Intermolecular Diels-Alder Cycloadditions of Furfural-Based Chemicals from Renewable Resources: A Focus on the Regio- and Diastereoselectivity in the Reaction with Alkenes.

A recent strong trend toward green and sustainable chemistry has promoted the intensive use of renewable carbon sources for the production of polymers, biofuels, chemicals, monomers and other valuable products. The Diels-Alder reaction is of great importance in the chemistry of renewable resources and provides an atom-economic pathway for fine chemical synthesis and for the production of materials. The biobased furans furfural and 5-(hydroxymethyl)furfural, which can be easily obtained from the carbohydrate part of plant biomass, were recognized as "platform chemicals" that will help to replace the existing oil-based refining to biorefining. Diels-Alder cycloaddition of furanic dienes with various dienophiles represents the ideal example of a "green" process characterized by a 100% atom economy and a reasonable E-factor. In this review, we first summarize the literature data on the regio- and diastereoselectivity of intermolecular Diels-Alder reactions of furfural derivatives with alkenes with the aim of establishing the current progress in the efficient production of practically important low-molecular-weight products. The information provided here will be useful and relevant to scientists in many fields, including medical and pharmaceutical research, polymer development and materials science.

Enantioselective hydrogenation of cyclic tetrasubstituted-olefinic dehydroamino acid derivatives.

An efficient asymmetric hydrogenation of cyclic tetrasubstituted-olefinic dehydroamino acid derivatives has been achieved with a Rh-ArcPhos catalyst, affording a series of α-acylamino-ß-alkyl tetrahydropyranones with two contiguous chiral centers in up to 96% ee and 1000 TON.

7-Amine-spiro[chromeno[4,3-b]quinoline-6,1'-cycloalkanes]: Synthesis and cholinesterase inhibitory activity of structurally modified tacrines.

Five new examples of 9,10-chloro(bromo)-7-amine-spiro[chromeno[4,3-b]quinoline-6,1'-cycloalkanes] - in which cycloalkanes = cyclopentane, cyclohexane, and cycloheptane - were synthesized at yields of 42-56%, using a sequential one-pot two-step cyclocondensation reaction of three different scaffolds of 2-aminobenzonitriles and the respective spiro[chroman-2,1'-cycloalkan]-4-ones, and using AlCl3 as the catalyst in a solvent-free method. Subsequently, the five new spirochromeno-quinolines and nine quinolines previously published by us (14 modified tacrine scaffolds) were subjected to AChE and BChE inhibitory activity evaluation. The molecule containing a spirocyclopentane derivative had the highest AChE and BChE inhibitory activity (IC50 = 3.60 and 4.40 µM, respectively), and in general, the non-halogenated compounds were better inhibitors of AChE and BChE than the halogenated molecules. However, the inhibitory potency of compounds 3a-n was weaker than that of tacrine. By molecular docking simulations, it was found that the size of the spirocarbocyclic moieties is inversely proportional to the inhibitory activity of the cholinesterases, probably because an increase in the size of the spirocyclic component sterically hindered the interaction of tacrine derivatives with the active site of tested cholinesterases. The findings obtained here may help in the design and development of new anticholinesterase drugs.

Design, synthesis and biological evaluation of diamino substituted cyclobut-3-ene-1,2-dione derivatives for the treatment of drug-resistant tuberculosis.

Mycobacterium tuberculosis (Mtb) ATP synthase is an important target for treating drug-resistant infections and sterilizing the bacteria, spurring intensive efforts to develop new TB therapeutics based on this target. In this work, four novel series including furan-2(5H)-ketone (3, 4), maleimide (5) and squaramide (6) derivatives were designed, respectively, through the strategy of scaffold morphing and hydrogen-bond introduction, using the selective Mtb ATP synthase inhibitor compound 2 as the lead compound. The result demonstrated that diamino substituted cyclobut-3-ene-1,2-dione compounds 6ab and 6ah displayed good to excellent in vitro anti-TB activities (MIC 0.452-0.963 µg/mL) with low cytotoxicity (IC50 > 64 µg/mL). In addition, not only did compound 6ab show effective activity against clinically isolated resistant strains, it also revealed good druggability profiles including improved metabolic stability, no hERG channel inhibition potential, and acceptable oral bioavailability. The preliminary result of docking study and in vitro anti-bedaquiline-resistant strain test compared to compound 2 suggested that Mtb ATP synthase is most likely the target of compound 6ab. The structure-activity relationship laid a good foundation for the identification of novel squaramides as a potential treatment of drug-resistant tuberculosis.

