)-2-hydroxyheptyl]oxetan-2-
one (XVII). To a solution of 0.71 g (2 mmol) of lactone
XVI in 6 ml of MeOH was added 0.05 g (0.2 mmol)
of pyridinium p-toluenesulfonate, and the mixture was
heated at 50°С for 2 h. After adding several drops of
Et3N the solvent was evaporated at a reduced pressure,
the target diastereomer was isolated by chromatography
(eluent petroleum ether–ethyl acetate, 40 : 1). Yield 0.48 g
(88%), [α]D –16.4° (c0.9, CHCl3). Spectral characteris-
tics of compound obtained coincided with the published
data [36].
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