Methods for enantioselective allylic alkylation of esters, lactones, and lactams with unactivated allylic alcohols

A method of synthesizing a pharmaceutical agent comprising preparing a compound of Formula (IX):

• comprising:
• treating a compound of Formula (I)
• with a compound of Formula (II) that is Formula (IIa) or Formula (IIb)
• in an organic solvent
• in the presence of a complex formed by contacting a Ni(0) source with a ligand L;
• wherein:
• X is O or N-PG;
• PG is a protecting group selected from benzyl, tosyl, benzoyl, Boc, methyl, and phenyl;
• R1 is methyl or ethyl;
• R2 is H, methyl, aralkenyl, aryl, or hetaryl;
• R8 and R9 are each H, or R8 and R9, taken together with the carbon atoms to which they are attached, form an aryl or heteroaryl ring;
• is a single bond when R8 and R9 are each H, and
• when R8 and R9, taken together with the carbon atoms to which they are attached, form an aryl or heteroaryl ring;
• L is selected from (R)-BINAP, (R)-H8-BINAP, (R)-Segphos, and (R)-P-phos;
• the Ni(0) source is Ni(COD)2;
• and
• the organic solvent is toluene, diethyl ether, methyl t-butyl ether (MTBE), tetrahydrofuran (THF), or dioxane, or a mixture thereof.