High Regioselectivity Research Articles

Structural basis of the Meinwald rearrangement catalysed by styrene oxide isomerase

Membrane-bound styrene oxide isomerase (SOI) catalyses the Meinwald rearrangement—a Lewis-acid-catalysed isomerization of an epoxide to a carbonyl compound—and has been used in single and cascade reactions. However, the structural information that explains its reaction mechanism has remained elusive. Here we determine cryo-electron microscopy (cryo-EM) structures of SOI bound to a single-domain antibody with and without the competitive inhibitor benzylamine, and elucidate the catalytic mechanism using electron paramagnetic resonance spectroscopy, functional assays, biophysical methods and docking experiments. We find ferric haem b bound at the subunit interface of the trimeric enzyme through H58, where Fe(III) acts as the Lewis acid by binding to the epoxide oxygen. Y103 and N64 and a hydrophobic pocket binding the oxygen of the epoxide and the aryl group, respectively, position substrates in a manner that explains the high regio-selectivity and stereo-specificity of SOI. Our findings can support extending the range of epoxide substrates and be used to potentially repurpose SOI for the catalysis of new-to-nature Fe-based chemical reactions.

Synthesis of Branch-Type 3-Allylindoles from N-Alkyl-N-cinnamyl-2-ethynylaniline Derivatives Using π-Allylpalladium Chloride Complex as a Catalyst.

The reaction of N-alkyl-N-cinnamyl-2-ethynylaniline derivatives 1 via annulation and aza-Claisen-type rearrangement easily afforded corresponding branch-type 3-allylindoles 2 with high regioselectivities in good yields using π-allylpalladium chloride complex as a catalyst.

Copper/Photoredox‐Catalyzed Regioselective 1,4‐Addition to 1,3‐Enynes: A Convenient Access to Perfluoroalkylated Allenes

Comprehensive SummaryA general and broadly applicable copper and photoredox dual‐catalyzed multicomponent 1,4‐perfluoroalkylcyanation of 1,3‐enynes has been developed. This protocol enjoys success with high regioselectivity, mild reaction conditions, and excellent functional‐group tolerance, allowing the facile synthesis of structurally diverse perfluoroalkylated allenes from readily available fluoroalkyl halides, 1,3‐enynes and TMSCN in a one‐pot manner. A reasonable mechanism has been proposed according to a series of control experiments.

Regioselective Propargylic Suzuki-Miyaura Coupling by SciPROP-Iron Catalyst.

The iron-catalyzed Suzuki-Miyaura cross-coupling of secondary propargyl electrophiles with lithium organoborates has been established. A propyl-bridged bulky bisphosphine ligand, SciPROP-TB, cooperated with the bulky TIPS substituent at the alkyne terminal position to achieve the cross-coupling reaction with exclusive propargylic selectivity. The reaction features high functional group compatibility, regioselectivity, and yield with a broad substrate scope. The reaction of an optically active chiral propargyl bromide proceeds with complete racemization, supporting a mechanism involving propargyl radical formation.

P(V)-Promoted Rh-Catalyzed Highly Regioselective Hydroformylation of Styrenes under Mild Conditions.

Hydroformylation of olefins is widely used in the chemical industry due to its versatility and the ability to produce valuable aldehydes with 100% atom economy. Herein, a hybrid phosphate promoter was found to efficiently promote rhodium-catalyzed hydroformylation of styrenes under remarkably mild conditions with high regioselectivities. Preliminary mechanistic studies revealed that the weak coordination between the Rhodium and the P=O double bond of this pentavalent phosphate likely induced exceptional reactivity and high ratios of branched aldehydes to linear products.

Deacylative arylation and alkynylation of unstrained ketones.

