Octane Core Research Articles

Cuparene-type sesquiterpenes with neuroprotective activities from the edible mushroom Flammulina filiformis

Four new cuparene-type sesquiterpenes, flammuterpenols A − D (1–4), along with one known congener (5) were isolated from the solid culture of edible mushroom Flammulina filiformis. Their structures with a benzoxabicyclo[3.2.1]octane core were elucidated by integrated multiple spectroscopic techniques, electronic circular dichroism, and single crystal X-ray diffraction analysis. Biologically, compounds 1–5 were evaluated in vitro for their neuroprotective effects against 6-hydroxydopamine induced cell death in human neuroblastoma SH-SY5Y cells. All of them exhibited remarkable neuroprotective effects possessing the EC50 values ranging from 0.93 ± 0.02 to 10.28 ± 0.10 μM. These findings not only enrich the structural diversity of cuparene-type sesquiterpenes, but also provide potential candidates for the further development of the neuroprotective agents.

Total Synthesis of (-)-Piericone D.

The total synthesis of (-)-piericone D, a potential antithrombotic dihydrochalcone featuring an [3.3.0] octane core, is reported. Salient features of our synthesis include a stereoselective β-O-glycosylation to install the asebogenin aglycone and a late-stage global deprotection followed by simultaneous lactonization. The convergent synthesis paved the way for further structure-activity relationship (SAR) studies of (-)-piericone D.

Total Synthesis of Pallamolides A-E.

We have achieved the first total synthesis of pallamolides A-E. Of these compounds, pallamolides B-E possess intriguing tetracyclic skeletons with novel intramolecular transesterifications. Key transformations include highly diastereoselective sequential Michael addition reactions to construct the bicyclo[2.2.2]octane core with the simultaneous generation of two quaternary carbon centers, a one-pot SmI2-mediated intramolecular ketyl-enoate cyclization/ketone reduction to generate the key oxabicyclo[3.3.1]nonane moiety, and an acid-mediated deprotection/oxa-Michael addition/β-hydroxy elimination cascade sequence to assemble the tetracyclic pallamolide skeleton. Kinetic resolution of ketone 14 through Corey-Bakshi-Shibata reduction enabled the asymmetric synthesis of pallamolides A-E.

Total Synthesis of Pallamolides A‐E

We have achieved the first total synthesis of pallamolides A‐E, of which pallamolides B‐E possess intriguing tetracyclic skeletons with novel intramolecular transesterifications. Key transformations include highly diastereoselective sequential Michael additions to construct the bicyclo[2.2.2]octane core with simultaneous generation of two quaternary carbon centers, a one‐pot SmI2‐mediated intramolecular ketyl‐enoate cyclization/ketone reduction to generate the key oxabicyclo[3.3.1]nonane moiety, and an acid‐mediated deprotection/oxa‐Michael addition/β‐hydroxy elimination cascade sequence to assemble pallamolides tetracyclic skeletons. Kinetic resolution of ketone 14 via Corey‐Bakshi‐Shibata reduction enabled the asymmetric synthesis of pallamolides A‐E.

Strategies for the Construction of Benzobicyclo[3.2.1]octane in Natural Product Synthesis.

Benzobicyclo[3.2.1]octane is a cage-like unique motif containing a bicyclo[3.2.1]octane structure fused with at least one benzene ring. It is found in various natural products that exhibit structural complexities and important biological activities. The total synthesis of natural products possessing this challenging structure has received considerable attention, and great advances have been made in this field during the past 15 years. This review summarizes thus far achieved chemical syntheses and synthetic studies of natural compounds featuring the benzobicyclo[3.2.1]octane core. It focuses on strategic approaches constructing the bridged structure, aiming to provide a useful reference for inspiring further advancements in strategies and total syntheses of natural products with such a framework.

Hysterolides A–I, dimeric or monomeric sesquiterpene lactones from Parthenium hysterophorus L.

Nine undescribed sesquiterpene lactones, including two pseudoguaianolide dimers (1 and 2), a pseudoguaiac dilactone (3), and six pseudoguaianolides (4–9), along with 13 known analogues (10–22) were isolated from Parthenium hysterophorus. Among them, hysterolide A (1) possesses an unusual carbon skeleton with a unique cyclobutane ring connecting two pseudoguaianolides. Hysterolide C (3) is a sesquiterpene dilactone incorporating a bicyclo[5.1.0]octane core. Spectroscopic analyses, 13C NMR and ECD calculations, and X-ray diffraction elucidated their structures and absolute configurations. Moreover, all the isolates were assayed for their anti-inflammatory activities by inhibiting LPS-induced nitric oxide production in BV-2 microglia cells, wherein, nine compounds displayed significant inhibitory activities with IC50 of 0.52–6.32 μM. Furthermore, the preliminary structure-activity relationship was also established.

