Asymmetric catalytic decarboxylative alkyl alkylation using low catalyst concentrations and a robust precatalyst

Abstract

with a palladium (II) catalyst under alkylation conditions.

1 - 40 . (canceled) 
     
     
         41 . A method for the preparation of a compound of formula (I): 
       
         
           
           
               
               
           
         
         the preparing comprising treating, with a Pd(II) catalyst in an organic solvent,
 (i) a compound of formula (II) or (III) or a salt thereof: 
 
       
       
         
           
           
               
               
           
         
         or
 (ii) a compound of formula (IV) or (V) or a salt thereof: 
 
       
       
         
           
           
               
               
           
         
         
           and a compound of formula (X): 
         
       
       
         
           
           
               
               
           
         
         wherein the Pd(II) catalyst is used in an amount from about 0.01 mol % to about 3 mol % relative to the compound of formula (II), (III), (IV), or (V), 
         wherein, as valence and stability permit, 
         R 1  represents hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, amino, or halo; 
         R 2 , R 3 , R 4 , R 5 , R 12 , R 13 , R 14 , and R 15  are independently selected for each occurrence from hydrogen, hydroxyl, halo, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate group, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, ether group, thioether group, ester group, amide, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, acylamino, aryl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl, 3- to 10-membered heterocyclyl, aralkyl, arylalkoxy, (5- to 10-membered heteroaryl)alkyl, (cycloalkyl)alkyl, and (3- to 10-membered heterocyclyl)alkyl; 
         W represents, as valence permits, —O—, —S—, —NR 6 —, —CR 7 R 8 —, —C(O)—, —CR 7 ═, or —N═; 
         R 6  represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O) (5- to 10-membered heteroaryl), —C(O)-(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(5- to 10-membered heteroaryl), —C(O)O-(5- to 10-membered heteroaryl)alkyl, —S(O) 2 (aryl), —S(O) 2 (alkyl), —S(O) 2 (haloalkyl), —OR 10 , —SR 10 , or —NR 10 R 11 ; 
         R 7  and R 8  each independently represent hydrogen, hydroxyl, halo, nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, haloalkyl, ether group, thioether group, ester group, amido, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, or acylamino; 
         or R 6 , R 7 , and R 8  taken together with a substituent on ring A and the intervening atoms, form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-membered heterocyclyl)alkenyl; 
         R 10  and R 11  are independently selected for each occurrence from hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, and alkynyl; and 
         ring A represents an optionally substituted cycloalkyl, 5- to 10-membered heterocyclyl, cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl, 
         wherein each heteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N, O, and S; and 
         wherein substituents on the alkyl, haloalkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkoxy, or amino are selected from halo, hydroxyl, carboxyl, alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group, thioformate group, alkoxy, phosphate group, phosphonate group, phosphinate, amino, amido, amidine group, imine group, cyano, nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group, sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered heterocyclyl, aralkyl, aromatic group, and 5- to 10-membered heteroaromatic group. 
       
     
     
         42 . A method of preparing a pharmaceutical agent, comprising preparing a compound of formula (I): 
       
         
           
           
               
               
           
         
         the preparing comprising treating, with a Pd(II) catalyst in an organic solvent,
 (i) a compound of formula (II) or (III) or a salt thereof: 
 
       
       
         
           
           
               
               
           
         
         or
 (ii) a compound of formula (IV) or (V) or a salt thereof: 
 
       
       
         
           
           
               
               
           
         
         
           and a compound of formula (X): 
         
       
       
         
           
           
               
               
           
