Mechanism and Enantioselectivity in QUINOX-Catalyzed Asymmetric Allylations of Aromatic Aldehydes: Solvent and Substituent Effects.

Computational investigations were conducted on the QUINOX-catalyzed asymmetric allylation of aromatic aldehydes with allyltrichlorosilanes. Our calculations provide evidence that the catalytic allylation can follow distinct mechanisms, depending on the solvent employed. In toluene and CH2Cl2, the QUINOX-catalyzed allylation predominantly follows an associative pathway, while in CH3CN, a dissociative pathway becomes more favorable. Noncovalent interactions, such as π-stacking effects for the associative mechanism and CH/π interactions for the dissociative mechanism, play a pivotal role in enantiostereodifferentiation in the asymmetric QUINOX-catalyzed reactions of benzaldehyde. Furthermore, the study unveils how different aldehyde substituents exert differing influences on the catalytic allylation reaction. Specifically, the QUINOX-catalyzed allylation of 4-(trifloromethyl)benzaldehyde displays a strong preference for the associative pathway, yielding excellent results in both yield and enantioselectivity. Conversely, 4-methoxybenzaldehyde tends to favor a dissociative mechanism with reduced yields and enantioselectivity. The mechanistic basis for these remarkable substituent effects on the catalytic allylation reaction was also elucidated. In summary, this research enhances our understanding of the QUINOX-catalyzed asymmetric allylation, shedding light on the role of solvents and substituents in the reaction mechanism and enantioselectivity.

New insights into the mechanism of synergetic photoredox/copper(i)-catalyzed carbocyanation of 1,3-dienes: a DFT study.

This work presents a DFT-based computational study to understand the mechanism, and regio- and enantioselectivities in the synergetic photoredox/copper(i)-catalyzed carbocyanation of 1,3-dienes with alkyl redox-active esters. The calculated results show an unprecedented copper catalytic mechanism, where the reaction follows a catalytic cycle involving CuI-only catalysis, instead of a Cu(i)/Cu(ii)/Cu(iii)/Cu(i) cycle as proposed in the experimental study. Moreover, it is found that the critical step involves the reaction of the cyanocopper(i) species with an allyl cation rather than the cyanocopper(ii) species reacting with an allyl radical as proposed in the experiment, and that the photocatalyst is regenerated via single electron transfer from the allyl radical to the oxidized photocatalyst. In the newly proposed photoredox/copper(i) catalysis, the reaction consists of four stages: (i) generation of the copper(i) active catalyst, (ii) formation of an allyl radical with oxidative quenching of the photoexcited species, (iii) generation of an allylcopper complex accompanied by the regeneration of the photocatalyst, and (iv) formation of the allyl cyanide product with the regeneration of the copper(i) active catalyst. The cyanation of the allyl cation is calculated to be the regio- and enantioselectivity-determining step. The excellent regio- and stereoselectivities are attributed to the favorable CH-π interaction between the substrate and catalyst as well as the small distortion of the substrate.

Computational study on the prototropic tautomerism between simple oxo-, thio-, carbon-, aza-hydrazones, and their respective azines.

Most hydrazone compounds prefer the azine tautomeric states. However, oxygen-/sulfur-substituted compounds prefer hydrazone tautomers. In this study, density functional theory at M062X level with the basis set of 6-311 + + g(2d, 2p), with MP2/cc-pVTZ for reference, was used to investigate the different tautomeric mechanisms between hydrazone and azine forms with oxygen, sulfur, carbon, and nitrogen as negative centers. The energetic stabilities are in the order as oxygen- < sulfur- < imine- < amidino- < carbene-substituted hydrazones with respect to their azine tautomeric structures. Resonance of the molecular structures might be the geometrical basis for their energy stabilities and were estimated based on HOMED indices. Further, the increased proton affinities in the trend as hydroxyl < sulfhydryl < imine terminal groups account for their increasing azine preferences. Proton release was examined for the reversible equilibrium from azine to hydrazone by calculating the transition energy barrier of H transfer. It is favorable to form hydrazone tautomers for oxygen and sulfur containing groups, while it is less favorable for amino-substituted ones. Azine form is the most stable tautomer for methyl substituted.

Kinetic resolution of cyclic benzylic azides enabled by site- and enantioselective C(sp3)-H oxidation.

