Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing alpha or beta amino acid or substituted amino acid...
Reexamination Certificate
2001-01-22
2002-04-02
Naff, David M. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing alpha or beta amino acid or substituted amino acid...
C435S108000, C435S115000, C435S116000, C435S280000
Reexamination Certificate
active
06365380
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the production of chiral organic compounds via catalyzed reactions. More particularly, the present invention relates to a catalytic system that includes both a metal catalyzed hydrogen-transfer system and an enzyme or microbial catalyzed oxidation system, and a process of using this system for the production of optically active amino acids.
2. Brief Description of Related Technology
Traditional chemical catalysis generally refers to processes in which chemical reactions are catalyzed by acids, bases, metals, metal salts or organometallic compounds, while biocatalysis is used to describe reactions catalyzed by proteins, enzymes, other biomolecules, or microorganisms. Traditional chemical catalysis has long been used in the chemical industry for production of petro chemicals, fine chemicals, and specialty chemicals. Although fermentation has long been applied in the manufacture of certain commodity chemicals, more recently biocatalysis has focused on the production of high value fine chemicals, especially chiral chemical intermediates for pharmaceuticals, and other biologically active agents.
Each type of catalysis has its advantages and shortcomings. Traditional chemical catalysis generally involves high temperature, high pressure, and low chemical selectivity, but typically is cost effective and efficient. Biocatalysis works under mild reaction conditions with high chemical selectivity and stereoselectivity, but is usually associated with high cost. These two types of catalysis are usually applied in quite different processes and are rarely associated with each other. For example, catalytic transfer hydrogenation reactions have been used widely in the reduction of a variety of functional groups of organic compounds, such as the reduction of ketones and aldehydes (Ram S.; Spicer, L. D.; Tetrahedron Lett. 1988. 29(31). 3741), olefins (Ranu, B. C.; Sarkar, A.; Tetrahedron, Lett. 1994. 35(46), 8649), azides (Gartiser, T.; Selve, C.; Delpuech, J.-J.; Tetrahedron Lett. 1983, 24(15), 1609), epoxides (Dragovich, P. S.; Prins, T. J.; Zhou, R.; J. Org. Chem. 1995, 60, 4922), nitrates (Barrett, A. G. M.; Spilling, C. D. Tetrahedron Lett. 1988, 29, 5733), and aromatic rings (Balezewski, P.; Joule, J. A. Syn. Commun., 1990, 20, 2815).
A catalytic transfer hydrogenation system typically involves a metal or a metal-complex catalyst such as palladium-carbon, and a hydrogen source such as ammonium formate or cyclohexene. The hydrogen source releases hydrogen or hydride as the reaction proceeds. A major advantage over conventional catalytic hydrogenation, which requires special apparatus for handling hydrogen gas and pressure, is that the reduction is usually conducted under atomspheric pressure without large excess of hydrogen gas. Although there have been many different catalysts and hydrogen sources in catalytic transfer hydrogenation systems, an ammonium formate/palladium on carbon (Pd-C) system is the most versatile and practical catalytic hydrogen transfer agent, and has been used for the reduction of various functionalities (Johnstone, R. A. W.; Wilby, A. H.; Entwistle, I. D. Chem. Rev., 1985, 85, 129). To the best of our knowledge, however, the system has never been applied in combination with a biocatalytic system, or in the presence of biocatalysts such as enzymes or microorganisms.
With the exception of glycine, each of the common amino acids exists as one of two optical isomers, termed levorotatory or dextrorotatory, depending upon the direction in which they cause a plane of polarized light to rotate. By convention, amino acids are also referred to as D- or L- based upon whether the configuration about the &agr;-carbon of the amino acid corresponds to the D- or L- stereoisomer (enantiomer) of glyceraldehyde, the arbitrary standard. Based upon that standard, most naturally-occurring amino acids are L-amino acids, despite that some of them are dextrorotatory when placed in aqueous solution at neutral pH.
On the other hand, amino acid oxidases and amino acid deaminases are classes of enzymes that catalyze the stereoselective oxidation of an amino acid to generate the corresponding ketoacid. According to their stereoselectivity, those enzymes that only oxidize the L-amino acids are called L-amino acid oxidases (or deaminases) while those which act only on the D-amino acids are called D-amino acid oxidases (or deaminases).
In the presence of both L- and D-amino acids, the L-amino acid oxidases (and deaminases) will oxidize only the L-amino acids, leaving the D-amino acids untouched, whereas the D-amino acid oxidases (and deaminases) will do just the opposite. Based upon this highly stereoselective nature, these enzymes have been used in combination with other enzymes or chemical reagents for the stereospecific conversion of amino acids from one enantiomer to the other. L-Amino acid deaminases (and oxidases) have been applied in combination with D-amino acid transaminases for the stereospecific conversion of L-amino acid to D-amino acids. The L-amino acid deaminase catalyzes the conversion of L-amino acids to the &agr;-ketoacids, which feed as substrates to D-amino acid transaminases, and are thus converted the D-amino acids.
Another application involves the use of amino acid oxidase enzymes in combination with sodium borohydride. In this case, an amino acid oxidase catalyzes the stereoselective dehydrogenation of the &agr;-amino group in an amino acid to generate an imine intermediate, which is immediately reduced back to the racemic amine or the racemic amino acid by sodium borohydride present in the system. Because the enzyme acts on only one specific enantiomer of the amino acid without affecting the other, it constantly converts this enantiomer to the racemate while allowing the other enantiomer to accumulate. The end result of this dynamic resolution is the complete conversion of the amino acid from one enantiomer to the other.
For example, the synthesis of L-proline from D-proline using D-amino acid oxidase and sodium borohydride is known. See Huh. et al., Journal of Fermentation and Bioengineering, Vol. 74, No. 3, 189-190 (1992). Similarly, the synthesis of L-pipecolic acid from D-pipecolic acid using D-amino acid oxidase and sodium borohydride also has been described. See Huh, et al., BioSci. Biotech. Biochem., 56 (12), 2081-2082 (1992). The conversion of D-alanine to L-alanine using D-amino acid oxidase and sodium borohydride and the conversion of L-Leucine to D-Leucine using L-amino acid oxidase and sodium borohydride are also known. See Hafner, et al.. Proc. Nat. Acad. Sci., Vol. 68, No. 5, 987-991 (1971).
However, the use of sodium borohydride in combination with amino acid oxidase enzymes to stereospecifically convert amino acids from one enantiomer to the other has several disadvantages that limit its industrial applications. Sodium borohydride and some of its derivatives are sensitive to water, and easily decompose in acid or neutral pH, at which the amino acid oxidase enzyme has the maximum activity and stability. For the reduction to be effective, the hydride reagent often has to be added slowly, in multiple intervals, over a long period of time, and in very large molar excess. The large excess of borohydrides often leads to rapid deactivation or destruction of the oxidase enzymes, as well as significant increase in the cost structure for a potential industrial process. Adding to the problem is that the reactions are carried out using purified enzymes, which are available only in very small quantities, and at great cost.
Thus, it would be highly desirable to provide a catalytic hydrogenation system in combination with an amino acid oxidase system to effect the stereospecific conversion of amino acids. In this new combination, the imine intermediate generated from the amino acid oxidase catalyzed dehydrogenation would be reduced back to the amino acid by catalytic hydrogenation instead of borohydride reduction. The catalytic hydrogenation system would comprise a metal catalyst and an
Ager David John
Laneman Scott
Liu Weiguo
Taylor Paul Phillip
Marshall Gerstein & Borun
Meller Mike
Naff David M.
PCBU Services, Inc.
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