Chiral silyl ethers and silanols are important synthetic intermediates and bioactive compounds.In this work,we developed a onepot remote desymmetrization/Peterson-olefination of silacyclopentene oxides with benzoic ac...Chiral silyl ethers and silanols are important synthetic intermediates and bioactive compounds.In this work,we developed a onepot remote desymmetrization/Peterson-olefination of silacyclopentene oxides with benzoic acids in the presence of Martin’s sulfurane.This new methodology not only realizes the atom-economy of Peterson olefination,but also represents a catalytic method for synthesis of silicon-stereogenic silyl ethers.Using a bulky chiral phosphoric acid 4i as organocatalyst,the reactions proceeded efficiently to afford various olefin-functionalized organosilyl ethers in excellent diastereoelectivities(up to 25/1 d.r.)and high enantioselectivities(up to 94%ee).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(1a) o...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 1a and 1b 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 HsNIT 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-substituent 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 γ-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
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
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
Atropisomeric anilides are one of important C-N axially chiral compounds.Compared with the A/-terminal functionalization to prepare such compounds,C-terminal functionalization strategies have been rarely reported.We d...Atropisomeric anilides are one of important C-N axially chiral compounds.Compared with the A/-terminal functionalization to prepare such compounds,C-terminal functionalization strategies have been rarely reported.We describe herein an efficient synthesis of axially chiral anilides enabled by Pd-catalyzed desymmetric Sonogashira cross-coupling reactions with the use of a newly identified Ming-Phos.Moderate to high yields with high enantioselectivities(up to 98%ee)were obtained.展开更多
Densely functionalized chiral nitrogen-containing heterocycles are ubiquitous in bioactive synthetic compounds and natural products.Herein,we report a nickel(Ni)-catalyzed enantioselective desymmetrizing aza-Heck cycl...Densely functionalized chiral nitrogen-containing heterocycles are ubiquitous in bioactive synthetic compounds and natural products.Herein,we report a nickel(Ni)-catalyzed enantioselective desymmetrizing aza-Heck cyclization of oxime esters with a commercially available chiral pyridinebis(oxazoline)(pybox)ligand.This reaction proceeds under mild reaction conditions,tolerates various functional groups,and leads to chiral 2-substituted-3,7a-dihydro-3aH-indoles.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
The precise control of multiple chiral elements through a single step catalytic process remains a significant challenge in asymmetric catalysis.Reported herein is rhodium-catalyzed three-component asymmetric carboamid...The precise control of multiple chiral elements through a single step catalytic process remains a significant challenge in asymmetric catalysis.Reported herein is rhodium-catalyzed three-component asymmetric carboamidation between aryl boronic acid,achiral strain-activated symmetric bicyclic olefins bearing a prochiral C-N or N-N axis,and dioxazolones.The reaction proceeded effectively in excellent enantio-and diastereoselectivity under mild conditions to produce the bicyclic framework with six contiguous chiral centers as well as a N-N or C-N chiral axis.The reaction featured excellent functional group tolerance,chemoselectivity,and stereoselectivity.Mechanistic studies indicated that the coupling system proceeded via initial transmetalation,followed by stereo-determining migratory insertion into the olefin and electrophilic amidation.展开更多
基金supported by the National Natural Science Foundation of China(22271276,21871254,21702203)the National Key Research and Development Program of China(2022YFC2105900)。
文摘Chiral silyl ethers and silanols are important synthetic intermediates and bioactive compounds.In this work,we developed a onepot remote desymmetrization/Peterson-olefination of silacyclopentene oxides with benzoic acids in the presence of Martin’s sulfurane.This new methodology not only realizes the atom-economy of Peterson olefination,but also represents a catalytic method for synthesis of silicon-stereogenic silyl ethers.Using a bulky chiral phosphoric acid 4i as organocatalyst,the reactions proceeded efficiently to afford various olefin-functionalized organosilyl ethers in excellent diastereoelectivities(up to 25/1 d.r.)and high enantioselectivities(up to 94%ee).
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 1a and 1b 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 HsNIT 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-substituent 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 γ-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.
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.
基金the funding support of NSFC(Nos.22031004,21921003,21901043)Shanghai Municipal Education Commission(No.20212308).
文摘Atropisomeric anilides are one of important C-N axially chiral compounds.Compared with the A/-terminal functionalization to prepare such compounds,C-terminal functionalization strategies have been rarely reported.We describe herein an efficient synthesis of axially chiral anilides enabled by Pd-catalyzed desymmetric Sonogashira cross-coupling reactions with the use of a newly identified Ming-Phos.Moderate to high yields with high enantioselectivities(up to 98%ee)were obtained.
基金The authors are grateful for financial support from the Chinese Academy of Science(grant no.XDB20020000)the National Natural Science Foundation of China(no.21933004)+2 种基金the Shenzhen STIC(nos.JCYJ20170412150507046 and JCYJ20170412150343516)the Shenzhen San-Ming Project(no.SZSM201809085)fellowship from the International Postdoctoral Exchange Fellowship Program(no.2020014 to H.C.Shen).
文摘Densely functionalized chiral nitrogen-containing heterocycles are ubiquitous in bioactive synthetic compounds and natural products.Herein,we report a nickel(Ni)-catalyzed enantioselective desymmetrizing aza-Heck cyclization of oxime esters with a commercially available chiral pyridinebis(oxazoline)(pybox)ligand.This reaction proceeds under mild reaction conditions,tolerates various functional groups,and leads to chiral 2-substituted-3,7a-dihydro-3aH-indoles.
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.
基金supported by the National Natural Science Foundation of China(21525208)the Fundamental Research Funds for the Central Universities(2020CSLZ005,GK202103031)
文摘The precise control of multiple chiral elements through a single step catalytic process remains a significant challenge in asymmetric catalysis.Reported herein is rhodium-catalyzed three-component asymmetric carboamidation between aryl boronic acid,achiral strain-activated symmetric bicyclic olefins bearing a prochiral C-N or N-N axis,and dioxazolones.The reaction proceeded effectively in excellent enantio-and diastereoselectivity under mild conditions to produce the bicyclic framework with six contiguous chiral centers as well as a N-N or C-N chiral axis.The reaction featured excellent functional group tolerance,chemoselectivity,and stereoselectivity.Mechanistic studies indicated that the coupling system proceeded via initial transmetalation,followed by stereo-determining migratory insertion into the olefin and electrophilic amidation.
