Tricyclic Framework Research Articles

Synthesis, antiviral activity against wild-type SARS-CoV-2 and molecular docking studies of new aryl(1,2-dithiolo[3,4-c]quinolin-1-ylidene)amines

Unlike most attempts to find compounds with activity against SARS-CoV-2 aimed at reusing approved drugs, our goal was to find compounds with antiviral activity among the 1,2-dithioloquinoline derivatives we synthesized. These compounds exhibit pleiotropic effects, having a novel structure compared to known pharmaceuticals. In this work, we diversified the structure of 1,2-dithioloquinoline by introducing various substituents (chlorine atom, ether, amide, sulfonamide groups, pharmacophore heterocycles) into different positions of this tricyclic framework. Using docking with further quantum chemical post-processing of calculations of the created virtual library of 404 structures, more than ten compounds of the aryl(4,4-dimethyl-4,5-dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-ylidene)amine series were discovered, synthesized and experimentally studied. The bioactive screening of newly synthesized compounds revealed that six of them demonstrate suppression of SARS-CoV-2 replication in Vero E6 cell culture in the micromolar range of EC50 values (from 0.27 to 98.48 μM). The best compound, in the structure of which fragments of tricyclic dithioloquinoline and streptocide are combined, demonstrated a highest ability to protect Vero E6 cells from SARS-CoV-2 with EC50 = 0.27 μM, as well as low cytotoxicity with a selectivity index SI > 370, exceeding all reference values compounds used in the study (remdesivir, GC376, ML188).

A Tricyclic Framework with Integrated B←N and Cyano Dual Functionalization for Superior n‐Type Organic Electronics

Abstractn‐Type conjugated polymers featuring low‐lying lowest unoccupied molecular orbital (LUMO) energy levels are essential for achieving high‐performance n‐type organic thin‐film transistors (OTFTs) and organic thermoelectrics (OTEs). However, the synthesis of acceptors with strong electron‐withdrawing characteristics presents a significant challenge. Herein, a peripheral functionalization strategy is employed on the tricyclic framework anthracene by introducing dual N,O‐bidentate BF2/B(CN)2 groups to enhance its electron‐withdrawing capability. This approach successfully navigates synthetic challenges, leading to the development of two novel acceptor building blocks: DBNF and DBNCN. Compared to the counterparts with a single N,O‐bidentate BF2/B(CN)2 moiety, DBNF and DBNCN exhibit an extended π‐backbone, enhanced molecular packing, and improved electron‐withdrawing properties. Utilizing these innovative acceptor monomers, copolymers, PDBNF and PDBNCN, are synthesized, which exhibit considerably suppressed LUMO ≈−4.0 eV. The deep LUMO of PDBNF together with its favourable bimodal packing orientation leads to remarkable electron mobility of 3.04 cm2 V−1 s−1 with improved stability in OTFTs. Importantly, efficient n‐doping in OTEs is achieved with PDBNCN, exhibiting exceptional conductivity of 95.5 S cm−1 and a maximum power factor of 147.8 μW m−1 K−2—among the highest reported for solution‐processed n‐type polymers. This work underscores the effectiveness of introducing dual B←N and cyano functionalities in attaining high‐performance n‐type plastic electronics.

A Tricyclic Framework with Integrated B←N and Cyano Dual Functionalization for Superior n-Type Organic Electronics.