Ketones are ubiquitous in bioactive natural products, pharmaceuticals, chemical feedstocks, and synthetic intermediates. Hence, deacylative coupling reactions enable the versatile elaboration of a plethora of chemicals to access complex drug candidates and natural products. Here, we present deacylative arylation and alkynylation strategies for the synthesis of a wide range of alkyl-tethered arenes and alkynes from cyclic ketones and methyl ketones under dual nickel/photoredox catalysis. This reaction begins by generating a pre-aromatic intermediate (PAI) through the condensation of the ketone and N'-methylpicolino-hydrazonamide (MPHA), followed by the oxidative cleavage of the PAI α-C─C bond to form an alkyl radical, which is subsequently intercepted by a Ni complex, facilitating the formation of diverse C(sp3)-C(sp2)/C(sp) bonds with remarkable generality. This protocol features a one-pot reaction capability, high regioselectivity and ring-opening efficiency, mild reaction conditions, and a broad substrate scope with excellent functional group compatibility.

Ligand-Controlled Regiodivergent Alkoxycarbonylation of Trifluoromethylthiolated Internal Alkynes.

Controlling the regioselectivity for the alkoxycarbonylation of unsymmetric internal alkynes is challenging. Herein, a palladium-catalyzed ligand-controlled regiodivergent alkoxycarbonylation of internal trifluoromethylthiolated alkynes was achieved. A series of α- or β-SCF3 acrylates from the same trifluoromethylthiolated alkyne were obtained with moderate to high yield and regioselectivity.

Double Regioselective Thermal Azide-Alkyne Cycloaddition of 1,3-Diynes.

A double regioselective cycloaddition reaction of 1,3-diynes with azide is reported to synthesize fully substituted 5-alkynyl-1,2,3-triazoles without any catalyst, metal, or other factor. Computational studies revealed that the 5-alkynyl-1,2,3-triazole derivative is both kinetically and thermodynamically favorable irrespective of the nature of the substituents at the alkyne termini in 1,3-diynes. The simplicity of the reaction, extremely high regioselectivity under metal-free conditions, wide substrate scope, and good to excellent yields might inspire further studies of the cycloaddition of 1,3-diynes in addition to click chemistry.

Environment Benign Bismuth Based Catalysts for the Expedite Regioselective Ring Opening of Epoxides Under Solvent Free Microwave Condition

AbstractBismuth‐based catalysts, namely Bi(PO4), (BiO)2CO3, BiF3, and Bi2(C2O4)3, are used as mild and efficient tools for the aminolysis of epoxides under solvent‐free conditions with microwave irradiation, which significantly reduced the reaction time. The catalysts employed are environment friendly, cost‐effective, and demonstrated high efficiency in terms of both high yields and regioselectivity.

Dithiophosphinylation of Allenyl Acetates: Access to 1,2-Bis(diphenylphosphino)ethane-Type Bidentate Ligands.

1,2-Bis(diphenylphosphino)ethanes (DPPEs) are versatile and immensely important ligands in transition metal catalysts. Here we report the dithiophosphinylation of readily available allenyl acetates to give DPPEs in high yields and regioselectivity. This protocol features a broad substrate scope and mild conditions, avoiding the use of transition metals and air-sensitive sources of phosphorus. Mechanism studies indicate that the reaction was accomplished via an SN2'-type addition-elimination followed by a 1,4-addition step.

Copper-Catalyzed Enantioselective 1,2-Allylation of Azadienes with Allylboronates.

Catalytic asymmetric 1,2-allylation of aurone-derived azadienes is very difficult to achieve due to the driving force for aromatization and the greater steric hindrance of 1,2-addition compared with 1,4-addition. By taking advantage of the ability of nitrogen ligated metal complexes, we successfully demonstrated the first example of copper-catalyzed 1,2-allylation of azadienes with allylboronates for the highly enantioselective synthesis of homoallylic amines. Meanwhile, the enantioenriched 1,4-addition products could also be obtained through a subsequent 3,3-sigmatropic rearrangement of the 1,2-addition products. Extensive DFT calculations were carried out to elucidate the origins of high regioselectivity (1,2- vs 1,4-) and enantioselectivity.

Chemoselective photocatalytic sulfenylamination of alkenes with sulfenamides via energy transfer

β-Amino sulfides hold significant biological importance, motivating the development of several methods for sulfenylamination of alkenes. However, these methods often involve a three-component system with limited alkene substrate range. In this study, we present a pioneering two-component approach utilizing readily accessible sulfenamides as efficient difunctionalization reagents. Key to its success is the careful selection of a suitable photosensitizer, which enables precise modulation of sulfenamides by promoting unprecedented energy transfer rather than traditional single-electron oxidation. This novel strategy leads to the concurrent formation of N- and S-radical species, ensuring high regioselectivity for both electron-neutral and electron-deficient alkenes. As a result, a wide range of valuable β-amino sulfides, including those with congested amine groups, can be readily synthesized. These findings highlight the potential of this method for the efficient synthesis of diverse functionalized β-amino sulfides.