[Synthesis of Cyclic Compounds Containing Aminobenzenesulfonamide].

This review, based on my research work, introduces and summarizes the synthesis and characterization of novel cyclic compounds containing aminobenzenesulfonamide. The review discusses the (1) development of sequential Nicholas and Pauson-Khand reactions for the synthesis of unique polyheterocyclic compounds, (2) production of 2-aminobenzenesulfonamide-containing cyclononyne (ABSACN) as a multifunctional click cycloalkyne agent, and (3) improvement of the intramolecular Pauson-Khand reaction of the nitroarene-enyne substrate for the synthesis of cyclopenta[c]piperidine alkaloids. This research work will facilitate the discovery of sulfonamide or sultam-based functional molecules and pharmaceuticals. Thus, I believe that aminobenzenesulfonamide derivatives are versatile and valuable chemical moieties not only in organic syntheses but also in the pharmaceutical industry. If you are interested in the details of this topic, please refer to the original papers.

Rhodium-Catalyzed (5 + 2) and (5 + 1) Cycloadditions Using 1,4-Enynes as Five-Carbon Building Blocks.

Cycloaddition reactions are a hallmark in organic synthesis because they provide an efficient way to construct highly substituted carbo- and heterocycles found in natural products and pharmaceutical agents. Most cycloadditions occur under thermal or photochemical conditions, but transition-metal complexes can promote reactions that occur beyond these circumstances. Transition-metal complexation with alkynes, alkenes, allenes, or dienes often alters the reactivity of those π-systems and facilitates access to diverse cycloaddition products. This Account describes our efforts toward the design of novel five-carbon synthons for use in rhodium-catalyzed (5 + n) cycloadditions, which include 3-acyloxy-1,4-enynes (ACEs) for (5 + 1) and (5 + 2) cycloadditions and 3-hydroxy-1,4-enynes (HYEs) for (5 + 1) cycloadditions. Furthermore, this Account includes relevant computational information, mechanistic insights, and applications of these cycloadditions in the synthesis of various highly substituted carbo- and heterocycles. The (5 + n) cycloaddition reactions presented herein share the following common mechanistic features: the 1,2-migration of an acyloxy group in propargyl esters or the ionization of a hydroxyl group in propargylic alcohols, oxidative cyclization to form a metallacycle, insertion of the one- or two-carbon component, and reductive elimination to yield the final product. In conjunction with a cationic rhodium catalyst, we used ACEs for the intramolecular (5 + 2) cycloaddition with tethered alkynes, alkenes, and allenes. In some cases, an electron-deficient phosphine ligand improved the reaction yields, especially when the ACE featured an internal alkyne. We also demonstrated that chirality could be efficiently transferred from a relatively simple starting material to a more complex bicyclic product. Products derived from ACEs with tethered alkenes and allenes contained one or more stereocenters, and high diastereoselectivity was achieved in most of these cases. For ACEs tethered to an allene, the reaction preferentially occurred at the internal alkene. We also switched the positions of the alkene and the alkyne in the 1,4-enyne of our original ACE to provide an inverted ACE variant, which produced products with complementary functionalities. After we successfully developed the Rh-catalyzed intramolecular (5 + 2) cycloaddition, we optimized conditions for the intermolecular version, which required a neutral rhodium catalyst and phosphine ligand. When a terminal alkyne was used as the two-carbon component, high regioselectivity was observed. While investigating the effect of esters on the rate of the intermolecular (5 + 2) cycloadditions, we determined that an electron-rich ester significantly accelerated the reaction. Subsequently, we demonstrated that (5 + 1) cycloadditions undergo this rate enhancement as well in the presence of an ester. Aside from ACEs, we synthesized HYEs in four steps from commercially available 2-aminobenzoic acid for use in the (5 + 1) cycloaddition. Mechanistically, HYEs were designed so that the aniline nitrogen could serve as the nucleophile and the -OH could serve as the leaving group. Using HYEs, we developed a novel method to make substituted carbazoles, dibenzofurans, and tricyclic compounds with a cyclohexadienone moiety. Although the occurrence of transition-metal-catalyzed acyloxy migrations has been known for decades, only recently has their synthetic value been realized. We hope our studies that employ readily available 1,4-enynes as the five-carbon components in (5 + n) cycloadditions can inspire the design of new two-component and multicomponent cycloadditions.

