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194
result(s) for
"Wang, Xi-Sheng"
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Tailoring d-band center of high-valent metal-oxo species for pollutant removal via complete polymerization
Polymerization-driven removal of pollutants in advanced oxidation processes (AOPs) offers a sustainable way for the simultaneous achievement of contamination abatement and resource recovery, supporting a low-carbon water purification approach. However, regulating such a process remains a great challenge due to the insufficient microscopic understanding of electronic structure-dependent reaction mechanisms. Herein, this work probes the origin of catalytic pollutant polymerization using a series of transition metal (Cu, Ni, Co, and Fe) single-atom catalysts and identifies the
d
-band center of active site as the key driver for polymerization transfer of pollutants. The high-valent metal-oxo species, produced via peroxymonosulfate activation, are found to trigger the pollutant removal via polymerization transfer. Phenoxyl radicals, identified by the innovative spin-trapping and quenching approaches, act as the key intermediate in the polymerization reactions. More importantly, the oxidation capacity of high-valent metal-oxo species can be facilely tuned by regulating their binding strength for peroxymonosulfate through
d
-band center modulation. A 100% polymerization transfer ratio is achieved by lowering the
d
-band center. This work presents a paradigm to dynamically modulate the electronic structure of high-valent metal-oxo species and optimize pollutant removal from wastewater via polymerization.
Polymerization-driven removal of pollutants in advanced oxidation processes (AOPs) allows for sustainable contamination abatement and resource recovery. Here, authors achieved pollutant removal via complete polymerization by tailoring
d
-band center of high-valent metal-oxo species.
Journal Article
Enantioselective cyanation via radical-mediated C–C single bond cleavage for synthesis of chiral dinitriles
Ring-opening reaction via selective cleavage of C–C bond is known as a powerful strategy for construction of complex molecules. Complementary to the ionic process focusing on mostly small ring systems, radical-mediated C–C bond cleavage offers a solution for further diverse enantioselective functionalization benefited from its mild conditions, whereas such asymmetric transformations are still limited to three-membered rings so far. Herein, we describe radical-mediated ring-opening and enantioselective cyanation of four- and five-membered cycloketone oxime esters to access chiral 1,5- and 1,6-dinitriles. Employment of dual photoredox/copper catalysis is essential for the asymmetric ring-opening cyanation of cyclopentanone oxime esters. Both reactions proceed under mild conditions giving chiral dinitriles in high yields and enantioselectivity with low catalyst loading and broad substrate scope. The products dinitriles can be converted to valuable optically active diamides and diamines. Mechanistic studies indicate that the benzylic radical generated via C–C single bond cleavage is involved in the catalytic cycle.
Ring-opening reaction via selective cleavage of C–C bond is a powerful strategy to increase molecular complexity. Here the authors present the facile synthesis of chiral 1,5- and 1,6-dinitriles via the radical-mediated ring-opening and enantioselective cyanation of cycloketone oxime esters.
Journal Article
Cobalt-catalyzed difluoroalkylation of tertiary aryl ketones for facile synthesis of quaternary alkyl difluorides
The selective incorporation of
gem
-difluoroalkyl groups into biologically active molecules has long been used as an efficient strategy for drug design and discovery. However, the catalytic C(sp
3
)-CF
2
bond-forming cross-coupling reaction for selective incorporation of difluoromethylene group into diverse alkyl chains, especially more sterically demanding secondary and tertiary functionalized alkanes, still remains as a major challenge. Herein, we describe a cobalt-catalyzed difluoroalkylation of tertiary aryl ketones for facile synthesis of quaternary alkyl difluorides, which exhibited high efficiency, broad scope and mild conditions. The synthetic utility of this method is demonstrated by late-stage difluoroalkylation of donepezil, a well-known acetylcholinesterase inhibitor used to treat the Alzheimer’s disease. Preliminary mechanistic investigations indicate that a difluoroalkyl radical is involved in a Co(I)/Co(III) catalytic cycle. This cobalt-catalyzed fluoroalkylation thus offers insights into an efficient way for the synthesis of fluoroalkylated bioactive molecules for drug discovery.
The catalytic C(sp
3
)-CF
2
bond formation is of high interest in drug design and discovery. Here, the authors report a cobalt-catalyzed difluoroalkylation of tertiary α-C-H bonds of aryl ketones for facile synthesis of quaternary alkyl difluorides and show the late-stage functionalization of marketed drugs.
