Parallel combinatorial approach to the discovery and optimization of catalysts and uses thereof

Abstract

The present invention provides methods and compositions, i.e. synthetic libraries of candidate compounds, useful in the discovery and optimization of compounds which catalyze at least one chemical transformation. In certain instances, the subject compounds catalyze a chemoselective, regioselective, stereoselective or enantioselective transformation.

We claim:  
     
         1 . A parallel, combinatorial method for the discovery and optimization of novel catalysts for chemical transformations, comprising: 
 (a) chemically synthesizing a variegated library of potential catalysts; and    (b) screening the library of potential catalysts to identify those members that catalyze the transformation of interest.    
     
     
         2 . The method of  claim 1 , wherein the potential catalysts comprise a natural or unnatural amino acid.  
     
     
         3 . The method of  claim 1 , wherein the library comprises a catalyst that catalyzes a stereoselective reaction.  
     
     
         4 . The method of  claim 1 , wherein the library comprises a catalyst that catalyzes a chemoselective and/or regioselective reaction.  
     
     
         5 . The method of  claim 1 , wherein the potential catalysts comprise a cyclic moiety selected from the group consisting of acridarsine, acridine, anthracene, arsindole, arsinoline, azepane, benzene, carbazole, carboline, chromene, cinnoline, furan, furazan, hexahydropyridazine, hexahydropyrimidine, imidazole, indane, indazole, indole, indolizine, isoarsindole, isobenzofuran, isochromene, isoindole, isophosphindole, isophosphinoline, isoquinoline, isorasinoline, isothiazole, isoxazole, morpholine, naphthalene, naphthyridine, oxazole, oxolane, perimidine, phenanthrene, phenanthridine, phenanthroline, phenarsazine, phenazine, phenomercurazine, phenomercurin, phenophosphazine, phenoselenazine, phenotellurazine, phenothiarsine, phenoxantimonin, phenoxaphosphine, phenoxarsine, phenoxaselenin, phenoxatellurin, phenothiazine, phenoxathiin, phenoxazine, phosphanthene, phosphindole, phosphinoline, phthalazine, piperazine, piperazine, piperidine, piperidine, pteridine, purine, pyran, pyrazie, pyrazole, pyridazine, pyridine, pyrimidine, pyrrolidine, pyrrolidine, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, selenanthrene, selenophene, tellurophene, tetrahydrofuran, tetrahydrothiophene, thianthrene, thiazole, thiolane, thiophene and xanthene.  
     
     
         6 . The method of  claim 1 , wherein the potential catalysts comprise a bicyclo[x.y.z]alkane, where x, y, and z are each independently integers greater than or equal to zero.  
     
     
         7 . The method of  claim 1 , wherein the potential catalysts comprise an asymmetric center.  
     
     
         8 . The method of  claim 1 , wherein the library of potential catalysts comprises a catalyst that is not superimposable on its mirror image.  
     
     
         9 . The method of  claim 1 , wherein the library comprises at least one hundred potential catalysts.  
     
     
         10 . The method of  claim 9 , wherein the library comprises at least one thousand potential catalysts.  
     
     
         11 . The method of  claim 10 , wherein the library comprises at least ten thousand potential catalysts.  
     
     
         12 . The method of  claim 1 , wherein the potential catalysts comprise a saccharide or oligosaccharide.  
     
     
         13 . The method of  claim 12 , wherein the saccharide, or oligosaccharide, consists of pentose sugars, hexose sugars, pentose azasugars, and/or hexose azasugars.  
     
     
         14 . The method of any of claims  1 - 13 , wherein the library is synthesized on a solid support.  
     
     
         15 . The method of any of claims  1 - 13 , wherein the library is synthesized in solution.  
     
     
         16 . The method of  claim 1 , wherein a selected catalyst is used as the lead structure for a second library of potential catalysts; said second library of potential catalysts is screened to identify those members that catalyze the transformation of interest; at least one of the members of the second library being an improved catalyst for the transformation of interest relative to the catalyst from the first library.  
     