Chemo-enzymatic cascades to produce cycloalkenes from bio-based resources.

Engineered enzyme cascades offer powerful tools to convert renewable resources into value-added products. Man-made catalysts give access to new-to-nature reactivities that may complement the enzyme's repertoire. Their mutual incompatibility, however, challenges their integration into concurrent chemo-enzymatic cascades. Herein we show that compartmentalization of complex enzyme cascades within E. coli whole cells enables the simultaneous use of a metathesis catalyst, thus allowing the sustainable one-pot production of cycloalkenes from oleic acid. Cycloheptene is produced from oleic acid via a concurrent enzymatic oxidative decarboxylation and ring-closing metathesis. Cyclohexene and cyclopentene are produced from oleic acid via either a six- or eight-step enzyme cascade involving hydration, oxidation, hydrolysis and decarboxylation, followed by ring-closing metathesis. Integration of an upstream hydrolase enables the usage of olive oil as the substrate for the production of cycloalkenes. This work highlights the potential of integrating organometallic catalysis with whole-cell enzyme cascades of high complexity to enable sustainable chemistry.

A convergent total synthesis of the kedarcidin chromophore: 20-years in the making.

The kedarcidin chromophore is a formidible target for total synthesis. Herein, we describe a viable synthesis of this highly unstable natural product. This entailed the early introduction and gram-scale synthesis of 2-deoxysugar conjugates of both L-mycarose and L-kedarosamine. Key advances include: (1) stereoselective allenylzinc keto-addition to form an epoxyalkyne; (2) α-selective glycosylations with 2-deoxy thioglycosides (AgPF6/DTBMP) and Schmidt donors (TiCl4); (3) Mitsunobu aryl etherification to install a hindered 1,2-cis-configuration; (4) atropselective and convergent Sonogashira-Shiina cyclization sequence; (5) Ohfune-based amidation protocol for naphthoic acid; (6) Ce(III)-mediated nine-membered enediyne cyclization and ester/mesylate derivatisation; (7) SmI2-based reductive olefination and global HF-deprotection end-game. The longest linear sequence from gram-scale intermediates is 17-steps, and HRMS data of the synthetic natural product was obtained for the first time.

Organocatalytic Asymmetric Cascade Reactions Based on Gamma-Nitro Carbonyl Compound.

The significant advancements in asymmetric organocascade reactions have been accomplished during the past decades, paving the way to the efficient and stereoselective construction of structurally complex scaffolds from simple and readily available starting materials. Nitro-containing cyclic compounds have become a privileged molecular library given their broad and promising activities in various therapeutic areas. In various approaches to build these valuable scaffolds, the utility of γ-nitrocarbonyl intermediates is one of the most efficient approaches due to its high efficiency, reliability and versatility. The strategies and catalyst systems described here highlight recent advances in the enantioselective synthesis of nitro-containing cyclic molecules via organocascade strategies based on γ-nitrocarbonyl intermediates. Various organocatalysts with distinct activation modes have found application in providing these sophisticated compounds. This review is organized according to the types of organocatalyst. These methods are of importance for the construction of complex chiral cyclic frameworks and the design of new pharmaceutical compounds. We believe that compounds based on nitro-containing cyclic skeletons have the potential to provide novel therapeutic agents and useful biological tools.

Cubanes in Medicinal Chemistry.

Cubane is a highly strained saturated hydrocarbon system that has historically been of interest in theoretical organic chemistry. More recently it has become a molecule of interest for biological applications due to its inherent stability and limited toxicity. Of greater significance is the ability to potentially functionalize cubane at each of its carbon atoms, providing complex biologically active molecules with unique spatial arrangements for probing active sites. These characteristics have led to an increased use of cubane in pharmaceutically relevant molecules. In this Perspective we describe synthetic methodology for accessing a range of functionalized cubanes and their applications in pharmaceuticals. We also provide some perspectives on challenges and future directions in the advancement of this field.

Synthesis of α-Arylated Cycloalkanones from Congested Trisubstituted Spiro-epoxides: Application of the House-Meinwald Rearrangement for Ring Expansion.