Journal Article
CF2H-synthon enables asymmetric radical difluoroalkylation for synthesis of chiral difluoromethylated amines
The difluoromethyl group is a crucial fluorinated moiety with distinctive biological properties, and the synthesis of chiral CF₂H-containing analogs has been recognized as a powerful strategy in drug design. To date, the most established method for accessing enantioenriched difluoromethyl compounds involves the enantioselective functionalization of nucleophilic and electrophilic CF₂H synthons. However, this approach is limited by lower reactivity and reduced enantioselectivity. Leveraging the unique fluorine effect, we design and synthesize a radical CF₂H synthon by incorporating isoindolinone into alkyl halides for asymmetric radical transformation. Here, we report an efficient strategy for the asymmetric construction of carbon stereocenters featuring a difluoromethyl group via nickel-catalyzed Negishi cross-coupling. This approach demonstrates mild reaction conditions and excellent enantioselectivity. Given that optically pure difluoromethylated amines and isoindolinones are key structural motifs in bioactive compounds, this strategy offers a practical solution for the efficient synthesis of CF₂H-containing chiral drug-like molecules.
The difluoromethyl group is a crucial fluorinated moiety, and the synthesis of chiral CF₂H-containing analogs is a powerful strategy in drug design and screening. Here, the authors report a strategy for the asymmetric construction of carbon stereocenters featuring a difluoromethyl group via nickel-catalyzed Negishi cross-coupling.
Journal Article
Asymmetric construction of allylicstereogenic carbon center featuring atrifluoromethyl group via enantioselective reductive fluoroalkylation
Emerging as a powerful tool for lead optimization in pharmaceutical research and development, to develop the facile, general protocols that allows the incorporation of fluorine-containing motif in drug candidates has accumulated enormous research interest in recent years. Among these important motifs, the incorporation of strategic motif CF
3
on aliphatic chain especially with the concomitant construction of trifluoromethylated alkanes bearing a CF
3
-substituted stereogenic carbon, is of paramount importance. Herein, we disclose an asymmetric nickel-catalyzed reductive trifluoroalkylation of alkenyl halides for enantioselective syntheses of diverse
α
-trifluoromethylated allylic alkanes, offering a general protocol to access the trifluoromethyl analogue to chiral
α
-methylated allylic alkanes, one of the most prevalent key components among natural products and pharmaceuticals. Utilities of the method including the application of the asymmetric trifluoroalkylation on multiple biologically active complex molecules, derivatization of transformable alkenyl functionality were demonstrated, providing a facile method in the diversity-oriented syntheses of CF
3
-containing chiral drugs and bioactive-molecules.
The efficient construction of trifluoromethylated alkanes bearing a CF
3
chiral center is of great importance in organic synthesis. Here, the authors disclose the enantioselective syntheses of α-trifluoromethylated allylic alkanes via reductive trifluoroalkylation.
Journal Article
Regio‐ and enantioselective nickel-alkyl catalyzed hydroalkylation of alkynes
The migratory insertion of metal-hydride into alkene has allowed regioselective access to organometallics, readily participating in subsequent functionalization as one conventional pathway of hydroalkylation, whereas analogous process with feedstock alkyne is drastically less explored. Among few examples, the regioselectivity of metal-hydride insertion is mostly governed by electronic bias of alkynes. To alter the regioselectivity and drastically expand the intermediate pools that we can access, one aspirational design is through alternative nickel-alkyl insertion, providing opposite regioselectivity induced by steric demand. Leveraging in situ formed nickel-alkyl species, we herein report the regio- and enantioselective hydroalkylation of alkynes with broad functional group tolerance, excellent regio- and enantioselectivity, enabling efficient route to diverse valuable chiral allylic amines motifs. Preliminary mechanistic studies indicate the aminoalkyl radical species can participate in metal-capture and lead to formation of nickel-alkyl, of which the migratory insertion is key to reverse regioselectivity observed in metal-hydride insertion.
Although the stereochemistry of nickel hydride addition to alkenes is well-explored, the analogous addition to another feedstock, alkynes, is less studied. Here the authors develop a regio- and enantioselective hydroalkylation of alkynes to produce chiral allylic amines, proceeding via migratory insertion of a nickel–alkyl species into an alkyne pi bond.
