Photochemical Fingerprinting Is a Sensitive Probe for the Detection of Synthetic Cannabinoid Receptor Agonists; toward Robust Point-of-Care Detection.

With synthetic cannabinoid receptor agonist (SCRA) use still prevalent across Europe and structurally advanced generations emerging, it is imperative that drug detection methods advance in parallel. SCRAs are a chemically diverse and evolving group, which makes rapid detection challenging. We have previously shown that fluorescence spectral fingerprinting (FSF) has the potential to provide rapid assessment of SCRA presence directly from street material with minimal processing and in saliva. Enhancing the sensitivity and discriminatory ability of this approach has high potential to accelerate the delivery of a point-of-care technology that can be used confidently by a range of stakeholders, from medical to prison staff. We demonstrate that a range of structurally distinct SCRAs are photochemically active and give rise to distinct FSFs after irradiation. To explore this in detail, we have synthesized a model series of compounds which mimic specific structural features of AM-694. Our data show that FSFs are sensitive to chemically conservative changes, with evidence that this relates to shifts in the electronic structure and cross-conjugation. Crucially, we find that the photochemical degradation rate is sensitive to individual structures and gives rise to a specific major product, the mechanism and identification of which we elucidate through density-functional theory (DFT) and time-dependent DFT. We test the potential of our hybrid "photochemical fingerprinting" approach to discriminate SCRAs by demonstrating SCRA detection from a simulated smoking apparatus in saliva. Our study shows the potential of tracking photochemical reactivity via FSFs for enhanced discrimination of SCRAs, with successful integration into a portable device.

B(C6 F5 )3 -Catalyzed E-Selective Isomerization of Alkenes.

Herein, we report the B(C6 F5 )3 -catalyzed E-selective isomerization of alkenes. The transition-metal-free method is applicable across a diverse array of readily accessible substrates, giving access to a broad range of synthetically useful products containing versatile stereodefined internal alkenes. The reaction mechanism was investigated by using synthetic and computational methods.

Noncovalent Interactions in the Oxazaborolidine-Catalyzed Enantioselective Mukaiyama Aldol.

Current models for oxazaborolidine-catalyzed transition-state structures are determined by C-H···O-B and C-H···O═S formyl hydrogen bonding between the electrophile and catalyst. However, selectivity in the oxazaborolidine-catalyzed Mukaiyama aldol cannot be fully rationalized using these models. Combined density functional theory and noncovalent interaction analyses reveal a new reaction model relying on C-H···O, C-H···π, and π-π interactions between the nucleophile, electrophile, and catalyst to induce selectivity.

Comparing the Performances of Force Fields in Conformational Searching of Hydrogen-Bond-Donating Catalysts.

Here, we compare the relative performances of different force fields for conformational searching of hydrogen-bond-donating catalyst-like molecules. We assess the force fields by their predictions of conformer energies, geometries, low-energy, nonredundant conformers, and the maximum numbers of possible conformers. Overall, MM3, MMFFs, and OPLS3e had consistently strong performances and are recommended for conformationally searching molecules structurally similar to those in this study.

Organocatalytic Enantioselective Sulfa-Michael Additions to α,ß-Unsaturated Diazoketones.

Enantioselective sulfa-Michael additions to α,ß unsaturated diazocarbonyl compounds have been developed. Quinine-derived squaramide was found to be the best catalyst to promote C-S bond formation in a highly stereoselective fashion for alkyl and aryl thiols. The easy-to-follow protocol allowed the preparation of 22 examples in enantiomeric ratios up to 97:3 and reaction yields up to 94%. The mechanism and origins of enantioselectivity were determined through density functional theory (DFT) calculations.

Density Functional Theory in the Prediction of Mutagenicity: A Perspective.

As a field, computational toxicology is concerned with using in silico models to predict and understand the origins of toxicity. It is fast, relatively inexpensive, and avoids the ethical conundrum of using animals in scientific experimentation. In this perspective, we discuss the importance of computational models in toxicology, with a specific focus on the different model types that can be used in predictive toxicological approaches toward mutagenicity (SARs and QSARs). We then focus on how quantum chemical methods, such as density functional theory (DFT), have previously been used in the prediction of mutagenicity. It is then discussed how DFT allows for the development of new chemical descriptors that focus on capturing the steric and energetic effects that influence toxicological reactions. We hope to demonstrate the role that DFT plays in understanding the fundamental, intrinsic chemistry of toxicological reactions in predictive toxicology.

Chiral Phosphoric Acid Catalysis: The Terada Model Revisited.

