Polycyclic Core Research Articles

Bay-Aminated Octaazaperopyrenedioxides (OAPPDOs) as Precursors for Diazepine and Diazepinone Derivatives.

Fully bay-aminated octaazaperopyrenedioxide (OAPPDO) derivatives have been accessible via Buchwald-Hartwig amination of the bay-chlorinated starting material. They were isolated as semiquinoidal species with a bent polycyclic core and characterized as nonfluorescent charge-transfer dyes. The corresponding secondary amines were synthesized by reduction and displayed typical absorption and emission behavior for perylene derivatives. One of the reduced amines served as a precursor for conversion of the secondary amino groups to 1,3-diazepine and -diazepinone units spanning the bay-area - seven-membered ring motifs hitherto unknown in perylene chemistry. The photophysical and electrochemical properties of the azaperylene dyes were investigated by absorption and emission spectroscopy supported by time-dependent density functional theory methods and cyclic voltammetry as well as differential pulse voltammetry.

Aryne Chemistry: Generation Methods and Reactions Incorporating Multiple Arynes.

Arynes hold significance for the efficient fusion of (hetero) arenes with diverse substrates, advancing the construction of complex molecular frameworks. Employing multiple equivalents of arynes is particularly effective in the rapid formation of polycyclic cores found in optoelectronic materials and bioactive compounds. However, the inherent reactivity of arynes often leads to side reactions, yielding unanticipated products and underlining the importance of a detailed investigation into the use of multiple arynes to fine-tune their reactivity. This review centers on methodologies and syntheses in organic reactions involving multiple arynes, categorizing based on mechanisms like cycloadditions, σ-bond insertions, nucleophilic additions, and ene reactions, and discusses aryne polymerization. The categorization based on these mechanisms includes two primary approaches: the first entails multiple aryne engagement within a single step while the second approach involves using a single equivalent of aryne sequentially across multiple steps, with both requiring strict reactivity control to ensure precise aryne participation in each respective step. Additionally, the review provides an in-depth analysis of the selection of aryne precursors, organized chronologically and by activation strategy, offering a comprehensive background that supports the main theme of multiple aryne utilization. The expectation remains that this comprehensive review will be invaluable in designing advanced syntheses engaging multiple arynes.

Energetics of proposed cyclizations for the biosynthesis of daphenoid A and artatrovirenols A and B

Both concerted [4 + 2] cycloadditions and stepwise carbocation-alkene cyclizations have been proposed as means to construct the complex polycyclic cores of the artatrovirenols and daphenoid natural products during their biosyntheses. Here the energetic feasibility of each of these reactions is assessed using density functional theory calculations. While none of the previously proposed processes can be ruled out, an alternative process with a lower barrier is proposed. This process would allow for formation of a key CC bond during the cyclase phase of terpenoid biosynthesis.

Intramolecular Heteroatom and Styryl Diels-Alder Reactions, Asymmetric Cycloadditions of Chiral 3-Phenylallyl Maleic Esters.

Polycyclic aryl naphthalene and tetralin dihydro arylnaphthalene lactone lignans possess anticancer and antibiotic activity. Related furo[3,4-c]pyranones, typified by the sequester-terpenoid isobolivianine, show similar antiproliferative bioactivity. Efficient syntheses of compounds featuring these polycyclic cores have proven challenging due to low yields and poor stereoselectivity. We report the synthesis of chiral cinnamyl but-2-enanoates and 3,3-diphenylallyl-but-2-enoates 1 as new Diels-Alder substrates. These compounds undergo [4 + 2]-cycloadditions to give furo[3,4-c]pyranones 2 in good yield (70%) and diastereoselectivity (7:1), together with naphthyl 3 and dihydronaphthyl tetralins 4 as minor products. Molecular structures and stereochemistries of the major products were verified using X-ray diffraction. Density functional theory calculations revealed that the cycloaddition process involves a bispericyclic/ambimodal process where there is a single transition state that leads to both intramolecular styryl Diels-Alder (ISDA) 3, 4 and intramolecular hetero Diels-Alder (IHDA) cycloadducts 2. With the elevated temperature conditions after cycloaddition, the resulting ISDA cycloadduct either undergoes [3,3]-sigmatropic rearrangement to the more stable major IHDA product or aromatization leading to the phenyltetralin.

From propenolysis to enyne metathesis: tools for expedited assembly of 4a,8a-azaboranaphthalene and extended polycycles with embedded BN.