Journal Article
Enantioselective Reductive Alkenylation of α‐CF2H (‐CF3) Amino Halides: Rapid Access to Chiral α‐CF2H (‐CF3) Allylamines
The incorporation of fluoroalkyl groups into drug candidates has garnered increasing attention in the pharmaceutical industry due to their ability to modulate lipophilicity, permeability, metabolic stability, and binding affinity. Despite significant advances realized, the means to introducing fluoroalkyl groups such as ─CF2H or ─CF3 in an enantioselective manner remain scarce. Herein, we report a Ni‐catalyzed enantioselective reductive alkenylation of α‐CF2H or ─CF3 amino chlorides with vinyl iodides. This method provides an efficient and modular technique for constructing stereocenters bearing a fluoroalkyl group. A key to success was the incorporation of an arylamide moiety with the substrates, which stabilizes the α‐fluoroalkyl radical intermediate, thus offering a de novo approach to access enantioenriched α‐CF2H (─CF3) allylamines. Our protocol is characterized by its mild reaction conditions, broad substrate scope, as well as excellent enantio—and chemo‐selectivity, even in the context of late‐stage functionalization. Difluoromethyl (CF2H) group, the bioisostere of hydroxyl thiol methyl or amide is privileged in medicinal chemistry due to hydrogen‐binding ability and lipophilic, metabolically stable, and chemical inert nature. However, enatioseleceive CF2H introduction remains challenging. We report a modular approach for the constructing stereocenters bearing CF2H or CF3 groups via Ni‐catalyzed asymmetric reductive alkenylation of α‐CF2H or ‐CF3 amino chlorides with vinyl iodides.
Journal Article
Photocatalytic Synthesis of Pentafluorosulfanyl Ketones, Acetals, and BCP Motifs Utilizing SF6
Sulfur hexafluoride (SF6), a chemically inert and stable gas essential to the electric power industry, poses severe environmental risks due to its persistence and high global warming potential. While traditional degradation methods are inefficient, photocatalytic single electron reduction (SER) enables SF6 activation into SF5 radicals, creating opportunities for both degradation and reutilization. The SF5 group, renowned for its strong electron-withdrawing, lipophilic, and bioisosteric features, has great potential in drug discovery, while efficient methods for synthesizing alkyl- or BCP-SF5 motifs remain scarce. As a safe, inexpensive, and atom-economical alternative to conventional SF5 reagents, SF6 serves as an ideal yet underexplored SF5 source. Herein, we present a photocatalytic strategy for the direct synthesis of diverse SF5-containing scaffolds, including ketones, acetals, and bicyclo[1.1.1]pentane derivatives. Derivatization studies demonstrate its synthetic versatility, particularly in accessing α-SF5-substituted acetaldehydes. Mechanistic and density functional theory (DFT) studies confirm the single electron reduction of SF6, highlighting a mild, efficient, and broadly applicable route for constructing SF5-functionalized architectures in fluorinated drug development.Sulfur hexafluoride (SF6), a chemically inert and stable gas essential to the electric power industry, poses severe environmental risks due to its persistence and high global warming potential. While traditional degradation methods are inefficient, photocatalytic single electron reduction (SER) enables SF6 activation into SF5 radicals, creating opportunities for both degradation and reutilization. The SF5 group, renowned for its strong electron-withdrawing, lipophilic, and bioisosteric features, has great potential in drug discovery, while efficient methods for synthesizing alkyl- or BCP-SF5 motifs remain scarce. As a safe, inexpensive, and atom-economical alternative to conventional SF5 reagents, SF6 serves as an ideal yet underexplored SF5 source. Herein, we present a photocatalytic strategy for the direct synthesis of diverse SF5-containing scaffolds, including ketones, acetals, and bicyclo[1.1.1]pentane derivatives. Derivatization studies demonstrate its synthetic versatility, particularly in accessing α-SF5-substituted acetaldehydes. Mechanistic and density functional theory (DFT) studies confirm the single electron reduction of SF6, highlighting a mild, efficient, and broadly applicable route for constructing SF5-functionalized architectures in fluorinated drug development.
Journal Article
Visible-light-induced, autopromoted nickel-catalyzed three-component arylsulfonation of 1,3-enynes and mechanistic insights
A light-induced, nickel-catalyzed three-component arylsulfonation of 1,3-enynes in the absence of photocatalyst is reported. This methodology exhibited mild conditions, broad scope and high efficiency, and its synthetic utility has been demonstrated by a concise total synthesis of sulfone-containing drug molecule. Detailed mechanistic studies indicated that this light induced nickel catalysis is autopromoted by
in situ
produced allene, which plays a key role as co-ligand in the photoactive excited state Ni(I) species for the LMCT process. The detailed elucidation of this light-induced nickel catalytic cycle may shed some lights on the exploitation of new catalytic activity and establishment of novel methods.
Journal Article