A three-step sequence for the synthesis of α-arylated cyclohexanones and the most challenging cycloheptanones is reported. First, an efficient one-pot synthesis of ß,ß'-disubstituted benzylidene cycloalkanes (styrenes) using the palladium-catalyzed Barluenga reaction from readily available feedstock chemicals is described. Furthermore, an epoxidation followed by the House-Meinwald rearrangement (HMR) of spiro-epoxides is reported to produce a number of α-arylated cycloalkanones upon ring expansion. Reactions catalyzed by bismuth triflate underwent quasi-exclusively ring expansion for all substrates (electronically poor and rich), with yields ranging from 15% to 95%, thus demonstrating the difficulty of achieving ring enlargement for electron-deficient spiro-epoxides. On the other hand, by means of catalysis with aluminum trichloride, the rearrangement of spiro-epoxides proceeded typically in high yields and with remarkable regioselectivity on a broader substrate scope. In this case, a switch of regioselectivity was achieved for spiro-epoxides with electron-withdrawing substituents which enable the method to be successfully extended to some chemospecific arene shifts and the synthesis of aldehydes bearing a α-quaternary carbon. While the HMR has been extensively studied for smaller ring enlargement, we are pleased to report herein that larger cyclohexanones and cycloheptanones can be obtained efficiently from more sterically demanding trisubstituted spiro-epoxides bearing electron-releasing and electron-neutral arene substituents.

Design, synthesis, docking, and antimicrobial evaluation of some novel pyrazolo[1,5-a] pyrimidines and their corresponding cycloalkane ring-fused derivatives as purine analogs.

Background: Over the years, pyrazolopyrimidine derivatives have been recognized as having antimicrobial activities. Recently, we reported different synthetic methods to prepare pyrazolopyrimidine derivatives as anticancer and antimicrobial agents. The studies showed that our previously reported 5-aminopyrazoles 2 act as a building block for the preparation of a variety of interesting pyrazolopyrimidines as purine analogs. Purpose: The objective of this study was to describe the direct new method for preparation of novel pyrazolo[1,5-a]pyrimidine derivatives and their corresponding cycloalkane ring-fused derivatives. Also, the new compounds were tested in vitro for their antibacterial and antifungal activity properties. Methods: Pyrazolo[1,5-a]pyrimidine derivatives were prepared by the reaction of our previously reported 5-aminopyrazoles 2 with suitable sodium salts of (hydroxymethylene) cycloalkanones and sodium salts of unsaturated ketones. Results: The structures of the new compounds were characterized according to their mass spectroscopy, 1H NMR, IR and elemental analyses. Compounds 8b, 10e, 10i, and 10n were the most active compounds against Gram-positive and Gram-negative bacterial species. Compound 10i with two moieties of 4-Br-C6H4 revealed increased reactivity compared with ampicillin as standard reference. Conclusion: About twenty two novel pyrazolo[1,5-a]pyrimidine derivatives and their corresponding cycloalkane ring-fused derivatives were prepared through the reaction of 5-aminopyrazoles 2 with different sodium salts of (hydroxymethylene) cycloalkanones and sodium salts of unsaturated ketones. The antibacterial and antifungal activities of the newly synthesized compounds were evaluated and revealed that compounds 8b, 10e, 10i, and 10n were the most active compounds against Gram-positive and Gram-negative bacterial strains.

A distinctive transformation based diversity oriented synthesis of small ring carbocycles and heterocycles from biocatalytically derived enantiopure α-substituted-ß-hydroxyesters.

A series of structurally novel small ring carbocyclic and heterocyclic molecules were accessed in an enantiopure fashion. The starting materials, α-substituted-ß-hydroxyesters, were achieved through the biocatalytic dynamic kinetic resolution of parent ß-ketoesters in an excellent enantio and diastereocontrolled way. The active functional groups present in the starting precursor, were then tuned sequentially through certain key transformations (functional group interconversions; FGIs) to yield several small molecular scaffolds in a diverse way. Specific transformations such as halocyclization, ene-yne metathesis, dipolar cycloaddition, Mitsunobu cyclization, ring closing metathesis and Pauson-Khand reactions were mainly applied to generate the diversity.

