Main-group metal-based asymmetric catalysts and applications thereof

Abstract

The present invention relates to a method and catalysts for the stereoselective addition of a nucleophile to a reactive π-bond of a substrate. The chiral, non-racemic catalysts of the present invention constitute the first examples of catalysts for nucleophilic additions that comprise a main-group metal and a tri- or tetra-dentate ligand.

1 - 15 . (canceled)  
     
     
         16 . A process of stereoselective chemical synthesis which comprises reacting a chiral or prochiral π-bond-containing substrate and a nucleophile in the presence of a chiral, non-racemic catalyst to produce a stereoisomerically-enriched product, wherein said π-bond-containing substrate comprises a carbon-carbon or carbon-heteroatom π-bond, said nucleophile comprises at least one pair of Lewis basic electrons, and said chiral, non-racemic catalyst comprises an asymmetric tridentate ligand complexed with a main-group metal atom.  
     
     
         17 . A stereoselective nucleophilic addition process which comprises: 
 combining a chiral or prochiral π-bond-containing substrate and a nucleophile in the presence of a chiral, non-racemic catalyst to produce a stereoisomerically enriched product, wherein said π-bond-containing substrate comprises at least one carbon-carbon or carbon-heteroatom π-bond, said nucleophile comprises at least one pair of Lewis basic electrons, and said chiral, non-racemic catalyst comprises a tridentate chiral ligand having at least one Schiff base nitrogen complexed with a main-group metal; and    maintaining the combination under conditions appropriate for said chiral, non-racemic catalyst to catalyze a stereoselective nucleophilic addition reaction between said chiral or prochiral π-bond-containing substrate and said nucleophile.    
     
     
         18 . The process of  claim 17 , wherein the main-group metal is selected from Groups 1, 2, 12, 13, or 14 of the periodic table.  
     
     
         19 . The process of  claim 17 , wherein the metal is a Group 12, 13, or 14 main-group metal.  
     
     
         20 . The process of  claim 17 , wherein the metal atom is selected from the set comprising Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba, Zn, Cd, Hg, B, Al, Ga, In, Si, Ge, and Sn.  
     
     
         21 - 23 . (canceled)  
     
     
         24 . The process of  claim 17 , wherein the π-bond-containing substrate is represented by the general formula 1, the nucleophile is represented by NuY, and the product of the subject process is represented by 2: 
 chiral, non-racemic catalyst                          wherein    R, R′, and R″ represent, independently for each occurrence, hydrogen, 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 ;    X is selected from the group comprising CR 2 , O, S, Se, and NR″;    Y is selected, independently for each occurrence, from the set comprising H, Li, Na, K, Mg, Ca, B, Al, Cu, Ag, Ti, Zr, SiR 3 , and SnR 3 ; and    Nu is selected from the set comprising conjugate bases of weak Bronsted acids and carbanions;    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.    
     
     
         25 . The process of  claim 24 , wherein R and R′ in 1 taken together form a carbocyclic or heterocyclic ring having from 4 to 8 atoms in the ring structure.  
     
     
         26 . The process of  claim 24 , wherein R and R′ are chosen such that 1 does not have an internal plane of symmetry.  
     
     
         27 . The process of  claim 17 , wherein the π-bond-containing substrate is selected from the group comprising aldehydes, conjugated enals, thioaldehydes, conjugated thioenals, selenoaldehydes, conjugated selenoenals, ketones, conjugated enones, thioketones, conjugated thioenones, selenoketones, conjugated selenoenones, imines, oximes, hydrazones, glyoxylates, pyruvates, conjugated enoates, α,β-unsaturated amides, α,β-unsaturated imides, lactones, thionolactones, thiolactones, dithiolactones, lactams, and thiolactams; and the nucleophile is selected from the group comprising conjugate bases of weak Bronsted acids and carbanions.  
     
     
         28 . The process of  claim 17 , which process is an enantioselective reaction.  
     
     
         29 . The process of  claim 17 , which process is a diastereoselective reaction.  
     
     
         30 . The process of  claim 29 , which diastereoselective reaction produces a kinetic resolution.  
     
     
         31 . The process of  claim 17 , wherein the chiral, non-racemic catalyst has a molecular weight of less than 5,000 a.m.u.  
     
