Enantioselective radical desymmetrization is a highly effective approach for rapidly creating enantioenriched molecules,introducing dramatically increased structural complexity from readily available prochiral or meso...Enantioselective radical desymmetrization is a highly effective approach for rapidly creating enantioenriched molecules,introducing dramatically increased structural complexity from readily available prochiral or meso compound feedstocks.Two strategic modes have been developed for these reactions,which differ in the nature of the stereo-determining steps.The first category deals primarily with the stereoselective desymmetrization of closed-shell radical precursors or functional reagents,whereas the second category achieves desymmetrization by stereoselectively functionalizing open-shell radical species.This mini-review explores the research progress in this growing field,aiming to elucidate mechanistic scenarios related to stereochemical control.Additionally,it offers insights into the challenges and opportunities that lie ahead for further development.展开更多
N-heterocyclic carbene-catalyzed enantioselective kinetic resolutions,dynamic kinetic resolutions,and desymmetrization reactions are systematically reviewed.The content is organized according to the activation modes i...N-heterocyclic carbene-catalyzed enantioselective kinetic resolutions,dynamic kinetic resolutions,and desymmetrization reactions are systematically reviewed.The content is organized according to the activation modes involved in these transformations.Future advances within this highly active research field are discussed from our perspectives on the topic.展开更多
Desymmetrization of prochiral 3-substituted glutaronitriles offers a new approach to access （S）-Pregabalin and （R）-Baclofen. A number of nitrilases from diverse sources were screened with 3-isobutylglutaronitriles...Desymmetrization of prochiral 3-substituted glutaronitriles offers a new approach to access （S）-Pregabalin and （R）-Baclofen. A number of nitrilases from diverse sources were screened with 3-isobutylglutaronitriles （1a） or 3-（4＇-chlorophenyl）glutaronitriles （1b） as the substrate. Some nitrilases were found to catalyze the desymmetric hydrolysis of la and lb to form optically active 3-（cyanomethyl）-5-methylhexanoic acid （2a） and 3-（4＇-chlorophenyl）-4-cyanobutanoic acid （2b） with high enantiomeric excesse （ee）, respectively. This cannot be achieved using traditional chemical hydrolysis. Among them, AtNIT3 generated （R）-2b whereas BjNIT6402 and HsN1T produced the opposite （S）-enantiomer with high conversions and ee values. Not only the nitrilases showed different activities and stereoselectivities toward these 3-substituted glutaronitriles, the 3-substitueut of the substrates also exerted great effect on the enzyme activity and stereoselectivity. （S）-2a and （S）-2b were prepared with high yields and ee values using BjNIT6402 and HsNIT as the biocatalysts, respectively. A straightforward Curtius rearrangement of （S）-2a and （S）-2b, followed by the acidic hydrolysis, afforded （S）-Pregabalin and （R）-Baclofen. This offers a new platform methodology for the synthesis of optically active β-substituted T-amino acids of pharmaceutical importance.展开更多
For the metal-catalyzed asymmetric hydrogenation of α-substituted ketones,cis reductive products are generally obtained due to steric hindrance of substituents.Herein,an unprecedented trans reductive products were ob...For the metal-catalyzed asymmetric hydrogenation of α-substituted ketones,cis reductive products are generally obtained due to steric hindrance of substituents.Herein,an unprecedented trans reductive products were observed in palladium-catalyzed hydrogenative desymmetrization of cyclic and acyclic 1,3-diketones,providing the chiral trans β-hydroxy ketones with two adjacent stereocenters including one α-tertiary or quaternary stereocenter with high enantioselectivity and diastereoselectivity.Mechanistic studies and DFT calculations suggested that the rarely observed diastereoselectivity reversal is ascribed to the charge-charge interaction between the palladium and aromatic ring of the substrate,which could not only result in the reversal of the diastereoselectivity,but also improve the reactivity.展开更多
Chiral BINAM-derived selenide/achiral acid co-catalyzed atroposelective electrophilic sulfenylation of pyrrole derivatives has been realized for the first time.A variety of C-N axially chiral sulfur-containing pyrrole...Chiral BINAM-derived selenide/achiral acid co-catalyzed atroposelective electrophilic sulfenylation of pyrrole derivatives has been realized for the first time.A variety of C-N axially chiral sulfur-containing pyrrole derivatives were readily obtained in moderate to good yields with moderate to excellent enantioselectivities.This catalytic system involves sequential desymmetrization and kinetic resolution.展开更多