Synthesis of the bicyclic butenolide core of pallamolide A: a biomimetic approach.

Pallamolide A is a 7,8-seco-labdane terpenoid possessing a unique bicyclo[2.2.2]octane core and a spiro-butenolide moiety. A biomimetic synthesis of the bicyclic butenolide core over 10 steps is reported, featuring an unexpected autoxidation ring opening, and a vinylogous Mukaiyama aldol reaction which was spontaneously followed by an unusual intramolecular vinylogous aldol reaction to assemble the spiro-butenolide moiety and bicyclic core of pallamolide A.

Nature-Inspired Tetrahydropentalene Building Blocks: Scalable Synthesis for Medicinal Chemistry Needs

Inspired by the bioactivity of natural compounds with a bicyclo[3.3.0]octane core, the study focuses on developing tetrahydropentalene-2,5-dione (2,5-THP-dione) derivatives as potential building blocks for the use in medicinal chemistry. Using the commercially available 2,5-THP-dione, a number of alkylated derivatives and a monofunctional ketone were synthesized. Using optimized protocols for synthesis, target compounds were obtained with high yields on a multigram scale. These compounds are promising derivatives for further chemical derivatization and therapeutic use, and thus highlight the value of 2,5-THP-dione in creating complex molecular structures for drug discovery, as well as the importance of tetrahydropentalene derivatives as valuable building blocks in synthetic chemistry.

Rapid Synthesis of Psychoplastogenic Tropane Alkaloids.

Tropane alkaloids are an important class of biologically active small molecules characterized by their 8-azabicyclo[3.2.1]octane core. Because of their numerous medicinal applications, microbial biosynthesis and a variety of chemical syntheses have been designed for individual family members. However, current approaches are not amenable to late-stage structural diversification at N8, C3, C6, or C7, positions that are critical for modulating the biological properties of these molecules. Here, we describe a general approach to the synthesis of tropane alkaloids and their analogues that relies on the construction of the 8-azabicyclo[3.2.1]octane core through aziridination of a cycloheptadiene intermediate, followed by vinyl aziridine rearrangement. Using this strategy, we synthesized six tropane alkaloids and several analogues in only 5-7 steps. Given that the tropane alkaloid scopolamine has been reported to promote structural neuroplasticity and produce antidepressant effects, we tested five tropane-containing compounds for their ability to promote dendritic spine growth in cultured cortical neurons. We found that the orientation of the C3 substituent may play a role in the psychoplastogenic effects of tropane alkaloids. Our work provides a robust platform for producing tropane analogs for future structure-activity relationship studies.

2-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring

The phenyl ring is a basic structural element in chemistry. Here, we show the design, synthesis, and validation of its new saturated bioisostere with improved physicochemical properties − 2-oxabicyclo[2.2.2]octane. The design of the structure is based on the analysis of the advantages and disadvantages of the previously used bioisosteres: bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, and cubane. The key synthesis step is the iodocyclization of cyclohexane-containing alkenyl alcohols with molecular iodine in acetonitrile. 2-Oxabicyclo[2.2.2]octane core is incorporated into the structure of Imatinib and Vorinostat (SAHA) drugs instead of the phenyl ring. In Imatinib, such replacement leads to improvement of physicochemical properties: increased water solubility, enhanced metabolic stability, and reduced lipophilicity. In Vorinostat, such replacement results in a new bioactive analog of the drug. This study enhances the repertoire of available saturated bioisosteres of (hetero)aromatic rings for the use in drug discovery projects.

Enantioselective Synthesis of Tropane Scaffolds by an Organocatalyzed 1,3-Dipolar Cycloaddition of 3-Oxidopyridinium Betaines and Dienamines.

Tropane alkaloids constitute a compound-class which is structurally defined by a central 8-azabicyclo[3.2.1]octane core. A diverse bioactivity profile combined with an unusual aza-bridged bicyclic framework has made tropanes molecules-of-interest within organic chemistry. Enantioselective examples of (5+2) cycloadditions between 3-oxidopyridinium betaines and olefins remain unexplored, despite 3-oxidopyridinium betaines being useful reagents in organic synthesis. The first asymmetric (5+2) cycloaddition of 3-oxidopyridinium betaines is reported, affording tropane derivatives in up to quantitative yield and with excellent control of peri-, regio-, diastereo-, and enantioselectivity. The reactivity is enabled by dienamine-activation of α,β-unsaturated aldehydes combined with in situ formation of the pyridinium reaction-partner. A simple N-deprotection protocol allows for liberation of the tropane alkaloid motif, and synthetic elaborations of the cycloadducts demonstrate their synthetic utility to achieve highly diastereoselective modification around the bicyclic framework. DFT computations suggest a stepwise mechanism where regio- and stereoselectivity are defined during the first bond-forming step in which the pyridinium dipole exerts critical conformational control over its dienamine partner. In the second bond-forming step, a kinetic preference toward an initial (5+4) cycloadduct was identified; however, a lack of catalyst turn-over, reversibility, and thermodynamic bias favoring a (5+2) cycloadduct rendered the reaction fully periselective.