Since Akiyama and Terada independently reported the introduction of chiral phosphoric acids (CPAs) as effective catalysts for Mannich-type reactions in 2004, the field of CPA catalysis has grown immensely. Terada reported in 2008 the first example of the activation of aldehydes by a CPA. Based on density functional theory (DFT) calculations, Terada proposed a dual activation mode for this enantioselective aza-ene-type reaction between an aldehyde and an enecarbamate. In this model, hydrogen bonds between the catalyst's hydroxyl group and the carbonyl oxygen and the catalyst's P═O and the formyl proton were observed; the nucleophile then attacks without coordination to the catalyst. This reaction model provided the mechanistic basis for understanding Terada's reaction and many other asymmetric transformations. In the present study, DFT calculations are reported that identify a lower-energy mechanism for this landmark reaction. In this new model, hydrogen bonds between the catalyst's hydroxyl group and the aldehyde oxygen and the catalyst's P═O and the NH group of the enecarbamate are seen. The new model rationalizes the stereoselective outcome of Terada's reaction and offers insight into why a more sterically demanding catalyst gives lower levels of enantioselectivity.

Understanding the mechanism of the chiral phosphoric acid-catalyzed aza-Cope rearrangement.

The first catalytic enantioselective aza-Cope rearrangement was reported in 2008 by Rueping et al. The reaction is catalyzed by a 1,1'-bi-2-naphthol-derived (BINOL-derived) phosphoric acid and achieved high yields and enantioselectivities (up to 97 : 3 er with 75% yield). This work utilizes Density Functional Theory to understand the mechanism of the reaction and explain the origins of the enantioselectivity. An extensive conformational search was carried out to explore the different activation modes by the catalyst and, the Transition State (TS) leading to the major product was found to be 1.3 kcal mol-1 lower in energy than the TS leading to the minor product. The origin of this stabilization was rationalized with NBO and NCI analysis: it was found that the major TS has a greater number of non-bonding interactions between the substrate and the catalyst, and shows stronger H-bond interactions between H atoms in the substrate and the O atoms in the phosphate group of the catalyst.

Control of Crystallinity and Stereocomplexation of Synthetic Carbohydrate Polymers from d- and l-Xylose.

Manipulating the stereochemistry of polymers is a powerful method to alter their physical properties. Despite the chirality of monosaccharides, reports on the impact of stereochemistry in natural polysaccharides and synthetic carbohydrate polymers remain absent. Herein, we report the cocrystallisation of regio- and stereoregular polyethers derived from d- and l-xylose, leading to enhanced thermal properties compared to the enantiopure polymers. To the best of our knowledge, this is the first example of a stereocomplex between carbohydrate polymers of opposite chirality. In contrast, atactic polymers obtained from a racemic mixture of monomers are amorphous. We also show that the polymer hydroxyl groups are amenable to post-polymerisation functionalization. These strategies afford a family of carbohydrate polyethers, the physical and chemical properties of which can both be controlled, and which opens new possibilities for polysaccharide mimics in biomedical applications or as advanced materials.

Highly Sensitive Real-Time Isotopic Quantification of Water by ATR-FTIR.

A method has been developed to reliably quantify the isotopic composition of liquid water, requiring only immersion of a "ReactIR" probe in the sample under test. The accuracy and robustness of this method has been extensively tested using a deuterium/protium system, and substantial improvements in sensitivity were obtained using highly novel chemical signal amplification methods demonstrating a standard deviation of 247 ppb D (a δD of 1.6 ‰). This compares favorably with other more costly and time-consuming techniques and is over 20 times more sensitive than any previously published FTIR study. Computational simulations of a model system match the experimental data and show how these methods can be adapted to a tritium/protium system.

Computational Studies of Chiral Hydroxyl Carboxylic Acids: The Allylboration of Aldehydes.

The mechanism of the asymmetric BINOL-derived hydroxyl carboxylic acid catalyzed allylboration of benzaldehyde was investigated using density functional theory calculations. A new reaction model is proposed, and the roles of the two Brønsted acidic sites of the catalyst elucidated. Catalyst distortion was found to be a key factor in determining stereoselectivity. The flexibility of the hydroxyl carboxylic acid catalyst leads to significant differences in the mechanism and origins of selectivity compared to the equivalent phosphoric acid catalyzed reaction.

Enantioselective Total Synthesis of (-)-Finerenone Using Asymmetric Transfer Hydrogenation.

