Short and efficient preparations of isoxazole-3-carboxylic acid and imino-oxopentanoic acid potent precursors of 4-hydroxyisoleucine

Article abstract of DOI:10.1016/j.tet.2006.02.056

Herein, we describe short and efficient syntheses of isoxazole-3-carboxylic acid 3a and imino-oxopentanoic acid 8 achiral precursors of 4-hydroxyisoleucine. The developed procedures involve readily available and cheap starting materials and can easily be

Full text of DOI:10.1016/j.tet.2006.02.056

Tetrahedron 62 (2006) 4430–4434
Short and efficient preparations of isoxazole-3-carboxylic acid and
imino-oxopentanoic acid potent precursors of 4-hydroxyisoleucine
Jean-Michel Becht, Sandra De Lamo Marin, Martine Maruani,
*
*
Alain Wagner and Charles Mioskowski
` ´ ´
Laboratoire de Synthese Bioorganique, UMR 7514 associee au CNRS, Faculte de Pharmacie,
´
Universite Louis Pasteur de Strasbourg, 74 Route du Rhin, 67400 Illkirch, France
Received 18 January 2006; revised 14 February 2006; accepted 20 February 2006
Available online 10 March 2006
Abstract—Herein, we describe short and efficient syntheses of isoxazole-3-carboxylic acid 3a and imino-oxopentanoic acid 8 achiral
precursors of 4-hydroxyisoleucine. The developed procedures involve readily available and cheap starting materials and can easily be
transposed to the large scale.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
stereoselective reductions of 3a and 8 will be reported in
due course.
It has been estimated that more than 200 million people in
the world will have diabetes mellitus in the next decade.
Therefore, the development of improved antidiabetic drugs
has concentrated huge interest in medicinal chemistry.1
(2S,3R,4S)-4-Hydroxyisoleucine 1a, a natural product
extracted from fenugreek seeds has emerged as a promising
candidate.2 However, production of this compound through
an extraction process is not practicable for pharmaceutical
supply. To date, only two stereoselective syntheses of
(2S,3R,4S)-1a have been reported.3,4 These syntheses suffer
from many drawbacks that prohibit their use for the large
scale production. For instance, they involve more than six
steps and proceed with low overall yields. They also require
the use of expensive starting materials, chiral auxiliaries as
well as enzymatic resolutions. For these reasons, we have
focused our attention to the development of a short and
efficient synthesis of the natural occurring (2S,3R,4S)-1a
and its corresponding lactone (3S,4R,5S)-3-amino-4,5-
dimethyl-2-oxotetrahydrofuran 1b from achiral 4,5-
dimethyl-isoxazole-3-carboxylic acid ethyl ester 3a and
2-methoxyimino-3-methyl-4-oxo-pentanoic acid ethyl ester
8 (Scheme 1). The compounds 1a and 1b can be obtained
using as a key step stereoselective reductions and kinetic
resolutions of 3a and 8.5,6 Herein, we describe straight-
forward and inexpensive methodologies for large scale
syntheses of substrates 3a and 8 from readily available
starting materials (Scheme 2).7 The results concerning
OH NH2
R
O
O
S
OH
S
S
R
H2N S
O
1a
1b
O N
O
NOMe
OEt
OEt
O
O
3a
8
Scheme 1. Retrosynthetic analysis for the synthesis of 1a and 1b.
3a
8
O
OH
O
OH
OEt
OEt
O
O
6
2a
Pathway A
Pathway C
Pathway B
O
O
O
O
O
O
OEt
OEt
EtO
OEt
EtO
H
O
Keywords: Achiral precursors; Organic phase; Stereoselective.
*
O
O
Corresponding authors. Tel.: C33 (0)3 90 24 42 97; fax: C33 (0)3 90 24
43 06; e-mail: mioskowski@bioorga.u-strasbg.fr
Scheme 2. Retrosynthetic analysis for the synthesis of 3a and 8.
