Search

A Pd-catalyzed carbonylative double cyclization approach to a novel class of S,O-bicyclic heterocycles is presented. It is based on the reaction between readily available 5-(methylthio)pent-1-yn-3-ols with CO in the presence of the PdI2/KI catalytic system carried out under oxidative conditions with oxygen as external oxidant. The process takes place through an ordered sequence of steps involving an initial 5-exo-dig S-cyclization (by intramolecular nucleoplilic attack by the thiomethyl group to the triple bond activated by coordination to the palladium center), followed by S-demethylation (by attack by the iodide anion), carbon monoxide insertion, O-cyclization (by intramolecular nucleophilic displacement of the hydroxyl group to the ensuing acylpalladium intermediate), and Pd(0) reoxidation. The method allows the construction of previously unreported 6,6a-dihydrothieno[3,2-b]furan-2(5H)-ones starting from simple substrates (5-(methylthio)pent-1-yn-3-ols and CO) with the formation of 3 new bonds and two cycles in one step, and has been successfully applied to the synthesis of variously substituted products (57–81 %, 17 examples).

Two novel seco-polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperbenzones A (1) and B (2), were isolated from the roots of Hypericum beanii, together with one known biosynthetic congener 3. Compound 1 incorporates a 6/5/5 ring system with an unprecedented spiro[bicyclo[3.3.0]octane-3,1ʹ-cyclohexane]-2,2ʹ-dione motif. The structures of 1 and 2 were determined by a combination of high resolution electrospray ionization mass spectroscopy (HRESIMS), nuclear magnetic resonance (NMR) spectroscopic analyses, gauge-independent atomic orbital (GIAO) NMR chemical shift calculation with DP4+ analyses, electronic circular dichroism (ECD) calculation, and X-ray diffraction analysis. A 1,2-seco retro-Claisen rearrangement from a bicyclo[3.3.1]nonane PPAP precursor and following chemodivergent radical cascade cyclizations are proposed as the key steps in the biosynthetic pathway to yield compounds 1 and 2. Biological investigations indicated that compounds 1 and 3 could decrease intracellular lipid accumulation in a palmitic acid-induced nonalcoholic steatohepatitis (NASH) cell model.

Chromones are the class of secondary metabolites that broadly occur in the plant kingdom in a noticeable quantity. This rigid bicyclic system has been categorized “as privileged scaffolds in compounds” in medicinal chemistry. Their wide biological responses have made them an important moiety in a drug discovery program. This review provides updates on the various methods of synthesis of chromones and biological applications in medicinal chemistry. Various synthetic strategies for the construction of chromones include readily available phenols, salicylic acid and its derivatives, ynones, chalcones, enaminones, and 2-hydroxyarylalkylketones as starting materials. Synthesis of chromones by using metal, metal-free, nanomaterials and different other catalysts is herein included. Details of diverse biological activities of chromone derviatives, such as anti-cancer, antimicrobial, anti-viral, anti-inflammatory, antioxidant, as Monoamine Oxidase-B (MAO-B) inhibitors, anti- Alzheimer’s agents, anti-diabetic agents, having antihistaminic potential, and acting as antiplatelet agents, are discussed.

Artificial membrane transporters that either use chalcogen bonds to facilitate transmembrane flux of anions or show high selectivity toward perchlorate anions are rare. In this work, we report on one such novel monopeptide-based transporter system, featuring both chalcogen bonds for highly efficient anion transport and high transport selectivity toward ClO4− anions. Structurally, these monopeptide molecules associate with each other via H-bonds to produce H-bonded 1D stack that not only one dimensionally but also directionally aligns the terminal bicyclic thiophene motifs to the same side. Functionally, these well-aligned thiophenes create a sulfur-rich transmembrane pathway, combinatorially fine-tunable to enable anions to efficiently cross the membrane in the increasing activity of Cl−

In recent years, the strategy of inhibiting the interactions of p53 with murine double minute 2 (MDM2) and murine double minute X (MDMX) has been proved to be a promising approach for tumor therapy. However, the poor proteolytical stability and low intracellular delivery efficiency of peptide inhibitors limit their clinical application. Here, we designed and synthesized the bicyclic stapled peptides based on p53 by combining all-hydrocarbon stapling and lactam stapling strategies. We demonstrated that bicyclic stapled peptide p53-16 significantly improved α-helicity and proteolytic stability. Especially, p53-16 showed nanomolar binding affinity for MDM2 and MDMX. In addition, p53-16 could penetrate the cell membrane, and selectively inhibited the activity of tumor cells via activating p53 pathway in vitro. Our data suggest that p53-16 is a potential dual inhibitor of MDM2 and MDMX interactions. The bicyclic stapling strategy is a promising drug design strategy for protein–protein interactions inhibitors.

