Copper Catalyzed Radical Asymmetric Reaction Of Terminal Alkyne

Chiral alkynes are not only important structural motifs in a myriad of natural products and drugs,but also valuable synthons in organic chemistry.Therefore,great efforts have been made toward their synthesis in the past few decades,such as the diastereoselective transformation of a chiral source,asymmetric nucleophilic addition of alkyne to ketones or imines,hydroalkynylation of alkenes,etc.However,the catalytic asymmetric radical transformation for the synthesis of chiral alkynes has been less developed even though radical reactions have inherently unique advantages,such as the high reactivity,good functional group tolerance,and less sensitivity towards steric crowdness.Therefore,the development of novel catalytic system to realize a series of the asymmetric radical alkynylations for the expedient assembly of chiral alkynes from diverse readily available feedstocks is highly desirable.The rational design of novel chiral anionic ligands to achieve the copper-catalyzedasymmetric radical transformations would be one promising strategy.The purpose of this thesis is to develop novel chiral anionic ligands to tune the reducing capability of copper catalyst,therefore initiating the radical reactions of easily available feedstocks with alkynes.Meanwhile,the designed chiral ligands would coordinate strongly with the copper acetylide species to provide an ideal chiral environment for the efficient stereocontrol over the highly reactive prochiral radical intermediates.To this end,a chiral cinchona-derived N,N,P-ligand has been designed and synthesized for the first time.The combination of this ligand with copper catalysis has been utilized to realize a number of asymmetric radical reactions of alkynes,delivering a wide range of chiral alkynes.With this strategy,the easily available racemic alkyl halides have been firstly utilizedas the radical precursors to react with terminal alkynes.Thus,a general copper-catalyzed asymmetric radical Sonogashira C(sp~3)-C(sp)cross-coupling reaction has been successfully developed.More than 120 examples of chiral alkynes have been constructed with high yield and high enantioselectivity(up to 99%).The reaction features a broad substrate scope,covering benzyl,allyl,propargyl,?-carbonyl,and?-cyanide substituted alkyl bromides and chlorides,as well as(hetero)aryl,alkyl,and silyl alkynes.More importantly,the industrial relevant acetylene and propyne are successfully accommodated.The potential utility of this method is further demonstrated in the synthesis of chiral bioactive molecules,medicinal compounds,and natural products,etc.Following the similar concept,a photoinduced copper-catalyzed asymmetric radical decarboxylative alkynylation cross-coupling reaction of racemic alkyl carboxylic acid derivatives and asymmetric oxidative cross-coupling of unactivated C(sp~3)-H bonds with terminal alkyne have been developed,respectively.Second,a copper-catalyzed intermolecular three-component asymmetric radical 1,2-carboalkynylation of alkenes has also been successfully developed with this catalytic system,providing straightforward access to chiral alkynes from readily available alkyl halides,alkenes,and terminal alkynes.The yield and ee of the products could be up 99%and 98%,respectively.The utilization of a cinchona alkaloid-derived multidentate N,N,P-ligand is crucial for the efficient radical generation from mildly diverse oxidative precursors by copper and the effective inhibition of the undesired Glaser coupling side reaction.The substrate scope is broad,covering(hetero)aryl-,alkynyl-,and aminocarbonyl-substituted alkenes,(hetero)aryl and alkyl as well as silyl alkynes,and tertiary to primary alkyl radical precursors with excellent functional group compatibility.Facile transformations of the obtained chiral alkynes have also been demonstrated,highlighting the excellent complementarity of this protocol to direct 1,2-dicarbofunctionalization reactions with C(sp~2/sp~3)-based reagents.In the end,a copper-catalyzed asymmetric radical 1,4-carboalkynylation of 1,3-enynes via the coupling of allenyl radicals with terminal alkynes has also been successfully developed with this catalytic system,providing diverse synthetically challenging tetrasubstituted chiral allenes.The enantiocontrol over the allenyl radicals is more challenging than the alkyl radicals due to the unique elongated linear configuration of the allenyl radicals that necessitates the stereo-differentiation of remote motifs away from the radical reaction site.A chiral N,N,P-ligand is crucial for both the reaction initiation and the enantiocontrol over the highly reactive allenyl radicals.More than 60 examples of tetrasubstituted chiral allenes could be constructed,and the yield and ee could be up to98%.The reaction features a broad substrate scope,covering a variety of(hetero)aryl and alkyl alkynes and 1,3-enynes as well as radical precursors with excellent functional group tolerance.In summary,we have developed a novel Cu(I)/chiral anionic ligand catalytic systemby designing a multidentate N,N,P-ligand based on cinchona alkaloid skeleton.This catalytic system has been used in several asymmetric radical reactions,such as the Sonogashira coupling with alkyl halides,1,2-carboalkynylation of alkenes,and the 1,4-carboalkynylation of 1,3-enynes,providing diverse chiral alkynes with excellent enantioselectivity.These strategies may find potent applications in organic synthesis,medicinal chemistry,as well as the industrial synthesis.It will further open the door for the development of more asymmetric radical reactions.