Relative Configuration Research Articles

Enantioselective Syntheses of Multiply Functionalized Six‐Membered Carbocycles from Nitroalkenes and γ,δ‐Unsaturated ß‐Ketoesters using Chiral Catalysts Derived from Cobalt(III) and 1,2‐Diphenylethylenediamine

AbstractCondensations of the title educts R4CH=CH(C=O)CH2CO2Et and R6CH=CHNO2 in the presence of NEt3 and the catalyst Λ‐[Co((S,S)‐dpen)3]3+2Cl−B(C6F5)4− (both 10 mol%, 0 °C; dpen=1,2‐diphenylethylenediamine) afford R6CHCH(NO2)CH(R4)CH2C(OH)CCO2Et, with three contiguous carbon stereocenters, as >99:1 to 85:15 mixtures of diastereomers (ten examples). The major diastereomers are isolated in 81–63% yields and 97–76% ee. When R4 and R6 are both aryl groups, additions of 1,1,3,3‐tetramethylquanidine/CH3CN epimerize the CHNO2 moieties, affording 78:22 to 67:33 mixtures of the new/old diastereomers (2 h, RT). Alternatively, epimerization to >99:1 mixtures occurs spontaneously over 4 weeks in hexanes/isopropanol. These transformations entail two consecutive Michael additions, and two crystal structures confirm the relative and absolute product configurations. These assignments are supported by NMR data in solution and literature studies of similar compounds. Overall, catalyst Λ‐[Co((S,S)‐dpen)3]3+2Cl−B(C6F5)4− affords superior yields and enantio‐ or diastereoselectivities compared to those previously reported for the title reaction.

Total Synthesis of (+)‐Discorhabdin V**

AbstractThe discorhabdin natural products are a large subset of pyrroloiminoquinone alkaloids with a myriad of biological activities. Despite garnering much synthetic attention, few members have thus far been completed, particularly those featuring a bridging carbon‐nitrogen bond that is found in numerous discorhabdins, including discorhabdin V. Herein we report the first total synthesis and full stereochemical assignment of (+)‐discorhabdin V. To access the pyrroloiminoquinone we developed a convergent N‐alkylation/oxidative aminocyclization/bromination cascade that joins two key components, which are both made on multigram scale. An intramolecular Heck reaction then forms the quaternary carbon center in an intermediate containing the carbon‐nitrogen bridge, and a reductive N,O‐acetal cyclization sequence introduces the final piperidine ring. Furthermore, we have established the relative configuration of (+)‐discorhabdin V through experimental NOESY data and DP4 NMR probability calculations. The absolute configuration of the natural product has also been determined by circular dichroism and the use of an amino acid derived chiral starting material. Our work represents one of only two reports of a total synthesis of a nitrogen‐bridged discorhabdin and paves the way for future biological evaluation of such compounds.

Total Synthesis of (+)-Discorhabdin V.

The discorhabdin natural products are a large subset of pyrroloiminoquinone alkaloids with a myriad of biological activities. Despite garnering much synthetic attention, few members have thus far been completed, particularly those featuring a bridging carbon-nitrogen bond that is found in numerous discorhabdins, including discorhabdin V. Herein we report the first total synthesis and full stereochemical assignment of (+)-discorhabdin V. To access the pyrroloiminoquinone we developed a convergent N-alkylation/oxidative aminocyclization/bromination cascade that joins two key components, which are both made on multigram scale. An intramolecular Heck reaction then forms the quaternary carbon center in an intermediate containing the carbon-nitrogen bridge, and a reductive N,O-acetal cyclization sequence introduces the final piperidine ring. Furthermore, we have established the relative configuration of (+)-discorhabdin V through experimental NOESY data and DP4 NMR probability calculations. The absolute configuration of the natural product has also been determined by circular dichroism and the use of an amino acid derived chiral starting material. Our work represents one of only two reports of a total synthesis of a nitrogen-bridged discorhabdin and paves the way for future biological evaluation of such compounds.

