Synthesis of tetronic acid derivatives from novel active esters of α-hydroxyacids

Article abstract of DOI:10.1002/jhet.5570390614

Active esters, produced by condensation of O-acetyl protected α-hydroxyacids with N-hydroxysuccinimide, react with anions of active methylene compounds to afford β,β′-tricarbonyl derivatives which upon deprotection undergo cyclization to 3-alkoxycarbonyl

Full text of DOI:10.1002/jhet.5570390614

Nov-Dec 2002
Synthesis of Tetronic Acid Derivatives from Novel
Active Esters of a -Hydroxyacids
1201
Christos Mitsos, Alexandros Zografos and Olga Igglessi-Markopoulou*
Laboratory of Organic Chemistry, Department of Chemical Engineering, National Technical University of
Athens, Zografou 157 73, Athens, Greece
Received May 7, 2002
Active esters, produced by condensation of O-acetyl protected a -hydroxyacids with N-hydroxysuccin-
imide, react with anions of active methylene compounds to afford b,b'-tricarbonyl derivatives which upon
deprotection undergo cyclization to 3-alkoxycarbonyl and 3-acyl tetronic acids. Incorporation of (S)-2-ace-
toxyphenylacetic acid in this reaction sequence enables the synthesis of optically active 5-phenyltetronic
acid derivatives.
J. Heterocyclic Chem., 39, 1201(2002).
The 3-acyltetronic unit, a structural feature known for
was introduced by Anchütz, who used a -acetoxyacid chlo-
rides as acylating agents of active methylene compounds
[11], and has been applied in the synthesis of various
5-substituted tetronic acids, though its application in the
synthesis of nonracemic products has been limited [12].
In order to improve this route, targeting the synthesis of
optically active products, we have considered the applica-
tion of alternative activation methods instead of the previ-
ously utilized acid chlorides. Derivatization of a -
aminoacids by way of the corresponding N-succinimidyl
(2,5-dioxopyrrolidin-1-yl) esters is a well-known activa-
tion method, being applied mainly in the synthesis of pep-
tides [13]. Prompted by the observation that related active
esters of anthranilic acids constitute efficient acylating
agents of b-keto esters for the production of quinolone
derivatives [14], we have investigated the application of
this activation method in the synthesis of 3-acyl and
3-alkoxycarbonyltetronic acids.
The requisite N-succinimidyl esters of a -acetoxyacids
were prepared by a standard protocol involving condensa-
tion of equimolar quantities of the O-acetyl protected
a -hydroxyacid and N-hydroxysuccinimide in the presence
of 1 equivalent of N,N'-dicyclohexylcarbodiimide
(Scheme 2). The desired active esters 1, RS-2 and S-2 were
isolated in very good yields, as pure stable solids, and used
in the next step without further purification.
many years to be present in mold metabolic products [1],
has been found during the last two decades in many natural
products exhibiting remarkable biological activities. The
antitumor antibiotics tetrocarcins [2], the antiviral antibi-
otic MM46115 [3] and kijanimicin, which displays activity
against a broad range of microorganisms [4], contain an
acylspirotetronic moiety [5]. The quartromicins, a family
of antibiotics with excellent antiviral activity against
herpes virus type 1, influenza virus type A and HIV, pos-
sess a unique structure comprising four tetronic acid sub-
units [6]. Tetronasin (ICI M139603) is an acyltetronic acid
ionophore of great interest due to its antibiotic, antipara-
sitic and growth promoting properties [7]. Some recently
isolated 3-alkanoyl-5-hydroxymethyltetronic acids display
inhibitory effect on HIV-1 protease [8] among other inter-
esting biological activities [9]. The wide range of biologi-
cal properties and the potency for pharmaceutical applica-
tions has attracted considerable interest on the develop-
ment of general methods for the synthesis of this group of
heterocyclic compounds [10].
