Diastereoselective cis to trans desymmetrization of dimethyl succinates

Article abstract of DOI:10.1016/S0957-4166(99)00252-9

Meso-succinates, readily available by Diels-Alder cycloaddition of dimethyl maleate or maleic anhydride followed by esterification, can be isomerized quantitatively from the cis to the trans isomers in the presence of lithium alkoxides. The reaction performed with enantiopure chiral lithium alkoxides yields diastereomeric trans-succinates in good yield and selectivity.

Full text of DOI:10.1016/S0957-4166(99)00252-9

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2505–2509
Diastereoselective cis to trans desymmetrization of dimethyl
succinates
Ivan Michieletto, Fabrizio Fabris ∗ and Ottorino De Lucchi
Dipartimento di Chimica, Università Ca’ Foscari di Venezia, Dorsoduro 2137, I-30123, Venezia, Italy
Received 28 May 1999; accepted 17 June 1999
Abstract
Meso-succinates, readily available by Diels–Alder cycloaddition of dimethyl maleate or maleic anhydride
followed by esterification, can be isomerized quantitatively from the cis to the trans isomers in the presence of
lithium alkoxides. The reaction performed with enantiopure chiral lithium alkoxides yields diastereomeric trans-
succinates in good yield and selectivity. © 1999 Elsevier Science Ltd. All rights reserved.
The practice of desymmetrization of meso compounds is becoming quite common in modern asym-
metric synthesis.1 These reactions are usually performed on CS-symmetric (meso) esters,2 anhydrides,3
ketones,4 epoxides5 or diols6 and to a minor extent on olefins7 and other substrates.8 The processes
leading to the desymmetrized product are, in most instances, reactions catalyzed by enzymes9 or by
enantiopure bases10 and acids.11 The clear advantage of this synthetic strategy is that, in principle, the
yields of the desired isomer are quantitative, without any waste of material due to the disposal of the
unwanted enantiomer.
Enantiopure E-1,2-dicarboxylic esters are valuable intermediates in the synthesis of many natural
or bioactive compounds because of the versatility of the ester moiety12 and as precursors of effective
ligands of chiral catalysts.13 As shown in Scheme 1, the synthesis of such compounds is achieved through
diastereoselective Diels–Alder cycloadditions of fumarate esters of enantiopure alcohols with appropriate
dienes.14 This strategy requires the previous preparation of the chiral dienophile and usually the reactions
are performed with high diastereoselectivities only at low temperatures and sometimes in the presence of
Lewis acids.
Our research was aimed at defining an alternative practical strategy of synthesis of such compounds
as represented for a general case in the second part of Scheme 1. This approach entails a cis–trans
desymmetrization plus transesterification of the readily available and inexpensive Diels–Alder cyclo-
adducts of dimethyl maleate. The final transformation leads to diastereoisomers that might be further
separated for obtaining enantiopure products. Because of our interest in high-symmetry chiral reagents,
this investigation was limited to succinates eventually leading to C2-symmetric chiral products.15
∗
Corresponding author.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00252-9

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Scheme 1.
The cis-9,10-dihydro-9,10-ethano-anthracene-dicarboxylic acid-11,12-dimethyl ester16 is the sub-
strate that was selected for testing the isomerization reaction and the performance of the various
enantiopure alcohols. At the outset, the reaction conditions to perform the reaction were determined.
While the use of alkoxides generated by sodium bases such as sodium hydride or metallic sodium led
to reaction mixtures contaminated by several by-products, the use of n-butyllithium, besides being more
practical, afforded very clean reaction mixtures composed exclusively of the products of interest and
specified below. The efficiency of lithium alkoxides in transesterification reactions is known.17
As shown in Table 1, best yields are obtained with low sterically demanding alcohols, but best selec-
tivities were obtained with more crowded alcohols such as 8-phenylmenthol and 2-phenylcyclohexanol.
These alcohols, denominated as convex chiral auxiliaries, are most often the most efficient in the transfer
of the chiral information.18 The reaction goes to completion to the final bis-transesterified product in
all instances, except for 2-phenylcyclohexanol and 8-phenylmenthol where complete transesterification
appears to occur with more difficulty. With these later alcohols, attempts to draw the reaction to
completion led to concomitant formation of a number of uncharacterized by-products. In the cases of
diacetone-D-glucose and quinine, only cis–trans isomerization occur, unfortunately with no selectivity.
Our concern was to determine if the cis to trans isomerization occurs before or after the transesterifica-
tion reaction. For this reason the reaction of 4 with lithium mentholate was followed via 1H NMR from
the mixing of the reagents. It was observed that the cis–trans isomerization occurs almost instantaneously,
while the transesterification takes about 24 h to reach completion (using a ca. 1 M lithium mentholate
solution in THF). It was also observed that the cis–trans isomerization occurs unselectively and that the
enrichment of one diastereomer over the other depends on the following transesterification reaction.
It is interesting to note that in the case of 2-phenylcyclohexanol and 8-phenylmenthol the diastereo-
meric ratio of the monomethyl, monomenthyl ester 6 (57:43 and 84:16) is lower than that of the
completely transesterified product 7 (76:23 and 96:4). This observation may indicate an equilibration
of the trans forms under the reaction conditions towards the thermodynamically more stable isomer or a
kinetically preferred transesterification of one diastereoisomer of 6. In order to obtain this information,
a single diastereoisomer 7 derived from menthol was subjected to the same condition of the reaction
1
(i.e. reaction with MeOLi). After a few minutes the H NMR of the reaction mixture revealed the
presence of both diastereomers in the final 6:4 ratio. It is thus concluded that the enrichment is actually
thermodynamically controlled.
The reaction with diols affords cis to trans isomerization only. No transesterification was detected in
these cases. While with 1,10-binaphthalene-2,20 -diol and diacetone-D-mannitol no enantiomeric excess
was observed for 5, a fair but significant 56% ee was obtained with hydrobenzoin. The higher efficiency
of this compound with respect to other diols has been noticed in other cases that have recently been
reviewed.19

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Table 1
Product distribution,a yield and diastereomeric ratiob (or enantiomeric excess)c in the reaction of 4
with lithium alkoxides
It is important to point out that in all cases the measure of the enantiomeric excesses (or diastereomeric
ratios) has been performed on the thermodynamically equilibrated reaction mixtures.
The best results obtained on substrate 4 were next transferred to other cycloadducts in order to
determine the generality of the method. Other dicarboxylic methyl esters that have been tested are
compounds 8 and 9 derived from 1,3-butadiene and 1,3-cyclohexadiene (Scheme 2). The synthesis of
these compounds is indicative of the variety of molecules that can be submitted to the desymmetrization
reaction and of the several methods available for the preparation of these substrates.
The slightly inferior results obtained both with 8 and 9 may be caused by the diminished steric
hindrance around the ester groups.
In our mind, the present method is a new approach to this class of compounds. Because of the high
crystallinity of the products, the diastereomerically pure adducts are readily available in synthetically
useful quantities. We think that the present method is a viable alternative to the reported routes.14

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Scheme 2.
Acknowledgements
This work was co-funded by MURST (Rome) within the national project “Stereoselezione in Sintesi
Organica. Metodologie e Applicazioni”.
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