Synthesis of (5S)-5-methylfuran-2(5H)-one and its dihydro derivative

Article abstract of DOI:10.1134/S1070428008120142

(5S)-5-Methylfuran-2(5H)-one and (5S)-5-methyltetrahydrofuran-2-one were synthesized starting from L-lactic acid ethyl ester.

Full text of DOI:10.1134/S1070428008120142

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 12, pp. 1804–1806. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © V.V. Loza, N.S. Vostrikov, M.S. Miftakhov, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 12,
pp. 1831–1833.
Synthesis of (5S)-5-Methylfuran-2(5H)-one
and Its Dihydro Derivative
V. V. Loza, N. S. Vostrikov, and M. S. Miftakhov
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: bioreg@anrb.ru
Received February 11, 2008
Abstract—(5S)-5-Methylfuran-2(5H)-one and (5S)-5-methyltetrahydrofuran-2-one were synthesized starting
from L-lactic acid ethyl ester.
DOI: 10.1134/S1070428008120142
The main application of commercially available
low-cost L-lactic acid in organic synthesis is prepara-
tion of chiral blocks containing α-methyl-substituted
secondary alcohol fragments or their synthetic equiv-
alents. Such fragments are present in molecules of
some important natural compounds. In particular,
L-lactic acid ethyl ester and (S)-(–)-1,2-epoxypropane
derived therefrom were used in the synthesis of phero-
mones [1], Nonactin [2], Brefeldin A [3], Recifeiolide
undoubted interest not only as synthetic equivalent of
ω-functionalized secondary methylalkanol (cf. satu-
rated analog II) but also as convenient stereodif-
ferentiating Michael acceptor.
Compounds I and II were synthesized according to
the following scheme. Initially, ethyl (2S)-(–)-2-(meth-
oxymethyloxy)propanoate (III) [6] was reduced with
(i-Bu) AlH at –78°C to obtain aldehyde IV which was
2
5
treated with methyl (triphenyl-λ -phosphanylidene)-
[4], etc. [5]. In the present communication we describe
acetate in methylene chloride at 20°C. As a result, we
the synthesis of γ-methyl-substituted butenolide I from
lactic acid ethyl ester (Scheme 1). Compound I attracts
isolated a mixture of E/Z-isomeric unsaturated esters V
and VI at a ratio of 2 :1 (according to the H NMR
1
Scheme 1.
OH
OEt
Me
O
Me
O
Me
O
O
O
I
II
Scheme 2.
OH
MeOCH Cl, (i-Pr) NEt
O
OMe (i-Bu) AlH
O
OMe
H
2
2
2
CH Cl , 0°C
CH Cl , –78°C
2
2
2 2
OEt
OEt
Me
Me
Me
O
O
O
III
IV
O
OMe
O
OMe
Ph P=CHCOOMe
3
CH Cl or H O, 20°C
Me
Me
2
2
2
I , CH Cl , Δ
+
2
2
2
OMe
MeO
VI
V
O
O
V
VI
1
804

SYNTHESIS OF (5S)-5-METHYLFURAN-2(5H)-ONE AND ITS DIHYDRO DERIVATIVE
1805
Scheme 3.
OH
HCl, MeOH, Δ
H , Pd/C, EtOAc
2
V
+
VI
Me
+
O
Me
O
Me
O
O
COOMe
VII
I
II
data), which cannot be separated by chromatography
on silica gel (Scheme 2). Our attempts to convert the
isomer mixture into E isomer V by the action of mo-
lecular iodine were unsuccessful. We succeeded only
in enriching the isomer mixture with the E isomer, so
chloromethyl methyl ether and 34.83 g (0.285 mol) of
ethyl(diisopropyl)amine were added under stirring, and
the mixture was stirred for 12 h at 20°C, adjusted to
pH 2 by adding hydrochloric acid, and extracted with
methylene chloride (3×100 ml). The extracts were com-
bined, washed with water until neutral reaction, and
dried over Na SO , the solvent was distilled off, and
1
that the ratio V:VI became 4:1 ( H NMR).