The synthesis of BN-containing molecules, which have an interesting isosteric relationship to their parent all-C cores, has drawn a great deal of attention as an avenue to alter and tune molecular function. Nevertheless, many cores with embedded BN are still hard to synthesize, and thus, further effort is required in this direction. Herein, we present an integrated approach to BN-containing polycycles rooted in an exceptionally clean B-N condensation of amines with a tri-allylborane. Having released propene as the only byproduct, the resulting BN precursors are seamlessly telescoped into BN-containing polycyclic cores via a set of additional methodologies, either developed here ad-hoc or applied for the first time for the synthesis of BN-cycles. As the "sharpening stone" of the process, BN-embedded naphthalene, which has previously only been obtained in low yield, can now be synthesized efficiently through propenolysis, ring-closing metathesis and a new high-yielding aromatization. As a more advanced application, an analogously obtained BN-containing bis-enyne is readily converted to BN-containing non-aromatic tetra-, penta- and hexacyclic structures via ring-closing enyne metathesis, followed by the Diels-Alder cycloaddition. The resulting air-sensitive structures are easily handled by preventive hydration (quaternization) of their B-N bridge; reverting this hydration restores the original Bsp2-Nsp2 structure. In the future, these structures may pave the way to BN-anthracenes and other π-extended BN-arenes.

Expanding Linker Dimensionality in Metal‐organic Frameworks for sub‐Ångstrom Pore Control for Separation Applications

AbstractMetal‐organic frameworks (MOFs) are a class of porous materials with high surface areas, which are acquiring rapid attention on an exponential basis. A significant characteristic of MOFs is their ability to act as adsorbents to selectively separate component mixtures of similar size, thereby addressing the technological need for an alternative approach to conventional distillation methods. Recently, MOFs comprising a 3‐Dimensional (3D) linker have shown outstanding capabilities for difficult separations compared to the parent 2‐Dimensional (2D) analogue. 3D‐linkers with a polycyclic core are underrepresented in the MOF database due to the widespread preferred use of 2D‐linkers and the misconceived high‐cost of 3D linkers. We summarize the recent research of 3D‐linker MOFs and highlight their beneficial employment for selective gas and hydrocarbon adsorption and separation. Furthermore, we outline forecasts in this area to create a platform for widespread adoption of 3D‐linkers in MOF synthesis.

Expanding Linker Dimensionality in Metal-organic Frameworks for sub-Ångstrom Pore Control for Separation Applications.

Metal-organic frameworks (MOFs) are a class of porous materials with high surface areas, which are acquiring rapid attention on an exponential basis. A significant characteristic of MOFs is their ability to act as adsorbents to selectively separate component mixtures of similar size, thereby addressing the technological need for an alternative approach to conventional distillation methods. Recently, MOFs comprising a 3-Dimensional (3D) linker have shown outstanding capabilities for difficult separations compared to the parent 2-Dimensional (2D) analogue. 3D-linkers with a polycyclic core are underrepresented in the MOF database due to the widespread preferred use of 2D-linkers and the misconceived high-cost of 3D linkers. We summarize the recent research of 3D-linker MOFs and highlight their beneficial employment for selective gas and hydrocarbon adsorption and separation. Furthermore, we outline forecasts in this area to create a platform for widespread adoption of 3D-linkers in MOF synthesis.

Synthesis and extraction ability of amide derivatives of calix[4]resorcinarene and 1,1′-dinaphthylmethane toward metal cations

Aminolysis of ester derivatives of 1,1′-dinaphthylmethane and rctt -calix[4]resorcinarene afforded a series of ligands, which differ in molecular platform structure, the number of electron-donating sites, the nature of terminal amide component, the nature and size of the spacers connecting the polycyclic core with amide group. Using liquid extraction method, the effect of ligand structural features on its ability to recognize and bind s -, p -, d -, f -metal cations was investigated, and the stoichiometry of formed complexes was calculated.

Deciphering the proficiency of aliphatic/aromatic functionality on a heteroatom embedded planar polycyclic core: towards advanced onsite detection of tetracycline and oxytetracycline

The structure–property correlation through harnessing the aliphatic/aromatic functionality in a heteroatom-embedded planar polycyclic core towards fluorescence-based onsite antibiotic detection using a smartphone-based prototype platform is presented.

Synthesis of BN-Polyarenes by a Mild Borylative Cyclization Cascade.

Reaction of BCl3 with suitably substituted o-alkynylanilines promotes a cascade reaction in which BN-polycyclic compounds are obtained via the formation of two new cycles and three new bonds in a single operational step. The reaction is highly efficient and takes place at room temperature, providing a very mild and straightforward strategy for the preparation of BN-aromatic compounds, which can be further transformed into a variety of BN-PAHs with different polycyclic cores and substituents.

Asymmetric Total Synthesis of (-)-Phaeocaulisin A.