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.056

J.-M. Becht et al. / Tetrahedron 62 (2006) 4430–4434
4431
2. Results and discussion
position of an ester function with an amine is generally
performed in the presence of an acid catalyst and an excess
of amine.12 By reacting non-symmetrical 1,3-diketones with
amines, mixtures of regioisomers are generally obtained.13
In some cases, the regioselectivity of this reaction can be
controlled by adjusting the pH of the reaction medium.13c,d
We have shown that a regioselective reaction occurs at the a
position of the ester group by using hydroxylamine
hydrochloride and at the g position by using the free
amine.11b Hydroxylamine hydrochloride was then added
slowly at rt to a solution of 2a in a 1:1 mixture of EtOH/
THF, giving 3a as the only product in 71% isolated yield.
The most common strategy for the synthesis of isoxazoles
involves cycloaddition reactions of a nitrone or a nitrile
oxide and an alkene or an alkyne.8 The major drawbacks of
these procedures are the low reactivity of the dipolarophiles
and the dimerisation side reactions of the nitrile oxides to
generate furoxanes.8 Moreover, these reactions require
expensive starting materials and are not easily amenable
to the large scale. Therefore, we have turned our attention to
the reaction of 2-hydroxy-3-methyl-4-oxo-pent-2-enoic
acid ethyl ester 2a with hydroxylamine to generate 3a
(Scheme 3). The first approach for the synthesis of 2a
involves the aldol condensation of the cheap and commer-
cially available butanone and diethyloxalate in the presence
of EtONa in EtOH at rt for 10 min (Scheme 2, pathway A).9
As expected, a mixture of 2-hydroxy-3-methyl-4-oxo-pent-
2-enoic acid ethyl ester 2a and 2-hydroxy-4-oxo-hex-2-
enoic acid ethyl ester 2b were obtained in quantitative yield
(Scheme 3). The separation of 2a and 2b by crystallization,
distillation or flash-chromatography on silica-gel or alumina
failed. Interestingly, we found a simple and efficient method
to isolate the desired compound 2a. EtOH was firstly
distillated under reduced pressure and the crude reaction
mixture dissolved in AcOEt. The organic phase was washed
with a saturated solution of brine and the aqueous phase was
In order to improve the yield obtained for the synthesis of 2a
(Scheme 3), we have investigated another pathway based on
a Baylis–Hillmann condensation of methylvinylketone
(MVK) and ethylglyoxalate (Scheme 2, pathway B).14 In
the presence of catalytic amounts of DABCO in dioxane, the
Baylis–Hillmann adduct 4 was isolated in 77% yield after
rapid filtration on silica-gel (Scheme 4). Noteworthy,
another Baylis–Hillmann strategy for the synthesis of 2a
implies as a key-step the condensation of 2-oxo-but-3-enoic
acid ethyl ester and acetaldehyde. Several reaction
conditions were tested for this purpose but we observed
only dimerisation of 2-oxo-but-3-enoic acid ethyl ester.
Interestingly, the C–C double bond isomerisation of 4 into
2a failed under acidic (i.e., formic acid, HCl, TFA) or basic
(i.e., K2CO3, t-BuOK, DBU) conditions. Similar results
were obtained in the presence of transition metal catalysts
(i.e., Ir, Ni, Pd, Ru, Rh). In each case, 4 was quantitatively
recovered. Compound 4 was then reduced with H2/Pd/
CaCO3 in EtOH at rt for 3 h to give 5 in 85% yield, followed
by Swern oxidation to afford 2a in 81% isolated yield.15 The
extraction of 2a was firstly performed with a phosphate
buffer (pH 6.8) or a borax buffer (pH 9.6). The desired
compound was, respectively, isolated in 42 and 75% yield.