A cyclic hydrazide catalyst bearing a pendant anthracene catalyzes the polyene cyclization of 1,5-hexadiene-2-carboxaldehydes. Bicyclic closure proceeds in substrates with non-activated terminating groups that fail to react with simple hydrazide catalysts. Computational analysis shows that stabilization through cation–π interactions throughout the reaction sequence leads to the enhanced reactivity of the catalyst.

A seven-step total synthesis of (+)-cylindricine D and epi-cylindricine D is described. The efficiency relies on the highly diastereoselective reductive bis-functionalization of N,O-protected (S)-pyroglutaminol by our recently improved protocol to build the N-α-tert-alkylamine motif, and a telescoped one-step four-reaction protocol to build the fused bicyclic ring system. (+)-Cylindricine C and its 2-epimer were synthesized by essentially the same sequence in eight steps. Acetylation of the latter then delivered (+)-cylindricine E and its 2-epimer, respectively.

Die enantiomerenreinen Valenzisomere (+)-und(−)−1 sowie (+)- und (−)−2 konnten als erste ihrer Art isoliert werden. Diese Verbindungen mit nichtplanaren, cyclisch konjugierten π-Elektronensystem und lokalisierten π-Bindungen im Grundzustand stehen miteinander im dynamischen Gleichgewicht. Die kinetischen Daten der dynamischen Prozesse - Ringinversion und Doppelbindungsverschiebung -wurden ebenfalls bestimmt (R=H, Me).

Das erste peri-anellierte[4n]π-Elektronensystem ohne aromatische Teilstruktur ist Cyclohepta[ef]heptalen (Pleiaheptalen). Zu seinen jetzt synthetisierten Derivaten gehört 1, R = Me, das ausschließlich mit der angegebenen Doppelbindungsverteilung entsteht. In Lösung stellt sich ein Gleichgewicht mit einem π-Bindungsisomer ein.

bicyclic [3.2.1] octane neolignans have garnered increasing interest, because of their unique structural features and biological activities. This study describes the isolation and identification of a new bicyclic octane neolignan 1 obtained through fractionation of the crude extract of the stem of Aniba firmula (Lauraceae family). The structure of bicyclic octane neolignan 1 was determined through NMR analysis and mass spectrometry data.

The annulation of N-cyclopropyl enamines to produce 1,4-dihydropyridine (1,4-DHP) derivatives is described. In the presence of molecular iodine (I2), an N-cyclopropyl enamine substrate undergoes iodination, opening of the cyclopropyl ring, and annulation with a second molecule of the substrate to form the 1,4-DHP product. This reaction is amenable to gram-scale operations under mild reaction conditions with no transition metals being required. Further transformations of the 1,4-DHPs leads to related pyridine and bicyclic frameworks.

Structural binary cleavage of 3,7-diamino-2,6-dinitro-1H,5H-pyrazolo-[1,2-a]pyrazole-1,5-dione 3, under nucleophilic conditions, leads to the formation of a monocyclic pyrazole unit of 5-amino-4-nitro-1,2-dihydro-3H-pyrazol-3-one, 4. Additionally, various salts of the pyrazole ring were synthesized and fully characterized. Detonation properties and mechanical sensitivities of 4 and other new compounds are remarkably improved compared to 3. This simple and efficient strategy is highly desirable for future studies on the development of insensitive and high performing materials.

Six new nonadride derivatives, named talarodrides A-F (1-6), were isolated from the Antarctic sponge-derived fungus Talaromyces sp. HDN1820200. All structures including the absolute configurations were deduced by extensive spectroscopic analysis and computational ECD calculations. Compounds 1-4 share a rare caged bicyclo[4.3.1]-deca-1,6-diene with a bridgehead olefin and maleic anhydride core skeleton, while compounds 5 and 6 possess the first case of a naturally occurring 5/7/6 methanocyclonona[c]furan skeleton. Talarodride A (1) and talarodride B (2) showed selective inhibitory effects against Proteus mirabilis and Vibrio parahemolyticus with MICs of 3.13-12.5 μM.

