This mini-review presents the authors＇ vision on the current status and future trends in the development of neuroprotective agents working via activation of nuclear factor erythroid 2-related factor 2 （Nrf2）, and i...This mini-review presents the authors＇ vision on the current status and future trends in the development of neuroprotective agents working via activation of nuclear factor erythroid 2-related factor 2 （Nrf2）, and in particular, via disruption of Nrf2-Keap 1 interaction. There are two opposite ＂chemical＂ mechanisms underlying such activation： the first one is a non-specific covalent modification of Keapl thiols, resulting in side effects of varied severity, and the second one is the shift of the Nrf2-Kelch-like ECH associated protein-1 （Keapl） binding equilibrium in the presence of a competitive and chemically benign displacement agent. At this point, no displacement activators exhibit sufficient biological activity in comparison with common Nrf2 activators working via Keapl thiol modification. Hence, the hope in therapeutics is now linked to the FDA approved dimethylfumarate, whose derivative, monomethylfumarate, as we demonstrated recently, is much less toxic but equally biologically potent and an ideal candidate for clinical trials right now. A newly emerging player is a nuclear inhibitor of Nrf2, BTB domain and CNC homolog 1 （Bach1）. The commercially developed Bachl inhibitors are currently under investigation in our laboratory showing promising results. In our viewpoint, the perfect future drug will present the combination of a displacement activator and Bach 1 inhibitor to insure safety and efficiency of Nrf2 activation.展开更多
Transition metal-catalyzed carbonylation reactions represent a direct and atom-economical approach to synthesize carbonyl compounds or their derivatives by using CO as a cheap and readily available C1 feedstock.While ...Transition metal-catalyzed carbonylation reactions represent a direct and atom-economical approach to synthesize carbonyl compounds or their derivatives by using CO as a cheap and readily available C1 feedstock.While carbonylation of C(sp^(2))-hybridized electrophiles (e.g.,aryl halides) is well developed,carbonylation of less reactive unactivated alkyl electrophiles remains challenging.Recently,the use of earth-abundant base metals including Cu,Co,Mn,Fe,Ni as catalysts has enabled advances in carbonylative coupling of alkyl electrophiles for approaching diverse carbonyl compounds or their derivatives,notably,some of which are of synthetic importance but difficult to be synthesized through previous reported methods.Herein,we have summarized and discussed these recent achievements in base-metal-catalyzed carbonylative C—C,C—N,C—O,C—X coupling and other carbonylation reactions of unactivated alkyl electrophiles using CO as C1 source.展开更多
An alkyl radical initiated cyclization/tandem reaction of alkyl bromides and alkyl electrophiles by using potassium metabisulphite(K_(2)S_(2)O_(5))as a connector is developed for the synthesis of various lactam-substi...An alkyl radical initiated cyclization/tandem reaction of alkyl bromides and alkyl electrophiles by using potassium metabisulphite(K_(2)S_(2)O_(5))as a connector is developed for the synthesis of various lactam-substituted alkyl sulfones.Notably,this process does not require a metal catalyst or metal powder reductant,highlighting its environmentally friendly features.The reaction demonstrates outstanding substrate adaptability and a high tolerance towards diverse functional groups.Furthermore,the biologically active molecules and commercially available drugs with a late-stage modification are also highly compatible with this transformation.Mechanistic studies revealed that the reaction proceeds through a single-step process involving intramolecular radical cyclization,"SO_(2)"insertion,and external alkyl incorporation.展开更多
