Search Results (109)

Hexahydrocannabinol (HHC), a hydrogenated derivative of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), is a semi-synthetic cannabinoid marketed as an alternative to Δ⁹-THC. Its hydroxylated metabolite, 8-hydroxyhexahydrocannabinol (8-OH-HHC), exists as four stereoisomers: (6aR,8R,9R,10aR), (6aR,8S,9S,10aR), (6aR,8S,9R,10aR), and (6aR,8R,9S,10aR). However, the lack of reference standards has hindered pharmacokinetic and forensic studies. This work reports the first stereoselective synthesis and structural confirmation of all four 8-OH-HHC stereoisomers. Two strategies were employed: hydroboration–oxidation and epoxidation–reduction. Hydroboration of Δ⁸-THC with BH₃·THF followed by oxidation predominantly produced anti-isomers (6aR,8R,9R,10aR) and (6aR,8S,9S,10aR) in moderate yields, along with small amounts of syn-isomer (6aR,8S,9R,10aR), suggesting an atypical mechanistic pathway. In contrast, syn-isomers (6aR,8S,9R,10aR) and (6aR,8R,9S,10aR) were accessed via epoxidation of Δ⁸-THC acetate using mCPBA and subsequent reduction with NaBH₃CN/BF₃·OEt₂, affording the desired products with moderate selectivity. Absolute configurations were confirmed by nuclear Overhauser effect spectroscopy (NOESY). These methods will facilitate future pharmacokinetic and forensic research and support the development of improved detection strategies. Full article

The western hemlock looper, Lambdina fiscellaria lugubrosa (Hulst) is a destructive defoliator of coniferous forests and a major cause of economic losses in forestry. A novel and efficient stereoselective synthesis of the sex pheromone of the western hemlock looper (1, 2 and 3) has been successfully achieved. The synthetic strategy integrates several key transformations, including Evans’ chiral auxiliaries, Grignard cross-coupling, hydroboration–oxidation, sulfone alkylation, and hydrogenation, providing an efficient and scalable approach for sex pheromone production. The three synthesized pheromone components were subsequently tested for their ability to attract Semiothisa cinerearia (Bremer & Grey) using both Y-tube and cage bioassays. Notably, compound 1 exhibited a cross-species attractive effect on S. cinerearia, a species that had not previously been documented to respond to the pheromone of L. fiscellaria lugubrosa. This discovery underscores the potential for cross-species attraction, broadens our understanding of pheromone specificity, and emphasizes the value of stereoselectively synthesized pheromones as molecular tools for cross-species pest monitoring and integrated pest management. Full article

Oat seeds contain peroxygenase, a heme enzyme localized in both the microsomal and the lipid droplet fractions, which are usually separated by multiple ultracentrifugation steps. In this work, it was shown that peroxygenase activity is retained in the lipid fraction (LF) of oat seeds, which is obtained by simple extraction of flour with organic solvents. The enzymatic activity of this crude preparation was tested in the oxidation of thioanisole in comparison with a peroxygenase-containing microsome preparation (MP) from the same plant source in both aqueous medium and pure organic solvents. In most cases, higher activity was observed in the LF preparation, which proved to be stable in organic solvents for at least 24 h, thus offering a good option for the oxidation of highly water-insoluble substrates. LF-peroxygenase maintained the same stereoselectivity features observed with MP, as also demonstrated in the epoxidation reaction of limonene. A protocol for the oxidation of thioanisole in CH₃CN was set up on a preparative scale, and the corresponding sulfoxide was obtained at concentration of 1.7 M and with 84% ee. Full article

Strategic scaffolds in molecules increase the possibility of obtaining derivatives with potential uses in scientific and industrial areas. The regio- and stereoselective reactions can be considered to gain these tactical motifs. Natural diterpenes are key molecules for reaching such aims. Among this class of compounds, neo-clerodanes are highlighted by the presence of a furan moiety in their chemical structure. This work describes a regio- and stereoselective strategy to gain beta-lactone and oxirane derivatives from kerlinic acid (1) when the β,γ-unsaturated carboxylic acid system is oxidized, preserving the furan moiety. Oxidation of 1 yielded salviaolide (2), suggesting regio- and stereoselective means. A reaction mechanism was proposed when oxidation of the acetate (1a), benzoate (1b), and methyl ester (1c) derivatives from 1 were gained. The obtention of the epoxide derivative 3, kernolide (4), and kernolide epoxide (5) also supported the reaction mechanism. X-ray diffraction analysis of 3, Karplus-type analyses, and DFT calculations from hypothetical intermediates revealed conformational preferences that guide the regioselectivity. The stereoselectivity was attributed to the natural origin of 1. All compounds were characterized by their physical and spectroscopical data. These results suggest the feasibility of promoting regioselective oxidation on neo-clerodane compounds, preserving the furan moiety. Full article