Improved yield was obtained by performing the extraction
1
extracted three times with AcOEt. H NMR showed that
compound 2b was selectively extracted from the crude
reaction mixture. The aqueous phase was then carefully
acidified to pH 6 with HCl 10% and extracted three times
with AcOEt. Noteworthy, by lowering the pH of the
aqueous phase below 6, lactonisation of 2a took place to
afford 3-ethoxy-3-hydroxy-4,5-dimethyl-3H-furan-2-one.10
We observed that washing the organic phase with water or
by using diethylether for the extraction, the separation of 2a
and 2b was much less efficient. After drying the combined
organic phases with MgSO4 and removal of the solvent
under vacuum, 2a was isolated in 35% yield (70% of the
presence in the crude reaction mixture).11a We then turned
our attention to the functionalization of 2a with hydro-
xylamine. The reaction of the carbonyl group at the a
O
O
OH
OEt
a
+
O
OH
O
O
O
+
OEt
4
OEt
H
O
O
2b
X
b
O
a
+
OH
O
OH
O
O
OH
c
OEt
OEt
OEt
OEt
OEt
EtO
O
O
O
2a
5
O
2a
d
b
O
N
O
N
OEt
O
3a
O
Scheme 4. Reagent and conditions: (a) DABCO, dioxane, rt, 30 h, 77%. (b)
Pd/CaCo3, H2, EtOH, rt, 3 h, 85%. (c) TFAA, DMSO, DCM, K78 8C, 2 h
then TEA, K78 8C to rt, 2 h, 81% (d) HONH2.HCl, EtOH/THF 1:1, rt, 24 h,
71%.
3a
Scheme 3. Reagent and conditions: (a) Na, EtOH, rt, 10 min, 35%. (b)
HONH2.HCl, EtOH/THF 1:1, rt, 24 h, 71%.

4432
J.-M. Becht et al. / Tetrahedron 62 (2006) 4430–4434
at pH 6 by using a KCl/NaOH buffer (pH 12). Under these
work-up conditions, pure 2a was obtained in 81% yield and
did not require further purification. Finally, by reacting 2a
with hydroxylamine hydrochloride in a 1:1 mixture of
EtOH/THF, 3a was isolated in 71% yield.
3. Conclusions
We have described short and efficient syntheses of achiral
4-hydroxyisoleucine precursors 3a and 8. The described
procedures require only cheap and readily available
substrates and can efficiently be transposed on the large
scale. The results concerning stereoselective reductions of
3a and 8 to generate optically pure 4-hydroxyisoleucine will
be reported in due course.
We then focused our attention to the synthesis of 8.
Compound 2a, synthesized as described above, was firstly
reacted with methoxylamine hydrochloride or with free
methoxylamine and catalytic amounts of acids in various
solvents (i.e., EtOH, EtOH/H2O, THF, THF/H2O). Unfortu-
nately, 8 was never obtained in reasonable yield (Scheme 5).
Complex reaction mixtures were generally observed. We
tried a completely different pathway based on the reaction of
2-hydroxy-4-oxo-pent-2-enoic acid ethyl ester 6 with
methoxylamine hydrochloride, followed by methylation
reaction to generate 8 (Scheme 2, pathway C). The aldol
condensation of acetone and diethyloxalate in the presence
of EtONa in EtOH at rt for 2 h gave pure 6 in 89% yield
(Scheme 5).9 This reaction has been transposed efficiently
on a 100 g scale without any noticeable loss in efficacy.
Several attempts to perform the methylation of 6 before the
amination reaction failed by using various bases (i.e.,
EtONa, t-BuOK, K2CO3), solvents (i.e., EtOH, DMF, THF,
acetone) or methylating reagents (i.e., MeI or dimethylsul-
fate). Complex reaction mixtures or dimethylated product
were generally obtained. Compound 6 was then firstly
reacted with benzyloxyamine, benzylamine and methox-
ylamine hydrochlorides at rt for 12 h in a 1:1 mixture EtOH/
H2O to afford the expected products in 43, 74 and 88%
yields, respectively.16 The methylation reaction conditions
were then optimized with 7 as model substrate. The use of
MeI, various bases (i.e., K2CO3, NaH, NaNH2) and solvents
(i.e., EtOH, DMF, acetone) did not afford the expected
product. Similar results were obtained with dimethylsulfate
as a methylating reagent. Degradation by-products were
also observed in this case. Better results were obtained by
reacting 7 in the presence of t-BuOK and MeI in THF.
Under these reaction conditions, we isolated 8 in 90% yield
after rapid filtration on silica-gel.
4. Experimental
4.1. General methods
1H and 13C NMR spectra were recorded using whether a 200
or 300 MHz instrument in CDCl3. Chemical shifts are
reported in parts per million (d) downfield from TMS. Spin
multiplicities are indicated by the following symbol: s
(singlet), d (doublet), t (triplet) and m (multiplet). IR
absorbances are reported in reciprocal centimeters (cmK1).
