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The first carbene-catalyzed asymmetric chemoselective cross silyl benzoin (Brook-Benzoin) reaction has been developed. Key steps of this reaction involve activation of the carbon-silicon bond of an acylsilane by a chiral N-heterocyclic carbene (NHC) catalyst to form a silyl acyl anion intermediate. These acyl anions then undergo an addition reaction with indole aldehydes in a highly chemo- and enantioselective manner to afford α-silyloxy ketones with excellent optical purities. The reaction mechanism of this cross Brook-Benzoin reaction was investigated through both experimental and computational methods. The chiral α-hydroxy ketone derivatives obtained by this approach show promising, agrochemically interesting activity against harmful plant bacteria.
(© 2022 Wiley-VCH GmbH.)

A new class of axially chiral thiazine molecules were constructed and showed promising antibacterial activities against the plant pathogen Xanthomonas oryzae pv. oryzae ( Xoo ). The axial chiralities of these compounds ( R - or S -atropisomer) showed clear impacts on the in vitro inhibitory activities against Xoo . An optimal molecule of this class with the ( S )-axially chiral configuration was identified to exhibit inhibitory activity against Xoo with an EC 50 value of 4.18 μg/mL. This inhibition efficiency is superior to that of two commercial antibacterial agrochemicals, thiodiazole-copper and bismerthiazol, as the positive controls. This hit compound also performed better than the controls in our in vivo studies. Preliminary mechanistic studies via scanning electron microscopy images showed that our hit compound at a concentration of 10 μg/mL destroyed the bacterial integrity of Xoo . Label-free quantitative proteomics analysis indicated that a total of 366 differentially expressed proteins of the rice plants were significantly influenced in the presence of our hit molecule.

Catalysis, Imidazoles, Methane analogs derivatives, Carboxylic Acids, and Ketones

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.
(© 2022. The Author(s).)

Trifluoromethylpyridine (TFMP) is a biologically active fragment formed by connecting trifluoromethyl and pyridine ring. As a result of its unique physical and chemical properties and outstanding biological activity, a variety of pesticide compounds with the TFMP fragment have been discovered and marketed and have played important roles in crop protection research. It is therefore a timely and valuable task to summarize the rationality on how to create new molecules containing TFMP fragments based on the structure-activity relationships, design mentality, and potential mechanism. This review gives a brief summary on the pesticides containing TFMP fragments in the past 5 years and introduces the latest progress of our group in this field. The aim is to provide readers with a convenient route to touch this topic and hopefully serve some educational purpose for graduate students as well.

Catalysis, Methane analogs derivatives, Stereoisomerism, Aldehydes, and Sulfones

A carbene-catalyzed sulfonylation reaction between enone aryl aldehydes and sulfonyl chlorides is disclosed. The reaction effectively installs sulfone moieties in a highly enantioselective manner to afford sulfone-containing bicyclic lactones. The sulfonyl chloride behaves both as an oxidant and a nucleophilic substrate (via its reduced form) in this N -heterocyclic carbene (NHC)-catalyzed process. The NHC catalyst provides both activation and stereoselectivity control on a very remote site of enone aryl aldehyde substrates. Water plays an important role in modulating catalyst deactivation and reactivation routes that involve reactions between NHC and sulfonyl chloride. Experimental studies and DFT calculations suggest that an unprecedented intermediate and a new oxidation mode of the NHC-derived Breslow intermediate are involved in the new asymmetric sulfonylation reaction.

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.
(© 2022. The Author(s).)

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.
(© 2022. The Author(s).)

Disclosed herein is the first carbene-organocatalyzed asymmetric addition of phosphine nucleophiles to the in situ generated α,β-unsaturated acyl azolium intermediates. Our reaction enantioselectively constructs carbon-phosphine bonds and prepares chiral phosphines with high optical purities. The phosphine products are suitable for transforming to chiral ligands or catalysts with applications in asymmetric catalysis. The diarylalkyl or trialkyl phosphine products from our catalytic reactions, air-sensitive and reactive in nature, can be trapped (and stored) in their sulfur-oxidized form for operational simplicities.
(© 2021 Wiley-VCH GmbH.)

Atropisomeric molecules have found proven applications and have shown promising potential in chemistry and medicine. The design of N-heterocyclic carbene (NHC) catalyzed reactions to construct atropisomerically enriched molecules has emerged as an important research topic in recent years. These reactions include kinetic resolutions, asymmetric desymmetrizations, central-to-axial chirality conversions, and cycloadditions. This Minireview evaluates and summarizes the progress in NHC-based organic catalysis for access to atropisomers, and briefly states our personal perspectives on the future advancement of this topic. NHC catalysis has provided rich and unique reaction modes that have led to success in the asymmetric synthesis of central-chiral molecules. It is expected that similar success could also be achieved in developing NHC catalysis to prepare atropisomeric molecules, including those not easily accessible by other methods.
(© 2021 Wiley-VCH GmbH.)

Nickel complexes ligated by strongly donating diphosphines catalyze enantioselective hydrogenation for the preparation of acyclic and cyclic β-amido esters. A combination of acetic acid and indium powder provides protons and electrons to form nickel hydrido complexes under umpolung hydrogenation conditions.

A carbene-catalyzed reaction to synthesize chiral dihydroisoquinolinones via an o -quinodimethane ( o -QDM) intermediate is disclosed. o -QDM reacts with cyclic sulfonic imines via annulation to afford highly enantioenriched dihydroisoquinolinone products. ESI-HRMS studies suggest a stepwise Mannich addition and acylation reaction pathway, and the pathways of the catalytic and uncatalyzed background reactions are evaluated via DFT calculations.

