An N-heterocyclic carbene(NHC)-catalysed retro-aldol/aldol cascade reaction of spirooxindole-basedβ-hydroxyaldehyde has been developed.The ring opening-closure process enables the diastereodivergent synthesis of spir...An N-heterocyclic carbene(NHC)-catalysed retro-aldol/aldol cascade reaction of spirooxindole-basedβ-hydroxyaldehyde has been developed.The ring opening-closure process enables the diastereodivergent synthesis of spirocyclopentaneoxindole products with four consecutive stereocenters by simply changing the reaction solvents(THF or DCE).The Michael/aldol/retro-aldol/aldol sequential protocol allows the diastereodivergent synthesis of spirocyclopentaneoxindoles from 3-substituted oxindole andα,β-unsaturated aldehyde under the relay catalysis of a chiral secondary amine and an NHC catalyst.Moreover,four stereoisomers of the product can be selectively provided by using different combinations of a chiral secondary amine and a solvent.展开更多
A rapid, one-pot and highly efficient protocol for the synthesis of pharmaceutically interesting functionalized 2-amino-3-cyano-4H-pyran and spirooxindole derivatives has been developed using commercially available Cs...A rapid, one-pot and highly efficient protocol for the synthesis of pharmaceutically interesting functionalized 2-amino-3-cyano-4H-pyran and spirooxindole derivatives has been developed using commercially available Cs F as a catalyst in the reaction of malononitrile and aryl aldehydes or isatins with 1,3-cyclohexanediones. The major advantages of this methodology are excellent yield at ambient temperature, very short reaction time（5–10 min）, and use of an inexpensive catalyst.展开更多
A series of spirooxindole-ferrocene hybrids bearing five or four contiguous chiral centers were designed and synthesized via organocatalysis.In vitro protein binding and cellular proliferation assays suggested that co...A series of spirooxindole-ferrocene hybrids bearing five or four contiguous chiral centers were designed and synthesized via organocatalysis.In vitro protein binding and cellular proliferation assays suggested that compound 5 d was the most potent mouse double minute 2 homolog(MDM2)inhibitor.In addition,mechanistic studies indicated that compound 5 d suppressed MDM2-mediated p53 degradation,induced apoptosis and promoted oxidative damage.Molecular docking studies have suggested that 5 d binds to MDM2 by mimicking the Trp23 and Leu26 residues of p53.This work can provide a basis for the development of novel multifunctional MDM2 inhibitors.The further exploration of more derivatives from this library and additional investigation of organocatalysis application in the development of new molecules may generate new potential lead compounds for cancer-targeted therapy.展开更多
A mild and efficient dearomatic [3＋2] annulation reaction of 3-nitro-7-azaindoles and Morita Baylis Hillman carbonates from isatins was developed catalyzed by DMAP, affording the corresponding polycyclic spirooxindol...A mild and efficient dearomatic [3＋2] annulation reaction of 3-nitro-7-azaindoles and Morita Baylis Hillman carbonates from isatins was developed catalyzed by DMAP, affording the corresponding polycyclic spirooxindoles containing fused azaindoline architectures and vicinal quaternary centers in excellent yields（up to 96%） with high regio- and diastereoselectivity（dr 〉 19：1）. Moderate enantioselectivity（79% ee） was obtained by employing a chiral DMAP-type Lewis base catalyst.展开更多
A highly efficient and direct approach was developed to construct the structurally diverse spirooxindole skeleton,which is an important basic motif in natural products.Both the 3,30-pyrrolidonyl spirooxindoles and spi...A highly efficient and direct approach was developed to construct the structurally diverse spirooxindole skeleton,which is an important basic motif in natural products.Both the 3,30-pyrrolidonyl spirooxindoles and spiroindolin-2-one dlactones were 2smoothly obtained by the intramolecular Dieckmann cyclization of oxindoles in excellent yield under mild conditions.展开更多