Polyketides with Anti-Inflammatory Activity from Trichoderma koningiopsis, a Rhizosphere Fungus from the Medicinal Plant Polygonum paleaceum.

Twelve new fungal polyketides, koningiopisins I-P (1-8) and trichoketides C-F (9-12), together with six known congeners (13-18), were isolated from Trichoderma koningiopsis, a rhizosphere fungus obtained from the medicinal plant Polygonum paleaceum. Their structures and absolute configurations were established by spectroscopic analysis, single-crystal X-ray diffraction, the modified Mosher's method, chemical derivatization, the octant rule, and 13C NMR and ECD calculations. Compounds 1-5 are tricyclic polyketides possessing an octahydrochromene framework with a 6,8-dioxabicyclo[3.2.1]octane core. Compounds 7 and 8 contain a unique ketone carbonyl group at C-7 and differ from other members of this group of compounds with the ketone carbonyl group at C-1. Compounds 1, 2, and 13 showed inhibitory activity on LPS-induced BV-2 cells on NO production with IC50 values of 14 ± 1, 3.0 ± 0.5, and 8.9 ± 2.7 μM, respectively.

Oxidative Coupling Approach to Sarpagine Alkaloids: Total Synthesis of (-)-Trinervine, Vellosimine, (+)-Normacusine B, and (-)-Alstomutinine C.

Sarpagine alkaloids are bioactive indole natural products that contain a highly rigid indole-fused 1-azabicyclo[2.2.2]octane, more than 100 members of which have been identified. Herein, a detailed examination of the intramolecular oxidative coupling between a ketone and a Weinreb amide for assembling the complex 1-azabicyclo[2.2.2]octane core structure of sarpagine family alkaloids is described. Precise late-stage manipulations of the ketone and Weinreb amide enable the divergent syntheses of (-)-trinervine, (+)-vellosimine, (+)-normacusine B, and (-)-alstomutinine C. Other notable transformations of the synthesis featured an aza-Achmatowicz/indole cyclization cascade to generate the azabicyclo[3.3.1]nonane structure, a regioselective elimination reaction to form the ethylidene motif embedded in the (+)-vellosimine and (+)-normacusine B structures, and a diastereoselective indole oxidative rearrangement to form the spirooxindole structure in (-)-alstomutinine C.

Oxidative Coupling Approach to Sarpagine Alkaloids: Total Synthesis of (−)‐Trinervine, Vellosimine, (+)‐Normacusine B, and (−)‐Alstomutinine C

AbstractSarpagine alkaloids are bioactive indole natural products that contain a highly rigid indole‐fused 1‐azabicyclo[2.2.2]octane, more than 100 members of which have been identified. Herein, a detailed examination of the intramolecular oxidative coupling between a ketone and a Weinreb amide for assembling the complex 1‐azabicyclo[2.2.2]octane core structure of sarpagine family alkaloids is described. Precise late‐stage manipulations of the ketone and Weinreb amide enable the divergent syntheses of (−)‐trinervine, (+)‐vellosimine, (+)‐normacusine B, and (−)‐alstomutinine C. Other notable transformations of the synthesis featured an aza‐Achmatowicz/indole cyclization cascade to generate the azabicyclo[3.3.1]nonane structure, a regioselective elimination reaction to form the ethylidene motif embedded in the (+)‐vellosimine and (+)‐normacusine B structures, and a diastereoselective indole oxidative rearrangement to form the spirooxindole structure in (−)‐alstomutinine C.

Hyperxylones A and B, two polycyclic polyprenylated acylphloroglucinols with a benzoyl substituted bicyclo[3.2.1]octane core from Hypericum beanii

Two new polycyclic polyprenylated acylphloroglucinols (PPAPs) possessing a rare benzoyl substituted bicyclo[3.2.1]octane core, hyperxylones A (1) and B (2), along with three new dearomatized isoprenylated acylphloroglucinols (DIAPs), hyperxylones C − E (3–5), were isolated from the roots of Hypericum beanii. The structures of 1–5 were determined by high-resolution electrospray ionization mass spectroscopy (HRESIMS) and 1D/2D nuclear magnetic resonance (NMR) spectroscopic analyses, gauge-independent atomic orbital (GIAO) NMR calculations, and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 were biomimetically semi-synthesized starting from 5 and 4, respectively, enabling the correct stereochemical assignment of 5 and 4. Moreover, compounds 1 and 2 showed anti-nonalcoholic steatohepatitis (NASH) activity by inhibiting lipid deposition in L02 cells; compounds 3 and 5 exhibited nitric oxide (NO) inhibitory activity in lipopolysaccharides (LPS)-induced RAW264.7 cells.