The mass spectra were recorded by the ionization technique
using ammonia gas. THF was distilled from sodium/
benzophenone. Acetone, EtOH and DMSO were dried on
˚
molecular sieves 4 A.
4.1.1. Preparations of 2-hydroxy-3-methyl-4-oxo-pent-2-
enoic acid ethyl ester (2a). Procedure 1. A solution of
EtONa is generated by reacting sodium (528 mmol, 12.1 g,
1.2 equiv) in anhydrous EtOH (800 mL) at rt for 2 h.
Butanone (440 mmol, 39.4 mL, 1.0 equiv) is then added
dropwise at rt and the reaction mixture is stirred at rt for 1 h.
Diethyloxalate (880 mmol, 119.5 mL, 2.0 equiv) is quickly
added at rt. After 10 min vigorous stirring, the solvent is
removed under reduced pressure and the crude reaction
mixture is dissolved in AcOEt (900 mL). The organic phase
is washed with a saturated solution of brine (900 mL). The
aqueous phase is again extracted with AcOEt (3!900 mL).
The aqueous phase is carefully acidified to pH 6 by adding
dropwise a solution of HCl 10% under vigorous stirring.
The aqueous phase is then extracted with AcOEt (3!
900 mL). The combined organic phases are dried with
MgSO4 and concentrated under reduced pressure to give 2a
and a dimeric structure in 35% yield (26.6 g).
O
O
OH
a
Procedure 2. Trifluoroacetic anhydride (82.5 mmol,
11.5 mL, 2.9 equiv) is added at K78 8C to a solution of
DMSO (6.5 mL) in DCM (100 mL). After 10 min stirring, a
solution of 5 (28.4 mmol, 5.0 g, 1.0 equiv) in DCM (30 mL)
is added dropwise at K78 8C. The resulting solution is stirred
at K78 8C for 2 h. Triethylamine (187 mmol, 26.1 mL,
6.6 equiv) is then added dropwise. The reaction mixture is
stirred for another 2 h at K78 8C, warmed to rt and poured
into a pH 12 buffer (12 mL) obtained from KCl 0.2 M
(25 mL) and NaOH 0.2 M (6 mL). The aqueous phase is
extracted with DCM (2!50 mL). The combined organic
phases are dried with MgSO4 and concentrated under
reduced pressure. The crude reaction mixture is purified by
flash-chromatography on silica-gel (eluant: hexane/AcOEt
7:3) to give 2a and a dimeric structure as an orange oil in 81%
+
OEt
O
6
O
OEt
EtO
O
O
NOMe
OEt
c
b
O
7
O
NOMe
OEt
O
OH
OEt
O
8
X
X
O
2a
1
yield (3.98 g). Orange oil. H NMR (200 MHz, CDCl3): d
1.36 (m, 6H), 1.97 (s, 3H), 2.24 (s, 3H), 2.30 (s, 2H), 4.32 (m,
Scheme 5. Reagent and conditions: (a) Na, EtOH, rt, 2 h, 89%. (b)
MeONH2.HCl, EtOH/H2O 1:1, rt, 12 h, 88%. (c) t-BuOK, THF, 0 8C,
30 min then Mel, 0 8C to rt, 12 h, 90%
4H). 13C NMR (50 MHz, CDCl3): d 11.2, 13.6, 28.8, 62.5,

J.-M. Becht et al. / Tetrahedron 62 (2006) 4430–4434
4433
101.1, 160.2, 190.5, 205.0. IR (CHCl3): 3452, 3054, 2987,
1731, 1264, 742, 703. M.S: [MCH]CZ173.
4.1.5. Preparation of 2-hydroxy-3-methyl-4-oxo-penta-
noic acid ethyl ester (5). Pd/CaCO3 (26.1 mmol, 1.8 g,
0.5 equiv) is added to a solution of 4 (52.2 mmol, 9.03 g,
1.0 equiv) in EtOH (200 mL). The mixture is purged several
times with H2. After 3 h vigorous stirring at rt, the crude
mixture is filtered with Celitew, washed with EtOH (2!