The stereoselective synthesis of trisubstituted alkenes has become a key topic in modern organic chemistry. At the same time, trisubstituted alkenes also serve as valuable starting materials for a wide range of transformations. However, it remains unclear to what extent these alkenes are utilized in comparison to their mono- and disubstituted counterparts. This review aims to provide a comprehensive overview of fundamental transformations involving all-carbon-substituted trisubstituted alkenes. The first section focuses on additions of carbon, oxygen, and nitrogen nucleophiles, as well as halogenation and carboxylation reactions. The second part discusses oxidative cleavage processes, while the final section addresses the cyclization and cycloisomerization reactions of trisubstituted alkenes. Full article

Inspired by naturally occurring bis-isochromans such as penicisteckins, we envisaged the first synthesis of biaryl-type bis-1-arylisochromans containing a stereogenic ortho-trisubstituted biaryl axis. We achieved the stereoselective synthesis of 5,5′-linked heterodimeric bis-isochromans containing both central and axial chirality elements by performing diastereoselective Suzuki–Miyaura biaryl coupling reactions on two optically active 1-arylpropan-2-ol derivatives, followed by two oxa-Pictet–Spengler cyclizations with aryl aldehydes or methoxymethyl chloride. We studied the diastereoselectivity of the cyclization step, separated the stereoisomeric products with chiral preparative HPLC and determined the absolute configuration through a combination of vibrational circular dichroism (VCD), NMR and single-crystal X-ray diffraction analysis. We demonstrated that different aryl groups could be introduced into the two isochroman subunits, since the dimethoxyaryl subunit reacted faster, enabling the two oxa-Pictet–Spengler cyclizations to be performed separately with different aryl aldehydes. We also explored the acid-catalyzed isomerization and oxidation to axially chiral ortho-quinones in order to produce stereoisomeric and oxidized analogs, respectively. We identified the antibacterial activity of our target bis-isochromans against Bacillus subtilis and Enterococcus faecalis with minimum inhibitory concentrations down to 4.0 and 0.5 μg/mL, respectively, which depend on the stereochemistry and substitution pattern of the bis-isochroman skeleton. Full article

Lupeol, a naturally occurring pentacyclic triterpenoid widely distributed in various medicinal plants, has attracted significant attention due to its diverse pharmacological properties. In this study, we report the synthesis and structural modification of 14 lupeol derivatives through selective functionalizations at C3 and C30 positions of the lupane skeleton, via the sequential chemoselective introduction of carbonyl moieties and the addition of organometallics. Emphasis has been given to the stereoselective alkylation at C3 using a range of carbanions, including organolithiums, organomagnesiums and organoindiums. The C30 position was modified through oxidative pathways to introduce several functionalities. Full article

This study reports an improved diastereoselective synthesis of substituted spiro[chromane-2,4′-pyrimidin]-2′(3′H)-ones via the acid-catalyzed condensation of 6-styryl-4-aryldihydropyrimidin-2-ones with resorcinol, 2-methylresorcinol, and pyrogallol. The optimized method allows for the isolation of diastereomerically pure products, with stereoselectivity controlled by varying acid catalysts (e.g., methanesulfonic acid vs. toluenesulfonic acid) and solvent conditions. The synthesized compounds were evaluated for antimicrobial and antioxidant activities. Notably, the (2S*,4R*,6′R*)-diastereomers exhibited significant antibacterial activity against both Gram-positive and Gram-negative bacterial strains with minimal inhibition concentration down to 2 µg/mL, while derivatives containing vicinal bisphenol moieties demonstrated potent antioxidant activity, with IC₅₀ values (12.5 µg/mL) comparable to ascorbic acid. Pharmacokinetic analysis of selected hit compounds revealed favorable drug-like properties, including high gastrointestinal absorption and blood-brain barrier permeability. These findings highlight the potential of spirochromane-pyrimidine hybrids as promising candidates for further development in the treatment of infectious diseases and oxidative stress-related pathologies. Full article

