1,3-Dipolar cycloaddition route to oxygen heterocyclic triones

Article abstract of DOI:10.1039/a707282a

1,3-Dipolar cycloadditon of nitrite oxides, formed in situ by dehydration of primary nitro compounds, with pyrrolidine enamines of protected γ-hydroxy-β-keto esters affords isoxazole-4-carboxylates; these are subjected to N-O bond cleavage and lactonisati

Full text of DOI:10.1039/a707282a

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1,3-Dipolar cycloaddition route to oxygen heterocyclic triones
Raymond C. F. Jones,*,a Kathryn A. M. Dullera and Simone I. E. Vultob
a Department of Chemistry, The Open University, Walton Hall, Milton Keynes, UK MK7 6AA
b Department of Chemistry, University of Nottingham, University Park, Nottingham,
UK NG7 2RD
1,3-Dipolar cycloadditon of nitrile oxides, formed in situ by dehydration of primary nitro compounds,
with pyrrolidine enamines of protected ã-hydroxy-â-keto esters affords isoxazole-4-carboxylates; these are
subjected to N᎐O bond cleavage and lactonisation to afford 3-acyltetronic acids and 3-acyl-4-hydroxy-
tetrahydropyran-2-ones.
The 3-acyltetrahydropyran-2,4-dione group is exemplified
Introduction
by alternaric acid 6,12 which has phytotoxic and antifungal
activities. A recent report describes the stereochemistry deter-
mination and a total synthesis.13
3-Acyltetronic acids (3-acyltetrahydrofuran-2,4-diones) and
their six-membered ring analogues, the 3-acyltetrahydropyran-
2,4-diones, form a structurally diverse group of biologically
active oxacyclic natural products containing the cyclic tricarb-
onyl moiety 1.1 This type of heterocyclic unit is seen also in
nitrogen analogues 2, the 3-acyltetramic acids and 3-acyl-4-
hydroxypyridin-2-ones,2 and is known to exist fully enolised.†,3
There is considerable interest in these heterocyclic triones,
particularly as antibiotics, antiviral and antifungal agents.
The range of biological properties displayed by the hetero-
cyclic triones makes them interesting targets for synthesis and
biological evaluation. Problems associated with handling these
highly polar moieties have prompted us to develop strategies
which avoid forming the enolic unit until the final stages of the
synthetic sequence.14
We propose a new approach, Scheme 1 (illustrated for five-
O
HO
HO
O
N
O
R3
R
O
R3
R2
n
X
O
O
R2
O
O
1; n = 0,1; X = O
2; n = 0,1; X = NR1
O
HO
O
O
O
N
N
R2
R1O
R3
H3C
H
O
O
R2
R1O
– O
N
C
R3
+
O
O
HO2CH2C
R
CO2Et
3; R = H
4
CO2Et
5; R = CH2CO2H
OH
OH
O
O
O
O
HO CO2H
R2
R1O
CH2
O2N CH2R3
+
6
CO2Et
Scheme 1
One of the first examples of this natural products class,
carolic acid 3 from Penicillium charlesii,4 exhibits an internal
ether of the 3-exo-enol tautomer.5 An early synthesis of this
and the related carlosic acid 4 was achieved by Bloomer
and Kappler.6 Further simply substituted acyltetronic acids
include carlic acid 5 and the recently synthesised agglomerin
A.1 Acyltetronic acid natural products carrying more complex
side chains include tetronasin7 and the closely related
tetronomycin,8 both from Streptomyces species, and for which
total syntheses have recently been reported.9 Others include
tetronolide, a novel antitumour antibiotic from Micromono-
spora chalcea KY1109,10 and kijanimicin.11
membered targets), combining the known disconnection of
3-acyltetramic acids to β-keto esters14 with the concept of
isoxazoles as masked 1,3-dicarbonyl compounds.15 The use of
isoxazole building blocks allows elaboration via non-polar
intermediates, and a late unmasking triggered by N᎐O bond
cleavage. A key point in this strategy is the C᎐C bond formation
that attaches the 3-acyl side-chain, which occurs in a 1,3-dipolar
cycloaddition and ensures regiospecific C-acylation of a 1,3-
dicarbonyl compound. The isoxazoles can be accessed by the
regiospecific 1,3-dipolar cycloaddition of a nitrile oxide to the
pyrrolidine enamine of a β-keto ester, followed by spontaneous
elimination of pyrrolidine to leave an isoxazole-4-carboxylate
ester.16 Deprotection of the oxygen substituent allows the
required lactonisation before opening of the isoxazole ring by
hydrogenation17 or other N᎐O bond cleavage method.18
† We illustrate a 3-exo-enol tautomer, one of the major tautomers for
the oxygen series [refs. 3(b),(c)]. Distribution between the four possible
enol tautomers is different between the oxygen series 1 and nitrogen
series 2.
J. Chem. Soc., Perkin Trans. 1, 1998
411

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We report herein details of our results which demonstrate
the application of this strategy as a synthetic approach to the
oxygen heterocyclic triones 1 (our studies on nitrogen hetero-
cycles 2 will be detailed separately).19
and triethylamine, yielded the two isoxazoles, ethyl 5-tert-
butoxymethyl-3-methylisoxazole-4-carboxylate 10 (63%) and
ethyl 5-benzyloxymethyl-3-methylisoxazole-4-carboxylate 11
(85%), respectively. The assigned regiochemistry is in accord
with that previously reported for cycloadditions between nitrile
oxides and β-enamino esters,16 and is substantiated by the sub-
sequent reactions; no product corresponding to the alternative
regioisomer was found.