50 mL) and concentrated under reduce pressure. The crude
product is purified by flash-chromatography on silica-gel
(eluant: hexane/AcOEt 7:3) to give a 62:38 mixture of
4.1.2. Preparation of 4,5-dimethyl-isoxazole-3-carboxy-
lic acid ethyl ester (3a). Hydroxylamine hydrochloride
(13.2 mmol, 917 mg, 1.2 equiv) is slowly added in 12
portions over 3 h to a solution of 2a (11.0 mmol, 1.90 g,
1.0 equiv) in a 1:1 mixture of EtOH/THF (30 mL). The
reaction mixture is stirred at rt for 24 h. The solvent is
removed under reduced pressure. The crude reaction
mixture is poured into a saturated solution of NaCl
(40 mL). The aqueous phase is extracted with AcOEt (3!
50 mL). The combined organic phases are dried with
MgSO4 and concentrated under reduced pressure. The
crude product is purified by flash-chromatography on silica-
gel (eluant: hexane/AcOEt 95:5) to give 3a in 71% yield
(1.32 g). Colorless oil. 1H NMR (200 MHz, CDCl3): d 1.39
(t, 3H, JZ7.2 Hz), 2.10 (s, 3H), 2.36 (s, 3H), 4.40 (q, 2H,
JZ7.2 Hz). 13C NMR (75 MHz, CDCl3): d 7.5, 10.9, 14.2,
61.8, 111.4, 154.9, 161.0, 167.6. IR (CH2Cl2): 2985, 2943,
1783, 1631, 1389, 1295, 1083, 934, 787, 650. M.S: [MC
H]CZ170.
1
diastereoisomers 5 in 85% yield (7.76 g). Orange oil. H
NMR (300 MHz, CDCl3): d 1.06 (d, 1.8H, JZ7.2 Hz), 1.17
(d, 1.2H, JZ7.2 Hz), 1.18 (t, 1.2H, JZ7.2 Hz), 1.22 (t,
1.8H, JZ7.2 Hz), 2.11 (s, 1.2H), 2.16 (s, 1.8H), 2.89 (m,
1H), 3.24 (d, 0.6H, JZ3.7 Hz), 3.37 (d, 0.4H, JZ6.9 Hz),
4.19 (m, 2.4H), 4.51 (m, 0.6H). 13C NMR (75 MHz,
CDCl3): d 10.4, 12.8, 14.2, 28.4, 28.9, 50.0, 50.1, 61.8, 62.1,
71.0, 72.5, 173.3, 173.4, 209.2, 210.2. IR (CH2Cl2): 3429,
2984, 1714, 1739, 1615, 1365, 1218, 1027, 973, 741, 585.
M.S: [MCH]CZ175.
4.1.6. Preparation of 2-hydroxy-4-oxo-pent-2-enoic acid
ethyl ester (6). A solution of EtONa is generated by
reacting sodium (336 mmol, 7.72 g, 1.2 equiv) in anhydrous
EtOH (800 mL) at rt for 2 h. A solution of diethyloxalate
(280 mmol, 38.0 mL, 1.0 equiv) in acetone (280 mmol,
20.6 mL, 1.0 equiv) is then added dropwise at rt. The
reaction mixture is vigorously stirred at rt for 2 h. The
solvent is then removed under reduced pressure and water
(400 mL) is poured to the crude reaction mixture. Ice
(100 g) is added, followed by concentrated sulfuric acid
(30 mL). The aqueous phase is extracted with AcOEt (3!
500 mL). The combined organic phases are dried with
MgSO4 and concentrated under reduced pressure to give 6
in 89% yield (39.4 g). Orange oil. 1H NMR (200 MHz,
CDCl3): d 1.35 (t, 3H, JZ7.1 Hz), 2.24 (s, 3H), 4.32 (q, 2H,
JZ7.1 Hz), 6.36 (s, 1H). 13C NMR (50 MHz, CDCl3): d
14.1, 27.7, 62.6, 102.2, 162.1, 167.0, 200.1. IR (CHCl3):
3561, 2987, 1739, 1643, 1602, 1465, 1419, 1370, 1269,
1212, 1119, 1018, 910, 776, 732. M.S: [MCNH4]CZ176.
