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Funding: Leverhulme Trust (Grant Number(s): RPG-2015-308), Leverhulme Trust (Grant Number(s): RPG-2018-362), Engineering and Physical Sciences Research Council (Grant Number(s): EP/R025754/1). Metal‐catalyzed C–N cross‐coupling generally forms C–N bonds by reductive elimination from metal complexes bearing covalent C‐ and N‐ligands. We have identified a Cu‐mediated C–N cross‐coupling that uses a dative N‐ligand in the bond forming event, which, in contrast to conventional methods, generates reactive cationic products. Mechanistic studies suggest the process operates via transmetalation of an aryl organoboron to a Cu(II) complex bearing neutral N‐ligands, such as nitriles or N‐heterocycles. Subsequent generation of a putative Cu(III) complex enables the oxidative C–N coupling to take place, delivering nitrilium intermediates and pyridinium products. The reaction is general for a range of N(sp) and N(sp2) precursors and can be applied to drug synthesis and late‐stage N‐arylation, and the limitations in the methodology are mechanistically evidenced. Publisher PDF

G.E.B. thanks the EPSRC and GSK for a PhD studentship. J.W.B.F. thanks the Leverhulme Trust for postdoctoral funding (RPG-2018-362). A Pd-catalyzed heteroannulation approach for the synthesis of C2 borylated indoles is reported. The process allows access to highly functionalized 2-borylated indole scaffolds with complete control of regioselectivity. The utility of the process is demonstrated in the synthesis of borylated sulfa drugs and in the concise synthesis of the Aspidosperma alkaloid Goniomitine. Publisher PDF

We describe enantioselective syntheses of strychnos and chelidonium alkaloids. In the first case, indole acetic acid esters were established as excellent partner nucleophiles for enantioselective cooperative isothiourea/Pd catalyzed α-alkylation. This provides products containing indole-bearing stereocenters in high yield and with excellent levels of enantioinduction in a manner that is notably independent of the N-substituent. This led to concise syntheses of (-)-akuammicine and (-)-strychnine. In the second case, the poor performance of ortho-substituted cinnamyl electrophiles in the enantioselective cooperative isothiourea/Ir catalyzed α-alkylation was overcome by appropriate substituent choice, leading to enantioselective syntheses of (+)-chelidonine, (+)-norchelidonine, and (+)-chelamine.

Neurodegenerative diseases such as Alzheimer's and Parkinson's are associated with protein misfolding and aggregation. Recent studies suggest that the small, rare and heterogeneous oligomeric species, formed early on in the aggregation process, may be a source of cytotoxicity. Thioflavin T (ThT) is currently the gold-standard fluorescent probe for the study of amyloid proteins and aggregation processes. However, the poor photophysical and binding properties of ThT impairs the study of oligomers. To overcome this challenge, we have designed Thioflavin X, (ThX), a next-generation fluorescent probe which displays superior properties; including a 5-fold increase in brightness and 7-fold increase in binding affinity to amyloidogenic proteins. As an extrinsic dye, this can be used to study unique structural amyloid features both in bulk and on a single-aggregate level. Furthermore, ThX can be used as a super-resolution imaging probe in single-molecule localisation microscopy. Finally, the improved optical properties (extinction coefficient, quantum yield and brightness) of ThX can be used to monitor structural differences in oligomeric species, not observed via traditional ThT imaging., Introducing ThX, a next-generation ThT derivative that allows for the early detection of amyloid aggregates at the bulk and single-aggregate levels.

Transition metal-mediated formation of C-N bonds is an essential synthetic methodology. The discovery of the Chan-Lam amination provided a C-N bond forming process that was mild, convenient, and inexpensive, offering an alternative to complementary methods using other transition metals (TMs). Over the past 20 years, this reaction has seen considerable development in its scope of application, uptake into industry, and understanding of its mechanism. This review provides an account of the development of the Chan-Lam amination, highlighting progress and notable examples of application since 2011. Focus is given to evolution in mechanistic understanding and selected applications of the methodology within medicinal and process chemistry.

Herein, we report a modular synthetic route to linear and branched homoallylic amines that operates through a sequential one-pot Lewis base/transition-metal catalyzed allylic alkylation/Hofmann rearrangement strategy. This protocol is operationally trivial, proceeds from simple and easily prepared substrates and catalysts, and enables all aspects of regio- and stereoselectivity to be controlled through a conserved experimental protocol. Overall, the high levels of enantio-, regio-, and diastereoselectivity obtained, in concert with the ability to access orthogonally protected or free amines, render this a straightforward and effective approach for the preparation of useful enantioenriched homoallylic amines. We have also demonstrated the utility of the products in the context of pharmaceutical synthesis.

