Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
1999-10-25
2003-07-29
Prouty, Rebecca E. (Department: 1652)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S716000, C568S322000, C568S811000, C435S133000, C435S155000, C435S156000, C552S293000, C552S291000
Reexamination Certificate
active
06600077
ABSTRACT:
FIELD OF THE INVENTION
The present invention is related to the production of quinic acid and more specifically, to methods of producing quinic acid and derivatives of quinic acid from the bioconversion of a carbon source.
BACKGROUND OF THE INVENTION
Quinic acid is an attractive chiral synthon with its highly functionalized, six-membered carbocyclic ring and multiple asymmetric centers. Both hydroquinone and benzoquinone, which are industrially important organic compounds, can be derived by magnesium (IV) dioxide oxidation of quinic acid. Woskrensensky, A.,
Justus Liebigs Ann. Chem
. 27:257 (1838). Quinic acid is an important molecule utilized as an enantiomerically pure starting material for the synthesis of various molecules, many of which are biologically important. For example, quinic acid is a useful starting material for the synthesis of FK-506, an immune suppressive agent useful in preventing organ transplant rejection. Rao, A. V. R. et al.,
Tetrahedron Lett
. 32:547 (1990). Additionally, quinic acid has been utilized in the synthesis of the neuraminidase inhibitor GS401 and GS4104, an important new pharmaceutical for the treatment of influenza. Barco, A. et al.,
Tetrahedron Asymmetry
8:3515 (1997). It is also utilized as a convenient source for the synthesis of many natural products that are otherwise difficult to obtain (e.g., mycosporin and D-myo-inositol-1,4,5-triphosphate. White et al.,
J. Am. Chem Soc
. 111(24):8970 (1989); Falck et al.,
J. Org. Chem
. 54(25):5851 (1989), respectively. In addition, quinic acid is utilized as a food additive, resolving agent and is being used experimentally in optical materials.
Quinic acid has previously been isolated from natural sources (e.g., cinchona bark, tobacco leaves, carrot leaves, etc.). However, the cost of isolating quinic acid from such sources precludes its use as an economically viable starting material. Quinic acid has been synthesized chemically, but such synthesis utilizes organic solvents, highly reactive reagents and hazardous waste and as such is not environmentally desirable. Therefore, there is a need for a cost effective, environmentally desirable method for the synthesis of quinic acid.
U.S. Pat. No. 5,798,236 describes a method for quinic acid production that uses a heterologous biocatalyst in which expression of quinate dehydrogenase from the
Klebsiella pneumoniae
qad gene in
Escherichia coli
results in conversion of 3-dehydroquinic acid (DHQ) into quinic acid. Fermentation of this organism,
E. coli
AB2848aroD/pKD136/pTW8090A (ATCC 69086) produces a mixture of quinic acid, DHQ, and 3-dehydroshikimic acid (DHS). While the relative molar ratio of the three products varies with fermentation conditions, the molar ratio of quinic acid to DHQ and to DHS fails to exceed 2:1:1. The appearance of DHQ as a major byproduct is likely due to product inhibition of quinate dehydrogenase by quinic acid. Alternatively, the specific activity of quinate dehydrogenase may be low due to poor expression of the Klebsiella gene in
E. coli
or due to instability of the plasmid carrying the qad locus. The appearance of DHS may represent some instability in the host organism itself.
Hydroquinone is a pseudocommodity chemical used in photographic developers, polymerization inhibitors and antioxidants. Annual production of hydroquinones is in the 40,000-50,000 ton range. Krumenacher, L. et al. Hydroquinone is currently synthesized via hydroperoxidation of p-diisopropylbenzene as well as oxidation of aniline or hydroxylation of phenol with hydrogen peroxide. U.S. Pat. No. 5,798,236; Krumenacher, L. et al. Aniline, phenol, or p-diisopropylbenzene are produced from carcinogenic benzene starting material, which is obtained from nonrenewable fossil fuel feedstocks. Methods have also been described for converting quinic acid to hydroquinone. U.S. Pat. No. 5,798,236. The quinic acid is over oxidized to benzoquinone via hydroquinone, and the benzoquinone is then converted back to hydroquinone.
