Selective control of parasitic nematodes using bioactivated nematicides.

Parasitic nematodes are a major threat to global food security, particularly as the world amasses 10 billion people amid limited arable land1-4. Most traditional nematicides have been banned owing to poor nematode selectivity, leaving farmers with inadequate means of pest control4-12. Here we use the model nematode Caenorhabditis elegans to identify a family of selective imidazothiazole nematicides, called selectivins, that undergo cytochrome-p450-mediated bioactivation in nematodes. At low parts-per-million concentrations, selectivins perform comparably well with commercial nematicides to control root infection by Meloidogyne incognita, a highly destructive plant-parasitic nematode. Tests against numerous phylogenetically diverse non-target systems demonstrate that selectivins are more nematode-selective than most marketed nematicides. Selectivins are first-in-class bioactivated nematode controls that provide efficacy and nematode selectivity.

Palladium-Catalyzed Synthesis of Linked Bis-Heterocycles─Synthesis and Investigation of Photophysical Properties.

A palladium-catalyzed domino C-N coupling/Cacchi reaction is reported. Design of photoluminescent bis-heterocycles, aided by density functional theory calculations, was performed with synthetic yields up to 98%. The photophysical properties of the products accessed via this strategy were part of a comprehensive study that led to broad emission spectra and quantum yields of up to 0.59. Mechanistic experiments confirmed bromoalkynes as competent intermediates, and a density functional theory investigation suggests a pathway involving initial oxidative addition into the cis C-Br bond of the gem-dihaloolefin.

Photo-Uncaging by C(sp3)-C(sp3) Bond Cleavage Restores ß-Lapachone Activity.

ß-Lapachone is an ortho-naphthoquinone natural product with significant antiproliferative activity but suffers from adverse systemic toxicity. The use of photoremovable protecting groups to covalently inactivate a substrate and then enable controllable release with light in a spatiotemporal manner is an attractive prodrug strategy to limit toxicity. However, visible light-activatable photocages are nearly exclusively enabled by linkages to nucleophilic functional sites such as alcohols, amines, thiols, phosphates, and sulfonates. Herein, we report covalent inactivation of the electrophilic quinone moiety of ß-lapachone via a C(sp3)-C(sp3) bond to a coumarin photocage. In contrast to ß-lapachone, the designed prodrug remained intact in human whole blood and did not induce methemoglobinemia in the dark. Under light activation, the C-C bond cleaves to release the active quinone, recovering its biological activity when evaluated against the enzyme NQO1 and human cancer cells. Investigations into this report of a C(sp3)-C(sp3) photoinduced bond cleavage suggest a nontraditional, radical-based mechanism of release beginning with an initial charge-transfer excited state. Additionally, caging and release of the isomeric para-quinone, α-lapachone, are demonstrated. As such, we describe a photocaging strategy for the pair of quinones and report a unique light-induced cleavage of a C-C bond. We envision that this photocage strategy can be extended to quinones beyond ß- and α-lapachone, thus expanding the chemical toolbox of photocaged compounds.

BF3-Catalyzed Intramolecular Fluorocarbamoylation of Alkynes via Halide Recycling.

A BF3-catalyzed atom-economical fluorocarbamoylation reaction of alkyne-tethered carbamoyl fluorides is reported. The catalyst acts as both a fluoride source and Lewis acid activator, thereby enabling the formal insertion of alkynes into strong C-F bonds through a halide recycling mechanism. The developed method provides access to 3-(fluoromethylene) oxindoles and γ-lactams with excellent stereoselectivity, including fluorinated derivatives of known protein kinase inhibitors. Experimental and computational studies support a stepwise mechanism for the fluorocarbamoylation reaction involving a turnover-limiting cyclization step, followed by internal fluoride transfer from a BF3-coordinated carbamoyl adduct. For methylene oxindoles, a thermodynamically driven Z-E isomerization is facilitated by a transition state with aromatic character. In contrast, this aromatic stabilization is not relevant for γ-lactams, which results in a higher barrier for isomerization and the exclusive formation of the Z-isomer.

Pd(0)/Blue Light Promoted Carboiodination Reaction - Evidence for Reversible C-I Bond Formation via a Radical Pathway.