Discovery of Potent Benzocycloalkane Derived Diapophytoene Desaturase Inhibitors with an Enhanced Safety Profile for the Treatment of MRSA, VISA, and LRSA Infections.

Blocking the biosynthesis process of staphyloxanthin has emerged as a promising antivirulence strategy. Our previous research revealed that diapophytoene desaturase was an attractive and druggable target against infections caused by pigmented Staphylococcus aureus. Benzocycloalkane-derived compounds were effective inhibitors of diapophytoene desaturase but limited by high hERG (human Ether-a-go-go Related Gene) inhibition activity. Here, we identified a new type of benzo-hepta-containing cycloalkane derivative as diapophytoene desaturase inhibitors. Among the fifty-eight analogues, 48 (hERG inhibition activity, half maximal inhibitory concentration, IC50, of 16.1 µM) and 51 (hERG inhibition activity, IC50 > 40 µM) were distinguished for effectively inhibiting the pigment production of Staphylococcus aureus Newman and three methicillin-resistant Staphylococcus aureus strains, and the four strains were highly sensitize to hydrogen peroxide killing without a bactericidal growth effect. In an in vivo assay, 48 and 51 displayed a comparable effect with linezolid and vancomycin in livers and hearts in mice against Staphylococcus aureus Newman and a more considerable effect against Mu50 and NRS271 with normal administration.

Thiabicyclononane-Based Antimicrobial Polycations.

Bicyclo[3.3.1]nonane (BCN) polycations were synthesized by the reaction of the bivalent electrophile thiabicyclo[3.3.1]nonane dinitrate with a series of simple bis(pyridine) nucleophiles. Oligomers of moderate chain length were formed in a modular approach that tolerated the inclusion of functionalized and variable-length linkers between the pyridine units. Post-polymerization modification via copper-catalyzed azide-alkyne cyloaddition was enabled by the inclusion of terminal alkyne groups in these monomers. Most of the resulting polymers, new members of the polyionene class, inhibited the growth of bacteria at the µg/mL level and killed static bacterial cells at polymer concentrations of tens of ng/mL, with moderate to good selectivity with respect to lysis of red blood cells. While resistance to the BCN polymers was developed only very slowly over multiple passages, a degradable version of the polycation was observed to make E. coli cells more susceptible to other quaternary ammonium based antimicrobials. Solid substrates (glass and crystalline silicon) covalently functionalized with a representative BCN polycation were also able to repetitively kill bacteria in solution at high rates and with cleaning by simple sonication between exposures.

Fine-Tuning Strain and Electronic Activation of Strain-Promoted 1,3-Dipolar Cycloadditions with Endocyclic Sulfamates in SNO-OCTs.

The ability to achieve predictable control over the polarization of strained cycloalkynes can influence their behavior in subsequent reactions, providing opportunities to increase both rate and chemoselectivity. A series of new heterocyclic strained cyclooctynes containing a sulfamate backbone (SNO-OCTs) were prepared under mild conditions by employing ring expansions of silylated methyleneaziridines. SNO-OCT derivative 8 outpaced even a difluorinated cyclooctyne in a 1,3-dipolar cycloaddition with benzylazide. The various orbital interactions of the propargylic and homopropargylic heteroatoms in SNO-OCT were explored both experimentally and computationally. The inclusion of these heteroatoms had a positive impact on stability and reactivity, where electronic effects could be utilized to relieve ring strain. The choice of the heteroatom combinations in various SNO-OCTs significantly affected the alkyne geometries, thus illustrating a new strategy for modulating strain via remote substituents. Additionally, this unique heteroatom activation was capable of accelerating the rate of reaction of SNO-OCT with diazoacetamide over azidoacetamide, opening the possibility of further method development in the context of chemoselective, bioorthogonal labeling.

Synthesis of Hydroxy-Functionalized Cyclic Olefin Copolymer and Its Block Copolymers with Semicrystalline Polyolefin Segments.

Synthesis of hydroxy-functionalized cyclic olefin copolymer (COC) is achieved with remarkably high activity (up to 5.96 × 107 g-polymer mol-Ti-1 h-1 ) and controlled hydroxy group in a wide range (≈17.1 mol%) by using ansa-dimethylsilylene (fluorenyl)(amido)titanium complex. The catalyst also promotes living/controlled copolymerization to afford novel diblock copolymers consisting of hydroxy-functionalized COC and semicrystalline polyolefin sequence such as polyethylene and syndiotactic polypropylene, where the glass transition temperature of the norbornene/10-undecen-1-ol segment and each block length are controlled by comonomer composition and copolymerization time, respectively.