Catalytic nonenzymatic kinetic resolution (KR) of racemates remains one of the most powerful tools to prepare enantiopure compounds, which dominantly relies on the manipulation of reactive functional groups. Moreover, catalytic KR of organic azides represents a formidable challenge due to the small size and instability of the azido group. Here, an effective KR of cyclic benzylic azides through site- and enantioselective C(sp3)-H oxidation is described. The manganese catalyzed oxidative KR reaction exhibits good functional group tolerance, and is applicable to a range of tetrahydroquinoline- and indoline-based organic azides with excellent site- and enantio-discrimination. Computational studies elucidate that the effective chiral recognition is derived from hydrogen bonding interaction between substrate and catalyst.

Xylarins A-D, Two Pairs of Diastereoisomeric Isoindoline Alkaloids from the Endolichenic Fungus Xylaria sp.

Two pairs of diastereoisomeric isoindoline alkaloids, xylarins A-D (1-4), were isolated from the endolichenic fungus Xylaria sp. Xylarins A and B (1 and 2) possess a previously undescribed 5/6/5-5/6 polycyclic scaffold, featuring a combination of a novel dihydrobenzofurone unit and an isoindoline unit, while xylarins C and D (3 and 4) contain an additional N,N-dimethylaniline at the C-3' position. Their structures were elucidated by comprehensive spectroscopic analyses combined with single-crystal X-ray diffraction and electronic circular dichroism calculations. The plausible biosynthetic pathways and gene clusters for 1-4 were proposed. Compound 1 exhibited significant antithrombotic activity.

Construction of Vicinal Quaternary Carbon Stereocenters Through Diastereo- and Enantioselective Oxidative 1,6-Conjugate Addition.

The asymmetric construction of vicinal quaternary carbon stereocenters with at least one moiety in acyclic systems is a formidable challenge. We disclose a solution involving diastereo- and enantioselective oxidative 1,6-conjugate addition. The practical asymmetric cross-dehydrogenative coupling of 2,2-diarylacetonitriles and diverse α-substituted cyclic 1,3-dicarbonyls proceeds, for vicinal quaternary carbon stereocenters with one center in acyclic systems, in excellent yields and stereoselectivities. The generality of the approach is further demonstrated by the stereoselective creation of vicinal quaternary carbon stereocenters with both centers in acyclic systems using acyclic ß-ketoesters as coupling partners. Computational studies elucidate the origins of both diastereo- and enantioselectivity.

Enantioselective Total Syntheses of Manginoids†A and†C and Guignardones†A and†C.

An enantioselective synthetic approach for preparing manginoids and guignardones, two types of biogenetically related meroterpenoids, is reported. This bioinspired and divergent synthesis employs an oxidative 1,3-dicarbonyl radical-initiated cyclization and cyclodehydration of the common precursor to forge the central ring of the manginoids and guignardones, respectively, at a late stage. Key synthetic steps include silica-gel-promoted semipinacol rearrangement to form the 6-oxabicyclo[3.2.1]octane skeleton and the Suzuki-Miyaura reaction of vinyl bromide to achieve fragment coupling. This synthesis protocol enables the asymmetric syntheses of four fungal meroterpenoids from commercially available materials.

Catecholic alkaloid sulfonates and aromatic nitro compounds from Portulaca oleracea and screening of their anti-inflammatory and anti-microbial activities.

Acidic compounds were enriched from a water decoction of Portulaca oleracea using 717 anion exchange resin column chromatography. A total of 22 compounds including 9 catecholamine derivatives, of which six were rare sulfonic acid derivatives, and 9 nitro derivatives, were further isolated through various column chromatographic methods, and their structures were elucidated by interpreting their spectroscopic data and ECD calculations. Among them, 16 compounds were isolated from P. oleracea for the first time, 8 of which were undescribed compounds and four compounds were natural products. Pharmacological screening indicated that cis-3-(3-nitro-4-hydroxyphenyl)-methyl acrylate exhibited anti-inflammatory activity, measured as inhibition of nitric oxide production in LPS-stimulated RAW264.7 macrophage cells, with an EC50 value of 18.0 µM, The compounds showed only weak anti-microbial activity with (2R)-(+)-2-chloro-3-(3-nitro-4-hydroxyphenyl)-propionic acid methyl ester inhibiting Candida albicans with a MIC of 256 µg/mL, and 3-methoxy-4,5-dinitrophenol inhibiting Shigella sonnei with a MIC of 512 µg/mL.