Spirocyclic architectures, which feature two rings sharing a single atom, are common in natural products and exhibit beneficial biological and material properties. Due to the significance of these architectures, biocatalytic dearomative spirocyclization has recently emerged as a powerful approach for constructing three-dimensional spirocyclic frameworks under mild, sustainable conditions and with exquisite stereocontrol. This review surveys the latest advances in biocatalyzed spirocyclization of all-carbon arenes (phenols and benzenes), aza-aromatics (indoles and pyrroles), and oxa-aromatics (furans). We highlight cytochrome P450s, flavin-dependent monooxygenases, multicopper oxidases, and novel metalloenzyme platforms that effect regio- and stereoselective oxidative coupling, epoxidation/semi-pinacol rearrangement, and radical-mediated cyclization to produce diverse spirocycles. Mechanistic insights gleaned from structural, computational, and isotope-labeling studies are discussed where necessary to help the readers further understand the reported reactions. Collectively, these examples demonstrate the transformative potential of biocatalysis to streamline access to spirocyclic scaffolds that are challenging to prepare through traditional methods, underscoring biocatalysis as a transformative tool for synthesizing pharmaceutically relevant spiroscaffolds while adhering to green chemistry paradigms to ultimately contribute to a cleaner and more sustainable future. Full article

We synthesized 16 representatives of a new class of tetraene macrodiolides with two pharmacophore cis,cis-1,5-diene fragments of the molecule in their structure in rather high yields (from 67 to 84%), which, in turn, were synthesized by a catalytic intermolecular cyclocondensation reaction of α,ω-alka-nZ,(n+4)Z-diendiols with α,ω-alka-nZ,(n+4)Z-diendioic acids using Hf(OTf)₄. The synthesis of starting substrates with 1Z,5Z-diene moieties with a high degree of stereoselectivity was carried out using the authors’ original reaction of catalytic homo-cyclomagnesiation of O-containing allenes. The cytotoxic potential of the examined compounds was assessed using the following cell lines: Jurkat, K562, U937, HL60, HEK293, and Wi-38 (fibroblasts). Biological tests of the synthesized compounds showed a direct effect on mitochondrial biogenesis by the dissociation of oxidation and phosphorylation and the release of cytochrome P450 into the cell cytosol, as well as the induction of mitochondrial apoptosis. The selectivity index demonstrates significant variability, ranging from approximately 2.5 to 5.3 for Jurkat cells and from 3.0 to 5.8 for the other cell lines. Full article

A stereoselective and scalable strategy for the synthesis of phosphorus-containing bicyclic and tricyclic compounds from 1-phenylphosphin-2-en-4-one 1-oxide is presented. This activated dienophile, available in both racemic and enantiopure forms, undergoes smooth [4+2] cycloadditions with acyclic and cyclic dienes, affording products with excellent yields and controlled stereochemistry. Notably, the cis/trans-fusion of the cycloadducts (phosphadecalones and phosphahexahydrochrysene) can be selectively controlled by fine-tuning the conditions of microwave-assisted cycloaddition reaction. The influence of temperature, time, and steric effects on cis/trans and endo/exo selectivity was examined in detail. The molecular structure, including the absolute configuration, of eight products has been determined by X-ray crystallography. These analyses further established the endo-selective nature of the cycloaddition, favoring the P=O face of the dienophile. Post-cycloaddition transformations of selected P-stereogenic phosphadecalone, such as isomerization, reduction and deoxygenation, demonstrate the synthetic versatility of the resulting products. Full article

