Polycyclic Scaffolds Research Articles

Different DNA Binding and Damage Mode between Anticancer Antibiotics Trioxacarcin A and LL-D49194α1.

Trioxacarcin A (TXN) is a highly potent cytotoxic antibiotic with remarkable structural complexity. The crystal structure of TXN bound to double-stranded DNA (dsDNA) suggested that the TXN interaction might depend on positions of two sugar subunits on the minor and major grooves of dsDNA. LL-D49194α1 (LLD) is a TXN analogue bearing the same polycyclic polyketide scaffold with a distinct glycosylation pattern. Although LLD was in a phase I clinical trial, how LLD binds to dsDNA remains unclear. Here, we solved the solution structures at high resolutions of palindromic 2″-fluorine-labeled guanine-containing duplex d(A1A2C3C4GFGFT7T8)2 and of its stable LLD and TXN covalently bound complexes. Combined with biochemical assays, we found that TXN-alkylated dsDNA would tend to keep DNA helix conformation, while LLD-alkylated dsDNA lost its stability more than TXN-alkylated dsDNA, leading to dsDNA denaturation. Thus, despite lower cytotoxicity in vitro, the differences of sugar substitutions in LLD caused greater DNA damage than TXN, thereby bringing about a completely new biological effect.

PTC in the polyenolate‐mediated [10+2]‐cycloaddition for the synthesis of α,α‐disubstituted amino acid precursors

Abstract. The manuscript describes a formal [10+2] higher‐order cycloaddition between 2‐benzylideneindan‐1‐ones and α‐alkilidene azlactones as higherene precursors and higherenofiles respectively. The reaction is realized under Brønsted‐base catalysis utilizing the phase transfer catalysis approach. The key intermediate is an isobenzofulvene‐derived polyenolate which acts as a 10‐electron component in the higher‐order cycloaddition. By using this strategy, a series of structurally diverse compounds containing a polycyclic hydrocarbon scaffold was prepared in 79‐99% yields. In addition, the potential of the obtained [10+2]‐cycloadducts has been confirmed by transformations, including the synthesis of a highly‐valuable alpha,alpha‐disubstituted N‐protected alpha‐aminoester.

Single-cell RNA sequencing facilitates the elucidation of the complete biosynthesis of the antidepressant hyperforin in St. John’s wort

Hyperforin is the compound responsible for the effectiveness of St. John’s wort (Hypericum perforatum) as an antidepressant, but its complete biosynthetic pathway remains unknown. Gene discovery based on co-expression analysis of bulk RNA-sequencing data or genome mining failed to discover the missing steps in hyperforin biosynthesis. In this study, we sequenced the 1.54-Gb tetraploid H. perforatum genome assembled into 32 chromosomes with the scaffold N50 value of 42.44 Mb. By single-cell RNA sequencing, we identified a type of cell, “Hyper cells”, wherein hyperforin biosynthesis de novo takes place in both the leaves and flowers. Through pathway reconstitution in yeast and tobacco, we identified and characterized four transmembrane prenyltransferases (HpPT1–4) that are localized at the plastid envelope and complete the hyperforin biosynthetic pathway. The hyperforin polycyclic scaffold is created by a reaction cascade involving an irregular isoprenoid coupling and a tandem cyclization. Our findings reveal how and where hyperforin is biosynthesized, enabling synthetic-biology reconstitution of the complete pathway. Thus, this study not only deepens our comprehension of specialized metabolism at the cellular level but also provides strategic guidance for elucidation of the biosynthetic pathways of other specializied metabolites in plants.

Rapid Construction of Polycyclic Skeletons via Brønsted-Base-Catalyzed Annulations of Ethylidene 1,3-Indenediones and Vinyl 1,2-Diketones.