The single-electron transfer-induced oxidative transformation of indoles has been extensively explored in recent years.However,research toward high enantioselective control in this reaction is rare.Herein,we report an...The single-electron transfer-induced oxidative transformation of indoles has been extensively explored in recent years.However,research toward high enantioselective control in this reaction is rare.Herein,we report an enantioselective catalytic single-electron transfer-induced oxidative rearrangement of cyclic indoles enabled by dual chiral copper/phosphoric acid catalysis.Using atmospheric oxygen(O_(2))as the terminal oxidant,the reactions of tetrahydro-β-carbolines,tetrahydropyrano[3,4-b]indoles and the challenging tetrahydrocarbazoles are all realized,providing diverse rearrangement products including pyrrolidinyl-,tetrahydrofuranyl-and cyclopentyl-bearing spiroindolinones in good yields with high enantioselectivities.The synthetic utility of this protocol was demonstrated in a concise synthesis of(+)-coerulescine and(+)-horsfiline.These findings would provide new insights and opportunities for future asymmetric oxidative radical reaction design.展开更多
A [3＋3] formal cycloaddition reaction between in situ formed azaoxyallyl cations and nitrones from isatins has been developed, furnishing a spectrum of spiro[1,2,4-oxadiazinan-5-one]oxindoles in good to excellent yie...A [3＋3] formal cycloaddition reaction between in situ formed azaoxyallyl cations and nitrones from isatins has been developed, furnishing a spectrum of spiro[1,2,4-oxadiazinan-5-one]oxindoles in good to excellent yields with excellent diastereoselectivity. This method provides direct and efficient access to potentially bioactive spirooxin- doles incorporating a six-membered heterocyclic scaffold.展开更多
Spirooxindole is a compound with a unique framework and broad bioactivities in medicine.In this study,we have reviewed various approaches or methods in synthesizing spirooxindole derivatives focused on green synthesis...Spirooxindole is a compound with a unique framework and broad bioactivities in medicine.In this study,we have reviewed various approaches or methods in synthesizing spirooxindole derivatives focused on green synthesis.Synthesis of spirooxindoles is mainly carried out through multicomponent reactions combined with various green approaches such as the use of heterogeneous catalysts(nano-sized,magnetic,metal-complex,and metal-organic framework catalysts),deep eutectic solvent,solvent-free reactions,catalyst-free reactions,as well as the use of ultrasonic and microwaves irradiation.The green method is carried out in addition to obtaining high yields,it also offers reductions in the use of hazardous chemicals,energy use,purification processes,and waste generation.As a result,green synthesis methods in the synthesis of spirooxindole derivatives are more environmentally friendly.展开更多
The novel spirooxindoline fused [1,3]oxazines were efficiently synthesized from Diels-Alder reaction of N-arylmaleimides with 1,2-dihydro-2-oxospiro[3H-indole-3,2＇-[2H,9aH-pyrido[2,1-b][l,3]oxazines], which were gene...The novel spirooxindoline fused [1,3]oxazines were efficiently synthesized from Diels-Alder reaction of N-arylmaleimides with 1,2-dihydro-2-oxospiro[3H-indole-3,2＇-[2H,9aH-pyrido[2,1-b][l,3]oxazines], which were generated in situ from three-component reactions of substituted pyridines and isatins with methyl propiolate, or di- methyl acetylenedicarboxylate. The stereochemistry of the products was clearly clarified by the analysis of 1H NMR data and single crystal structures of the obtained polycyclic compounds.展开更多
Concise assembly of spirooxindoles is of great significance but a challenging task in modern organic synthesis.Described herein is an unusual base-promoted[4+2]spiroannulation of rarely used isatin-derivedβ-silylcarb...Concise assembly of spirooxindoles is of great significance but a challenging task in modern organic synthesis.Described herein is an unusual base-promoted[4+2]spiroannulation of rarely used isatin-derivedβ-silylcarbinols with o-halogen aromatic ketones,which enables rapid and modular synthesis of six-membered carbocyclic spirooxindoles in high yields with excellent functional group tolerance(>50 examples).Mechanistic experiments revealed that this reaction involved a Peterson olefination,Michael addition and intramolecular C(sp^(3))arylation cascade.The variegated synthetic derivatization of target products and successful construction of bioactive molecules further illustrate the synthetic potential in spirooxindole-related drug discovery.展开更多