n-Type conjugated polymers featuring low-lying lowest unoccupied molecular orbital (LUMO) energy levels are essential for achieving high-performance n-type organic thin-film transistors (OTFTs) and organic thermoelectrics (OTEs). However, the synthesis of acceptors with strong electron-withdrawing characteristics presents a significant challenge. Herein, a peripheral functionalization strategy is employed on the tricyclic framework anthracene by introducing dual N,O-bidentate BF2/B(CN)2 groups to enhance its electron-withdrawing capability. This approach successfully navigates synthetic challenges, leading to the development of two novel acceptor building blocks: DBNF and DBNCN. Compared to the counterparts with a single N,O-bidentate BF2/B(CN)2 moiety, DBNF and DBNCN exhibit an extended π-backbone, enhanced molecular packing, and improved electron-withdrawing properties. Utilizing these innovative acceptor monomers, copolymers, PDBNF and PDBNCN, are synthesized, which exhibit considerably suppressed LUMO ≈-4.0 eV. The deep LUMO of PDBNF together with its favourable bimodal packing orientation leads to remarkable electron mobility of 3.04 cm2 V-1 s-1 with improved stability in OTFTs. Importantly, efficient n-doping in OTEs is achieved with PDBNCN, exhibiting exceptional conductivity of 95.5 S cm-1 and a maximum power factor of 147.8 μW m-1 K-2-among the highest reported for solution-processed n-type polymers. This work underscores the effectiveness of introducing dual B←N and cyano functionalities in attaining high-performance n-type plastic electronics.

Chiron approach toward the synthesis of the fused tricyclic core of epi-parvistemonine A

A stereoselective synthesis of fused tricyclic framework of epi-parvistemonine A from D-glucono-δ-lactone is described. The synthetic strategic is based on the stereoselective construction of the 7-membered cyclic skeleton via a cross-metathesis reaction followed by a Michael type cyclization promoted by Tf2O.

Lewis Acid‐Catalyzed Tandem Annulation of Propargylic Alcohols with 2‐Allylphenols and Their Anti‐tumor Activities

AbstractA novel bismuth(III) trifluoro‐methanesulfonate‐catalyzed and environmentally benign synthetic strategy for the construction of a wide range of structurally diverse, sophisticated [5,6,5]‐oxygen‐containing tricyclic frameworks with easy‐to handle propargylic alcohols and 2‐allylphenols as substrates in the presence of Bi(OTf)3 and AgOTf is described. This Lewis acid catalyzed [3+2] annulation protocol, which tolerates a great deal of functional groups, proceeds through a sequential Meyer‐Schuster rearrangement, nucleophilic substitution, 5‐exo‐trig cyclization, 5‐endo‐trig cyclization, and proton exchange sequences, affording a versatile approach for accessing oxygen‐containing tricyclic skeletons in moderate‐to‐excellent yields. In addition, most of the obtained compounds exhibited anti‐tumor activities against three types of human cancer cell lines in vitro, including Caco‐2 colon cancer cells, MCF‐7 breast cancer cells, and Hepg‐2 liver cancer cells.

Construction and Modification of Nitrogen-Rich Polycyclic Frameworks: A Promising Fused Tricyclic Host-Guest Energetic Material with Heat Resistance, High Energy, and Low Sensitivity.

The construction and modification of novel energetic frameworks to achieve an ideal balance between high energy density and good stability are a continuous pursuit for researchers. In this work, a fused [5,6,5]-tricyclic framework was utilized as the energetic host to encapsulate the oxidant molecules for the first time. A series of new pyridazine-based [5,6] and [5,6,5] fused polycyclic nitrogen-rich skeletons and their derivatives were designed and synthesized. Two strategies, amino oxidation and host-guest inclusion, were used to modify the skeleton in only one step. All compounds exhibit good comprehensive properties (Td(onset) > 200 °C, ρ > 1.85 g cm-3, Dv > 8400 m s-1, IS > 20 J, FS > 360 N). Benefiting from the pyridazine-based fused tricyclic structure with more hydrogen bonding units and larger conjugated systems, the first example of [5,6,5]-tricyclic host-guest energetic material triamino-9H-pyrazolo[3,4-d][1,2,4]triazolo[4,3-b]pyridazine-diperchloric acid (10), shows high decomposition temperature (Td(onset) = 336 °C), high density and heats of formation (ρ = 1.94 g cm-3, ΔHf = 733.4 kJ mol-1), high detonation performance (Dv = 8820 m s-1, P = 36.2 GPa), high specific impulse (Isp = 269 s), and low sensitivity (IS = 30 J, FS > 360 N). The comprehensive performance of 10 is superior to that of high-energy explosive RDX and heat-resistant explosives such as HNS and LLM-105. 10 has the potential to become a comprehensive advanced energetic material that simultaneously satisfies the requirements of high-energy and low-sensitivity explosives, heat-resistant explosives, and solid propellants. This work may give new insights into the construction and modification of a nitrogen-rich polycyclic framework and broaden the applications of fused polycyclic framework for the development of host-guest energetic materials.

