Optimization of a Resolution Process Allowing Access to Both Enantiomers of the Versatile Chiral Phosphine Ligand...

Broadly effective, chiral monodentate phosphine ligands in asymmetric catalysis are relatively rare. sSPhos is a versatile, axially chiral phosphine that is capable of inducing high levels of enantioselectivity in a number of palladium-catalyzed transformations, including atroposelective Suzuki-Miyaura cross-coupling, arylative dearomatization, and carboetherification reactions. We have previously reported the chiral resolution of sSPhos by salt formation with quinidine, permitting the isolation of the (R) enantiomer. That process possessed several limitations, including relatively small scale, inability to access the (S) enantiomer, the requirement to presynthesize a trifluoroacetate salt of the dihydroquinine, and a maximum ee of 98% of (R)-sSPhos. In this work, we report further optimization and development of that procedure to permit it to be performed on a large scale. This simplified process permits the protonated, zwitterionic form of (R)-sSPhos to be obtained in >99% ee and (S)-sSPhos in 98% ee. The new modified procedure includes a resolution of racemic sSPhos by crystallization and was demonstrated on an 80 g scale to give access to both enantiomers of sSPhos in high ee and good yield. It is notable that the (S)-sSPhos enantiomer had previously been available only through preparative separation. We anticipate that this will assist in the incorporation of sSPhos as a chiral ligand in screening libraries and facilitate industrial application.