Indoloquinazolines functionalized at C-12, which are structural analogs of the natural alkaloid cephalanthrin B, are readily constructed via Ph3P/I2-mediated one-pot reactions of isatins with aromatic alcohols. In the presence of excess phenols, the C-12 aryloxy ester products are obtained in moderate to good yields under mild conditions. Moreover, fused bicyclic hydroxyaryl derivatives such as 8-hydroxyquinoline give rise to novel C-12 spiro-γ-lactone derivatives. A reactive iminium cation species derived from dehydration of the C-12 hydroxy ester precursor is proposed as the transient intermediate responsible for these transformations.

The development of chiral borane Lewis acid catalysts opened the door for transition-metal-free catalyzed asymmetric organic reactions. Herein, we have summarized our work on the preparation of two classes of novel chiral bicyclic bisborane Lewis acid catalysts derived from C 2-symmetric [3.3.0] dienes and [4.4] dienes, respectively. These catalysts not only form frustrated Lewis pairs with Lewis bases to catalyze asymmetric hydrogenation reactions but also activate Lewis basic functional groups in traditional Lewis acid catalyzed asymmetric reactions.1 Introduction2 Synthesis of C 2-Symmetric Fused Bicyclic Bisborane Catalysts and Their Use in Imine Hydrogenation3 Synthesis of Spiro Bicyclic Bisborane Catalysts and Their Use in ­N-Heteroarene Reduction4 Other Types of Asymmetric Reactions Promoted by Chiral ­Bicyclic Bisborane Catalysts5 Conclusion

Reaction of six-membered cyclic nitronates with disubstituted ketenes affords hitherto unknown saturated oxazolo[3,2-b][1,2]oxazines possessing up to four contiguous stereogenic centers. The process involves a tandem of [3+2]-cycloaddition across the C═O bond of ketene, followed by a spontaneous [1,3]-rearrangement of transient vinylidene-substituted bicyclic nitrosoacetals. DFT calculations of the mechanism suggest that the [1,3]-O,C-shift proceeds through a recyclization of a biradical intermediate formed by an unusually mild homolytic cleavage of the N-O bond. The resulting products can be utilized as precursors of other fused 1,2-oxazines derivatives, in particular 1,2-oxazino-1,2,4-triazin-3-ones.

Palladium-catalysed diastereoselective hydroesterification of alkenes assisted by the coordinative hydroxyl group in the substrate afforded a variety of chiral γ-butyrolactones bearing two stereocenters. Employing the carbonylation-lactonization products as the key intermediates, the route from the alkenes with single chiral center to chiral THF-fused bicyclic γ-lactones containing three stereocenters was developed.

The bicyclic amido-substituted silicon(I) ring compound Si4 {N(SiMe3 )Mes}4 2 (Mes=Mesityl=2,4,6-Me3 C6 H2 ) features enhanced zwitterionic character and different reactivity from the analogous compound Si4 {N(SiMe3 )Dipp}4 1 (Dipp=2,6-i Pr2 C6 H3 ) due to the smaller mesityl substituents. In a reaction with the N-heterocyclic carbene NHC Me4 (1,3,4,5-tetramethyl-imidazol-2-ylidene), we observe adduct formation to give Si4 {N(SiMe3 )Mes}4 ⋅ NHC Me4 (3). This adduct reacts further with the Lewis acid BH3 to yield the Lewis acid-base complex Si4 {N(SiMe3 )Mes}4 ⋅ NHC Me4 ⋅ BH3 (4). Coordination of AlBr3 to 2 leads to the adduct 5. Calculated proton affinities and fluoride ion affinities reveal highly Lewis basic and very weak Lewis acidic character of the low-valent silicon atoms in 1 and 2. This is confirmed by protonation of 1 and 2 with Brookharts acid yielding 6 and 7. Reaction with diphenylacetylene only occurs at 111 °C with 2 in toluene and is accompanied by fragmentation of 2 to afford the silacyclopropene 8 and the trisilanorbornadiene species 9.