         
         wherein the Pd(II) catalyst is used in an amount from about 0.01 mol % to about 3 mol % relative to the compound of formula (II), (III), (IV), or (V), 
         wherein, as valence and stability permit, 
         R 1  represents hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, amino, or halo; 
         R 2 , R 3 , R 4 , R 5 , R 12 , R 13 , R 14 , and R 15  are independently selected for each occurrence from hydrogen, hydroxyl, halo, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate group, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, ether group, thioether group, ester group, amide, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, acylamino, aryl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl, 3- to 10-membered heterocyclyl, aralkyl, arylalkoxy, (5- to 10-membered heteroaryl)alkyl, (cycloalkyl)alkyl, and (3- to 10-membered heterocyclyl)alkyl; 
         W represents, as valence permits, —O—, —S—, —NR 6 —, —CR 7 R 8 —, —C(O)—, —CR 7 ═, or —N═; 
         R 6  represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O) (5- to 10-membered heteroaryl), —C(O)-(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(5- to 10-membered heteroaryl), —C(O)O-(5- to 10-membered heteroaryl)alkyl, —S(O) 2 (aryl), —S(O) 2 (alkyl), —S(O) 2 (haloalkyl), —OR 10 , —SR 10 , or —NR 10 R 11 ; 
         R 7  and R 8  each independently represent hydrogen, hydroxyl, halo, nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, haloalkyl, ether group, thioether group, ester group, amido, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, or acylamino; 
         or R 6 , R 7 , and R 8  taken together with a substituent on ring A and the intervening atoms, form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-membered heterocyclyl)alkenyl; 
         R 10  and R 11  are independently selected for each occurrence from hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, and alkynyl; and 
         ring A represents an optionally substituted cycloalkyl, 5- to 10-membered heterocyclyl, cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl, 
         wherein each heteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N, O, and S; and 
         wherein substituents on the alkyl, haloalkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkoxy, or amino are selected from halo, hydroxyl, carboxyl, alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group, thioformate group, alkoxy, phosphate group, phosphonate group, phosphinate, amino, amido, amidine group, imine group, cyano, nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group, sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered heterocyclyl, aralkyl, aromatic group, and 5- to 10-membered heteroaromatic group. 
       
     
     
         43 . A method comprising
 (a) preparing a compound of formula (I):   
       
         
           
           
               
               
           
         
         the preparing comprising treating with a Pd(II) catalyst in an organic solvent,
 (i) a compound of formula (II) or (III) or a salt thereof: 
 
       
       
         
           
           
               
               
           
         
         or
 (ii) a compound of formula (IV) or (V) or a salt thereof: 
 
       
       
         
           
           
               
               
           
         
         
           and a compound of formula (X): 
         
       
       
         
           
           
               
               
           
         
         wherein the Pd(II) catalyst is used in an amount from about 0.01 mol % to about 3 mol % relative to the compound of formula (II), (III), (IV), or (V); and 
         (b) synthesizing a pharmaceutical agent from the compound of formula (I), 
         wherein, as valence and stability permit, 
         R 1  represents hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, amino, or halo; 
         R 2 , R 3 , R 4 , R 5 , R 12 , R 13 , R 14 , and R 15  are independently selected for each occurrence from hydrogen, hydroxyl, halo, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate group, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, ether group, thioether group, ester group, amide, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, acylamino, aryl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl, 3- to 10-membered heterocyclyl, aralkyl, arylalkoxy, (5- to 10-membered heteroaryl)alkyl, (cycloalkyl)alkyl, and (3- to 10-membered heterocyclyl)alkyl; 
         W represents, as valence permits, —O—, —S—, —NR 6 —, —CR 7 R 8 —, —C(O)—, —CR 7 ═, or —N═; 
         R 6  represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O) (5- to 10-membered heteroaryl), —C(O)-(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(5- to 10-membered heteroaryl), —C(O)O-(5- to 10-membered heteroaryl)alkyl, —S(O) 2 (aryl), —S(O) 2 (alkyl), —S(O) 2 (haloalkyl), —OR 10 , —SR 10 , or —NR 10 R 11 ; 
         R 7  and R 8  each independently represent hydrogen, hydroxyl, halo, nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, haloalkyl, ether group, thioether group, ester group, amido, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, or acylamino; 
         or R 6 , R 7 , and R 8  taken together with a substituent on ring A and the intervening atoms, form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-membered heterocyclyl)alkenyl; 
         R 10  and R 11  are independently selected for each occurrence from hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, and alkynyl; and 
         ring A represents an optionally substituted cycloalkyl, 5- to 10-membered heterocyclyl, cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl, 
         wherein each heteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N, O, and S; and 
         wherein substituents on the alkyl, haloalkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkoxy, or amino are selected from halo, hydroxyl, carboxyl, alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group, thioformate group, alkoxy, phosphate group, phosphonate group, phosphinate, amino, amido, amidine group, imine group, cyano, nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group, sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered heterocyclyl, aralkyl, aromatic group, and 5- to 10-membered heteroaromatic group. 
       