2
4
With a view to obtain pure E isomer V, we tried to
use the procedure described in [7] for the olefination of
the residue was distilled at 178–180°C. Yield 18.54 g
–
1
(
90%), colorless liquid. IR spectrum, ν, cm : 1734,
aldehydes with phosphoranes in water. According to
1
5
1273, 1159, 1124. H NMR spectrum, δ, ppm: 1.26 t
[
7], the reaction of methyl (triphenyl-λ -phosphanyli-
(
3H, CH , J = 7 Hz), 1.39 d (3H, CH , J = 6.9 Hz),
3
3
dene)acetate with chiral α-methyl-substituted aldehyde
structurally related to compound IV was not accom-
panied by racemization, and the corresponding olefina-
tion product was isolated as a mixture of E and Z
isomers at a ratio of 87:13. However, aldehyde IV re-
3
4
1
.35 s (3H, OCH ), 4.15 q (3H, 4-H, J = 7.1 Hz),
2
1
3
.65 s (2H, OCH O). C NMR spectrum, δ , ppm:
2
C
3.99 (CH ), 18.39 (CH ), 55.64 (OCH ), 60.71
3
3
3
(
OCH CH ), 95.69 (OCH O), 172.87 (C=O).
2 3 2
5
acted with methyl (triphenyl-λ -phosphanylidene)ace-
(2S)-(–)-2-(Methoxymethyloxy)propanal (IV).
A solution of 4.26 g (30 mmol) of (i-Bu) AlH in 50 ml
tate in aqueous medium to produce compounds V and
VI at a ratio of 1:3 (Z isomer prevailed), i.e., the ster-
eoselectivity was the opposite to that reported in [7].
2
of anhydrous methylene chloride was added dropwise
over a period of 10 min to a solution of 4.0 g
(
25 mmol) of ester III in 200 ml of anhydrous methyl-
Acid hydrolysis of isomer mixture V/VI gave a dif-
ficultly separable mixture of trans-alcohol VII and
lactone I (Scheme 3). Obviously, the latter was formed
from the hydrolysis product of Z isomer VI, and the
isomer ratio was conserved. Unsaturated lactone I was
quantitatively converted into saturated analog II under
standard hydrogenation conditions. Taking into ac-
count published data [8], the optical rotation of II
corresponded to almost 100% enantiomeric purity.
ene chloride, cooled to –78°C. The mixture was
allowed to warm up to –40°C over a period of 2 h and
then to 5°C, and 5 ml of water was slowly added drop-
wise under vigorous stirring to avoid self-heating. The
mixture was stirred for 2 h at room temperature, and
the resulting gel-like material was filtered and washed
with water and hot methylene chloride. The organic
phase was separated, the aqueous phase was extracted
with methylene chloride (3×50 ml), and the extracts
were combined with the organic phase, washed with
a saturated solution of sodium chloride, and dried over
EXPERIMENTAL
The IR spectra were recorded from thin films on
MgSO . The solvent was carefully evaporated to ob-
tain 3.1 g of a pale green liquid residue which was
purified by column chromatography on silica gel using
4
1
13
a UR-20 spectrophotometer. The H and C NMR
spectra were measured on a Bruker AM-300 spectrom-
eter at 300 and 75.47 MHz, respectively, using CDCl3
as solvent and TMS as internal reference. Analytical
thin-layer chromatography was performed on Silufol
plates. The optical rotations were determined on
a Perkin–Elmer 241-MC polarimeter.
hexane–Et
spectrum, ν, cm : 2721, 1734, 1240, 1030. H NMR
spectrum, δ, ppm: 1.37 d (3H, CH , J = 7.2 Hz), 3.40 s
(3H, OCH ), 4.03 d.d (1H, J = 7.2, 1.4 Hz), 4.73 s (2H,
OCH O), 9.70 d (1H, CHO, J = 1.4 Hz).
