Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
1998-04-22
2001-11-13
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C502S200000, C502S172000, C540S484000, C546S224000, C548S336100, C548S557000, C548S537000, C560S103000, C560S138000, C564S027000, C564S056000
Reexamination Certificate
active
06316616
ABSTRACT:
BACKGROUND OF THE INVENTION
During the course of a chemical reaction, the reactants may undergo a series of transformations comprising passing through transition states (local energy maxima) and intermediates (local energy minima) until the products are formed. In molecular terms, these transformations reflect changes in bond lengths, angles, etc. The evolution from reactants to products, in a reaction that does not pass through any intermediates, may be viewed simply as involving formation of a transition state which decomposes to yield the products. The overall rate of this simple reaction can be expressed in terms of the equilibrium constants characterizing the equilibria between the reactants, the transition state, and the products.
Under these circumstances, catalysis can be regarded as a stabilization of the transition state for the reaction. A catalyst is a substance that increases the rate of a reaction, by lowering the energy of the transition state, and is recovered substantially unchanged at the end of the reaction. Although the catalyst is not consumed, it is agreed that the catalyst participates in the reaction. Despite the commercial importance of catalysis, major limitations are associated with both enzymatic and non-enzymatic catalysis. Economically-viable, efficient, and reliable transition metal-catalyzed processes are relatively few in number. The industrial utility of such processes may be diminished by their high operating costs, the incompatibility of the requisite reagents with environmental or toxicological imperatives, or difficulties associated with the isolation and purification of the desired products. Furthermore, non-enzymatic catalysts are not yet known for many important chemical reactions. Enzymatic catalysis depends on the existence and discovery of naturally occurring enzymes with the appropriate specificity and catalytic function to perform a particular reaction. Enzymes are not known for many, if not most, chemical transformations.
The immune system has been shown to have the ability to generate various de novo antibody catalysts. In short, antibodies are elicited to a hapten designed to mimic the transition state of the reaction of interest; the resulting antibodies are then screened for catalytic activity. Advances in the design of transition state analogues, and in the methods of generation and screening of antibodies to those analogues have resulted in catalytic antibodies for a wide range of chemical transformations (cf. inter alia: Romesberg et al.
Science
1998, 279, 1929-1933; Heine et al.
Science
1998, 279, 1934-1940; and references therein). Of course, an approach to catalysis based upon catalytic antibodies is limited in scope. First, this approach presupposes a knowledge of the transition state for a transformation. Second, it may be difficult or impossible to synthesize the required transition state analogue(s). Finally, antibodies are proteins and are subject to the limitations associated with polypeptides, e.g. susceptibility to proteolytic degradation, high molecular weight, and poor solubility characteristics.
The present invention overcomes the aforementioned limitations by providing a novel approach to the discovery and optimization of new catalysts. The invention provides a parallel combinatorial method for the preparation, evaluation, and optimization of organic molecules as convenient, readily obtainable and inexpensive catalysts possessing a high degree of specificity and efficiency. In certain embodiments, catalysts that do not rely on a transition metal ion for activity are provided. In other embodiments, this invention is useful in increasing the rate of chemical reactions which can also be catalyzed by enzymes such as oxidoreductases, transferases, hydrolases, lyases, isomerases and ligases. In certain embodiments, this invention is useful in increasing the rate of chemical reactions for which no catalysts, either enzymatic or non-enzymatic, are known presently. Such reactions include, among others, oxidations, reductions, additions, condensations, eliminations, substitutions, cleavages, rearrangements, and kinetic resolutions.
In accordance with this invention, the subject catalysts may increase the rate of a chemical reaction by more than a factor of one hundred, preferably more than a factor of one thousand, and most preferably more than a factor of ten thousand.
Furthermore, research into the relationship between catalyst structure and catalytic properties is a central theme in such active and disparate fields as asymmetric synthesis, medicinal chemistry, process chemistry, selective catalysis, bioremediation, sensor discovery and development, bioorganic chemistry, and bioinorganic chemistry. The numerous advances made recently in these fields underscore the utility of catalysts with well-defined structural, electronic and/or stereochemical features. However, the de novo rational design of such catalysts remains extremely challenging, if not unattainable at present, especially if novel physical and chemical properties are sought. In this context, a systematic method for the expedient generation of new classes of catalysts will be of great value.
Immobilization, or isolation within a semi-permeable membrane, of a catalyst would enable the reuse of a catalyst without the need for tedious isolation and purification protocols; additionally, this approach may help avoid the common problems of gradual degradation and/or fouling of catalysts. In this regard, Kobayashi and Nagayama recently disclosed the development of immobilized, microencapsulated Lewis acid catalysts that are both recoverable and reusable (
J. Am. Chem. Soc
. 1998, 120, 2985). Furthermore, these researchers found that in some cases the activity of the encapsulated catalysts is even greater than that of the non-encapsulated catalysts. Examples of the activity and reuse of enzymes contained within semi-permeable membranes have been reported by Whitesides, Bednarski, and others. The catalysts of the present invention may be immobilized and/or isolated within semi-permeable membranes and used as such.
SUMMARY OF THE INVENTION
The present invention provides methods and compositions, i.e. synthetic libraries of compounds, for identifying novel compounds which catalyze at least one chemical transformation. The subject method comprises: (a) chemically synthesizing a variegated library of candidate catalysts; and (b) screening the library of candidate catalysts to isolate/identify those members that catalyze a given reaction. Utilizing the techniques of combinatorial chemistry, e.g., direct characterization, encoding, spatially addressing and/or deconvolution, the molecular identity of individual members of the library of candidate catalysts can be ascertained in a screening format. Another aspect of the present invention pertains to kits for carrying out the instant method. Still another aspect of the present invention provides compositions including one or more of the catalysts identified by the instant method.
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Borman Stu, “Combinatorial Catalysts : Methods devised to create arrays of catalysts to screen for enantioselective activity”, Chemical and Engineering News, vol. 74, No. 45 pp. 37-39 (Nov. 4, 1996).
Francis B. M. and Jacobsen N. E., “Discovery of Novel Catalysts for Alkene Epoxidation from Metal-Binding Combinatorial Libraries”, Angewandte Chemie Int. Ed. Engl. vol. 38 No. 7 : 937-941 (Apr. 1, 1999).
Gennari et al., “Combinatorial Libraries: Studies in Molecular Recognition and the Quest for New Catalysts”, Liebigs Annalen/Recueil
Jacobsen Eric N.
Sigman Matthew S.
Foley Hoag & Eliot LLP
Gordon Dana M.
McKane Joseph K.
President and Fellows of Harvard College
Wright Sonya N.
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