(-)-Finerenone is a nonsteroidal mineralocorticoid receptor antagonist currently in phase III clinical trials for the treatment of chronic kidney disease in type 2 diabetes. It contains an unusual dihydronaphthyridine core. We report a 6-step synthesis of (-)-finerenone, which features an enantioselective partial transfer hydrogenation of a naphthyridine using a chiral phosphoric acid catalyst with a Hantzsch ester. The process is complicated by the fact that the naphthyridine exists as a mixture of two atropisomers that react at different rates and with different selectivities. The intrinsic kinetic resolution was converted into a kinetic dynamic resolution at elevated temperature, which enabled us to obtain (-)-finerenone in both high yield and high enantioselectivity. DFT calculations have revealed the origin of selectivity.

Enantioselective S-H Insertion Reactions of α-Carbonyl Sulfoxonium Ylides.

The first example of enantioselective S-H insertion reactions of sulfoxonium ylides is reported. Under the influence of thiourea catalysis, excellent levels of enantiocontrol (up to 95 % ee) and yields (up to 97 %) are achieved for 31 examples in S-H insertion reactions of aryl thiols and α-carbonyl sulfoxonium ylides.

Photocatalytic α-Tertiary Amine Synthesis via C-H Alkylation of Unmasked Primary Amines.

A practical, catalytic entry to α,α,α-trisubstituted (α-tertiary) primary amines by C-H functionalisation has long been recognised as a critical gap in the synthetic toolbox. We report a simple and scalable solution to this problem that does not require any in situ protection of the amino group and proceeds with 100 % atom-economy. Our strategy, which uses an organic photocatalyst in combination with azide ion as a hydrogen atom transfer (HAT) catalyst, provides a direct synthesis of α-tertiary amines, or their corresponding γ-lactams. We anticipate that this methodology will inspire new retrosynthetic disconnections for substituted amine derivatives in organic synthesis, and particularly for challenging α-tertiary primary amines.

Density Functional Theory Transition-State Modeling for the Prediction of Ames Mutagenicity in 1,4 Michael Acceptors.

Assessing the safety of new chemicals, without introducing the need for animal testing, is a task of great importance. The Ames test, a widely used bioassay to assess mutagenicity, can be an expensive, wasteful process with animal-derived reagents. Existing in silico methods for the prediction of Ames test results are traditionally based on chemical category formation and can lead to false positive predictions. Category formation also neglects the intrinsic chemistry associated with DNA reactivity. Activation energies and HOMO/LUMO energies for thirty 1,4 Michael acceptors were calculated using a model nucleobase and were further used to predict the Ames test result of these compounds. The proposed model builds upon existing work and examines the fundamental toxicant-target interactions using density functional theory transition-state modeling. The results show that Michael acceptors with activation energies <20.7 kcal/mol and LUMO energies < -1.85 eV are likely to act as direct mutagens upon exposure to DNA.

Vinylidene Homologation of Boronic Esters and its Application to the Synthesis of the Proposed Structure of Machillene.

Alkenyl boronic esters are important reagents in organic synthesis. Herein, we report that these valuable products can be accessed by the homologation of boronic esters with lithiated epoxysilanes. Aliphatic and electron-rich aromatic boronic esters provided vinylidene boronic esters in moderate to high yields, while electron-deficient aromatic and vinyl boronic esters were found to give the corresponding vinyl silane products. Through DFT calculations, this divergence in mechanistic pathway has been rationalized by considering the stabilization of negative charge in the C-Si and C-B bond breaking transition states. This vinylidene homologation was used in a short six-step stereoselective synthesis of the proposed structure of machillene, however, synthetic and reported data were found to be inconsistent.

Mechanistic Insights into a Chiral Phosphoric Acid-Catalyzed Asymmetric Pinacol Rearrangement.

The first catalytic enantioselective pinacol rearrangement was reported by Antilla and co-workers in 2010. The reaction was catalyzed by a chiral phosphoric acid and resulted in high levels of enantioselectivity (up to 96% ee). The present study uses density functional theory to investigate the mechanism and origins of stereoselectivity of this important reaction and to explain the difference in selectivity between different catalysts. An OH···O hydrogen bond between the intermediate indolyl alcohol and the phosphate group from the catalyst together with a CH···O hydrogen bond between the indole and the phosphate group were observed in the preferred activation mode for the stereodetermining [1,2]-aryl shift. A stronger CH···O interaction in the major transition state was found to contribute to the high levels of enantioselectivity. A more bulky catalyst (TRIP) was found to impede the formation of the key CH···O interaction, leading to lower levels of enantioselectivity.