Brønsted-base-catalyzed diversified annulations between ethylidene 1,3-indenediones and vinyl 1,2-diketones have been achieved, delivering three types of products containing oxabicyclo[3.2.1]octane, spiro[4.5]decane, and branched triquinane skeletons, respectively, which widely exist in natural products and bioactive substances. Two unprecedented reaction modes have been disclosed, and the reactions could be readily scaled up. The protocol shows the potential of 1,2-diketone-mediated reactions in the rapid construction of complicated polycyclic scaffolds.

Asymmetric Synthesis and Biological Evaluation of Platensilin, Platensimycin, Platencin, and Their Analogs via a Bioinspired Skeletal Reconstruction Approach.

Platensilin, platensimycin, and platencin are potent inhibitors of β-ketoacyl-acyl carrier protein synthase (FabF) in the bacterial and mammalian fatty acid synthesis system, presenting promising drug leads for both antibacterial and antidiabetic therapies. Herein, a bioinspired skeleton reconstruction approach is reported, which enables the unified synthesis of these three natural FabF inhibitors and their skeletally diverse analogs, all stemming from a common ent-pimarane core. The synthesis features a diastereoselective biocatalytic reduction and an intermolecular Diels-Alder reaction to prepare the common ent-pimarane core. From this intermediate, stereoselective Mn-catalyzed hydrogen atom-transfer hydrogenation and subsequent Cu-catalyzed carbenoid C-H insertion afford platensilin. Furthermore, the intramolecular Diels-Alder reaction succeeded by regioselective ring opening of the newly formed cyclopropane enables the construction of the bicyclo[3.2.1]-octane and bicyclo[2.2.2]-octane ring systems of platensimycin and platencin, respectively. This skeletal reconstruction approach of the ent-pimarane core facilitates the preparation of analogs bearing different polycyclic scaffolds. Among these analogs, the previously unexplored cyclopropyl analog 47 exhibits improved antibacterial activity (MIC80 = 0.0625 μg/mL) against S. aureus compared to platensimycin.

Transition Metal-Catalyzed Dual C-H Activation/Annulation Reactions Involving Internal Alkynes.

Recently, transition metal-catalyzed ortho-C-H bond activation/annulations involving two internal alkyne molecules have been extensively used to synthesize highly substituted polycyclic aromatic scaffolds. Such reactions have emerged as a powerful atom and step-economical strategy for the assembly of multifunctional bioactive molecules. In this context, we focused on the recent achievements of dual C-H bond activation/annulations, as well as functionalization reactions involving diaryl/alkyl alkynes.

Gd(III)-Catalyzed Regio-, Diastereo-, and Enantioselective [4 + 2] Photocycloaddition of Naphthalene Derivatives.

Catalytic asymmetric dearomatization (CADA) reactions have evolved into an efficient strategy for accessing chiral polycyclic and spirocyclic scaffolds from readily available planar aromatics. Despite the significant developments, the CADA reaction of naphthalenes remains underdeveloped. Herein, we report a Gd(III)-catalyzed asymmetric dearomatization reaction of naphthalene with a chiral PyBox ligand via visible-light-enabled [4 + 2] cycloaddition. This reaction features application of a chiral Gd/PyBox complex, which regulates the reactivity and selectivity simultaneously, in excited-state catalysis. A wide range of functional groups is compatible with this protocol, giving the highly enantioenriched bridged polycycles in excellent yields (up to 96%) and selectivity (up to >20:1 chemoselectivity, >20:1 dr, >99% ee). The synthetic utility is demonstrated by a 2 mmol scale reaction, removal of directing group, and diversifications of products. Preliminary mechanistic experiments are performed to elucidate the reaction mechanism.

