Organocatalytic Enantioselective [1,2]-Stevens Rearrangement of Azetidinium Salts.

The first organocatalyzed enantioselective [1,2]-Stevens rearrangement is reported. 4-Alkylideneproline derivatives are produced in up to 86% yield and in up to 90:10 er, with recrystallization enhancing er up to >99.5:0.5. Product configuration was opposite that predicted by existing stereochemical models for this organocatalyst class, and DFT calculations revealed a novel mode of asymmetric induction. The adaptability of this catalytic strategy for asymmetric [1,2]-Stevens rearrangements of other heterocyclic amines was demonstrated.

Isothiourea-Catalysed Acylative Dynamic Kinetic Resolution of Tetra-substituted Morpholinone and Benzoxazinone Lactols.

The development of methods to allow the selective acylative dynamic kinetic resolution (DKR) of tetra-substituted lactols is a recognised synthetic challenge. In this manuscript, a highly enantioselective isothiourea-catalysed acylative DKR of tetra-substituted morpholinone and benzoxazinone-derived lactols is reported. The scope and limitations of this methodology have been developed, with high enantioselectivity and good to excellent yields (up to 89%, 99:1 er) observed across a broad range of substrate derivatives incorporating substitution at N(4) and C(2), di- and spirocyclic substitution at C(5)- and C(6)-position, as well as benzannulation (>35 examples in total). The DKR process is amenable to scale-up on a 1 g laboratory scale. The factors leading to high selectivity in this DKR process have been probed through computation, with an N-C=O•••isothiouronium interaction identified as key to producing ester products in highly enantioenriched form.

Acetate Assistance in Regioselective Hydroamination of Allenamides: A Combined Experimental and Density Functional Theory Study.

A key factor in the development of selective nucleophilic addition to allenamides is controlling the reactivity of electrophilic intermediates, which is generally achieved using an electrophilic activator via conjugated iminium intermediates. In this combined experimental and computational study, we show that a general and highly chemoselective hydroamination of allenamides can be accomplished using a combination of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and NaOAc. Experimental mechanistic studies revealed that HFIP mediates proton transfer to activate the allenamide, while the acetate additive significantly contributes to N-selective interception. This strategy enables a general hydroamination of allenamides without the use of metals. We demonstrated that various functionalized 1,3-diamines could be readily synthesized and diversified into value-added structural motifs. Detailed mechanistic investigations using the density functional theory revealed the role of NaOAc in the formation of reactive electrophilic intermediates, which ultimately governed the selective formation of 1,3-diamine products. Critically, calculations of the potential energy surface around the proton-transfer transition state revealed that two different reactive electrophilic intermediates were formed when NaOAc was added.

Elucidation of the role of metals in the adsorption and photodegradation of herbicides by metal-organic frameworks.

Here, four MOFs, namely Sc-TBAPy, Al-TBAPy, Y-TBAPy, and Fe-TBAPy (TBAPy: 1,3,6,8-tetrakis(p-benzoic acid)pyrene), were characterized and evaluated for their ability to remediate glyphosate (GP) from water. Among these materials, Sc-TBAPy demonstrates superior performance in both the adsorption and degradation of GP. Upon light irradiation for 5 min, Sc-TBAPy completely degrades 100% of GP in a 1.5 mM aqueous solution. Femtosecond transient absorption spectroscopy reveals that Sc-TBAPy exhibits enhanced charge transfer character compared to the other MOFs, as well as suppressed formation of emissive excimers that could impede photocatalysis. This finding was further supported by hydrogen evolution half-reaction (HER) experiments, which demonstrated Sc-TBAPy's superior catalytic activity for water splitting. In addition to its faster adsorption and more efficient photodegradation of GP, Sc-TBAPy also followed a selective pathway towards the oxidation of GP, avoiding the formation of toxic aminomethylphosphonic acid observed with the other M3+-TBAPy MOFs. To investigate the selectivity observed with Sc-TBAPy, electron spin resonance, depleted oxygen conditions, and solvent exchange with D2O were employed to elucidate the role of different reactive oxygen species on GP photodegradation. The findings indicate that singlet oxygen (1O2) plays a critical role in the selective photodegradation pathway achieved by Sc-TBAPy.

