An effective one-pot synthesis of 5-substituted tetronic acids

Article abstract of DOI:10.1021/jo034083o

An expeditious one-pot synthesis of 5-substituted tetronic acids from aldehydes and terminal conjugated alkyne as starting materials is described. The entire process embodies two consecutive chemical events: a catalytic domino reaction to build the 1,3-dioxolane scaffolds 5 and a two-step acid-catalyzed trans-acetalization-lactonization reaction to furnish the tetronic acid derivatives 6.

Full text of DOI:10.1021/jo034083o

to generate the γ-lactonic ring.8 Also, 1,3-dioxolan-4-
ones,9 2-dioxolanones,10 and substituted 3-furanones11
have been used as templates in the synthesis of these
molecules. To the best of our knowledge, a one-pot
synthesis of tetronic acid derivatives using cheap, com-
mercially available, and nonelaborated starting materials
has not been described.12 We report here on a simple,
general, and effective one-pot method to obtain 5-substi-
tuted tetronic acids. The method comprises two consecu-
tive processes: a catalytic domino reaction to build the
1,3-dioxolane intermediates 513 and a two-step acid-
catalyzed trans-acetalization-lactonization reaction to
furnish the tetronic acid derivatives 6 (Scheme 1).
Domino processes,14 when they are performed in a
catalytic manner, constitute a powerful and economical
synthetic way to introduce chemical and structural
complexity. The search for and development of this kind
of chemical processes is a great challenge in organic and
medicinal chemistry.15 Recently, we described13 a domino
process based on the catalytic generation of a reactive
An Effective On e-P ot Syn th esis of
5-Su bstitu ted Tetr on ic Acid s
David Tejedor Arago´n,†,‡ Gloria V. Lo´pez,†,§
Fernando Garc´ıa-Tellado,*,†,|
J ose´ J uan Marrero-Tellado,‡, Pedro de Armas,†,| and
David Terrero†,#
Instituto de Productos Naturales y Agrobiologı´a,
CSIC, Avda. Astrofı´sico Francisco Sa´nchez 3,
38206 La Laguna, Tenerife, Spain, Instituto Universitario
de Bio-orga´nica Antonio Gonza´lez, Universidad de La
Laguna, Avda. Astrofı´sico Francisco Sa´nchez 2, 38206 La
Laguna, Tenerife, Spain, and Instituto Canario de
Investigacio´n del Ca´ncer, Avda. Astrofı´sico Francisco
Sa´nchez 2, 38206 La Laguna, Tenerife, Spain
fgarcia@ipna.csic.es
Received J anuary 23, 2003
Abstr a ct: An expeditious one-pot synthesis of 5-substituted
tetronic acids from aldehydes and terminal conjugated
alkyne as starting materials is described. The entire process
embodies two consecutive chemical events: a catalytic dom-
ino reaction to build the 1,3-dioxolane scaffolds 5 and a two-
step acid-catalyzed trans-acetalization-lactonization reac-
tion to furnish the tetronic acid derivatives 6.
(3) (a) Mitsos, C. A.; Zografos, A. L.; Igglessi-Markopoulou, O. J .
Org. Chem. 2000, 65, 5852-5853. (b) Ge, P.; Kirk, K. L. J . Org. Chem.
1996, 61, 8671-8673. (c) Hori, K.; Kazuno, H.; Nomura, K.; Yoshii, E.
Tetrahedron Lett. 1993, 24, 2183-2186. (d) Witiak, D. T.; Tehim, A.
K. J . Org. Chem. 1990, 55, 1112-1114. (e) Booth, P. M.; Fox, C. M. J .;
Ley, S. V. J . Chem. Soc., Perkin Trans. 1 1987, 121-129. (f) Branda¨nge,
S.; Flodman, L.; Norberg, A. J . Org. Chem. 1984, 49, 927-928. (g)
Ireland, R. E.; Thompson, W. J . J . Org. Chem. 1979, 44, 3041-3052.
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1485-1491. (i) Bell, P. M.; Sørensen, E.; Balieu, E. Acta Chem. Scand.
1968, 22, 3251-3255.