A novel Ag-mediated dialkylation reaction of alkenes was disclosed,in which AgF was essential to activate C-H bond of acetonitrile.This reaction provided an efficient way to nitrile-containing spirooxindoles from read...A novel Ag-mediated dialkylation reaction of alkenes was disclosed,in which AgF was essential to activate C-H bond of acetonitrile.This reaction provided an efficient way to nitrile-containing spirooxindoles from readily available(1H-indol-3-yl)methanamine derivatives.展开更多
An efficient asymmetric[4+2]cyclization of hydroxyphenyl indolinone with azlactone for the synthesis of spirooxindoleδ-lactone has been developed,which realized the first asymmetric reaction of hydroxyphenyl indolino...An efficient asymmetric[4+2]cyclization of hydroxyphenyl indolinone with azlactone for the synthesis of spirooxindoleδ-lactone has been developed,which realized the first asymmetric reaction of hydroxyphenyl indolinone.A series of intricate structures with congested vicinal quaternary chiral centers were provided in good yields with excellent enantioselectivities via the in situ generated o-QM from hydroxyphenyl indolinone.展开更多
Oxindoles are a structurally unique subclass of monoterpenoid indole alkaloids(MIAs)with significant medicinal values such as neuroprotective and anticancer properties and are predominantly found in the Rubiaceae plan...Oxindoles are a structurally unique subclass of monoterpenoid indole alkaloids(MIAs)with significant medicinal values such as neuroprotective and anticancer properties and are predominantly found in the Rubiaceae plant family.Recent research has only just begun to uncover the biosynthetic pathways of this complex MIA subclass.Here,we report the discovery,characterization,and functional reconstitution of a four-enzyme pathway from Cephalanthus occidentalis(button bush)that enables the complete de novo biosynthesis of heteroyohimbine-type oxindole alkaloids in engineered yeast.Through transcriptomic mining and biochemical validation,we identified and characterized an ajmalicine synthase(CoAJS),a heteroyohimbine/yohimbine/corynanthe C3-oxidase(CoHYC3O),a C3-reductase(CoHYC3R),and an oxindole synthase(CoOIS)capable of converting strictosidine aglycone into 3-epi-ajmalicine and subsequently into the oxindole alkaloids mitraphylline and isomitraphylline.Saturation kinetics of CoOIS revealed comparable catalytic efficiencies for 3-epi-ajmalicine and its C20 epimer akuammigine,indicating substrate tolerance within the heteroyohimbine subclass.Yeast-based reconstruction of the pathway successfully yielded both mitraphylline epimers and the spirooxindole uncarine F.This work elu-cidates the enzymatic logic behind oxindole formation and expands the toolkit for MIA scaffold diversification and synthetic biology.展开更多
The functionalized spiro[indoline-3,40-pyrano[3,2-h]quinolines] were efficiently prepared in high yields from three-component reaction of 8-hydroxyquinoline, isatins and malononitrile or ethyl cyanoacetate in ethanol ...The functionalized spiro[indoline-3,40-pyrano[3,2-h]quinolines] were efficiently prepared in high yields from three-component reaction of 8-hydroxyquinoline, isatins and malononitrile or ethyl cyanoacetate in ethanol at room temperature for about 12 h in the presence of piperidine.展开更多
One novel spiro-compound（C_（26）H_（21）NO_3） has been synthesized and characterized by means of NMR spectroscopy,elemental analyses and X-ray diffraction. The single crystal belongs to the monoclinic system,space ...One novel spiro-compound（C_（26）H_（21）NO_3） has been synthesized and characterized by means of NMR spectroscopy,elemental analyses and X-ray diffraction. The single crystal belongs to the monoclinic system,space group P21/c with a = 8.8039（7）,b = 24.123（2）,c = 10.0751（9） ？,β = 108.403（3）°,M3r = 395.44,V = 2030.3（3） ？~3,Z = 4,D_c = 1.294 g/cm,F（000） = 832.0,μ = 0.085 mm^（-1）,R = 0.0801 and wR = 0.2228. The title compound shows good activities against Micrococcus tetragenus,Bacillus cereus,Bacillus subtilis,Staphylococcus aureus,S.albus and Escherichia coli.展开更多
A simple and efficient three component procedure has been developed for the synthesis of highly substituted spiro[indolo-3,100-indeno[1,2-b]quinolin]-2,4,11＇-triones by one pot three component condensation of enamino...A simple and efficient three component procedure has been developed for the synthesis of highly substituted spiro[indolo-3,100-indeno[1,2-b]quinolin]-2,4,11＇-triones by one pot three component condensation of enaminones, isatin and indane-1,3-dione in ethanol：water（1：1） in presence of ceric ammonium nitrate（CAN） as catalyst. This method provides several advantages such as lesser reaction time, high yield of products and operational simplicity. The antimicrobial activity of some of the compounds has been investigated against six microbial strains, some of the tested compounds showed good antimicrobial activity.展开更多
