Incorporating fluorine into azoles is not only a common practice but also an essential tactic in medicinal chemistry, due to their ability to fine-tune a molecule's physicochemical, pharmacokinetic, and pharmacodynamic profiles. The strategic introduction of fluorine into nitrogen-containing five-membered heterocycles can significantly enhance metabolic stability, membrane permeability, and binding affinity-key factors in modern drug development. This review provides an up-to-date overview of key synthetic strategies for monofluorination, difluoromethylation, and trifluoromethylation across 11 prominent azoles: 1,2,3-triazoles, 1,2,4-triazoles, tetrazoles, pyrazoles, imidazoles, pyrroles, isoxazoles, oxazoles, thiazoles, thiadiazoles, and isothiazoles. This review aims to identify current limitations in the field and delineate existing research gaps that present further opportunities for innovation in these domains, which are essential for propelling pharmaceutical and biomedical research. By integrating new synthetic advancements and diverse strategies to access them, this review aims to serve as both a practical guide and a source of inspiration for chemists exploring the next generation of fluorinated azole pharmaceuticals.

Isothioureas (ITUs) represent a powerful family of (chiral) Lewis base organocatalysts. Interestingly, the Brønsted basicity of these frequently used compounds has so far not systematically been investigated. Thus, we have now determined the p values of the most privileged (chiral) ITUs in acetonitrile (ACN) and DMSO by using NMR. Employing Wallace's chemical shift imaging NMR method, the herein investigated ITUs were found to be weak Brønsted bases with p values in the range of 16.8-17.9 in ACN and 6.3-7.8 in DMSO.

Fluorinated molecules are core to contemporary drug discovery programs and critical for advancing innovation in numerous fields. In merging these important chemical themes, fluorinated Diels-Alder cycloaddition products are a particularly attractive subset of compounds with significant utility. Herein, an in-depth computational and experimental study of fluorine substitution effects on dienophile partners in Diels-Alder reactions is reported. Of particular focus to this study is understanding the origin of reaction rate deceleration as a consequence of employing fluorinated dienophiles and the factors controlling vs. -selectivity. To unlock insight into this unique reactivity, density function theory calculations, distortion/interaction-activation strain models, energy decomposition analysis and natural bond orbital analysis, among other computational methods, were applied. In addition, the influence of oriented external-electric-field-effects (OEEFs) and local electric field effects were explored. To further probe this effect, experimental studies of charge-enhanced Diels-Alder reactivity with fluorinated dienophiles were conducted. Collectively, this work offers novel mechanistic understanding pertinent to Diels-Alder reactions of fluorinated dienophiles providing valuable fluorinated scaffolds.

This manuscript describes a study of diverse reaction outcomes that stem from the ionization of -alkynyl-Prins adducts. Experimental results have demonstrated unexpected behavior in the nitrogen-containing systems compared to the analogous oxygen derivatives derived from -Prins/-Nazarov sequences. In-depth experimental studies and computational analysis revealed an intricate mechanism involving competing -Nazarov and -Nazarov pathways. These findings further elucidate the reaction chemistry of 3--pentadienyl cation intermediates, and expand their utility in synthetic transformations.

The iboga alkaloids are a family of monoterpene indole alkaloids first discovered from the root of . The major alkaloid constituent in the root, ibogaine, has garnered interest for its anti-addictive properties. Ibogaine has been shown to reduce opiate, amphetamine, alcohol, and nicotine self-administration in rodents. However, ibogaine itself is less than optimal as a treatment in humans for Substance Abuse Disorder (SUD) due to its cardiotoxicity and hallucinogenic potential. Instead, ibogaine is an attractive lead for drug discovery efforts. Indeed, several notable programs have been launched to both elucidate ibogaine's mechanism of action and reduce its toxicity. While there have been over twenty total syntheses of ibogamine, ibogaine, and closely related family members, there are far fewer syntheses of recently isolated iboga alkaloids. In this targeted review, we discuss the synthetic strategies applied to the synthesis of classical and non-classical iboga alkaloids.

We describe the first total syntheses of tabernanthine and ibogaline. Entry to these iboga alkaloid natural products is enabled by a thermal coupling of indoles and aziridines to furnish the requisite nosyl tryptamine starting materials. This route features a Friedel-Crafts type alkylation to form the key indole-isoquinuclidine C-C bond. Finally, a regio- and diastereoselective hydroboration-oxidation enables C-N bond formation to close the isoquinuclidine ring system and deliver tabernanthine and ibogaline in 10 and 14% yield respectively. Both syntheses were completed in eight steps.

-BuNI/KSO mediated C-N coupling between aldehydes and amides is reported. A strong electronic effect is observed on the aromatic aldehyde substrates. The transformylation from aldehyde to amide takes place exclusively when an aromatic aldehyde bears electron-donating groups at either the or position of the formyl group, while the cross-dehydrogenative coupling dominates in the absence of these groups. Both the density functional theory (DFT) thermochemistry calculations and experimental data support the proposed single electron transfer mechanism with the formation of an acyl radical intermediate in the cross-dehydrogenative coupling. The -BuNI/KSO mediated oxidative cyclization between 2-aminobenzamide and aldehydes is also reported, with four quinazolin-4(3)-ones prepared in 65-99% yields.