A rhodium-catalyzed desymmetrization reaction for enantioselective methyl C-H arylation is achieved by utilizing an in situ arylating reagent via nucleophilic cyclization of o-aminoaryl alkyne.The reaction results in ...A rhodium-catalyzed desymmetrization reaction for enantioselective methyl C-H arylation is achieved by utilizing an in situ arylating reagent via nucleophilic cyclization of o-aminoaryl alkyne.The reaction results in chiral indoles containing all-carbon quaternary stereocenters under atmospheric conditions,with a wide range of substrates exhibiting good enantioselectivity(44 examples).Mechnism and DFT studies show that the stereocontrol is reasonably achieved through the collaborative control of a large silicon substituted chiral ligand and C-H···π,LP···πinteractions between aryl rings of the carboxylate group and the substrate.Control experiments demonstrate that Rh-aryl bond formation via in situ nucleophilic cyclization is more critical for reaction efficiency than via C-H activation of the nucleophilic cyclization byproduct.展开更多
A Ru-catalyzed hydrogenative desymmetrization of 2,2,5-trisubstituted cyclohexane-1,3-diones was developed for construction of three stereocenters including two coherent and discontiguous chiral centers and a chiral q...A Ru-catalyzed hydrogenative desymmetrization of 2,2,5-trisubstituted cyclohexane-1,3-diones was developed for construction of three stereocenters including two coherent and discontiguous chiral centers and a chiral quaternary carbon with excellent enantio-and diastereoselectivities.Stereodivergent synthesis of four stereoisomers could be conducted with high enantioselectivities.The desymmetrization could be achieved at gram scale without loss of reactivity and optical purity,and a formal synthesis of bioactive molecule(-)-isocelorbicol was completed.展开更多
Morpholines are widespread in many biologically and catalytically active agents,thus being an important aim of pharmaceutical and synthetic chemists.However,efficient strategies for the catalytic asymmetric synthesis ...Morpholines are widespread in many biologically and catalytically active agents,thus being an important aim of pharmaceutical and synthetic chemists.However,efficient strategies for the catalytic asymmetric synthesis of chiral morpholines bearing crowded stereogenic centers still remain elusive.Herein,we disclose a Cu-catalyzed asymmetric propargylic amination/desymmetrization strategy to help resolve this challenge.As a result,two kinds of structurally various chiral morpholines bearing rich functional groups and N-a-quaternary stereocenters were produced with high efficiency and selectivity(42 examples,up to91%yield,97:3 er and>19:1 dr).In addition,a series of transformations were performed to demonstrate the synthetic utility of this methodology.In particular,a hit compound for new antitumor drugs was identified through cellular evaluation.Furthermore,mechanistic investigations reveal that,hydrogen bonding in the key copper-allenylidene intermediate together withπ-πstacking aids remote enantioinduction.展开更多
α-Imino metal carbenes are versatile intermediates in organic synthesis,and have broad applications in the assembly of divergent N-heterocycles.However,the catalytic enantioselective desymmetrization based onα-imino...α-Imino metal carbenes are versatile intermediates in organic synthesis,and have broad applications in the assembly of divergent N-heterocycles.However,the catalytic enantioselective desymmetrization based onα-imino metal carbenes has not been developed to date.Herein,we disclose an enantioselective desymmetrizing C(sp^(2))-H functionalization of azide-ynamides viaα-imino copper carbenes,leading to the efficient assembly of divergent chiral indoloazepines in generally moderate to excellent yields with high enantioselectivities.Notably,this reaction represents the first enantioselective desymmetrization based onα-imino metal carbenes.Further synthetic transformations and biological tests show the potential utility of this method.Moreover,computational studies are employed to elucidate the reaction mechanism and the origin of enantioselectivity.展开更多
