Core Skeleton Research Articles

Regio- and Stereoselective Synthesis of the Core Structure of Hexahydrobenzo[c]phenanthridine Alkaloids via Redox-Neutral Cp*Rh(III)-Catalyzed C-H/N-H Annulation of Cyclic Alkenes with Benzamides.

A highly stereo- and regioselective synthesis of the core skeleton of hexahydrobenzo[c]phenanthridine-type alkaloids is reported herein for the first time. A wide range of substrate scope, excellent functional group tolerance, and good to excellent yields were observed. This protocol gives very concise and efficient access to the core skeleton of chelidonine alkaloids as compared to the earlier approaches.

Identification of critical lines for enhancing disaster resilience of power systems with renewables based on complex network theory

Natural disasters, such as typhoons and earthquakes, pose great challenges to power system resilience and power supply reliability. It is widely acknowledged that critical transmission lines play a significant role in enhancing the resilience and reliability of power systems under severe natural disasters. In order to improve the disaster resilience of power systems with renewables, a critical line identification approach is proposed in this work based on the complex network theory. Firstly, the concept of core skeleton network (CSN) of power systems with renewables is introduced and a two-step strategy is presented to optimise the CSNs of the concerned power system considering the variable outputs of renewables. Then, a statistical salience method incorporating edge salience and the state-of-the-art null model in complex network theory is proposed to identify critical lines of each CSN and the concerned power system with renewables. Finally, the effectiveness of the proposed critical lines identification approach is verified by simulations on the modified IEEE 118-bus system with renewables, Guangdong Provincial Power System (GPPS) and Zhejiang Provincial Power System (ZPPS) in China. Simulation results show that by using the proposed approach, the critical transmission lines can be effectively identified, not requiring a predefined number of critical lines.

Total Synthesis of the Nagelamides - Synthetic Studies toward the Reported Structure of Nagelamide D and Nagelamide E Framework.

The nagelamides are a small subset of the oroidin family of marine sponge-derived alkaloids and are, for the most part, dimeric in nature. As part of our efforts to develop synthetic access to this family, a Stille cross-coupling strategy is used to construct the bis-imidazolyl core skeleton. Reduction of the bis-vinylimidazole delivered the core framework of nagelamide D. Introduction of the 2-amino groups via the corresponding azides and introduction of the pyrrolecarboxamides through a double Mitsunobu reaction using a pyrrole hydantoin provided the putative structure of nagelamide D. The spectroscopic data for the synthetic and sponge-derived materials did not match well, whereas the spectroscopic data were a good match for closely related oroidin alkaloids, supporting the structure of the synthetic material. The structure of the synthetic material was further corroborated by obtaining an X-ray crystal structure of a derivative. Electrocyclization of an advanced precursor affords a dihydrobenzimidazole, which is expected to serve as a key intermediate en route to nagelamide E and ageliferin.

Total Synthesis of (-)-Daphnezomines A and B.

Daphnezomines A and B are structurally unusual Daphniphyllum alkaloids that contain a unique aza-adamantane core skeleton. Herein, a modular approach to these alkaloids is presented that exploits a diverse array of reaction strategies. Commencing from a chiral pool terpene-(S)-carvone, the azabicyclo[3.3.1]nonane backbone, which occurs widely in Daphniphyllum alkaloids, was easily accessed through a Sharpless allylic amination and a palladium-catalyzed oxidative cyclization. A protecting group enabled a stereoselective B-alkyl Suzuki-Miyaura coupling sequence and an Fe-mediated hydrogen atom transfer (HAT)-based radical cyclization were then applied to construct C6 and C8 stereocenters. A final epimer locking strategy enabled the assembly of the highly congested aza-adamantane core, thereby achieving the first total synthesis of (-)-daphnezomines A and B in 14 steps.

