Catalytic Asymmetric Construction Of C-P Bonds And Applications To Synthesis Of Unnatural Amino Acids

Peptide drugs have been increasingly used in clinical treatment of various diseases in the past 20 years, and there are at least 100 species of marketed peptide drugs and more than 600 species in the clinical research stage. An important factor restricting the development of peptide drugs is the instability of peptide drugs. Peptide drugs containing unnatural acids are generally more stable towards proteolysis, and in some cases substituting the natural amino acids with the unnatural amino acid result in improved activity. In view of this, catalytic asymmetric synthesis of a variety of non-natural amino acids is very important to the development of peptide drugs.This dissertation includes seven chapters. The first chapter reviewed the recent developments in metal catalyzed asymmetric addition of phosphorus nucleophiles. In the second section, we achieved highly enantioselective 1,4-addition of dialkyl phosphites to α,β-unsaturated carbonyl compounds and imines using a dinuclear Zn catalyst. The third part is the research of dialkyl phosphine oxides. By using the dinuclear Zn/pyridine system, dialkyl phosphine oxides were introduced in catalytic asymmetric transformations for the first time and the phospha-Michael reaction of dialkyl phosphine oxide with various a,P-unsaturated compounds was disclosed. The fourth part is about highly efficient asymmetric Michael addition of diaryl phosphine oxides to bidentate α,β-unsaturated N-acylated oxazolidin-2-ones. In the fifth chapter, we have identified N-acyl pyrrole phosphonates as a class of highly reactive nucleophiles, and achieved the asymmetric addition of the present HWE reagent to imines and the corresponding Mannich adducts were further transformed to aryl substituted aza-MBH products, in which access to both E/Z isomers is achieved by a switch in the base source. In the following part, a highly diastereo- and enantioselective asymmetric Mannich reaction of 5H-oxazol-4-ones was achieved, which led to the first catalytic asymmetric synthesis of syn-a-alkyl-norstatine derivatives by using diethyl phosphoramidates as the additive. The last section is the summary of each chapter in this dissertation.This dissertation is focused on catalytic asymmetric building of unnatural amino acids with the participation of organophosphorus reagents. Through the study in the first few chapters, we achieved the catalytic asymmetric synthesis of a series of amino phosphonic acids. The last two chapters are about catalytic asymmetric construction of two types of challenging unnatural β-amino acids.