Results and discussion
Whilst investigating new methodology to form the 3-acyl-
tetramic acids and the six-membered ring 3-acylpyridones 2, we
turned our attention to the related oxygen-containing hetero-
cycles 1, the acyltetronic acids and their six-membered ring
analogues. We hoped to apply the same type of methodology,
namely a 1,3-dipolar cycloaddition strategy to form an isoxa-
zole which acts as a masking structure, in the formation of these
oxygen heterocycles.20 The retrosynthetic strategy for the five-
membered series, Scheme 1, suggests a γ-functionalised ethyl
acetoacetate as a starting material.
Thus ethyl acetoacetate was brominated at the 4-(γ)-position
by treatment with bromine in chloroform to give the bromo
ester 7 (86%).21 The bromine atom was then substituted by
treatment of the bromo ester 7 with dry tert-butyl alcohol or
benzyl alcohol, in the presence of sodium hydride, to form the
tert-butyl ether 8 (45%) or benzyl ether 9 (48%), respectively,
Scheme 2. These yields are moderate but comparable to those
reported previously.22
The next target was the formation of the furan ring in each
case. By analogy with our findings in the 3-acylpyrrolidine-2,4-
dione series19a such cyclisation was not expected to occur
spontaneously on removal of the oxygen protecting group, pre-
sumably due to steric constraints in the bicyclic system with so
many sp2 centres and the planarity of the target lactone func-
tion, therefore further activation of the carboxy-group was
required. The ethoxycarbonyl groups of 10 and 11 were hydro-
lysed by heating at reflux with aqueous sodium hydroxide, yield-
ing the carboxylic acids, 5-tert-butoxymethyl-3-methylisox-
azole-4-carboxylic acid 12 (94%) and 5-benzyloxymethyl-3-
methylisoxazole-4-carboxylic acid 13 (85%), respectively. Acti-
vation of this carboxy-group was achieved by formation of the
mixed anhydride with ethyl chloroformate and triethylamine.
These intermediates were not isolated but used directly in the
next stage of the process. Removal of the side-chain oxygen
protecting groups, tert-butyl in 12 and benzyl in 13, was
achieved by treatment with two equivalents of HBr in acetic
acid which resulted in a spontaneous cyclisation. In contrast to
the results found in the nitrogen series19a the expected bicycle
was not formed but cleavage of the isoxazole ring also occurred
to give 3-(1-aminoethylidene)tetrahydrofuran-2,4-dione hydro-
bromide 14,‡ in a yield of 35% from the tert-butyl ether 12 and
a poor 19% from the benzyl ether 13. This is a novel method for
N᎐O bond reduction as far as we are aware. Samples of the salt
14 from both the tert-butyl and benzyl precursors were separ-
ately and easily transformed into the 3-acetyltetronic acid 15
by treatment with 2  sodium hydroxide solution at room tem-
perature. An excellent yield of 84% was obtained when using
material originating from the tert-butyl ether 12 and 72% when
using material from the benzyl ether 13.
O
O
O
O
i
OEt
OEt
Br
7
ii (R = But )
iii (R = CH2Ph)
O
O
OEt
RO
8; R = But
9; R = CH2Ph
3-Methyl-4,6-dihydrofuro[3,4-d]isoxazol-4-one 16, originally
expected from the deprotection step described above, was pre-
pared in a disappointing 6% yield by the treatment of 5-tert-
butoxymethyl-4-carboxy-3-methylisoxazole 12 with trifluoro-
acetic anhydride in trifluoroacetic acid, Scheme 3. In addition,
Scheme 2 Reagents and conditions: i, Br2, CHCl3, 0–25 ЊC; then N2
stream; ii, NaH, ButOH; iii, NaH, PhCH2OH
These two β-keto esters were then converted into their pyr-
rolidine enamines by reaction with pyrrolidine in toluene under
Dean–Stark conditions.16 Reaction of the enamines, formed
from the two β-keto esters 8 and 9, with acetonitrile oxide
generated in situ from nitroethane, phosphorus oxychloride
‡ This intermediate is drawn as the enamino ketone tautomer for con-
venience; we have no further information on the tautomer population.
NH3 Br–
O
O
N
O
N
O
i, ii
iii
iv
RO
RO
CO2Et
O
CO2Et
RO
O
CO2H
8; R = But
10; R = But
14
12; R = But
9; R = CH2Ph
11; R = CH2Ph
13; R = CH2Ph
vi (R = But )
v
vii
(R = But )
HO
O
N
O
N
O
O
viii or ix
X
HO
CO2Et
17
O
O
O
15
16
x, v
Scheme 3 Reagents and conditions: i, pyrrolidine, toluene, reflux; ii, EtNO2, Et3N, POCl3, 0–5 ЊC; iii, 2  NaOH aq., reflux; iv, HBr–AcOH (2 mol
equiv.); v, 2  NaOH aq., 25 ЊC; vi, trifluoroacetic anhydride, trifluoroacetic acid; vii, trifluoroacetic acid; viii, p-TsOH, toluene, reflux; ix, NaOEt,
EtOH, reflux; x, H2, Pd–C, 25 ЊC
412
J. Chem. Soc., Perkin Trans. 1, 1998

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this sample proved difficult to purify. Formation of the
furanone ring was also achieved by the treatment of 5-tert-
butoxymethyl-4-carboxy-3-methylisoxazole 12 with trifluoro-
acetic acid to form 4-ethoxycarbonyl-5-hydroxymethyl-3-
methylisoxazole 17 (46%). Cyclisation of 17 was attempted with
toluene-4-sulfonic acid in refluxing toluene but led to the
recovery of starting material, the same result being achieved
after heating at reflux with sodium ethoxide in ethanol. Form-
ation of the tetronic acid was realised after hydrogenation
followed by treatment with aqueous base to form 3-acetyl-
tetronic acid 15, Scheme 3, in 42% yield.