Mechanism and Origins of Enantio- and Regioselectivities in Catalytic Asymmetric Minisci-Type Addition to Heteroarenes.

This work presents a density functional theory (DFT) study on the mechanism and origins of enantio- and regioselectivities in dual photoredox/chiral Brønsted acid-catalyzed asymmetric Minisci-type addition of carbon-centered radicals to N-heteroarenes [Science, 2018, 360, 419-422]. The previously proposed mechanism has been partially revised. First, photoexcited *[IrIII] is reductively quenched by TRIP anion rather than the experimentally proposed neutral radical generated from the chiral Brønsted acid cycle. Second, final product formation involves a hydrogen-atom transfer (HAT) from a neutral radical intermediate to the TRIP radical, instead of single-electron transfer (SET) to *[IrIII]. The TRIP catalyst has been shown to play a triple role by reductively quenching *[IrIII] with its anion form, activating the substrate, and inducing asymmetry. The calculated results rationalize the experimentally observed enantio- and regioselectivities and reveal that the enantioselectivity of the reaction originates from the hydrogen-bond interaction between TRIP and the N-H group of the carbon-centered radical, and the regioselectivity arises from the electron-withdrawing inductive effect from the protonated N-atom and the intramolecular hydrogen-bond interaction between the acetylamino group and the protonated pyridine ring. We also provide explanations for the experimentally observed a dramatic decrease in enantioselectivity when changing substrate or radical precursor and rationalize the solvent-controlled switch of regioselectivity.

δ-Cyano substituted para-quinone methides enable access to unsymmetric tri- and tetraarylmethanes containing all-carbon quaternary stereocenters.

para-Quinone methides bearing an electron-withdrawing cyano group at the exocyclic methylene δ-position were identified as valuable 1,6-conjugate addition building blocks for acyclic all-carbon quaternary stereocenter construction. A wide variety of electron-rich arenes as nucleophiles were tolerated, effectively furnishing diverse unsymmetrical triarylmethanes bearing all-carbon quaternary stereocenters. The robust transformable abilities of the cyano group provide a platform to access other valuable functional group-containing unsymmetrical tri- and tetraarylmethanes that are otherwise difficult to be prepared. Computational studies supported the hypothesis that the cyano group at the δ-position tunes the molecular electron-density distribution, and the stability of para-quinone methides is enhanced by lowering their polymerizability.

Computational Study on Why and How of Nonconventional meta-C-H Arylation of Electron-Rich Arenes via Pd/Quinoxaline-Based Ligand/Norbornene Cooperative Catalysis.

By performing density functional theory (DFT) calculation, this work aims at understanding the nonconventional meta-C-H arylation reaction of electronic-rich arenes with aryl iodide via a Pd/quinoxaline-based ligand/norbornene cooperative catalysis. The reaction is indicated to be initiated either from the ortho-C-H carbopalladation to give the meta-monoarylation product via a sequence of subsequent steps, including norbornene insertion, meta-C-H activation, oxidative addition, and reductive elimination via the Pd(II)/Pd(IV)/Pd(II) redox cycle, norbornene extrusion, and protodepalladation, or from the para-C-H carbopalladation to form the meta-diarylation product via two sequential arylation processes following similar mechanisms. The initial carbopalladation process promoted by the ligand is characterized as the rate-determining step of the reaction. The calculated mechanism shows the distinct role of the norbornene as a transient mediator that enables the final C-H arylation at the same meta-position wherever the initial carbopalladation occurs at either ortho- or para-position. The Pd/ligand/norbornene cooperative catalysis is essential for achieving the exclusive meta-selectivity of the C-H arylation of electron-rich arenes.

Terpenoids from the Chinese liverwort Odontoschisma grosseverrucosum and their antifungal virulence activity.

Eight undescribed terpenoids, namely, odongrossins A-H, together with two known terpenoids were isolated from Odontoschisma grosseverrucosum Stephani (Cephaloziaceae). Their structures were established based on NMR data, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction measurements. Odongrossin A and odongrossin G displayed moderate anti-virulence activities against CDR1-and CDR2-efflux-pump-deficient Candida albicans DSY654. Further investigation of odongrossin A revealed that it inhibited adhesion and biofilm formation on C. albicans DSY654. The results regarding the transcription levels of genes demonstrated that odongrossin A could regulate the expression of genes that are associated with the virulence of C. albicans DSY654.

