Asymmetric Construction And Application Of Nonnatural Amino Acids By Organocatalysis

More and more peptide and protein drugs are used in clinical treatment,helding a growing 10% of the pharmaceutical market share,with drug pipeline success rates twice that of small molecule drugs.The key factors restricting the development of peptide drugs are structural instability,poor membrane penetration and oral availability.The replacement of non-natural amino acids and modification of peptides can improve the stability,bioavailability generally and pharmacological effects in some cases for peptide drugs,thereby increasing the drug properties of polypeptide molecules.On the other hand,non-natural amino acid molecules are also important bioactive substances or drug molecules.Therefore,the realization of high stereoselectivity synthesis of diverse non-natural amino acids and the modification of peptides by asymmetric catalysis are of great significance for the development of innovative drugs.In the past two decades,asymmetric organocatalysis has become one of the most fruitful research fields in organic chemistry because of its non-toxicity,easy operation,mild reaction conditions and wide application.Herein,asymmetric organocatalysis is used to achieve the asymmetric synthesis of two types of unnatural amino acid derivatives and asymmetric specific modification of tryptophan based on indole chemistry and stereoselective reaction by asymmetric organocatalysis.It is hoped that this study will provide useful chemical entities for drug discovery based on amino acid and polypeptide molecules.The dissertation includes five chapters.The first chapter reviewed the non-natural amino acids including the strategies of asymmetric synthesis and modification of amino acids.From chapter 2 to chapter 4,we have carried out three studies on the asymmetric synthesis and modification of amino acids.First of all,we have developed a chiral thiourea-catalyzed asymmetric Michael addition reaction of oxazolone with dehydroalanine,and achieved asymmetric construction of diaminodiacid derivatives with high stereoselectivity and enantioselectivity.The reaction can be used to synthesize chiral diaminodiol compounds and ?-lactam compounds.Then we studied the asymmetric dearomatization reaction of 2,3-disubstituted indoles with ?,?-alkynyl-?-imino ester.Under mild conditions,only a simple one-step reaction can provide an efficient and facile approach for the construction of ?-amino acid esters with axially chiral tetrasubstituted allenes.And the reaction has excellent regioselectivity,diastereoselective and enantioselectivity.It is also possible to synthesize a diaminodiacid compound and an amino acid derivative having an active molecular skeleton structure by using the reaction.Furthermore,we have found that products of different configurations can be obtained using different phosphoric acid catalysts.Finally,we have achieved the reaction of asymmetric alkylation with the N1-and C2-positions of a 3-substituted indole by changing the reaction conditions.And it can also be used to specific modification for tryptophan and oligopeptide molecules containing tryptophan.The fifth chapter is the summary of each chapter and prospect.