Having successfully formed 3-acetyltetronic acid 15 via this
isoxazole strategy we looked to expand the methodology to the
incorporation of other side-chains at C-3. To assemble the core
structures of carolic 3 and carlic 5 acids4–6 we required a 4-
hydroxy-1-oxobutyl group at C-3. The source of this required
functionality was 4-nitrobutyl acetate 18, prepared in low yield
from 4-bromobutyl acetate with sodium nitrite in dimethyl
sulfoxide. The enamine generated from the benzyl ether 9 was
reacted with 4-nitrobutyl acetate, triethylamine and phosphorus
oxychloride to produce the desired 3-(3-acetoxypropyl)-5-benz-
yloxymethyl-4-ethoxycarbonylisoxazole 19, although contam-
inated with 4-nitrobutyl acetate which has the same polarity.
Hydrogenation of this crude material used two equivalents of
hydrogen and was shown to have both cleaved the isoxazole ring
and removed the benzyl group. Base treatment of the crude
product led to 3-(tetrahydrofuran-2-ylidene)tetrahydrofuran-
2,4-dione 20 (45%) as a mixture of E- and Z-isomers, Scheme
4.23
O
N
OH
Me
i, ii
O
O
Me
Me
O
O
22
iii
21
O
NH2
Me
O
HO
iv
Me
O
O
Me
O
O
23
24
Scheme 5 Reagents and conditions: i, pyrrolidine, toluene, reflux;
ii, EtNO2, Et3N, POCl3, 0–5 ЊC; iii, H2, Pd–C; iv, 2  NaOH aq., 25 ЊC
Elmer 1720X FT spectrometer. 1H NMR spectra were recorded
using the following instruments: at 80 MHz on a Bruker
WP80SY, at 250 MHz on a Bruker WM250, at 270 MHz on a
JEOL JNM-EX270 or at 400 MHz on a Bruker AM400.
J Values are given in Hz. 13C NMR spectra were recorded on a
JEOL JNM-EX270 instrument at 68 MHz or a Bruker AM400
at 100 MHz and multiplicities were determined using DEPT
sequences. Mass spectra were recorded on AEI MS902, VG
7070E or VG Autospec spectrometers using electron impact as
the ionisation technique, unless FAB (fast atom bombardment)
is indicated. Microanalytical data were obtained using a Perkin-
Elmer 240B elemental analyser. All solvents were dried and
distilled prior to use.
O
O
N
i, ii
(CH2)3OAc
PhCH2O
CO2Et
PhCH2O
CO2Et
Ethyl 4-bromo-3-oxobutanoate 7 was prepared as reported21
in 86% yield. Ethyl 4-tert-butoxy-3-oxobutanoate 8 and ethyl
4-benzyloxy-3-oxobutanoate 9 were prepared as reported22 in
45 and 48% yields, respectively.
19
9
iii
Ethyl 5-tert-butoxymethyl-3-methylisoxazole-4-carboxylate 10
Ethyl 4-tert-butoxy-3-oxobutanoate 8 (2.02 g, 10.00 mmol) and
pyrrolidine (0.90 cm3, 11.00 mmol) in toluene (30 cm3) were
heated together at reflux under Dean–Stark conditions for 2 h.
After this period the solution was cooled and excess solvent
evaporated under reduced pressure. To the residue in chloro-
form (30 cm3) were added triethylamine (4.18 cm3, 30.00 mmol)
and nitroethane (0.79 cm3, 11.00 mmol). The mixture was
cooled to 0 ЊC and phosphorus oxychloride (1.03 cm3, 11.00
mmol) in chloroform (10 cm3) added dropwise over 45 min. The
mixture was then stirred a further 16 h at room temperature
before the deep red–brown solution was poured into water (20
cm3). The separated organic layer was washed successively with
hydrochloric acid (6 , 20 cm3), aqueous sodium hydroxide (5%
w/v, 20 cm3) and brine (20 cm3), dried (MgSO4) and evaporated
under reduced pressure to yield a brown oil. Purification by
flash column chromatography on silica gel eluting with light
petroleum (bp 40–60 ЊC)–ethyl acetate (2:1 v/v) yielded the title
compound as a yellow oil (1.52 g, 63%) (Found: MHϩ Ϫ But,
185.0686; C, 59.2; H, 8.0; N, 5.6%. C12H19NO4 requires
MH Ϫ But, 185.0688; C, 59.5; H, 7.9; N, 5.8%); νmax(film)/cmϪ1
2977, 2937, 2874, 1720, 1612, 1457, 1366, 1181 and 1106; δH(250
MHz; CDCl3) 1.29 [s, 9H, C(CH3)3], 1.39 (t, 3H, J 7,
OCH2CH3) 2.44 (s, 3H, 3-CH3), 4.34 (q, 2H, J 7, OCH2CH3)
and 4.81 (s, 2H, OCH2); δC(100 MHz; CDCl3) 11.3, 13.9 and
27.0 (CH3), 55.3 and 60.4 (CH2), 74.4, 108.8, 159.2, 161.5 and
174.3 (C); m/z 185 (MHϩ Ϫ But), 184 (Mϩ Ϫ But), 140 (100%)
and 57 (But).