An efficient route to 3-acyl and 3-alkoxycarbonyl-
tetronic acids, illustrated in Scheme 1, comprises the C-
acylation reaction of b-keto and malonic esters with acti-
vated derivatives of O-acetyl protected a -hydroxyacids as
the critical step. Deprotection of the b,b'-tricarbonyl inter-
mediates is accompanied by spontaneous cyclization to
3-acyl and 3-alkoxycarbonyltetronic acids. This approach
Scheme 2
Scheme 1
Subsequently, the efficiency of these novel active esters as
acylating agents of active methylene compounds was exam-
ined (Scheme 3). The reaction protocol involved the addi-
tion of 1 equivalent of the solid active ester 1 or 2 to a dis-
persion of 2 equivalents of the anion of a malonic ester 3 (or

1202
C. Mitsos, A. Zografos and O. Igglessi-Markopoulou
Vol. 39
Table 1
H nmr Data of Compounds 5-9 (deuteriochloroform solutions)
a b-keto ester 4), generated by the action of sodium
hydride, in anhydrous benzene. The reaction mixture was
stirred at room temperature for 2-5 hours and the C-acyla-
tion product extracted with water and isolated after acidi-
fication of the aqueous extracts with 10% hydrochloric
acid. The crude C-acylation products were obtained in
oily form containing small amounts of the corresponding
active methylene compound and were used in the next
step without purification. The identity of compounds 5-10
1
Product
d (ppm)
2.14 (3H, s, OCOCH ), 3.81 (6H, s, CO CH ), 4.85 (2H, s,
5
6
3
2
3
CH OAc), 5.01 (1H, s, CHCO)
2
2.19 (3H, s, OCOCH ), 3.77 (3H, s, CO CH ), 3.79 (3H, s,
3
2
3
CO CH ), 5.93 (1H, s, CHCO), 6.32 (1H, s, PhCH), 7.3-7.5
2
3
(5H, m, Ph)
7
8
9
1.26 (6H, t, J=7Hz, CO CH CH ), 2.20 (3H, s, OCOCH ),
1
2
2
3
3
was confirmed by the H nmr spectral data (Table 1). The
4.1-4.3 (4H, m, CO CH CH ), 5.92 (1H, s, CHCO), 6.33 (1H,
2
2
3
presence of a singlet resonance in the region 5-6 ppm,
attributable to the methine proton of a b,b'-tricarbonyl
moiety, indicates that the acylated malonates 5-7 possess
the keto form in deuterochloroform solutions. On the con-
trary, the acylated b-keto esters 8-10 exist in an enol tau-
tomeric form, as indicated by the presence of a low-field
resonance at approximately 17.6 ppm, prominently
assigned to the proton of an enol.
s, PhCH), 7.3-7.5 (5H, m, Ph)
1.35 (3H, t, J=7Hz, CO CH CH ), 2.18 (3H, s, OCOCH ),
2
2
3
3
2.45 (3H, s, CCOCH ), 4.27 (2H, q, J=7Hz, CO CH CH ),
3
2
2
3
5.13 (2H, s, CH OAc), 17.68 (1H, s, OH)
2
0.97 (3H, t, J=7Hz, CH CH CH ), 1.34 (3H, t, J=7Hz,
2
2
3
CO CH CH ), 1.6-1.8 (2H, m, CH CH CH ), 2.17 (3H, s,
2
2
3
2
2
3
OCOCH ), 2.73 (2H, t, J=7Hz, CH CH CH ), 4.26 (2H, q,
3
2
2
3
J=7Hz, CO CH CH ), 5.10 (2H, s, CH OAc), 17.6 (1H, s,
2
2
3
2
OH)
0.97 (3H, t, J=7Hz, CH CH CH ), 1.35 (3H, t, J=7Hz,
10
2
2
3
CO CH CH ), 1.6-1.8 (2H, m, CH CH CH ), 2.19 (3H, s,
2
2
3
2
2
3
Scheme 3
OCOCH ), 2.76 (2H, t, J=7Hz, CH CH CH ), 4.26 (2H, q, J=
3
2
2
3
7Hz, CO CH CH ), 6.39 (1H, s, PhCH), 7.3-7.6 (5H, m, Ph)
2
2
3
Deprotection of the hydroxyl group was expected to
induce cyclization of compounds 5-10 to the desired
tetronic acid derivatives. Removal of the O-acetyl group
was attempted under basic (KOH, MeOH or EtOH,
method A) or acidic conditions (HCl, MeOH or EtOH,
H O, method B). Actually, deprotection was accomplished
2
under both reaction protocols to provide, after spontaneous
lactonization, 3-alkoxycarbonyl and 3-acyltetronic acids
(11-13 and 14-16, respectively), in moderate overall yields
(Table 2).