Spirooxindoles play an important role in drug discove ry and development.The development of efficient methods for the synthesis of spirooxindoles from easily available sta rting materials is of curre nt interest Herei...Spirooxindoles play an important role in drug discove ry and development.The development of efficient methods for the synthesis of spirooxindoles from easily available sta rting materials is of curre nt interest Herein,we report in detail the In(OTf)3-catalyzed[3+3]annulation of spirocyclopropyl oxindoles and 1,4-di-thiane-2,5-diol,which allows the facile preparation of spiro[indoline-3,4'-thiopyran]-2-ones bearing(tetrahydro)thiopyran skeleton.展开更多
Owing to their challenging structures and promising biological profiles,spirooxindole alkaloids have long attracted much attention from the synthetic community.Herein,we wish to describe a concise,protecting-group-fre...Owing to their challenging structures and promising biological profiles,spirooxindole alkaloids have long attracted much attention from the synthetic community.Herein,we wish to describe a concise,protecting-group-free total synthesis of cabucine oxindole A,a putative natural spirooxindole alkaloid and a possible biosynthetic congener of cabucine and palmirine.Key transformations of our approach include a one-step,organocatalytic and enantioselective construction of the spiro[pyrrolidine-3,3'-oxindole]moiety and a Korte rearrangement to furnish the final dihydropyran motif.Biological investigation of 1 and its synthetic intermediates revealed lactone 2 as a mild MOLT-4 and MCF7 cell line inhibitor.展开更多
The combination of isatin, barbituric acid, and cyclohexane-1,3-dione derivatives in the presence of alum （KAI（SO4）2· 12H2O） as a catalyst for 15 min was found to be a suitable and efficient method for the sy...The combination of isatin, barbituric acid, and cyclohexane-1,3-dione derivatives in the presence of alum （KAI（SO4）2· 12H2O） as a catalyst for 15 min was found to be a suitable and efficient method for the synthesis of spiro[chromeno[2,3-d]pyrimidine-5,3＇-indoline]-tetraones.展开更多
The three-component reaction of thiazole （benzothiazole）, dialkyl but-2-ynedioate, and isatinylidene malononi- triles in toluene at 110-120 ℃ in a sealed tube afforded a mixture of cis/trans-isomers of functionaliz...The three-component reaction of thiazole （benzothiazole）, dialkyl but-2-ynedioate, and isatinylidene malononi- triles in toluene at 110-120 ℃ in a sealed tube afforded a mixture of cis/trans-isomers of functionalized di- astereoisomeric spiro[indoline-3,7＇-thiazolo[3,2-a]pyridines] and spiro[benzo[4,5]thiazolo[3,2-a]pyridine-3,3＇-in- dolines] in good yields. Both cis-isomers and trans-isomers were successfully separated out and fully characterized with spectroscopy and single crystal determination. Under similar conditions, the three-component reaction con- taining 2-（1,3-dioxo-lH-inden-2（3H）-ylidene）malononitrile resulted in spiro[indene-2,7＇-thiazolo[3,2-a]pyridine] derivatives.展开更多
基金financial support from Ministry of Science and Technology of China (No.2019ZX09721001-008)National Natural Science Foundation of China (Nos.81773890,22001024,82073997)the “Thousand Talents Program” of Sichuan Province and Xinglin Scholar Research Premotion Project of CDUTCM。
文摘An N-heterocyclic carbene(NHC)-catalysed retro-aldol/aldol cascade reaction of spirooxindole-basedβ-hydroxyaldehyde has been developed.The ring opening-closure process enables the diastereodivergent synthesis of spirocyclopentaneoxindole products with four consecutive stereocenters by simply changing the reaction solvents(THF or DCE).The Michael/aldol/retro-aldol/aldol sequential protocol allows the diastereodivergent synthesis of spirocyclopentaneoxindoles from 3-substituted oxindole andα,β-unsaturated aldehyde under the relay catalysis of a chiral secondary amine and an NHC catalyst.Moreover,four stereoisomers of the product can be selectively provided by using different combinations of a chiral secondary amine and a solvent.