O
NH2
O
iv
O
(CH2)3OAc
O
O
O
O
20
Scheme 4 Reagents and conditions: i, pyrrolidine, toluene, reflux;
ii, 4-nitrobutyl acetate 18, Et3N, POCl3, 0–5 ЊC; iii, H2, Pd–C, 25 ЊC;
iv, NaOH aq., 25 ЊC
In the six-membered ring oxygen series, the 3-acylpyran-2,4-
diones, a useful starting point for model reactions is the com-
mercial, racemic 4-hydroxy-6-methyl-5,6-dihydro-2H-pyran-2-
one 21. The corresponding enamine was synthesised in the
same manner as described for the β-keto esters 8 and 9, by
heating with pyrrolidine under Dean–Stark conditions. This
enamine was again reacted, without isolation, with acetonitrile
oxide to form the isoxazole 22 (25%). The N᎐O bond of the
isoxazole was cleaved quantitatively by catalytic hydrogenation
to yield the intermediate amino ketone 23‡ which was not
characterised but underwent hydrolysis with 2  sodium hydr-
oxide to produce 3-(1-hydroxyethylidene)-6-methyltetrahydro-
2H-pyran-2,4-dione 24 (26%), Scheme 5.
We have thus succeeded in validating our new cycloaddition–
isoxazole strategy for the synthesis of 3-acyltetronic acids 1 and
3-acyltetrahydropyran-2,4-diones 2.
Experimental
Melting points were determined using a Kofler hot stage appar-
atus and are uncorrected. IR spectra were recorded on a Perkin-
Ethyl 5-benzyloxymethyl-3-methylisoxazole-4-carboxylate 11
The procedure described for the preparation of 5-tert-
J. Chem. Soc., Perkin Trans. 1, 1998
413

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butoxymethyl-4-ethoxycarbonyl-3-methylisoxazole 10 was util-
ised incorporating the following quantities: ethyl 4-benzyloxy-
3-oxobutanoate 9 (13.55 g, 57.00 mmol), pyrrolidine (4.05 g,
57.00 mmol), triethylamine (17.33 g, 171.00 mmol), nitroethane
(4.73 g, 62.70 mmol) and phosphorus oxychloride (9.63 g, 62.70
mmol) to yield the title compound as a yellow oil (13.32 g, 85%)
(Found: MHϩ, 276.1256. C15H17NO4 requires MH, 276.1235);
νmax(film)/cmϪ1 2982, 1722, 1613, 1454, 1296 and 1106; δH(250
MHz; CDCl3) 1.33 (t, 3H, J 7, OCH2CH3), 2.45 (s, 3H, 3-CH3),
4.31 (q, 2H, J 7, OCH2CH3), 4.63 (s, 2H, OCH2), 4.89 (s, 2H,
PhCH2) and 7.35 (s, 5H, Ph); δC(100 MHz; CDCl3) 11.4 and
13.9 (CH3), 60.7, 62.2 and 73.2 (CH2), 109.8 (C), 127.7, 128.2
and 130.3 (CH), 137.0, 159.6, 161.2 and 173.1 (C); m/z 276
(MHϩ), 170, 105 (100%) and 91 (PhCH2ϩ).
benzyloxymethyl-4-carboxy-3-methylisoxazole 13 using the
above method, in 19% yield.
3-(1-Hydroxyethylidene)tetrahydrofuran-2,4-dione-
(3-acetyltetronic acid) 15
3-(1-Aminoethylidene)tetrahydrofuran-2,4-dione
hydrobro-
mide 14 (100.00 mg, 0.45 mmol) in aqueous sodium hydroxide
(2 , 5 cm3) was stirred at room temperature for 3 h. Careful
acidification to pH 1 with concentrated hydrochloric acid,
extraction with chloroform (3 × 20 cm3), drying (MgSO4) and
evaporation of the organic extracts yielded the title compound
as an off-white solid (53.70 mg, 84%), mp 80–82 ЊC (lit.,24 81–
83 ЊC) (Found: Mϩ, 142.0263; C6H6O4 requires M, 142.0266);
νmax(CHCl3)/cmϪ1 1770, 1698, 1673 and 1610; δH(400 MHz;
CDCl3) 2.55 (s, 3H, CH3, tautomer 1), 2.57 (s, 3H, CH3, tauto-
mer 2), 4.57 (s, 2H, CH2, tautomer 1) and 4.57 (s, 2H, CH2,
tautomer 2); δC(68 MHz; CDCl3) 19.6 (CH3, tautomer 2), 22.0
(CH3, tautomer 1), 68.8 (CH2, tautomer 1), 73.6 (CH2, tauto-
mer 2), 97.7 (C, tautomer 2), 100.6 (C, tautomer 1), 168.2 (C,
tautomer 1), 176.5 (C, tautomer 2), 188.1 (C, tautomer 2) 192.0
(C, tautomer 2), 193.9 (C, tautomer 1) and 197.8 (C, tautomer
1); m/z 142 (Mϩ, 93%), 127 and 84 (100).