Compared to ubiquitous functional groups such as alcohols, carboxylic acids, amines, and amides, which serve as central "actors" in most organic reactions, sulfamates, phosphoramidates, and di--butyl silanols have historically been viewed as "extras". Largely considered functional group curiosities rather than launch-points of vital reactivity, the chemistry of these moieties is under-developed. Our research program has uncovered new facets of reactivity of each of these functional groups, and we are optimistic that the chemistry of these fascinating molecules can be developed into truly general transformations, useful for chemists across multiple disciplines. In the ensuing sections, I will describe our efforts to develop new reactions with these "unusual" functional groups, namely sulfamates, phosphoramidates, and di--butyl silanols.

We herein report a two-step approach for the enantioselective synthesis of novel chiral δ-lactams. By using a cooperative chiral ITU/achiral Pd-catalyst system, this protocol proceeds via an asymmetric α-allylation of activated aryl esters first, followed by an acid-mediated lactam formation. A variety of differently substituted products could be obtained with usually high levels of enantioselectivities and in reasonable yields (16 examples, up to 98 : 2 er and 73 % yield over two steps). In addition, further utilizations of the products via transformations of the exocyclic double bond were successfully carried out as well.

Distinct aggregated proteins are correlated with numerous neurodegenerative diseases and the development of ligands that selectively detect these pathological hallmarks is vital. Recently, the synthesis of thiophene-based optical ligands, denoted bi-thiophene-vinyl-benzothiazoles (bTVBTs), that could be utilized for selective assignment of tau pathology in brain tissue with Alzheime's disease (AD) pathology, was reported. Herein, we investigate the ability of these ligands to selectively distinguish tau deposits from aggregated amyloid-β (Aβ), the second AD associated pathological hallmark, when replacing the terminal thiophene moiety with other heterocyclic motifs. The selectivity for tau pathology was reduced when introducing specific heterocyclic motifs, verifying that specific molecular interactions between the ligands and the aggregates are necessary for selective detection of tau deposits. In addition, ligands having certain heterocyclic moieties attached to the central thiophene-vinylene building block displayed selectivity to aggregated Aβ pathology. Our findings provide chemical insights for the development of ligands that can distinguish between aggregated proteinaceous species consisting of different proteins and might also aid in creating novel agents for clinical imaging of tau pathology in AD.

We herein report a two-step protocol for the asymmetric synthesis of novel chiral benzofused ϵ-lactones starting from O-protected hydroxymethyl-para-quinone methides and activated aryl esters. By using chiral isothiourea Lewis base catalysts a broad variety of differently substituted products could be obtained in yields of around 50 % over both steps with high levels of enantioselectivities, albeit low diastereoselectivities only.

Lycorane is a pentacyclic core presented in alkaloids isolated from the family of herbaceous flowering plants. Members of this class of natural products have shown to display important biological properties including analgesic, antiviral, and antiproliferative activities. This review presents the known synthetic routes toward α-, β-, γ-, and δ-lycoranes. α-(19 routes), β-(10 routes), γ-(38 routes), and δ-(6 routes).

Fluorinated carbohydrates are valuable tools for enzymological studies due to their increased metabolic stability compared to their non-fluorinated analogues. Replacing different hydroxyl groups within the same monosaccharide by fluorine allows to influence a wide range of sugar-receptor interactions and enzymatic transformations. In the past, this principle was frequently used to study the metabolism of highly abundant carbohydrates, while the metabolic fate of rare sugars is still poorly studied. Rare sugars, however, are key intermediates of many metabolic routes, such as the pentose phosphate pathway (PPP). Here we present the design and purely chemical synthesis of a set of three deoxyfluorinated analogues of the rare sugars d-xylulose and d-ribulose: 1-deoxy-1-fluoro-d-ribulose (), 3-deoxy-3-fluoro-d-ribulose () and 3-deoxy-3-fluoro-d-xylulose (). Together with a designed set of potential late-stage radio-fluorination precursors, they have the potential to become useful tools for studies on the complex equilibria of the non-oxidative PPP.

YM-254890 and FR900359 are potent and selective inhibitors of the Gq/11-signaling pathway. As such, they have been attractive targets for both synthesis and biological studies. Yet in spite of this effort, a versatile synthetic approach to the molecules that allows for the rapid construction of a variety of non-natural and labelled analogs and an increase in the amount of those analogs available remains elusive. We report here a convergent building block approach to the molecules that can solve this challenge.