     
         32 - 47 . (canceled)  
     
     
         48 . A method for catalyzing a stereoselective nucleophilic addition reaction which comprises: 
 combining a chiral or prochiral π-bond-containing substrate and a nucleophile in the presence of a chiral, non-racemic catalyst to produce a stereoisomerically enriched product, wherein said π-bond-containing substrate comprises at least one carbon-carbon or carbon-heteroatom π-bond, said nucleophile comprises at least one pair of Lewis basic electrons, and said chiral catalyst comprises a chiral tridentate ligand complexed with a main-group metal; and    maintaining the combination under conditions appropriate for said chiral, non-racemic catalyst to catalyze a stereoselective nucleophilic addition reaction between said π-bond-containing substrate and said nucleophile.    
     
     
         49 . The method of  claim 48 , wherein the chiral tridentate ligand of the chiral catalyst is represented by the general formula:  
       
         
           
           
               
               
           
         
       
       in which 
 Z 1 , Z 2 , and Z 3  each represent a Lewis base;  
 the E 1  moiety, taken with Z 1 , Z 2  and M, and the E 2  moiety, taken with Z 2 , Z 3  and M, each, independently, form a heterocycle;  
 R 80  and R 8 , each independently are absent, hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiolamines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH 2 ) m —R 7 , or any two or more of the R 80  and R 81  substituents taken together form a bridging substituent;  
 R 7  represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;  
 m is zero or an integer in the range of 1 to 8;  
 M represents a main-group metal; and  
 A represents a counteranion or a nucleophile,  
 wherein the tridentate ligand is asymmetric.  
 
     
     
         50 - 61 . (canceled)  
     
     
         62 . A method of realizing a stereoselective addition of a nucleophile to a prochiral or chiral π-bond-containing substrate, wherein the π-bond-containing substrate is represented by the general formula 1, and the nucleophile is represented by NuY, to give a product represented by 2:  
       
         
           
           
               
               
           
         
       
       wherein 
 said chiral, non-racemic catalyst comprises a tridentate ligand;  
 R, R′, and R″ represent, independently for each occurrence, hydrogen, 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 ;  
 X is selected from the group comprising CR 2 , O, S, Se, and NR″;  
 Y is selected, independently for each occurrence, from the set comprising H, Li, Na, K, Mg, Ca, B, Al, Cu, Ag, Ti, Zr, SiR 3 , and SnR 3 ; and  
 Nu is selected from the set comprising conjugate bases of weak Bronsted acids and carbanions;  
 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; and  
 which method comprises reacting said π-bond-containing substrate with said nucleophile in the presence of at least a catalytic amount of a chiral metallosalenate catalyst.  
 
     
     
         63 . (canceled)  
     
     
         64 . (canceled)  
     
     
         65 . The method of  claim 62 , wherein R, and R′ are chosen such that 1 does not have an internal plane of symmetry.  
     
     
         66 . The method of  claim 62 , wherein the π-bond-containing substrate is selected from the group comprising aldehydes, conjugated enals, thioaldehydes, conjugated thioenals, selenoaldehydes, conjugated selenoenals, ketones, conjugated enones, thioketones, conjugated thioenones, selenoketones, conjugated selenoenones, imines, oximes, hydrazones, glyoxylates, pyruvates, conjugated enoates, α,β-unsaturated amides, α,β-unsaturated imides, lactones, thionolactones, thiolactones, dithiolactones, lactams, and thiolactams; and the nucleophile is selected from the group comprising conjugate bases of weak Bronsted acids and carbanions.  
     
     
         67 - 70 . (canceled)  
     
     
         71 . The method of  claim 62 , which process is an enantioselective reaction.  
     
     
         72 . The method of  claim 62 , which process is a diastereoselective reaction.  
     
     
         73 . The method of  claim 72 , which diastereoselective reaction produces a kinetic resolution.  
     
     
         74 - 77 . (canceled)  
     
     
         78 . A method of providing a chiral, non-racemic α-amino nitrile, comprising reacting a prochiral or chiral imine with hydrogen cyanide, or a surrogate thereof, in the presence of a chiral, non-racemic catalyst such that a chiral, non-racemic α-amino nitrile is formed, wherein the chiral, non-racemic catalyst comprises an asymmetric tridentate ligand complexed with a main-group metal atom, said complex having a planar or trigonal pyramidal geometry.  
     
     
         79 . The method of  claim 49 , wherein the chiral, non-racemic tridentate ligand of the chiral catalyst is represented by the general formula:  
       
         
           
           
               
               
           
         
       
       wherein R 106  represents a hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiolamine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester, or —(CH 2 ) m —R 7 ; each of R 112  and R′ 112  is absent or represent one or more covalent substitutions of the heterocycle to which it is attached; R 7  represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.