5-tert-Butoxymethyl-3-methylisoxazole-4-carboxylic acid 12
5-tert-Butoxymethyl-4-ethoxycarbonyl-3-methylisoxazole 10
(1.30 g, 5.39 mmol) and sodium hydroxide (0.24 g, 5.92 mmol)
in water (15 cm3) were heated together at reflux for 4 h. After
this period the mixture was cooled, washed with chloroform (10
cm3), the aqueous layer acidified to pH 3 with concentrated
hydrochloric acid and the resultant precipitate filtered under
suction. The white solid was dissolved in chloroform and the
solution dried (MgSO4) and evaporated under reduced pressure
to yield the title compound as a white solid (1.08 g, 94%), mp
110–111 ЊC (Found: Mϩ Ϫ Me, 198.0760; C, 56.4; H, 7.3; N,
6.6%. C10H15NO4 requires M Ϫ Me, 198.0766; C, 56.3; H, 7.1;
N, 6.6%); νmax(CHCl3)/cmϪ1 2670, 1738 and 1124; δH(250 MHz;
CDCl3) 1.32 [s, 9H, C(CH3)3], 2.49 (s, 3H, 3-CH3) and 4.36 (s,
2H, OCH2); δC(68 MHz; CDCl3) 11.5 and 27.2 (CH3), 56.1
(CH2), 75.7, 108.7, 160.3, 166.1 and 175.1 (C); m/z 198
(Mϩ Ϫ Me), 157 (MHϩ Ϫ But), 140, 82 and 57 (But).
3-Methyl-4,6-dihydrofuro[3,4-d]isoxazol-4-one 16
5-tert-Butoxymethyl-3-methylisoxazole-4-carboxylic acid 12
(0.21 g, 1.00 mmol) and trifluoroacetic anhydride (0.13 g, 0.60
mmol) were stirred together in trifluoroacetic acid (2 cm3) for
2 h at room temperature. Diethyl ether (5 cm3) was then added
and the separated ether layer washed with saturated aqueous
sodium hydrogen carbonate (5 cm3), dried (MgSO4) and
evaporated under reduced pressure to yield the title compound
as an off-white solid (8.30 mg, 6%), mp 198–200 ЊC (Found:
Mϩ, 139.0269. C6H5NO3 requires M, 139.0269); δH(250 MHz;
CDCl3) 2.30 (s, 3H, CH3) and 4.82 (s, 2H, OCH2); δC(68 MHz;
CD3OD) 11.5 (CH3), 63.7 (CH2), 110.2, 161.5, 164.8 and 177.3
(C); m/z 139 (Mϩ) and 81 (100%).
5-Benzyloxymethyl-3-methylisoxazole-4-carboxylic acid 13
The procedure for the preparation of 5-tert-butoxymethyl-3-
methylisoxazole-4-carboxylic acid 12 was utilised incorporating
the following quantities: ethyl 5-benzyloxymethyl-3-methyl-
isoxazole-4-carboxylate 11 (1.20 g, 4.36 mmol), sodium hydr-
oxide (0.19 g, 4.79 mmol) and water (15 cm3) to yield the title
compound as a white solid (0.91 g, 85%), mp 111–112 ЊC
(Found: MHϩ, 248.0924; C, 63.0; H, 5.3; N, 5.4%. C13H13NO4
requires MH, 248.0923; C, 63.1; H, 5.3; N, 5.7%); νmax(CHCl3)/
cmϪ1 1712 and 1117; δH(250 MHz; CDCl3) 2.49 (s, 3H, 3-CH3),
4.07 (s, 2H, OCH2), 4.91 (s, 2H, PhCH2) and 7.35 (s, 5H, Ph);
δC(68 MHz; CDCl3) 11.5 (CH3), 62.5 and 73.5 (CH2), 109.2 (C),
128.0, 128.7 and 128.4 (CH), 136.8, 160.1, 167.1 and 174.9 (C);
m/z 248 (MHϩ), 141 (MHϩ Ϫ PhCH2O, 100%) and 91
(PhCH2ϩ).
Ethyl 5-hydroxymethyl-3-methylisoxazole-4-carboxylate 17
Ethyl 5-tert-butoxymethyl-3-methylisoxazole-4-carboxylate 10
(4.00 g, 17.00 mmol) in trifluoroacetic acid (40 cm3) was stirred
at room temperature for 1 h. After stirring diethyl ether was
added (400 cm3) and the organic phase was washed with satur-
ated aqueous sodium hydrogen carbonate, dried (Na2SO4), fil-
tered and evaporated under reduced pressure. The residue was
purified by column chromatography on silica eluting with light
petroleum (bp 40–60 ЊC)–ethyl acetate (1:1 v/v) yielded the title
compound as a clear oil (1.40 g, 46%) (Found: Mϩ, 185.0659.
C8H11NO4 requires M, 185.0688); νmax(film)/cmϪ1 3417, 2984,
2939, 1723, 1609, 1108 and 782; δH(250 MHz; CDCl3) 1.40
(t, 3H, J 7, OCH2CH3), 2.45 (s, 3H, 3-CH3), 4.37 (q, 2H, J 7,
OCH2CH3) and 4.88 (s, 2H, CH2OH); δC(68 MHz; CDCl3) 12.0
and 14.4 (CH3), 61.8 and 59.9 (CH2), 109.9, 160.0, 163.3 and
177.2 (C); m/z 185 (Mϩ) and 138 (100%).
3-(1-Aminoethylidene)tetrahydrofuran-2,4-dione hydrobromide
14
To 5-tert-Butoxymethyl-3-methylisoxazole-4-carboxylic acid
12 (0.43 g, 2.00 mmol) in anhydrous THF (30 cm3) at 0 ЊC was
added triethylamine (0.28 cm3, 2.00 mmol) and the mixture
stirred for 10 min. Ethyl chloroformate (0.19 cm3, 2.00 mmol)
was then added and the resultant suspension stirred for 15 h at
room temperature before filtration and evaporation of the solv-
ent to yield the mixed anhydride. To the crude mixed anhydride
was added hydrogen bromide in acetic acid (32% w/v, 1.06 cm3,
4.2 mmol) and the solution stirred for 16 h at room temper-
ature. Addition of dry diethyl ether resulted in precipitation of
the product which was isolated by filtration under suction and
dried to yield the title compound as a pale cream solid (156.40
mg, 35%), mp 200–204 ЊC (Found: Mϩ Ϫ HBr, 141.0424.
