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The applications of axially chiral benzonitriles and their derivatives remain mostly unexplored due to their synthetic difficulties. Here we disclose an unusual strategy for atroposelective access to benzonitriles via formation of the nitrile unit on biaryl scaffolds pre-installed with stereogenic axes in racemic forms. Our method starts with racemic 2-arylbenzaldehydes and sulfonamides as the substrates and N-heterocyclic carbenes as the organocatalysts to afford axially chiral benzonitriles in good to excellent yields and enantioselectivities. DFT calculations suggest that the loss of p -toluenesulfinate group is both the rate-determining and stereo-determining step. The axial chirality is controlled during the bond dissociation and CN group formation. The reaction features a dynamic kinetic resolution process modulated by both covalent and non-covalent catalytic interactions. The axially chiral benzonitriles from our method can be easily converted to a large set of functional molecules that show promising catalytic activities for chemical syntheses and anti-bacterial activities for plant protections. Nitriles have proven to be useful functional groups in pharmaceuticals and polymers, both as active moieties themselves or as easy precursors to further transformations, but synthesis of benzonitriles with axial chirality has often been difficult. Here the authors make axially chiral benzonitriles via N-heterocyclic carbene organocatalysis via a dynamic kinetic resolution process.

The carbene and photocatalyst co-catalyzed radical coupling of acyl electrophile and a radical precursor is emerging as attractive method for ketone synthesis. However, previous reports mainly limited to prefunctionalized radical precursors and two-component coupling. Herein, an N -heterocyclic carbene and photocatalyst catalyzed decarboxylative radical coupling of carboxylic acids and acyl imidazoles is disclosed, in which the carboxylic acids are directly used as radical precursors. The acyl imidazoles could also be generated in situ by reaction of a carboxylic acid with CDI thus furnishing a formally decarboxylative coupling of two carboxylic acids. In addition, the reaction is successfully extended to three-component coupling by using alkene as a third coupling partner via a radical relay process. The mild conditions, operational simplicity, and use of carboxylic acids as the reacting partners make our method a powerful strategy for construction of complex ketones from readily available starting materials, and late-stage modification of natural products and medicines. The combination of carbene- and photocatalysis has enabled unorthodox routes to ketone syntheses, but usually requires engineered or activated substrates. Herein the authors present a carbene- and photocatalytic decarboxylative radical coupling of carboxylic acids and acyl imidazoles, in which the carboxylic acids are directly used as radical precursors.

Axially chiral styrenes bearing a chiral axis between a sterically non-congested acyclic alkene and an aryl ring are difficult to prepare due to low rotational barrier of the axis. Disclosed here is an N -heterocyclic carbene (NHC) catalytic asymmetric solution to this problem. Our reaction involves ynals, sulfinic acids, and phenols as the substrates with an NHC as the catalyst. Key steps involve selective 1,4-addition of sulfinic anion to acetylenic acylazolium intermediate and sequential E -selective protonation to set up the chiral axis. Our reaction affords axially chiral styrenes bearing a chiral axis as the product with up to > 99:1 e.r ., > 20:1 E / Z selectivity, and excellent yields. The sulfone and carboxylic ester moieties in our styrene products are common moieties in bioactive molecules and asymmetric catalysis. Axially chiral styrenes bearing a chiral axis between a sterically non-congested acyclic alkene and an aryl ring are difficult to prepare due to low rotational barrier of the axis. Here the authors present a method to form axially chiral styrenes bearing sulfones and carboxylic acids via NHC catalysis.