Table 2
Tetronic Acids Synthesized from Active Esters 1 and 2
Product
R
Y
Cyclization
Method
Overall
Yield (%)
11
H
OMe
OMe
A
B
A
B
A
A
B
A
A
A
A
32
41
34
55
21
26
45
29
37
53
33
RS-12
Ph
S-12
RS-13
Ph
Ph
OMe
Oet
S-13
14
15
Ph
H
H
Oet
Me
n-Pr
n-Pr
RS-16
Ph
(i) N-succinimidyl ester (1 equiv.), NaH (2 equiv.), active methylene
compound (2 equiv.), benzene, rt, 2-5 h; (ii) Method A: KOH, R'OH, rt,
Production of enantiomerically pure tetronic acids
would be feasible by the implementation of optically pure
3-4 h; (iii) Method B: HCl, R'OH, H O, rt, 1 day.
2

Nov-Dec 2002
1203
Synthesis of Tetronic Acid Derivatives from Novel Active Esters of a -Hydroxyacids
In the case of compounds 14, 15 and 16, bearing an acyl
substituent at position 3, the b,b'-tricarbonyl keto form is
also excluded, as indicated by the H nmr spectra in deute-
rochloroform solutions (Table 3). However, the presence
of two signals for the methylene group of 5-unsubstituted
compounds 14 and 15 reveals the existence of two differ-
ent enol forms in unequal proportions. The same conclu-
sion is derived for the 5-substituted compound 16, show-
a -hydroxyacids as starting materials in this reaction
sequence. Thus, the N-succinimidyl ester of 2S-ace-
toxyphenylacetic acid (O-acetyl-S-mandelic acid) was pre-
pared by the same procedure and utilized as acylating
agent of malonic esters. The crude products S-6 and S-7,
which were isolated by the usual procedure, displayed
optical activity, indicating that during this step only partial,
if any, racemization occurred. Cyclization of S-6 and S-7
was effected using method A (KOH, MeOH or EtOH) to
afford 3-alkoxycarbonyl 5S-phenyltetronic acids S-12 and
S-13, which displayed specific rotations +107 and +126,
respectively (c 0.5 in acetone). Although, the optical purity
of these novel products needs to be evaluated, these pre-
liminary results support the importance of this methodol-
ogy for the synthesis of 5-substituted tetronic acids in non-
racemic form.
1
ing two signals for the methine proton at position 5. The
13
coexistence of two tautomeric forms is proved by the
C
nmr spectra, exhibiting two signals for all carbons of 14
and 15 (Table 4). The relative proportions of these two tau-
tomers, estimated by the integration of the proton signal of
methylene or methine at position 5, is about 3:2 for all
three compounds.
Establishment of equilibrium, favoring one of the two
forms, is the most prominent interpretation of these results.
The enol tautomers of 3-acyltetronic acids and the possible
equilibria between them are presented in Scheme 4.
Tetronic acid derivatives are presented in Scheme 3 with
the 4-hydroxyfuran-2-one tautomeric form, consistent
with the structure of the parent compound. In the case of
the 3-alkoxycarbonyl substituted products 11, 12 and 13,
nmr spectroscopic data support the existence of an enol
tautomeric form in deuteriochloroform solutions, as indi-
Scheme 4
1
cated by the presence of only one set of signals in both H
13
and C nmr spectra. The absence of the methine proton
resonance in the range 5-6 ppm, characteristic of the b,b'-
tricarbonyl moiety, establishes the enol structure of these
compounds.
Table 3
1
H nmr Spectral Data of 3-Acyltetronic Acids 14-16 [a]
Product
d (ppm)
ab:cd
14
2.55 (1.8H, s, CH , ab), 2.56 (1.2H, s, CH , cd), 4.56 60:40
3
3
(0.8H, s, CH , cd), 4.67 (1.2H, s, CH , ab), 10.51 (1H,
2
2
br, OH)
1.01 (m, CH ), 1.75 (m, CH Me), 2.91 (m, COCH ),
15
16
61:39
60:40
3
2
2
4.56 (0.8H, s, CH , cd), 4.67 (1.2H, s, CH , ab)
2
2
1.02 (m, CH ), 1.74 (m, CH Me), 2.94 (m, COCH ),
3
2
2
5.57 (0.8H, s, CH , cd), 5.69 (1.2H, s, CH , ab), 7.39
(5H, br, Ph), 11.00 (1H, br, OH)
2
2
All four enol tautomers are stabilized through hydrogen
bonding of the enol to the adjacent carbonyl.