Total Syntheses of (±)-Acetoxymarsupellone and (±)-Marsupellins A, B, and D Enabled by a Reductive Cyclization and Semipinacol Rearrangement Strategy.

We report herein the total syntheses of three marsupellin-family sesquiterpenoids, (±)-acetoxymarsupellone and (±)-marsupellins B and D, in 14-19 steps from our known precursor, making marsupellin A also accessible from marsupellin B through a known procedure. The critical tricyclic framework bearing the challenging C7 bridgehead all-carbon quaternary center is strategically constructed through a Ti-mediated reductive cyclization and semipinacol rearrangement sequence. This study provides a general approach to the syntheses of (ent-)longipinane-type molecules.

A Domino Dearomative ipso-Annulation/Desymmetrization Approach: Stereoselective Access to Tricyclic Alkaloid Skeletons.

Herein, we reveal an unprecedented domino annulation of N-benzyl-acrylamides with 1,3-dicarbonyls for the assembly of fused tricyclic alkaloid frameworks incorporating a spirocycle via an alkylation/dearomative ipso-annulation/Michael addition (desymmetrization) sequence. This conversion involves three carbon-carbon bond formations, generating four chiral carbons, including three quaternary carbon centers, in a single diastereomer in one pot under identical reaction conditions. The synthetic potential of this atom-economic method is illustrated by modifications of the functional groups present in the products obtained.

Discovery of sesquiterpenoids from the roots of Chloranthus henryi Hemsl. var. hupehensis (Pamp.) K. F. Wu and their anti-inflammatory activity by IKBα/NF-κB p65 signaling pathway suppression

Phytochemical analysis of Chloranthus henryi var. hupehensis roots led to the identification of a new eudesmane sesquiterpenoid dimer, 18 new sesquiterpenoids, and three known sesquiterpenoids. Among the isolates, 1 was a rare sesquiterpenoid dimer that is assembled by a unique oxygen bridge (C11-O-C8′) of two highly rearranged eudesmane-type sesquiterpenes with the undescribed C16 carbon framework. (+)-2 and (−)-2 were a pair of new skeleton dinorsesquiterpenoids with a remarkable 6/6/5 tricyclic ring framework including one γ-lactone ring and the bicyclo[3.3.1]nonane core. Their structures were elucidated using spectroscopic data, single-crystal X-ray diffraction analysis, and quantum chemical computations. In the LPS-induced BV-2 microglial cell model, 17 suppressed IL-1β and TNF-α expression with EC50 values of 6.81 and 2.76 µM, respectively, indicating its excellent efficacy in inhibiting inflammatory factors production in a dose dependent manner and without cytotoxicity. In subsequent mechanism studies, compounds 3, 16, and 17 could reduce IL-1β and TNF-α production by inhibiting IKBα/p65 pathway activation.

Stereoselective Preparation of the Tricyclic Hexasubstituted Spirocyclopropane Core of Cyclohelminthol X.

This study focused on synthesizing the tricyclic hexasubstituted spirocyclopropane-core framework 2 of cyclohelminthol X (1), an antifungal cytotoxin isolated from Helminthosporium velutinum yone96 in a stereoselective manner. The synthesis features an SN2-type cyclopropanation of the quaternary chloride 23 generated via a retro-Michael-type ring-opening reaction of an 8-azatricyclo[4.3.0.12,5]deca-3,7,9-trione derivative 22. The successful synthesis confirmed the structure of 1, resolving the ambiguity from the absence of X-ray crystallographic analysis. The prepared models exhibited potent cytotoxicity.