Spurred by the alleged relevance of the thia-Michael reaction in the bioactivity of various classes of cinnam(o)yl natural products and by the development of a quick NMR assay to study this reaction, we have carried o...Spurred by the alleged relevance of the thia-Michael reaction in the bioactivity of various classes of cinnam(o)yl natural products and by the development of a quick NMR assay to study this reaction, we have carried out a systematic study of the "native" reactivity of these compounds with dodecanethiol and cysteamine as models, respectively, of simple thiols and reactive protein thiols that can benefit from iminium ion catalysis in Michael reactions. Cinnamoyl esters and amides, as well as cinnamyl ketones and oximes, did not show any reactivity with the two probe thiols, while cinnamaldehyde(1a) reacted with cysteamine to afford a mixture of a thiazoline derivative and compounds of multiple addition, and with aliphatic thiols to give a single bis-dithioacetal(6). Chalchones and their vinylogous C5-curcuminoid derivatives were the only cinnamoyl derivatives that gave a thiaMichael reaction. From a mechanistic standpoint, loss of conjugation in the adduct might underlie the lack of a native Michael reactivity. This property is restored by the presence of another conjugating group on the carbonyl, as in chalcones and C5-curcuminoids. A critical mechanistic revision of the chemical and biomedical literature on cinnamaldehyde and related compounds seems therefore required.展开更多
Regiodivergent catalysis provides an efficient strategic approach for the construction of architecturally different molecules from the same starting materials. In this field, the intermolecular regiodivergent 1,2-difu...Regiodivergent catalysis provides an efficient strategic approach for the construction of architecturally different molecules from the same starting materials. In this field, the intermolecular regiodivergent 1,2-difunctionalization of alkenes with two electrophiles is still a challenging task. A ligand-controlled, nickel-catalyzed regiodivergent dicarbofunctionalization of alkenes using both aryl/vinyl halides and acetals as electrophiles under mild reductive reaction conditions has been accomplished. This study provides a general approach to accessing both β-methoxyl esters and γ-methoxyl esters from readily available acrylates,aryl halides and acetals. Experimental mechanistic evidence supports that the difference in regioselective outcomes is attributed to the ligand tuning the reactivity of the nickel catalyst, which results in different catalytic cycles operating for these two reaction conditions.展开更多
Direct transformation of five-membered zirconacycles to carbocyclic compounds is of great synthetic interest.The reaction of zirconacycles with electrophiles containing at least two reactive functional groups or an ox...Direct transformation of five-membered zirconacycles to carbocyclic compounds is of great synthetic interest.The reaction of zirconacycles with electrophiles containing at least two reactive functional groups or an oxidant affords various carbocycles through cross coupling,addition,and/or oxidative coupling reactions.In this paper,we present our recent results on the zirconacycle-mediated formation of carbocycles,including:(1) 1,1-cycloaddition of oxalyl dichloride with zirconacycles;(2) benzoquinone-promoted coupling of zirconacyclopentadienes in the presence of CuCl;(3) cycloaddition of zirconacyclopentadienes to quinones;(4) cycloaddition of zirconacyclopentadiene with 2-bromoacrylate,2-bromoacrylaldehyde and 3-bromofuran-2,5-dione in the presence of CuCl;(5) one-pot coupling of two alkynes and an alkene to form cyclohexene derivatives via zirconacyclopentadienes;and(6) dianionic cycloaddition of decatetraenes with esters or acyl chlorides to form nine-membered carbocycles.展开更多
The trifluoromethylthio group （SCF3） is a fluorine chemotype that has experienced a strong acceleration of in- terest in the recent years. It is particularly true of the construction of new fluorinated architectures...The trifluoromethylthio group （SCF3） is a fluorine chemotype that has experienced a strong acceleration of in- terest in the recent years. It is particularly true of the construction of new fluorinated architectures by electrophilic trifluoromethylthiolation. The spread of knowledge was already very active in this research domain in the sixties; however, gaseous and highly toxic trifluoromethanesulfenyl chloride （CF3SC1） was the only reagent available at that time. Nowadays, one really can speak of a revival in the field thanks to the rapid development of a wide pano- ply of reagents that are stable and easy to handle. This review provides a historical perspective of the development of shelf-stable electrophilic trifluoromethylthiolation reagents.展开更多