Interconversions a to b and c to d involving displacement
[a] In deuteriochloroform solutions.
Table 4
C nmr Spectral Data of 3-Acyltetronic Acids 14-15 [a]
13
Product Tautomer
C-2
C-3
C-4
C-5
C-6
R'
14
15
ab
cd
ab
cd
168.4
176.6
168.3
176.9
100.7
97.8
100.2
97.2
198.1
192.5
198.2
192.3
68.8
73.7
68.7
73.5
194.2
188.4
197.7
192.2
22.0
19.6
36.7 (CH ), 18.3 (CH ), 13.5 (CH )
2 2 3
34.4 (CH ), 19.3 (CH ), 13.5 (CH )
2
2
3
[a] In deuteriochloroform solutions.

1204
C. Mitsos, A. Zografos and O. Igglessi-Markopoulou
Vol. 39
(deuteriochloroform): d 2.19 (3H, s, CH3), 2.78 [4H, s, (CH2)2],
6.31 (1H, s, CHOAc), 7.4-7.6 (5H, m, Ph); 13C nmr (deuteri-
ochloroform): d 20.3 (CH3), 25.4 [(CH2)2], 72.4 (CHOAc), 128.2
(C-3'), 129.1 (C-2'), 130.1 (C-4'), 132.2 (C-1'), 164.9 (COON),
168.5 (CON), 169.8 (OCOMe).
of the enolic proton along the hydrogen bond are presumed
to be fast on the nmr time scale to be observed [15]. On the
contrary, intercorversion ab to cd is expected to be slow
enough to give discrete sets of signals in the nmr spectra.
In accordance with these considerations, the two sets of
signals are observed in the nmr spectra of compounds 14,
15 and 16. These may be attributed to a weighted average
of interconversions between a to b and c to d. Form ab is
assigned as the dominant form, in agreement with previous
spectroscopic studies [16].
In conclusion, reaction of novel N-hydroxysuccinimidyl
esters of a -hydroxyacids with active methylene com-
pounds offers an efficient route to tetronic acid derivatives
bearing electron withdrawing substituents at position 3.
Preparation of nonracemic 5-substituted tetronic acids is
feasible through the utilization of suitable optically active
a -hydroxyacids as starting materials.
Anal. Calcd for C14H13NO6: C, 57.73; H, 4.50; N, 4.81.
Found: C, 57.81; H, 4.43; N, 4.69.
(S)-2-Acetoxyphenylacetic Acid 2,5-Dioxopyrrolidin-1-yl Ester
((S)-2).
Following the same procedure as above, active ester (S)-2 was
obtained as a white solid (5.15 g, 93%), mp 125-126 °C; [a ]20
D
+55.8 (c 2 in acetone); 1H nmr (deuteriochloroform): d 2.19 (3H,
s, CH3), 2.78 [4H, s, (CH2)2], 6.31 (1H, s, CHOAc), 7.4-7.6 (5H,
m, Ph); 13C nmr (deuteriochloroform): d 20.3 (CH3), 25.4
[(CH2)2], 72.4 (CHOAc), 128.2 (C-3'), 129.1 (C-2'), 130.1 (C-4'),
132.2 (C-1'), 164.9 (COON), 168.5 (CON), 169.8 (OCOMe).
General Procedure for the Preparation of Compounds 5-10.
The appropriate active methylene compound 3 (or 4) (5.0
mmol) was added dropwise to a dispersion of sodium hydride
(60% sodium hydride in oil; 5.0 mmol, 0.22 g) in anhydrous ben-
zene (25 mL) and the thick slurry thus formed was stirred at room
temperature for 1 hour. The active ester 1 (or 2) (2.5 mmol) was
added and the mixture stirred at room temperature for 2-5 hours.
The reaction mixture was extracted with water (2´ 5 mL) and the
combined aqueous extracts acidified with 10% hydrochloric acid
under cooling in an ice-water bath. The acidified solution was
extracted with dichloromethane (5´ 10 mL) and the combined
extracts dried over sodium sulfate and evaporated in vacuo to
afford the C-acylation product in an oily form. Crude products 5-
10 derived with this procedure were used for the production of
tetronic acids without further purification.
EXPERIMENTAL
Melting points were determined on a Gallenkamp MFB-595
apparatus and are uncorrected. The nmr spectra were recorded on
a Varian Gemini-2000 300 MHz spectrometer. Chemical shifts
are quoted in ppm (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiple, br = broad); J values are given in Hz.
