Catalytic Asymmetric Tandem Conjugate Addition-Electrophilic Halogenation Reaction

The Cu-catalyzed asymmetric conjugate addition of alkylzinc reagent toα,β-unsaturated compounds is a fundamental and important class of carbon-carbon bond-forming reactions in which monodentate phosphine ligands are found to be more reactive and efficient. And the use of heteroatom-based reagents as the terminal electrophile in the tandem conjugate addition-electrophilic trapping reactions remains a large challenge. In this work, Cu-catalyzed asymmetric conjugate addition of dialkylzincs to acyclic alkylideneβ-ketoesters and tandem conjugate addition- electrophilic halogenation reaction have been successfully realized using new BINOL-derived bulky phosphoramidite ligand.3,3’-Disubstituted binol phosphoramidite ligands were prepared from optically pure BINOL. By introducting the bulky groups directly at the 3,3’-positions of the binaphthol backbone, eleven axial chirality BINOL-derived phosphoramidite ligands were obtained.In the presence of 3,3’-Disubstituted binol phosphoramidite ligands, copper-catalyzed asymmetric conjugate addition of dialkylzincs to acyclic alkylideneβ-ketoesters afforded the corresponding chiralβ-ketoesters derivatives with two contiguous stereogenic centers in high yields and enantioselectivities (up to 98% ee) but with moderate to high diastereoselectivity (up to 32:1 dr).Subsequently, copper-catalyzed asymmetric tandem conjugate addition- electrophilic fluorination sequence has also been realized using BINOL-derived phosphoramidite ligands, and the“Long-Arm”effect of the ligands could significant influence the ee value. Under this strategy, the tandem fluorinated products, containing two adjacent carbon- and fluorine-substituted tertiary and quaternary stereocenters, are obtained in 72-91% yield with high diastereo- and enantioselectivity (up to 99:1 dr, 98% ee). Furthermore, the presence of theβ-ketoester moiety allows for access to optically enriched alcohols with three contiguous stereogenic centers, and the absolute configuration of the tandem fluorinated products are determined according to X-ray diffraction. The structures of the precatalytic copper complexes or the active catalytic species were discussed preliminary based on the results of 31P NMR、MS and DFT data.This asymmetric tandem protocol was also extended to the conjugate addition- electrophilic chlorination, a series of tandem chlorinated products were obtained in 71-85% yield with moderate to high diastereoselectivity (up to 99:1 dr) and 64-98% enantioselectivity. Further extending this protocol to catalytic tandem conjugate addition-electrophilic bromination is also proved to be feasible, affording the corresponding tandem brominated products with 71-91% yield, 76-98% ee values and moderate to high diastereoselectivity.