C6H8NO3Br requires M Ϫ HBr, 141.0426); νmax(KBr)/cmϪ1
1738, 1662 and 1625; δH(250 MHz; CD3OD) 2.55 (s, 3H, CH3)
and 4.50 (s, 2H, OCH2); δC(100 MHz; CD3OD) 18.7 (CH3), 70.7
(CH2), 90.2, 171.2, 173.2 and 195.6 (C); m/z 141 (Mϩ Ϫ HBr,
100%), 83 and 79.
3-(1-Hydroxyethylidene)tetrahydrofuran-2,4-dione
(3-acetyltetronic acid) 15
Ethyl 5-hydroxymethyl-3-methylisoxazole-4-carboxylate 17
(2.44 g, 13.18 mmol) and palladium on charcoal (10%, 0.24 g,
2.66 mmol) were stirred together under hydrogen (1 atm) until
hydrogen absorption ceased (591.00 cm3, 26.37 mmol). After
this period the mixture was filtered through Kieselgühr and the
filtrate evaporated under reduced pressure to yield a white solid.
To this material was added aqueous sodium hydroxide (2 , 150
cm3) and the mixture stirred at room temperature for 3 h before
acidification to pH 1 with concentrated hydrochloric acid. The
product was extracted with chloroform, the organic extracts
were dried (MgSO4) and evaporated under reduced pressure to
yield the title compound as a white solid (0.78 g, 42%), identical
to that described above.
The hydrobromide salt 14 was also prepared from 5-
414
J. Chem. Soc., Perkin Trans. 1, 1998

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4-Nitrobutyl acetate 18
(0.80 cm3, 8.58 mmol) to yield the title compound as a yellow
4-Bromobutyl acetate (10.00 g, 51.55 mmol) was poured into a
stirred solution of dimethyl sulfoxide (60 cm3) and sodium
nitrite (6.18 g, 89.50 mmol) immersed in a water bath held at
room temperature. Stirring was continued for 4 h after which
the mixture was poured into ice–water (120 cm3) and pentane
(200 cm3). After separation, the aqueous layer was further
extracted with pentane (4 × 20 cm3), the combined organic
extracts were washed with water (4 × 20 cm3), dried (MgSO4)
and evaporated under reduced pressure. Purification by column
chromatography on silica, eluting with light petroleum (bp
40–60 ЊC)–ethyl acetate (9:1 v/v) yielded the title compound
as a clear oil (0.83 g, 10%) (Found: Mϩ Ϫ HOAc, 101.0428.
C6H11NO3 requires M Ϫ HOAc, 101.0477); νmax(film)/cmϪ1
3582, 2962, 1737, 1552, 1368 and 1240; δH(250 MHz; CDCl3)
1.76 (m, 2H, O2NCH2CH2), 2.07 (s, 3H, OCH3), 2.09 (m, 2H,
CH2CH2OAc), 4.12 (t, 2H, CH2OAc) and 4.44 (t, 2H,
CH2NO2); δC(68 MHz; CDCl3) 20.7 (CH3), 23.9, 25.3, 63.0 and
74.8 (CH2), 170.7 (C); m/z 101 (Mϩ Ϫ HOAc) and 43 (100%).
solid (0.32 g, 25%), mp 72–73 ЊC (Found: Mϩ, 167.0594; C,
57.4; H, 5.5; N, 8.3%. C8H9NO3 requires M, 167.0582; C, 57.47;
H, 5.43, N, 8.38%); νmax(CHCl3)/cmϪ1 1729, 1632, 1368, 1322,
1241, 1189 and 1028; δH(250 MHz; CDCl3) 1.60 (d, 3H, J 6, 6-
CH3), 2.46 (s, 3H, 3-CH3), 2.99 (dd, 1H, CHCHH), 3.25 (dd,
1H, CHCHH) and 4.82 (m, 1H, CHCH2); δC(68 MHz; CDCl3)
10.06 and 20.42 (CH3), 29.83 and 75.06 (CH2), 106.59, 158.06,
160.83 and 176.03 (C); m/z 167 (Mϩ), 123 (100%), 81 and 67.
3-(1-Hydroxyethylidene)-6-methyltetrahydro-2H-pyran-2,4-
dione 24
3,6-Dimethyl-6,7-dihydro-4H-pyrano[3,4-d]isoxazol-4-one 22
(0.16 g, 0.96 mmol) in ethanol (5 cm3) was stirred with pal-
ladium on charcoal (10% w/w, 1.6 mg) under hydrogen (1 atm),
until hydrogen absorption ceased after 24 h. The suspension
was filtered through Kieselgühr and the filtrate evaporated
under reduced pressure to yield a white solid (0.15 g, 97%). To
this solid was added aqueous sodium hydroxide (2 , 15 cm3)
and the solution stirred for 2.5 h at room temperature before
acidification to pH 1 with concentrated hydrochloric acid. The
resultant precipitate was filtered under suction and the filtrate
extracted with chloroform (3 × 50 cm3). The extracts and fil-
tered solid were combined, and the solution was dried (MgSO4)
and evaporated under reduced pressure to yield a pale yellow
solid. Recrystallisation from diethyl ether gave the title com-
pound as an off-white solid (42.5 mg, 26%), mp 98–99 ЊC
(Found: Mϩ, 170.0578; C, 56.6; H, 5.9%. C8H10O4 requires M,
170.0579; C, 56.47; H, 5.92); νmax(CHCl3)/cmϪ1 1713 and 1568;
δH(250 MHz; CDCl3) 1.47 (d, 3H, 6-CH3), 1.65 (1H, br s, OH),
2.62 (s, 3H, 3-CH3), 2.65 (m, 2H, CHCH2) and 4.52 (m, 1H,
CHCH2); δC(68 MHz; CDCl3) 20.6 and 26.5 (CH3), 39.4 (CH2),
70.3 (CH), 103.2 164.3, 195.0 and 201.08 (C); m/z 170 (Mϩ),
129 (100%) and 69.