The syntheses of regioisomers of calix[6]crown-6 under a metal carbonate template were highly metal cation-dependent and the 1,2-bridged isomer (H4 L 1,2) catches Cs+ very efficiently in its deep and good-fit pocket similar to a baseball glove., We report the formation of heavy alkali metal complexes of bicyclic host molecules including the caesium(I) complex that catches the central metal ion with the deep pocket of the host similar to a baseball glove. For this, three regioisomers of singly bridged calix[6]crown-6 [1,2-bridged (H4 L 1,2), 1,3-bridged (H4 L 1,3) and 1,4-bridged (H4 L 1,4)] have been synthesized by alkyl­ation of calix[6]arene with penta­ethyl­ene glycol di­tosyl­ate in the presence of M 2CO3 (M = Na, K, Rb and Cs). The larger the cation size of the metal carbonate, the higher the yield of the H4 L 1,4 isomer, indicating the size-based template effect. A combination of H4 L 1,2 and RbOH allowed isolation of the mononuclear rubidium(I) complex (1) in which the metal center is six-coordinated in a loose fashion, the remaining two oxygen donors in the crown loop and two phenols in the calix rim are uncoordinated. Notably, the complexation of H4 L 1,2 with CsOH yielded the mononuclear caesium(I) complex (2), in which all possible ten binding sites on the deep and good-fit pocket participate in coordination via high cooperativity between the crown loop and calix rim, similar to a baseball glove. In dipolar organic solution, the caesium(I) complex 2 remains intact. H4 L 1,4 afforded a dicesium(I) complex (3) and adjacent complexes are linked by intermolecular cation–π interactions, giving rise to a pseudo one-dimensional coordination polymer. These results provide insight into the metal carbonate-dependent synthesis of calix[6]crowns and the influence of regioisomers on caesium(I) complexation.

Daphniphyllum alkaloids have complex molecular structures; consequently, their synthesis can be challenging. A new method for the construction of the [7-5-5] tricyclic core of Daphniphyllum alkaloids was developed. The bicyclo[5.3.0]decane skeleton was constructed through a divinylcyclopropane rearrangement of a cyclopentenone derivative with a vinylcyclopropyl group at the β-position. After introduction of a 2-iodoethyl group by a regioselective Michael addition with phenyl vinyl selenone, the [7-5-5] tricyclic system was formed by intramolecular alkylation of a cyclopentadienyl anion species.

Bicyclo[1.1.1]pentanes (BCPs) are important in drug design as sp3-rich bioisosteres of arenes and tert-butyl groups; however, the preparation of BCPs with adjacent quaternary carbons is barely known. We report a facile synthesis of α-quaternary BCPs using organophotoredox and hydrogen atom transfer catalysis in which α-keto radicals, generated through oxidation of β-ketocarbonyls, undergo efficient addition to [1.1.1]propellane. The BCP products can be transformed into a variety of useful derivatives, including enantioenriched BCPs featuring α-quaternary stereocenters.

Compared to related electrophilic species, O-acyloxocarbenium ions (AOIs) have been much less utilized in organic synthesis due to the lack of an efficient formation method. Here, we present a facile and simple approach for the generation of AOI from ester and acetal groups. Based on our AOI system with a pendant nucleophile, we obtained a unique bridged bicyclic system via an epoxonium-like transition state. The proposed mechanism is based on experimental and computational studies.

α-Trifluoromethyl azocanes are accessible from 2-(trifluoropropan-2-ol) piperidines by metal-free ring-expansion involving a bicyclic azetidinium intermediate. The opening of the azetidinium intermediate was achieved by various nucleophiles (amines, alcoholates, carboxylates, phosphonates, halides and pseudo-halides) with an excellent regio- diastereo- and enantioselectivity and in good yields. The relative configuration of the piperidines and azocanes were assigned and the deprotected azocanes offer opportunities for further derivatization.

Low-temperature NMR studies with a 4-C-methyl-4-O-benzoyl galactopyranosyl donor enable the observation and characterization of a bridged bicyclic dioxacarbenium ion arising from participation by a distal ester. Variable-temperature NMR studies reveal this bridged ion to decompose at temperatures above ≈-30 °C. In the absence of the methyl group, the formation of a bicyclic ion is not observed. It is concluded that participation by typical secondary distal esters in glycosylation reactions is disfavored in the ground state conformation of the ester from which it is stereoelectronically impossible. Methylation converts the secondary ester to a conformationally more labile tertiary ester, removes this barrier, and renders participation more favorable. Nevertheless, the minor changes in selectivity in model glycosylation reactions on going from the secondary to the tertiary esters at both low and room temperature argue against distal group participation being a major stereodirecting factor even for the tertiary system.