Stereoselective synthesis of E, E / E, Z isomers based on 1-(4- iodophenyl)-2,5-divinyl-1H-pyrrole core skeleton: A configuration-controlled fluorescence characteristics and highly selective anti-cancer activity

The E and Z isomeric intermediates based on ethyl/methyl-2-cyano-3-(5-formyl-1-(4-iodo-phenyl)-1H-pyrrol-2-yl)acrylate have been synthesized and these intermediates (E or Z) were further stereo-selectively converted into their respective E, E or E, Z isomers of diethyl/dimethyl-3,3'-(1-(4-iodophenyl)-1H-pyrrole-2,5-diyl)bis (2-cyanoacrylate) at the first time. The E, E isomers of both 2a and 3a, in solid state displayed higher quantum efficiency with longer fluorescent lifetime as compared to E, Z isomers. Notably, the E, E isomers proved to be better AIEs while, E, Z isomer of 2a has eminent anticancer activity against human nasopharyngeal carcinoma. A simple and straight forward strategy has been firstly developed to utilize the impact of configuration on fluorescence and anti-cancer activity.

Fluorescence sensor for organophosphorus pesticide detection based on the alkaline phosphatase-triggered reaction

The threat of organophosphorus pesticide (OPP) residue to food safety and human health has caused widespread concern. In this paper, a sensitive fluorescence sensor for OPP detection was constructed based on the alkaline phosphatase (ALP) -triggered in situ reaction. In this method, ALP catalyses the dephosphorylation of the substrate l-ascorbic acid 2-phosphate sesquimagnesium salt hydrate (AAP) to generate l-ascorbic acid (AA). AA instantly combines with o-phenylenediamine (OPD) to form 3-(1,2-dihydroxyethyl)furo[3,4-b]quinoxalin-1(3H)-one (DFQ), which contains a quinoxaline core skeleton fluorophore and emits a strong fluorescence intensity at 425 nm. The existence of OPPs inhibits the activity of ALP and the production of AA and DFQ. As a result, the fluorescence intensity obviously decreases. Under optimal conditions, the fluorescence intensity linearly depends on the logarithm of chlorpyrifos concentration over a wide range of 20 pg/mL ∼1000 ng/mL with a detection limit of 15.03 pg/mL (S/N = 3), which is lower than the previously reported values. The sensor with its satisfactory accuracy and precision has been successfully applied to the detection of chlorpyrifos in leeks and celery samples with recoveries of 94.5–106.7% and an inter-assay relative standard deviation (RSD) below 11.51%. OPPs can be semiquantitatively determined by the colour changes in ultraviolet light. The superiority of the sensor is due to its visual simplicity without complex fluorescence labelling procedures and costly instruments.

Enantioselective Allylation of Oxocarbenium Ions Catalyzed by Bi(OAc)3/Chiral Phosphoric Acid

Phthalides as the crucial core skeletons are found extensively in natural products and biological active molecules. Herein we disclose an asymmetric allylation of 3-hydroxyisobenzofuran-1(3H)-ones ...

Cyclic Imines in Ugi and Ugi-Type Reactions.

Ugi four-component reactions (U-4CRs) are widely recognized as being highly efficient for the synthesis of pseudopeptides. However, the products of these reactions are not so interesting as drug candidates because they are not conformationally restricted enough for a potent interaction with biological targets. One possible way to overcome this problem is to replace amine and oxo components in the U-4CRs with cyclic imines in so-called Joullié-Ugi three-component reactions (JU-3CRs). This approach provides a robust single-step route to peptide moieties connected to N-heterocyclic motifs that are found as core skeletons in many natural products and pharmaceutical compounds. JU-3CRs also provide much better diastereoselectivity than their four-component analogues. We survey here the redesign of many synthetic routes for the efficient preparation of a wide variety of three-, five-, six-, and seven-membered heterocyclic compounds connected to the peptide backbone. Additionally, in the Ugi reactions based on the cyclic imines, α-acidic isocyanides, or azides can be replaced with normal isocyanides or acids, respectively, leading to the synthesis of N-heterocycles attached to oxazoles or tetrazoles, which are of great pharmaceutical significance. This Review includes all research articles related to Ugi reactions based on the cyclic imines to the year 2020 and will be useful to chemists in designing novel synthetic routes for the synthesis of individual and combinatorial libraries of natural products and drug-like compounds.

Visible-Light-Induced Palladium-Catalyzed Intermolecular Narasaka-Heck Reaction at Room Temperature.

