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 (I): 
       
         
           
           
               
               
           
         
         by treating a compound of formula (II): 
       
       
         
           
           
               
               
           
         
         or a salt thereof; 
         with a Pd or Ni catalyst comprising a chiral ligand; 
         an optionally substituted aryl halide, optionally substituted aryl pseudohalide, optionally substituted heteroaryl halide, an optionally substituted heteroaryl pseudohalide, or 
       
       
         
           
           
               
               
           
         
       
       and
 a base; 
 wherein, as valence and stability permit, 
 ring A represents an optionally substituted heterocycloalkyl, or heterocycloalkenyl group; 
 R in each occurrence independently represents optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —OR 10 , —SR 10 , or —NR 10 R 11 ; 
 R 1  represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl, —C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(heteroaryl), —C(O)O(heteroaralkyl), —S(O) 2 (aryl), —S(O) 2 (alkyl), —S(O) 2 (haloalkyl), —OR 10 , —SR 10 , or —NR 10 R 11 ; 
 or R 1  taken together with a substituent on ring A and the intervening atoms, form an optionally substituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group; 
 or a substituent on ring A taken together with another substituent on ring A and the intervening atoms, form an optionally substituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group; 
 R 2  represents substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aryl, heteroaralkyl, heteroaralkenyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, alkoxy, amino, or halo; 
 R 10  and R 11  are independently selected for each occurrence from hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, and alkynyl; 
 X is a halogen or pseudohalide; and 
 Y represents optionally substituted aryl, optionally substituted heteroaryl, or 
 
       
         
           
           
               
               
           
         
       
     
     
         155 . (canceled) 
     
     
         156 . The method of  claim 154 , wherein the compound of formula (I) is represented by formula (Ib): 
       
         
           
           
               
               
           
         
         the compound of formula (II) is represented by formula (IIb): 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 5  and R 6  each independently represent hydrogen, hydroxyl, halogen, nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, haloalkyl, ether, thioether, ester, amido, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, or acylamino; 
         or any two occurrences of R 1 , R 5 , and R 6 , taken together with the intervening atoms, form an optionally substituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group. 
       
     
     
         157 . (canceled) 
     
     
         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 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 . The method of  claim 154 , whereby the compound of formula (I) is enantioenriched. 
     
     
         165 .- 173 . (canceled)