Chiral phosphines for palladium-catalyzed asymmetric α-arylation of ester enolates to produce tertiary stereocenters in high enantioselectivity

A method of asymmetrically synthesizing an α-aryl compound of Formula I:

• or a pharmaceutically acceptable salt thereof, the method comprising the step of reacting a compound of Formula II with a compound of Formula III in the presence of a palladium catalyst, an activator, a compound of Formula IV, and optionally a solvent, to produce the asymmetric α-aryl compound of Formula I:
• wherein:
• * is an asymmetric carbon atom;
• the compound of Formula III is the (E)- or (Z)—OSiR7R8R9 isomer;
• the palladium catalyst is selected from PdMe2(TMEDA), Pd(dba)7, and Pd(OAc)2;
• the solvent is an aromatic solvent;
• Ar is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl group, which is optionally independently substituted with 1, 2 or 3 R4 groups;
• is a single or double bond, wherein either all of the are single bonds or all of the are double bonds;
• R1 is independently selected from hydrogen, alkyl, aryl, and arylalkyl;
• R2 and R3 are each independently selected from alkyl, cycloalkyl, aryl and arylalkyl;
• each R4 is independently selected from hydrogen, amino, halogen, hydroxyl, nitro, cyano, alkyl, alkenyl, alkynyl, perfluoroalkyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, (CH2)jOR11, (CH2)jC(O)R11, (CH2)jC(O)OR11, (CH2)jOC(O)R11, (CH2)jNR12R13, (CH2)jC(O)NR12R13, (CH2)jOC(O)NR12R13, (CH2)jNR14C(O)R11, (CH2)jNR14C(O)OR11, (CH2)jNR14C(O)NR12R13, (CH2)jS(O)mR11, and (CH2)jS(O)mNR12R13, wherein each j is independently an integer selected from 0 to 6, and each m is independently an integer selected from 0 to 2;
• R5 is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl, which is optionally independently substituted with 1, 2 or 3 R10 groups;
• R6 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted arylalkyl, which is optionally independently substituted with 1, 2 or 3 R10 groups;
• R7, R8 and R9 are each independently selected from alkyl, aryl and arylalkyl;
• each R10 is independently selected from hydrogen, amino, halogen, hydroxyl, nitro, cyano, alkyl, alkenyl, alkynyl, perfluoroalkyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, (CH2)jOR11, (CH2)jC(O)R11, (CH2)jC(O)OR11, (CH2)jOC(O)R11, (CH2)jNR12R13, (CH2)jC(O)NR12R13, (CH2)jOC(O)NR12R13, (CH2)jNR14C(O)R11, (CH2)jNR14C(O)OR11, (CH2)jNR14C(O)NR12R13, (CH2)j S(O)mR11, and (CH2)jS(O)mNR12R13, wherein each j is independently an integer selected from 0 to 6, and each m is independently an integer selected from 0 to 2;
• R11 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
• and
• R12, R13, R14 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or R14 is as described above, and R12 and R13 are joined together with the nitrogen atom to which they are attached, to form a substituted or unsubstituted 3- to 7-membered hetercycloalkyl or substituted or unsubstituted 5-membered heteroaryl, wherein the 3- to 7-membered hetercycloalkyl is selected from aziridine, azetidine, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and azepanyl;
• and the 5-membered heteroaryl is selected from pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indolyl, purinyl, benzimidazolyl, quinolinyl, and isoquinolinyl.