     
         17 . The method of  claim 16 , wherein the described process is reiterated between one and ten additional times to provide at least one improved catalyst for the transformation of interest.  
     
     
         18 . The method of claims  1 ,  16  or  17 , wherein a selected catalyst catalyzes a transformation selected from the set comprising kinetic resolutions, regioselective reactions, chemoselective reactions, diastereoselective reactions, stereoselective reactions, functional group interconversions, hydrogenations, oxidations, reductions, resolutions of racemic mixtures, cycloadditions, sigmnatropic rearrangements, electrocyclic reactions, ring-openings, carbonyl additions, carbonyl reductions, olefin additions, olefin reductions, imine additions, imine reductions, olefin epoxidations, olefin aziridinations, carbon-carbon bond formations, carbon-heteroatom bond formations, and heteroatom-heteroatom bond formations.  
     
     
         19 . The method of  claim 1 ,  16 , or  17 , wherein the catalysts are selected based on the observation of a detectable event.  
     
     
         20 . The method of  claim 19 , wherein the detectable event is a member of the set comprising the evolution of a gas, the emission of a photon, and the formation of a precipitate.  
     
     
         21 . A library of potential catalysts, and the individual members thereof, having the following general structure:  
       
         
           
           
               
               
           
         
       
       wherein 
 the sphere represents a solid support;  
 Linker 1  and Linker 2  are independently selected from the group consisting of difunctional molecules with or without sidechains and/or stereocenters;  
 amino acid represents a natural or unnatural amino acid; and  
 the catalytic moiety is selected from the set comprising the catalytically-active portions of known catalysts.  
 
     
     
         22 . The library and individual catalysts of  claim 21 , wherein 
 Linker 1  and Linker 2  are independently selected from the set comprising diamines, diols, amino alcohols, and diacids; and    the catalytic moiety is selected from the set comprising salenates, porphyrins, Schiff base-containing moieties, diketopiperazines, oligoamines, oligoalcohols, amino alcohols, oligopeptides, and oligonucleotides.    
     
     
         23 . The library and individual catalysts of  claim 22 , wherein the catalytic moiety is mono-, di-, tri-, or tetra-dentate with respect to a substrate.  
     
     
         24 . The library of claims  21 ,  22  or  23 , wherein the library comprises at least one hundred potential catalysts.  
     
     
         25 . The library of claims  21 ,  22  or  23 , wherein the library comprises at least one thousand potential catalysts.  
     
     
         26 . The library of claims  21 ,  22  or  23 , wherein the library comprises at least ten thousand potential catalysts.  
     
     
         27 . The library and individual catalysts of claims  21 ,  22  or  23 , wherein a selected catalyst is used as the lead structure for a second library of potential catalysts; said second library of potential catalysts is screened to identify those members that catalyze the transformation of interest; at least one of the members of the second library being an improved catalyst for the transformation of interest relative to the catalyst from the first library.  
     
     
         28 . The library and individual catalysts of  claim 27 , wherein the described process is reiterated between one and ten additional times to provide at least one improved catalyst for the transformation of interest.  
     
     
         29 . The method of claims  27  or  28 , wherein a selected catalyst catalyzes a transformation selected from the set comprising kinetic resolutions, regioselective reactions, chemoselective reactions, diastereoselective reactions, stereoselective reactions, functional group interconversions, hydrogenations, oxidations, reductions, resolutions of racemic mixtures, cycloadditions, sigmatropic rearrangements, electrocyclic reactions, ring-openings, carbonyl additions, carbonyl reductions, olefin additions, olefin reductions, imine additions, imine reductions, olefin epoxidations, olefin aziridinations, carbon-carbon bond formations, carbon-heteroatom bond formations, and heteroatom-heteroatom bond formations.  
     
     
         30 . The method of claims  27  or  28 , wherein the catalysts are selected based on the observation of a detectable event.  
     
     
         31 . The method of  claim 30 , wherein the detectable event is a member of the set comprising the evolution of a gas, the emission of a photon, and the formation of a precipitate.  
     