Diversely regio-oxidative degradation of konjac glucomannan by lytic polysaccharide monooxygenase AA10 and generating antibacterial hydrolysate

Konjac glucomannan (KGM) hydrolysate exhibit various biological activities and health-promoting effects. Lytic polysaccharide monooxygenases (LPMOs) play an important role on enzymatic degradation of recalcitrant polysaccharides to obtain fermentable sugars. It is generally accepted that LPMOs exhibits high substrate specificity and oxidation regioselectivity. Here, a bacteria-derived SmAA10A, with chitin-active with strict C1 oxidation, was used to catalyse KGM degradation. Through ethanol precipitation, two hydrolysed KGM components (4 kDa (KGM-1) and 5 kDa (KGM-2)) were obtained that exhibited antibacterial activity against Staphylococcus aureus. In natural KGM, KGM-1, and KGM-2, the molar ratios of mannose to glucose were 1:2.19, 1:3.05, and 1:2.87, respectively, indicating that SmAA10A preferentially degrades mannose in KGM. Fourier-transform infrared spectroscopy and scanning electron microscopy imaging revealed the breakage of glycosylic bonds during enzymatic catalysis. The regioselectivity of SmAA10A for KGM degradation was determined based on the fragmentation behaviour of the KGM-1 and KGM-2 oligosaccharides and their NaBD4-reduced forms. SmAA10A exhibited diverse oxidation degradation of KGM and generated single C1-, single C4-, and C1/C4-double oxidised oligosaccharide forms. This study provides an alternative method for obtaining KGM degradation components with antibacterial functions and expands the substrate specificity and oxidation regioselectivity of bacterial LPMOs.

Regioselective chain‐straightening polymerization of α‐olefins through 2,ω‐enchainment using amine–imine nickel catalysts

AbstractThe control of the regioselectivity of metal‐catalyzed α‐olefins polymerization is of everlasting interest. Most nickel and palladium catalysts show high regioselectivity involving 2,1‐insertion of α‐olefins and 1,ω‐enchainment chain‐straightening, especially α‐diimine nickel catalysts. In this contribution, we report extremely rare regioselective chain‐straightening polymerization of α‐olefins through 2,ω‐enchainment using unsymmetrical amine–imine nickel catalysts. The polymerizations of α‐olefins (1‐hexene, 1‐octene, and 1‐decene) were studied in detail, and the effects of catalyst structure, reaction temperature, and monomer concentration on the polymerization activity and the regioselectivity were examined. The unsymmetrical N‐substituents of the amine–imine nickel catalysts play a crucial role in the regioselectivity. High regioselectivity involving 80.4% 1,2‐insertion and 84.5% 2,ω‐enchainment is realized to produce amorphous polyolefins without melting temperatures.

Photoredox-Cobaloxime Catalysis for Selective Oxidative Dehydrogenative [4+2] Annulation of Imidazo-Fused Heterocycles with Alkenes.

A selective oxidative [4+2] annulation of alkenes with imidazo-fused heterocycles has been developed by using the synergistic combination of photoredox and cobaloxime catalysts. It allows facile access to various imidazole-fused polyaromatic scaffolds accompanied by H2 evolution. This protocol features high regioselectivity as well as a broad substrate scope. Detailed mechanistic studies indicate that twice the electron/H transfer processes facilitated by this catalytic system achieve the annulation π-extension of imidazo-fused heterocycles with alkenes.

Palladium-Copper-Catalyzed Oxidative Intermolecular [2 + 2 + 2] Coupling-Annulation: Regioselective Synthesis of Multiaryl-Substituted Benzenes.