Structural and Electronic Impacts of the Axial Substitution at the Phosphorus Center of C(sp3)‐Bridged P‐Heterotriangulenes

AbstractThe structural and electronic properties of the dimethylmethylene‐bridged P‐heterotriangulene have been systematically modulated by functionalization of its phosphorus center. The optoelectronic properties of the obtained derivatives in solution were characterized by UV/Vis absorption and emission spectroscopy, cyclic voltammetry and 31P NMR spectroscopy. The solid state structures were analyzed by X‐ray crystallography. The experimental results were corroborated by density functional theory calculations which revealed the crucial influence of the axial substitution on the bowl‐shaped geometry of the phosphorus‐centered polycyclic scaffold, which is proportional to the s‐character of the P−X bond. The advantage of the bowl‐shaped P‐heterotriangulene scaffold was demonstrated by successful co‐crystallization with fullerene C60.

Indenoannulated Tridecacyclene: An All-Carbon Seven-Stage Redox-Amphoter.

We disclose an indenoannulated tridecacyclene comprising a central cyclooctatetraene moiety with multiple adjacent pentagonal rings which is accessible in a concise synthetic sequence. The saddle-shaped geometry of the non-benzenoid polycyclic scaffold and its unique packing behavior in the solid state were characterized by X-ray crystallography. In electrochemical studies, the compound undergoes seven reversible redox events comprising five reductions and two oxidations. The dicationic and dianionic species obtained by chemical oxidation and reduction, respectively, were characterized spectroscopically in solution. Density functional theory calculations were applied to provide insights into aromaticity evolution in the respective charged species, highlighting the beneficial effect of the non-benzenoid moieties on charge stabilization.

Electrochemical Cascade Cyclization of N‐Centered Radicals with Electro‐Deficient Alkynes

AbstractIndoline‐fused polycyclic scaffolds are virtually universal in biological and pharmaceutical. Here we demonstrate a facile electrooxidative cascade cyclization for indoline‐based derivatives, employing amidyl radicals with ynones under mild conditions. The efficient method enables the formation of two new C−N and C−C bonds in a single step with high regioselectivity. Various indoline‐based tetracyclic 6/5/6/6 skeletons can be achieved through a biscyclization/dehydrogenation cascade process. Additionally, this electrochemical strategy proceeds in a sustainable metal‐ and oxidant‐free condition, with H2 being the solely byproduct.

Design, synthesis and evaluation of structurally diverse polycyclic harmaline scaffolds as anticancer agents

This is the first example of harmaline scaffolds as acceptor/acceptor-based N–C–C synthons and evaluation of 3at as an anticancer agent.

"One pot" synthesis of quinazolinone-[2,3]-fused polycyclic scaffolds in a three-step reaction sequence.

Diverse quinazolinone-[2,3]-fused polycyclic skeletons occupy a prominent position in drug discovery. Even with currently available methods there still remain unmet needs for flexible access to such structures. Herein, we have explored a mild "one pot" procedure for the construction of various quinazolinone-[2,3]-fused polycycles. The procedure involves Pd-catalyzed carbonylation of N-(2-iodophenyl)acetamides, release of the masked terminal amine, and two sequential and spontaneous cyclizations. This generally applicable approach features easy assembly of precursors from readily available starting materials, mild reaction conditions, non-cumbersome operation, and polycyclic diversity.

Direct photochemical intramolecular [4 + 2] cycloadditions of dehydrosecodine-type substrates for the synthesis of the iboga-type scaffold and divergent [2 + 2] cycloadditions employing micro-flow system.

