One-pot synthesis of tetronic acids from esters

Article abstract of DOI:10.1055/s-2008-1032061

Tetronic acids substituted by various groups were synthesized in one pot from the corresponding aryl- or heteroarylacetic acid esters and hydroxyacetic acid esters, by a tandem process involving a transesterification and a subsequent Dieckmann cyclization

Full text of DOI:10.1055/s-2008-1032061

386
LETTER
One-Pot Synthesis of Tetronic Acids from Esters
O
ne-PotSynthesis
uof Tetronic
r
Acids
f
ro
é
m
Esters lie Mallinger, Thierry Le Gall,* Charles Mioskowski
CEA Saclay, iBiTecS, Service de Chimie Bioorganique et de Marquage, Bât. 547, 91191 Gif-sur-Yvette Cedex, France
Fax +33(1)69087991; E-mail: thierry.legall@cea.fr
Received 28 September 2007
Dedicated to the memory of the late Dr. Charles Mioskowski
synthesis of pulvinic acids.7 We envisaged to prepare
these compounds from substituted alkyl arylacetates,
which are readily available from the corresponding aryl
halides or aryl triflates, owing to recently reported cross-
coupling methods.8
Abstract: Tetronic acids substituted by various groups were syn-
thesized in one pot from the corresponding aryl- or heteroarylacetic
acid esters and hydroxyacetic acid esters, by a tandem process in-
volving a transesterification and a subsequent Dieckmann cycliza-
tion.
Key words: cyclizations, esters, heterocycles, lactones, ring clo-
sure
We reasoned that under certain conditions, it would be
possible to effect the direct preparation of tetronic acids
from an alkyl arylacetate and an alkyl hydroxyacetate.
This implies that a transesterification process would occur
at first, the diester formed being then suitable for the
Dieckmann condensation. In this Letter, we report our
first results concerning this study.
Many natural products having biological properties con-
tain in their structure a tetronic acid, or 4-hydroxybuteno-
lide, moiety (Figure 1).1 Examples of these natural
products include ascorbic acid, or vitamin C, and pulvinic
acid, a member of a large family of mushroom pigments.2
Various bases have been employed to realize the Dieck-
mann condensation. We chose to use potassium tert-bu-
toxide (2.2 equiv), available in anhydrous form as a
solution in THF. The conditions tested using methyl 4-
methoxyphenylacetate 1a and methyl glycolate 2a as the
two components of the process, either in THF or in DMF,
are summarized in Table 1.
O
HO
HO
O
O
O
3
O
O
H
HO
5
OH
HO
HO2C
pulvinic acid
Table 1 Optimization of the Preparation of Tetronic Acid 3a
OH
ascorbic acid
MeO
tetronic acid
MeO
O
Figure 1 Structures of tetronic acid (parent compound), ascorbic
KOt-Bu
acid, and pulvinic acid
+
HO
CO2R
CO2Me
O
HO
1a
(1 equiv)
2a R = Me
2b R = Et
(1.1 equiv)
3a
Several synthetic methods to generate tetronic acids have
been developed.1 Among these methods, the Dieckmann
cyclization has been widely employed and is still of much
use.3,4 It relies on the treatment of a glycolic ester with a
base (Scheme 1).
Entry
R
KOt-Bu Solvent
Temp
Time
(h)
Yield
(%)
(equiv)
1
2
3
4
5
6
7
Me
Me
Me
Me
Me
Et
2.2
2.2
2.2
2.2
2.2
2.2
1.1
THF
THF
THF
DMF
DMF
DMF
DMF
r.t.
16
2
67
79
85
90
90
66
34
O
R1
R2 R3
O
reflux
reflux
r.t.
base
R1
OR4
O
O
16
2
HO
R3
O
R2
Scheme 1 Usual preparation of tetronic acids via Dieckmann con-
r.t.
16
3
densation
r.t.
We recently became interested in the synthesis of 3-
aryltetronic acids. Such compounds have been reported as
insecticides,5 anti-oxidant, and anti-inflammatory com-
pounds,6 and could also be of use as building blocks in the
Me
r.t.
16
In THF, the reaction proceeded readily at room tempera-
ture, leading to the expected 4-hydroxy-3-(4-methoxy-
phenyl)-2-(5H)furanone (3a)9 in 67% yield after 16 hours
(entry 1). At reflux, the reaction occurred more rapidly