基金SAIF Panjab University for providing analytical facilities for characterization of compounds
文摘A rapid, one-pot and highly efficient protocol for the synthesis of pharmaceutically interesting functionalized 2-amino-3-cyano-4H-pyran and spirooxindole derivatives has been developed using commercially available Cs F as a catalyst in the reaction of malononitrile and aryl aldehydes or isatins with 1,3-cyclohexanediones. The major advantages of this methodology are excellent yield at ambient temperature, very short reaction time（5–10 min）, and use of an inexpensive catalyst.
基金supported by grants from the National Natural Science Foundation(Nos.21772131,81672552,81773890,82073997)the Fundamental Research Funds of Science&Technology Department of Sichuan Province(Nos.2019YFSY0004,2017JY0226,2019YFS0298)Project First-Class Disciplines Development supported by CDUTCM。
文摘A series of spirooxindole-ferrocene hybrids bearing five or four contiguous chiral centers were designed and synthesized via organocatalysis.In vitro protein binding and cellular proliferation assays suggested that compound 5 d was the most potent mouse double minute 2 homolog(MDM2)inhibitor.In addition,mechanistic studies indicated that compound 5 d suppressed MDM2-mediated p53 degradation,induced apoptosis and promoted oxidative damage.Molecular docking studies have suggested that 5 d binds to MDM2 by mimicking the Trp23 and Leu26 residues of p53.This work can provide a basis for the development of novel multifunctional MDM2 inhibitors.The further exploration of more derivatives from this library and additional investigation of organocatalysis application in the development of new molecules may generate new potential lead compounds for cancer-targeted therapy.
基金financial support from the NSFC(21572135 and 21321061)
文摘A mild and efficient dearomatic [3＋2] annulation reaction of 3-nitro-7-azaindoles and Morita Baylis Hillman carbonates from isatins was developed catalyzed by DMAP, affording the corresponding polycyclic spirooxindoles containing fused azaindoline architectures and vicinal quaternary centers in excellent yields（up to 96%） with high regio- and diastereoselectivity（dr 〉 19：1）. Moderate enantioselectivity（79% ee） was obtained by employing a chiral DMAP-type Lewis base catalyst.
基金the Natural Science Foundation of Yunnan Province(2014FA008 and 2015FB167)the Program for Changjiang Scholars and Innovative Research Team in University(IRT13095).
文摘A highly efficient and direct approach was developed to construct the structurally diverse spirooxindole skeleton,which is an important basic motif in natural products.Both the 3,30-pyrrolidonyl spirooxindoles and spiroindolin-2-one dlactones were 2smoothly obtained by the intramolecular Dieckmann cyclization of oxindoles in excellent yield under mild conditions.
