Improved procedure for the preparation of cis-2,4-dimethylglutaranhydride

Article abstract of DOI:10.1080/00397910600781497

Addition of 2.5 mol% DBU to a mixture of isomeric 2,4-dimethylglutaric anhydrides in ethyl acetate promotes crystallization-induced transformation, affording the pure cis -2,4-dimethylglutaric anhydride in 87% yield. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600781497

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Improved Procedure for the Preparation of
cis‐2,4‐Dimethylglutaranhydride
Radomir N. Saicic a b
a Institut de Chimie des Substances Naturelles–Centre National de la
Recherche Scientifique, Gif sur Yvette, France
b Faculty of Chemistry, University of Belgrade, Belgrade, Serbia and
Montenegro
Version of record first published: 27 Oct 2006.
To cite this article: Radomir N. Saicic (2006): Improved Procedure for the Preparation of
cis‐2,4‐Dimethylglutaranhydride, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 36:17, 2559-2562
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Synthetic Communicationsw, 36: 2559–2562, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600781497
Improved Procedure for the Preparation of
cis-2,4-Dimethylglutaranhydride
Radomir N. Saicic
Institut de Chimie des Substances Naturelles–Centre National de la
Recherche Scientifique, Gif sur Yvette, France, and Faculty of Chemistry,
University of Belgrade, Belgrade, Serbia and Montenegro
Abstract: Addition of 2.5 mol% DBU to a mixture of isomeric 2,4-dimethylglutaric
anhydrides in ethyl acetate promotes crystallization-induced transformation, affording
the pure cis-2,4-dimethylglutaric anhydride in 87% yield.
Keywords: Crystallization, DBU, 2,4-dimethylglutaric anhydride, isomerization
Meso-2,4-glutaric anhydride 1 (i.e., cis-2,4-glutaric anhydride) is a valuable
building block in the synthesis of natural products and biologically active
compounds. Some synthetic applications of this compound involve its desym-
metrization and conversion, by various methods,[1,2] into Prelog–Djerassi
lactonic acid, the constituent of several macrolide antibiotics (e.g., methymy-
cin,[3] erythromycin,[4] etc.), as well as useful synthetic intermediate (e.g.,
6-deoxyerythronolide B).[5] Other variants include the conversion of the
meso-anhydride 1 into advanced intermediates in syntheses of a number of
complex antibiotics, such as Monensin-A,[6] Maduramicin,[6] Mucinolide
V,[7] Salynomycin,[8] Okilactomycin,[9] and pheromone Multistriatin,[10] to
mention just a few examples. Amino-derivatives have also been prepared.[11]
Various methods have been developped for the desymmetrization of 1,
which include fractional crystallization of the corresponding diastereoiso-
meric salts with chiral amines,[6] enzymatic resolutions,[12,13] as well as
catalytic asymmetric solvolyses of 1,[14] the latter being recently achieved
Received in Poland February 3, 2006
Address correspondence to Radomir N. Saicic, Faculty of Chemistry, University of
Belgrade, Studentski trg 16, P. O. Box 158, 11000 Belgrade, Serbia and Montenegro.
E-mail: rsaicic@chem.bg.ac.yu
2559