O (1:1) as eluent. Yield 2.6 g (90%). IR
2
–
1
1
3
3
2
Ethyl (2S)-(–)-2-(methoxymethyloxy)propanoate
III). A solution of 15 g (0.127 mol) of (S)-(–)-lactic
acid ethyl ester in 50 ml of anhydrous methylene
chloride was cooled to 0°C, 14.58 g (0.195 mol) of
Methyl (2E,4S)-4-(methoxymethyloxy)pent-2-en-
oate (V) and methyl (2Z,4S)-4-(methoxymethyloxy)-
pent-2-enoate (VI). a. Aldehyde IV, 1 g (8.5 mmol),
was dissolved in 20 ml of anhydrous methylene
(
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

1
806
LOZA et al.
5
chloride, 3.2 g (9.5 mmol) of methyl (triphenyl-λ -
phosphanylidene)acetate was added, and the mixture
was stirred for 1 h. The solvent was removed, and the
residue was subjected to chromatography on silica gel
adjusted to pH 5 by adding an aqueous solution of
NaHCO , and the aqueous phase was saturated with
solid sodium chloride and extracted with ethyl acetate
(3×50 ml). The extracts were combined, washed with
3
using hexane–ethyl acetate (3:1) as eluent to isolate
water, and dried over MgSO , and the solvent was dis-
tilled off to obtain 0.9 g of a yellow oily liquid which
was additionally purified by column chromatography
4
1
1
.3 g (88%) of isomer mixture V/VI (2:1, H NMR) as
an oily material.
on silica gel using CHCl –MeOH (40:1) as eluent.
3
b. Aldehyde IV, 1 g (8.5 mmol), was dissolved in
2
(
0 ml of distilled water, 3.2 g (9.5 mmol) of methyl
Methyl (2E,4S)-4-hydroxypent-2-enoate (VII).
5
–1
triphenyl-λ -phosphanylidene)acetate was added, and
IR spectrum, ν, cm : 3435, 1718, 1305, 1274.
1
the mixture was stirred for 2 h. The precipitate of
triphenylphosphine oxide was separated by decanting,
the aqueous phase was extracted with methylene chlo-
ride (3×50 ml), the extracts were combined and dried
H NMR spectrum, δ, ppm: 1.28 d (3H, CH
3
, J =
),
4.40 m (1H, 4-H), 5.95 d.d (1H, 2-H, J = 1.7, 15.7 Hz),
6.8 Hz), 1.60 br.s (1H, OH), 3.65 s (3H, OCH
3
13
6.90 d.d (1H, 3-H, J = 4.6, 15.7 Hz). C NMR spec-
4
over MgSO , the solvent was removed, and the residue
trum, δ
C 3 3
, ppm: 22.52 (CH ), 51.50 (OCH ), 66.87 (C ),
4
2
3
was subjected to chromatography on silica gel using
118.88 (C ), 151.43 (C ), 167.08 (C=O).
hexane–ethyl acetate (3:1) as eluent to isolate 1.25 g
(5S)-5-Methylfuran-2(5H)-one (I). Yellow oily
1
20
(
85%) of isomer mixture V/VI (1 :3, H NMR) as
liquid, [α] = +26.2° (c = 0.6, CHCl ). IR spectrum, ν,
D
3
–
1
1
an oily material.
cm : 1757, 1600. H NMR spectrum, δ, ppm: 1.38 d
–
1 1
(
(
5
7
3H, CH , J = 6.6 Hz), 5.05 m (1H, 5-H), 6.03 d.d
E Isomer V. IR spectrum: ν 1300 cm . H NMR
3
1H, 3-H, J = 1.9, 5.7 Hz), 7.38 d.d (1H, 4-H, J = 1.4,
spectrum, δ, ppm: 1.25 d (3H, CH , J = 6.9 Hz), 3.32 s
3
1
3
.7 Hz). C NMR spectrum, δ , ppm: 18.63 (CH ),
(
3H, OCH ), 3.70 s (3H, OCH ), 4.20 m (1H, 4-H),
C 3
3
3
5
3
4
2
9.64 (C ), 121.09 (C ), 157.44 (C ), 173.18 (C ).
