Chemistry: molecular biology and microbiology – Process of utilizing an enzyme or micro-organism to destroy... – Resolution of optical isomers or purification of organic...
Reexamination Certificate
1999-06-25
2001-04-03
Saucier, Sandra E. (Department: 1651)
Chemistry: molecular biology and microbiology
Process of utilizing an enzyme or micro-organism to destroy...
Resolution of optical isomers or purification of organic...
Reexamination Certificate
active
06210956
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates optically active cis-1,3-cyclohexanedicarboxylic acid monoesters of high enantiomeric purity. The invention also relates a method of preparing optically active cis-1,3-cyclohexanedicarboxylic acid monoesters of high enantiomeric purity. The monoesters may be used as chiral precursors for non-naturally occuring amino acids such as those used to prepare a variety of pharmaceuticals. The monoesters or their derivatives may also be used as chiral polyester modifiers to change the plasticity, melting point, glass transition temperature, chirality or other properties of the polyester.
2. Description of the Related Art
Enzyme-catalyzed hydrolysis reactions are known methods for the generation of asymmetry within a molecule. Oftentimes racemic mixtures of a compound are subjected to enzyme-catalyzed hydrolysis to aid in the resolution of the racemic mixture, i.e. the separation of a racemic mixture into its two optically active components. However, such reactions are often inefficient and at best afford a 50% yield of each enantiomer. In an effort to improve efficiency, enzyme-catalyzed hydrolysis of prochiral meso substrates rather than racemic mixtures has been attempted.
Enantioselective enzyme-catalyzed hydrolysis of cis-1,2-isomers of cyclohexane-dicarboxylic acid diesters has been achieved using the enzyme pig liver esterase. Jones et al.,
J. Org. Chem
. 52, 4565 (1987); Gais et al.,
Leibings Ann. Chem
. 687 (1986); Lam et al.,
J. Am. Chem. Soc
. 110, 4409 (1988); Schneider et al.,
Angew. Chem. Int. Ed. Engl
. 23, 67 (1984). The 1,2-isomers have found use in the synthesis of both pharmaceutically active materials and natural products. Turbanti et al.,
J. Med. Chem
. 36, 699 (1993); EP 337,348; Hamilton et al.,
J. Org. Chem
. 58, 7263 (1993); WO 92 10,099; Brion et al.,
J. Tetrahedron Lett
. 34, 4889 (1994); Borzilleri et al.,
J. Am. Chem. Soc
. 116, 9789 (1994).
There have also been reports of the desymmetrization of both cis-1,3-cyclopentane-dicarboxylic anhydride via enzymatic alcoholysis and cis-1,3-cyclopentanedicarboxylic acid diesters via enzyme-catalyzed hydrolysis. Chenevert et al.,
Tetrahedron; Asymmetry
. 3, 199 (1992); Chenevert et al.,
Chem. Lett
. 93 (1994). However, only a single sense of asymmetry, i.e. one enantiomer, was realized in each case. Furthermore, the one enantiomer could only be obtained in ≦91% ee.
In theory, such selective reactions of one of the prochiral groups of the meso substrate would lead to the “desymmetrization” of the meso substrate and theoretically may optimally afford a 100% yield of an optically pure product. This type of process has been termed the “meso trick.” Enzyme-catalyzed hydrolysis of a “meso” substrate would also offer the advantage of producing a single species where the reaction of a racemate produced two—an ester of one enantiomer and an alcohol or acid of the other. Thus, an additional separation step is avoided by application of a desymmetrization reaction.
Thus, despite the processes described above, there remains a need in the art for a process for producing optically active cis-1,3-cyclohexanedicarboxylic acid monoesters that offers high enantioselectivity.
SUMMARY OF THE INVENTION
It has now been discovered that by use of a lipase, a cis-1,3-cyclohexanedicarboxylic acid diester may be converted to an optically active cis-1,3-cyclohexanedicarboxylic acid monoester with a high degree of enantioselectivity (>90% ee).