4.1.3. Preparation of 5-hydroxy-3,4-dimethyl-4,5-dihy-
dro-isoxazole-5-carboxylic acid ethyl ester (3b). Hydro-
xylamine hydrochloride (13.2 mmol, 917 mg, 1.2 equiv)
and sodium acetate (13.2 mmol, 1.08 g, 1.2 equiv) are
added in one portion to a solution of 2a (11.0 mmol, 1.90 g,
1.0 equiv) in EtOH (60 mL). The reaction mixture is stirred
at rt for 4 h. The solvent is removed under reduced pressure.
The crude reaction mixture is poured into a saturated
solution of NaHCO3 (10 mL). The aqueous phase is
extracted with dichloromethane (3!40 mL). The combined
organic phases are washed with distilled water (2!20 mL),
dried with MgSO4 and concentrated under reduced pressure.
The crude reaction mixture is purified by crystallization in
diethyl ether to give 3b in 92% yield (1.81 g). White solid.
1H NMR (300 MHz, CDCl3): d 1.28 (d, 3H, JZ7.5 Hz),
1.35 (t, 3H, JZ7.2 Hz), 1.99 (s, 3H), 3.70 (q, 1H, JZ
7.5 Hz), 4.32 (q, 2H, JZ7.2 Hz). 13C NMR (50 MHz,
CDCl3): d 8.3, 10.9, 13.6, 49.7, 62.8, 102.5, 159.3, 168.6.
M.S: [MCH]CZ188.
4.1.7. Preparation of 2-methoxyimino-4-oxo-pentanoic
acid ethyl ester (7). A solution of N-methoxylamine
hydrochloride (190 mmol, 15.9 g, 1.0 equiv) in water
(150 mL) is added dropwise at rt to a solution of 6
(190 mmol, 33.4 g, 1.0 equiv) in a mixture of EtOH
(300 mL) and water (150 mL). The reaction mixture is
stirred at rt for 12 h. The solvent is then removed under
vacuum and water (200 mL) is poured to the crude reaction
mixture. The aqueous phase is extracted with AcOEt (3!
400 mL). The combined organic phases are dried with
MgSO4 and concentrated under reduced pressure. The crude
reaction mixture is rapidly filtered on silica-gel to give 7 in
88% yield (34.4 g). Orange oil. 1H NMR (300 MHz,
CDCl3): d 1.36 (t, 3H, JZ7.2 Hz), 2.21 (s, 3H), 3.72 (s,
2H), 4.07 (s, 3H), 4.34 (q, 2H, JZ7.2 Hz). 13C NMR
(75 MHz, CDCl3): d 13.9, 29.5, 40.0, 61.9, 63.3, 146.3,
162.8, 203.8. IR (CHCl3): 2982, 2941, 1716, 1375, 1308,
1215, 1230, 1049, 1026, 732. M.S: [MCNH4]CZ205.
4.1.4. Preparation of 3-acetyl-2-hydroxy-but-3-enoic
acid ethyl ester (4). DABCO (5.3 mmol, 594 mg,
0.09 equiv) is added in one portion at 0 8C to a solution of
methylvinylketone (60 mmol, 4.9 mL, 1.0 equiv) and
ethylglyoxalate 50% w in toluene (72.0 mmol, 14.2 mL,
1.2 equiv) in dioxane (30 mL). The reaction mixture is
warmed to rt for 30 h. The crude reaction mixture is then
poured in HCl 10% (10 mL) and the aqueous phase is
extracted with AcOEt (2!50 mL). The combined organic
phases are dried with MgSO4 and concentrated under
reduced pressure. The crude reaction mixture is rapidly
filtered on silica-gel (eluant: hexane/AcOEt 1:2) to give 4 in
77% yield (7.98 g). Orange oil. 1H NMR (300 MHz,
CDCl3): d 1.25 (t, 3H, JZ7.2 Hz), 2.37 (s, 3H), 3.44 (d,
1H, JZ6.1 Hz), 4.23 (q, 2H, JZ7.2 Hz), 4.82 (d, 1H, JZ
6.1 Hz), 6.14 (s, 1H), 6.22 (s, 1H). 13C NMR (50 MHz,
CDCl3): d 14.1, 26.0, 62.1, 70.9, 128.7, 146.1, 172.6, 198.5.