A palladium-catalyzed Narasaka-Heck reaction by a domino cross-coupling reaction with aromatic alkenes under blue LED irradiation at room temperature was developed. The undesired β-hydride elimination of the hybrid alkyl palladium radical species was prohibited, enabling a broad range of oxime esters to undergo 5-exo cyclization and subsequent coupling with olefins. The practicality of the method was well illustrated by the construction of a nitrogen bridgehead tricycle as a core skeleton of alkaloids.

Fusicoccane-derived diterpenoids with bridgehead double-bond-containing tricyclo[9.2.1.03,7]tetradecane ring systems from Alternaria brassicicola.

Fusicoccane-derived diterpenoids bearing a unique bridgehead double-bond-containing tricyclo[9.2.1.03,7]tetradecane (5-9-5 ring system) core skeleton represent a rarely reported class of rearranged terpenoids, which traced back to fusicoccanes with a classical dicyclopenta[a,d]cyclooctane (5-8-5 ring system) core skeleton via a crucial Wagner-Meerwein rearrangement reaction. In this research, alterbrassicenes B-D (1-3), three new rearranged fusicoccane diterpenoids bearing a rare bridgehead double-bond-containing tricyclo[9.2.1.03,7]tetradecane core skeleton, together with two known congeners, brassicicenes O and K (4 and 5), were isolated from the modified cultures of fungus Alternaria brassicicola. Their structures were elucidated by comprehensive analyses of the NMR and HRESIMS data, and the absolute configurations of 1 and 4 were further confirmed via a combination of 13C NMR and ECD calculations and single-crystal X-ray diffraction analysis (Cu Kα). Interestingly, alterbrassicene B (1) represented the second case of bridgehead C-10-C-11 double-bond-containing natural products with a bicyclo[6.2.1]undecane core skeleton, and also featured an undescribed oxygen bridge between C-6 and C-14 to construct an unprecedentedly caged tetracyclic system. Alterbrassicenes B-D showed moderate cytotoxic activity against certain human tumor cell lines with IC50 values in the range of 15.87-36.85μM.

Hierarchical porous organic hyper-cross-linked polymers containing phthalazinone and carbazole moieties for gas uptake and fluorescence properties

Based on rigid and twisted heterocyclic phthalazinone unit as the core skeleton, novel hierarchical porous carbazole-containing porous organic polymers (PCMOPs) were successfully constructed through Friedel-Crafts reaction (PCMOP-Hs) and oxidation coupling reaction (PCMOP-Os), respectively, with anhydrous FeCl3 as catalyst. The structures of resultant PCMOPs were characterized by FT-IR, 13C CP-MAS NMR and WXRD. PCMOP-Hs displayed higher BET surface area (660–675 m2 g−1), CO2 uptake capacity (11.8–12.1 wt%, 273 K, 1 bar) and CO2/N2 selectivity (up to 78.46, IAST) than those of PCMOP-Os, respectively. Even though, PCMOP-Os both displayed high sensitivity and selectivity with the fluorescent quenching rate value up to 83% for 2,4-dinitrotoluene (DNT) and 70% for nitrobenzene (NB) in low concentration (10−2 mol/L). The properties along with large-scale and low-cost preparation make these hierarchical POPs potential candidates for gas storage and separation as well as fluorescence detection of explosives application.

Rh-Catalyzed C-H Amination/Annulation of Acrylic Acids and Anthranils by Using -COOH as a Deciduous Directing Group: An Access to Diverse Quinolines.

A method for the synthesis of diverse polysubstituted quinolines from readily available acrylic acids and anthranils has been developed. The weakly coordinating -COOH directing group, which can be tracelessly removed in the cascade cyclization, is essential for this reaction. Diverse polysubstituted quinolines were obtained under mild reaction conditions with simple H2O and CO2 as byproducts. More importantly, 1,2,3,4-tetrahydroacridine, which is the core skeleton of tacrine (an Alzheimer's disease drug), was conveniently synthesized.