     
         32 . A parallel, combinatorial method for the discovery and optimization of catalysts for a transformation from the set comprising the Strecker reaction, the aldol addition, the aldol condensation, the Michael addition, the Claisen rearrangement, the Cope rearrangement, the dihydroxylation of olefins, the epoxidation of olefins, the aziridination of olefins, the Darzen's condensation, the Diels-Alder reaction, the hetero-Diels-Alder reaction, the ene reaction, the hetero-ene reaction, the Wittig rearrangement, the Nazarov cyclization, the asymmetric addition of Grignard reagents to carbon-heteroatom π-bonds, the asymmetric addition of organolithium reagents to carbon-heteroatom π-bonds, the asymmetric Robinson annulation, and the Simmons-Smith reaction.  
     
     
         33 . A catalyst represented by the following general structure:  
       
         
           
           
               
               
           
         
       
       wherein 
 B represents a monocyclic or polycyclic group;  
 C 1 , C 2  and C 3  each represent chiral carbon atoms;  
 X represents O, S or NH;  
 J represents a linker group including at least one functional group capable of acting as a hydrogen bond donor;  
 R 103  represents either a hydrogen bond donor, a Lewis basic group, or a group with both characteristics;  
 R 104  represents a sterically bulky, aliphatic or cycloaliphatic substituent of up to 20 carbons (preferably 2-10);  
 R 105  is absent, or represents one or more additional substituents of B selected from the group consisting of alkyl, alkenyl, alkynyl, acyl, thioacyl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH 2 ) m —R 80 ; and  
 R 106  and R 107  each independently represent alkyl, alkenyl, alkynyl, acyl, thioacyl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH 2 ) m —R 80 , or  
 R 106  and R 107  taken together with C 2  and C 3  form a ring having from 4 to 8 atoms in the ring;  
 R 108  and R 109  each independently represent an alkyl, represent alkyl, alkenyl, alkynyl, acyl, thioacyl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH 2 ) m —R 80 , with the proviso that R 108  and (C(X)R 109 ) are not identical (this proviso is implied by the aforementioned chirality of C 1 );  
 R 80  represents an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle; and  
 m is an integer in the range 0 to 8 inclusive.  
 
     
     
         34 . A catalyst according to  claim 33 , wherein X is S or O.  
     
     
         35 . A catalyst according to  claim 33 , wherein R 103  is —NH 2 , —OH, or —SH, or a lower alkyl group substituted thereby.  
     
     
         36 . A catalyst according to  claim 33 , wherein R 104  is attached to B at a position both ortho to R 103 , and meta to the imine substituent on B.  
     
     
         37 . A catalyst according to  claim 33 , wherein R 104  is a lower alkyl or alkoxyl group.  
     
     
         38 . A catalyst according to  claim 33 , wherein R 106  and R 107  are C 3 -C 8  alkyl groups, or, together with C 2  and C 3  form a ring having from 4 to 8 atoms in the ring.  
     
     
         39 . A catalyst according to  claim 33 , wherein 
 J is represented by —NH—Y—NH—;    Y is selected from the group consisting of                          Q 1  represents S or O; and    R 46  represents hydrogen, a lower alkyl or an aryl.    
     
     
         40 . A catalyst according to  claim 39 , wherein Y is —C(═Q 1 )—; and Q 1  is O or S.  
     
     
         41 . A catalyst according to  claim 33 , wherein R 108  represents an alkyl, heteroalkyl, aryl or heteroaryl group.  
     
     
         42 . A catalyst according to  claim 33 ,  39 , or  40 , wherein R 108  represents a side-chain of a naturally occurring cc-amino acid or analog thereof.  
     
     
         43 . A catalyst according to  claim 42 , wherein R 109  represents an amino group.  
     