In this paper, the activities of electrophilic sites on benzene ring of 4-substituted anilines and their acyl compounds were studied with the quantitative indicator of multiphilicity descriptor. Four substituents were...In this paper, the activities of electrophilic sites on benzene ring of 4-substituted anilines and their acyl compounds were studied with the quantitative indicator of multiphilicity descriptor. Four substituents were synthe- sized with microwave irradiation in good yields to verify the quantitative analysis data. Friedel-Crafts acylation was carried out by the microwave method for the first time.展开更多
We analysed the photooxidation reaction in the electro-(1O2) and nucleophilic (O2•−) reaction of 2-pyridone azo derivatives. First, we calculated the energy (enthalpies) of tautomers formation, which is a measure of d...We analysed the photooxidation reaction in the electro-(1O2) and nucleophilic (O2•−) reaction of 2-pyridone azo derivatives. First, we calculated the energy (enthalpies) of tautomers formation, which is a measure of durability and the probability of their formation. We performed the light fastness calculations of the monoazopyridone dyes. Using the semi-empirical methods of quantum chemistry AM1 and PM3, the reactivity indicators of superdelocalisability (SrE(N)) and the electron density distribution in ground state on the highest occupied HOMO orbital and the lowest unoccupied excited state LUMO in 2-pyridone phenylazo derivatives were calculated. Superdelocalisability coefficients enable the stability to oxidising agents of various chemical molecules depending on the tautomeric forms in which they may occur. The results of the electron density calculations at the HOMO and LUMO boundary orbitals allow to determine the tendency to electrophilic attack with singlet oxygen 1O2 or nucleophilic attack of the superoxide anion O2•−on a specific atom in the molecule. The structure of the dyes was optimised with MM+, MD and AM1 or PM3 until a constant energy value was achieved with a convergence criterion of 0.01 kcal/mol.展开更多
An efficient synthesis of the electrophilic reagent,S-(1,3-dioxoisoindolin-2-yl)O,O-diethyl phosphorothioate(SDDP)is described.Moreover,the synthetic applications of SDDP wherein the transfer of the SP(O)(OEt)_(2) moi...An efficient synthesis of the electrophilic reagent,S-(1,3-dioxoisoindolin-2-yl)O,O-diethyl phosphorothioate(SDDP)is described.Moreover,the synthetic applications of SDDP wherein the transfer of the SP(O)(OEt)_(2) moiety occurs were investigated.In this manner,SDDP underwent facile SP(O)(OEt)_(2) transfer with electron-rich substrates such as ketones,indoles,and thiols to formα-phosphorothiolated ketones,3-phosphorothiolated indoles and S-phosphorothiolated thioethers,respectively.展开更多
基金supported in part by grants from NIH NS062165,NS060885,Michael J Fox Foundation for Parkinson’s ResearchParfore Parkinson,National Parkinson Foundation(CSRA chapter) to BT+1 种基金Winifred Masterson Burke FoundationThomas Hartman Foundat ion for Parkinson’s disease to IGG
文摘This mini-review presents the authors＇ vision on the current status and future trends in the development of neuroprotective agents working via activation of nuclear factor erythroid 2-related factor 2 （Nrf2）, and in particular, via disruption of Nrf2-Keap 1 interaction. There are two opposite ＂chemical＂ mechanisms underlying such activation： the first one is a non-specific covalent modification of Keapl thiols, resulting in side effects of varied severity, and the second one is the shift of the Nrf2-Kelch-like ECH associated protein-1 （Keapl） binding equilibrium in the presence of a competitive and chemically benign displacement agent. At this point, no displacement activators exhibit sufficient biological activity in comparison with common Nrf2 activators working via Keapl thiol modification. Hence, the hope in therapeutics is now linked to the FDA approved dimethylfumarate, whose derivative, monomethylfumarate, as we demonstrated recently, is much less toxic but equally biologically potent and an ideal candidate for clinical trials right now. A newly emerging player is a nuclear inhibitor of Nrf2, BTB domain and CNC homolog 1 （Bach1）. The commercially developed Bachl inhibitors are currently under investigation in our laboratory showing promising results. In our viewpoint, the perfect future drug will present the combination of a displacement activator and Bach 1 inhibitor to insure safety and efficiency of Nrf2 activation.