Canataxpropellane in 26 steps

Meet the popular anticancer drug Taxol’s quirky cousin: canataxpropellane. Chemists at the University of Konstanz have now synthesized the elusive compound for the first time, creating enough of the taxane for scientists to study its bioactivity (Science 2020, DOI: 10.1126/science.aay9173). Because canataxpropellane’s natural source, the Taxus canadensis shrub, ekes out the compound in minuscule quantities, scientists haven’t been able to evaluate its biological properties. Even though it has just 24 carbon atoms, canataxpropellane’s complex architecture makes it a beast to synthesize. It has Taxol’s core skeleton, but it also contains three additional C–C bonds that bridge the compound. Those three bonds “totally change the overall strategy of approaching the molecule” so that it must be distinct from Taxol syntheses, says Tanja Gaich, who led the synthetic effort. Canataxpropellane’s other structural challenges include two propellanes—motifs in which three rings share a single C–C bond. Canataxpropellane has 12 contiguous stereocenters. Five of

Synthesis, structure and magnetic properties of a decanuclear Fe(III)/oxo cluster

An iron (III) cluster, namely [Fe10(μ3–O)8L8(NO3)6] (1), has been synthesized by treatment of Fe(NO3)3·9H2O with 3,5–dimethyl–1–(hydroxymethyl)–pyrazole (HL) under ambient temperature. The core skeleton of {FeIII10} can be regarded as a pear-like cage with eight triangular {FeIII3(μ3–O)} units, in which each three FeIII centers is held together by one μ3–O2− group with FeIII centers as corner-sharing triangle units. Importantly, {FeIII10} cluster is not only stable in solid state but also in solution, which is confirmed by powder X-ray diffraction (PXRD) pattern and electrospray ionization mass spectrometry (ESI-MS), respectively. Furthermore, 1 shows antiferromagnetic exchange behavior arising from the interactions between the iron(III) centers.

Pseudotargeted screening and determination of constituents in Qishen granule based on compound biosynthetic correlation using UHPLC coupled with high-resolution MS.

Detection and determination of many known/unknown compounds in traditional Chinese medicines have always been challenging. To comprehensively identify compounds in Qishen granule, which is a widely prescribed herbal formula for treating chronic heart failure, a pseudotargeted screening method was proposed based on compound biosynthetic correlation using ultra high-performance liquid chromatography coupled with high-resolution mass spectrometry. Firstly, all possible compounds of Qishen granule were classified into nine types according to their core skeletons, and potential analogue molecular formulas were predicted according to core compound-related biosynthetic correlations, such as methylation, hydroxylation, and glucosidation. Secondly, nine pseudocompound databases consisting of core compounds, deduced biosynthetic correlations, and predicted analogue molecular formulas were established. Then, compounds of interest were directly located by pseudotargeted screening of high resolution mass spectrometry data and further verified by target tandem mass spectrometry. As a result, 213 constituents were identified and 21 of them were determined as potential new compounds. This demonstrated that pseudotargeted screening based on compound biosynthetic correlations significantly facilitated the processing of extremely large information data and improved the efficiency of compound identification. This research provided essential data for exploration of effective substances in Qishen granule and enriched the methodology for comprehensive characterization of constituents in complex traditional Chinese medicines.

Inhibition of human carboxylesterases by ginsenosides: structure\u2013activity relationships and inhibitory mechanism

BackgroundHuman carboxylesterases (hCES) are key serine hydrolases responsible for the hydrolysis of a wide range of endogenous and xenobiotic esters. Although it has been reported that some ginsenosides can modulate the activities of various enzymes, the inhibitory effects of ginsenosides on hCES have not been well-investigated.MethodsIn this study, more than 20 ginsenosides were collected and their inhibitory effects on hCES1A and hCES2A were assayed using the highly specific fluorescent probe substrates for each isoenzyme. Molecular docking simulations were also performed to investigate the interactions between ginsenosides and hCES.ResultsAmong all tested ginsenosides, Dammarenediol II (DM) and 20S-O-β-(d-glucosyl)-dammarenediol II (DMG) displayed potent inhibition against both hCES1A and hCES2A, while protopanaxadiol (PPD) and protopanaxatriol (PPT) exhibited strong inhibition on hCES2A and high selectivity over hCES1A. Introduction of O-glycosyl groups at the core skeleton decreased hCES inhibition activity, while the hydroxyl groups at different sites might also effect hCES inhibition. Inhibition kinetic analyses demonstrated that DM and DMG functioned as competitive inhibitors against hCES1A-mediated d-luciferin methyl ester (DME) hydrolysis. In contrast, DM, DMG, PPD and PPT inhibit hCES2A-mediated fluorescein diacetate (FD) hydrolysis via a mixed manner.ConclusionThe structure–inhibition relationships of ginsenosides as hCES inhibitors was investigated for the first time. Our results revealed that DM and DMG were potent inhibitors against both hCES1A and hCES2A, while PPD and PPT were selective and strong inhibitors against hCES2A.