The therapeutic properties of Curcuma (ginger and turmeric’s family) have long been known in traditional medicine. However, only recently have guaiane-type sesquiterpenes extracted from Curcuma phaeocaulis been submitted to biological testing, and their enhanced bioactivity was highlighted. Among these compounds, phaeocaulisin A has shown remarkable anti-inflammatory and anticancer activity, which appears to be tied to the unique bridged acetal moiety embedded in its tetracyclic framework. Prompted by the promising biological profile of phaeocaulisin A and by the absence of a synthetic route for its provision, we have implemented the first enantioselective total synthesis of phaeocaulisin A in 17 steps with 2% overall yield. Our route design builds on the identification of an enantioenriched lactone intermediate, tailored with both a ketone moiety and a conjugated alkene system. Taking advantage of the umpolung carbonyl-olefin coupling reactivity enabled by the archetypal single-electron transfer (SET) reductant samarium diiodide (SmI2), the lactone intermediate was submitted to two sequential SmI2-mediated cyclizations to stereoselectively construct the polycyclic core of the natural product. Crucially, by exploiting the innate inner-sphere nature of carbonyl reduction using SmI2, we have used a steric blocking strategy to render sites SET-unreceptive and thus achieve chemoselective reduction in a complex substrate. Our asymmetric route enabled elucidation of the naturally occurring isomer of phaeocaulisin A and provides a synthetic platform to access other guaiane-type sesquiterpenes from C. phaeocaulis—as well as their synthetic derivatives—for medicinal chemistry and drug design.

Catalytic Control of Spiroketal Formation in Rubromycin Polyketide Biosynthesis.

The medically important bacterial aromatic polyketide natural products typically feature a planar, polycyclic core structure. An exception is found for the rubromycins, whose backbones are disrupted by a bisbenzannulated [5,6]‐spiroketal pharmacophore that was recently shown to be assembled by flavin‐dependent enzymes. In particular, a flavoprotein monooxygenase proved critical for the drastic oxidative rearrangement of a pentangular precursor and the installment of an intermediate [6,6]‐spiroketal moiety. Here we provide structural and mechanistic insights into the control of catalysis by this spiroketal synthase, which fulfills several important functions as reductase, monooxygenase, and presumably oxidase. The enzyme hereby tightly controls the redox state of the substrate to counteract shunt product formation, while also steering the cleavage of three carbon‐carbon bonds. Our work illustrates an exceptional strategy for the biosynthesis of stable chroman spiroketals.

Catalytic Control of Spiroketal Formation in Rubromycin Polyketide Biosynthesis

AbstractThe medically important bacterial aromatic polyketide natural products typically feature a planar, polycyclic core structure. An exception is found for the rubromycins, whose backbones are disrupted by a bisbenzannulated [5,6]‐spiroketal pharmacophore that was recently shown to be assembled by flavin‐dependent enzymes. In particular, a flavoprotein monooxygenase proved critical for the drastic oxidative rearrangement of a pentangular precursor and the installment of an intermediate [6,6]‐spiroketal moiety. Here we provide structural and mechanistic insights into the control of catalysis by this spiroketal synthase, which fulfills several important functions as reductase, monooxygenase, and presumably oxidase. The enzyme hereby tightly controls the redox state of the substrate to counteract shunt product formation, while also steering the cleavage of three carbon‐carbon bonds. Our work illustrates an exceptional strategy for the biosynthesis of stable chroman spiroketals.

HIV-1 Integrase Inhibitors with Modifications That Affect Their Potencies against Drug Resistant Integrase Mutants.

Integrase strand transfer inhibitors (INSTIs) block the integration step of the retroviral lifecycle and are first-line drugs used for the treatment of HIV-1/AIDS. INSTIs have a polycyclic core with heteroatom triads, chelate the metal ions at the active site, and have a halobenzyl group that interacts with viral DNA attached to the core by a flexible linker. The most broadly effective INSTIs inhibit both wild-type (WT) integrase (IN) and a variety of well-known mutants. However, because there are mutations that reduce the potency of all of the available INSTIs, new and better compounds are needed. Models based on recent structures of HIV-1 and red-capped mangabey SIV INs suggest modifications in the INSTI structures that could enhance interactions with the 3′-terminal adenosine of the viral DNA, which could improve performance against INSTI resistant mutants. We designed and tested a series of INSTIs having modifications to their naphthyridine scaffold. One of the new compounds retained good potency against an expanded panel of HIV-1 IN mutants that we tested. Our results suggest the possibility of designing inhibitors that combine the best features of the existing compounds, which could provide additional efficacy against known HIV-1 IN mutants.