Synthesis of Fused-Ring Pyrrolizine Derivatives via a Copper-Catalyzed Radical Cascade Cyclization

AbstractHerein, an atom-economic method for the synthesis of fused-ring pyrrolizine derivatives by a cycloaddition reaction of easily accessible N-substituted pyrrole-2-carboxaldehydes with N-substituted maleimides in the presence of di-tert-butyl peroxide has been successfully developed. A total of 23 compounds were obtained by using this method, with a maximum yield of 72%, providing a practical and efficient method for the synthesis of tricyclic pyrrolizine frameworks.

Novel benzophenones cavephenones A and B from cave-derived Aspergillus fumigatus GZWMJZ-152

Two novel racemic benzophenones A and B (1 and 2) were isolated from the cave-derived fungus Aspergillus fumigatus GZWMJZ-152. Compound 1 contains a rare highly oxidized cyclohexanone-furan part, and was probably biosynthesized from desmethylsulochrin and uncommon 3-hydroxy-5-methoxy-2-methylbenzoquinone. Compound 2 contains a quinone-pyran-benzene tricyclic framework, which was speculated to be formed by two parts of 3-hydroxy-5-methoxy-2-methylbenzoquinone. In addition, compounds 1 and 2 exhibited potent antioxidant capacity with ORAC values of 0.88 and 2.82 μM TE/μM, respectively.

Photocatalytic Tandem Radical Cyclization Enables Expeditious Total Synthesis of Epoxyhinokiol Analogues for Anticancer Activity Evaluation.

A photocatalytic radical cascade with an unusual endo-trig cyclization was developed, which enables the efficient assembly of divergent tricyclic diterpenoid frameworks. The first total synthesis of abietane 10-epi-epoxyhinoliol was thus achieved in six steps by a subsequent reductive coupling of i-PrBr under photoredox/nickel dual catalysis. Inhibitory tests of chiral 10-epi-epoxyhinoliol and its analogues in 4T1 cancer cells demonstrated the critical role of the C12 hydroxyl group, leading to a discovery of the simplified analogue with better activity.

Access to [6‐7‐6]‐Icetexanes through Sequential Cascade Cyclization and Biomimetic Ring Expansion

AbstractWe herein report an efficient synthetic method for preparing [6‐7‐6]‐icetexane derivatives. This approach employs our previously designed copper‐catalyzed intramolecular cyclization of enyne‐aryl carbonyl substrates to generate a [6‐6‐6]‐tricyclic abietane framework and a subsequent ring expansion protocol for the [6‐7‐6] scaffold. By synergizing these protocols, we established a highly efficient pathway for synthesizing icetexane compounds from readily available enyne‐aryl starting materials, exhibiting remarkable versatility in accommodating various functional groups while delivering consistently high yields.

Generation and Application of Homoallylic α,α-Diboryl Radicals via Diboron-Promoted Ring-Opening of Vinyl Cyclopropanes: cis-Diastereoselective Borylative Cycloaddition.

Carbon-centered radicals stabilized by adjacent boron atoms are underexplored reaction intermediates in organic synthesis. This study reports the development of vinyl cyclopropyl diborons (VCPDBs) as a versatile source of previously unknown homoallylic α,α-diboryl radicals via thiyl radical catalyzed diboron-directed ring opening. These diboryl stabilized radicals underwent smooth [3+2] cycloaddition with a variety of olefins to provide diboryl cyclopentanes in good to excellent diastereoselectivity. In contrast to the trans-diastereoselectivity observed with most of the dicarbonyl activated VCPs, the cycloaddition of VCPDBs showed a remarkable preference for formation of cis-cyclopentane diastereomer which was confirmed by quantitative NOE and 2D NOESY studies. The cis-stereochemistry of cyclopentane products enabled a concise intramolecular Heck reaction approach to rare tricyclic cyclopentanoid framework containing the diboron group. The mild reaction conditions also allowed a one-pot VCP ring-opening, cycloaddition-oxidation sequence to afford disubstituted cyclopentanones. Control experiments and DFT analysis of reaction mechanism support a radical mediated pathway and provide a rationale for the observed diastereoselectivity. To the authors' knowledge, these are the first examples of the use of geminal diboryl group as an activator of VCP ring opening and cycloaddition reaction of α-boryl radicals.