Integrating High-Resolution Mass Spectral Data, Bioassays and Computational Models to Annotate Bioactives in Botanical Extracts: Case Study Analysis of C. asiatica Extract Associates Dicaffeoylquinic Acids with Protection against Amyloid-ß Toxicity.

Rapid screening of botanical extracts for the discovery of bioactive natural products was performed using a fractionation approach in conjunction with flow-injection high-resolution mass spectrometry for obtaining chemical fingerprints of each fraction, enabling the correlation of the relative abundance of molecular features (representing individual phytochemicals) with the read-outs of bioassays. We applied this strategy for discovering and identifying constituents of Centella asiatica (C. asiatica) that protect against Aß cytotoxicity in vitro. C. asiatica has been associated with improving mental health and cognitive function, with potential use in Alzheimer's disease. Human neuroblastoma MC65 cells were exposed to subfractions of an aqueous extract of C. asiatica to evaluate the protective benefit derived from these subfractions against amyloid ß-cytotoxicity. The % viability score of the cells exposed to each subfraction was used in conjunction with the intensity of the molecular features in two computational models, namely Elastic Net and selectivity ratio, to determine the relationship of the peak intensity of molecular features with % viability. Finally, the correlation of mass spectral features with MC65 protection and their abundance in different sub-fractions were visualized using GNPS molecular networking. Both computational methods unequivocally identified dicaffeoylquinic acids as providing strong protection against Aß-toxicity in MC65 cells, in agreement with the protective effects observed for these compounds in previous preclinical model studies.

Dual Function of N-Iodosuccinimide for C(sp3)-B Bond Activation.

A practical method for C(sp3)-B bond activation was developed. Using a combination of alkyl trifluoroborates and N-iodosuccinimide (NIS), various C(sp3)-heteroatom bonds were readily generated in an efficient manner. Mechanistic studies revealed the bifunctional ability of NIS: mediating the formation of reactive halogenated intermediates and activating them via halogen bonding. This electrophilic activation of the reaction center enables the utilization of general heteroatom nucleophiles, which are used in a limited capacity in traditional 1,2-metalate rearrangements.

Investigating Substituent Interactions with Cationic Catalysts.

Rates of isothiourea catalyzed silylation and acylation reactions were measured for substrates with various electronic substituents at the aryl group. Through these measurements, the intermolecular interactions between cationic catalyst intermediates and different aryl groups were explored. These studies were performed to understand how changes in the catalyst structure affected electrostatic intermolecular interactions. Three different catalysts (N-methylimidazole and two isothioureas) were employed that varied in their ability to delocalize their cationic nature. The results show that more delocalization on the catalyst reduces the sensitivity to the electronics on the aryl group. Surprisingly, the isothiourea with a fused benzene ring provided additional points of interaction with groups that contained lone-pairs, significantly affecting the overall rate. This work helps explore the interactions that dominate in these types of catalytic systems, to aid in future organocatalysis development. Density functional theory (DFT) studies further confirmed isothiourea/aryl ring interaction with the alcohol substrate in the acylation process, which confirmed these hypotheses. Electron rich or lone-pair bearing functional groups stabilize the cationic catalyst core, thereby stabilizing the transition states and accelerating the reaction. It was also discovered that in one case, the formation of a stable substrate dimer was responsible for its lower reactivity.

Light-Driven Enantioselective Carbene-Catalyzed Radical-Radical Coupling.

An enantioselective carbene-catalyzed radical-radical coupling of acyl imidazoles and racemic Hantzsch esters is disclosed. This method involves the coupling of an N-heterocyclic carbene-derived ketyl radical and a secondary sp3 -carbon radical and allows access to chiral α-aryl aliphatic ketones in moderate-to-good yields and enantioselectivities without any competitive epimerization. The utility of this protocol is highlighted by the late-stage functionalization of various pharmaceutical compounds and is further demonstrated by the transformation of the enantioenriched products to biologically relevant molecules. Computational investigations reveal the N-heterocyclic carbene controls the double-facial selectivity of the ketyl radical and the alkyl radicals, respectively.