The central-to-axial chirality conversion represents a fascinating class of chemical processes consisting of the destruction of stereogenic centers and the simultaneous installation of axial chiral elements,which prov...The central-to-axial chirality conversion represents a fascinating class of chemical processes consisting of the destruction of stereogenic centers and the simultaneous installation of axial chiral elements,which provides efficient methods for the preparation of axially chiral compounds.However,developing catalytic asymmetric approaches for constructing these central chirality precursors and the efficient central-to-axial chirality conversion remains a challenge due to the requirement of aromatization or elimination process.In this work,we have developed an unprecedented enantioselective intramolecular FriedelCrafts alkylation with unactivated-ketone carbonyls from which a chiral tertiary alcohol was generated with high efficiency and excellent enantioselectivity.In addition,the central-to-axial chirality conversion strategy has been successfully applied to the synthesis of enantioenriched biaryls via a less-explored carbocation-initiated rearrangement and aromatization under the promotion of Lewis acid.This methodology provided a straightforward and sustainable access to a broad range of biaryl-2-carboxylic acid and in excellent yields(up to 92%)and excellent central-to-axial chirality conversion(up to 99%conversion percentage).This work could be a great model for developing new methods for synthesizing axially chiral biaryls and a general protocol for the rearrangement and aromatization of carbocations for further functionalization.展开更多
Desymmetrization reactions provide a powerful approach for the construction of complex molecules. Various methods have been developed for the selective monoprotection of symmetrical diols;however, their application to...Desymmetrization reactions provide a powerful approach for the construction of complex molecules. Various methods have been developed for the selective monoprotection of symmetrical diols;however, their application to large-scale operations is limited. In this study, the monotetrahydropyranylation of symmetrical diols in a flow reactor has been developed, whereby the length of the flow reactor tube and the amount of acid were optimized. A higher selectivity for the monoprotected derivative was observed when the reaction was performed in a flow reactor compared with that observed in a conventional batch experiment. The efficient flow method developed herein can be applied to large-scale synthesis by numbering up the flow reactor without affecting the selectivity and yield. Since monoprotection can be achieved without using a large excess of diol, our developed flow method is effective when expensive diol must be used.展开更多
Highly efficient synthesis of the entitled compound was achieved from a readily availablemyo-inositol derivative. The key step involved a desymmetrization with (+)-camphor dimethylketal to give two diastereomers. The ...Highly efficient synthesis of the entitled compound was achieved from a readily availablemyo-inositol derivative. The key step involved a desymmetrization with (+)-camphor dimethylketal to give two diastereomers. The two diastereomers could be used to synthesize the samecompound by changing the orders to introduce the protective groups.展开更多
AstereodivergentPd/Cucatalyst systemforasymmetric desymmetric alkylation of allylic geminal dicarboxylates has been developed,which was successfully applied to the asymmetric synthesis of β-hydroxycarbonylmotifs bear...AstereodivergentPd/Cucatalyst systemforasymmetric desymmetric alkylation of allylic geminal dicarboxylates has been developed,which was successfully applied to the asymmetric synthesis of β-hydroxycarbonylmotifs bearing a versatile carbon-carbon double bond in an enantio-and diastereodivergent manner.A wide scope of substrates including challenging alkylsubstituted,2-substituted,and3,3′-disubstitutedallylic species are compatible with this catalytic system,delivering the substituted products in high to excellent yieldsandwith excellent diastereo-(upto>20:1 dr)and enantioselectivities(up to>99%ee).Furthermore,the mechanism of this dual Pd/Cu catalytic system including:(1)the desymmetrization process ofgeminal dicarboxylates;(2)the origin of regioselectivity(branched or linear);(3)the enantio-and diastereoselectivity observed by changing the combinations of two chiral metal catalysts,have been carefully investigated by theoretical calculations.展开更多
基金Financial support from the National Natural Science Foundation of China (grant nos.22025103,92256301,21831002,22271133,22101122,and 22201127)the National Key R&D Program of China (grant nos.2021YFF0701604 and 2021YFF0701704)+1 种基金New Cornerstone Science Foundation through the XPLORER PRIZE,Shenzhen Science and Technology Program (grant nos.KQTD20210811090112004 and JCYJ20220818100600001)Shenzhen Key Laboratory of Cross-Coupling Reactions (grant no.ZDSYS20220328104200001).