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Yoda, H. J . Chem. Soc., Perkin Trans. 1 2002, 500-502. (b) Momose,
T.; Toyooka, N.; Takeuchi, Y. Heterocycles 1986, 24, 1429-1431. (c)
Svendsen, A.; Boll, P. M. Tetrahedron 1973, 29, 4251-4258.
(5) Synthesized using the Claisen condensation: (a) Brandaenge,
S.; Flodman, L.; Norbreg, A. J . Org. Chem. 1984, 49, 927-928. (b)
Pollet, P.; Gelin, S. Tetrahedron 1978, 34, 1453-1455. (c) Damon, R.
E.; Luo, T.; Schlessinger, R. H. Tetrahedron Lett. 1976, 32, 2749-2752.
(6) Synthesized using the Blaise reaction with cyanhydrins. (a)
Reference 2b. (b) Duffield, M. J . J .; Regan, A. C. Tetrahedron:
Asymmetry 1996, 7, 663-666. (c) Veronese, A.; Callegari, R.; Bertazzo,
A. Heterocycles 1991, 32, 2205-2215. (d) Kitazume, T. J . Fluorine
Chem. 1987, 35, 287-294. (e) Krepski, L. R.; Lynch, L. E.; Heilmann,
S. M.; Rasmussen, J . K. Tetrahedron Lett. 1985, 26, 981-984.
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T.; Ohta, S. Synlett 1997, 8, 909-910. (b) Wrobel, J . E.; Ganem, B. J .
Org. Chem. 1983, 48, 3761-3764.
Tetronic acids (4-hydroxy-5H-furan-2-one) form a sub-
class of â-hydroxybutenolides with the generic structure
1.1 The best known members of this family are vitamin
C (ascorbic acid) 2 and pennicillic acid 3. A great number
of these compounds and their metabolites are found in
many natural products, which exhibit a wide array of
biological properties.1,2
(8) (a) Lieb, F.; Benet-Buchholtz, J .; Facke, T.; Fischer, R.; Graff,
A.; Lefebvre, I. M.; Stetter, J . Tetrahedron 2001, 57, 4133-4137. (b)
Schobert, R.; Mueller, S.; Bestmann, H.-J . Synlett 1995, 5, 425-426.
(c) Sato, M.; Sasaki, J .; Sugita, Y.; Yasuda, S.; Sakoda, H.; Kaneko, C.
Tetrahedron 1991, 47, 5689-5706.
Several strategies have been used for the preparation
of 5-substituted tetronic acids. Most of them utilize either
a Dieckmann reaction2a,3 or a cyclization of a suitable
â-ketoester derivative bearing a γ-halogen atom4 or a
γ-oxygenated function.5-7 Other methods utilize ketenes
(9) Ramage, R.; Griffiths, G. J .; Shutt, F. E.; Sweeney, J . N. A. J .
Chem. Soc., Perkin Trans. 1 1984, 1539-1545.
(10) Matso, K.; Sakaguchi, Y. Heterocycles 1996, 43, 2553-2556.
(11) Desmaele, D. Tetrahedron 1992, 48, 2925-2934.
(12) Although the method described by Schobert et al.8b is a true
one-pot synthesis of tetronic acid derivatives, the ketenylidenetri-
phenylphosphorane reagent needs to be elaborated.
† Instituto de Productos Naturales y Agrobiolog´ıa.
‡ Instituto Canario de Investigacio´n del Ca´ncer.
§ On leave from Universidad de La Repu´blica, Uruguay.
| Associate researcher at the Instituto Canario de Investigacio´n del
Ca´ncer.
(13) de Armas, P.; Garc´ıa-Tellado, F.; Marrero-Tellado, J . J .; Tejedor,
D.; Maestro, M. A.; Gonza´lez-Platas, J . Org. Lett. 2001, 3, 1905-1908.
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Chemistry; Shibasaki, M., Stoddart, J . F., Vo¨gtle, F., Eds.; Wiley-
VCH: Weinheim, 2000; pp 39-64. (b) Filippini, M. H.; Rodriguez, J .