Photocyclisation reactions offer a convenient and versatile method for constructing complex polycyclic scaffolds, particularly in the synthesis of natural products. While the [2 + 2] photocycloaddition reaction is well-established and extensively reported, the [4 + 2] counterpart via direct photochemical means remains challenging and relatively unexplored. In this work, we devised the rapid assembly of the iboga-type scaffold through photochemical intramolecular Diels-Alder reaction using a common biomimetic dehydrosecodine-type intermediate having vinyl indole and dihydropyridine (DHP) sub-units. Exploiting a micro-flow system, the medicinally important iboga-type scaffold was obtained up to 77% yield under mild, neutral conditions at room temperature. This study demonstrated the site-selective activation of the DHP moiety by direct UV-LED irradiation, eliminating the need for external photocatalysts or photosensitisers and showing good tolerance to a wide range of stabilised dehydrosecodine-type substrates. By adjusting the spatial arrangement of the DHP ring and the vinyl indole group, this versatile photochemical approach efficiently facilitates both [4 + 2] and [2 + 2] cyclisations, assembling architecturally complex multicyclic scaffolds. Precise photoactivation of the DHP subunit, generating short-lived biradical species, enabled the new way of harnessing the hidden but innately pre-encoded reactivity of the polyunsaturated dehydrosecodine-type intermediate. These photo-mediated [4 + 2] cyclisation and divergent [2 + 2] cycloadditions are distinct from biosynthetic processes, which are mainly mediated through concerted thermal cycloadditions.

Substrate‐ and Catalyst‐Controlled C−H Bond Activation/Annulation for Construction of Pyrido[2,3,4‐de]quinazolinones and Indolo[1,2‐c]quinazolinones

AbstractA substrate and catalyst‐controlled synthetic strategy was employed to construct two distinct types of fused polycyclic heterocycles, namely pyrido[2,3,4‐de]quinazolinones and indolo[1,2‐c]quinazolinones. The most notable advantage of this method is its ability to rapidly generate two different polycyclic scaffolds via a simple C−H activation and subsequent cyclization cascade pathway. Specifically, sulfoxonium ylides played a crucial role in both transformations, serving as a two‐carbon synthon and a one‐carbon synthon, to independently construct the two fused polycyclic scaffolds through [4+2] and [4+1] annulation pathways, respectively.

Multigram Synthesis of Dimethyl Stellane-1,5-Dicarboxylateas a Key Precursor for the ortho-Benzene Mimics.

Herein we present previously unavailable C(sp3)-rich polycyclic hydrocarbon scaffolds which have a potential to become valuable tools in medicinal chemistry and crop science as saturated bioisosteres of benzenoids. We have developed a scalable protocol (up to 50 g from a single synthetic run) for the synthesis of tricyclo[3.3.0.03,7]octane (bisnoradamantane or stellane) 1,5-dicarboxylic acid derivatives. X-ray crystallographic analysis of the stellane 1,5-dicarboxylic acid dimethyl ester has revealed that this scaffold is an optimal saturated isostere for ortho-disubstituted benzene where substituents exhibit the in-plane topology. The synthetic protocol is based on the oxidative cyclization of dimethyl octahydropentalene-2,5-dicarboxylate (DMOD) through lithiation followed by I2 oxidation. The reaction outcome is determined by the stereochemistry of the substrate. While the endo,endo cis-DMOD, exclusively gives the "unwanted" Claisen cyclization product the exo,endo cis- and exo,exo cis- stereoisomers afford the desired stellane 1,5-dicarboxylic acid dimethyl ester quantitatively. DFT computations have revealed that the reaction proceeds via the dianion of dimethyl octahydropentalene-2,5-dicarboxylate, which undergoes SET oxidation by I2 to form a radical anion. The subsequent cyclization followed by a second SET oxidation gives desired stellane derivative.

Tetradehydro-Diels-Alder Reactions of Flexible Arylalkynes via Folding Inside a Molecular Cage.

The tetradehydro-Diels-Alder (TDDA) reaction is a useful transformation for the rapid assembly of polycyclic scaffolds from simple linear precursors in a single synthetic step. However, the reaction requires careful substrate design and harsh reaction conditions to overcome the inherent entropic cost for this transformation. Herein we report an efficient site-selective TDDA transformation within a self-assembled Pd6L4 cage. Despite the large size, the flexibility of the employed substrates allows for efficient encapsulation within the host cavity. The rate of thermal cyclization of the encapsulated guest was found to be greatly enhanced, and high product selectivity for an unsymmetrical substrate was observed. The efficiency of this system relies on the precise conformational control of the substrate within the confined space of the host cage.