3-(Tetrahydrofuran-2-ylidene)tetrahydrofuran-2,4-dione 20
The procedure described for the preparation of ethyl 5-tert-
butoxymethyl-3-methylisoxazole-4-carboxylate 10 was utilised
incorporating the following quantities: ethyl 4-benzyloxy-3-
oxobutanoate 9 (0.93 g, 3.95 mmol), pyrrolidine (0.28 g, 3.95
mmol), triethylamine (1.20 g, 11.85 mmol), 4-nitrobutyl acetate
18 (0.70 g, 4.35 mmol) and phosphorus oxychloride (0.67 g,
4.35 mmol) to yield ethyl 5-benzyloxymethyl-3-(3-acetoxy-
propyl)isoxazole-4-carboxylate 19 (a) and 4-nitrobutyl acetate
18 (b) as a yellow oil which could not be separated, even after
repeated column chromatography; δH(250 MHz; CDCl3) 1.33
(t, 3H, J 7, OCH2CH3, a), 1.75 (m, 2H, CH2CH2NO2, b), 2.05
(m, 2H, CH2CH2OAc, a,b), 2.05 (s, 3H, OAc, a,b), 2.97 (t, 2H, J
7.5, CH2CH2CH2OAc, a), 4.11 (t, 2H, J 6.3, CH2OAc, b), 4.15
(t, 2H, J 6.4, CH2OAc, a), 4.31 (q, 2H, J 7, OCH2CH3, a), 4.42
(t, 2H, J 7, CH2NO2, b), 4.65 (s, 2H, OCH2, a), 4.89 (s, 2H,
PhCH2, a) and 7.35 (s, 5H, Ph, a); δC(68 MHz; CDCl3) 14.1
(CH3, a), 20.8 (CH3, b), 20.8 (CH2, a), 22.7 (CH2, a), 24.1 (CH2,
b), 25.4 (CH2, b), 26.5 (CH2, a), 60.9 (CH2, b), 62.4 (CH2, a),
63.1 (CH2, b), 63.6 (CH2, a), 73.4 (CH2, a), 75.0 (CH2, b), 109.5
(C, a), 128.4 (CH, a), 137.1 (C, a), 161.4 (C, a), 162.4 (C, a),
170.9 (C, a), 171.0 (C, a) and 173.6 (C, a). This mixture was
used directly in the next step.
The procedure outlined for the synthesis of 3-acetyltetronic
acid 15 from 17 was used incorporating the following quanti-
ties: 3-(3-acetoxypropyl)-5-benzyloxymethyl-4-ethoxycarbonyl-
isoxazole 19 (0.14 g, mixture as described above, approx. 0.40
mmol), palladium on charcoal (10%, 0.02 g), hydrogen (17.92
cm3, 0.80 mmol) and aqueous sodium hydroxide (2 , 10 cm3)
to yield the title compound (30 mg, 45%) as a 5:4 mixture of Z
and E isomers (Found: Mϩ, 168.0430. C8H8O4 requires M,
168.0423); δH(250 MHz; CDCl3)§ 2.22 (m, 2H, OCH2CH2,
E,Z), 3.37 (t, 2H, OCH2CH2CH2, E,Z), 4.43 [s, 2H,
OCH2C(O), Z], 4.45 [s, 2H, OCH2C(O), E], 4.72 (t, 2H,
OCH2CH2, Z) and 4.74 (t, 2H, OCH2CH2, E); δC(68 MHz;
CDCl3)¶ 21.7 (CH2, E,Z), 33.3 (CH2, E), 33.7 (CH2, Z), 72.0
(CH2, E), 72.5 (CH2, Z), 77.6 (CH2, Z), 78.2 (CH2, E), 96.1 (C,
Z), 97.0 (C, E), 168.1 (C, Z), 172.3 (C, E), 186.6 (C, E), 187.4
(C, Z), 196.3 (C, E) and 200.2 (C, Z).
Acknowledgements
We thank EPSRC for a studentship (K. A. M. D.) and the EU
for ERASMUS funding (S. I. E. V.).
References
1 For leading references, see: S. V. Ley, M. L. Trudell and D. J.
Wadsworth, Tetrahedron, 1991, 47, 8285; also refs. 4–13 below.
2 For leading references, see: R. C. F. Jones, M. J. Begley, G. E.
Peterson and S. Sumaria, J. Chem. Soc., Perkin Trans. 1, 1990, 1959;
B. J. L. Royles, Chem. Rev., 1995, 95, 1981; D. R. Williams, P. D.
Lowder and Y.-G. Gu, Tetrahedron Lett., 1997, 38, 327; R. E. Dolle
and K. C. Nicolaou, J. Am. Chem. Soc., 1986, 107, 1691, 1695.
