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A palladium-catalyzed spirocyclization reaction is reported and proposed to arise via diastereoselective insertion of an oxabicycle into a palladacycle. The cycloadduct undergoes a post-catalytic retro-Diels–Alder step to furnish a previously inaccessible cis-alkene.

A Pd(0)/blue light catalyzed carboiodination reaction is reported. A simple, air-stable catalytic system, utilizing [Pd(allyl)Cl]

A widely appreciated principle is that all reactions are fundamentally reversible. Observing reversible transition metal-catalyzed reactions, particularly those that include the cleavage of C–C bonds, are more challenging. The development of the palladium- and nickel-catalyzed carboiodination reactions afforded access to the syn- and anti-diastereomers of the iodo-dihydroisoquinolone products. Using these substrates, an extensive study investigating the catalytic reversibility of the C–C bond formation using a different palladium catalyst was undertaken. A combination of experimental and computational studies led to the discovery of a variety of new methodologies and concepts key to understanding the process of reversible C–C bond formations.

These data are the R scripts, environments, output used for analyzing chemoproteomics data. The volcano plot shown in the manuscript is based on the DEP R package. To validate the enrichment output from DEP, the proteomics data was also processed with the proDA package. Filename (7 files) Description combined_protein_Int.txt Output from database search hdac6_dep_submitted.R script used to process data (from DEP package) hdac6_dep_submitted.R.RData workspace environment from DEP package hdac6probecontrol_dep.csv exported list of p-value and fold-change from DEP hdac6probecontrol_proda.csv exported list of p-value and fold-change from proDA hdac6proda_submitted.R proDA script hdac6proda_submitted.RData proDA workspace environment, PXD039880 - the raw data is also uploaded to PRIDE.

The activation of C–C bonds via transition metal catalysis has become an increasingly popular strategy in organic synthesis. An emerging method to cleave C–C bonds is to facilitate a β-carbon elimination using rhodium or palladium catalysis. This elementary step typically relies on a thermodynamic driving force, such as the relief of ring strain or steric strain. More recently, the use of neopentyl metal species or chelation assistance has enabled this difficult transformation. This review will cover recent synthetic applications of β-carbon eliminations under palladium and rhodium catalysis.1 Introduction2 Chelation-Assisted β-Carbon Elimination Reactions3 β-Carbon Elimination from Neopentyl–Pd Species4 Pd-Catalyzed Catellani Reactions5 β-Carbon Elimination Reactions of Cyclopropanes6 Conclusion

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, enabling the formal insertion of alkynes into strong C–F bonds. Our proposed mechanism involves fluoride addition to the alkyne via a nucleophilic fluoroborate species, followed by cyclization onto the carbamoyl moiety with concomitant release of fluoride. The developed method provides access to 3-fluoromethylene oxindoles and γ-lactams with excellent stereoselectivity, including fluorinated derivatives of known protein kinase inhibitors.

The reaction of alkene-tethered trifluoroacetimidoyl chlorides with trialkyl phosphites furnishes 1-amino-2,2,2-trifluoroalkylphosphonates. The products were generated in moderate to good yields, and the scalability of this process was showcased. Partial hydrolysis of the phosphonate moiety was achieved. The cyclization is proposed to occur via formation of an imidoyl phosphonate intermediate that becomes susceptible to nucleophilic attack at nitrogen through the strong electron-withdrawing groups at the imidoyl carbon.

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.

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.

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.

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.

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.

(4+3)-Annulations are incredibly versatile reactions which combine a 4-atom synthon and a 3-atom synthon to form both 7-membered carbocycles as well as heterocycles. We have previously reviewed transition-metal-catalyzed (4+3)-annulations. In this review, we will cover examples involving bases, NHCs, phosphines, Lewis and Brønsted acids as well as some rare examples of boronic acid catalysis and photocatalysis. In analogy to our previous review, we exclude annulations involving cyclic dienes like furan, pyrrole, cyclohexadiene or cyclopentadiene, as Chiu, Harmata, Fernándes and others have recently published reviews encompassing such substrates. We will however discuss the recent additions (2010–2020) to the literature on (4+3)-annulations involving other types of 4-atom-synthons.1 Introduction2 Bases3 Annulations Using N-Heterocyclic Carbenes3.1 N-Heterocyclic Carbenes (NHCs)3.2 N-Heterocyclic Carbenes and Base Dual-Activation4 Phosphines5 Acids5.1 Lewis Acids5.2 Brønsted Acids6 Boronic Acid Catalysis and Photocatalysis7 Conclusion

A scalable nickel-catalyzed carboiodination reaction generating 6-membered carbocycles is reported. NiI2 and P(OEt)3, as the ligand and reducing agent, provided decorated iodo-tetrahydronaphthalene...

