Nickle-catalyzed Asymmetric Reductive Cyclization To Construct Chiral Tertiary Alcohols And Development And Application Of N-halamine Hydrogel

Chiral tertiary alcohol are important structures in organic synthesis.Alicyclic and heterocyclic compounds(pyrrolidine,indole,tetrahydrofuran)containing chiral tertiary alcohol are also widely present in some natural products and chiral drugs.A pyrrolidine skeleton containing a chiral tertiary alcohol is present in the HIV inhibitor nifevirol.Therefore,how to construct the chiral tertiary alcohol structure efficiently has always been one of the hot research directions in the field of organic synthesis,and it is also a research significance and challenging topic.The use of transition metal catalyzed coupling is one of the most practical methods to construct C-C bonds.In the past half century,the application of palladium catalysts has been unprecedentedly developed.Nickel as the element directly above palladium in the periodic table,has many of the same chemical reactivity and selectivity as palladium.At the same time,nickel element has a smaller atomic radius and may show more excellent reactivity in some reactions.In terms of industrial applications,palladium catalysts are difficult to be applied to industrial production on a large scale due to their high price and global reserves.Compared with palladium catalysts,nickel catalysts' low price and abundant earth reserves make it have broader application prospects in the future.In this paper,we are focusing on how to construct various structures containing chiral tertiary alcohol,such as: pyrrolidine,cyclopentane,tetrahydrofuran,etc.Finally,we successfully developed three nickel-catalyzed highly enantioselective intramolecular reductive cyclizations of alkynone,which efficiently realized the construction of chiral tertiary alcohol and the synthesis of a series of chiral aliphatic and heterocyclic derivatives.At the same time,the reaction mechanism was discussed in depth.This paper can be divided into the following parts:In the first part,based on previous studies,we have successfully achieved nickel-catalyzed intramolecular reductive cyclization of highly enantioselective alkynone compounds by using large-sterically hindered electron-rich monophosphine ligands.This reaction has a strong substrate universality.We have constructed a series of pyrrolidine derivatives containing chiral tertiary alcohol structures with excellent yields and 99:1er enantioselectivity.We also used React IR to supplement the mechanism proposed by the predecessors.The successful preparation of the gram-level reaction also indirectly proves the practicality of the reaction.In the second part,in order to more perfect the breadth and depth of this kind of reaction,we tried to develop a methodology for constructing chiral aliphatic ring structures.Finally,the chiral monophosphine ligand(S)-BIDIME was used to successfully construct cyclopentane containing chiral tertiary silyl ether structure,and the absolute configuration of the product was determined by the single crystal data.This method has excellent reactivity,enantioselectivity and substrate universality.In order to understand the reaction mechanism,the reaction mechanism was deeply explored through React IR and computational chemistry.In the third part,after completing the above two types of reactions,we think about how to make the reaction more perfect.Based on the previous literature,we have developed a nickel-catalyzed asymmetric tandem cyclization reaction to construct a chiral tertiary alcohol heterocyclic reaction containing tetra-substituted olefins.Compared with the previous reaction,the aryl substitution on the olefin can be realized while completing the construction of the tertiary alcohol.The choice of different aryl boronic acid reagents can greatly expand the breadth of the reaction.Finally,we successfully constructed a series of chiral pyrrolidines and tetrahydrofurans containing tetra-substituted olefins using N-heteroacetylenone and O-heteroacetylenone substrates.In the fourth part:Hydrogel can provide a high-quality moist environment for wounds due to its excellent water absorption,promote wound healing and less scars.However,the preparation of hydrogels with antibacterial activity often involves a complicated synthesis process,which greatly increases the cost of preparation.In this paper,we use cheap sodium hyaluronate to carry out a one-step N-halogenation reaction and successfully obtain a new type of N-halamine-based hydrogel NCHA.The stability test and multiple scale experiments show that it has the basic conditions for industrial production.At the same time,through systematic biological evaluation,it is proved that the hydrogel has excellent antibacterial activity and biocompatibility.The use of animal model experiments fully proved its potential for future applications in the field of biomedicine.In summary,reactions reported in this paper contributes to the methodological field of constructing chiral tertiary alcohol.Compared with traditional methods,the method in this paper fully reflects the advantages of this methodology due to its excellent yield and enantioselectivity.At the same time,the use of cheap metal nickel catalysts greatly increases the possibility of future industrial applications of the reaction methodology.