The reaction of 2,3-dihydropyridines with sulfonyl halides surprisingly yielded open chain dienes with sulfonylimine structure. The products were specific out of several possible isomers and, therefore, a separation of isomers was not necessary. All new compounds were characterized using FT-IR spectroscopy, HRMS, and NMR spectroscopy. A bicyclic by-product from the reaction of a 2,3-dihydropyridine with mesyl chloride was isolated and its structure elucidated using a single X-ray crystal analysis. Some biological activities, like antimicrobial and cytotoxic properties were investigated. Graphic abstract

We have compared and contrasted the effect of the halogen substituents on the stability and reactivity of singlet (s) and triplet (t) forms of bicyclic silylenes (1-15s and 1t-15t, receptively) at B3LYP/6-311 + + G** level of theory. All novel bicyclic silylene scrutinized show singlet ground state and the highest and lowest stability belong to silylenes 4 (ΔEs−t = 71.36 kcal/mol) and 5 (17.89 kcal/mol), respectively. This clearly demonstrates the effect of our imposed structure and intermolecular interactions. The nonbonding electrons at the halogenated atoms of silylenes 9 and 10s appear to have a tendency to interact with the empty p orbital of the silylene centers and form the $$ \sigma $$ (Br(endo)−Si (2)) and $$ \sigma $$ (I(exo)−Si (1)) and $$ \sigma $$ (I(endo)−Si (2)) bonds, respectively. Also, they have high electrophilicity (ω = 4.78 and 5.51 eV). The purpose of the present work was to assess the effects of halogen substituents on the stability (ΔEs−t), ΔEHOMO−LUMO, nucleophilicity (N), electrophilicity (ω), and proton affinity (ΔEPA). Finally, we introduce silylene 1 and 11 s with rather high stability (ΔEs−t = 39.28 and 38.33 kcal/mol, respectively) and N (3.52 and 3.03 eV, respectively) has high negative ΔEPA (-206.09 and − 355.97 kcal/mol, respectively) that can be applied as accumulated multidentate ligands. We have compared and contrasted the effects of halogen substituents on the stability and reactivity of singlet (s) and triplet (t) forms silylenes (1-15s and 1t-15t, receptively) at B3LYP/6-311 + + G** level of theory. All novel silylenes show singlet ground state and the highest and lowest stability belongs to silylene 4 (ΔEs−t = 71.36 kcal/mol) and 5 (17.89 kcal/mol), respectively. This stability can be related to their intermolecular interactions. The nonbonding electrons at the halogenated atoms of silylenes 9 and 10s appear to have a tendency to interact with the empty p orbital of the silylene centers and form the $$ \sigma $$ (Br(endo)−Si (2)) and $$ \sigma $$ (I(exo)−Si (1)) and $$ \sigma $$ (I(endo)−Si (2)) bonds, respectively.

The present paper aims to study the biological properties of a series of bicyclic monoterpene alcohols. Firstly, we tested the obtained compounds for fungicidal activity against clinical and reference strains of microscopic fungi. Next, we determined the minimum inhibitory concentration of these compounds comparing to other drugs widely used in practical medicine (fluconazole, terbinafine). At this stage, we found that ( −)-myrtenol (47 MIC and 23.5 μg/ml) exhibits the most promising activity against filamentous and yeast fungi, respectively. Then, we have studied the membrane-protective and antioxidant activities of the obtained compounds and found out that ( −)-cis-verbenol and ( −)-myrtenol exhibit the highest activity on the model of erythrocytes oxidative hemolysis. Interestingly, among all the studied bicyclic monoterpene alcohols, the alcohols of the pinane series have been found to be the most promising. The obtained results from the present study suggest that ( −)-myrtenol would be a leading compound for further studies in terms of possible practical application.

[Image: see text] Comprehensive synthetic strategies afforded a diverse set of structurally unique bicyclic proline-containing arginase inhibitors with a high degree of three-dimensionality. The analogs that favored the Cγ-exo conformation of the proline improved the arginase potency over the initial lead. The novel synthetic strategies reported here not only enable access to previously unknown stereochemically complex proline derivatives but also provide a foundation for the future synthesis of bicyclic proline analogs, which incorporate inherent three-dimensional character into building blocks, medicine, and catalysts and could have a profound impact on the conformation of proline-containing peptides and macrocycles.

Generation of renewable polymers is a long-standing goal toward reaching a more sustainable society, but building blocks in biomass can be incompatible with desired polymerization type, hampering the full implementation potential of biomaterials. Herein, we show how conceptually simple oxidative transformations can be used to unlock the inherent reactivity of terpene synthons in generating polyesters by two different mechanisms starting from the same α-pinene substrate. In the first pathway, α-pinene was oxidized into the bicyclic verbanone-based lactone and subsequently polymerized into star-shaped polymers via ring-opening polymerization, resulting in a biobased semicrystalline polyester with tunable glass transition and melting temperatures. In a second pathway, polyesters were synthesized via polycondensation, utilizing the diol 1-(1′-hydroxyethyl)-3-(2′-hydroxy-ethyl)-2,2-dimethylcyclobutane (HHDC) synthesized by oxidative cleavage of the double bond of α-pinene, together with unsaturated biobased diesters such as dimethyl maleate (DMM) and dimethyl itaconate (DMI). The resulting families of terpene-based polyesters were thereafter successfully cross-linked by either transetherification, utilizing the terminal hydroxyl groups of the synthesized verbanone-based materials, or by UV irradiation, utilizing the unsaturation provided by the DMM or DMI moieties within the HHDC-based copolymers. This work highlights the potential to apply an oxidative toolbox to valorize inert terpene metabolites enabling generation of biosourced polyesters and coatings thereof by complementary mechanisms.

