Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Containing at least one abnormal peptide link – e.g. – gamma...
Reexamination Certificate
2001-06-14
2003-05-06
Raymond, Richard L. (Department: 1624)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Containing at least one abnormal peptide link, e.g., gamma...
C549S523000, C549S524000, C549S531000
Reexamination Certificate
active
06559283
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the use of homochiral poly-&bgr;-amino acids as catalysts for enantioselective organic reactions, in particular for catalytic enantioselective epoxidation of carbon—carbon double bonds. Furthermore, special homochiral poly-&bgr;-amino acids and their preparation are provided.
2. Description of the Background
Catalytic enantioselective organic reactions are among the most well-known and important organic transformations for the introduction of enantioselectivity into organic molecules by synthetic means. Furthermore, in industry processes are preferred in which the catalyst can be recovered and reused. The combination of both aspects leads to most superior enantioselective processes suitable for large scale production of organic molecules.
Poly-&bgr;-peptides, known to textile chemists as Nylon-3 polymers, have been prepared and studied for the last 50 years. Two distinct approaches to the preparation of poly-&bgr;-peptides exist. Firstly, a number of polymerization reactions where a suitably activated monomer is polymerized, under more-or-less controlled conditions, to generate a range of polymer lengths, have been reported. This first approach has been developed largely with the textile industry in mind and thus the focus has been on the preparation of long polymer chains. In addition the polymerization method has found some application in the preparation of polymer chains for use in structural studies, i.e. for the preparation of &bgr;-analogues of poly-&agr;-amino acids.
The second approach is to utilize stepwise peptide bond synthesis, in which a protected &bgr;-amino acid is coupled to the peptide chain, the protecting group removed and the sequence repeated. Clearly, this latter method has the advantage that defined primary structures can be prepared. Thus a range of monomers can be utilized and it is possible to prepare a range of defined length homopolymers. Within the field of stepwise synthesis two main approaches exist; solution phase and solid phase synthesis (D. S. Breslow, G. E. Hulse, and A. S. Matlack,
J. Am. Chem. Soc.,
1957, 79, 3760; J. Kovacs, R. Ballina, R. L. Rodia, D. Balasubramamnian, and J. Applequist,
J. Am. Chem. Soc.,
1965, 87, 119; H. R. Kricheldorf, &agr;-Aminoacid-N-Carboxy Anhydrides and Related Heterocycles, ed., Springer-Verlag, 1987; H. R. Kricheldorf, 36. Anionic Ring-opening polymerization: NCAs, ed. G. Allen and J. C. Bevington; J. Sebenda, 35. Anion Ring-Opening Polymerization: Lactams, ed. G. Allen and J. C. Bevington; M. García-Alveraz, A. Martínez de Ilarduya, S. León, C. Alemán, and S. Muñoz-Guerra,
J. Phys. Chem. A,
1997, 101, 4215; G. Guichard and D. Seebach, Chimia, 1997, 51, 315; Seebach et al. Helv. Chim. Acta, 1996, 79, 913 u. 2043; Marti et al. Tetrahedron Lett. 1997, 38, 6145).
It is known that poly-&agr;-amino acids are useful as catalysts in enantioselective organic reactions. In particular the epoxidation of carbon—carbon double bonds (EP 991233642.3 and EP 99123643.1) is described. Heretofore, nothing has been described about poly-&bgr;-amino acids with regard to their use as catalysts in enantioselective organic reactions.
SUMMARY OF THE INVENTION
It is an object of the present invention is to provide more catalysts suitable for enantioselective organic reactions.
It is another object to provide a method of catalyzing an enantioselective reaction.
Unexpectedly, homochiral poly-&bgr;-amino acids, in particular homochiral homo-poly-&bgr;-amino acids, can be used as catalysts in enantioselective organic reactions. In a preferred embodiment, homochiral poly-&bgr;-amino acids are used in the epoxidation of carbon—carbon double bonds (i.e. —C═C—). It is especially preferred to use supported or crosslinked poly-&bgr;-amino acids.
Accordingly, the objects of the present invention are accomplished with a method of catalyzing an enantioselective reaction, comprising:
reacting a substrate in the presence of a homochiral poly-&bgr;-amino acid under conditions to produce a product, wherein the product is enantiomeric and one enantiomer of the product is produced in excess.
The objects of the present invention are also accomplished with a supported or crosslinked homochiral poly-&bgr;-amino acid.
A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
The reaction conditions used for epoxidation may be the same as those mentioned for poly-&agr;-amino acids. Therefore, it is most favorable to conduct the epoxidation in a biphasic or triphasic system as described in EP 99123642.3 and EP 99123643.1, both incorporated herein by reference.
The epoxidation is preferably accomplished with H
2
O
2
in any kind of modification, that means as aqueous solution, as a complex with nitrogen containing compounds, e.g. urea-hydrogen peroxide, as percarbonate, perborate, and any similar source of active oxygen. The substrates for the epoxidation are carbon—carbon double bonds in any kind of organic molecule. The described method runs especially well for carbon—carbon double bonds attached to an electron-withdrawing group, resulting in an electron-poor double bond. Substrates to be epoxidized are preferably those described in EP 99123642.3, incorporated herein by reference.
It is especially advantageous to use catalysts pertinent to the invention for enantioselective organic reactions because the insoluble catalysts can be recovered easily after usage and can be used again. Normally, the reaction mixtures are worked up using techniques well-known to those skilled in the art. The soluble products, i.e. the epoxides, are separated in an advantageous manner by filtering off the poly-&bgr;-amino acid and is worked up in an aqueous medium. If required, chromatography on silica gel or recrystallisation may then be performed for purification purposes. The insoluble catalysts can then be dried and reused.
The application of these new catalysts can be carried out in various ways. In many cases a simple batch process is preferable. A number of approaches to varying the properties of the catalysts have been taken; it is possible to use a range of supports and adsorbents which facilitate other methods of application. Here it is pertinent to mention the use as insoluble catalyst, which is—as discussed above—easy to separate by filtration and recycle as well as the use in a fixed-bed-column or a membrane reactor in a continuous process (DE 199 10 691.6; Rissom et al., Tetrahedron Asymmetry 1999, 10, 923-928, both incorporated herein by reference).
As can be seen in the working examples enantioselective induction on epoxidation by catalysts according to the invention is achieved in almost >70% ee at a conversion of >90%. The enantiomeric excess (ee) achieved in the present invention may be at least 5%, 10%, 15%, 25%, 50%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 99.5% ee. The conversion may be at least 5%, 10%, 15%, 25%, 50%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 99.5%.
In a additional embodiment, the present invention is directed to supported or crosslinked homochiral poly-&bgr;-amino acids, in particular homochiral homo-poly-&bgr;-amino acids.
The support can be fixed to the poly-&bgr;-amino acids by a covalent bond or by adsorption. Supports suitable for adsorptive means are well-known to those skilled in the art. In particular those selected from the group comprising SiO
2
-containing compounds, nitrocellulose, cellulose or carbon black are preferred. Most preferred are those SiO
2
-containing compounds described in EP 99123643.1, incorporated herein by reference. The amounts of poly-&bgr;-amino acids per unit support can also be deduced from EP 99123643.1, incorporated herein by reference.
Supports with regard to covalent bonding are preferably selected from the group comprising resins (i.e. epoxide-containing such as eupergit, Merrifield, Wang, Tentagel etc.) and polysiloxanes.
Burkhardt Olaf
Coffey Paul
Drauz Karlheinz
Roberts Stan M.
Skidmore John
Degussa - AG
Raymond Richard L.
Tucker Zachary C.
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