Chemical structures and cell-death-inducing activities of metabolites produced by Penicillium maximae

Two previously undescribed compounds, maximeroterpenoid I (1) and maximazaphilone V (5), together with five known compounds (2–4, 6, and 7) were isolated from the airborne-derived fungus Penicillium maximae JKYM-AK2. The planar chemical structures and relative configurations of 1 and 5 were elucidated by high-resolution mass spectrometry and 1D and 2D NMR spectroscopy. The absolute configuration of 1 and 5 were established by comparing experimental and predicted electronic circular dichroism data. We isolated JBIR-113 (3), which has an interesting cyclic peptide structure, in relatively high yield (0.37 % from the EtOAc-soluble fraction); therefore, P. maximae JKYM-AK2 is a rich source of this unique peptide. The azaphilones [5, (+)-isochromophilone IX (6), and (+)-isochromophilone VI (7)] induce significant Adriamycin-treated HeLa-cell death.

Iridoids from the aerial parts of Adenosma caeruleum with their nitric oxide inhibitory effects

Three new iridoids, adenocaeroids A−C (1−3), and seven known analogs, umbellatolide B (4), pedicularis-lactone (5), iridolactone (6), artselaenin C (7), eucommiol (8), rehmaglutin D (9), and 3-deoxy-artselaenin C (10) were isolated from the aerial parts of Adenosma caeruleum. Their chemical structures were identified by the comprehensive spectroscopic methods, including 1D and 2D NMR and HRESI mass spectra. The relative configurations of 1−3 were established by analyzing their NOESY spectra as well as by DFT-GIAO NMR calculations followed by ML-J-DP4, DP4+, and DU8 methods. The absolute configurations of 1−3 were determined by comparing experimental and calculated ECD spectra and specific optical rotation values. All of the compounds, except 7 and 10, inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-activated BV2 microglial cells in a dose-dependent manner, with IC50 values ranging from 28.4−61.8 µM. However, none of the compounds showed inhibitory effect on protein-tyrosine phosphatase 1B (PTP1B) activity.

Cytotoxic evaluation of new polyhydroxylated steroids from the Red Sea soft coral Litophyton mollis (Macfadyen, 1936)

An efficient column chromatography of the CH2Cl2/MeOH crude extract from the soft coral Litophyton mollis (Macfadyen, 1936) yielded seven steroids, including five 4α-methylated steroids (1–5) and two 19-oxygenated steroids (6–7). Notably, both compounds 3 and 7 are new, identified as (22E)-4α,24-dimethyl-5α-cholesta-22,24(28)-dien-3β,8β-diol (3) and (22E,24R)-7β-acetoxy-24-methyl-cholesta-5,22-dien-3β,19-diol (7). The chemical structures and relative configurations were elucidated through comprehensive spectroscopic analyses, including 1D and 2D NMR, as well as HRESIMS analysis. The cytotoxicity of metabolites 1–7 was evaluated against three cancer cell lines: MCF-7, HepG2, and NCI-1299. Remarkably, metabolites 6 and 7 exhibited strong cytotoxic activity against MCF-7, with IC50 values of 8.6 and 8.4 μM, respectively, while also showing moderate effects against NCI-1299, with IC50 values of 15.7 and 15.1 μM, respectively. Additionally, steroids 4 and 5 displayed weak cytotoxicity against all three cell lines, with IC50 values in the ranges of 34.7–37.5 and 30.8–46.3 μM, respectively.

The physical acceptability conditions and the strategies to obtain anisotropic compact objects

We studied five methods to include anisotropy, or unequal stress distributions, in general relativistic matter configurations. We used nine acceptability conditions that the metric and physical variables must meet to determine if our models were astrophysically viable. Our analysis found the most effective way to introduce anisotropy while keeping a simple density profile. We also found a practical “rule of thumb” that relates the density at the boundary to the density at the centre of relativistic matter distributions. Additionally, we calculated the configuration radius and encountered that values observed by NICER for PSR J0740+6620 are consistent with several acceptable matter configurations, both isotropic and anisotropic.

