Acetylation And Propargylation Of Thioxazolidone And Oxazolidone To Construct Chiral α,α-Disubstituted Amino Acid Precursors

α,α-Disubstituted amino acids and their derivatives have important research value in bioorganic chemistry and pharmaceutical chemistry,and play an important role in the development of peptides and the inhibition of enzyme activity.Because of the existence of quaternary chiral centers,they have better conformation and metabolic stability than natural α-amino acids,so it is of great significance to synthesize asymmetrically α,α-disubstituted amino acids containing quaternary chiral centers.In this paper,amino acid derived 4-benzyl-2-phenyl-2-thioxazole-5 ketone(thioxazolone for short)and 4-benzyl-2-phenyl-2-oxazole-5 ketone(oxazolone for short)substrates were used as nucleophiles,which is centered on the construction ofα,α-disubstituted amino acid precursors,including two parts of the research content.Part 1: Asymmetric alkynylation reaction of thioxazolidone or oxazolidone substrate with 1-(2-aryl acetylene)-1,2-benzoiodoxycyclopentane-3(1H)-ketone substrate(ArEBX)catalyzed by salt phase transfer of chiral quaternary phosphonium.The second part: Cu-Pybox catalyzed the asymmetric propyl acetylation of thioxazolone and oxazolone substrates.In the first part of the study,quaternary phosphonium salt was used as catalyst to research the asymmetric alkynylation of thioxazolone with oxazolone substrates.First,by screening different catalysts,solvents,bases and temperatures,we determined the optimal conditions for the alkynylation reaction of thioxazolone and oxazolone substrates.Then,we studied the suitability of the reaction substrate,and the results showed that most of our alkynylated products were obtained with good yield and enantioselectivity by changing the substituents on thioxazolidone or oxazolidone.Next,we explored the applicability of Ar-EBX substrates.When the para-position or metaposition of the benzene ring connected to the acetylene group is connected with the electron-withdrawing group or electron-donating group,the yield and enantioselectivity can also be maintained roughly.The absolute configuration of product 4ah was confirmed by single crystal X-Ray diffraction.For the stereoselectivity of this reaction,we propose a possible transition state model to predict the chiral induction process.At the same time,in order to reflect the potential application value of our work,the alkynylated products were ring-opened by benzylamine and methanol to obtain the corresponding α,α-dissubstituted amino acid derivatives.The reaction yield was very high and the optical purity remained unchanged.In the second part of the study,we used Cu-Pybox complex as catalyst to research the asymmetric propargyl reaction between thioxazolone and oxazolone substrates.We first compared the propargyl reactions of thioxazolone and thioxazolone substrates,and found that only the asymmetric propargyl reactions of thioxazolone could be carried out normally.Then we screened the solvents,copper salts,ligands and bases for the propargyl reaction of thioxazolidone,and finally obtained the propargyl product of thioxazolidone with good yield,enantioselectivity and diastereoselectivity.The asymmetric propargyl of thioxazolidone still needs to be further optimized.