3 (a) M. J. Nolte, P. S. Steyn and P. L. Wessels, J. Chem. Soc., Perkin
Trans. 1, 1980, 1057; (b) S. Gelin and P. Pollet, Tetrahedron Lett.,
1980, 21, 4491; (c) H. B. Broughton and P. R. Woodward,
J. Comput.-Aided Mol. Design, 1990, 4, 5147.
4 P. W. Clutterbuck, W. N. Haworth, H. Raistrick, G. Smith and
M. Stacey, Biochem. J., 1934, 28, 94.
5 O. Simonsen, T. Reffstrup and P. M. Boll, Tetrahedron, 1980, 36,
795.
6 J. L. Bloomer and F. E. Kappler, J. Chem. Soc., Perkin Trans. 1,
1976, 1485.
7 D. H. Davies, E. W. Snape, P. J. Suter, T. J. King and C. P. Falshaw,
J. Chem. Soc., Chem. Commun., 1981, 1073.
8 C. Keller-Juslen, H. D. King, M. Kuhn, H. R. Loosli, W. Pache,
T. J. Petcher, H. P. Weber and A. von Wartburg, J. Antibiot., 1982,
35, 142.
9 (a) Tetronasin: K. Hori, H. Kazuno, K. Nomura and E. Yoshii,
Tetrahedron Lett., 1993, 34, 2183; see also S. V. Ley, J. A. Clase, D. J.
Mansfield and H. M. L. Osborn, J. Heterocycl. Chem., 1996, 33,
1533; (b) tetronomycin: K. Hori, N. Hikage, A. Inagaki, S. Mori,
K. Nomura and E. Yoshii, J. Org. Chem., 1992, 57, 2888.
10 N. Hirayama, M. Kasai, K. Shirahata, Y. Ohashi and Y. Sasada,
Bull. Chem. Soc. Jpn., 1982, 55, 2984.
11 A. K. Mallams, M. S. Puar and R. R. Rossman, J. Am. Chem. Soc.,
1981, 103, 3938, 3940.
12 P. W. Brian, P. J. Curtis, H. G. Hemming, C. H. Unwin and J. M.
Wright, Nature, 1949, 164, 534.
3,6-Dimethyl-6,7-dihydro-4H-pyrano[3,4-d]isoxazol-4-one 22
The procedure outlined for the synthesis of ethyl 5-tert-
butoxymethyl-3-methylisoxazole-4-carboxylate 10 was utilised
incorporating the following quantities: 4-hydroxy-6-methyl-5,6-
dihydro-2H-pyran-2-one 21 (1.00 g, 7.80 mmol), pyrrolidine
(0.72 cm3, 8.58 mmol), triethylamine (3.26 cm3, 23.40 mmol),
nitroethane (0.62 cm3, 8.58 mmol) and phosphorus oxychloride
§ Signals of E and Z isomers assigned from 1H–13C COSY spectrum.
¶ Signal of E and Z isomers assigned by analogy.23
J. Chem. Soc., Perkin Trans. 1, 1998
415

View Article Online
Vulto, J. Chem. Soc., Perkin Trans. 1, 1994, 2513; (b) R. C. F. Jones,
G. Bhalay, P. A. Carter, K. A. M. Duller and S. I. E. Vulto,
Synlett, 1995, 149.
13 H. Tabuchi, T. Hamamoto, S. Miki, T. Tejima and A. Ichihara,
J. Org. Chem., 1994, 59, 4749.
14 R. C. F. Jones and J. M. Patience, J. Chem. Soc., Perkin Trans. 1,
1990, 2350.
15 K. G. B. Torssell, Nitrile Oxides, Nitrones and Nitronates in Organic
Synthesis, VCH Publishers, New York, 1988, pp. 9, 129; P. G.
Baraldi, A. Barco, S. Benetti, G. P. Pollini and D. Simoni, Synthesis,
1987, 857.
20 For a related approach to the podoblastins, see: H. Kawakami,
S. Hirokawa, M. Asaoka and H. Takei, Chem. Lett., 1987, 85.
21 A. Svendsen and P. M. Boll, Tetrahedron, 1973, 29, 4251.
22 J. L. Van der Baan, J. W. F. K. Barnick and F. Bickelhaupt,
Tetrahedron, 1978, 34, 223.
23 J. P. Jacobsen, T. Reffstrup, R. E. Cox, J. S. E. Holker and P. M. Boll,
Tetrahedron Lett., 1978, 12, 1081.
16 G. Stork and J. E. McMurry, J. Am. Chem. Soc., 1967, 89, 5461,
5463
17 G. Stork, S. Danishefsky and M. Ohashi, J. Am. Chem. Soc., 1967,
89, 5459.
24 K. Tanaka, K. Matsuo, Y. Nakaizumu, Y. Takashita, Y, Tachibana,
Y. Sawamura and S. Kohda, Chem. Pharm. Bull., 1979, 27, 1901.
18 N. R. Natale, Tetrahedron Lett., 1982, 23, 5009; M. Nitta and T.
Kobayashi, J. Chem. Soc., Chem. Commun., 1982, 877. C. J. Easton,
C. M. Hughes, K. D. Kirby, G. P. Savage, G. W. Simpson and
E. R. T. Tiekink, J. Chem. Soc., Chem. Commun., 1994, 2035.
19 For preliminary communication of part of this work, see: (a)
R. C. F. Jones, G. Bhalay, P. A. Carter, K. A. M. Duller and S. I. E.
Paper 7/07282A
Received 8th October 1997
Accepted 3rd November 1997
416
J. Chem. Soc., Perkin Trans. 1, 1998