Organocatalyzed Divergent Synthesis Chiral Lactams And Esters Derivatives

Chiral molecules play an important role in life evolution and production due to their special structure and properties.Facing of increasing demand for complex chiral molecules,the synthesis of them with high efficiency and low cost has become a tough problem deserve deep researching.In this thesis,focusing on the efficient construction of complex chiral molecules,using organocatalysis as a tool and divergent synthesis as a strategy,the organotatalyzed efficient synthesis of lactams and esters bearing multichiral centers were studided.We realized the chemical divergent synthesis of chiral lactams and amino acid ester derivatives,and developed the method of stereodivergent synthesis of δ-lactam diastereomers bearing two chiral centers.In addition,the synthesis of chiral medium-ring lactone compounds was also explored.Chapter 1: The background of organocatalytic divergent synthesis reactions and the establishment of the research content of the thesis.The introduction of this chapter discusses the challenges and tasks faced by synthetic chemistry from the perspective of the relationship between chiral molecules and the development of human society.It leads to the concept of “green and sustainable chemistry”,and then puts forward the strategy of “organocatalytic divergent synthesis” to constructing chiral molecules efficiently.Next,the development and representative work of organocatalysis are briefly described,the definition and classification of divergent synthesis are introduced,and the representative examples of chemical divergent and stereodivergent synthesis reactions which catalyzed by organocatalysis in recent years are mainly reviewed.Finally,through the investigation,comparison,and summary of the literature,combined with the advantages of organocatalysis and divergent synthesis,based on the efficient,green,and sustainable chiral molecular construction method,we established the content of this thesis.Chapter 2: Solvent-directed chemical divergent synthesis of chiral β-lactam and amino acid ester derivatives.β-Lactams and amino acid derivatives play an irreplaceable role in life activities.They are not only the basic molecules of proteins but also the basic skeleton of many drugs.Therefore,it is necessary to develop efficient synthesis methods for such molecules.We designed that the chiral nucleophile obtained by organocatalysis will perform a one-step stereospecific addition to the imine to form a key chiral intermediate.Next,under different solvent conditions,this intermediate undergoes intramolecular reaction or solvent-involved intermolecular reaction to regenerate the chiral catalyst and afford different target products.At last,solventdirected chemical divergent synthesis of different chiral target molecules was achieved.Chapter 3: Stereodivergent synthesis has always been a challenging topic in asymmetric synthesis.The current stereodivergent synthesis is mainly achieved through a synergistic catalytic strategy.In this strategy,two chiral active species activate two substrates independently to generate two chiral intermediates.The synthesis of four diastereoisomers can be achieved by the combination of two chiral catalysts or ligands.We designed a new strategy to achieve the complete synthesis of four diastereoisomers of δ-lactam with two consecutive chiral centers: the highly stereoselective kinetic product was first obtained under the activation of a bifunctional organocatalyst,then the kinetic product underwent the base-mediated epimerization to obtain the more stable thermodynamically product.The relationship between kinetic products and thermodynamic products is diastereoisomer.We only need to use another catalyst with the opposite configuration to synthesize the other two isomers.Compared with the traditional synergistic catalysis,this strategy can realize the stereodivergent synthesis by using only one chiral catalyst,which is simple and efficient.Chapter 4: Synthesis of medium-ring lactone compounds bearing two continuous chiral centers.The construction of medium-and macro-ring compound skeletons has always been a difficulty due to the adverse entropy effect,and the synthesis of mediumrings with multiple chiral centers is a challenge.Based on the work in the third chapter,we used the cyclobutanone ester with high tension as the C4 synthon,and selected theα,β-unsaturated carbonyl compound as another 4-atom synthon.Under the catalysis of bifunctional organocatalyst,the high-efficiency synthesis of 8-membered medium-ring chiral lactone derivatives was achieved.Chapter 5: The summary and outlook were conducted to this thesis as well as to asymmetric organocatalysis.