Radical-induced 1,2-metallate rearrangements of boronate complexes are an emerging and promising class of reactions that allow multiple new bonds to be formed in a single, tuneable reaction step. These reactions involve the addition of an alkyl radical, typically generated from an alkyl iodide under photochemical activation, to a boronate complex to produce an α-boryl radical intermediate. From this α-boryl radical, there are two plausible reaction pathways that can trigger the product forming 1,2-metallate rearrangement: iodine atom transfer (IAT) or single electron transfer (SET). Previous steady state techniques have struggled to differentiate these pathways. Here we apply state-of-the-art time-resolved infrared absorption spectroscopy to resolve all the steps in the reaction cycle, by mapping production and consumption of the reactive intermediates over picosecond to millisecond timescales. We apply this technique to a recently reported reaction involving the addition of an electron-deficient alkyl radical to the strained σ‑bond of a bicyclo[1.1.0]butyl boronate complex to form a cyclobutyl boronic ester. We show that the previously proposed SET mechanism does not adequately account for the observed spectral and kinetic data. Instead, we demonstrate that IAT is the preferred pathway for this reaction and is likely to be operative for other reactions of this type.

The influence of fluorination on the acid-base properties and the capacity of structurally related 6-5 bicyclic compounds – 1,3-benzodiazole 1, 1,2,3-benzotriazole 2 and 2,1,3-benzoselenadiazole 3 to σ-hole interactions, i.e. hydrogen (1 and 2) and chalcogen (3) bondings, is studied experimentally and computationally. The tetrafluorination increases Brønsted acidity of diazole and triazole scaffolds and Lewis acidity of selenadiazole scaffold and decreases basicity. Increased Brønsted acidity facilitates anion binding via the formation of hydrogen bonds; particularly, tetrafluorinated derivative of 1 (compound 4) binds Cl–. Increased Lewis acidity of tetrafluorinated derivative of 3 (compound 10), however, is not enough for binding with Cl– and F– via the formation of chalcogen bonds in contrast to previously studied Te analog of 10. It is suggested that the maximum positive values of molecular electrostatic potential at the σ-holes, VS,max, can be reasonable metrics in the further design and synthesis of new anion receptors, with selenadiazole–diazole / triazole hybrids as a special target. Related chlorinated compounds are also discussed. Introduction Design and synthesis of new anion receptors functioning via various σ-hole interactions,[1] e.g. hydrogen and chalcogen bondings (Brønsted and Lewis acidity, respectively), attract much current attention, particularly due to potential biomedical, technological and environmental applications.[2-4] Effective tool in the field is polyfluorination, for (hetero) aromatics affecting many properties significant for chemistry, materials science and biomedicine, including a capacity to σ-hole interactions.[1,5-9] Structurally-related, 1,2-diaminobenzene-derived, 1,3- benzodiazole (benzimidazole) 1, 1,2,3-benzotriazole 2, and 2,1,3-benzoselenadiazole 3, already having numerous applications in current chemistry, materials science and biomedicine,[7,10] are appropriate targets for studying effects of polyfluorination on Brønsted (1 and 2) and Lewis (3) acidity and anion-binding properties (Scheme 1).

[Image: see text] The synthesis and pharmacological activities of a new series of piperazinyl quinazolin-4-(3H)-one derivatives acting toward the α2δ-1 subunit of voltage-gated calcium channels (Ca(v)α2δ-1) are reported. Different positions of a micromolar HTS hit were explored, and best activities were obtained for compounds containing a small alkyl group in position 3 of the quinazolin-4-(3H)-one scaffold and a 3-methyl-piperazin-1-yl- or 3,5-dimethyl-piperazin-1-yl-butyl group in position 2. The activity was shown to reside in the R enantiomer of the chain in position 2, and several eutomers reached single digit nanomolar affinities. Final modification of the central scaffold to reduce lipophilicity provided the pyrido[4,3-d]pyrimidin-4(3H)-one 16RR, which showed high selectivity for Ca(v)α2δ-1 versus Ca(v)α2δ-2, probably linked to its improved analgesic efficacy-safety ratio in mice over pregabalin.