A Pd(0)/blue light catalyzed carboiodination reaction is reported. A simple, air-stable catalytic system, utilizing [Pd(allyl)Cl]2 and DPEPhos, generated a variety of iodinated hetero- and carbocycles including oxindoles, dihydrobenzofurans, indolines, a chromane, and a tetrahydronaphthalene. This protocol was tolerant of sensitive functional groups including free carboxylic acids, phenols, and anilines, as well as pyridines, while delivering products in up to 94% yield. Support for a reversible C-I bond formation via a single electron mechanism was obtained using a deuterium labeled substrate and a stoichiometric neopentylpalladium species.

Catalytic asymmetric transformations of oxa- and azabicyclic alkenes.

Oxa- and azabicyclic alkenes can be readily activated by transition-metal complexes with facial selectivity, because of the intrinsic reactivity of strained bicyclic structures. Synthetically, these compounds are important synthons that offer an important platform for the construction of biologically/medicinally significant compounds with two or more stereocenters. This Review comprehensively compiles the diverse catalytic processes involving the enantioselective transformations of oxa- and azabicyclic alkenes. It has been organized according to reaction type, including asymmetric ring opening (ARO) reactions, hydrofunctionalizations, cycloadditions and C-H activation reactions. The ARO section has been subdivided based on the type of nucleophiles employed, and further subdivided based on the metal used, with a separate topic dedicated to asymmetric ring-opening metathesis. Lastly, the presentation of each method/group of reactions is accompanied by concise discussions on their advantages and limitations.

Accessing Unsymmetrically Linked Heterocycles through Stereoselective Palladium-Catalyzed Domino Cyclization.

A palladium-catalyzed strategy is presented to synthesize unsymmetrically linked heterocycles within stereoselective tetrasubstituted olefins. This reaction is proposed to occur via a vinyl-PdII intermediate capable of initiating the cyclization of various alkyne-tethered nucleophiles. Products are formed in up to 96 % yield and excellent stereoselectivities are obtained using low catalyst loadings. This transformation was scalable up to 1 mmol and mechanistic studies suggest a syn-carbopalladation of the carbamoyl chloride followed by PdII -catalyzed cyclization of alkyne-tethered nucleophiles.

Dearomative Cyclopropanation of Naphthols via Cyclopropene Ring-Opening.

The dearomatization of 2-naphthols represents a simple method for the construction of complex 3D structures from simple planar starting materials. We describe a cyclopropanation of 2-naphthols that proceeds via cyclopropene ring-opening using rhodium and acid catalysis under mild conditions. The vinyl cyclopropane molecules were formed with high chemoselectivity and scalability, which could be further functionalized at different sites. Both computational and experimental evidence were used to elucidate the reaction mechanism.

Metal-Catalyzed Approaches toward the Oxindole Core.

The oxindole scaffold is a privileged structural motif that is found in a variety of bioactive targets and natural products. Moreover, derivatives of the oxindole structure are widely present in a number of biologically relevant compounds and are key intermediates in the synthesis of diverse natural products and pharmaceuticals. Therefore, novel methods to obtain oxindoles remain of high priority in synthetic organic chemistry.Over the past several decades, novel transition-metal-catalyzed methodologies have been applied toward the synthesis of a variety of heterocycles. A detailed mechanistic understanding facilitates the disruption of traditional catalytic pathways to access useful synthetic intermediates. The strategies employed have generally revolved around the generation of high-energy organometallic intermediates, which undergo cyclization reactions through domino processes. Domino cyclization methodologies are therefore attractive, as they allow facile access to functionalized oxindoles containing all-carbon quaternary centers or tetrasubstituted olefins with high chemo- and stereoselectivities. Furthermore, these developed synthetic strategies can often be easily applied in the syntheses of other related scaffolds.In this Account, we discuss the three unique strategies that our group has leveraged for the synthesis of valuable oxindole scaffolds. The first section in this Account outlines the use of an initial oxidative addition to a C(sp2)-X bond, followed by a migratory insertion, yielding a neopentyl species amenable to a variety of subsequent functionalizations. From this reactive neopentyl metal species, we have reported C-X reductive eliminations, anionic capture cascade reactions, and intramolecular C-H functionalization processes. The second section of this Account summarizes our group's findings on 1,2-insertions of a metal-nucleophile species across an unsaturation, generating a reactive organometallic intermediate; subsequent reactions with tethered electrophiles form the desired heterocyclic core. We have explored a wide array of transition metal-catalyzed strategies using this approach, including rhodium-catalyzed conjugate additions, an asymmetric copper-catalyzed borylcupration, and a palladium(II)-catalyzed chloropalladation protocol. The final section of this Account details the use of dual-metal catalysis to perform a cyclization through a C-H functionalization-allylation domino reaction. Throughout this Account, we provide details of mechanistic studies that better enabled our understanding of the domino processes.Overall, our group has developed methods exploiting the unique reactivity of palladium, nickel, copper, rhodium, and ruthenium catalysts to develop methods toward a wide array of oxindole scaffolds. On the basis of the utility, diversity, and applicability of the strategies developed, we believe that they will prove to be highly useful in the syntheses of other important targets and inspire further development and mechanistic understanding of various metal-catalyzed processes.