     
         44 . A catalyst represented by the following general structure:  
       
         
           
           
               
               
           
         
       
       wherein 
 A represents a monocyclic or polycyclic group;  
 B represents a monocyclic or polycyclic group;  
 C 1  represents a chiral carbon atom;  
 X represents O, S or NH;  
 R 103  represents either a hydrogen bond donor, a Lewis basic group, or a group with both characteristics;  
 R 104  represents a sterically bulky, aliphatic or cycloaliphatic substituent of up to 20 carbons;  
 R 105  is absent, or represents one or more additional substituents of B selected from the group consisting of alkyl, alkenyl, alkynyl, acyl, thioacyl, alkylithio,. imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH 2 ) m —R 80 ; and  
 R 108  and R 109  each independently represent an alkyl, represent alkyl, alkenyl, alkynyl, acyl, thioacyl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH 2 ) m —R 80 , with the proviso that R 108  and (C(X)R 109 ) are not identical (this proviso is implied by the aforementioned chirality of C 1 );  
 R 110  is absent, or represents one or more additional substituents of A selected from the group consisting of alkyl, alkenyl, alkynyl, acyl, thioacyl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH 2 ) m —R 80 .  
 R 80  represents an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle; and  
 m is an integer in the range 0 to 8 inclusive.  
 
     
     
         45 . A catalyst according to  claim 44 , wherein A is a cycloalkyl having 5, 6 or 7 carbons in the ring structure.  
     
     
         46 . A catalyst represented by the following general formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 X represents, independently for each occurrence, O, S, or NR;  
 R, R 1 , R 2 , and R 3  represent, independently for each occurrence, H, alkyl, aryl, heteroalkyl, or heteroaryl;  
 R 4  represents H, alkyl, heteroalkyl, aryl, heteroaryl, formyl, or acyl;  
 R 2  is absent or occurs no more than 4 times; and  
 n is an integer selected from the range 0 to 2 inclusive.  
 
     
     
         47 . A catalyst according to  claim 46 , wherein 
 X represents, independently for each occurrence, O or S;    R, R 1 , R 2 , and R 3  represent, independently for each occurrence, H, alkyl, aryl, heteroalkyl, or heteroaryl;    R 4  represents alkyl, heteroalkyl, aryl, or heteroaryl;    R 2  is absent; and    n is an integer selected from the range 0 to 2 inclusive.    
     
     
         48 . A catalyst according to  claim 47 , wherein 
 X represents, independently for each occurrence, O or S;    R, R 1 , R 2 , and R 3  represent, independently for each occurrence, H, alkyl, aryl, heteroalkyl, or heteroaryl;    R 4  represents formyl or acyl;    R 2  is absent; and    n is an integer selected from the range 0 to 2 inclusive.    
     
     
         49 . A catalyst according to  claim 33 ,  44 , or  46 , wherein said catalyst catalyzes an enantioselective or diastereoselective transformation that produces a product with an enantiomeric or diastereomeric excess, respectively, of at least 75%.  
     
     
         50 . A catalyst according to  claim 33 ,  44 , or  46 , wherein said catalyst catalyzes an enantioselective or diastereoselective transformation that produces a product with an enantiomeric or diastereomeric excess, respectively, of at least 80%.  
     
     
         51 . A catalyst according to  claim 33 ,  44 , or  46 , wherein said catalyst catalyzes an enantioselective or diastereoselective transformation that produces a product with an enantiomeric or diastereomeric excess, respectively, of at least 85%.  
     
     
         52 . A catalyst according to  claim 33 ,  44 , or  46 , wherein said catalyst catalyzes an enantioselective or diastereoselective transformation that produces a product with an enantiomeric or diastereomeric excess, respectively, of at least 90%.  
     
     
         53 . A catalyst according to  claim 33 ,  44 , or  46 , wherein said catalyst catalyzes an enantioselective or diastereoselective transformation that produces a product with an enantiomeric or diastereomeric excess, respectively, of at least 95%.  
     
     
         54 . A catalyst according to  claim 33 ,  44 , or  46 , wherein said catalyst catalyzes an enantioselective or diastereoselective transformation that produces a product with an enantiomeric or diastereomeric excess, respectively, of at least 98%.