Nematode parasites of humans and livestock pose a significant burden to human health, economic development, and food security. Anthelmintic drug resistance is widespread among parasites of livestock and many nematode parasites of humans lack effective treatments. Here, we present a nitrophenyl-piperazine scaffold that induces motor defects rapidly in the model nematode Caenorhabditis elegans. We call this scaffold Nemacol and show that it inhibits the vesicular acetylcholine transporter (VAChT), a target recognized by commercial animal and crop health groups as a viable anthelmintic target. We demonstrate that it is possible to create Nemacol analogs that maintain potent in vivo activity whilst lowering their affinity to the mammalian VAChT 10-fold. We also show that Nemacol synergizes with the anthelmintic ivermectin to kill C. elegans. Hence, Nemacol represents a promising new anthelmintic scaffold that acts through an identified viable anthelmintic target.One sentence summaryA small molecule screen identifies a vesicular acetylcholine transporter inhibitor scaffold that incapacitates parasitic nematodes

The diastereoselective synthesis of sulfonylated indolines is reported. A palladium-catalyzed dearomative sulfination of (aza)indole-tethered aryl iodides generates reactive benzylic sulfinates. These intermediates react with electrophiles in a one-pot, two-step process to generate sulfonylated products in good yields and excellent diastereoselectivity. This three-component sequence demonstrates good scalability and can be applied toward the synthesis of sulfonamides. Additionally, further derivatizations of aryl iodide containing products furnish spiro- and alkynylated indoline products.

An ortho-amination, ipso-C-H arylation mediated by palladium/norbornene cooperative catalysis is reported. This reaction proceeds through a sequential intermolecular C-N bond formation process followed by intramolecular C-H activation of a tethered arene. The products, aminated phenanthridinones, were generated in moderate to good yields. This method is also applicable to the formation of dibenzazepinones.

Organoboronates represent a cornerstone functional group in modern synthesis owing to their unique reactivity and divergent synthetic capability. Copper catalysis has become one of the most powerfu...

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.

A dearomative electrophilic fluorination of 2-methylindoles is reported, delivering 3,3-difluoroindolines bearing an exomethylidene. The model substrate was synthesized on up to a 20 mmol scale and was purified by a practical recrystallization as a crystalline bench-stable, yet reactive solid. The olefin is amphoteric and can react both as a nucleophile and as an electrophile. A wide range of metal-free, palladium, rhodium, and copper reactions was explored, forming new C-H, C-B, C-C (alkyl and aryl), C-N, C-O, C-P, and C-S bonds.

A (4+3)-cycloaddition combines a four-atom synthon and three-atom synthon to form seven-membered rings. In the past decade, many improvements have been made to this class of cycloaddition, including excellent diastereo- and enantioselectivities, both intra- and intermolecularly. Through the strategic use of transition-metal catalysts, acids, bases, and organocatalysts, it is possible to perform the cycloaddition on a variety of substrates, generating novel seven-membered rings. With these advances, (4+3)-cycloaddition has also been applied to the synthesis of biologically relevant compounds and natural products. We exclude the cycloadditions of cyclic dienes such as furan, pyrrole, cyclohexadiene or cyclopentadiene as Chiu, Harmata, Mascareñas­ and others have recently published thorough reviews on that topic. We will however discuss the recent additions (2009–2020) to the literature for the (4+3)-cycloadditions involving other types of four-atom synthons.1 Introduction2 Rhodium2.1 Cyclopropanation/Cope Rearrangement2.2 C–H activation3 Gold, Silver4 Copper5 Palladium, Platinum, Iridium6 Dual-Activation7 Conclusion

This work reports the enantioselective formal transfer of a carbamoyl iodide across a 1,1-disubstituted styrene using Ni-catalysis. Employing an air-stable Ni(II) precatalyst and a commercially ava...

