A new efficient synthesis of alkyl substituted Δ2-butenolides

Article abstract of DOI:10.1016/S0040-4039(01)00534-2

A new three-step route to 2-alkyl substituted Δ²-butenolides from 3-alkyltetronic acids is described.

Full text of DOI:10.1016/S0040-4039(01)00534-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3657–3658
A new efficient synthesis of alkyl substituted D2-butenolides
Felix S. Pashkovsky,* Yadviga M. Katok, Tatyana S. Khlebnicova and Fedor A. Lakhvich
Institute of Bioorganic Chemistry of National Academy of Sciences, Kuprevicha str. 5/2, Minsk 220141, Belarus
Received 2 November 2000; revised 21 March 2001; accepted 29 March 2001
Abstract—A new three-step route to 2-alkyl substituted D2-butenolides from 3-alkyltetronic acids is described. © 2001 Elsevier
Science Ltd. All rights reserved.
D2-Butenolides are structural components of numerous
natural products such as acetogenins,1 muconolac-
tones,2 leptospharin,3 and strigol.4 Most of them have
cytotoxic, antitumour, antimalarial, immunosuppres-
sive, and pesticidic activities and other types of biologi-
cal action.5 An interest in a,b-unsaturated lactones had
been aroused after their antibiotic properties were dis-
covered. The specific action of these antibiotics is
mainly due to the presence of an unsaturated g-lactone
ring. Optically active D2-butenolides are important and
versatile synthons for naturally occurring compounds
containing the g-butyrolactone ring.6 Therefore, devel-
opment of an effective method for the synthesis of
D2-butenolides is of great synthetic and practical value.
available 3-alkyltetronic acids.7 The method consists in
cyanoborohydride reduction of the enamino derivatives
of tetronic acids in acidic medium, followed by retro-
Michael elimination of the amine moiety from the
aminolactones formed. Thus, boiling of 3-alkyltetronic
acids 2a–c with pyrrolidine in toluene results in the
formation of the corresponding enaminolactones 3a–c8
in 80–90% yields, though the yield of sterically crowded
enaminolactone 3d is lower (50–60%) and prolonged
heating or addition of p-toluenesulfonic acid as a cata-
lyst does not enhance the yield. Reduction of the conju-
gated double bond in enaminolactones 3a–d with
sodium cyanoborohydride in 2N methanolic hydrogen
chloride solution proceeds smoothly at room tempera-
ture. After removal of the solvent in vacuo and work-
up of the reaction mixture with an aqueous solution of
sodium hydroxide, aminolactones 4a–d were formed as
This communication describes a new three-step route to
2-alkyl substituted D2-butenolides from the readily
Keywords: 3-alkyltetronic acids; enaminolactones; sodium cyanoborohydride; D2-butenolides.
* Corresponding author. E-mail: evk@ns.iboch.ac.by
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00534-2

3658
F. S. Pashko6sky et al. / Tetrahedron Letters 42 (2001) 3657–3658
a mixture of diastereomers. We have found that amino-
lactones 4a–d, at reflux in toluene, in the presence of
silica gel undergo a retro-Michael elimination of the
pyrrolidine moiety to give D2-butenolides 1a–d9 in
yields of 55–65% (starting from 3a–d). It should be
noted that the use of crude 4a–d in the final step of the
scheme does not diminish the yield of the target
butenolides.
hedron: Asymmetry 1996, 7, 663; (d) Effenberger, F.;
Syed, J. Tetrahedron: Asymmetry 1998, 9, 817; (e)
Schobert, R.; Muller, S.; Bestmann, H.-J. Synlett 1995,
425. For the synthesis of 3-alkyl substituted tetronic acids
from the readily accessible 3-acyl(arylideneacyl)tetro-
nates, see: (f) Akhrem, A. A.; Lakhvich, F. A.; Liss, L.
G.; Khripach, V. A.; Filchenkov, N. A.; Kozinyetz, V.
A.; Pashkovsky, F. S. Dokl. Akad. Nauk SSSR 1990, 311,
1381; (g) Lakhvich, F. A.; Pashkovsky, F. S.; Liss, L. G.
Russ. Z. Org. Chem. 1992, 28, 1626.
The 2-alkyl substituted D2-butenolides 1a–d thus
obtained are excellent precursors for the synthesis of
biologically active 10-oxa-PG analogues.10
8. To a stirred suspension of tetronic acids 2a–d (0.01 mol)
in 30 mL of toluene, pyrrolidine 1.0 mL (0.012 mol) was
added dropwise. The reaction mixture was refluxed for
5–8 h with azeotropic removal of the water formed. Then
the solution obtained was evaporated to dryness and the
residue was passed through a silica gel column (CHCl3)
to give the corresponding 4-(1-pyrrolidinyl)furan-2(5H)-
ones 3a–d in yields of 50–90%.
Acknowledgements
Financial support provided by INTAS (grant 97-0084)
and the Belorussian Foundation for Basic Research
(grant 98-143) is greatly appreciated.
9. To 1 mmol of 3a–d in 5 mL MeOH was added ca. 0.5 mg
of methyl orange followed by several drops of 6N HCl in
MeOH to form a deep-red coloured solution. Then 0.15 g
(2.4 mmol) of NaBH3CN was introduced portionwise
over 2–3 h with simultaneous addition of 6N HCl at a
rate sufficient to maintain the red colour of the indicator.
The rate of reaction could be estimated by the acid
consumed and by TLC of the mixture. MeOH was
removed in vacuo. After dilution of the residue with H2O
(5 mL), Et2O (15 mL) was introduced and then on
stirring a 1N aq. solution of NaOH was added dropwise
until the colour of the aqueous phase had turned to
yellow. The aqueous phase was extracted with Et2O
(2×10 mL). The organic layers were combined and evapo-
rated to dryness to give a mixture of diastereomeric
aminolactones 4a–d. Crude 4a–d were refluxed for 6–12 h
in toluene (10 mL) containing silica gel (2 g) until full
conversion into butenolides (TLC monitoring). The silica
gel was filtered off and washed with toluene (2×10 mL).
The combined organic phases were evaporated in vacuo
and the residue was purified by column chromatography
(Et2O–hexane) to give pure 1a–d (55–65% yield). All new
compounds reported herein give satisfactory microanaly-
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