Epidithiodiketopiperazines (ETPs) possess remarkably diverse biological activities and have attracted significant synthetic attention. The preparation of analogues is actively pursued; however, they are structurally challenging, and more direct and modular methods for their synthesis are desirable. To this end, the utility of a bifunctional triketopiperazine building block for the straightforward synthesis of ETPs is reported. A modular strategy consisting of enolate alkylation followed by site-selective nucleophile addition enables the concise synthesis of (±)-hyalodendrin and a range of analogues.

Metal‐catalyzed C–N cross‐coupling generally forms C−N bonds by reductive elimination from metal complexes bearing covalent C‐ and N‐ligands. We have identified a Cu‐mediated C–N cross‐coupling that uses a dative N‐ligand in the bond‐forming event, which, in contrast to conventional methods, generates reactive cationic products. Mechanistic studies suggest the process operates via transmetalation of an aryl organoboron to a CuII complex bearing neutral N‐ligands, such as nitriles or N‐heterocycles. Subsequent generation of a putative CuIII complex enables the oxidative C–N coupling to take place, delivering nitrilium intermediates and pyridinium products. The reaction is general for a range of N(sp) and N(sp2) precursors and can be applied to drug synthesis and late‐stage N‐arylation, and the limitations in the methodology are mechanistically evidenced., Cu(OTf)2 promotes the oxidative arylation of nitriles and N‐heterocycles to generate ionic products. Mechanistic studies suggest the process operates via reductive elimination from a CuIII complex bearing neutral N‐ligands to generate nitrilium and pyridinium products. The reaction is general for a range of N(sp) and N(sp2) precursors and can be applied to drug synthesis and late‐stage N‐arylation.

Metal-catalyzed C–N cross-coupling generally forms C–N bonds by reductive elimination from metal complexes bearing covalent C- and N-ligands. We have identified a Cu-mediated C–N cross-coupling that uses a dative N-ligand in the bond forming event, which, in contrast to conventional methods, generates reactive cationic products. Mechanistic studies suggest the process operates via transmetalation of an aryl organoboron to a Cu(II) complex bearing neutral N-ligands, such as nitriles or N-heterocycles. Subsequent generation of a putative Cu(III) complex enables the oxidative C–N coupling to take place, delivering nitrilium intermediates and pyridinium products. The reaction is general for a range of N(sp) and N(sp2) precursors and can be applied to drug synthesis and late-stage N-arylation, and the limitations in the methodology are mechanistically evidenced.

The first asymmetric cooperative Lewis base/palladium catalyzed benzylic alkylation of acyclic esters is reported. This reaction proceeds via stereodefined C1-ammonium enolate nucleophiles. Critical to its success was the identification of benzylic phosphate electrophiles, which were uniquely reactive. Alkylated products were obtained with very high levels of enantioselectivity, and this method has been applied toward the synthesis of the thrombin inhibitor DX-9065a.

Chemoselective Suzuki-Miyaura cross-coupling generally requires a designed deactivation of one nucleophile towards transmetallation. Here we show that boronic acids can be chemoselectively reacted in the presence of ostensibly equivalently reactive boronic acid pinacol (BPin) esters by kinetic discrimination during transmetallation. Simultaneous electrophile control allows sequential chemoselective cross-couplings in a single operation in the absence of protecting groups.

Neurodegenerative diseases such as Alzheimer’s and Parkinson’s are associated with protein misfolding and aggregation. Recent studies suggest that the small, rare and heterogeneous oligomeric species, formed early on in the aggregation process, may be a source of cytotoxicity. Thioflavin T (ThT) is currently the gold-standard fluorescent probe for the study of amyloid proteins and aggregation processes. However, the poor photophysical and binding properties of ThT impairs the study of oligomers. To overcome this challenge, we have designed Thioflavin X, (ThX), a next-generation fluorescent probe which displays superior properties; including a 5-fold increase in brightness and 7-fold increase in binding affinity to amyloidogenic proteins. As an extrinsic dye, this can be used to study unique structural amyloid features both in bulk and on a single-aggregate level. Furthermore, ThX can be used as a super-resolution imaging probe in single-molecule localisation microscopy. Finally, we demonstrate that ThX can be used to detect a distinct oligomeric species, not observed via traditional ThT imaging.