General Hydroamination of Allenamides: Mechanistic Insights with an Acetate Adduct and 1,1,1,3,3,3-Hexafluoro-2-propanol.

The 1,1,1,3,3,3-hexafluoro-2-propanol-assisted allenamide activation enables metal-free regioselective intermolecular interception of amines, constituting a general C-N bond formation process for accessing value-added 1,3-diamines. Exclusive N-chemoselectivity (vs C for anilines) and regioselectivity were achieved for a broad range of substrates. Late-stage modification and further transformations of the 1,3-diamine products showcased the practicability and benefits of this strategy. Experimental mechanistic studies revealed that 1,1,1,3,3,3-hexafluoro-2-propanol mediates the proton transfer for activation of the allenamide. Density functional theory computations revealed the role of NaOAc in the formation of the reactive electrophilic intermediate, which ultimately governs the selective formation of the 1,3-diamine product.

Stereospecific Acylative Suzuki-Miyaura Cross-Coupling: General Access to Optically Active α-Aryl Carbonyl Compounds.

A novel strategy for the stereospecific Pd-catalyzed acylative cross-coupling of enantiomerically enriched alkylboron compounds has been developed. The protocol features an extremely high level of enantiospecificity to allow facile access to synthetically challenging and valuable chiral ketones and carboxylic acid derivatives. The use of a sterically encumbered and electron-rich phosphine ligand proved to be crucial for the success of the reaction. Furthermore, on the basis of experimental and computational studies, a unique mechanism for the transmetalation, assisted by the noncovalent interactions of the C(sp3)-based organoboron reagent, has been identified.

Regiodivergent metal-catalyzed B(4)- and C(1)-selenylation of o-carboranes.

Regiodivergent transition metal-catalyzed B(4)- and C(1)-selenylation reactions of o-carboranes have been demonstrated. Namely, Ru(ii)-catalysis selectively generated B(4)-selenylated o-carboranes from the reaction of o-carborane acids with arylselenyl bromides with the release of carbon dioxide. In contrast, Pd(ii) catalysis provided exclusively C(1)-selenylated o-carboranes from the decarboxylative reaction of o-carborane acids with diaryl diselenides. In contrast to previous milestones in this area, these reactions demonstrate broad substrate scope with excellent yields. Combination of these methods leads to the formation of B(4)-C(1)-diselenylated o-carboranes. DFT studies revealed the mechanism of the Ru-process, with initial selenylation of the carborane cluster discovered to be essential for an energetically reasonable decarboxylation. This results in selenylation on the B(4) position prior to the decarboxylation event at C(1). This contrasted with the Pd-process in which the ready decarboxylation at C(1) leads to selenylation at C(1).

Alkyl Sulfonyl Fluorides Incorporating Geminal Dithioesters as SuFEx Click Hubs via Water-Accelerated Organosuperbase Catalysis.

Sulfur(VI) fluoride exchange (SuFEx) is recognized as another emerging tool for click chemistry. The preparation of the functionalized alkyl sulfonyl fluorides as key SuFEx hubs via C(sp3)-C(sp3) bond formation is exceptionally challenging. We report herein a new efficient method for accessing alkyl sulfonyl fluorides incorporating γ-geminal dithioester via phosphazene catalysis. The aqueous, neutral organosuperbase catalytic system amplifies the reactivity by taking advantage of the hydrophobic amplification. SuFEx-active products are applied to the click connection of bioactive molecules. Density functional theory studies show that the selective outcome of the product is guided by an ion-pair organosuperbase catalyst assembly that is potentially stabilized by a hydrogen-bonding interaction between the catalyst and the DTM in the C(sp3)-C(sp3) bond-forming transition structure.

Enantioselective Copper-Catalyzed Borylative Amidation of Allenes.