Chem. Rev. 1999, 99, 27-76. (c) Tietze, L. F. Chem. Rev. 1996, 96,
115-136. (d) Bunce, R. A. Tetrahedron 1995, 51, 13103-13160.
(15) (a) Wess, G.; Urmann, M.; Sickenberger, B. Angew. Chem., Int.
Ed. 2001, 40, 3341-3350. (b) Arya, P.; Chou, D. T. H.; Baek, M. G.
Angew. Chem., Int. Ed. 2001, 40, 339-346. (c) Drews, J . Science 2000,
287, 1960-1964. (d) Schriber, S. L. Science 2000, 287, 1964-1969. (e)
Nicolaou, K. C.; Montagnon, T.; Ulven, T.; Baran, P. S.; Zhong, Y.-L.;
Sarabia, F. J . Am. Chem. Soc. 2002, 124, 5718-5728.
Instituto Universitario de Bioorga´nica Antonio Gonza´lez.
On leave from Universidad Auto´noma de Santo Domingo, Repu´b-
#
lica Dominicana.
(1) Haynes, L. J .; Plimmer, J . R. Q. Rev. Chem. Soc. 1960, 14, 292-
315.
(2) (a) Sodeoka, M.; Sampe, R.; Kojima, S.; Baba, Y.; Usui, T.; Ueda,
K.; Osada, H.; J . Med. Chem. 2001, 44, 3216-3222. (b) Bu¨hler, H.;
Bayer, A.; Effenberg, F. Chem. Eur. J . 2000, 6, 2564-2571 and
references therein.
10.1021/jo034083o CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/27/2003
J . Org. Chem. 2003, 68, 3363-3365
3363

TABLE 1
SCHEME 1. On e-P ot Syn th esis of 5-Su bstitu ted
Tetr on ic Acid s
% yielda,b
B
entry
1
R
A
C
4a
4b
Me
6a 3f
7a
6b
7b
6c
6d
6e
6f
69
5
65
5
SCHEME 2. On e-P ot Syn th esis of th e Tetr on ic
Acid Der iva tives 6
2
n-Pr
3
4
5
6
4c
4d
4e
4f
i-Pr
t-Bu
58
56
65
62
47
CH2dCH(CH2)2
BnOCH2
58
48c
intermediates 5 in excellent yields and high efficiency.
The synthesis of 5 involves the creation of two C-O bonds
and one C-C bond with both atom economy and struc-
ture economy. These 1,3-dioxolanes 5 are suitable scaf-
folds to generate the 3-oxo-γ-lactone ring core of the
tetronic acids with different patterns of substitution at
C-5. Thus, simple trans-acetalization liberates the re-
quired γ-hydroxy â-ketoester intermediates, which lac-
tonize to furnish the tetronic acid derivatives 6 (Scheme
2b). Tetronic acid derivatives are quite reactive toward
aldehydes to give dilactone compounds 7.17 Because the
trans-acetalization reaction liberates 1 equiv of aldehyde,
formation of dilactones 7 can involve a serious loss of
product. Fortunately, under controlled conditions, 1,3-
dioxolanes 5 selectively furnish tetronic acid derivatives
6. When both processes are carried out in the same flask,
without the isolation of intermediates, in a one-pot
fashion, the resulting chemical system constitutes a very
appealing reaction manifold for the synthesis of substi-
tuted tetronic acid derivatives (see Table 1). The scope
and effectiveness of the method is demonstrated by the
results given in Table 1. 5-Alkyl-substituted tetronic acid
derivatives are quite accessible regardless off the rami-
fication grade of the alkyl chain (entries 1-4). Aldehydes
4a and 4b require 24 h of acid-catalyzed alcoholysis to
yield the expected tetronic derivatives 6a and 6b in good
yields. After 24 h, a remaining amount of dioxolanes 5
(6%) is still present in the reaction medium and dilactone
7 (5%) begins to appear. Longer reaction times lower the
tetramate yield favoring the dilactone production. In the
case of the more sterically demanding aldehydes 4c and
4d , an excess of aldehyde (4 equiv) and longer reaction
time for the acid-catalyzed trans-acetalization of the
dioxolane intermediates are required to improve the yield
from a modest 45-50% to a better 60-65% (entries 3,
4). In the reaction with isobutanal, the amount of
unreacted dioxolane 5c obtained decreases from 18% at
24 h to 10% at 72 h. Similarly, unreacted 5d decreases
from 13% to 5%. In both cases, there is no significant
formation of the corresponding dilactones due to the
steric volume of the R group in these aldehydes. Tetra-
conjugated acetylide by the Michael addition of triethyl-
amine to the terminal conjugated alkynoate in the
presence of an aldehyde. The key to this system is the
low pKa value of these terminal conjugated alkynoates
(pKa < 18.8).16 The whole process is outlined in Scheme
2a. The generated ammonium acetylide I reacts with one
molecule of aldehyde to give the ammonium alkoxide II
which, in turn, reacts with another molecule of aldehyde
to furnish the intermediate vinylammonium III. This
anion deprotonates to the starting alkynoate generating
the 1,3-dioxolane 5 and acetylide I which reinitiates the
cycle. This domino process builds up the 1,3-dioxolane
(16) Kresge, A. J .; Pruszynski, P. J . Org. Chem. 1991, 56, 4808-
4811.