Carboxylic acids are common moieties in medicines. They can be converted to phthalidyl esters as prodrugs. Unfortunately, phthalidyl esters are now mostly prepared in racemic forms. This is not desirable because the two enantiomers of phthalidyl esters likely have different pharmacological effects. Here we address the synthetic challenges in enantioselective modification of carboxylic acids via asymmetric acetalizations. The key reaction step involves asymmetric addition of a carboxylic acid to the catalyst-bound intermediate. This addition step enantioselectively constructs a chiral acetal unit that lead to optically enriched phthalidyl esters. A broad range of carboxylic acids react effectively under mild and transition metal-free conditions. Preliminary bioactivity studies show that the two enantiomers of chlorambucil phthalidyl esters exhibit different anti-cancer activities to inhibit the growth of Hela cells. Our catalytic strategy of asymmetric acetalizations of carboxylic acids shall benefit future development of chiral phthalidyl ester prodrugs and related molecules. Phthalidyl esters, commonly used prodrug moieties, are mostly prepared as a racemate. Here, the authors report an N-heterocylcic carbene-catalysed enantioselective acetalization of carboxylic acids and dialdehydes to give phthalidyl esters in high yields with good enantioselectivity.

Oxidation of indoles is a fundamental organic transformation to deliver a variety of synthetically and pharmaceutically valuable nitrogen-containing compounds. Prior methods require the use of either organic oxidants ( meta -chloroperoxybenzoic acid, N-bromosuccinimide, t -BuOCl) or stoichiometric toxic transition metals [Pb(OAc) 4 , OsO 4 , CrO 3 ], which produced oxidant-derived by-products that are harmful to human health, pollute the environment and entail immediate purification. A general catalysis protocol using safer oxidants (H 2 O 2 , oxone, O 2 ) is highly desirable. Herein, we report a unified, efficient halide catalysis for three oxidation reactions of indoles using oxone as the terminal oxidant, namely oxidative rearrangement of tetrahydro-β-carbolines, indole oxidation to 2-oxindoles, and Witkop oxidation. This halide catalysis protocol represents a general, green oxidation method and is expected to be used widely due to several advantageous aspects including waste prevention, less hazardous chemical synthesis, and sustainable halide catalysis. Indole oxidation represents a fundamental organic transformation delivering valuable nitrogen compounds. Here, the authors report a general halide catalysis protocol applied to three classes of oxidation reactions of indoles with oxone as a sustainable terminal oxidant.

The activation of the α-carbons of carboxylic esters and related carbonyl compounds to generate enolate equivalents as nucleophiles is one of the most powerful strategies in organic synthesis. We reasoned that the horizons of chemical synthesis could be greatly expanded if the typically inert β-carbons of saturated esters could be used as nucleophiles. However, despite the rather significant fundamental and practical values, direct use of the β-carbons of saturated carbonyl compounds as nucleophiles remains elusive. Here we report the catalytic activation of simple saturated ester β-carbons as nucleophiles (β-carbon activation) using N -heterocyclic carbene organocatalysts. The catalytically generated nucleophilic β-carbons undergo enantioselective reactions with electrophiles such as enones and imines. Given the proven rich chemistry of ester α-carbons, we expect this catalytic activation mode for saturated ester β-carbons to open a valuable new arena for new and useful reactions and synthetic strategies. Direct β-carbon activation of saturated carbonyl compounds represents a significant fundamental challenge in organic chemistry. Here, the catalytic activation of saturated ester β- sp 3 carbon as nucleophile via N -heterocyclic carbene organocatalysis is reported. The catalytically generated nucleophilic β-carbon undergoes enantioselective reactions with various electrophiles.

Conformational isomerization can be guided by weak interactions such as chalcogen bonding (ChB) interactions. Here we report a catalytic strategy for asymmetric access to chiral sulfoxides by employing conformational isomerization and chalcogen bonding interactions. The reaction involves a sulfoxide bearing two aldehyde moieties as the substrate that, according to structural analysis and DFT calculations, exists as a racemic mixture due to the presence of an intramolecular chalcogen bond. This chalcogen bond formed between aldehyde (oxygen atom) and sulfoxide (sulfur atom), induces a conformational locking effect, thus making the symmetric sulfoxide as a racemate. In the presence of N–heterocyclic carbene (NHC) as catalyst, the aldehyde moiety activated by the chalcogen bond selectively reacts with an alcohol to afford the corresponding chiral sulfoxide products with excellent optical purities. This reaction involves a dynamic kinetic resolution (DKR) process enabled by conformational locking and facile isomerization by chalcogen bonding interactions. Conformational isomerization of organic molecules can be guided by noncovalent interactions. Here, the authors report the synthesis of chiral sulfoxides catalyzed by N-heterocyclic carbenes; intramolecular chalcogen bonding interactions are key for conformational locking.

