Gem-disubstituted pyrrolidines, piperazines, and diazepanes, and compositions and methods of making the same

Abstract

Described here are transition metal-catalyzed enantioselective arylation and vinylation reactions of α-substituted lactams, such as γ-lactams. The use of various electrophiles and ligands are described, and result in the construction of α-quaternary centers in good yields (up to 91% yield) and high enantioselectivities (up to 97% ee).

1 .- 153 . (canceled) 
     
     
         154 . A method comprising preparing a compound of formula (IV): 
       
         
           
           
               
               
           
         
         by treating a compound of formula (III) 
       
       
         
           
           
               
               
           
         
         or a salt thereof, 
         with a Pd(0) catalyst and a ligand L under alkylation conditions, 
         wherein, as valence and stability permit, 
         R 21  is —C(O)aryl or —C(O)heteroaryl, optionally substituted with alkoxy, alkyl, or haloalkyl; 
         R 22  is —C(O)OR 22a , —C(O)aryl, or —C(O)heteroaryl, wherein each of aryl and heteroaryl is optionally substituted with alkoxy, alkyl, or haloalkyl; 
         R 22a  is C 1-6  alkyl, C 6-10  aryl, or C 5-9  heteroaryl; 
         R 23  is H, halogen, alkynyl, alkenyl, or C 1-6  alkyl, each optionally substituted with cyano, OH, alkoxy, aryloxy, acyl, alkoxycarbonyl, halogen, aryl, or —NHC(O)OR 23a ; 
         R 23a  is C 1-6  alkyl, (C 6-10  aryl)alkyl, or (C 5-9  heteroaryl)alkyl; 
         R 24  is H or halogen; and 
         p is 0. 
       
     
     
         155 .- 156 . (canceled) 
     
     
         157 . The method of  claim 154 , wherein:
 the compound of formula (IV) is a compound of formula (IVa)   
       
         
           
           
               
               
           
         
         and the compound of formula (III) is a compound of formula (IIIa): 
       
       
         
           
           
               
               
           
         
         or a salt thereof, 
         wherein, as valence and stability permit, 
         R 21  is —C(O)aryl or —C(O)heteroaryl, optionally substituted with alkoxy, alkyl, or haloalkyl; 
         R 22  is —C(O)OR 22a , —C(O)aryl, or —C(O)heteroaryl, wherein each of aryl and heteroaryl is optionally substituted with alkoxy, alkyl, or haloalkyl; 
         R 22a  is C 1-6  alkyl, C 6-10  aryl, or C 5-9  heteroaryl; 
         R 23  is H, or C 1-6  alkyl optionally substituted with cyano, OH, alkoxy, aryloxy, acyl, or —NHC(O)OR 23a ; 
         R 23a  is C 1-6  alkyl, (C 6-10  aryl)alkyl, or (C 5-9  heteroaryl)alkyl; and 
         R 24  is H or halogen. 
       
     
     
         158 . (canceled) 
     
     
         159 . The method of  claim 154 , wherein the Pd or Ni catalyst is Ni(COD) 2 , Pd(dmdba) 2 , or Pd 2 (dmdba) 3 . 
     
     
         160 . The method of  claim 154 , wherein:
 the catalyst is a Pd catalyst and the chiral ligand is an enantioenriched ferrocelane ligand, wherein the enantioenriched ferrocelane ligand is 1,1′-bis[(2S,5S)-2,5-diethyl-1-phospholanyl]ferrocene, 1,1′-bis[(2S,5S)-2,5-dimethyl-1-phospholanyl]ferrocene, or 1,1′-bis[(2S,5S)-2,5-diisopropyl-1-phospholanyl]ferrocene,   or   the catalyst is a Ni catalyst and the chiral ligand is an enantioenriched Josiphos ligand.   
     
     
         161 . The method of  claim 154 , wherein the ligand L is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         162 . The method of  claim 154 , wherein the aryl halide or aryl pseudohalide is selected from bromobenzene, chlorobenzene, iodobenzene, phenyl triflate, and chlorotoluene. 
     
     
         163 . The method of  claim 154 , wherein the base is selected from hexamethyldisilazane sodium salt (NaHMDS), KHMDS, LiHMDS, and lithium tert-butoxide (tBuOLi). 
     
     
         164 . (canceled) 
     
     
         165 . The method of  claim 157 , whereby the compound of formula (IVa) is enantioenriched. 
     
     
         166 .- 170 . (canceled) 
     
     
         171 . A compound of formula (III) or formula (IV): 
       
         
           
           
               
               
           
         
         wherein, as valence and stability permit, 
         R 21  is —C(O)aryl or —C(O)heteroaryl, each optionally substituted with alkoxy, alkyl, or haloalkyl; 
         R 22  is —C(O)OR 22a , —C(O)aryl, or —C(O)heteroaryl, wherein each of aryl and heteroaryl are optionally substituted with alkoxy, alkyl, or haloalkyl; 
         R 22a  is C 1-6  alkyl, C 6-10  aryl, or C 5-9  heteroaryl, wherein each of aryl and heteroaryl are optionally substituted with alkoxy, alkyl, or haloalkyl; 
         R 23  is H, halogen, alkynyl, alkenyl, or C 1-6  alkyl, each optionally substituted with OH, cyano, alkoxy, aryloxy, acyl, alkoxycarbonyl, halogen, aryl, or —NHC(O)OR 23a ; 
         R 23a  is C 1-6  alkyl, (C 6-10  aryl)alkyl, or (C 5-9  heteroaryl)alkyl; 
         R 24  is H or halogen; and 
         p is 0, 
         or 
         a compound of Formula (VIII): 
       