文摘Enantioselective radical desymmetrization is a highly effective approach for rapidly creating enantioenriched molecules,introducing dramatically increased structural complexity from readily available prochiral or meso compound feedstocks.Two strategic modes have been developed for these reactions,which differ in the nature of the stereo-determining steps.The first category deals primarily with the stereoselective desymmetrization of closed-shell radical precursors or functional reagents,whereas the second category achieves desymmetrization by stereoselectively functionalizing open-shell radical species.This mini-review explores the research progress in this growing field,aiming to elucidate mechanistic scenarios related to stereochemical control.Additionally,it offers insights into the challenges and opportunities that lie ahead for further development.
基金supported by the National Natural Science Foundation of China (21961006,32172459,22371057)Science and Technology Department of Guizhou Province (Qiankehejichu-ZK[2021]Key033)+1 种基金Program of Introducing Talents of Discipline to Universities of China (111 Program,D20023) at Guizhou UniversityFrontiers Science Center for Asymmetric Synthesis and Medicinal Molecules,Department of Education,Guizhou Province (Qianjiaohe KY (2020)004),Guizhou University (China)。
文摘N-heterocyclic carbene-catalyzed enantioselective kinetic resolutions,dynamic kinetic resolutions,and desymmetrization reactions are systematically reviewed.The content is organized according to the activation modes involved in these transformations.Future advances within this highly active research field are discussed from our perspectives on the topic.
基金financially supported by the Chinese Academy of Sciences (KSZD-EW-Z-015)the CAS Agenda to Provide S&T Support and Services for the National Strategic Emerging Industries
文摘Desymmetrization of prochiral 3-substituted glutaronitriles offers a new approach to access （S）-Pregabalin and （R）-Baclofen. A number of nitrilases from diverse sources were screened with 3-isobutylglutaronitriles （1a） or 3-（4＇-chlorophenyl）glutaronitriles （1b） as the substrate. Some nitrilases were found to catalyze the desymmetric hydrolysis of la and lb to form optically active 3-（cyanomethyl）-5-methylhexanoic acid （2a） and 3-（4＇-chlorophenyl）-4-cyanobutanoic acid （2b） with high enantiomeric excesse （ee）, respectively. This cannot be achieved using traditional chemical hydrolysis. Among them, AtNIT3 generated （R）-2b whereas BjNIT6402 and HsN1T produced the opposite （S）-enantiomer with high conversions and ee values. Not only the nitrilases showed different activities and stereoselectivities toward these 3-substituted glutaronitriles, the 3-substitueut of the substrates also exerted great effect on the enzyme activity and stereoselectivity. （S）-2a and （S）-2b were prepared with high yields and ee values using BjNIT6402 and HsNIT as the biocatalysts, respectively. A straightforward Curtius rearrangement of （S）-2a and （S）-2b, followed by the acidic hydrolysis, afforded （S）-Pregabalin and （R）-Baclofen. This offers a new platform methodology for the synthesis of optically active β-substituted T-amino acids of pharmaceutical importance.
基金supported by the National Natural Science Foundation of China(21871255,21532006,21873096)Chinese Academy of Sciences(XDB17020300,XDB17010200)
文摘For the metal-catalyzed asymmetric hydrogenation of α-substituted ketones,cis reductive products are generally obtained due to steric hindrance of substituents.Herein,an unprecedented trans reductive products were observed in palladium-catalyzed hydrogenative desymmetrization of cyclic and acyclic 1,3-diketones,providing the chiral trans β-hydroxy ketones with two adjacent stereocenters including one α-tertiary or quaternary stereocenter with high enantioselectivity and diastereoselectivity.Mechanistic studies and DFT calculations suggested that the rarely observed diastereoselectivity reversal is ascribed to the charge-charge interaction between the palladium and aromatic ring of the substrate,which could not only result in the reversal of the diastereoselectivity,but also improve the reactivity.
