Nickel-Catalyzed Enantioselective Coupling Reactions of Fluorinated Sorbamides with Aldehydes Affording Anti -Configured β-Di(tri)fluoromethyl Alcohol Derivatives

High Resolution Image Download MS PowerPoint Slide A catalyst generated in situ from a bench-stable nickel stilbene complex and the axially chiral VAPOL-derived phosphoramidite ligand L1 is capable of affecting the asymmetric reductive coupling of aldehydes with 6,6-difluorosorbamide or 6,6,6-trifluorosorbamide derivatives and related fluorinated compounds using Et 3 B as the promoter. The ligand controls the regioselective course and imposes excellent levels of asymmetric induction onto the reaction that generates di(tri)fluoromethylated stereogenic centers concomitant with an adjacent secondary alcohol from the prochiral substrates. Because the resulting structural motif constitutes a fluorinated bioisostere of a common type of anti -configured deoxypropionate unit, the new method potentially qualifies for a “fluoride scan” of numerous bioactive (natural) products. A mechanistic study revealed that one cannot extrapolate from the nickel speciation in solution and/or accessible by crystallization to the actual site of the polarized 1,3-diene at which the reductive C–C-bond formation will take place. Moreover, the only detectable complex derived from the Ni(0) precatalyst, L1, and a trifluoromethylated sorbamide is off the catalytic cycle; it serves as a “reservoir”, as clearly manifested in the negative nonlinear effect ((−)-NLE) between the optical purity of L1 and that of the resulting product. A DFT study allowed these observations to be rationalized and a mechanism of the reaction to be proposed.