(17) Zimmer, H.; Hillstrom, W. W.; Schmidt, J . C.; Seemuth, P. D.;
Vo¨geli, R. J . Org. Chem. 1978, 43 1541-1544 and references therein.
3364 J . Org. Chem., Vol. 68, No. 8, 2003

4-Hyd r oxy-5-m eth yl-5H-fu r a n -2-on e (6a ): mp 113-114 °C
(lit.3f mp 112-115 °C). Dila cton e 7a : mixture of diastereomers;
mates featuring a functionalized alkyl chain in the form
of a terminal double bond can be synthesized in good
yields from the appropriate aldehyde (entry 5). This
functionality can be further used to elaborate more
complex molecules or to join this molecule to other
biologically active structures.18 The biologically relevant
5-hydroxymethyl derivatives19 are obtained in good yields
with partial recovery of the starting aldehyde in the form
of its dialkyl acetal (entry 6). Aromatic aldehydes are not
reactive enough to be used as starting materials in these
processes. 2,5-Diaryl-substituted dioxolane intermedi-
ates 5, if formed, do not give a clean and synthetically
useful acid-catalyzed trans-acetalization-lactonization
reaction.
In summary, we have developed an effective one-pot
synthesis of 5-substituted tetronic acid derivatives using
methyl propiolate and aldehydes as starting materials.
The method embodies two consecutive chemical events:
a quite efficient and atom-economy domino process
followed by an effective and controlled acid-catalyzed
trans-acetalization.
1
mp 176.5-180.0 °C; H NMR (CDCl3, 400 MHz) δ 1.35 (d, 3H,
J ) 7.3 Hz), 1.50 (d, 6H, J ) 6.9 Hz), 4.12-4.16 (m, 1H), 3.20
(broad s, 1H), 4.78-4.85 (m, 2H), 12.80 (broad s, 1H); 13C NMR
(CDCl3, 50.3 MHz, major isomer) δ 178.7, 178.7, 102.0, 76.2, 20.7,
18.2, 17.3; IR (CHCl3) ν 3018, 1701, 1651, 1629, 1450, 1348 cm-1
;
MS m/z (rel intensity) 254 (M+, 11), 239 (31), 141 (15), 146 (16),
69 (32), 68 (100), 53 (21). Anal. Calcd for C8H10O3: C, 56.69; H,
5.55. Found: C, 56.70; H, 5.26.
4-Hyd r oxy-5-p r op yl-5H-fu r a n -2-on e (6b ): mp 74.5-76.5
°C; 1H NMR (CDCl3, 400 MHz) δ 0.95 (t, 3H, J ) 7.4 Hz), 1.42-
1.51 (m, 2H), 1.61-1.68 (m, 1H), 1.91-1.98 (m, 1H), 4.84 (dd,
1H, J ) 7.7, 3.7 Hz), 5.06 (s, 1H); 13C NMR (CDCl3, 50.3 MHz)
δ 184.1, 178.3, 88.7, 80.7, 33.3, 17.5, 13.5; IR (CHCl3) ν 3030,
2966, 1807, 1759, 1633 cm-1; MS m/z (rel intensity) 142 (M+,
4.1), 100 (100), 99 (22), 72 (35), 71 (67), 57 (10). Anal. Calcd for
C7H10O3: C, 59.15; H, 7.09. Found: C, 59.21; H, 7.08.
