Bis-quarternary cinchona alkaloid salts as asymmetric phase transfer catalysts

A process for stereoselectively producing a compound of Formula A:

• wherein:
• Q forms a fused 5- or 6-membered aromatic carbocyclic or heterocyclic ring, each optionally substituted with 1 to 4 RC groups,
• each RA and each RB are independently hydrogen, halogen, hydroxy, amino or an organic substituent group, and one RA and one RB may be joined together to form a mono-, bi- or tricyclic carbocyclic or heterocyclic ring system, optionally substituted with 1 to 4 RC groups,
• RC is hydrogen, halogen, hydroxy, amino or an organic substituent group,
• PG is a nitrogen protecting group and (*) represents an asymmetric center,
• the process comprising initiating a reaction of a compound of Formula B
• with a compound of Formula C
• wherein W is a functional group that has leaving ability, in a water-immiscible organic phase in the presence of a bis-quaternary cinchona alkaloid salt and a base in an aqueous phase to form a biphasic medium comprising the aqueous phase and water-immiscible organic phase,
• wherein the bis-quaternary cinchona alkaloid salt has the chemical structure of Formula I
• wherein:
• R1 is selected from ethyl and vinyl,
• R2 is selected from hydrogen and methoxy,
• R3 and R4 are independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, heteroaryl, —C1-4alkyl-aryl and —C1-4alkyl-heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, heteroaryl and the aryl and heteroaryl portions of —C1-4alkyl-aryl and —C1-4alkyl-heteroaryl are optionally substituted with one to five substituents independently selected from R6,
• R5 is selected from the group consisting of hydrogen, C(O)R, C(O)OR, CONRR′, and C1-6alkyl,
• R6 is selected from the group consisting of C1-4alkyl, C1-4haloalkyl, aryl, C1-4alkoxy, hydroxy, CN, CO2R, CONRR′, SR, SO2R, SO3R, PR2, PO(OR)2, PO(OR)(NRR′), PO(NRR′)2, P(OR)2, P(OR)(NRR′), P(NRR′)2, SiRR′R″, B(OR)2, C(O)R, NRR′, NO2, and halogen,
• each R, R′ and R″ is independently selected from the group consisting of, H, C1-4alkyl, hydroxy and C1-4alkoxy, and
• each X and Y are independently anions selected from halide, OH, HSO4, SO4, BF4, SbF6, carboxylate, carbonate, hydrogencarbonate, NO3, sulfonate, hexafluorophosphate, phosphate, hydrogen phosphate, and perchlorate,

A bis-quaternary cinchona alkaloid salt having the chemical structure of Formula II:

• wherein:
• R1 is selected from ethyl and vinyl,
• R2 is selected from hydrogen and methoxy,
• Ar1 is aryl or heteroaryl, wherein said aryl and heteroaryl groups are optionally substituted with one to five substituents independently selected from R3,
• Ar2 is aryl or heteroaryl, wherein said aryl and heteroaryl groups are optionally substituted with one to five substituents independently selected from R3,
• each R3 is independently selected from the group consisting of C1-4 alkyl, C1-4haloalkyl, aryl, C1-4alkoxy, hydroxy, CN, C1-4acyl, N(R4)2, NO2, halogen, O-Phenyl and (C═O)OC1-4alkyl,
• each R4 is independently H or C1-4alkyl, and
• each X and Y are independently anions selected from halide, OH, HSO4, SO4, BF4, SbF6, carboxylate, carbonate, hydrogencarbonate, NO3, sulfonate, hexafluorophosphate, phosphate, hydrogen phosphate and perchlorate.