Quinazolinones, a class of nitrogen-containing heterocyclic compounds, occupy a crucial position in medicinal chemistry and materials science due to their significant application potential. In recent years, the catalytic asymmetric synthesis of axially chiral quinazolinones has emerged as a prominent research area, driven by their prospective applications in the development of bioactive molecules, design of chiral ligands, and fabrication of functional materials. This review comprehensively summarizes recent advancements in the catalytic asymmetric synthesis of axially chiral quinazolinones, with a particular focus on the construction strategies for the three major structural types: the C–N axis, N–N axis, and C–C axis. Key synthetic methodologies, including atroposelective halogenation, kinetic resolution, condensation–oxidation, and photoredox deracemization, are discussed in detail. In addition, the review provides an in-depth analysis of the applications of various catalytic systems, such as peptide catalysis, enzymatic catalysis, metal catalysis, chiral phosphoric acid catalysis, and others. Despite the substantial progress made thus far, several challenges remain, including the expansion of the substrate scope, enhanced control over stereoselectivity, and further exploration of practical applications, such as drug discovery and asymmetric catalysis. These insights are expected to guide future research towards the development of novel synthetic strategies, the diversification of structural variants, and a comprehensive understanding of their biological activities and catalytic functions. Ultimately, this will foster the continued growth and evolution of this rapidly advancing field. Full article

Cytochrome P450 enzymes (CYPs) are versatile heme-containing monooxygenases involved in the metabolism of endogenous and exogenous compounds, as well as natural product biosynthesis. Their ability to catalyze regio- and stereoselective oxidation reactions makes them valuable in pharmaceuticals, fine chemicals, and biocatalysis. However, wild-type CYPs suffer from low catalytic efficiency, limited substrate specificity, and instability under industrial conditions. Recent advances in protein engineering—rational design, semi-rational design, and directed evolution—have enhanced their activity, stability, and substrate scope. These strategies have enabled CYPs to be engineered for applications like C–H functionalization, carbene transfer, and complex molecule biosynthesis. Despite progress, challenges remain in optimizing efficiency, expanding substrate ranges, and scaling production for industrial use. Future directions include integrating CYPs with other biocatalysts, improving high-throughput screening, and applying machine learning to enzyme design. This review highlights recent developments and the promising future of engineered CYPs in sustainable chemistry, drug development, and high-value chemical production. Full article

Pesticides, essential for controlling pests and weeds, significantly boost agricultural productivity. However, their excessive use leads to substantial contamination of environmental matrices, including soil and water. Organophosphorus compounds, which constitute more than 30% of the global use of insecticides and herbicides, are particularly concerning, and their widespread application raises alarms among environmentalists and regulatory agencies due to their high toxicity to aquatic organisms. Therefore, to avoid the spread of these compounds within the environment, the contaminated sites may be treated with various methods. This study explored a soil detoxification procedure utilizing gaseous ozone. As a representative of organophosphorus pesticides, chlorfenvinphos was utilized as soil contaminant. This compound is still reported to occur in a number of environmental matrixes. The method used in this study involved the exposure of the soil matrix in a fluidized state to an ozone-enriched atmosphere. The ozonation procedure enabled the removal of the pesticide from the soil matrix. During its oxidation, some degradation products were detected; in particular, they included 2,4-dichlorobenzoic acid and 2-chloro-1-(2,4-dichloro-phenyl)-ethanone, whose presence was confirmed by a GC-MS system and the NIST database. However, they also underwent degradation. Moreover, on the basis of stereoselective reaction of Z and E isomers, the pesticide degradation pathway was proposed. Additionally, the efficacy of this detoxication method was evaluated using a combination of chronic and acute toxicity tests, employing Eisenia foetida earthworms as bioindicators. On the basis of the obtained results, it can be concluded that organophosphorus herbicides containing unsaturated bonds in their structure, including glyphosate, can be removed using this method. Full article

Salens are a class of important ligands and have been widely applied in asymmetric catalytic organic reactions. Enlarged salen-like ligands containing flexible chains were synthesized from L-phenylalanine, ethane/propanediamines, and salicylaldehydes, and successfully utilized in the scandium-catalyzed enantioselective Michael addition of indoles and enones (2-cinnamoylpyridine 1-oxides). The catalytic system demonstrates excellent reactivity and stereoselective control over electron-rich indole substrates with up to 99% yield and 99% enantiomeric excess. The enlarged Salen ligands with flexible and rigid combined linkers fit their coordination with large rare earth elements. Their coordination abilities were tuned by the electronic effect of substituents on their salicylaldehyde moiety, facilitating the construction of excellent chiral environments in the scandium(III)-catalyzed asymmetric Michael addition of indoles to 2-cinnamoylpyridine 1-oxides. Full article