Strategies to capitalize on enolate intermediates generated from stereoselective conjugate borylation to α,β-unsaturated carbonyl systems are surprisingly rare despite the ubiquity of Michael acceptors, and the potential to generate valuable scaffolds bearing multiple stereocenters. Herein, we report a mild and stereoselective copper-catalyzed conjugate borylation/Mannich cyclization reaction. This strategy is feasible with a broad range of Michael acceptors, and can be leveraged to generate versatile borylated tetrahydroquinoline scaffolds bearing three contiguous stereocenters. The synthetic potential of these complex heterocycles has been explored through a series of derivatization studies., Copper-catalyzed enantio- and diastereoselective conjugate borylation across Michael acceptors, with subsequent Mannich-type cyclization, was utilized to construct tetrahydroquinoline scaffolds containing three contiguous stereocenters.

Nematode parasites of humans, livestock and crops pose a significant burden on human health and welfare. Alarmingly, parasitic nematodes of animals have rapidly evolved resistance to anthelmintic drugs, and traditional nematicides that protect crops are facing increasing restrictions because of poor phylogenetic selectivity. Here, we present a pipeline that exploits multiple motor outputs of the model nematode C. elegans for nematicide discovery. This pipeline yielded multiple compounds that selectively kill and/or immobilize diverse nematode parasites. We focus on one compound that induces violent convulsions and paralysis that we call Nementin. We find that Nementin agonizes neuronal dense core vesicle release, which in turn agonizes cholinergic signaling. Consequently, Nementin synergistically enhances the potency of widely-used non-selective acetylcholinesterase inhibitors (AChEIs), but in a nematode-selective manner. Nementin therefore has the potential to reduce the environmental impact of toxic AChEI pesticides used to control nematode infections and infestations.Significance StatementParasitic nematodes pose a considerable burden to human health and food security. Small molecules that have traditionally been used to control these parasites have either been banned because of toxicity concerns or are being rendered ineffective because of the evolution of resistance. Significant gaps in our nematicidal toolkit are therefore becoming an alarming problem. Here, we describe our discovery of Nementin, a small molecule that disrupts the nematode nervous system but is ineffective against non-targeted organisms. We find that Nementin also enhances the activity of non-selective pesticides but does so in a nematode-selective manner. Hence, Nementin is an innovative solution to combat parasitic nematodes in a safe and phylum-selective manner.One-Sentence SummaryA C. elegans-based screening pipeline identifies a selective nematicide that also potentiates acetylcholinesterase inhibitors.

Parasitic nematodes are a major threat to global food security, particularly as the world amasses 10 billion people amidst limited arable land. Most traditional nematicides have been banned due to poor nematode-selectivity, leaving farmers with inadequate controls. Here, we use the model nematode Caenorhabditis elegans to identify a family of selective imidazothiazole nematicides, called selectivins, that undergo cytochrome p450-dependent bioactivation exclusively in nematodes. At low parts-per-million concentrations, selectivins perform comparably well with commercial nematicides to control root infection by Meloidogyne incognita – the world’s most destructive plant-parasitic nematode. Tests against a wide range of phylogenetically diverse non-target systems demonstrate that selectivins are more nematode-selective than nearly all marketed nematicides. Thus, selectivins are first-in-class bioactivated nematode controls that provide efficacy as well as much-needed nematode selectivity.

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.

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.

We report a Rh-catalyzed tandem isomerization–allylation sequence for the generation of α-quaternary aldehydes, starting from unsymmetrical diallyl carbonates. This reaction features a highly selec...

A Ni-catalyzed C–S cross-coupling using only NiI2 (0.5–2.5 mol%) and P(OiPr)3 (2.0–10.0 mol%) is reported. Using an air-stable Ni(II) precatalyst, and a cheap and commercially available ligand, a scalable and robust method was developed to cross-couple various thiophenols and styryl bromides, including some sterically encumbered thiols, an α-bromocinnamaldehyde as well as a thiolation-cyclization.

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.

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.

The rhodium-catalyzed asymmetric ring opening reaction of oxabicyclic alkenes is shown to be an efficient method for synthesizing chiral heterocycles. We demonstrate that the pairwise combination of chiral catalyst with chiral amino-acid-derived pronucleophiles results in a stereodivergent synthesis of diastereomeric hydroxyesters. A favorable conformational preference induces the subsequent lactonization of one diastereomer leading to the highly enantioselective synthesis of oxazinones.

A diastereo- and enantioselective synthesis of boron-containing cyclobutanols is reported. We exploit an enantioselective borylcupration to generate a chiral benzylic copper intermediate that is in...