Lithium-Mediated Asymmetric1,2-Addition Of3-En-1-ynes To Ketones And One-pot Robinson Annulation/Electrophilic Fluorination Reaction

Optically active propargyl alcohols are important and versatile building blocksfor the synthesis of a wide range of natural products, chiral drugs and functionalmaterials. Addition of metallated terminal alkynes to carbonyl compounds isconsidered as an effective route for the synthesis of chiral propargyl alcohols and hasgained considerable significance in recent years, but the nucleophiles are largelyrestricted to single acetylene in such reactions. Addition of functional terminalalkynes to carbonyl compounds to get the progargyl alcohols will have broadapplication prospects in the synthesis of organic molecules.In the first part, an efficient enantioselective1,2-addition of terminal3-en-1-ynesto ketones has been developed.3,3’-Disubstitued binol ligands were prepared andapplied in the addition of alkynyl lithium to ketones. Variations of reaction parameters(ligands, solvent, temperature, additive and catalyst loading) were investigated. Weexplored the scope of this alkynylation reaction by varying the terminal3-en-1-ynesand the ketones. The corresponding chiral tertiary propargylic alcohols weresynthesized in80–98%yields with70–93%ee. The absolute configuration of oneproduct was determined to be R by the X-ray diffraction. Additionally, we obtainedthe Pauson-Khand cycloaddtion product in68%yield without detectable loss ofenantioselectivity. Efavirenz analogues were synthesized via simple transformationsfrom1-(5-chloro-2-nitrophenyl)-2,2,2-trifluoroethanone.The application of organofluorine compounds has received extensive attention inthe area of pharmaceutical industry, agrochemistry and materials science due to theirunique chemical, physical and biologiacal properties. Application of the tandemreactions for the construction of organofluorine molecules are still in great demand. Inthe second part, we developed a base-mediated one-pot reaction of β-ketoesters withα,β-unsaturated ketones and N-fluoro-N-(phenylsulfonyl) benzenesulfonamide (NFSI)via Robinson annulations/electrophilic fluorination sequence. By using this process, aseries of fluorinated cyclohexenone derivatives with a tetrasubstituted carbonstereocenter were obtained in71–99%yields with excellent diastereoselectivity (dr upto99/1) under mild conditions.