Bioactive Compounds from an Endophytic Pezicula sp. Showing Antagonistic Effects against the Ash Dieback Pathogen.

A fungal endophyte originating from the Canary Islands was identified as a potent antagonist against the fungal phytopathogen Hymenoscyphus fraxineus, which causes the devastating ash dieback disease. This endophyte was tentatively identified as Pezicula cf. ericae, using molecular barcoding. Isolation of secondary metabolites by preparative high-performance liquid chromatography (HPLC) yielded the known compounds CJ-17,572 (1), mycorrhizin A (3) and cryptosporioptides A-C (4-6), besides a new N-acetylated dihydroxyphenylalanin derivative 2, named peziculastatin. Planar structures were elucidated by NMR and HRMS data, while the relative stereochemistry of 2 was assigned by H,H and C,H coupling constants. The assignment of the unknown stereochemistry of CJ-17,572 (1) was hampered by the broadening of NMR signals. Nevertheless, after semisynthetic conversion of 1 into its methyl derivatives 7 and 8, presumably preventing tautomeric effects, the relative configuration could be assigned, whereas comparison of ECD data to those of related compounds determined the absolute configuration. Metabolites 1 and 3 showed significant antifungal effects in vitro against H. fraxineus. Furthermore, 4-6 exhibited significant dispersive effects on preformed biofilms of S. aureus at concentrations up to 2 µg/mL, while the biofilm formation of C. albicans was also inhibited. Thus, cryptosporioptides might constitute a potential source for the development of novel antibiofilm agents.

The Panopticon reloaded: A critical analysis of performance management systems in the trans-European transport network policy

This article examines Performance Management Systems (PMSs) as socio-technical policy instruments for shaping power relations in megaprojects. Employing an abductive approach, it innovatively applies Foucault's Panopticon theory to the case of the Lyon-Turin railway, a megaproject funded by the European Union's Trans-European Transport Network policy. Our research reveals that PMSs operate as intellectual technologies that enable megaproject promoters to establish control over participants and align their collective behavior with planned policy objectives. We find that this process follows three Foucauldian panoptic principles: hierarchical observation, where participants are organized under nested managerial tiers, establishing vertical lines of command; examination, which uncovers performance flaws; and normalization, which standardizes behavior across the megaproject field. We argue that: PMSs can be employed by policy-makers as instruments to instil governability and shape the collective behavior of megaproject participants consistently with planned policy goals; no matter how effective the panoptic scheme is, there are always avenues of resistance available among those perceiving the megaproject as a threat; and, the configuration and constitution of power relations in megaprojects involve a complex interplay of discipline, sovereignty, and security mechanisms.

Three previously undescribed metabolites from Cordyceps cicadae JXCH-1, an entomopathogenic fungus

Three previously undescribed compounds, cordycicadione (1), cordycicadin F (2), and 7-hydroxybassiatin (3), were isolated from the cultures of Cordyceps cicadae JXCH1, an entomopathogenic fungus. Their structures and relative configurations were elucidated primarily by NMR spectroscopic analysis. The absolute configurations of 1 and 2 were determined by ECD calculations. Single-crystal X-ray diffraction method was adopted to determine the absolute configuration of 3. Compound 2 is a polycyclic polyketide with an unusual enol ether moiety and a spiro ring. The compounds obtained in this study were subjected to screening their inhibition against the proliferation of the human lung cancer cell line A549 and the production of nitric oxide in murine macrophages RAW264.7.Graphical

An optimized visualization and quantitative protocol for in-depth evaluation of lymphatic vessel architecture in the liver.