基金Z.-M.Chen thanks National Natural Science Foundation of China(22071149,21871178)Natural Science Foundation of Shanghai(23ZR1428200)financial support.H.Ke thanks Natural Science Foundation of Jiangxi Province(20202ACBL213005)for financial support.
文摘Chiral BINAM-derived selenide/achiral acid co-catalyzed atroposelective electrophilic sulfenylation of pyrrole derivatives has been realized for the first time.A variety of C-N axially chiral sulfur-containing pyrrole derivatives were readily obtained in moderate to good yields with moderate to excellent enantioselectivities.This catalytic system involves sequential desymmetrization and kinetic resolution.
基金financial support for this work from the National Key R&D Program of China(No.2021YFC0864700)the National Natural Science Foundation of China(Nos.21801066,U1804283 and 82130103)+2 种基金the Central Plains Scholars and Scientists Studio Fund(No.2018002)the project funded by the Natural Science Foundation of Henan(Nos.222300420056,222300420204)the China Postdoctoral Science Foundation(Nos.2020M682307,2021T140183)。
文摘A rhodium-catalyzed desymmetrization reaction for enantioselective methyl C-H arylation is achieved by utilizing an in situ arylating reagent via nucleophilic cyclization of o-aminoaryl alkyne.The reaction results in chiral indoles containing all-carbon quaternary stereocenters under atmospheric conditions,with a wide range of substrates exhibiting good enantioselectivity(44 examples).Mechnism and DFT studies show that the stereocontrol is reasonably achieved through the collaborative control of a large silicon substituted chiral ligand and C-H···π,LP···πinteractions between aryl rings of the carboxylate group and the substrate.Control experiments demonstrate that Rh-aryl bond formation via in situ nucleophilic cyclization is more critical for reaction efficiency than via C-H activation of the nucleophilic cyclization byproduct.
基金the National Natural Science Foundation of China(21532006,21690074)Chinese Academy of Sciences(XDB17020300,SSW-SLH035)。
文摘A Ru-catalyzed hydrogenative desymmetrization of 2,2,5-trisubstituted cyclohexane-1,3-diones was developed for construction of three stereocenters including two coherent and discontiguous chiral centers and a chiral quaternary carbon with excellent enantio-and diastereoselectivities.Stereodivergent synthesis of four stereoisomers could be conducted with high enantioselectivities.The desymmetrization could be achieved at gram scale without loss of reactivity and optical purity,and a formal synthesis of bioactive molecule(-)-isocelorbicol was completed.
基金supported by the National Key R&D Program of China(2023YFE0110100)the National Natural Science Foundation of China(22271113,92256301,21822103,and 21820102003)。
文摘Morpholines are widespread in many biologically and catalytically active agents,thus being an important aim of pharmaceutical and synthetic chemists.However,efficient strategies for the catalytic asymmetric synthesis of chiral morpholines bearing crowded stereogenic centers still remain elusive.Herein,we disclose a Cu-catalyzed asymmetric propargylic amination/desymmetrization strategy to help resolve this challenge.As a result,two kinds of structurally various chiral morpholines bearing rich functional groups and N-a-quaternary stereocenters were produced with high efficiency and selectivity(42 examples,up to91%yield,97:3 er and>19:1 dr).In addition,a series of transformations were performed to demonstrate the synthetic utility of this methodology.In particular,a hit compound for new antitumor drugs was identified through cellular evaluation.Furthermore,mechanistic investigations reveal that,hydrogen bonding in the key copper-allenylidene intermediate together withπ-πstacking aids remote enantioinduction.