Dila cton e 7b: mixture of diastereomers; mp 132.5-135.0 °C;
1H NMR (CDCl3, 400 MHz) δ 0.88 (t, 3H, J ) 7.3 Hz), 0.96 (t,
6H, J ) 7.3 Hz), 1.21-1.26 (m, 2H), 1.36-1.60 (m, 4H), 1.60-
1.69 (m, 2H), 1.69-1.75 (m, 2H), 1.91-1.99 (m, 2H), 4.04-4.10
(m, 1H), 2.80 (broad s, 1H), 4.75-4.78 (m, 2H), 12.17 (broad s,
1H); 13C NMR (CDCl3, 50.3 MHz, major isomer) δ 178.3, 178.2,
101.4, 79.6, 33.9, 33.4, 25.7, 20.8, 17.7, 13.7, 13.5; IR (CHCl3) ν
2963, 1698, 1648, 1629, 1466, 1652 cm-1; MS, m/z (rel intensity)
338 (M+, 1.0), 295 (15), 154 (34), 100 (20), 81 (17), 71 (17), 68
(100). Anal. Calcd for C8H10O3: C, 63.89; H, 7.74. Found: C,
63.84; H, 7.74.
Exp er im en ta l Section
Melting points are uncorrected. 1H NMR and 13C NMR spectra
of CDCl3 solutions were recorded either at 200 and 50 MHz or
at 500 and 125 MHz, respectively. FT-IR spectra were measured
in chloroform solutions. Flash column chromatography was
carried out with silica gel (particle size less than 0.020 mm)
using appropriate mixtures of ethyl acetate and hexanes as
eluent. Dichloromethane was distilled from CaH2. Triethylamine
was distilled from potassium hydroxide pellets. All other materi-
als were obtained from commercial suppliers and used as
received.
Products 6a -f exist in solution as an equilibrium of the keto
and enol tautomers. The solutions used to obtain the NMR
spectra of products 6a -e contain predominantly the enol form;
therefore, the spectral data correspond to this tautomer. On the
other hand, the solution used to obtain the NMR spectra of
product 6f contains predominantly the other tautomers; there-
fore, the spectral data correspond to the keto form.
Gen er a l P r oced u r e. Meth od A. Triethylamine (0.6 mmol)
was added to a cooled (-78 °C) solution of methyl propiolate (3
mmol) and aldehyde (6.3 mmol) in dry CH2Cl2 (3 mL). The
reaction mixture was stirred for 2 h at this temperature.
Concentrated HCl (0.2 mL, ∼2.5 mmol of H+) and 2-propanol
(57 mL) were added, and the resulting solution was heated at
60 °C for 24 h. Evaporation of the solvent at reduced pressure
followed by flash chromatography (eluent gradiant: ethyl acetate/
hexane from 2:8 to 6:4) yielded tetronic acid derivatives 6a -g
as crystalline compounds. The amount of concentrated acid and
2-propanol was carefully studied so that the maximum yield of
tetronic acids was obtained with respect to the formation of
dilactones.
4-Hyd r oxy-5-isop r op yl-5H-fu r a n -2-on e (6c): mp 96.5-98.0
1
°C; H NMR (CDCl3, 400 MHz) δ 0.86 (d, 3H, J ) 6.9 Hz), 1.08
(d, 3H, J ) 7.0 Hz), 2.17-2.27 (m, 1H), 4.72 (d, 1H, J ) 3.1 Hz),
5.09 (s, 1H); 13C NMR (CDCl3, 50.3 MHz) δ 183.3, 178.5, 89.6,
84.8, 29.5, 18.6, 14.7; IR (CHCl3) ν 3018, 2971, 1803, 1759, 1709,
1623 cm-1; MS m/z (rel intensity) 142 (M+, 20), 114 (80), 100
(100), 72 (79), 71 (67), 69 (30). Anal. Calcd for C7H10O3: C, 59.15;
H, 7.09. Found: C, 59.46; H, 7.25.