The liver lymphatic system is essential for maintaining tissue fluid balance and immune function. The detailed structure of lymphatic vessels (LVs) in the liver remains to be fully demonstrated. The aim of this study is to reveal LV structures in normal and diseased livers by developing a tissue-clearing and coimmunolabeling protocol optimized for the tissue size and the processing time for three-dimensional (3-D) visualization and quantification of LVs in the liver. We showed that our optimized protocol enables in-depth exploration of lymphatic networks in the liver, consisting of LVs along the portal tract (deep lymphatic system) and within the collagenous Glisson's capsule (superficial lymphatic system) in different species. With this protocol, we have shown 3-D LVs configurations in relation to blood vessels and bile ducts in cholestatic mouse livers, in which LVs were highly dilated and predominantly found around highly proliferating bile ducts and peribiliary vascular plexuses in the portal tract. We also established a quantification method using a 3-D volume-rendering approach. We observed a 1.6-fold (P < 0.05) increase in the average diameter of LVs and a 2.4-fold increase (P < 0.05) in the average branch number of LVs in cholestatic/fibrotic livers compared with control livers. Furthermore, cholestatic/fibrotic livers showed a 4.3-fold increase (P < 0.05) in total volume of LVs compared with control livers. Our optimized protocol and quantification method demonstrate an efficient and simple liver tissue-clearing procedure that allows the comprehensive analysis of liver lymphatic system.NEW & NOTEWORTHY This article showed a comprehensive 3-D-structural analysis of liver lymphatic vessel (LV) in normal and diseased livers in relation to blood vessels and bile ducts. In addition to the LVs highly localized at the portal tract, we revealed capsular LVs in mouse, rat, and human livers. In cholestatic livers, LVs are significantly increased and dilated compared with normal livers. Our optimized protocol provides detailed spatial information for LVs remodeling in normal and pathological conditions.

Costunosides A-C: cytotoxic sesquiterpene lactones from the rhizomes of Aucklandia costus Falc.

Three new eudesmane type rare sesquiterpene lactone galactosides, costunosides A-C (1-3) were isolated from the rhizomes of Aucklandia costus along with ten known compounds (4-13). Costunosides A-C (1-3) are the first example of naturally eudesmane glycosides containing a β-galactopyranoside moiety. The structure and relative configurations of these compounds were established by comprehensive analysis of MS and, in particular 1D/2D NMR spectroscopic data. The isolated compounds were tested against a panel of human cancer cell lines, where compounds 3, 6 and 7 have shown promising cytotoxic activity against PC-3, HCT-116 and A549 cell lines with IC50 values in the range of 3.4 µM to 9.3 µM, respectively. Costunosides A-C (1-3) were also screened for inhibition assay of acetyl-cholinesterase (AChE), and butyrylcholinesterase (BChE) and found inactive at a concentration of 10 µM.

The Dynamics of Mobility and Immobility in the Face of Danger: Polish Jewish Migrations during the 1930s from Below

Abstract This article draws on the exhaustive reconstruction of the transnational migration trajectories of Jewish and Catholic inhabitants from a small Polish town during the interwar period to explore the social and relational dimensions of migration. Implementing a mesoscopic analytical scale, the authors quantitatively and qualitatively analyse dense and varied historical material. They examine the relationship between relational configurations of mobility and immobility, as well as the increasing dangers faced by Polish Jews in the decade leading up to the war and the destruction of their communities. This change of scale gauges the specific impact of the temporal context – namely rising peril and anti-Semitic violence against Polish Jews in the 1930s – on the dynamics of mobility. It also leads to a better understanding of the importance and nature of obstacles to migration. By doing so, the authors advocate for a social history of migrations and connections that considers emigration as the product of relational configurations in societies of origin. Moreover, they show that ties, so often described as resources in analyses of migration, can also be burdens when it comes to escaping persecution.

Subplenones A-J: Dimeric Xanthones with Antibacterial Activity from the Endophytic Fungus Subplenodomus sp. CPCC 401465.