A palladium-catalyzed intermolecular [2 + 2 + 2] oxidative coupling-annulation of terminal alkenes and alkynes using copper(II) as the oxidant has been developed through direct C-C bond formation. These reactions provide effective access to multiaryl-substituted benzenes with high regioselectivity in the absence of any ligands. The features of this protocol are broad substrate scope, and high atom and step economy. The aggregation-induced emission properties of selected products were further investigated. These synthesized multiaryl-substituted benzenes may be worth exploring for further applications in the fields of advanced functional materials or drugs.

Microwave-assisted palladium-catalyzed conjugate addition of arylsilanes to alkynes

Organosilanes, extensively employed as nucleophiles in coupling reactions, have seen limited application in the catalytic regioselective addition to unsaturated hydrocarbons. In this study, we present a microwave-assisted, palladium-catalyzed conjugate addition reaction involving arylsilanes and activated alkynes. This methodology for the catalytic functionalization of alkynes with organosilicon reagents offers a straightforward route to creating multisubstituted alkenes, boasting high regioselectivity. This efficient and versatile reaction tolerates a broad range of functional groups and substrates, heralding a potent new avenue in synthetic strategy.

Pd‐Catalyzed Highly Regioselective Hydroesterification of Terminal Alkyl Olefins with Formates

Comprehensive SummaryA Pd‐catalyzed regioselective hydroesterification of alkyl terminal olefins with aryl formates is described. A wide variety of linear carboxylic esters bearing various functional groups can be obtained in good yields with high regioselectivities under mild reaction conditions by using 1,2‐DTBPMB or (p‐F‐Ph)3P as ligand. The reaction process is operationally simple and requires no handling of toxic CO or strong acid. The resulting aryl esters can be readily converted to other carboxylic acid derivatives.

Controllable 1,3-Bis-Functionalization of 2-Nitroglycals with High Regioselectivity and Stereoselectivity Enabled by a H-Bond Catalyst.

The selective modification of carbohydrates is significant for producing their unnatural analogues for drug discovery. C1-functionalization (glycosylation) and C1,C2-difunctionalization of carbohydrates have been well developed. In contrast, C3-functionalization or C1,C3-difunctionalization of carbohydrates remains rare. Herein, we report such processes that efficiently and stereoselectively modify carbohydrates. Specifically, we found that trifluoroethanol (TFE) could promote 1,3-bis-indolylation/pyrrolylation of 2-nitroglycals generated carbohydrate derivatives in up to 93% yield at room temperature; slightly reducing the temperature could install two different indoles at the C1- and C3-positions. Switching TFE to a bifunctional amino thiourea catalyst leads to the generation of C3 monosubstituted carbohydrates, which could also be used to construct 1,3-di-C-functionalized carbohydrates. This approach produced a range of challenging sugar derivatives (over 80 examples) with controllable and high stereoselectivity (single isomer for over 90% of the examples). The potential applications of the reaction were demonstrated by a set of transformations including the synthesis of bridged large-ring molecules and gram scale reactions. Biological activities evaluation demonstrated that three compounds exhibit a potent inhibitory effect on human cancer cells T24, HCT116, AGS, and MKN-45 with IC50 ranged from 0.695 to 3.548 μM.

Regio‐ and Atroposelective Ring‐Opening of 1H‐Benzo[4,5]oxazolopyridinones

AbstractThe development of new methods for regio‐ and stereoselective activation of C−O bonds in ethers holds significant promise for synthetic chemistry, offering advantages in terms of environmental sustainability and economic efficiency. Moreover, the C−N atropisomers represent a fascinating and crucial chiral system, extensively found in natural products, pharmaceutical leads, and the frameworks of advanced materials. In this work, we have introduced a nickel‐catalyzed regio‐ and enantioselective carbon‐oxygen arylation reaction for atroposelective synthesis of N‐arylisoquinoline‐1,3(2H,4H)‐diones. The high regioselectivity of C−O cleavage benefits from the high stability of the in situ formed (amido)ethenolate via oxidative addition. Additionally, the self‐activation of the aryl C−O bond facilitates the reaction under mild conditions, leading to outstanding enantioselectivities. The diverse post‐functionalizations of the axially chiral isoquinoline‐1,3(2H,4H)‐diones further highlighted the utility of this protocol in preparing valuable C−N atropisomers, including the chiral phosphine ligands.