(entry 2), although the best result was obtained after 16
SYNLETT 2008, No. 3, pp 0386–0388
Advanced online publication: 16.01.2008
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x.
x
x.
2
0
0
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DOI: 10.1055/s-2008-1032061; Art ID: D30807ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Synthesis of Tetronic Acids from Esters
387
Table 2 One-Pot Preparation of Tetronic Acids 3
O
R1
KOt-Bu, 1 M in THF
R2 R3
CO2R4
(2.2 equiv)
R1
CO2Me
+
O
HO
conditions A or B
16 h
HO
R3
R2
1
2
3
(1 equiv)
(1.1 equiv)
Entry
Ester 1
1b
Hydroxyester 2 Product 3 R1
R2
H
R3
H
R
Conditionsa Yield (%)
1
2
2a
2a
2a
2a
2c
2c
2d
2d
2e
2f
3b
3c
3c
3d
3e
3e
3f
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Et
A
A
B
B
A
B
A
B
B
B
97
61
59
70
97
96
72
64
60
39
1c
4-BrC6H4
4-BrC6H4
thien-2-yl
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
H
H
3
1c
H
H
4
1d
H
H
5
1a
H
Me
Me
Me
Me
Bu
Ph
6
1a
H
7
1a
Me
Me
H
8
1a
3f
9
1a
3g
3h
10
1a
H
Me
a Conditions A: THF, reflux; conditions B: DMF, r.t.
hours (85% yield, entry 3).10 In DMF, the reactions were reaction of 1b with ethyl 2-hydroxyhexanoate 2e yielded
all carried out at room temperature. After two hours, a the corresponding adduct 3g in 60% yield (entry 9). The
very good yield was obtained, which was not improved af- reaction with methyl mandelate 2f was found to be more
ter 16 hours (entries 4 and 5).10 The reaction also proceed- sluggish, leading to the expected C5-phenyl-substituted
ed well using ethyl glycolate 2b (entry 6). A reaction tetronic acid 3h in only 39% yield (entry 10).
performed using only 1.1 equivalents of KOt-Bu led to a
much lower yield of adduct (entry 7).
The overall pathway leading to the formation of the
tetronic acids is depicted in Scheme 2. A transesterifica-
It is worthy of note that the preparation of compound 3a, tion of the methyl ester 1 by the alkoxide generated by
carried out on a larger scale, by the usual Dieckmann con- deprotonation of hydroxyester 2 would yield ester 4,
densation was reported to proceed in 67% yield,9 while which can then be converted to the corresponding tetronic
our one-pot process afforded 3a up to 90% yield.
acid by the usual Dieckmann condensation.
The preparation of other tetronic acids was then realized,
as summarized in Table 2. On the basis of our preliminary
study, two conditions were applied: either in THF at re-
flux (conditions A) or in DMF at room temperature (con-
ditions B). All the reactions were ran overnight (16 h),
because shorter reaction times led to incomplete reactions
in some cases.
R1
CO2Me
R2 R3
KO CO2Me
R2 R3
HO CO2Me
1
KOt-Bu
– KOMe
2
R2 R3
CO2Me
R2 R3
O CO2Me
O
OK
KOt-Bu
R1
R1
O
O
At first, several tetronic acids were prepared from methyl
glycolate 2a and methyl acetates 1b–d substituted by
phenyl, 4-bromophenyl, and thien-2-yl groups, respec-
tively (entries 1–4). They were obtained in 59–97% yield.
Using either conditions A or B, tetronic acid 3c was ob-
tained in almost the same yield (entries 2 and 3).
4
R1
O
– KOMe
HO
R3
R2
3
Then, tetronic acids substituted at C5 were prepared from
methyl 4-methoxyphenylacetate (1a) and hydroxyesters
2c–f (entries 5–10). Conditions A and B were found to be
equally efficient in producing tetronic acid 3e, substituted
at C5 by a methyl group (97% and 96% yield, entries 5 and
6). They also allowed the preparation of C5-disubstituted
tetronic acid 3f (72% and 64% yield, entries 7 and 8). The
Scheme
pathway
2
Tandem transesterification–Dieckmann cyclization
In conclusion, we report a direct synthesis of tetronic ac-
ids from a hydroxyester and an aryl- or heteroarylacetate
by a one-pot method, which should be of value particular-
Synlett 2008, No. 3, 386–388 © Thieme Stuttgart · New York