An approach for the copper-catalyzed synthesis of enantioenriched amides bearing an α-stereogenic center is disclosed. This method involves the addition of an allyl copper species to an isocyanate and allows access to α-substituted chiral amides in high yields and high-to-excellent enantioselectivities. The utility of α-vinyl ß-boryl amides in synthesis is highlighted by the diversification of products to afford highly useful scaffolds. DFT calculations reveal that the catalyst preferentially coordinates to the oxygen of the isocyanate. Enantiocontrol arises from the steric repulsion between the boryl group and the stereodirecting phenyl of the chiral ligand.

Cu(II)-Catalyzed Unsymmetrical Dioxidation of gem-Difluoroalkenes to Generate α,α-Difluorinated-α-phenoxyketones.

A Cu-based catalyst system convergently couples gem-difluoroalkenes with phenols under aerobic conditions to deliver α,α-difluorinated-α-phenoxyketones, an unstudied hybrid fluorinated functional group. Composed of α,α-difluorinated ketone and α,α-difluorinated ether moieties, these compounds have rarely been reported as a synthetic intermediate. Computational predictions and later experimental corroboration suggest that the phenoxy-substituted fluorinated ketone's sp3-hybridized hydrate form is energetically favored relative to the respective nonether variant and that perturbation of the electronic character of the ketone can further encourage the formation of the hydrate. The more facile conversion between ketone and hydrate forms suggests that analogues should readily covalently inhibit proteases and other enzymes. Further functionalization of the ketone group enables access to other useful fluorinated functional groups.

DyKAT by DiCat: Stereoconvergent Dienamine-Catalyzed Claisen Rearrangements.

This Claisen rearrangement establishes the feasibility of DyKAT of γ-epimeric enals via dienamine formation to afford enantioenriched products. γ-Aryl and -alkyl enals, and exocyclic enals that introduce quaternary centers, are all amenable substrates. Products are readily converted into pyrrolidines or cyclopentenols. Notably, a reactive dienamine intermediate has been isolated from a catalytic reaction, fully characterized, and converted to product upon reexposure to reaction conditions. Product configuration arises from a directing C-H···π interaction in the transition state.

Computation-Assisted Identification of Bioactive Compounds in Botanical Extracts: A Case Study of Anti-Inflammatory Natural Products from Hops.

The slow pace of discovery of bioactive natural products can be attributed to the difficulty in rapidly identifying them in complex mixtures such as plant extracts. To overcome these hurdles, we explored the utility of two machine learning techniques, i.e., Elastic Net and Random Forests, for identifying the individual anti-inflammatory principle(s) of an extract of the inflorescences of the hops (Humulus lupulus) containing hundreds of natural products. We fractionated a hop extract by column chromatography to obtain 40 impure fractions, determined their anti-inflammatory activity using a macrophage-based bioassay that measures inhibition of iNOS-mediated formation of nitric oxide, and characterized the chemical composition of the fractions by flow-injection HRAM mass spectrometry and LC-MS/MS. Among the top 10 predictors of bioactivity were prenylated flavonoids and humulones. The top Random Forests predictor of bioactivity, xanthohumol, was tested in pure form in the same bioassay to validate the predicted result (IC50 7 µM). Other predictors of bioactivity were identified by spectral similarity with known hop natural products using the Global Natural Products Social Networking (GNPS) algorithm. Our machine learning approach demonstrated that individual bioactive natural products can be identified without the need for extensive and repetitive bioassay-guided fractionation of a plant extract.

Dinuclear Pt(II) Complexes with Red and NIR Emission Governed by Ligand Control of the Intramolecular Pt-Pt Distance.

