Chiral Brønsted Acid-Catalyzed Asymmetric Allyl(propargyl)boration Reaction of <i>ortho</i>-Alkynyl Benzaldehydes: Synthetic Applications and Factors Governing the Enantioselectivity

Chiral Brønsted acid-catalyzed allyl­(propargyl)­boration of <i>ortho</i>-alkynyl benzaldehydes gives rise to ω-alkynyl homoallylic­(homopropargylic)­alcohols that can be further transformed to complex molecular scaffolds via subsequent hydroalkoxylation, ring-closing enyne metathesis (RCEYM), or intramolecular Pauson–Khand reaction (PKR). Optimizations of each two-step transformation is reported. A strong dependence between enantioselectivities and the nature of the substitution at the alkynyl moiety is observed, showcasing that the triple bond is not merely a spectator in this transformation. Density functional theory (DFT) calculations (M06-2X/6-311+G­(d,p)–IEFPCM//B3LYP/6-31G­(d)) show that this dependence is the result of the steric and electronic properties of the alkyne substituent

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,β-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

Base-Mediated Cascade Rearrangements of Aryl-Substituted Diallyl Ethers

Two base-mediated cascade rearrangement reactions of diallyl ethers were developed leading to selective [2,3]-Wittig–oxy-Cope and isomerization–Claisen rearrangements. Both diaryl and arylsilyl-substituted 1,3-substituted propenyl substrates were examined, and each exhibits unique reactivity and different reaction pathways. Detailed mechanistic and computational analysis was conducted, which demonstrated that the role of the base and solvent was key to the reactivity and selectivity observed. Crossover experiments also suggest that these reactions proceed with a certain degree of dissociation, and the mechanistic pathway is highly complex with multiple competing routes

Efficient Biosynthesis of Fungal Polyketides Containing the Dioxabicyclo-octane Ring System

Aurovertins are fungal poly­ketides that exhibit potent inhibition of adenosine triphosphate synthase. Aurovertins contain a 2,6-dioxa­bicyclo­[3.2.1]­octane ring that is proposed to be derived from a polyene precursor through regio­selective oxidations and epoxide openings. In this study, we identified only four enzymes required to produce auro­vertin E. The core poly­ketide synthase produces a polyene α-pyrone. Following pyrone <i>O-</i>methylation by a methyl­transferase, a flavin-dependent mono-oxygenase and an epoxide hydrolase can iteratively transform the terminal triene portion of the precursor into the dioxa­bicyclo­[3.2.1]­octane scaffold. We demonstrate that a tetra­hydro­furanyl polyene is the first stable intermediate in the transformation, which can undergo epoxidation and anti-Baldwin 6-<i>endo</i>-tet ring opening to yield the cyclic ether product. Our results further demonstrate the highly concise and efficient ways in which fungal biosynthetic pathways can generate complex natural product scaffolds

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