Total Synthesis of Leptochartamides A and B: Two Enantiomeric Pairs of Hydroxybenzyl Dimers from a Deep-Sea Fungus Leptosphaerulina chartarum.

Leptochartamides A and B (±1 and ±2), two pairs of enantiomeric hybrids with the same cyclo-bridged skeleton containing an unusual dioxa-azabicyclo[3.2.1]octane core system, were isolated from the deep-sea-derived fungus Leptosphaerulina chartarum. Their structures were determined by detailed spectroscopic analysis, single-crystal X-ray diffraction, electronic circular dichroism calculations, and the total synthesis. Compounds 2a and 2b showed selective cytotoxicity against Ewings sarcoma cells A673, with IC50 values of 8.98 ± 0.23 and 4.18 ± 0.27 μM, respectively. The colony formation assay of compounds 2a and 2b against A673 cells was completed.

Hyperxylones a and B, Two Polycyclic Polyprenylated Acylphloroglucinols with a Benzoyl Substituted Bicyclo[3.2.1]Octane Core from Hypericum Beanii

Hyperxylones a and B, Two Polycyclic Polyprenylated Acylphloroglucinols with a Benzoyl Substituted Bicyclo[3.2.1]Octane Core from Hypericum Beanii

Computational and Further Experimental Explorations of the Competing Cascades Following Claisen Rearrangements of Aryl Propargyl Ethers: Substituent Effects on Reactivity and Regioselectivity.

We report a computational investigation of two reaction cascades occurring following the Claisen rearrangements of aryl propargyl ethers to the alternate ortho positions in unsymmetrical reactants. Our computations explain how substituents influence reactivity and regioselectivity. Rearrangement to the substituted ortho carbon leads to a tricyclo[3.2.1.0]octane core, while rearrangement to an unsubstituted ortho carbon leads to a benzopyran. Density functional theory with ωB97X-D indicates that these reactions involve rate-determining Claisen rearrangements followed by subsequent reaction cascades of the Claisen rearrangement products depending on the presence or absence of a substituent at the ortho carbon.

Highly Diastereoselective Intramolecular Asymmetric Oxidopyrylium-olefin [5 + 2] Cycloaddition and Synthesis of 8-Oxabicyclo[3.2.1]oct-3-enone Containing Ring Systems.

We have the investigated base mediated asymmetric intramolecular oxidopyrylium-alkene [5 + 2]-cycloaddition reaction which resulted in the synthesis of functionalized tricyclic ring systems containing an 8-oxabicyclo[3.2.1]octane core. Intramolecular cycloaddition constructed two new rings, three new stereogenic centers, and provided a tricyclic cycloadduct with high diastereoselectivity and isolated yield. We incorporated an α-chiral center and an alkoxy alkene tether on the substrates and examined the effect of the size of alkyl groups and alkene tether length on diastereoselectivity. The requisite substrates for the oxidopyrylium-alkene cycloaddition reaction were synthesized in a few steps involving alkylation of optically active α-hydroxy amide, furyllithium addition, reduction of resulting ketone, and Achmatowicz reaction followed by acylation of a lactol intermediate. We have proposed stereochemical models for the [5 + 2] cycloaddition reaction via the oxidopyrylium ylide. Interestingly, the alkoxy substituent on the stereocenter and the chain length are responsible for the degree of stereoselectivity of the cycloadduct.

Antiproliferative Activity of the Cyclization Products of 1-(2-Oxocyclohexyl)Ethane-1,1,2,2-Tetracarbonitrile and α,β-Unsaturated Aldehydes

The antiproliferative activity of previously obtained 3-R-6-imino-2,7-dioxabicyclo[3.2.1.]octane-4,4,5-tricarbonitriles was tested on 59 cell lines obtained from human lung, colon, brain, ovary, kidney, prostate, and breast tumors and leukemia and melanoma. The most pronounced effect was observed against blood cancer cell lines of leukemia. The strength of the activity and specificity of the compounds on certain types of cells were related directly to the nature of the 3-substituent on the 2,7-dioxabicyclo[3.2.1]octane core. Compounds with multiple bonds and alkyl radicals exhibited more pronounced cytotoxic activity. A compound with a coumarin moiety showed high activity exceeding those of reference drugs (dacarbazine, cisplatin) with respect to kidney cancer cell lines.