基金Fundamental Research Funds for the Central Universities and Natural Science Foundation of Hunan Province(2022JJ30122,2023JJ10003)for financial support.
文摘Transition metal-catalyzed carbonylation reactions represent a direct and atom-economical approach to synthesize carbonyl compounds or their derivatives by using CO as a cheap and readily available C1 feedstock.While carbonylation of C(sp^(2))-hybridized electrophiles (e.g.,aryl halides) is well developed,carbonylation of less reactive unactivated alkyl electrophiles remains challenging.Recently,the use of earth-abundant base metals including Cu,Co,Mn,Fe,Ni as catalysts has enabled advances in carbonylative coupling of alkyl electrophiles for approaching diverse carbonyl compounds or their derivatives,notably,some of which are of synthetic importance but difficult to be synthesized through previous reported methods.Herein,we have summarized and discussed these recent achievements in base-metal-catalyzed carbonylative C—C,C—N,C—O,C—X coupling and other carbonylation reactions of unactivated alkyl electrophiles using CO as C1 source.
基金the Scientific Research Fund of Hunan Provincial Education Department(21B0262 and 22B1094)the Natural Science Foundation of Hunan Province(2022JJ40857)the Hunan Provincial Innovation Foundation For Postgraduate(CX20230757)forfinancial support.
文摘An alkyl radical initiated cyclization/tandem reaction of alkyl bromides and alkyl electrophiles by using potassium metabisulphite(K_(2)S_(2)O_(5))as a connector is developed for the synthesis of various lactam-substituted alkyl sulfones.Notably,this process does not require a metal catalyst or metal powder reductant,highlighting its environmentally friendly features.The reaction demonstrates outstanding substrate adaptability and a high tolerance towards diverse functional groups.Furthermore,the biologically active molecules and commercially available drugs with a late-stage modification are also highly compatible with this transformation.Mechanistic studies revealed that the reaction proceeds through a single-step process involving intramolecular radical cyclization,"SO_(2)"insertion,and external alkyl incorporation.
文摘Spurred by the alleged relevance of the thia-Michael reaction in the bioactivity of various classes of cinnam(o)yl natural products and by the development of a quick NMR assay to study this reaction, we have carried out a systematic study of the "native" reactivity of these compounds with dodecanethiol and cysteamine as models, respectively, of simple thiols and reactive protein thiols that can benefit from iminium ion catalysis in Michael reactions. Cinnamoyl esters and amides, as well as cinnamyl ketones and oximes, did not show any reactivity with the two probe thiols, while cinnamaldehyde(1a) reacted with cysteamine to afford a mixture of a thiazoline derivative and compounds of multiple addition, and with aliphatic thiols to give a single bis-dithioacetal(6). Chalchones and their vinylogous C5-curcuminoid derivatives were the only cinnamoyl derivatives that gave a thiaMichael reaction. From a mechanistic standpoint, loss of conjugation in the adduct might underlie the lack of a native Michael reactivity. This property is restored by the presence of another conjugating group on the carbonyl, as in chalcones and C5-curcuminoids. A critical mechanistic revision of the chemical and biomedical literature on cinnamaldehyde and related compounds seems therefore required.
基金supported by the National Natural Science Foundation of China (21871211, 21774029, 22122107)the Fundamental Research Funds for Central Universities (2042019kf0208)。
文摘Regiodivergent catalysis provides an efficient strategic approach for the construction of architecturally different molecules from the same starting materials. In this field, the intermolecular regiodivergent 1,2-difunctionalization of alkenes with two electrophiles is still a challenging task. A ligand-controlled, nickel-catalyzed regiodivergent dicarbofunctionalization of alkenes using both aryl/vinyl halides and acetals as electrophiles under mild reductive reaction conditions has been accomplished. This study provides a general approach to accessing both β-methoxyl esters and γ-methoxyl esters from readily available acrylates,aryl halides and acetals. Experimental mechanistic evidence supports that the difference in regioselective outcomes is attributed to the ligand tuning the reactivity of the nickel catalyst, which results in different catalytic cycles operating for these two reaction conditions.