Accordingly, the invention relates a method of preparing an optically active cis-1,3-cyclohexanedicarboxylic acid monoester by contacting under aqueous conditions a substituted or unsubstituted cis-1,3-cyclohexanedicarboxylic acid diester of formula (I):
with a lipase capable of enantioselectively converting the diester to a substituted or unsubstituted cis-1,3-cyclohexanedicarboxylic acid monoester in >90% enantiomeric excess of either formula (II) or formula (III):
The invention also relates a method of preparing an optically active cis-1,3-cyclohexanedicarboxylic acid monoester by reacting a mixture of substituted or unsubstituted cis- and trans-1,3-cyclohexanedicarboxylic acids under conditions sufficient to convert the cis- and trans-1,3-cyclohexanedicarboxylic acids to a substituted or unsubstituted cis-cyclic anhydride, esterifying the cis-cyclic anhydride to produce a substituted or unsubstituted cis-1,3-cyclohexanedicarboxylic acid diester of formula (I):
and contacting under aqueous conditions the diester of formula (I) with a lipase capable of enantioselectively converting the diester to a substituted or unsubstituted cis-1,3-cyclohexanedicarboxylic acid monoester in >90% enantiomeric excess of formula (II) or formula (III):
The invention further relates a composition comprising a substituted or unsubstituted cis-1,3-cyclohexanedicarboxylic acid monoester in >90% enantiomeric excess of either formula (II) or formula (III):
The invention still further relates a substituted or unsubstituted cis-1,3-cyclohexanedicarboxylic acid monoester of formula (II):
The invention also relates a substituted or unsubstituted cis-1,3-cyclohexanedicarboxylic acid monoester of formula (III):
The invention further relates a racemic composition comprising a substituted or unsubstituted cis-1,3-cyclohexanedicarboxylic acid monoester of formula (II) and formula (III):
DETAILED DESCRIPTION OF THE INVENTION
One embodiment of the invention is a method of preparing an optically active substituted or unsubstituted cis-1,3-cyclohexanedicarboxylic acid monoester by contacting under aqueous conditions a substituted or unsubstituted cis-1,3-cyclohexanedicarboxylic acid diester of formula
with a lipase capable of enantioselectively converting the diester to a substituted or unsubstituted cis-1,3-cyclohexanedicarboxylic acid monoester of either formula (II) or formula (III) in >90% enantiomeric excess:
In formulae (I), (II) and (III), R
1
and R
2
are, independently, a substituted or unsubstituted, linear or branched C
2
-C
12
alkyl group. Preferably, R
1
and R
2
are the same. In a preferred embodiment, R
1
and R
2
are the same linear C
2
-C
4
alkyl group, most preferably R
1
and R
2
are each an ethyl group.
The C4, C5, and C6 positions of the cyclohexane ring of the diester and the cyclohexane ring of the monoester may be substituted with any substituent known in the art such that conversion of the precursor diester to the monoester is not effected. Preferably, the “meso” symmetry of the diester is maintained. Suitable substituents include, but are not limited to, C
1
-C
12
alkyl, aryl, heteroaryl, halide (e.g. chloro and bromo), ether, and sulfide groups.
The method of the invention may employ any lipase, commercially available or otherwise, which enantioselectively converts a diester of formula (I) to a substituted or unsubstituted cis-1,3-cyclohexanedicarboxylic acid monoester of formula (II) or formula (III) in >90% enantiomeric excess. The lipase may be used in either a purified or unpurified state. Any amount of purified or unpurified lipase may be used since the reaction generally runs until conversion to the monoester is complete. The time to complete the reaction may depend on the amount of lipase used. The lower the amount of active lipase added, the longer the reaction time. The greater the amount of active lipase added, the shorter the reaction time. Generally, hydrolysis is complete once the monoester of formula (II) or formula (III) forms and enters the aqeuous phase of a biphasic organic/aqueous system, as discussed below, to form a charged species and thus can no longer react with the lipase. Preferably, the purified or unpurified lipase is added such that the weight ratio of the substrate diester of formula (I) to lipase ranges from about 1-1000. In a preferred embodiment, the weight ratio of substrate diester to unpurified lipase ranges from about 1-50, more preferably from about 2-25, most preferably from about 3-11. In a preferred embodiment, the weight ratio of substrate diester to pu
Blake Michael J.
Eastman Chemical Company
Gwinnetl Harry J.
Saucier Sandra E.
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