Mechanism and Origin of MAD-Induced Ni/N-Heterocyclic Carbene-Catalyzed Regio- and Enantioselective C-H Cyclization of Pyridines with Alkenes.

This work presents a DFT-based computational study on the regio- and enantioselective C-H functionalization of pyridines with alkenes at the relatively unreactive C4-position, which was successfully achieved by Shi et al. [J. Am. Chem. Soc. 2019, 141, 5628-5634] using Ni0 /N-heterocyclic carbene (NHC) catalysis under the assistance of an aluminum-based Lewis acid additive (2,6-tBu2 -4-Me-C6 H2 O)2 AlMe (MAD). The calculations indicate that the selective functionalization involves a three-step mechanism in which a unique H-migration assisted oxidation metalation (HMAOM) step is identified as the rate- and enantioselectivity-determining step. The newly proposed mechanism can well rationalize the experimental observation that the preferred product is the endo-type (vs. exo-type), R-configuration (vs. S-configuration) product at the C4 (vs. C2) position, and also unveil the reasons that the NHC ligand and the MAD additive can facilitate the reaction.

Theoretical Insight into Palladium(II)-Counterion-Ligand Cooperative Regiodivergent Syntheses of Indolo[3,2-c]coumarins and Benzofuro[3,2-c]quinolinones from Diphenylethyne Derivatives.

With two distinct active sites, 2-hydroxy-2'-amino-diphenylethyne derivatives can offer benzofuro[3,2-c]quinolinones via the O-attack/N-carbonylation cyclization or indolo[3,2-c]coumarins via the N-attack/O-carbonylation cyclization. This work presents a density functional theory-based computational study to understand the mechanism and origin of the palladium(II)-catalyzed regiodivergent reactivity of diphenylethyne derivatives. It is indicated that the reaction features a palladium(II)-counterion-ligand cooperative catalysis. The O-attack/N-carbonylation cyclization mainly benefits from the inductive effect of the rigid electron-withdrawing bidentate nitrogen ligand and the stabilization of the 3c-4e bond between the trifluoroacetate (TFA) anion and the hydroxyl group in the substrate for the precursor and transition state, while the viability of the N-attack/O-carbonylation cyclization stems intrinsically from the stronger nucleophilicity of the N atom as well as the important π-π interaction between the flexible electron-rich bidentate phosphine ligand and the substrate. Moreover, these calculations propose an unconventional reductive elimination mechanism for the transformation from Pd(II) to Pd(0), where the intramolecular nucleophilic attack of the N/O atom on the carbonyl C atom results in the formal reductive elimination product. The calculated overall barriers of 14.8 kcal/mol for Pd(TFA)2 with the bidentate nitrogen ligand and 23.9 kcal/mol for Pd(OTf)2 with the bidentate phosphine ligand are qualitatively consistent with the mild experimental conditions.

Terpenoids from the Chinese liverwort Heteroscyphus coalitus and their anti-virulence activity against Candida albicans.

In this study, 14 previously undescribed terpenoids were isolated from the Chinese liverwort Heteroscyphus coalitus (Hook.) Schiffner, including a rare harziane type diterpenoid, heteroscyphsic acid A; eight ent-clerodane diterpenoids, heteroscyphsic acids B-I; four labdane diterpenoids, heteroscyphins A-D; and one guaiane sesquiterpene, heteroscyphin E; as well as a known ent-junceic acid. Their structures were determined by a combination of MS, NMR spectroscopy, electronic circular dichroism (ECD) and single crystal X-ray diffraction analyses. The anti-virulence activity of the isolated compounds against Candida albicans DSY654 demonstrated that most of them could block hyphal growth at concentrations ranging from 4-32 µg/ml. Further investigation of the most active compound, heteroscyphin D, revealed that it could suppress the ability of C. albicans DSY654 to adhere to A549 cells and form biofilms, and modulate the transcription of related genes in this fungus.

Dual Chalcogen-Chalcogen Bonding Catalysis.