(5S)-5-Methyltetrahydrofuran-2-one (II). Com-
4
1
.70 s (2H, OCH O), 5.95 d.d (1H, 4-H, J = 1.4,
2
5.7 Hz), 6.82 d.d (1H, 3-H, J = 5.8, 15.7 Hz).
C NMR spectrum, δ , ppm: 20.38 (CH ), 51.41
1
3
pound I, 100 mg (1.02 mmol), was dissolved in 5 ml
of ethyl acetate, 0.02 g of Pd/C was added, and the
mixture was stirred for 5 h under hydrogen. When the
initial compound disappeared (TLC), the mixture was
filtered, and the filtrate was evaporated. Yield 99 mg,
C
3
4
(OCH ), 52.20 (OCH ), 70.20 (C ), 94.00 (OCH O),
3 3 2
2
3
1
20.32 (C ), 148.98 (C ), 165.94 (C=O).
Z Isomer VI. IR spectrum: ν 1400 cm . H NMR
spectrum, δ, ppm: 1.20 d (3H, CH , J = 6.6 Hz), 3.31 s
–
1 1
3
2
0
oily liquid, [α] = –39° (c = 1, CH Cl ); published
D
2
2
(
3H, OCH ), 3.67 s (3H, OCH ), 4.15m (1H, 4-H),
3 3
2
0
data [8]: [α] = –36.8° (c = 1.44, CH Cl , ee 99.5%).
IR spectrum: ν 1790 cm . H NMR spectrum, δ, ppm:
D
2
2
4
1
.58 s (2H, OCH O), 5.75 d.d (1H, 2-H, J = 2.3,
2
–
1 1
1.7 Hz), 6.15 d.d (1H, 3-H, J = 8.2, 11.7 Hz).
C NMR spectrum, δ , ppm: 20.38 (CH ), 51.16
1
3
1.37 d (3H, CH , J = 7 Hz), 2.4 m (4H, 3-H, 4-H),
3
C
3
4
2
4.58 m (1H, 5-H).
(
OCH ), 69.45 (C ), 94.96 (OCH O), 118.90 (C ),
3
2
3
1
51.75 (C ), 165.93 (C=O).
Isomerization of mixture V/VI. Isomer mixture
REFERENCES
1
2
3
4
. Wintzer, K., Weber, R., and Schurig, K., Tetrahedron
Lett., 1981, vol. 22, p. 55.
. Schmidt, U., Gombos, J., Haslinger, E., and Zak, H.,
Chem. Ber., 1976, vol. 109, p. 2628.
V/VI, 100 mg (0.57 mmol), was dissolved in 5 ml of
methylene chloride, a solution of 20 mg of iodine in
5
ml of methylene chloride was added, and the mixture
was heated for 2 h under reflux. The mixture was
treated with a solution of Na S O , filtered, and ex-
. Kitahara, T., Mori, K., and Matsui, M., Tetrahedron Lett.,
2
2
3
1
979, vol. 20, p. 3021.
tracted with methylene chloride (3×10 ml). The com-
bined extracts were washed with water and dried over
. Utimoto, K., Uchida, K., Yamada, M., and Nozaki, H.,
Tetrahedron Lett., 1977, vol. 18, p. 3641.
MgSO , and the solvent was removed to obtain 95 mg
4
1
5. Gombos, J., Haslinger, F., and Schmidt, U., Chem. Ber.,
976, vol. 109, p. 1645.
of isomer mixture V/VI at a ratio of 4:1 ( H NMR) as
1
an oily material.
6
. Banfi, L., Bernardi, A., Colombo, L., Gennary, C., and
Scolastico, C., J. Org. Chem., 1984, vol. 49, p. 3784.
. El-Batta, A., Jang, Ch., Zhao, W., Annes, R., Cooksy, A.L.,
and Berdahl, M., J. Org. Chem., 2007, vol. 72, p. 5244.
8. Okahama, T., Kitamura, M., and Noyori, R., Tetrahedron
Lett., 1990, p. 5509.
Acid hydrolysis of isomer mixture V/VI. Isomer
mixture V/VI, 1.2 g (6.8 mmol), was dissolved in 5 ml
of boiling moist methanol, 0.1 ml of concentrated
hydrochloric acid was added, and the mixture was
heated for 1 h under reflux. The mixture was then
7
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008