基金the National Natural Science Foundation of China(Nos.22261010,22201053,22461012)Guizhou Provincial Major Scientific and Technological Program,China(No.QKHZDZX[2024]015)for financial support。
文摘The single-electron transfer-induced oxidative transformation of indoles has been extensively explored in recent years.However,research toward high enantioselective control in this reaction is rare.Herein,we report an enantioselective catalytic single-electron transfer-induced oxidative rearrangement of cyclic indoles enabled by dual chiral copper/phosphoric acid catalysis.Using atmospheric oxygen(O_(2))as the terminal oxidant,the reactions of tetrahydro-β-carbolines,tetrahydropyrano[3,4-b]indoles and the challenging tetrahydrocarbazoles are all realized,providing diverse rearrangement products including pyrrolidinyl-,tetrahydrofuranyl-and cyclopentyl-bearing spiroindolinones in good yields with high enantioselectivities.The synthetic utility of this protocol was demonstrated in a concise synthesis of(+)-coerulescine and(+)-horsfiline.These findings would provide new insights and opportunities for future asymmetric oxidative radical reaction design.
文摘A [3＋3] formal cycloaddition reaction between in situ formed azaoxyallyl cations and nitrones from isatins has been developed, furnishing a spectrum of spiro[1,2,4-oxadiazinan-5-one]oxindoles in good to excellent yields with excellent diastereoselectivity. This method provides direct and efficient access to potentially bioactive spirooxin- doles incorporating a six-membered heterocyclic scaffold.
基金The authors gratefully acknowledge financial support from the Universitas Islam Negeri Syarif Hidayatullah Jakarta through the grant of BOPTN 2023[Contract number:UN.01/KPA/189/2023].
文摘Spirooxindole is a compound with a unique framework and broad bioactivities in medicine.In this study,we have reviewed various approaches or methods in synthesizing spirooxindole derivatives focused on green synthesis.Synthesis of spirooxindoles is mainly carried out through multicomponent reactions combined with various green approaches such as the use of heterogeneous catalysts(nano-sized,magnetic,metal-complex,and metal-organic framework catalysts),deep eutectic solvent,solvent-free reactions,catalyst-free reactions,as well as the use of ultrasonic and microwaves irradiation.The green method is carried out in addition to obtaining high yields,it also offers reductions in the use of hazardous chemicals,energy use,purification processes,and waste generation.As a result,green synthesis methods in the synthesis of spirooxindole derivatives are more environmentally friendly.
基金This work was financially supported by the National Natural Science Foundation of China （Grant No. 21272200） and the Priority Academic Program Development of Jiangsu Higher Education Institutions. We would also like to express our sincere thanks to the Analysis Center of Yangzhou University for providing all necessary instruments for characterization of structures.
文摘The novel spirooxindoline fused [1,3]oxazines were efficiently synthesized from Diels-Alder reaction of N-arylmaleimides with 1,2-dihydro-2-oxospiro[3H-indole-3,2＇-[2H,9aH-pyrido[2,1-b][l,3]oxazines], which were generated in situ from three-component reactions of substituted pyridines and isatins with methyl propiolate, or di- methyl acetylenedicarboxylate. The stereochemistry of the products was clearly clarified by the analysis of 1H NMR data and single crystal structures of the obtained polycyclic compounds.
基金financial support of National Natural Science Foundation of China(21901193,22271314 and 22377097)the innovation foundation of Key Laboratory of Green Chemical Engineering Process of Ministry of Education(GCX2023002).
文摘Concise assembly of spirooxindoles is of great significance but a challenging task in modern organic synthesis.Described herein is an unusual base-promoted[4+2]spiroannulation of rarely used isatin-derivedβ-silylcarbinols with o-halogen aromatic ketones,which enables rapid and modular synthesis of six-membered carbocyclic spirooxindoles in high yields with excellent functional group tolerance(>50 examples).Mechanistic experiments revealed that this reaction involved a Peterson olefination,Michael addition and intramolecular C(sp^(3))arylation cascade.The variegated synthetic derivatization of target products and successful construction of bioactive molecules further illustrate the synthetic potential in spirooxindole-related drug discovery.