The noncovalent S···O bonding interaction is an evolutionary force that has been smartly exploited by nature to modulate the conformational preferences of proteins. The employment of this type of weak noncovalent force to drive chemical reactions is promising yet remains largely elusive. Herein, we describe a dual chalcogen-chalcogen bonding catalysis strategy that the distinct chalcogen atoms simultaneously interact with two chalcogen-based electron donors to give rise to the catalytic activity, thus facilitating chemical reactions. Conventional approaches to the Rauhut-Currier-type reactions require the use of strongly nucleophilic Lewis bases as essential promoters. The implementation of this dual chalcogen-chalcogen bonding catalysis strategy allows the simultaneous Se···O bonding interaction between chalcogen-bonding donors and an enone and an alcohol, enabling the realization of the Rauhut-Currier-type reactions in a distinct way. The further implementation of a consecutive dual Se···O bonding catalysis approach enables the achievement of an initial Rauhut-Currier-type reaction to give an enone product which further undergoes an alcohol-addition induced cyclization reaction. This work demonstrates that the nearly linear chalcogen-bonding interaction can differentiate similar alkyl groups to give rise to regioselectivity. Moreover, the new strategy shows its advantage as it not only enables less reactive substrates working efficiently but tolerates inaccessible substrates using conventional methods.

Redox deracemization of ß,γ-alkynyl α-amino esters.

The first non-enzymatic redox deracemization method using molecular oxygen as the terminal oxidant has been described. The one-pot deracemization of ß,γ-alkynyl α-amino esters consisted of a copper-catalyzed aerobic oxidation and chiral phosphoric acid-catalyzed asymmetric transfer hydrogenation with excellent functional group compatibility. By using benzothiazoline as the reducing reagent, an exclusive chemoselectivity at the C[double bond, length as m-dash]N bond over the C[triple bond, length as m-dash]C bond was achieved, allowing for efficient deracemization of a series of α-amino esters bearing diverse α-alkynyl substituent patterns. The origins of chemo- and enantio-selectivities were elucidated by experimental and computational mechanistic investigation. The generality of the strategy is further demonstrated by efficient deracemization of ß,γ-alkenyl α-amino esters.

Probing the Interconversion of Labdane Lactones from the Chinese Liverwort Pallavicinia ambigua.

We report on the spontaneous, reversible intramolecular transesterification of natural labdane lactones. Through extensive spectroscopic analysis, the interconversion between the two tautomers was investigated, which could be retarded when the free hydroxy group was acetylated or the exocyclic double bond of the lactone ring was mutated. Besides, a conversion mechanism was postulated, and the energy barriers were calculated by density functional theory calculations. Furthermore, the tautomers were found to inhibit the virulence of the efflux pump-deficient Candida albicans DSY654.

Polyketides from the endolichenic fungus Eupenicillium javanicum and their anti-inflammatory activities.

Seven undescribed polyketides javanicols A-E, 5-epi-citreoviridin and 5-epi-isocitreoviridin, together with five known compounds, were isolated from the endolichenic fungus Eupenicillium javanicum. The structures of these polyketides were determined by means of extensive spectroscopic analyses, electronic circular dichroism (ECD) calculations and gauge-independent atomic orbital (GIAO) NMR shift calculations. These compounds were evaluated for potential anti-inflammatory activity against LPS-activated RAW 264.7 cells. Javanicol E and (+)-terrein displayed moderate inhibitory effects on NO production, with IC50 values of 17.00 and 13.46 µM, respectively.

DFT Study on Photosensitizer-Free Visible-Light-Mediated Au-Catalyzed cis-Difunctionalization of Alkynes: Mechanism and Selectivities as Compared to Rh Catalysis.

Density functional theory (DFT) calculations were performed to investigate the photosensitizer-free visible-light-mediated gold-catalyzed cis-difunctionalization of alkynes with aryl diazonium salts. The detailed reaction mechanism is established, and the observed regio- and chemoselectivities are rationalized. The results are compared to those of the rhodium-catalyzed cis-difunctionalization of alkynes. It is indicated that the excitation of the aryl diazonium salt initiates the photocatalytic cycle, and the following single-electron transfer between the Au(I) catalyst and the excited aryl diazonium salt affords the key aryl radical. Both gold- and rhodium-catalyzed reactions involve two major steps: alkyne insertion into the M-N or M-C bond (M = Au, Rh), and C-C or C-N reductive elimination from the M(III) center. The cis-difunctionalized product can be obtained by the trimethylsilyl (TMS)-substituted alkyne through the gold catalysis or by the Ph-substituted alkyne through the rhodium catalysis. The catalyst-dependent reactivity switch of TMS- and Ph-substituted alkynes is attributed to the catalyst-induced shift of the rate-determining step.