基金supported by the National Natural Science Foundation of China(22331004,22125108 and 22121001)the National Fund for Fostering Talents of Basic Science NFFTBS(J1310024)。
文摘α-Imino metal carbenes are versatile intermediates in organic synthesis,and have broad applications in the assembly of divergent N-heterocycles.However,the catalytic enantioselective desymmetrization based onα-imino metal carbenes has not been developed to date.Herein,we disclose an enantioselective desymmetrizing C(sp^(2))-H functionalization of azide-ynamides viaα-imino copper carbenes,leading to the efficient assembly of divergent chiral indoloazepines in generally moderate to excellent yields with high enantioselectivities.Notably,this reaction represents the first enantioselective desymmetrization based onα-imino metal carbenes.Further synthetic transformations and biological tests show the potential utility of this method.Moreover,computational studies are employed to elucidate the reaction mechanism and the origin of enantioselectivity.
基金supported by the National Natural Science Foundation of China(22022704,21977097,22271291),Chinese Academy of Sciences。
文摘The central-to-axial chirality conversion represents a fascinating class of chemical processes consisting of the destruction of stereogenic centers and the simultaneous installation of axial chiral elements,which provides efficient methods for the preparation of axially chiral compounds.However,developing catalytic asymmetric approaches for constructing these central chirality precursors and the efficient central-to-axial chirality conversion remains a challenge due to the requirement of aromatization or elimination process.In this work,we have developed an unprecedented enantioselective intramolecular FriedelCrafts alkylation with unactivated-ketone carbonyls from which a chiral tertiary alcohol was generated with high efficiency and excellent enantioselectivity.In addition,the central-to-axial chirality conversion strategy has been successfully applied to the synthesis of enantioenriched biaryls via a less-explored carbocation-initiated rearrangement and aromatization under the promotion of Lewis acid.This methodology provided a straightforward and sustainable access to a broad range of biaryl-2-carboxylic acid and in excellent yields(up to 92%)and excellent central-to-axial chirality conversion(up to 99%conversion percentage).This work could be a great model for developing new methods for synthesizing axially chiral biaryls and a general protocol for the rearrangement and aromatization of carbocations for further functionalization.
文摘Desymmetrization reactions provide a powerful approach for the construction of complex molecules. Various methods have been developed for the selective monoprotection of symmetrical diols;however, their application to large-scale operations is limited. In this study, the monotetrahydropyranylation of symmetrical diols in a flow reactor has been developed, whereby the length of the flow reactor tube and the amount of acid were optimized. A higher selectivity for the monoprotected derivative was observed when the reaction was performed in a flow reactor compared with that observed in a conventional batch experiment. The efficient flow method developed herein can be applied to large-scale synthesis by numbering up the flow reactor without affecting the selectivity and yield. Since monoprotection can be achieved without using a large excess of diol, our developed flow method is effective when expensive diol must be used.
文摘Highly efficient synthesis of the entitled compound was achieved from a readily availablemyo-inositol derivative. The key step involved a desymmetrization with (+)-camphor dimethylketal to give two diastereomers. The two diastereomers could be used to synthesize the samecompound by changing the orders to introduce the protective groups.
基金supported by the National Natural Science Foundation of China(nos.21620102003,21831005,21901158,and 21991112)the Shanghai Sailing Program(no.19YF1421900)+3 种基金Shanghai Municipal Education Commission(no.201701070002E00030)National Key R&D Program of China(no.2018YFE0126800)the Science and Technology Commission of Shanghai Municipality(no.19JC1430100)Zhiyuan Scholar Program(no.ZIRC2020-04).
文摘AstereodivergentPd/Cucatalyst systemforasymmetric desymmetric alkylation of allylic geminal dicarboxylates has been developed,which was successfully applied to the asymmetric synthesis of β-hydroxycarbonylmotifs bearing a versatile carbon-carbon double bond in an enantio-and diastereodivergent manner.A wide scope of substrates including challenging alkylsubstituted,2-substituted,and3,3′-disubstitutedallylic species are compatible with this catalytic system,delivering the substituted products in high to excellent yieldsandwith excellent diastereo-(upto>20:1 dr)and enantioselectivities(up to>99%ee).Furthermore,the mechanism of this dual Pd/Cu catalytic system including:(1)the desymmetrization process ofgeminal dicarboxylates;(2)the origin of regioselectivity(branched or linear);(3)the enantio-and diastereoselectivity observed by changing the combinations of two chiral metal catalysts,have been carefully investigated by theoretical calculations.