基金We are grateful for financial support from 973 Program(No.2011CB808700)NSFC(Nos.21225210,20923005 and 21121062)+1 种基金STCSM(No.11JC1415000)the CAS/SAFEA International Partnership Program for Creative Research Teams.
文摘A novel Ag-mediated dialkylation reaction of alkenes was disclosed,in which AgF was essential to activate C-H bond of acetonitrile.This reaction provided an efficient way to nitrile-containing spirooxindoles from readily available(1H-indol-3-yl)methanamine derivatives.
基金We thank the Qingdao Marine Science and Technology Center(No.2022QNLM030003-2)the Fundamental Research Funds for the Central Universities,Taishan Scholar Program of Shandong Province(No.tsqn201909056)National Natural Science Foundation of China(No.22171251)for financial support.
文摘An efficient asymmetric[4+2]cyclization of hydroxyphenyl indolinone with azlactone for the synthesis of spirooxindoleδ-lactone has been developed,which realized the first asymmetric reaction of hydroxyphenyl indolinone.A series of intricate structures with congested vicinal quaternary chiral centers were provided in good yields with excellent enantioselectivities via the in situ generated o-QM from hydroxyphenyl indolinone.
基金supported by a Natural Sciences and Engineering Research Council of Canada(NSERC)Discovery Grant and a New Brunswick Innovation Foundation(NBIF)Research Assistantship Initiative Grant to Y.Q.
文摘Oxindoles are a structurally unique subclass of monoterpenoid indole alkaloids(MIAs)with significant medicinal values such as neuroprotective and anticancer properties and are predominantly found in the Rubiaceae plant family.Recent research has only just begun to uncover the biosynthetic pathways of this complex MIA subclass.Here,we report the discovery,characterization,and functional reconstitution of a four-enzyme pathway from Cephalanthus occidentalis(button bush)that enables the complete de novo biosynthesis of heteroyohimbine-type oxindole alkaloids in engineered yeast.Through transcriptomic mining and biochemical validation,we identified and characterized an ajmalicine synthase(CoAJS),a heteroyohimbine/yohimbine/corynanthe C3-oxidase(CoHYC3O),a C3-reductase(CoHYC3R),and an oxindole synthase(CoOIS)capable of converting strictosidine aglycone into 3-epi-ajmalicine and subsequently into the oxindole alkaloids mitraphylline and isomitraphylline.Saturation kinetics of CoOIS revealed comparable catalytic efficiencies for 3-epi-ajmalicine and its C20 epimer akuammigine,indicating substrate tolerance within the heteroyohimbine subclass.Yeast-based reconstruction of the pathway successfully yielded both mitraphylline epimers and the spirooxindole uncarine F.This work elu-cidates the enzymatic logic behind oxindole formation and expands the toolkit for MIA scaffold diversification and synthetic biology.
基金supported by the National Natural Science Foundation of China (Nos. 21172189, 21572196)the Priority Academic Program Development of Jiangsu Higher Education Institutions
文摘The functionalized spiro[indoline-3,40-pyrano[3,2-h]quinolines] were efficiently prepared in high yields from three-component reaction of 8-hydroxyquinoline, isatins and malononitrile or ethyl cyanoacetate in ethanol at room temperature for about 12 h in the presence of piperidine.
基金Project supported by the Natural Science Foundation of Hainan Province(No.20162033)the Cultivation Research Foundation of Hainan Medical University(HY2015-02)
文摘One novel spiro-compound（C_（26）H_（21）NO_3） has been synthesized and characterized by means of NMR spectroscopy,elemental analyses and X-ray diffraction. The single crystal belongs to the monoclinic system,space group P21/c with a = 8.8039（7）,b = 24.123（2）,c = 10.0751（9） ？,β = 108.403（3）°,M3r = 395.44,V = 2030.3（3） ？~3,Z = 4,D_c = 1.294 g/cm,F（000） = 832.0,μ = 0.085 mm^（-1）,R = 0.0801 and wR = 0.2228. The title compound shows good activities against Micrococcus tetragenus,Bacillus cereus,Bacillus subtilis,Staphylococcus aureus,S.albus and Escherichia coli.