Subplenones A-J (1-10), 10 new xanthone dimers, have been isolated and characterized from the endophytic fungus Subplenodomus sp. CPCC 401465, which resides within the Chinese medicinal plant Gentiana straminea. The isolation process was guided by antibacterial assays and molecular-networking-based analyses. The chemical structures of these compounds were elucidated through the interpretation of nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectrometry (HRESIMS) data. Furthermore, the relative configuration of the compounds was determined using NMR and single-crystal X-ray diffraction analyses, and the absolute configuration was established using electronic circular dichroism calculations. All of the isolated compounds exhibited significant inhibitory activity against Gram-positive bacteria. Notably, compounds 1, 5, and 7 displayed remarkable inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA) ATCC 700698, with a minimum inhibitory concentration (MIC) of 0.25 μg/mL, and against vancomycin-resistant Enterococcus faecium (VRE) ATCC 700221, with MIC values ranging from 0.5 to 1.0 μg/mL.

Synthesis of Highly Substituted 1,2,4-Triazole-Based 3-Nitrochromanes through Aza-Michael Addition Reaction under Catalyst- and Base-Free Conditions

AbstractA simple and efficient aza-Michael addition reaction of 1,2,4-triazoles to functionalized 2-aryl-3-nitro-2H-chromenes has been demonstrated under catalyst- and base-free conditions. In this transformation, one intermolecular C–N bond formation is achieved at room temperature. A series of highly substituted 1,2,4-triazole-based 3-nitrochromanes were produced in good to excellent yields, up to 86%. The relative configuration of the Michael adducts was confirmed by X-ray crystallographic analysis. High yield, easy accessibility and a wide variety of functional group tolerance are the key features of this aza-Michael­ addition reaction.

Photochemistry of β-γ-Unsaturated Spirolactones

β-γ-unsaturated spirolactones are easily available by Birch reduction. We describe their photochemistry in the presence of or without carbonyl compounds. The spirolactones show a distinct absorption band at 230 nm, which is not present in other cyclohexadienes. We explain this behavior by an interaction of the double bonds with the carbonyl group through space, further proven by TDDFT calculations. This allows their direct excitation with UV-C light. Interestingly, we obtain only products of an oxa-di-π-methane rearrangement, hitherto unknown for lactones. This speaks for a reaction pathway starting from singlet states, confirmed by calculated relative energies of biradical intermediates. Although polymerization is the main side reaction, we were able to isolate tricyclic lactones in moderate yields in a pure form. In the presence of benzaldehyde or benzophenone, excitation with UV-B light was possible, leading to H-atom abstraction in the allylic position and formation of alcohols. With an electron-rich double bond, the Paternó–Büchi products were isolated as well. The different diastereomers were separated by column chromatography or HPLC. Their relative configurations were determined using NOESY measurements or X-ray structure analysis. Overall, β-γ-unsaturated spirolactones show a remarkably different photochemistry compared to other cyclohexadienes, affording new products in only a few steps.

OSMAC Approach and Cocultivation for the Induction of Secondary Metabolism of the Fungus Pleotrichocladium opacum.

The application of an OSMAC (One Strain-Many Compounds) approach on the fungus Pleotrichocladium opacum, isolated from a soil sample collected on the coast of Asturias (Spain), using different culture media, chemical elicitors, and cocultivation techniques resulted in the isolation and identification of nine new compounds (8, 9, 12, 15-18, 20, 21), along with 15 known ones (1-7, 10, 11, 14, 19, 22-25). Compounds 1-9 were detected in fungal extracts from JSA liquid fermentation, compounds 10-12 were isolated from a solid rice medium, whereas compounds 14 and 15 were isolated from a solid wheat medium. Addition of 5-azacytidine to the solid rice medium caused the accumulation of compounds 16-18, whereas adding N-acetyl-d-glucosamine triggered the production of two additional metabolites, 19 and 20. Finally, cocultivation of the fungus Pleotrichocladium opacum with Echinocatena sp. in a solid PDA medium led to the production of five additional natural products, 21-25. The structures of the new compounds were elucidated by HRESIMS and 1D and 2D NMR as well as by comparison with literature data. DP4+ and mix-J-DP4 computational methods were applied to determine the relative configurations of the novel compounds, and in some cases, the absolute configurations were assigned by a comparison of the optical rotations with those of related natural products.