Synthesis of 1,2-Disubstituted Adamantane Derivatives by Construction of the Adamantane Framework.

This review summarizes achievements in the synthesis of 1,2-disubstituted adamantane derivatives by the construction of the tricyclic framework either by total synthesis or by ring expansion/contraction reactions of corresponding adamantane homologues. It is intended to complement reviews focusing on the preparation of 1,2-disubstituted derivatives by C-H functionalization methods.

Palladium-Catalyzed [3 + 2] Annulation of ortho-Substituted Iodoarenes with Maleimides via a Consecutive Double Heck-type Strategy.

Herein, we report an efficient [3 + 2] annulation of ortho-substituted iodoarenes with maleimides via a palladium-catalyzed consecutive double Heck-type strategy, leading to fused tricyclic frameworks of pharmaceutical relevance. The protocol ensued through consecutive inter- and intramolecular Heck couplings effectively. This approach was compatible with a large variety of substrates and functional groups, and it was remarkably tolerated with unprotected maleimide.

Escape from Hydrofunctionalization: Palladium Hydride‐Enabled Difunctionalization of Conjugated Dienes and Enynes

AbstractPalladium hydrides are traditionally employed in hydrofunctionalization (i.e. monofunctionalization) of conjugated dienes and enynes, owning to its facile protic hydropalladation of electron‐rich (or neutral) unsaturated bonds. Herein, we report a mild PdH‐catalyzed difunctionalization of conjugated dienes and enynes. This protocol is enabled by the chemoselectivity switch of the initial hydropalladation step achieved by visible light enhancement of hydricity of PdH species. This method allows for cascade annulation of dienes and enynes with various easily available and abundant substrates, such as acrylic acids, acrylic amides, and Baylis–Hillman adducts, toward a wide range of alkenyl or alkynyl lactones, lactams, and tetrahydrofurans. This protocol also provides an easy access to complex spiro‐fused tricyclic frameworks.

Escape from Hydrofunctionalization: Palladium Hydride-Enabled Difunctionalization of Conjugated Dienes and Enynes.

Palladium hydrides are traditionally employed in hydrofunctionalization (i.e. monofunctionalization) of conjugated dienes and enynes, owning to its facile protic hydropalladation of electron-rich (or neutral) unsaturated bonds. Herein, we report a mild PdH-catalyzed difunctionalization of conjugated dienes and enynes. This protocol is enabled by the chemoselectivity switch of the initial hydropalladation step achieved by visible light enhancement of hydricity of PdH species. This method allows for cascade annulation of dienes and enynes with various easily available and abundant substrates, such as acrylic acids, acrylic amides, and Baylis-Hillman adducts, toward a wide range of alkenyl or alkynyl lactones, lactams, and tetrahydrofurans. This protocol also provides an easy access to complex spiro-fused tricyclic frameworks.

Asymmetric Synthesis of the epi-Vinigrol Tricyclic Core Enabled by a Wolff Rearrangement Strategy and Formal Total Synthesis of (-)-Vinigrol.

A new approach to construct the tricyclic framework of the diterpenoid vinigrol is described. The challenging 1,5-butanodecahydronaphthalene core was established efficiently and diastereoselectively through a combination of type II [5 + 2] cycloaddition and Wolff rearrangement. In addition, a formal total synthesis of (-)-vinigrol was achieved in 12 steps, in which Baran's intermediate was efficiently produced from a known compound by a two-step sequence involving a stereoselective α-hydroxylation and a diastereoselective α-ketol rearrangement.