Ultra-Sonicated One-Pot Synthesis of Potent Bioactive Biscoumarin and Polycyclic Pyranodichromenone Scaffolds in Aqueous Media: A Complementary Tool to Organic Synthesis

AbstractPresent study involves the synthesis of bis-coumarins and novel polycyclic pyranodichromenones using a catalyst-free approach under ultrasonic irradiation in an aqueous medium. The chemical structures of the synthesized compounds were characterized using FTIR, 1H NMR, and 13C NMR spectroscopy. The antibacterial and antifungal activities of the compounds were evaluated against Gram-positive (S. aureus, B. cereus) and Gram-negative bacteria (P. aeruginosa, E. coli), as well as the fungus C. albicans, using the disc diffusion method. Several compounds exhibited excellent activity against the tested microorganisms. Moreover, the antioxidant potential of the synthesized products was assessed using 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethyl­benzothiazoline-6-sulfonic acid) (ABTS) free radical scavenging, and total antioxidant capacity (TAC) assays. Promising antioxidant activity was observed for certain compounds. Computational studies using density functional theory (DFT) were conducted to investigate the molecular reactivity and electronic properties of the synthesized compounds. Quantum mechanical parameters such as Ionization Potential (IP), Electron Affinity (EA), Mulliken Electronegativity (χ), Chemical Potential (μ), and Electrophilicity Index (ω) were calculated. The study highlights the efficiency and eco-friendliness of ultrasonic-assisted processes, contributing to the advancement of sustainable chemistry.

Rh(III)-Catalyzed Successive C–H Activations of 2-Phenyl-3H-indoles and Cyclization Cascades to Construct Highly Fused Indole Heteropolycycles

Rh(III)-catalyzed successive C-H activations of 2-phenyl-3H-indoles and cyclization cascades with diazo compounds were developed to construct highly fused indole heteropolycycles with a broad range of substrates and good yields. In particular, this transformation included two successive C-H activations and unusual [3+3] and [4+2] sequential cyclization cascades, in which the diazo compound played a different role in the two cyclization processes, while simultaneously forming a highly fused polycyclic indole scaffold with a new quaternary carbon center.

Catalyst-Controlled Annulations of Strained Cyclic Allenes with π-Allylpalladium Complexes.

Strained cyclic allenes are a class of in situ-generated fleeting intermediates that, despite being discovered more than 50 years ago, has received significantly less attention from the synthetic community compared to related strained intermediates. Examples of trapping strained cyclic allenes that involve transition metal catalysis are especially rare. We report the first annulations of highly reactive cyclic allenes with in situ-generated π-allylpalladium species. By varying the ligand employed, either of two isomeric polycyclic scaffolds can be obtained with high selectivity. The products are heterocyclic and sp3-rich and bear two or three new stereocenters. This study should encourage the further development of fragment couplings that rely on transition metal catalysis and strained cyclic allenes for the rapid assembly of complex scaffolds.

Application of Metal-Free Dearomatization Reaction as a Sustainable Strategy to Direct Access Complex Cyclic Compounds.

The highly efficient construction of complicated heterocyclic frameworks in an atom- and step-economic manner is still one of the cores of synthetic chemistry. Dearomatization reactions show the unique advantage for the construction of functionalized heterocycles and have attracted widespread attention over the past two decades. The metal-free approach has proved to be a green and sustainable paradigm for the synthesis of spirocyclic, polycyclic and heterocyclic scaffolds, which are widely present in natural products and bioactive molecules. In this review, the advances in the recent six years (2017-2023) in metal-free dearomatization reactions are highlighted. Emphasis is placed on developments in the field of organo-catalyzed dearomatization reactions, oxidative dearomatization reactions, Brønsted acid- or base-promoted dearomatization reactions, photoredox-catalyzed dearomatization reactions, and electrochemical oxidation dearomatization reactions.