IR (CH2Cl2): 3481, 2985, 2938, 1741, 1681, 1636, 1371,
1216, 1027, 912, 741, 585. M.S: [MCH]CZ173.
4.1.8. Preparation of 2-methoxyimino-3-methyl-4-oxo-
pentanoic acid ethyl ester (8). A 1 M solution of t-BuOK
in THF (174 mmol, 174.0 mL, 1.5 equiv) is added dropwise
at 0 8C to a solution of 7 (116 mmol, 23.9 g, 1.0 equiv) in

4434
J.-M. Becht et al. / Tetrahedron 62 (2006) 4430–4434
Tetrahedron Lett. 2001, 42, 8415. (g) Burkhart, D. J.; Zhou,
P.; Blumenfeld, A.; Twamley, B.; Natale, N. R. Tetrahedron
2001, 57, 8039. (h) Chuang, C.-P.; Wu, Y.-L.; Jiang, M.-C.
Tetrahedron 1999, 55, 11229. (i) Piaz, V. D.; Giovannoni,
M. P.; Castellana, C. J. Med. Chem. 1997, 40, 1417.
6. (a) Bartoli, G.; Cupone, G.; Dalpozzo, R.; De Nino, A.;
Maiuolo, L.; Procopio, A.; Tagarelli, A. Tetrahedron Lett.
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Tetrahedron Lett. 1982, 23, 3123.
anhydrous THF (1200 mL). The reaction mixture is stirred
at 0 8C for 30 min. Methyl iodide (174 mmol, 10.8 mL,
1.5 equiv) is then added at 0 8C. The reaction mixture is
warmed to rt for 12 h. The solvent is removed under vacuum
and HCl 10% (300 mL) is poured to the crude reaction
mixture. The aqueous phase is extracted with AcOEt (3!
500 mL). The combined organic phases are dried with
MgSO4 and concentrated under reduced pressure. The crude
reaction mixture is rapidly filtered on silica-gel to give 8 in
90% yield (21.4 g). White solid. 1H NMR (200 MHz,
CDCl3): d 1.29 (d, 3H, JZ7.1 Hz), 1.37 (t, 3H, JZ7.1 Hz),
2.10 (s, 3H), 3.92 (q, 1H, JZ7.1 Hz), 4.07 (s, 3H), 4.35 (q,
2H, JZ7.1 Hz). 13C NMR (75 MHz, CDCl3): d 11.5, 13.7,
27.2, 45.0, 61.8, 63.1, 151.1, 162.4, 203.5. IR (CHCl3):
2987, 2941, 1721, 1375, 1254, 1176, 1044, 913, 734, 652.
M.S: [MCNH4]CZ219.
7. Becht, J.-M.; Catala, C.; De Lamo Marin, S.; Wagner, A.;
Mioskowski, C., patent PCT/FR03/03542, 2002.
8. (a) Padwa, A. In Comprehensive Organic Synthesis; Trost, B.,
Ed.; Pergamon: New York, 1992; pp 1069–1109. (b) Wade,
P. A. In Comprehensive Organic Synthesis; Trost, B., Ed.;
Pergamon: New York, 1992; pp 1111–1168. (c) Torsell,
K. B. G. Nitrile Oxides, Nitrones and Nitronates in Organic
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Acknowledgements
`
We thank the Ministere de la Recherche et de
l’Enseignement Superieur for financial support of this
9. Manfredini, S.; Simoni, D.; Zanirato, V.; Casolari, A.
Tetrahedron Lett. 1988, 29, 3997.
´
work through a MENRT grant to J.-M. Becht and Innodia
through grants to S. De Lamo Marin and M. Maruani.
10. Reaction of 2a in acidic medium (pH!6) leads to 3-ethoxy-3-
hydroxy-4,5-dimethyl-3H-furan-2-one:
O
OH
O
Acidic medium
(pH < 6)
O
EtO
HO
References and notes
O
OEt
2a
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HONH .HCl, NaOAc
OH
O
2
EtOH, rt, 4 h
EtO
+
dimer
O
2a
O
N
HO
EtO
3. (a) Wang, Q.; Ouazzani, J.; Sasaki, N. A.; Potier, P. Eur.
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O
3b
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