Catalytic Asymmetric Dihalogenation Of Alkenes And Alkynes

Halogen elements are prevalently present in natural products,bioactive molecules as well as pharmaceuticals.They also serve as flexible and practical functional groups for the synthesis of valuable chemical raw materials and drug intermediates.In many cases,halogens in these compounds are in the form of chiral carbon-halogen bonds.Asymmetric halo-functionalization/dihalogenation of alkenes has been widely recognized as one of the most straightforward and effective approaches to access the chiral halogenated compounds.Since the first report on asymmetric dichlorination of alkenes in 2011,a variety of efficient strategies have been established for the diversified dihalogenation of olefins in the last decade.These reactions have displayed unique advantages in the enantioselective construction of structurally diversified natural products.Nevertheless,most documented strategies are accompanied by significant limitations.For instance,each strategy is applicable to only one type of dihalogenation reaction;the substrate generality is fairly confined for most cases;the pursuit of high reaction efficiency and enantiocontrol remains a challenging task.Meanwhile,commonly used halogenation reagents are highly active and unstable,and alkali halides,as the most stable,abundant,and cheapest halogen reagents,are rarely utilized in organocatalytic asymmetric dihalogenation reactions due to their poor solubility in organic solvents and weak interaction with chiral catalysts.On the other hand,the extension of the asymmetric dihalogenation strategy to alkyne substrates has never been realized,although it offers a direct and efficient approach for the construction of axially chiral alkene scaffolds.This may be attributed to the lower reactivity of alkynes towards electrophilic addition as compared to corresponding alkenes and the poor instability of double bond involved in chiral three-member-ring halonium ion intermediates.Consequently,the development of a novel and universal strategy to realize the asymmetric and versatile dihalogenation of alkenes and alkynes with alkali halides is of great synthetic importance.It has been verified that urea and thiourea groups are able to form effective hydrogen bonds with diverse types of anions.In this thesis,a novel strategy for organocatalytic asymmetric versatile dihalogenation of alkenes and alkynes with alkali metal halides as the halogenation reagents was established,exploiting the unique interaction between a judiciously installed urea directing group on substrates and halogen anions.The main content of this thesis includes:The asymmetric chloro-bromination reaction of alkenes was first explored under the catalysis of cinchona base.N-Bromosuccinimide(NBS)was used as electrophile and lithium chloride(5-10 equiv.)was employed as nucleophile.Both E-and Z-alkenes were compatible with this set of reaction conditions to provide the desired vicinal bromochlorinated alkanes in high yields and stereoselectivity.Similar results could be obtained when the reaction was performed on a gram scale.The interaction between urea and chloride anion was demonstrated by ~1H NMR,HRMS and a series of control experiment s.A reasonable stereocontrol model was also proposed.Next,asymmetric dibromination of alkenes was accomplished with LiBr nucleophile.All the examined alkenes could be converted into ortho-dibrominated alkane products in good yields(>80%)with excellent stereoselectivities(>90%ee and dr>20:1).It should be noted that Na Br and KBr were also compatible for this reaction to give the products in competitive outcomes,which represents the first report for the application of these salts in organocatalytic asymmetric synthesis.In addition,KF could be used as a nucleophile in the asymmetric dihalogenation reaction to give the fluorobrominated alkanes with excellent stereocontrol,albeit with moderate yields.Meanwhile,all four possible stereoisomers could be accessed by tuning the configuration of olefin and the chirality of organocatalyst.Finally,this urea-directed asymmetric dihalogenation reaction was extended to alkyne substrates and both chloro-bromination and dibromination were efficiently achieved.The expected dihalogenated axially chiral styrenes were produced in up to 99%yield with up to 91%ee.The high efficiency and atroposelectivity were preserved for gram-scale synthesis.The urea group of generated dihalogenated products could be readily removed via photoredox catalysis to give the correspondinga,b-unsaturated aldehyde in a synthetic useful yield without erosion of the enantiopurity,further enhancing the practical utility of the developed strategy.