Morusalones A-D, Diels-Alder Adducts with 6/7/6/6/6/6 Hexacyclic Ring Systems as Potential PTP1B Inhibitors from Cell Cultures of Morus alba.

Morusalones A-D (1-4), a new class of Diels-Alder adducts featuring unprecedented 6/7/6/6/6/6 hexacyclic core skeletons with a unique bridged cycloheptenone ring, were isolated from Morus alba cell cultures. The biosyntheses for 1-4 were proposed through an unusual Diels-Alder cycloaddition with quinostilbenes as dienophiles and prenyl 2-phenylbenzofuran as a diene to yield the typical methylhexene unit and a rare intramolecular nucleophilic addition to form the cycloheptenone ring. Compounds 1-4 exhibited protein tyrosine phosphatase 1B inhibitory activity.

Total Synthesis of (–)-Alstofolinine A: Selected Furan Oxidation/ Cyclization Cascade

Indole-fused tetracyclic ring systems containing nitrogen atoms are common core skeletons of many indole alkaloids such as sarpagine, macroline, and ajmaline. Efficient and stereoselective construction of these ring systems can promote the development of the corresponding alkaloid syntheses. In this article, we briefly summarize our current progress toward the application of the aza-Achmatowicz reaction and indole nucleophilic addition reaction cascade for the first asymmetric total synthesis of the macroline-type indole alkaloid (–)-Alstofolinine A. Our synthetic strategy is based on furan oxidation/rearrangement and proceeds from easily accessible materials such as indole and furan derivatives.

Enantioselective Formal Total Synthesis of (-)-Quinagolide.

The enantioselective formal total synthesis of (-)-quinagolide has been accomplished in a linear sequence of 8 purification steps from pyridine. The key steps are (a) organocatalyzed Diels-Alder reaction for fixing all three stereocenters on piperidine ring; (b) protecting group enabled deoxygenation of isoquinuclidine skeleton under Birch reduction condition; (c) Lewis acid (TiCl4) catalyzed intramolecular Friedel-Crafts cyclization of dicarboxylic acid; and (d) one-pot diastereoselective ketone reduction-intramolecular cyclization to form oxazolidinone which enables trans-geometry installation. During the course of the synthesis, an interesting reductive cleavage of the C-N bond in the electron-deficient isoquinuclidine skeleton under the Birch reduction conditions has been observed. This is the first synthetic effort to access the core skeleton of (-)-quinagolide.

Unique processes yielding pure azaphilones in Talaromyces atroroseus.

Azaphilones are a class of fungal pigments, reported mostly in association with Monascus species. In Asian countries, they are used as food colourants under the name of "red yeast rice" and their production process is well described. One major limitation of current production techniques of azaphilones is that they always occur in a mixture of yellow, orange and red pigments. These mixtures are difficult to control and to quantify. This study has established a controlled and reproducible cultivation protocol to selectively tailor production of individual pigments during a submerged fermentation using another fungal species capable of producing azaphilone pigments, Talaromyces atroroseus, using single amino acids as the sole nitrogen source. The produced azaphilone pigments are called atrorosins and are amino acid derivatives of the known azaphilone pigment Penicillium purpurogenum-orange (PP-O), with the amino acid used as nitrogen source incorporated into the core skeleton of the azaphilone. This strategy was successfully demonstrated using 18 proteinogenic amino acids and the non-proteinogenic amino acid ornithine. Two cultivation methods for production of the pure serine derivative (atrorosin S) have been further developed, with yields of 0.9 g/L being obtained. Yielding pure atrorosins through switching from KNO3 to single amino acids as nitrogen source allows for considerably easier downstream processing and thus further enhances the commercial relevance of azaphilone producing fungal cell factories.