Structure Revision of Type B Polycyclic Polyprenylated Acylphloroglucinols Fused to a Partly Reduced Furan Ring.

Four previous papers reported the isolation and structural determination of 10 polycyclic polyprenylated acylphloroglucinols (PPAPs), uraliones F, G, K, and O, attenuatumiones E and F, and scabrumiones A-D, from Hypericum species. Their structures were identified as type B PPAPs that featured not only the characteristic acyl group at C-3 of the bicyclo[3.3.1]nonane core but also a partly reduced furan ring fused to the C-1-C-2-O-2 atoms of the core. However, the 1D and 2D NMR data of these compounds were more consistent with type A PPAPs that featured not only the acyl group at C-1 but also a partially reduced furan ring fused to the C-3-C-2-O-2 atoms of the core. Now we revise these 10 previously proposed structures to the corresponding type A PPAPs via NMR analysis. Additionally, we propose a rule that uses NMR data to determine whether a particular PPAP that is fused to a partly reduced furan ring at C-3-C-2-O-2 or C-1-C-2-O-2 is type A or type B, respectively. We also propose a rule to assign the relative configurations of corresponding type A PPAPs at C-18 and revise the configurations of sampsonione N, hypericumoxides A-C, and hyperscabin G.

Residual‐Chemical‐Shift‐Anisotropy‐Based Enantiodifferentiation in Lyotropic Liquid Crystalline Phases Based on Helically Chiral Polyacetylenes

AbstractAnisotropic NMR spectroscopy, revealing residual dipolar couplings (RDCs) and residual chemical shift anisotropies (RCSAs) has emerged as a powerful tool to determine the configurations of synthetic and complex natural compounds. The deduction of the absolute in addition to the relative configuration is one of the primary goals in the field. Therefore, the investigation of the enantiodiscriminating capabilities of chiral alignment media becomes essential. While RDCs and RCSAs are now used for the determination of the relative configuration routinely, RCSAs have not been measured in chiral alignment media such as chiral liquid crystals. Herein, we present this application by measuring RCSAs for chiral analytes such as indanol and isopinocampheol in the lyotropic liquid crystalline phase of an L‐valine derived helically chiral polyacetylenes. We have also demonstrated that a single 1D 13C−{1H} NMR spectrum suffices to get the RCSAs circumventing the necessity to acquire two spectra at two alignment conditions.

Residual-Chemical-Shift-Anisotropy-Based Enantiodifferentiation in Lyotropic Liquid Crystalline Phases Based on Helically Chiral Polyacetylenes.

Anisotropic NMR spectroscopy, revealing residual dipolar couplings (RDCs) and residual chemical shift anisotropies (RCSAs) has emerged as a powerful tool to determine the configurations of synthetic and complex natural compounds. The deduction of the absolute in addition to the relative configuration is one of the primary goals in the field. Therefore, the investigation of the enantiodiscriminating capabilities of chiral alignment media becomes essential. While RDCs and RCSAs are now used for the determination of the relative configuration routinely, RCSAs have not been measured in chiral alignment media such as chiral liquid crystals. Herein, we present this application by measuring RCSAs for chiral analytes such as indanol and isopinocampheol in the lyotropic liquid crystalline phase of an L-valine derived helically chiral polyacetylenes. We have also demonstrated that a single 1D 13 C-{1 H} NMR spectrum suffices to get the RCSAs circumventing the necessity to acquire two spectra at two alignment conditions.