     
     
         44 . The method of  claim 43 , wherein the compound of formula (I) is represented by formula (Ia): 
       
         
           
           
               
               
           
         
       
       and
 the compound of formula (II) is represented by formula (IIa): 
 
       
         
           
           
               
               
           
         
       
       and
 the compound of formula (III) is represented by formula (IIIa): 
 
       
         
           
           
               
               
           
         
         wherein: 
         B, D, and E independently for each occurrence represent, as valence permits, O, S, NR 6 , CR 7 R 8 , C(O), CR 7 , or N; provided that no two adjacent occurrences of W, B, D, and E are NR 6 , O, S, or N; 
         or any two occurrences of R 6 , R 7 , and R 8  on adjacent W, B, D, or E groups, taken together with the intervening atoms, form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-membered heterocyclyl)alkenyl; 
         each occurrence of  independently represents a double bond or a single bond as permitted by valence; and 
         m and n are integers each independently selected from 0, 1, and 2. 
       
     
     
         45 . The method of  claim 44 , wherein the sum of m and n is 0, 1, 2, or 3. 
     
     
         46 . The method of  claim 44 , wherein each occurrence of W, B, D, and E is each independently —CR 7 R 8 —, or —CR 7 —, or —C(O)—. 
     
     
         47 . The method of  claim 46 , wherein one occurrence of W, B, D, and E is —CR 7 R 8 — or —C(O)—, and the remaining three are —CR 7 R 8 —;
 optionally wherein R 7  and R 8 , independently for each occurrence, are selected from hydrogen, hydroxyl, halo, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, and amido. 
 
     
     
         48 . The method of  claim 44 , wherein at least two adjacent occurrences of W, B, D, and E are —CR 7 —. 
     
     
         49 . The method of  claim 48 , wherein W and B are each —CR 7 — and m is 1;
 optionally wherein R 7  is independently selected for each occurrence from hydrogen, hydroxyl, halo, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, amino, alkoxy, aryloxy, alkylamino, amido, and acylamino; or 
 the occurrence of R 7  on W and the occurrence of R 7  on B are taken together to form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl. 
 
     
     
         50 . The method of  claim 44 , wherein at least one occurrence of W, B, D, and E is —NR 6 —. 
     
     
         51 . The method of  claim 50 , wherein W is —NR 6 —; optionally wherein at least one occurrence of the remaining B, D, and E is —NR 6 — or O. 
     
     
         52 . The method of  claim 50 , wherein R 6  represents, independently for each occurrence, hydrogen or optionally substituted alkyl, aralkyl, (5- to 10-membered heteroaryl)alkyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), or —S(O) 2 (aryl). 
     
     
         53 . The method of  claim 44 , wherein at least one occurrence of W, B, D, and E is —O—. 
     
     
         54 . The method of  claim 43 , wherein W represents —O—, —S—, —NR 6 —, —CR 7 R 8 —, or —CR 7 ═. 
     
     
         55 . The method of  claim 43 , wherein R 2 , R 3 , R 4 , R 5 , R 12 , R 13 , R 14 , and R 15  are each hydrogen. 
     
     
         56 . The method of  claim 43 , wherein R 1  represents substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, or halo. 
     
     
         57 . The method of  claim 43 , wherein the Pd(II) catalyst is selected from Pd(OC(O)R) 2 , Pd(OAc) 2 , PdCl 2 , Pd(PhCN) 2 Cl 2 , Pd(CH 3 CN) 2 Cl 2 , PdBr 2 , Pd(acac) 2 , [Pd(allyl)Cl] 2 , Pd(TFA) 2 , and pre-formed Pd(II)-ligand complex;
 wherein R c  is optionally substituted alkyl, alkenyl, alkynyl, aryl, 5- to 10-membered heteroaryl, aralkyl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl, 5- to 10-membered heterocyclyl, (cycloalkyl)alkyl, or (5- to 10-membered heterocyclyl)alkyl.   
     
     
         58 . The method of  claim 43 , wherein the Pd(II) catalyst is Pd(OAc) 2 . 
     
     
         59 . The method of  claim 43 , wherein the Pd(II) catalyst is used in an amount from about 0.02 mol % to about 2.5 mol % relative to the compound of formula (II), (III), (IV), or (V). 
     
     
         60 . The method of  claim 43 , wherein the Pd(II) catalyst further comprises a chiral ligand. 
     
     
         61 . The method of  claim 60 , wherein the chiral ligand is used in an amount from about 0.1 mol % to about 100 mol % relative to the compound of formula (II), (III), (IV), or (V). 
     
     
         62 . The method of  claim 43 , wherein the organic solvent is selected from methyl tert-butyl ether, toluene, and 2-methyltetrahydrofuran. 
     
     
         63 . The method of  claim 43 , whereby the compound of formula (I) is enantioenriched.