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

A method for the preparation of a compound of formula (Ia):

• comprising treating a compound of formula (IVa) or (Va) or a salt thereof:
• with a compound of formula (X):
• and
• a Pd(II) catalyst, wherein the Pd(II) catalyst is used in an amount from about 0.02 mol % to about 1 mol % relative to the compound of formula (IVa) or of formula (Va), and
• wherein, as valence and stability permit,
• R1 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, or halo;
• R2, R3, R4, R5, R12, R13, R14, and R15 are independently selected for each occurrence from hydrogen, and alkyl;
• W represents —NR6;
• B, D, and E independently for each occurrence represent, as valence permits, CR7R8, C(O) or CR7;
• R6 represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl, —C(O)—(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(heteroaryl), —C(O)O—(5- to 10-membered heteroaryl)alkyl;
• R7 and R8 each independently represent hydrogen, hydroxyl, halogen group, nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, (5- to 10-membered heteroaryl)alkyl, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkenyl, alkynyl, cyano, carboxyl, sulfate group, amino, alkoxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, 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 any two occurrences of R6, R7, and R8 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, 3- to 10-membered heterocyclyl, or (3- to 10-membered heterocyclyl)alkenyl group;
• each occurrence of independently represents a double bond or a single bond as permitted by valence;
• m and n are integers each independently selected from 0, 1, and 2;
• Ra represents optionally substituted alkyl, aryl, or alkoxyl;
• and
• X represents a halide group, carbonate group, sulfonate group, acetate group, or carboxylate group;
• wherein each heteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N, O, and S;
• 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, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, or amino are selected from a halogen group, hydroxyl, carboxyl, alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group, thioformate group, alkoxy, phosphate group, phosphonate group, phosphinate group, amino, amido, amidine group, imine group, cyano, nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group, sulfamoyl, sulfonamido, sulfonyl, 3- to 10-membered heterocyclyl, aralkyl, aromatic group, and 3- to 10-membered heteroaromatic moiety.