Palladium catalyzes a domino Heck arylation and alkylation of nonconjugated cyclodienes to produce trans isomers of disubstituted cyclohexenes in exceptionally high enantiomeric ratios, reaching 100:1 to 200:1 in many cases. Importantly, the interactions of the two CF bonds of Josiphos and the sodium ion of malonates facilitates stereoselective allylic attack through DFT calculations and experiments. This is a new type of attractive noncovalent interactions found in organometallic catalysis.

Symmetric 1,3-diketones with fluorine or fluorinated substituents on the prochiral carbon remain to be established. Herein, we have developed a novel prochiral fluorinated oxindanyl 1,3-diketone and successfully applied these substrates in carbene-catalyzed asymmetric desymmetrization. Accordingly, a versatile strategy for asymmetric generation of organofluorines with fluorine or fluorinated methyl groups has been developed. Multiple stereogenic centers were selectively constructed with satisfactory outcomes. Structurally diverse enantioenriched organofluorines were generated with excellent results in terms of yields, diastereoselectivities, and enantioselectivities. Notably, exchanging fluorinated methyl groups to fluorine for this prochiral 1,3-diketones leads to switchable stereoselectivity. Mechanistic aspects and origin of stereoselectivity were studied by DFT calculations. Notably, some of the prepared organofluorines demonstrated competitive antibacterial activities.
(Copyright © 2021 Guanjie Wang et al.)

The construction of an isoquinoline skeleton typically starts with benzene derivatives as substrates with the assistance of acids or transition metals. Disclosed here is a concise approach to prepare isoquinoline analogues by starting with pyridines to react with β-ethoxy α,β-unsaturated carbonyl compounds under basic conditions. Multiple substitution patterns and a relatively large number of functional groups (including those sensitive to acidic conditions) can be tolerated in our method. In particular, our protocol allows for efficient access to tricyclic isoquinolines found in hundreds of natural products with interesting bioactivities. The efficiency and operational simplicity of introducing structural complexity into the isoquinoline frameworks can likely enable the collective synthesis of a large set of natural products. Here we show that fredericamycin A could be obtained via a short route by using our isoquinoline synthesis as a key step.
(This journal is © The Royal Society of Chemistry.)

Azolium cumulenolates are a special type of intermediates in N-heterocyclic carbene catalysis. They contain elongated linear structures with three contiguous C=C bonds and sterically unhindered α-carbon atoms. These structural features make it difficult to develop enantioselective reactions for these intermediates. Here we disclose the first carbene-catalyzed highly enantioselective addition reactions of azolium cumulenolates. The reaction starts with alkynals as the precursors for azolium cumulenolate intermediates that undergo enantioselective addition to activated ketones. From the same set of substrates, both allene and spirooxindole products can be obtained with high yields and excellent enantioselectivities. The allene moieties in our optically enriched products carry rich reactivities and can be transformed to diverse molecules. The spirooxindole scaffolds in our products are important structural motifs in natural products and medicines.
(© 2021 Wiley-VCH GmbH.)

An NHC-catalyzed atroposelective reaction between ynals and urazoles is disclosed. The reaction establishes a chiral C-N axis via an atroposelective [3 + 2] annulation/desymmetrization process. Our reaction allows efficient access to axially chiral and heteroatom-rich urazole derivatives with potential applications in bioactive molecules and catalysis.

4,5-Dihydropyridazinones bearing an aryl substituent at the C6-position are important motifs in drug molecules. Herein, we developed an efficient protocol to access aryl-dihydropyridazinone molecules via carbene-catalyzed asymmetric annulation between dinucleophilic arylidene hydrazones and bromoenals. Key steps in this reaction include polarity-inversion of aryl aldehyde-derived hydrazones followed by chemo-selective reaction with enal-derived α,β-unsaturated acyl azolium intermediates. The aryl-dihydropyridazinone products accessed by our protocol can be readily transformed into drugs and bioactive molecules.
(This journal is © The Royal Society of Chemistry.)

Nickel-catalyzed Heck reaction of cycloalkenes delivers unusual conjugated arylated isomers. Nickel(0) catalysts ligated by chelating dialkylphosphines effectively activate not only aryl triflates as electrophiles, but also less reactive aryl mesylates, tosylates and pivalates. The omission of bases allows nickel hydride species to exist long enough to perform in situ olefin isomerization of initial Heck adducts.

A catalytic atroposelective cycloaddition reaction between thioureas and ynals is developed. This reaction features the first NHC-catalyzed addition of thioureas to acetylenic acylazolium intermediates to eventually set up C-N axial chirality with excellent optical purities. The obtained axially chiral thiazine derivative products bear multiple functional groups and are feasible for further transformations.
(© 2021 Wiley-VCH GmbH.)

A new mode of carbene-catalyzed heteroatom activation and asymmetric reactions is disclosed. The reaction starts with addition of a carbene catalyst to a (benz)imidazole-derived aldimine substrate. Subsequent oxidation and proton transfer lead to the formation of a catalyst-bound triaza-diene as the key intermediate, in which the nitrogen atom at a site remote to the catalyst-substrate bond is activated. This unusual triaza-diene intermediate then undergoes highly enantioselective reactions with activated ketones through a concerted asynchronous pathway, as supported by mechanistic studies and preliminary density function theory calculation.
(© 2021 Wiley-VCH GmbH.)