Using Transition State Modeling To Predict Mutagenicity for Michael Acceptors.

The Ames mutagenicity assay is a long established in vitro test to measure the mutagenicity potential of a new chemical used in regulatory testing globally. One of the key computational approaches to modeling of the Ames assay relies on the formation of chemical categories based on the different electrophilic compounds that are able to react directly with DNA and form a covalent bond. Such approaches sometimes predict false positives, as not all Michael acceptors are found to be Ames-positive. The formation of such covalent bonds can be explored computationally using density functional theory transition state modeling. We have applied this approach to mutagenicity, allowing us to calculate the activation energy required for α,ß-unsaturated carbonyls to react with a model system for the guanine nucleobase of DNA. These calculations have allowed us to identify that chemical compounds with activation energies greater than or equal to 25.7 kcal/mol are not able to bind directly to DNA. This allows us to reduce the false positive rate for computationally predicted mutagenicity assays. This methodology can be used to investigate other covalent-bond-forming reactions that can lead to toxicological outcomes and learn more about experimental results.

Chronology of CH···O Hydrogen Bonding from Molecular Dynamics Studies of the Phosphoric Acid-Catalyzed Allylboration of Benzaldehyde.

CH···O hydrogen bonds involving formyl groups have been invoked as a crucial factor controlling many asymmetric transformations. We conducted quasi-classical direct molecular dynamics simulations on the phosphoric acid-catalyzed allylboration of benzaldehyde to understand the synergy between the phosphoric acid OH···O hydrogen bond and the secondary CH···O formyl hydrogen bond as the reaction occurs. In the gas phase, both the CH···O and OH···O hydrogen bonds are enhanced from reactants to transition states. In toluene, the trend of H-bond enhancement is observed with a smaller magnitude because of solvent caging. The strength of the formyl hydrogen bond in the TS, a second CH···O interaction between the P═O oxygen and ortho-hydrogen of the phenyl ring and the OH···O hydrogen bond were determined using quantum mechanical calculations (4.6, 1.0, and 14.5 kcal mol-1, respectively).

Theory and Modeling of Asymmetric Catalytic Reactions.

Modern density functional theory and powerful contemporary computers have made it possible to explore complex reactions of value in organic synthesis. We describe recent explorations of mechanisms and origins of stereoselectivities with density functional theory calculations. The specific functionals and basis sets that are routinely used in computational studies of stereoselectivities of organic and organometallic reactions in our group are described, followed by our recent studies that uncovered the origins of stereocontrol in reactions catalyzed by (1) vicinal diamines, including cinchona alkaloid-derived primary amines, (2) vicinal amidophosphines, and (3) organo-transition-metal complexes. Two common cyclic models account for the stereoselectivity of aldol reactions of metal enolates (Zimmerman-Traxler) or those catalyzed by the organocatalyst proline (Houk-List). Three other models were derived from computational studies described in this Account. Cinchona alkaloid-derived primary amines and other vicinal diamines are venerable asymmetric organocatalysts. For α-fluorinations and a variety of aldol reactions, vicinal diamines form enamines at one terminal amine and activate electrophilically with NH(+) or NF(+) at the other. We found that the stereocontrolling transition states are cyclic and that their conformational preferences are responsible for the observed stereoselectivity. In fluorinations, the chair seven-membered cyclic transition states is highly favored, just as the Zimmerman-Traxler chair six-membered aldol transition state controls stereoselectivity. In aldol reactions with vicinal diamine catalysts, the crown transition states are favored, both in the prototype and in an experimental example, shown in the graphic. We found that low-energy conformations of cyclic transition states occur and control stereoselectivities in these reactions. Another class of bifunctional organocatalysts, the vicinal amidophosphines, catalyzes the (3 + 2) annulation reaction of allenes with activated olefins. Stereocontrol here is due to an intermolecular hydrogen bond that activates the electrophilic partner in this reaction. We have also studied complex organometallic catalysts. Krische's ruthenium-catalyzed asymmetric hydrohydroxyalkylation of butadiene involves two chiral ligands at Ru, a chiral diphosphine and a chiral phosphate. The size of this combination strains the limits of modern computations with over 160 atoms, multiple significant steps, and a variety of ligand coordinations and conformations possible. We found that carbon-carbon bond formation occurs via a chair Zimmerman-Traxler-type transition structure and that a formyl CH···O hydrogen bond from aldehyde CH to phosphate oxygen, as well as steric interactions of the two chiral ligands, control the stereoselectivity.