Synthesis of Renewable Triketones, Diketones, and Jet-Fuel Range Cycloalkanes with 5-Hydroxymethylfurfural and Ketones.

A series of renewable C9 -C12 triketones with repeating [COCH2 CH2 ] units were synthesized in high carbon yields (ca. 90 %) by the aqueous-phase hydrogenation of the aldol-condensation products of 5-hydroxylmethylfurfural (HMF) and ketones over an Au/TiO2 catalyst. Compared with the reported routes, this new route has many advantages such as being environmentally friendly, having fewer steps, using a cheaper and reusable catalyst, etc. The triketones as obtained can be used as feedstocks in the production of conducting or semi-conducting polymers. Through a solvent-free intramolecular aldol condensation over solid-base catalysts, the triketones were selectively converted to diketones, which can be used as intermediates in the synthesis of useful chemicals or polymers. As another application, the tri- and diketones can also be utilized as precursors for the synthesis of jet-fuel range branched cycloalkanes with low freezing points (224-248 K) and high densities (ca. 0.81 g mL-1 ).

Synthesis of jet fuel range branched cycloalkanes with mesityl oxide and 2-methylfuran from lignocellulose.

Jet fuel range branched cycloalkanes with high density (0.82 g mL(-1)) and low freezing point (217-219 K) was first prepared by the solvent-free intramolecular aldol condensation of the trione from the hydrolysis of the alkylation product of mesityl oxide and 2-methylfuran (or the one-pot reaction of mesityl oxide, 2-methylfuran and water), followed by hydrodeoxygenation (HDO).

The Prowess of Photogenerated Amine Radical Cations in Cascade Reactions: From Carbocycles to Heterocycles.

Cascade reactions represent a class of ideal organic reactions because they empower efficiency, elegance, and novelty. However, development of cascade reactions remains a daunting task for synthetic chemists. Radicals are known to be well suited for cascade reactions. Compared with widely used carbon-based radicals, nitrogen-based radicals, such as neutral aminyl radicals and protonated aminyl radicals (amine radical cations), are underutilized, although they are behind some notable synthetic methods such as the Hofmann-Löffler-Freytag reaction. The constraint on their usage is generally attributed to the limited number of available stable precursors. Since amine radical cations offer increased reactivity and selectivity in chemical transformations compared with neutral aminyl radicals, their generation is of utmost importance. Recently, a surge of reports has been revealed using visible light photoredox catalysis. It has been demonstrated that amines can act as an electron donor in a reductive quenching cycle while the amine itself is oxidized to the amine radical cation. Although a number of methods exist to generate amine radical cations, the photochemical formation of these species offers many practical advantages. In this Account, we discuss our journey to the development of annulation reactions with various π-bonds and electrophilic addition reactions to alkenes using photogenerated amine radical cations. Various carbocycles and heterocycles are produced by these reactions. In our annulation work, we first show that single electron photooxidation of cyclopropylanilines to the amine radical cations triggers ring opening of the strained carbocycle, producing distonic radical cations. These odd-electron species are shown to react with alkenes and alkynes to yield the corresponding cyclopentanes and cyclopentenes in an overall redox neutral process. Further development of this annulation reaction allows us to achieve the [4 + 2] annulation of cyclobutylanilines with alkynes. In our work on electrophilic addition reactions to alkenes, we reveal that photogenerated amine radical cations are capable of undergoing the electrophilic addition reactions to alkenes to form a variety of indoles and indolines. This chemistry represents a rare oxidative C-N bond-forming reaction using visible light. Conclusions drawn from observational results and proposed mechanisms are outlined in this Account. Additionally, open discussion of our successes and deficiencies in our experiences will give readers helpful insights as to how these species tend to react. The overall utility of photogenerated amine radical cations has yet to reach its full potential. With our current results, we anticipate more new transformations can still be derived from the ring opening processes of cyclopropylanilines and cyclobutylanilines under visible light photocatalysis. Additionally, since utilizing photogenerated amine radical cations in C-N bond-forming reactions has practically been absent in literature, we are confident more new reactions have yet been exploited.