Multifaceted activity of polyciclic MDR revertant agents in drug-resistant leukemic cells: Role of the spacer

A small library of derivatives carrying a polycyclic scaffold recently identified by us as a new privileged structure in medicinal chemistry was designed and synthesized, aiming at obtaining potent MDR reverting agents also endowed with antitumor properties. In particular, as a follow-up of our previous studies, attention was focused on the role of the spacer connecting the polycyclic core with a properly selected nitrogen-containing group. A relevant increase in reverting potency was observed, going from the previously employed but-2-ynyl- to a pent-3-ynylamino moiety, as in compounds 3d and 3e, while the introduction of a triazole ring proved to differently impact on the activity of the compounds. The docking results supported the data obtained by biological tests, showing, for the most active compounds, the ability to establish specific bonds with P-glycoprotein. Moreover, a multifaceted anticancer profile and dual in vitro activity was observed for all compounds, showing both revertant and antitumor effects on leukemic cells. In this respect, 3c emerged as a “triple-target” agent, endowed with a relevant reverting potency, a considerable antiproliferative activity and a collateral sensitivity profile.

An Endo‐Selective Epoxide‐Opening Cascade for the Fast Assembly of the Polycyclic Core Structure of Marine Ladder Polyethers

AbstractThe rapid synthesis of marine ladder polyethers from polyepoxide precursors (in analogy with the biosynthetic pathway hypothesized by Nakanishi) is hampered by the fact that the exo‐selective epoxide‐opening cyclization cascade that gives THF‐type polyethers is preferred over the endo‐selective cascade that gives the desired products. We found that perfluoro‐tert‐butanol (PFTB) cooperating with 1‐ethyl‐3‐methylimidazolium tetrafluoroborate ([EMIM]BF4) can promote endo‐selective epoxide‐opening cyclization reactions of trisubstituted epoxy alcohols. Starting from readily accessible homochiral polyepoxy alcohols with a methyl group at all the endo‐cyclization sites, we were able to construct polyethers up to five consecutive fused 6‐, 7‐, and/or 8‐membered rings in one step. Notably, molecules with the 7/7/6/6 and 7/7/6/7/6 polyether frameworks of hemibrevetoxin B and brevenal, respectively, could be synthesized in 40 % and 17 % chemical yields.

Control of Stereoselectivity in Diverse Hapalindole Metabolites is Mediated by Cofactor-Induced Combinatorial Pairing of Stig Cyclases.

Stereospecific polycyclic core formation of hapalindoles and fischerindoles is controlled by Stig cyclases through a three-step cascade involving Cope rearrangement, 6-exo-trig cyclization, and a final electrophilic aromatic substitution. Reported here is a comprehensive study of all currently annotated Stig cyclases, revealing that these proteins can assemble into heteromeric complexes, induced by Ca2+ , to cooperatively control the stereochemistry of hapalindole natural products.

Control of Stereoselectivity in Diverse Hapalindole Metabolites is Mediated by Cofactor‐Induced Combinatorial Pairing of Stig Cyclases

AbstractStereospecific polycyclic core formation of hapalindoles and fischerindoles is controlled by Stig cyclases through a three‐step cascade involving Cope rearrangement, 6‐exo‐trig cyclization, and a final electrophilic aromatic substitution. Reported here is a comprehensive study of all currently annotated Stig cyclases, revealing that these proteins can assemble into heteromeric complexes, induced by Ca2+, to cooperatively control the stereochemistry of hapalindole natural products.

Modular Synthesis of Polycyclic Alkaloid Scaffolds via an Enantioselective Dearomative Cascade.

The polycyclic core of the akuammiline alkaloids can be synthesized from simple tryptamine and tryptophol derivatives via a Ag(I)-catalyzed enantioselective dearomative cyclization cascade sequence. The complex tetracyclic scaffolds are prepared via a rapid, versatile, three-step modular synthesis from simple commercially available indole derivatives in high yields and enantiomeric excess (up to 99% yield and >99% ee).

Recent advances in the synthesis of plakortin-type polyketides.

Plakortin-type polyketides represent a growing family of sponge-derived marine natural products that display notable structural and biological diversity. In particular, a series of polycyclic plakortin polyketides, namely hippolachnin A and gracilioethers, have been identified in recent years, which attract immense interest from the synthetic community owing to their unique molecular architectures and promising biomedical potential. A number of elegant total syntheses of these targets and some synthetic studies have been performed through either bio-inspired or rationally designed strategies. This focused review aims to provide an up-to-date summary of the progress in the chemical synthesis of plakortin polyketides, with an emphasis on the key synthetic elements enabling the rapid assembly of their core skeletons.