Acetoxyacetic Acid 2,5-Dioxopyrrolidin-1-yl Ester (1).
A solution of N,N'-dicyclohexylcarbodiimide (72 mmol, 14.86
g) in anhydrous tetrahydrofuran (50 ml) was added dropwise
over a period of 1 hour to a solution of acetoxyacetic acid (72
mmol, 8.51 g) and N-hydroxysuccinimide (72 mmol, 8.29 g) in
anhydrous tetrahydrofuran (120 ml) under cooling in an ice-
water bath. The mixture was stirred at 0 °C for 1 hour, then at
room temperature for 4 hours, and left standing at 4 °C for 2 days.
The precipitated solid was filtered off and the filtrate evaporated
in vacuo. The solid residue was treated with diethyl ether, col-
lected by filtration and washed with diethyl ether to afford com-
pound 1 as a white solid (14.12 g, 91%), mp 86-88 °C; 1H nmr
(deuteriochloroform): d 2.17 (3H, s, CH3), 2.85 [4H, s, (CH2)2],
4.94 (2H, s, CH2OAc); 13C nmr (deuteriochloroform): d 20.1
(CH3), 25.4 [(CH2)2], 58.3 (CH2OAc), 163.8 (COON), 168.6
(CON), 169.8 (OCOMe).
General Procedures for the Synthesis of Tetronic Acids 11-16.
(i) Method A. A solution of potassium hydroxide (5.0 mmol,
0.3 g) in the minimum required volume of methanol (or absolute
ethanol) was added to a solution of the crude C-acylation product
in methanol (or absolute ethanol) (5 mL) under cooling in an ice-
water bath and the mixture was stirred at room temperature for 3-
4 h. The reaction mixture was acidified with 10% hydrochloric
acid under cooling in an ice-water bath. The final product was
either precipitated and collected by filtration, or extracted with
dichloromethane (5´ 10 mL) and isolated in solid form after dry-
ing over sodium sulfate and evaporation in vacuo of the com-
bined extracts.
(ii) Method B. Hydrochloric acid (10%, 10 mL) was added to a
solution of the crude C–acylation product in methanol (or
absolute ethanol) (5 mL) under cooling in an ice-water bath and
the mixture was stirred at room temperature for 1 day. The final
product was either precipitated and collected by filtration, or
extracted with dichloromethane (5´ 10 mL) and isolated in solid
form after drying over sodium sulfate and evaporation in vacuo
of the combined extracts.
Anal. Calcd for C8H9NO6: C, 44.66; H, 4.22; N, 6.51. Found:
C, 44.52; H, 4.28; N, 6.37.
(RS)-2-Acetoxyphenylacetic Acid 2,5-Dioxopyrrolidin-1-yl
Ester ((RS)-2).
A solution of N,N'-dicyclohexylcarbodiimide (50 mmol, 10.32
g) in anhydrous tetrahydrofuran (20 ml) was added dropwise
over a period of 1.5 hours to a solution of RS-2-acetoxypheny-
lacetic acid (50 mmol, 8.85 g) and N-hydroxysuccinimide (50
mmol, 5.75 g) in anhydrous tetrahydrofuran (50 ml) under cool-
ing in an ice-water bath. The mixture was stirred at room temper-
ature for 6 hours and left standing overnight at 4 °C. The precipi-
tated solid was filtered off and the filtrate evaporated in vacuo.
The solid residue was treated with diethyl ether, collected by fil-
tration and washed with diethyl ether to afford compound (RS)-2
as a white solid (12.10 g, 83%), mp 122-125 °C; 1H nmr
3-Methoxycarbonyltetronic Acid (11).
Following methods A and B compound 11 was isolated in 32
and 41% overall yields, respectively, as a white solid, mp 128-
129 °C; 1H nmr (deuteriochloroform): d 3.96 (3H, s, CH3), 4.80
(2H, s, CH2); 13C nmr (deuteriochloroform): d 50.9 (CH3), 66.2
(C-5), 93.1 (C-3), 162.0 (C-2), 169.3 (CO2Me), 185.6 (C-4).

Nov-Dec 2002
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Synthesis of Tetronic Acid Derivatives from Novel Active Esters of a -Hydroxyacids
REFERENCES AND NOTES
Anal. Calcd for C6H6O5: C, 45.58; H, 3.82. Found: C, 45.81;
H, 3.94.