It would thus be desirable to provide a method for the production of quinic acid, which method utilizes a carbon source as a starting material which can be derived from a renewable resource. It would also be desirable to provide a method for the production of quinic acid in which quinic acid is the major product at high concentrations compared to by-products such as DHQ and DHS.
It would also be desirable to provide a method for the production of hydroquinone from quinic acid. It would be further desirable for the method to be inexpensive and utilize non-toxic and non-carcinogenic reactants. It would also be desirable for such a method to produce high-purity hydroquinone in good yields without overoxidation of quinic acid to benzoquinone.
SUMMARY OF THE INVENTION
A bioengineered synthesis scheme for production of quinic acid from a carbon source is provided. In one embodiment, the bioconversion methods of the present invention comprise the microbe-catalyzed conversion of a carbon source to quinic acid. As shown in the synthesis scheme of
FIG. 1
, the microbe-catalyzed conversion step of the present invention requires three enzymes which are provided by a recombinant microbe. In a preferred embodiment, the recombinant microbe is
Escherichia coli
designed to cause reduction of 3-dehydroquinate to quinic acid instead of dehydration of 3-dehydroquinate to dehydroshikimate.
The biocatalytic synthesis of quinic acid provided herein is environmentally benign, economically attractive, and utilizes abundant renewable sources as a starting material.
Also provided are methods for the conversion of quinic acid to hydroquinone. In one embodiment, quinic acid is initially oxidized to 3,4,5-trihydroxycyclohexanone 1 (FIG.
4
). In a preferred embodiment, quinic acid is oxidized by reaction with hyperchloric acid. Subsequent heating of 3,4,5-trihydroxycyclohexanone 1 yields hydroquinone.
REFERENCES:
patent: 5798236 (1998-08-01), Frost et al.
Knowles, G., Radioelem. Anal.: 23rd, 87-94, 1980.*
Falck, J.R. et al., “Enantiospecific Synthesis Of D-myo-Inositol 1,4,5-Trisphosphate From (-)-Quinic Acid,”J. Org. Chem. 54(25):5851-5852 (1989).
Mitsuhashi, S. et al., “Aromatic Biosynthesis—XIII. Conversion Of Quinic Acid To 5-Dehydroquinic Acid By Quinic Dehydrogenase,”Biochim. Biophys. Acta15:268-280 (1954).
Rao, A.V.R. et al., “Studies Directed Towards The Synthesis Of Immunosuppressive Agent FK-506: Synthesis Of The Entire Top-Half,”Tetrahedron Lett. 32(4):547-550 (1991).
White, J.D. et al., “The Synthesis And Absolute Configuration Of Mycosporins. A Novel Application Of The Staudinger,”J. Am. Chem Soc. 111(24):8970-8972 (1989).
Barco, A. et al., “D-(-)-Quinic Acid: A Chiron Store For Natural Product Synthesis,”Tetrahedron Asymmetry8:3515-3545 (1997).
Brown, K.D. et al., “Transport And Utilization Of The Biosynthetic Intermediate Shikimic Acid InEscherichia coli,” Biochim. Biophys. Acta428:550-562 (1976).
Draths, K.M. et al., “Biocatalysis And Nineteenth Century Organic Chemistry: Conversion Of D-Glucose Into Quinoid Organics,”J. Am. Chem. Soc. 114(24):9725-9726 (1992).
Draths, K.M. et al., “Environmentally Compatible Synthesis Of Catechol From D-Glucose,”J. Am. Chem. Soc. 117:2395-2400 (1995).
Dell, K.A. et al., “Identification And Removal Of Impediments To Biocatalytic Synthesis Of Aromatics From D-Glucose: Rate-Limiting Enzymes In The Common Pathway Of Aromatic Amino Acid Biosynthesis,”J. Am. Chem. Soc. 115:11581-11589 (1993).
Frost John W.
Frost Karen M.
Board of Trustees operating Michigan State University
Prouty Rebecca E.
Ramirez Delia
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