Macrolactones exhibit distinct conformational and configurational properties and are widely found in natural products, medicines, and agrochemicals. Up to now, the major effort for macrolactonization is directed toward identifying suitable carboxylic acid/alcohol coupling reagents to address the challenges associated with macrocyclization, wherein the stereochemistry of products is usually controlled by the substrate’s inherent chirality. It remains largely unexplored in using catalysts to govern both macrolactone formation and stereochemical control. Here, we disclose a non-enzymatic organocatalytic approach to construct macrolactones bearing chiral planes from achiral substrates. Our strategy utilizes N-heterocyclic carbene (NHC) as a potent acylation catalyst that simultaneously mediates the macrocyclization and controls planar chirality during the catalytic process. Macrolactones varying in ring sizes from sixteen to twenty members are obtained with good-to-excellent yields and enantiomeric ratios. Our study shall open new avenues in accessing macrolactones with various stereogenic elements and ring structures by using readily available small-molecule catalysts. Macrolactones exhibit distinct conformational and configurational properties and are widely found in natural products but catalysts to govern both macrolactone formation and stereochemical control remain largely unexplored. Here, the authors disclose an N-heterocyclic carbene (NHC)-catalyzed enantioselective synthesis of chiral macrolactones varying in ring size from sixteen to twenty members that feature distinct configurationally stable planar stereogenicity.

A carbene-catalyzed chemoselective reaction of unsymmetric enedials is disclosed. The reaction provides a concise access to bicyclic furo[2,3-b]pyrroles derivatives in excellent selectivity. A main challenge in this reaction is chemoselective reaction of the two aldehyde moieties in the enedial substrates. Mechanistic studies via experiments suggest that our chemoselectivity controls are mostly achieved on the reducing properties of different sited Breslow intermediates. Several side reactions processes and the corresponding side adducts are also studied by high resolution mass spectroscopy analysis. Our method allows for efficient assembly of the furo[2,3-b]pyrrole structural moieties and their analogues widely found in natural products and pharmaceuticals. Chemoselective reactions of two or multiple functional groups with similar reactivities remain an ongoing challenge in chemistry. Here the authors disclosed a chemoselective reaction of enedial and observed that the high chemoselectivity is mainly controlled via redox (rather than steric) properties of the substrate/catalyst.

In general, the P-centered ring-opening of quaternary phosphirenium salts (QPrS) predominantly leads to hydrophosphorylated products, while the C-centered ring-opening is primarily confined to intramolecular nucleophilic reactions, resulting in the formation of phosphorus-containing cyclization products instead of difunctionalized products generated through intermolecular nucleophilic processes. Here, through the promotion of ring-opening of three-member rings by iodine anions and the quenching of electronegative carbon atoms by iodine cations, we successfully synthesize β -functionalized vinylphosphine oxides by the P-addition of QPrS intermediates generated in situ. Multiple β- iodo-substituted vinylphosphine oxides can be obtained with exceptional regio- and stereo-selectivity by reacting secondary phosphine oxides with unactivated alkynes. In addition, a variety of β -functionalized vinylphosphine oxides converted from C-I bonds, especially the rapid construction of benzo[ b ]phospholes oxides, demonstrates the significance of this strategy. P-centered ring-opening of quaternary phosphirenium salts (QPrS) predominantly leads to hydrophosphorylated products, while the C-centered ring-opening results mainly in the formation of phosphorus-containing cyclization products. Here the authors synthesize β-functionalized vinylphosphine oxides by the P addition of QPrS intermediates generated in situ.