Iron-Catalyzed Reductive Cyclization by Hydromagnesiation: A Modular Strategy Towards N-Heterocycles.

A reductive cyclization to prepare a variety of N-heterocycles, through the use of ortho-vinylanilides, is reported. The reaction is catalyzed by an inexpensive and bench-stable iron complex and generally occurs at ambient temperature. The transformation likely proceeds through hydromagnesiation of the vinyl group, and trapping of the in situ generated benzylic anion by an intramolecular electrophile to form the heterocycle. This iron-catalyzed strategy was shown to be broadly applicable and was utilized in the synthesis of substituted indoles, oxindoles and tetrahydrobenzoazepinoindolone derivatives. Mechanistic studies indicated that the reversibility of the hydride transfer step depends on the reactivity of the tethered electrophile. The synthetic utility of our approach was further demonstrated by the formal synthesis of a reported bioactive compound and a family of natural products.

Recent Strategies for Carbon-Halogen Bond Formation Using Nickel.

Nickel catalysis has demonstrated the capability of performing a broad range of synthetically challenging transformations over the last decade. Though recent literature has focused on the formation of C-C and C-N bonds, a variety of breakthroughs in the field of C-X bond generation have also been reported. A diverse range of strategies using nickel have been developed, in an effort to expand the scope and synthetic utility of these halogenation methods. This Minireview will cover six emerging strategies in this field including: oxidatively induced C-X reductive elimination, triflate-to-halogen exchange reactions, directed C-H halogenation, non-directed electrophilic C-H halogenation of arenes, enantioselective α-fluorination of carbonyl containing compounds, and 1,2-difunctionalization-halogenation reactions. The final section has been split into two parts: nickel-catalyzed hydrohalogenation and nickel-catalyzed carbohalogenation reactions.

Enantio- and Diastereodivergent Sequential Catalysis Featuring Two Transition-Metal-Catalyzed Asymmetric Reactions.

This study demonstrates the feasibility and inherent benefits of combining two distinct asymmetric transition-metal-catalyzed reactions in one pot. The reported transformation features a Pd-catalyzed asymmetric allylic alkylation and a Rh-catalyzed enantioselective 1,4-conjugate addition, effectively converting simple allyl enol carbonate precursors into enantioenriched cyclic ketones with two remote stereocenters. Despite the anticipated challenges associated with controlling stereoselectivity in such a complex system, the products are obtained in enantiomeric excesses ranging up to >99 % ee, exceeding those obtained from either of the individual asymmetric reactions. In addition, since the stereoselectivity of both steps is under catalyst control, this one-pot reaction is enantio- and diastereodivergent, enabling facile access to all stereoisomers from the same set of starting materials.

Enantioselective Synthesis of Spiro-oxiranes: An Asymmetric Addition/Aldol/Spirocyclization Domino Cascade.

Enantioenriched spiro-oxiranes bearing three contiguous stereocenters were synthesized using a rhodium-catalyzed asymmetric addition/aldol/spirocyclization sequence. Starting from a linear substrate, the cascade enabled the formation of a spirocyclic framework in a single step. sp2 - and sp-hybridized carbon nucleophiles were found to be competent initiators for this cascade, giving arylated or alkynylated products, respectively. Derivatization studies demonstrated the synthetic versatility of both the epoxide and the alkyne moieties of the products. DFT calculations were used to reconcile spectroscopic discrepancies observed between the solution- and solid-state structures of the products.