[1] L. J. Haynes and J. R. Plimmer, Quart. Rev., 13, 292
(1959), and references cited therein.
[2] F. Tomita, T. Tamaoki, K. Shirahata, M. Kasai, M.
Morimoto, S. Ohkubo, K. Mineura and S. Ishii, J. Antibiot., 33, 668
(1980).
[3] R. J. Ashton, M. D. Kenig, K. Luk, D. N. Planterose and
G. Scott-Wood, J. Antibiot., 43, 1387 (1990).
[4] J. A. Waitz, A. C. Horan, M. Kalyanpur, B. K. Lee, D.
Loebenberg, J. A. Marquez, G. Miller and M. G. Patel, J. Antibiot.,
34, 1101 (1981).
(RS)-3-Methoxycarbonyl-5-phenyltetronic Acid ((RS)-12).
Following methods A and B compound (RS)-12 was isolated
in 34 and 55% overall yields, respectively, as a white solid, mp
1
141-142 °C; H nmr (deuteriochloroform): d 3.97 (3H, s, CH3),
5.85 (1H, s, CH), 7.3-7.5 (5H, m, Ph); 13C nmr (deuteriochloro-
form): d 52.7 (CH3), 78.6 (C-5), 94.1 (C-3), 126.5-129.2-130.0-
132.2 (5-Ph), 166.4 (CO2Me), 166.8 (C-2), 190.3 (C-4).
Anal. Calcd for C12H10O5: C, 61.54; H, 4.30. Found: C, 61.34;
H, 4.21.
[5] N. Hirayama, M. Kasai, K. Shirahata, Y. Ohashi and Y.
Sasada, Bull. Chem. Soc. Jpn., 55, 2984 (1982); K. Luk and S. A.
Readshaw, J. Chem. Soc., Perkin Trans. 1, 1641 (1991); A. K.
Mallams, M. S. Puar, R. R. Rossman, A. T. McPhail, R. D.
Macfarlane and R. L. Stephens, J. Chem. Soc., Perkin Trans. 1, 1497,
(1983).
[6] T. Kusumi, A. Ichikawa, H. Kakisawa, M. Tsunakawa, M.
Konishi and T. Oki, J. Am. Chem. Soc., 113, 8947 (1991); W. R.
Roush and D. A. Barda, Tetrahedron Lett., 38, 8781 (1997).
[7] D. H. Davies, E. W. Snape, P. J. Suter, T. J. King and C. P.
Falshaw, J. Chem. Soc., Chem. Commun., 1073 (1981); S. V. Ley, J.
A. Clase, D. J. Mansfield and H. M. I. Osborn, J. Heterocyclic
Chem., 33, 1533 (1996).
(S)-3-Methoxycarbonyl-5-phenyltetronic Acid ((S)-12).
Following method A compound (S)-12 was isolated in 21%
overall yield as a white solid, mp 139-140 °C; [a]20D +107 (c 0.5
1
in acetone); H nmr (deuteriochloroform): d 3.97 (3H, s, CH3),
5.85 (1H, s, CH), 7.3-7.5 (5H, m, Ph); 13C nmr (deuteriochloro-
form): d 52.7 (CH3), 78.6 (C-5), 94.1 (C-3), 126.5-129.2-130.0-
132.2 (5-Ph), 166.4 (CO2Me), 166.8 (C-2), 190.3 (C-4).
(RS)-3-Ethoxycarbonyl-5-phenyltetronic Acid ((RS)-13).
Following methods A and B compound (RS)-13 was isolated
in 26 and 45% overall yields, respectively, as a white solid, mp
1
141-143 °C (lit [17] mp 139-141 °C); H nmr (deuteriochloro-
[8] B. E. Roggo, F. Petersen, R. Delmendo, H. B. Jenny, H. H.
Peter and J. Roesel, J. Antibiot., 47, 136 (1994); B. E. Roggo, P. Hug,
S. Moss, F. Raschdorf and H. H. Peter, J. Antibiot., 47, 143 (1994).
[9] M. Sodeoka, R. Sampe, T. Kagamizono and H. Osada,
Tetrahedron Lett., 37, 8775 (1996), and references cited therein.
[10] J. L. Bloomer and F. E. Kappler, J. Chem. Soc., Perkin
Trans. 1, 1485, (1976); P. M. Booth, C. M. J. Fox and S. V. Ley, J.