Red and near-infrared (NIR) phosphorescent double-decker dinuclear Pt(II) complexes were synthesized, and their structural and spectroscopic properties were characterized. The Pt(II) complexes, which are composed of achiral ligands and are themselves chiral, were shown to exist as racemic mixtures using single-crystal X-ray crystallography. The Pt(II) complexes have different intramolecular Pt-Pt distances that are governed by the electronic characteristics of the component C^N ligands. Specifically, strengthening of π-back-donation between Pt(II) and N atom of the C^N ligand leads to shortening of the Pt-Pt distance. The results of both experimental and computational investigations show that the Pt-Pt distances in the dinuclear Pt(II) complexes significantly influence the band gap energies and corresponding emission wavelengths. Consequently, the uncovered C^N ligand based method to finely control intramolecular Pt-Pt distances in dinuclear Pt(II) complexes can be utilized as a guideline for the design of the double-decker dinuclear Pt(II) complexes with red and NIR tuned phosphorescence.

Silaborative Assembly of Allenamides and Alkynes: Highly Regio- and Stereocontrolled Access to Bi- or Trimetallic Skipped Dienes.

A highly stereo- and regiocontrolled multicomponent approach to skipped 1,4-dienes decorated with one boryl and two silyl functionalities is described. This Pd-catalyzed atom-economical union of allenamides, alkynes, and Me2 PhSiBpin (or Et3 SiBpin) proceeds without the use of phosphine ligands, instead relying on chelation through the internal amide group of the allenamide sulfonyl. A variety of alkynes, including those derived from complex bioactive molecules, can be efficiently coupled with allenamides and Me2 PhSiBpin in good yields and with excellent selectivity. The synthetic potential was demonstrated through multiple valuable chemoselective transformations, establishing new disconnections for functionalized dienes. Density functional theory calculations revealed that the reaction first proceeded through borylation of the allenamide, followed by silylation of the alkyne and then reductive elimination, which convergently assemble the skipped 1,4-diene.

Light-Driven Carbene Catalysis for the Synthesis of Aliphatic and α-Amino Ketones.

Single-electron N-heterocyclic carbene (NHC) catalysis has gained attention recently for the synthesis of C-C bonds. Guided by density functional theory and mechanistic analyses, we report the light-driven synthesis of aliphatic and α-amino ketones using single-electron NHC operators. Computational and experimental results reveal that the reactivity of the key radical intermediate is substrate-dependent and can be modulated through steric and electronic parameters of the NHC. Catalyst potential is harnessed in the visible-light driven generation of an acyl azolium radical species that undergoes selective coupling with various radical partners to afford diverse ketone products. This methodology is showcased in the direct late-stage functionalization of amino acids and pharmaceutical compounds, highlighting the utility of single-electron NHC operators.

Assessing the oxidative potential of PAHs in ambient PM2.5 using the DTT consumption assay.

The oxidative potential (OP) of atmospheric fine particulate matter (PM2.5) has been linked to organic content, which includes polycyclic aromatic hydrocarbons (PAHs). The OP of 135 individual PAHs (including six subclasses) was measured using the dithiolthreitol (DTT) consumption assay. The DTT assay results were used to compute the concentration of each PAH needed to consume 50% of the DTT concentration in the assay (DTT50), and the reduction potential of the PAHs (ΔGrxn). Computed reduction potential results were found to match literature reduction potential values (r2 = 0.97), while DTT50 results had no correlations with the computed ΔGrxn values (r2 < 0.1). The GINI equality index was used to assess the electron distribution across the surface of unreacted and reacted PAHs. GINI values correlated with ΔGrxn in UPAH, HPAH, and OHPAH subclasses, as well as with all 135 PAHs in this study but did not correlate with DTT50, indicating that electron dispersion is linked to thermodynamic reactions and structural differences in PAHs, but not linked to the OP of PAHs. Three ambient PM2.5 filters extracts were measured in the DTT assay, alongside mixtures of analytical standards prepared to match PAH concentrations in the filter extracts to test if the OP follows an additive model of toxicity. The additive prediction model did not accurately predict the DTT consumption in the assay for any of the prepared standard mixtures or ambient PM2.5 filter extracts, indicating a much more complex model of toxicity for the OP of PAHs in ambient PM2.5. This study combined computed molecular properties with toxicologically relevant assay results to probe the OP of anthropogenically driven portions of ambient PM2.5, and results in a better understanding of the complexity of ambient PM2.5 OP.