388
A. Mallinger et al.
LETTER
Angew. Chem. Int. Ed. 2003, 42, 1289. (b) Heurtaux, B.;
Lion, C.; Le Gall, T.; Mioskowski, C. J. Org. Chem. 2005,
70, 1474. (c) Desage-El Murr, M.; Nowaczyk, S.; Le Gall,
T.; Mioskowski, C. Eur. J. Org. Chem. 2006, 1489.
(d) Willis, C.; Bodio, E.; Bourdreux, Y.; Billaud, C.;
Le Gall, T.; Mioskowski, C. Tetrahedron Lett. 2007, 48,
6421.
ly in the context of a total synthesis. This is a tandem pro-
cess involving a transesterification and a subsequent
Dieckmann condensation. Tetronic acids that are either
unsubstituted, monosubstituted, or disubstituted at C5 can
be obtained from the corresponding hydroxyacetates. Fur-
ther developments based on this tandem process are cur-
rently under way.
(8) Lloyd-Jones, G. C. Angew. Chem. Int. Ed. 2002, 41, 953; and
references therein.
(9) Campbell, A. C.; Maidment, M. S.; Pick, J. H.; Stevenson,
D. F. M. J. Chem. Soc., Perkin Trans. 1 1985, 1567.
(10) Typical Experimental Procedures for Compound 3a
In DMF: To a solution of methyl 4-methoxyphenylacetate
(0.318 mL, 2.0 mmol) and methyl glycolate (0.170 g, 2.2
mmol) in DMF (10 mL) was added a 1 M solution of
KOt-Bu in THF (4.4 mL, 4.4 mmol). The solution was
stirred under argon at r.t. for 2 h. The reaction mixture was
then poured into cooled 1 N HCl (15 mL). The aqueous
phase was extracted with EtOAc (3 × 10 mL), the combined
organic layers were washed several times with brine, dried
over Na2SO4. After filtration and concentration in vacuo, the
residue was purified by column chromatography [silica gel,
200:1, then CH2Cl2–MeOH (95:5) containing 0.2% AcOH],
to give compound 3a as a white solid (0.370 g, 90%).
In THF: To a solution of methyl 4-methoxyphenylacetate
(0.318 mL, 2.0 mmol) and methyl glycolate (0.170 g, 2.2
mmol) in anhyd, degassed THF (10 mL) was added a 1 M
solution of KOt-Bu in THF (4.4 mL, 4.4 mmol). The
suspension obtained was refluxed under argon for 16 h.
After cooling to r.t., the reaction mixture was poured into
1 N HCl (15 mL). Treatment and purification as above
afforded compound 3a as a white solid (0.350 g, 85%).
Compound 3a: mp 228 °C (lit. 9: 228–229 °C). IR (neat):
2955, 1695, 1641, 1610, 1514, 1426, 1398, 1351, 1297,
1256, 1169, 1053, 1030, 1022, 960, 836, 736 cm–1. 1H NMR
(400 MHz, acetone-d6): d = 3.81 (s, 3 H, OCH3), 4.76 (s, 2
H, CH2), 6.95 (d, J = 9.0 Hz, 2 H, CH), 7.94 (d, J = 9.0 Hz,
2 H, CH), 10.94 (br s, 1 H, OH). 13C NMR (100 MHz,
acetone-d6): d = 55.5 (OCH3), 66.6 (C5), 100.3 (C3), 114.3
(C3¢), 123.8 (C1¢), 129.2 (C2¢), 159.4 (C4¢), 172.1, 173.5 (C2,
C4). MS (ESI-TOF): m/z = 207 [M + H]+.
References and Notes
(1) Reviews: (a) Tejedor, D.; Garcia-Tellado, F. Org. Prep.
Proced. Int. 2004, 36, 33. (b) Zografos, A. L.; Georgiadis,
D. Synthesis 2006, 3157.
(2) (a) Gill, M.; Steglich, W. Prog. Chem. Org. Nat. Prod. 1987,
51, 1. (b) Rao, Y. S. Chem. Rev. 1976, 76, 625.
(3) For reviews on the Dieckmann condensation, see:
(a) Davis, B. R.; Garrett, P. J. In Comprehensive Organic
Synthesis, Vol. 2; Trost, B. M.; Fleming, I., Eds.; Pergamon:
Oxford, 1991, 806–829. (b) Schaefer, J. P.; Bloomfield, J. J.
Org. React. 1967, 15, 1.
(4) For recent syntheses of tetronic acids via Dieckmann
condensation, see: (a) Pulvinones: Bernier, D.; Moser, F.;
Brückner, R. Synthesis 2007, 2240. (b) See also: Bernier,
D.; Brückner, R. Synthesis 2007, 2249. (c) Retipolide E,
ornatipolide: Ingerl, A.; Justus, K.; Hellwig, V.; Steglich, W.
Tetrahedron 2007, 63, 6548. (d) Abyssomicin C, atrop-
abyssomicin C, and abyssomicin D: Nicolaou, K. C.;
Harrison, S. T. J. Am. Chem. Soc. 2007, 129, 429. (e) (+)-
Tetronolide: Boeckman, R. K. Jr.; Shao, P.; Wrobleski, S.
T.; Boehmler, D. J.; Heintzelman, G. R.; Barbosa, A. J.
J. Am. Chem. Soc. 2006, 128, 10572. (f) Quartromicins:
Trullinger, T. K.; Qi, J.; Roush, W. R. J. Org. Chem. 2006,
71, 6915. (g) Secretase inhibitors: Larbig, G.; Schmidt, B.
J. Comb. Chem. 2006, 8, 480.
(5) Bretschneider, T.; Benet-Buchholtz, J.; Fischer, R.; Nauen,
R. Chimia 2003, 57, 697; and references therein.
(6) Weber, V.; Rubat, C.; Duroux, E.; Lartigue, C.; Madesclaire,
M.; Coudert, P. Bioorg. Med. Chem. 2005, 13, 4552.
(7) For previous studies on the synthesis of pulvinic derivatives
in our laboratory, see: (a) Desage-El Murr, M.; Nowaczyk,
S.; Le Gall, T.; Mioskowski, C.; Amekraz, B.; Moulin, C.
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