Sequential Pd0 - and PdII -Catalyzed Cyclizations: Enantioselective Heck and Nucleopalladation Reactions.

An enantioselective consecutive cyclization/coupling process, catalyzed by palladium is reported. Stereoinduction arises from an enantioselective carbopalladation, generating an intermediate which promotes a nucleopalladation step. The dual cyclization sequence was compatible with a variety of alkyne-tethered oxygen- and nitrogen-centered nucleophiles, and a variety of alkenyl-tethered aryl iodides, to forge numerous bisheterocycles in good yields and high regio- and enantioselectivities.

Cycloisomerization of Carbamoyl Chlorides in Hexafluoroisopropanol: Stereoselective Synthesis of Chlorinated Methylene Oxindoles and Quinolinones.

Hexafluoroisopropanol (HFIP) was employed as an additive for the generation of 3-(chloromethylene)oxindoles via the chloroacylation of alkyne-tethered carbamoyl chlorides. This reaction avoids the use of a metal catalyst and accesses products in high yields and stereoselectivities. Additionally, this reaction is scalable and proved amenable to a series of product derivatizations, including the synthesis of nintedanib. The reactivity of alkene-tethered carbamoyl chlorides with hexafluoroisopropanol (HFIP) was harnessed towards the synthesis of 2-quinolinones.

Cobalt-Catalyzed Enantioselective Hydroarylation of 1,6-Enynes.

An asymmetric hydroarylative cyclization of enynes involving a C-H bond cleavage is reported. The cobalt-catalyzed cascade generates three new bonds in an atom-economical fashion. The products were obtained in excellent yields and excellent enantioselectivities as single diastereo- and regioisomers. Preliminary mechanistic studies indicate that the reaction shows no intermolecular C-H crossover. This work highlights the potential of cobalt catalysis in C-H bond functionalization and enantioselective domino reactivity.

Enantioselective Cobalt-Catalyzed Intermolecular Hydroacylation of 1,6-Enynes.

We report a cobalt-catalyzed hydroacylation of 1,6-enynes with exogenous aldehydes in a domino sequence to construct enantioenriched ketones. The products were obtained in good yields with excellent regio-, diastereo-, and enantioselectivity. Furthermore, the chiral products served as valuable precursors to access complex spirocyclic scaffolds with three contiguous stereocenters. The asymmetric hydroacylation process exhibited no C-H crossover and no KIE, thus indicating that the C-H bond cleavage was not involved in the turnover-limiting step.

Intramolecular Copper(I)-Catalyzed Interrupted Click-Acylation Domino Reaction.

Acyl substituted triazoles are valuable scaffolds, but the direct synthesis of these moieties from terminal alkynes by copper catalysis remains unexplored. We report a robust, general, and efficient method using a simple CuI/2,2'-bipyridine catalytic system. This transformation involves a copper catalyzed azide-alkyne cycloaddition (CuAAC) followed by an intramolecular acylation onto a carbamoyl chloride. The reaction proceeds under mild conditions, tolerates several functional groups, and is readily scalable. This method represents a novel strategy towards the synthesis of complex heterocycles by a CuAAC/acylation domino process.

Rhodium(I)/Zn(OTf)2 -Catalyzed Asymmetric Ring Opening/Cyclopropanation of Oxabenzonorbornadienes with Phosphorus Ylides.

The strong binding ability of P-ylides with transition metals limits the utilization of stabilized P-ylide as nucleophiles in asymmetric organometallic catalysis. Herein we describe the first rhodium-catalyzed asymmetric ring-opening reaction of P-ylides utilizing oxabicyclic alkenes as the electrophilic partner. Various P-ylides including ester-, ketone- and amide-style P-ylides are all applicable. This asymmetric reaction occurs through the cleavage of two bridgehead C-O bonds and the formation of two C-C bonds, and oxabenzonorbornadienes are used as 1,4-biselectrophiles, thus providing access to benzonorcaradienes in good yields with high enantioselectivity and perfect diastereoselectivity. The present protocol also constitutes the first highly enantioselective direct catalytic asymmetric cyclopropanation of stabilized P-ylide nucleophiles.