5-ter t-Bu tyl-4-h yd r oxy-5H-fu r a n -2-on e (6d ): mp 131.5-
133.0 °C; 1H NMR (CDCl3, 400 MHz): δ 1.06 (s, 9H), 4.53 (s,
1H), 5.04 (s, 1H); 13C NMR (CDCl3, 50.3 MHz): δ 183.9, 178.2,
90.4, 87.9, 25.6, 25.5; IR (CHCl3) ν 3018, 2971, 1803, 1759, 1709,
1623 cm-1; MS m/z (rel intensity) 156 (M+, 11), 100 (100), 99
(57), 72 (63), 71 (80). Anal. Calcd for C8H12O3: C, 61.52; H, 7.74.
Found: C, 61.37; H, 7.73.
5-Bu t -3-en yl-4-h yd r oxy-5H-fu r a n -2-on e (6e): mp 53.5-
55.0 °C; 1H NMR (CDCl3, 400 MHz) δ 1.67-1.88 (m, 2H), 2.12-
2.21 (m, 2H), 4.77-4.81 (m, 1H), 5.00 (s, 1H), 4.95-5.06 (m, 2H),
5.65-5.78 (m, 1H); 13C NMR (CDCl3, 50.3 MHz) δ 184.5, 178.5,
137.2, 116.8, 89.7, 80.7, 31.4, 29.2; IR (CHCl3) ν 3018, 2930, 1807,
1760, 1644, 1222 cm-1; MS m/z (rel intensity) 154 (M+, 0.8), 110
(100), 83 (12), 72 (18), 55 (54). Anal. Calcd for C8H10O3: C, 62.33;
H, 6.54. Found: C, 62.46; H, 6.61.
5-Ben zyloxym eth yl-4-h yd r oxy-5H-fu r a n -2-on e (6f): mp
65.0-67.0 °C; 1H NMR (CDCl3, 400 MHz) δ 3.06 (d, 1H, J )
22.5 Hz), 3.17 (d, 1H, J ) 22.5 Hz), 3.79-3.88 (m, 2H), 4.47 (d,
1H, J ) 12.2 Hz), 4.54 (d, 1H, J ) 12.2 Hz), 4.74-4.76 (m, 1H),
7.26-7.35 (m, 5H); 13C NMR (CDCl3, 50.3 MHz) δ 204.2, 170.3,
136.7, 128.5, 128.0, 127.5, 85.3, 73.7, 68.4, 38.2; IR (CHCl3) ν
3018, 2930, 2866, 1807, 1760, 1672, 1225 cm-1; MS m/z (rel
intensity) 220 (M+, 12), 107 (13), 91 (100), 65 (7.8). Anal. Calcd
for C12H12O4: C, 65.45; H, 5.49. Found: C, 65.69; H, 5.42.
Meth od B. Same as method A but using a larger excess of
aldehyde (12 mmol).
Meth od C. Same as method A, but using a longer trans-
acetalization time (72 h) under more concentrated conditions (25
mL of i-PrOH).
Ack n ow led gm en t. This research was supported by
the Spanish Ministerio de Ciencia y Tecnolog´ıa (PB98-
0443-C02-02 and PPQ2002-04361-C04-03). D.T.A. thanks
the Instituto Canario de Investigacio´n del Ca´ncer for
financial support. G.V.L. thanks the University of La
Laguna for an Intercampus grant.
(18) Brohm, D.; Metzger, S.; Bhargava, A.; Mu¨ller, O.; Lieb, F.;
Waldmann, H. Angew. Chem., Int. Ed. 2002, 41, 307-311.
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54-58. (b) Roggo, B. E.; Hug, P.; Moss, S.; Raschdorf, F.; Peter, H. H.;
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J O034083O
J . Org. Chem, Vol. 68, No. 8, 2003 3365