Herein we report, a rhodium-catalyzed Fujiwara-Moritani-type reaction of unactivated terminal alkenes and benzoic acid derivatives bearing electron donating residues under mild conditions. The acid functionality acts as a traceless directing group delivering products alkenylated in -position to the electron donating substituent in contrast to the usually obtained - and -substitution in Friedel-Crafts-type reactions. Remarkably, the new C-C bond is formed to the C2 of the terminal olefin, in contrast to similar reported transformations. Initially formed mixtures of - and -double bond isomers can be efficiently isomerized to the more stable -products.

Cyclopropanation reactions between C and different malonates decorated with monosaccharides and steroids using the Bingel-Hirsch methodology have allowed the obtention of a new family of hybrid compounds in good yields. A complete set of instrumental techniques has allowed us to fully characterize the hybrid derivatives and to determine the chemical structure of monocycloadducts. Besides, the proposed structures were investigated by cyclic voltammetry, which evidenced the exclusive reductive pattern of fullerene Bingel-type monoadducts. Theoretical calculations at the DFT-D3(BJ)/PBE 6-311G(d,p) level of the synthesized conjugates predict the most stable conformation and determine the factors that control the hybrid molecules' geometry. Some parameters such as polarity, lipophilicity, polar surface area, hydrophilicity index, and solvent-accessible surface area were also estimated, predicting its potential permeability and capability as cell membrane penetrators. Additionally, a molecular docking simulation has been carried out using the main protease of SARS-CoV-2 (Mpro) as the receptor, thus paving the way to study the potential application of these hybrids in biomedicine.

Asymmetric organocatalysis has experienced a long and spectacular way since the early reports over a century ago by von Liebig, Knoevenagel and Bredig, showing that small (chiral) organic molecules can catalyze (asymmetric) reactions. This was followed by impressive first highly enantioselective reports in the second half of the last century, until the hype initiated in 2000 by the milestone publications of MacMillan and List, which finally culminated in the 2021 Nobel Prize in Chemistry. This short Perspective aims at providing a brief introduction to the field by first looking on the historical development and the more classical methods and concepts, followed by discussing selected advanced recent examples that opened new directions and diversity within this still growing field.

An expedient method for the synthesis of cyclic carbonates from homoallylic carbonic acid esters by means of photo-aerobic selenium-π-acid multicatalysis is reported. Until now, conceptually related methods commonly relied either on the stoichiometric addition of electrophiles onto the substrate's alkene moiety or the presence of pre-installed leaving groups in allylic position of said alkene to - in part, catalytically - initiate an intramolecular attack by an adjacent carbonic acid ester group. In sharp contrast, the current study shows that the C-C double bond of homoallylic carbonic acid esters can be directly activated by the catalytic interplay of a pyrylium dye and a diselane using ambient air as the sole oxidant and visible light as an energy source.

is a Gram-negative bacteria associated with drug resistance and infection in healthcare settings. An understanding of both the biological roles and antigenicity of surface molecules of this organism may provide an important step in the prevention and treatment of infection through vaccination or the development of monoclonal antibodies. With this in mind, we have performed the multistep synthesis of a conjugation-ready pentasaccharide -glycan from with a longest linear synthetic sequence of 19 steps. This target is particularly relevant due to its role in both fitness and virulence across an apparently broad range of clinically relevant strains. Synthetic challenges include formulating an effective protecting group scheme as well as the installation of a particularly difficult glycosidic linkage between the anomeric position of a 2,3-diacetamido-2,3-dideoxy-D-glucuronic acid and the 4-position of D-galactose.

Two templates used in -directed C-H functionalisation under metal catalysis do not direct -C-H borylation under electrophilic borylation conditions. Using BCl only Lewis adduct formation with Lewis basic sites in the template is observed. While combining BBr and the template containing an amide linker only led to amide directed C-H borylation, with no pyridyl directed borylation. The amide directed borylation is selective for the borylation of the aniline derived unit in the template, with no borylation of the phenylacetyl ring - which would also form a six membered boracycle - observed. In the absence of other aromatics amide directed borylation on to phenylacetyl rings can be achieved. The absence of -borylation using two templates indicates a higher barrier to pyridyl directed borylation relative to amide directed borylation and suggests that bespoke templates for enabling -directed electrophilic borylation may be required.

Herein, a new scaffold for anion recognition based on a tripodal tris(pyrrolamide) motif is presented. The receptors were able to bind to a variety of anions with high affinity. Using density functional theory methods, the three-dimensional geometry of the receptor-anion complex was calculated. These calculations show that the receptors bind anions via a preorganized cavity of amide and pyrrole hydrogen bond donor groups. Based on these findings, homochiral tris(pyrrolamide) receptors were prepared, which produced as much as a 1.6-fold greater affinity for ()-(+)-mandelate over ()-(-)-mandelate, demonstrating the ability to differentiate between these enantiomeric anions. The interaction of ()-(+)-mandelate and ()-(-)-mandelate within the homochiral receptor was examined by solution NMR spectroscopy and density functional theory calculations. These findings indicate that the preorganized positioning of the pyrrole groups and subsequent sterics allows to differentiate between the stereoisomeric anions.