       
         
           
           
               
               
           
         
         wherein, as valence and stability permit, 
         R 21  is —C(O)aryl or —C(O)heteroaryl, each optionally substituted with alkoxy, alkyl, or haloalkyl; 
         R 23b  is H, or C 1-6  alkyl optionally substituted with CN, OH, alkoxy, aryloxy, amino, acyl, or —NHC(O)R 23c ; 
         R 23c  is C 1-6  alkyl, (C 6-10  aryl)alkyl or (C 5-9  heteroaryl)alkyl; and 
         R 24  is H or halogen, 
         or 
         a compound of Formula (IX) or (X): 
       
       
         
           
           
               
               
           
         
         wherein, as valence and stability permit, 
         R 23d  is H, or is C 1-6  alkyl optionally substituted with cyano, OH, alkoxy, aryloxy, acyl, —NHC(O)OR 23a ; 
         R 23a  is C 1-6  alkyl, (C 6-10  aryl)alkyl, or (C 5-9  heteroaryl)alkyl; and 
         R 24  is H or halogen, 
         or 
         a compound of formula (XI): 
       
       
         
           
           
               
               
           
         
         wherein, as valence and stability permit, 
         R 21  is —C(O)aryl or —C(O)heteroaryl, each optionally substituted with alkoxy, alkyl, or haloalkyl; 
         R 24  is H or halogen; and 
         R 23e  is H, or is C 1-6  alkyl optionally substituted with halogen, OH, aryl, aryloxy, CN, acyl, or amino. 
       
     
     
         172 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         173 . A method comprising preparing a compound of formula (VIII): 
       
         
           
           
               
               
           
         
         by treating a compound of formula (IVa): 
       
       
         
           
           
               
               
           
         
         with TFA in a solvent; 
         wherein, as valence and stability permit, 
         R 21  is —C(O)aryl or —C(O)heteroaryl, optionally substituted with alkoxy, alkyl, or haloalkyl; 
         R 22  is Boc; 
         R 23  is H, or is C 1-6  alkyl optionally substituted with CN, alkoxy, aryloxy, acyl, or —NHC(O)OR 23a ; 
         R 23a  is C 1-6  alkyl, (C 6-10  aryl)alkyl, or (C 5-9  heteroaryl)alkyl; 
         R 24  is H or halogen; 
         R 23b  is H; or is C 1-6  alkyl optionally substituted with halogen, OH, CN, alkoxy, aryloxy, amino, acyl, or —NHC(O)OR 23c ; and 
         R 23c  is (C 6-10  aryl)alkyl or (C 5-9  heteroaryl)alkyl, 
         or 
         a method comprising preparing a compound of formula (IX): 
       
       
         
           
           
               
               
           
         
         by treating a compound of formula (IVa): 
       
       
         
           
           
               
               
           
         
         or a salt thereof, 
         with LiOH in a first solvent, 
         wherein, as valence and stability permit, 
         R 21  is —C(O)aryl or —C(O)heteroaryl, optionally substituted with alkoxy, alkyl, or haloalkyl; 
         R 22  is Boc; 
         R 23  is H, or C 1-6  alkyl optionally substituted with halogen, OH, cyano, alkoxy, aryloxy, acyl, or —NHC(O)OR 23a ; 
         R 23a  is C 1-6  alkyl, (C 6-10  aryl)alkyl, or (C 5-9  heteroaryl)alkyl; 
         R 23d  is H, or is C 1-6  alkyl optionally substituted with halogen, OH, alkoxy, aryloxy, acyl, or —NHC(O)OR 23a ; and 
         R 24  is H or halogen, 
         or 
         a method comprising preparing a compound of formula (XI): 
       
       
         
           
           
               
               
           
         
         by treating a compound of formula (IVa): 
       
       
         
           
           
               
               
           
         
         or a salt thereof, 
         with hydrogen gas in the presence of a Pd/C catalyst in a first solvent, to form a first product mixture; 
         filtering the first product mixture, to form a crude first product; and 
         treating the crude first product with TFA in a second solvent; 
         wherein, as valence and stability permit, 
         R 21  is —C(O)aryl or —C(O)heteroaryl, optionally substituted with alkoxy, alkyl, or haloalkyl; 
         R 22  is Boc; 
         R 23  is H, or is C 1-6  alkyl optionally substituted with halogen, OH, alkoxy, aryloxy, CN, aryl, or —NHC(O)OR 23a ; 
         R 23a  is C 1-6  alkyl, (C 6-10  aryl)alkyl, or (C 5-9  heteroaryl)alkyl; 
         R 23e  is H, or is C 1-6  alkyl optionally substituted with halogen, OH, aryl, aryloxy, CN, acyl, or amino; and 
         R 24  is H or halogen.