The natural schweinfurthins are stilbenes with significant antiproliferative activity and an uncertain mechanism of action. To obtain a fluorescent analogue with minimal deviation from the natural structure, a coumarin ring system was annulated to the D-ring, creating a new analogue of schweinfurthin F. This stilbene was prepared through a convergent synthesis, with a Horner-Wadsworth-Emmons condensation employed to form the central stilbene olefin. After preparation of a tricyclic phosphonate via a recent and more efficient modification of the classic Arbuzov reaction, condensation was attempted with an appropriately substituted bicyclic aldehyde but the coumarin system did not survive the reaction conditions. When olefin formation preceded generation of the coumarin, the stilbene formation proceeded smoothly and ultimately allowed access to the targeted coumarin-based schweinfurthin analogue. This analogue displayed the desired fluorescence properties along with significant biological activity in the National Cancer Institute's 60-cell line bioassay, and the pattern of this biological activity mirrored that of the natural product schweinfurthin F. This approach gives facile access to new fluorescent analogues of the natural schweinfurthins and should be applicable to other natural stilbenes as well.

Subcritical water extraction is an efficient technique for extracting components from various plants by changing the polarity of water. β-caryophyllene is a natural bicyclic sesquiterpene with the highest content found among black pepper essential oils. In this study, the efficiency of extraction and yield of β-caryophyllene from black pepper were investigated using a subcritical water extraction technique. The optimal conditions of β-caryophyllene (1.19 ± 0.38 mg/g), and caryophyllene oxide (0.82 ± 0.38 mg/g) were obtained from black pepper under extraction conditions of 170 °C/10 min, and 200 °C/15 min, respectively. As the extraction temperature was increased, β-caryophyllene oxidation proceeded and the extraction content of caryophyllene oxide increased. It is anticipated that both β-caryophyllene and caryophyllene oxide with high biological activity can be used to selectively extract compounds using subcritical water extraction, which will be helpful in industrial applications.

The development of efficient synthetic methods for accessing enantioenriched α-chiral amines is of great importance in the disciplines of medicinal and synthetic organic chemistry. Enantioselective Rh-catalyzed 1,2-addition reactions to activated imine derivatives are regarded as useful protocols for forming α-chiral amines. This personal account outlines our efforts to develop chiral bicyclo[2.2.1]heptadiene ligands for Rh-catalyzed asymmetric additions of various organoboron reagents to a wide range of imine derivatives. Transformations of the thus-obtained adducts into known natural products or molecules of pharmaceutical importance serve to confirm their synthetic usefulness.

The gas- and liquid-phase hydrogenation of bicyclo[2.2.1]hepta-2,5-diene (norbornadiene) in the presence of the Pd/γ-Al2O3 (PK-25) industrial palladium catalyst in an n-heptane medium at 75–200°С is studied. The reaction products are identified, the main reaction routes are established, and the material balance is studied. The effect of preferable adsorption of norbornadiene compared to other components of the system on the palladium active site is confirmed. A relationship between possible modes of norbornadiene coordination and the product structure is considered. A parallel-sequential scheme is proposed for the mechanism of the process on the basis of the obtained experimental and theoretical data.

We report improved synthesis of the bicyclo[2.2.2]octadiene(BCOD)-fused 5,15-diazaporphyrin and meso-substituted derivatives by metal-template aza-annulation reaction. The obtained compounds act as the soluble precursors of tetrabenzo-5,15-diazaporphyrin (TBDAP) by thermal conversion. The substituents at meso-positions make significant differences in the optical properties and morphology in the thin film upon thermal conversion.

Bicyclic hydrocarbons, and bicyclo[1.1.1]pentanes (BCPs) in particular, are playing an emerging role as saturated bioisosteres in pharmaceutical, agrochemical and materials chemistry. Taking advantage of strain-release strategies, prior synthetic studies have featured the synthesis of bridgehead-substituted (C1, C3) BCPs from [1.1.1]propellane. Here, we describe an approach to access multisubstituted BCPs via intramolecular cyclization. In addition to C1,C3-disubstituted BCPs, this method also enables the construction of underexplored multisubstituted (C1, C2 and C3) BCPs from readily accessible cyclobutanones. The broad generality of this method has also been examined through the synthesis of a variety of other caged bicyclic molecules, ranging from [2.1.1] to [3.2.1] scaffolds. The modularity afforded by the pendant bridgehead boron pinacol esters generated during the cyclization reaction has been demonstrated through several downstream functionalizations, highlighting the ability of this approach to enable the programmed and divergent synthesis of multisubstituted bicyclic hydrocarbons. Bicyclic hydrocarbons, and bicyclo[1.1.1]pentanes in particular, are playing an emerging role as saturated bioisosteres in pharmaceutical, agrochemical and materials intramolecular coupling approach has been developed for the modular construction of underexplored multisubstituted strained bicyclic hydrocarbons, ranging from [1.1.1] to [3.2.1] scaffolds.