文摘A simple and efficient three component procedure has been developed for the synthesis of highly substituted spiro[indolo-3,100-indeno[1,2-b]quinolin]-2,4,11＇-triones by one pot three component condensation of enaminones, isatin and indane-1,3-dione in ethanol：water（1：1） in presence of ceric ammonium nitrate（CAN） as catalyst. This method provides several advantages such as lesser reaction time, high yield of products and operational simplicity. The antimicrobial activity of some of the compounds has been investigated against six microbial strains, some of the tested compounds showed good antimicrobial activity.
基金financial support from the National Natural Science Foundation of China(No.81660576)the Project of Guizhou Province Qian Ke He GZ[2015]4001Guizhou Discipline Construction Project(No.GNYL[2017]008)。
文摘Spirooxindoles play an important role in drug discove ry and development.The development of efficient methods for the synthesis of spirooxindoles from easily available sta rting materials is of curre nt interest Herein,we report in detail the In(OTf)3-catalyzed[3+3]annulation of spirocyclopropyl oxindoles and 1,4-di-thiane-2,5-diol,which allows the facile preparation of spiro[indoline-3,4'-thiopyran]-2-ones bearing(tetrahydro)thiopyran skeleton.
基金Financial support from SZSTI(Nos.JCY120170817110515599,KQTD20150717103157174)the National Natural Science Founda tion of China(Nos.21772082 and 21971104)+3 种基金the Guangdong Innovative Program(No.2019BT02Y335)the Guangdong Provin cial Key Laboratory of Catalysis(No.2020B121201002)the Shen zhen Key Laboratory of Small Molecule Drug Discovery and Syn thesis(No.ZDSY520190902093215877)the Shenzhen Nobel Prize Scientists Laboratory Project(C17783101)is greatly appreci-ated.The authors are grateful to Prof.Qing Ye(SUSTech)for assis-tance with XRD analysis.
文摘Owing to their challenging structures and promising biological profiles,spirooxindole alkaloids have long attracted much attention from the synthetic community.Herein,we wish to describe a concise,protecting-group-free total synthesis of cabucine oxindole A,a putative natural spirooxindole alkaloid and a possible biosynthetic congener of cabucine and palmirine.Key transformations of our approach include a one-step,organocatalytic and enantioselective construction of the spiro[pyrrolidine-3,3'-oxindole]moiety and a Korte rearrangement to furnish the final dihydropyran motif.Biological investigation of 1 and its synthetic intermediates revealed lactone 2 as a mild MOLT-4 and MCF7 cell line inhibitor.
文摘The combination of isatin, barbituric acid, and cyclohexane-1,3-dione derivatives in the presence of alum （KAI（SO4）2· 12H2O） as a catalyst for 15 min was found to be a suitable and efficient method for the synthesis of spiro[chromeno[2,3-d]pyrimidine-5,3＇-indoline]-tetraones.
基金This work was financially supported by the National Natural Science Foundation of China （No. 21172189） and the Priority Academic Program Development of Jiangsu Higher Education Institutions. We also wanted to give sincerely thanks to the Analysis Center of Yangzhou University for providing all necessary in- struments for characterization of structures.
文摘The three-component reaction of thiazole （benzothiazole）, dialkyl but-2-ynedioate, and isatinylidene malononi- triles in toluene at 110-120 ℃ in a sealed tube afforded a mixture of cis/trans-isomers of functionalized di- astereoisomeric spiro[indoline-3,7＇-thiazolo[3,2-a]pyridines] and spiro[benzo[4,5]thiazolo[3,2-a]pyridine-3,3＇-in- dolines] in good yields. Both cis-isomers and trans-isomers were successfully separated out and fully characterized with spectroscopy and single crystal determination. Under similar conditions, the three-component reaction con- taining 2-（1,3-dioxo-lH-inden-2（3H）-ylidene）malononitrile resulted in spiro[indene-2,7＇-thiazolo[3,2-a]pyridine] derivatives.