基金supported by the National Natural Science Foundation of China (20172032, 20872076)the Doctoral Program of Higher Education (200800030072)
文摘Direct transformation of five-membered zirconacycles to carbocyclic compounds is of great synthetic interest.The reaction of zirconacycles with electrophiles containing at least two reactive functional groups or an oxidant affords various carbocycles through cross coupling,addition,and/or oxidative coupling reactions.In this paper,we present our recent results on the zirconacycle-mediated formation of carbocycles,including:(1) 1,1-cycloaddition of oxalyl dichloride with zirconacycles;(2) benzoquinone-promoted coupling of zirconacyclopentadienes in the presence of CuCl;(3) cycloaddition of zirconacyclopentadienes to quinones;(4) cycloaddition of zirconacyclopentadiene with 2-bromoacrylate,2-bromoacrylaldehyde and 3-bromofuran-2,5-dione in the presence of CuCl;(5) one-pot coupling of two alkynes and an alkene to form cyclohexene derivatives via zirconacyclopentadienes;and(6) dianionic cycloaddition of decatetraenes with esters or acyl chlorides to form nine-membered carbocycles.
文摘The trifluoromethylthio group （SCF3） is a fluorine chemotype that has experienced a strong acceleration of in- terest in the recent years. It is particularly true of the construction of new fluorinated architectures by electrophilic trifluoromethylthiolation. The spread of knowledge was already very active in this research domain in the sixties; however, gaseous and highly toxic trifluoromethanesulfenyl chloride （CF3SC1） was the only reagent available at that time. Nowadays, one really can speak of a revival in the field thanks to the rapid development of a wide pano- ply of reagents that are stable and easy to handle. This review provides a historical perspective of the development of shelf-stable electrophilic trifluoromethylthiolation reagents.
文摘In this paper, the activities of electrophilic sites on benzene ring of 4-substituted anilines and their acyl compounds were studied with the quantitative indicator of multiphilicity descriptor. Four substituents were synthe- sized with microwave irradiation in good yields to verify the quantitative analysis data. Friedel-Crafts acylation was carried out by the microwave method for the first time.
文摘We analysed the photooxidation reaction in the electro-(1O2) and nucleophilic (O2•−) reaction of 2-pyridone azo derivatives. First, we calculated the energy (enthalpies) of tautomers formation, which is a measure of durability and the probability of their formation. We performed the light fastness calculations of the monoazopyridone dyes. Using the semi-empirical methods of quantum chemistry AM1 and PM3, the reactivity indicators of superdelocalisability (SrE(N)) and the electron density distribution in ground state on the highest occupied HOMO orbital and the lowest unoccupied excited state LUMO in 2-pyridone phenylazo derivatives were calculated. Superdelocalisability coefficients enable the stability to oxidising agents of various chemical molecules depending on the tautomeric forms in which they may occur. The results of the electron density calculations at the HOMO and LUMO boundary orbitals allow to determine the tendency to electrophilic attack with singlet oxygen 1O2 or nucleophilic attack of the superoxide anion O2•−on a specific atom in the molecule. The structure of the dyes was optimised with MM+, MD and AM1 or PM3 until a constant energy value was achieved with a convergence criterion of 0.01 kcal/mol.
基金generous financial support by National Natural Science Foundation of China(No.21472133)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)Key Laboratory of Organic Synthesis of Jiangsu Province(No.KJS1749).
文摘An efficient synthesis of the electrophilic reagent,S-(1,3-dioxoisoindolin-2-yl)O,O-diethyl phosphorothioate(SDDP)is described.Moreover,the synthetic applications of SDDP wherein the transfer of the SP(O)(OEt)_(2) moiety occurs were investigated.In this manner,SDDP underwent facile SP(O)(OEt)_(2) transfer with electron-rich substrates such as ketones,indoles,and thiols to formα-phosphorothiolated ketones,3-phosphorothiolated indoles and S-phosphorothiolated thioethers,respectively.