Bicyclic lactams can be prepared from diethyl aminomalonate and substituted benzaldehydes by formation of a dimerised imidazolidine cycloadduct followed by a Dieckmann ring closure. The resulting N,N-heterocycles are metal-chelating but show no antibacterial activity.

The initial objective of our work was to synthesize a series of 2-amino-4H-pyran-3-carbonitriles to be tested for their antifungal activities against economically relevant phytopathogenic fungi. Fourteen compounds were prepared in up to 94% yield and shown percentages of Botrytis cinerea inhibition above 70%. Despite the promising biological results, we observed that stock solutions prepared for biological tests showed color changing when kept for a few days on the laboratory bench, under room conditions, illuminated by common LED daylight tubes (4500–6000 k). This prompted us to investigate the possible photo-induced degradation of our compounds. FT-IR ATR experiments evidenced variations in the expected bands for functional of -amino-4H-pyran-3-carbonitriles stored under LED daylight. Following, HPLC–UV analysis showed reductions in the intensity of chromatographic peaks of 2-amino-4H-pyran-3-carbonitriles, and but not for solutions kept in the dark. A solution of (E)-2-amino-8-(4-nitrobenzylidene)-4-(4-nitrophenyl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile underwent 84.4% of conversion after 72 h of exposure to continuous LED daylight in a BOD chamber, and the reaction product was isolated in 36% yield and characterized as (E)-7-cyano-5-(4-nitrobenzylidene)-8-(4-nitrophenyl)bicyclo[4.2.0]oct-1(6)-ene-7-carboxamide (7*). Despite freshly prepared solutions of 2-amino-4H-pyran-3-carbonitriles produced antifungal activities, these solutions lost biological activity when left on the bench for a week. Besides, compound 7* formed from photo-induced degradation of 7 also showed no antifungal activity. With this, we hope to bring two contributions: (1) production of cyclobutenes through photochemical reactions of 2-amino-4H-pyran-3-carbonitriles can be carried out through exposure to simple white LED daylight; (2) biological applications of such 2-amino-4H-pyran-3-carbonitriles may be impaired by their poor photostability.

Bicyclic structures were synthesized by LACASA-DA cycloaddition reaction using (S)-BINOL as a chiral inductor. The N-2 pyridazine position was protected; the hydroxyl group was carbonylated to form...

The discovery of a novel 2-aminotetrahydropyridine class of BACE1 inhibitors is described. Their pKa and lipophilicity were modulated by a pending sulfonyl group, while good permeability and brain penetration were achieved via intramolecular hydrogen bonding. BACE1 selectivity over BACE2 was achieved in the S3 pocket by a novel bicyclic ring system. An optimization addressing reactive metabolite formation, cardiovascular safety, and CNS toxicity is described, leading to the clinical candidate JNJ-67569762 (12), which gave robust dose-dependent BACE1-mediated amyloid β lowering without showing BACE2-dependent hair depigmentation in preclinical models. We show that 12 has a favorable projected human dose and PK and hence presented us with an opportunity to test a highly selective BACE1 inhibitor in humans. However, 12 was found to have a QT effect upon repeat dosing in dogs and its development was halted in favor of other selective leads, which will be reported in the future.

A new highly transformed sorbicillinoid derivative, trichoreesin A (1), and four known monomeric sorbicillinoids, sorbicillin (2), 2',3'-dihydrosorbicillin (3), 3-demethylsorbicillin (4), and sohirnone A (5), were discovered from Trichoderma reesei Z56-8, an epiphyte from the marine brown alga Sargassum sp. The structure and relative configuration of 1 were determined by interpretation of UV, IR, NMR, and MS signals, and its absolute configuration was assigned by analysis of ECD data aided by quantum chemical calculations. This is the first survey of metabolites from marine algicolous T. reesei. Compound 1 represents the first bicyclic vertinolide derivative, and it possesses inhibition of several marine phytoplankton species.