Chem. Soc., Perkin Trans. 1, 121, (1987); D. J. Ager and S. J. Mole,
Tetrahedron Lett., 29, 4807 (1988); M. Sato, J. Sakaki, K. Takayama,
S. Kobayashi, M. Suzuki and C. Kaneko, Chem. Pharm. Bull., 38, 94
(1990); M. Yamashita, H. Murai, A. Mittra, T. Yoshioka, I.
Kawasaki, M. Gotoh, T. Higashi, R. Hatsuyama and S. Ohta,
Heterocycles, 48, 2327 (1998).
form): d 1.41 (3H, t, J=7.1, CH3), 4.43 (2H, q, J=7.1, CH2), 5.83
(1H, s, CH), 7.3-7.5 (5H, m, Ph); 13C nmr (deuteriochloroform):
d 14.0 (CH3), 62.2 (CH2), 78.5 (C-5), 94.2 (C-3), 126.5-129.2-
129.9-132.4 (5-Ph), 166.3 (CO2Me), 166.6 (C-2), 190.3 (C-4).
(S)-3-Ethoxycarbonyl-5-phenyltetronic Acid ((S)-13).
Following method A compound (S)-13 was isolated in 29%
overall yield as a white solid, mp 143-144 °C; [a]20D +126 (c 0.5
1
in acetone); H nmr (deuteriochloroform): d 1.42 (3H, t, J=7.1,
CH3), 4.43 (2H, q, J=7.1, CH2), 5.83 (1H, s, CH), 7.3-7.5 (5H, m,
Ph); 13C nmr (deuteriochloroform): d 14.0 (CH3), 62.2 (CH2),
78.5 (C-5), 94.2 (C-3), 126.5-129.2-129.9-132.4 (5-Ph), 166.3
(CO2Me), 166.6 (C-2), 190.3 (C-4).
[11] R. Anschütz, Chem. Ber., 36, 466 (1903).
[12] J. Matsubara, K. Nakao, Y. Hamada and T. Shioiri,
Tetrahedron Lett., 33, 4187 (1992); C. A. Mitsos, A. L. Zografos and
O. Igglessi-Markopoulou, J. Org. Chem., 65, 5852 (2000).
[13] G. W. Anderson, J. E. Zimmerman and F. M. Callahan, J.
Am. Chem. Soc., 86, 1839 (1964).
[14] C. Mitsos, A. Zografos and O. Igglessi-Markopoulou,
Chem. Pharm. Bull., 48, 211 (2000).
[15] J. V. Barkley, J. Markopoulos and O. Markopoulou, J.
Chem. Soc., Perkin Trans. 2, 1271 (1994).
[16] S. Gelin and P. Pollet,Tetrahedron Lett., 21, 4491 (1980).
[17] T. P. C. Mulholland, R. Foster and D. B. Haydock, J.
Chem. Soc., Perkin Trans. 1, 1225 (1972).
[18] F. H. Andresen, A. Svendsen and P. M. Boll, Acta Chem.
Scand., B28, 130 (1974).
[19] K. Nomura, K. Hori, M. Arai and E. Yoshii, Chem. Pharm.
Bull., 34, 5188 (1986).
[20] M. P. Sibi, M. T. Sorum, J. A. Bender and J. A. Gaboury,
Synth. Commun., 22, 809 (1992).
3-Acetyltetronic Acid (14).
Following method A compound 14 was isolated in 37% over-
all yield as a white solid, mp 77-78 °C (diethyl ether-light petro-
leum ether); (lit [18] mp 78-80 °C, [19] mp 77-79 °C); H and
13C nmr spectral data, see Tables 3 and 4.
1
3-Butanoyltetronic Acid (15).
Following method A compound 15 was isolated in 53% overall
yield as a white solid, mp 75-78 °C (light petroleum ether); (lit [20]
mp 78-80 °C); 1H and 13C nmr spectral data, see Tables 3 and 4.
(RS)-3-Butanoyl-5-phenyltetronic Acid ((RS)-16).
Following method A compound (RS)-16 was isolated in 33%
overall yield as a white solid, mp 106-107 °C (dichloromethane-light
petroleum ether); 1H and13C nmr spectral data, see Tables 3 and 4.
Anal. Calcd for C14H14O4: C, 68.28; H, 5.73. Found: C, 68.42;
H, 5.61.