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R. N. Saicic
with high selectivity.[15] However, the known methods of preparation of 1 are
not very efficient. This compound is still obtained by a modification[4,16] of
von Auwers method,[17] as delineated in Scheme 1. The problematic step in
this sequence is the last one, that is, the formation of the anhydride. This
compound is obtained as a mixture of diastereoisomers, from which the
required meso-derivative 1 is isolated by multiple fractional crystallizations,
and the yield of the pure compound does not exceed 35%. Although the
original von Auwers procedure has been recently improved,[9,13] this issue
was not addressed. The compound is commercially available, though only
in small quantities and at a very high price. (Sigma-Aldrich, Catalog
No. S494208; 25 mg/101.1 euro, on January 13, 2006.)
Recently, in the context of our project directed toward the total synthesis
of Abyssomicin,[18] we needed 1. We found it both inconvenient and uneco-
nomical to isolate only ꢀ30% of 1 by multiple crystallizations, while
rejecting the most of the crude, diastereoisomeric product mixture.
Therefore, we considered the possibility of isomerizing the anhydride.
Given the higher crystallinity of the required meso-isomer, we hoped that,
under the appropriate conditions, isomerization could be followed by crystal-
lization, resulting in a crystallization-induced transformation. The reactive
nature of acyl anhydride imposed the nonnucleophilic nature of the basic
catalyst and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) appeared as a
suitable choice. The crude anhydride mixture was prepared as previously
described, by treatment of stereoisomeric acids with acetyl chloride. The
1H NMR analysis showed this material to be ꢀ1 : 1 mixture of cis and
trans-isomers. Without distillation, or any other preliminary purification, the
crude mixture was dissolved in ethyl acetate and treated with 2.5 mol% of
DBU. To our pleasure, crystallization afforded the pure 1 in 87%, mp
91.8–92.3 8C (mp lit.[9] 89.5–92.5 8C; mp lit.[16] 91.4–92.8 8C; mp lit.[4]
1
91.4–92.8 8C). H NMR analysis showed this product to contain less than
3% of the trans-isomer. This compares favorably with the product obtained
by repeated crystallizations, as described earlier, which was found to
contain up to 7% of the trans-diastereoisomer. The product was stable in
Scheme 1.

cis-2,4-Dimethylglutaranhydride
2561
solution, which indicates that no DBU occluded in the crystals (which could
induce subsequent isomerization in solution).
The described modification affords the product of superior purity in 85%
yield (as compared to 35% previously described), simplifies the isolation
procedure, and lowers considerably the cost of preparation of this valuable
and expensive synthetic intermediate.
EXPERIMENTAL
a,a0-Dimethylglutaric Acid
This mixture of stereoisomers was obtained from methyl diethylmalonate and
ethyl a-bromopropanoate, as described elsewhere.[4,9,13,16]
cis-2,4-Dimethylglutaranhydride 1
A mixture of a,a0-dimethylglutaric acid (mixture of stereoisomers from the
previous step; 73 g; 0.456 mol) and acetyl chloride (204.7 g; 186 mL) was
stirred at rt for 20 h, and then heated to reflux for 1 h. The excess acetyl
chloride was removed under reduced pressure, and the residue (69 g) was
dissolved in hot ethyl acetate (33 mL). To this solution, DBU (1.6 g;
10 mmol; 2.3 mol%) was added, and the mixture was left at 4 8C for a few
hours. The crystals were filtered, washed with cold (220 8C) ethyl acetate,
and dried under reduced pressure (0.02 mmHg) to give 46 g of 1. The
mother liquor was concentrated under reduced pressure, the residue (20.8 g)
was dissolved in hot ethyl acetate (9.3 mL), and the procedure was repeated
(no additional DBU is added) to give an additional 7.6 g of crystals. Repetition
of the procedure with the concentrated mother liquor (dissolved in 3.5 mL of
ethyl acetate) gave an additional 3.13 g of crystalline material. The combined,
1
white crystalline material (56.7 g; 87.6%) has mp 91.8–92.3 8C and H and
13C NMR data identical to those previously reported.[13] The purity of the
sample, that is, the content of the d,l-isomer, was determined by integration
of peaks at 2.05 ppm (1 H from the methylene group in 1) and at 1.90 ppm
(2 H, methylene group in the d,l-isomer).
ACKNOWLEDGMENT
The author is grateful to Professor Pierre Potier (deceased on February 3,
2006), Professor Jean-Yves Lallemand and Dr. Jean Boivin (Institut de
Chimie des Substances Naturelles) for their kind hospitality, and to Dr.
Mikhail Ermolensko and Dr. Emmanuel Roulland for stimulating discussions.

2562
R. N. Saicic
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