Cooperative catalysis enables the direct enantioselective α-allylation of linear prochiral esters using Si-substituted allyl electrophiles. The Si-substituent directs the regioselectivity of enantioselective bond formation and provides products containing synthetically versatile pentafluorophenyl ester and vinylsilane moieties. Critical to the efficacy of this process was the recognition that the ancillary ligand on palladium could be altered to prevent formation of a deleterious ether by-product, whilst retaining enantioselectivity through the Lewis base catalyst. Flexibility such as this is unique to cooperative catalysis events and provides efficient access to an array of enantioenriched products that are orthogonally functionalized and easily modified.

Protein aggregation into amyloid deposits and oxidative stress are key features of many neurodegenerative disorders including Parkinson's and Alzheimer's disease. We report here the creation of four highly sensitive bifunctional fluorescent probes, capable of H 2 O 2 and/or amyloid aggregate detection. These bifunctional sensors use a benzothiazole core for amyloid localization and boronic ester oxidation to specifically detect H 2 O 2 . We characterized the optical properties of these probes using both bulk fluorescence measurements and single-aggregate fluorescence imaging, and quantify changes in their fluorescence properties upon addition of amyloid aggregates of α-synuclein and pathophysiological H 2 O 2 concentrations. Our results indicate these new probes will be useful to detect and monitor neurodegenerative disease.

Control of boronic acid speciation is presented as a strategy to achieve nucleophile chemoselectivity in the Suzuki-Miyaura reaction. Combined with simultaneous control of oxidative addition and transmetallation, this enables chemoselective formation of two C-C bonds in a single operation, providing a method for the rapid preparation of highly functionalized carbogenic frameworks.

Chemoselective Suzuki-Miyaura cross-coupling has emerged as a powerful method for the rapid preparation of sp2-and sp3-hybridized carbon frameworks based on control of the oxidative addition or transmetallation events. The field of chemoselective transmetallation has recently seen considerable development with several different strategies emerging including protected boronic acids, neighboring group activation, and chemoselective speciation. Herein, these state-of-the-art approaches towards chemoselective Suzuki-Miyaura cross-coupling are highlighted.

A chemoselective tandem reaction of a multi-reactive, two electrophile + two nucleophile, system is reported. An allylation/cross-coupling process of a haloaryl aldehyde, an aryl BPin, and an allyl BPin can be controlled using a temperature gradient to overcome natural reactivity profiles and allow two sequential chemoselective C–C bond formations without intervention. This process offers efficient access to an array of functionalised products including pharmaceutical and natural product scaffolds.

Organoboron reagents have been synonymous with organic chemistry for over half a century and continue to see widespread application today; for example, classic reactions such as hydroboration and Suzuki-Miyaura cross-coupling are regularly practiced throughout the chemical community. In particular, applications of organoboron compounds have underpinned pharmaceutical and agrochemical development on both discovery and process scales for decades. Although it is noteworthy that these seminal reactions have stood the test of time, continually increasing pressure to improve efficiency in chemical synthesis demands innovation. Over the past few years, through an explosion in the number of new methods for the installation and manipulation of organoboron functional groups, as well as the understanding of their mechanistic operation, organoboron chemistry has risen to this challenge.

The synthesis of functionalized oxindoles and benzofuranones via oxidation of 2-BMIDA indoles and benzofurans, respectively, is described. Interconversion of boron species (BMIDAaBF3K) was necessary to enable oxidation and overcome boronic acid stability issues associated with a difficult BMIDA hydrolysis. Overall, a robust process was developed that allowed access to a small library of oxindole and benzofuranone products and facilitated the step-efficient synthesis of biologically-active compounds containing the oxindole pharmacophore.

Palladium-catalysed coupling reactions based on a novel and easy-to-synthesise difluorinated organotrifluoroborate were used to assemble precursors to 6π-electrocyclisations of three different types. Electrocyclisations took place at temperatures between 90 and 240 oC, depending on the central component of the π-system; non-aromatic trienes were most reactive, but even systems which required the temporary dearomatisation of two arenyl sub-units underwent electrocyclisation, albeit at elevated temperatures. Photochemical conditions were effective for these more demanding reactions. The package of methods delivered a structurally-diverse set of fluorinated arenes, spanning a 20 kcal mol-1 range of reactivity, by a flexible route.

The reaction is applied in the synthesis of key intermediate (VII) for BET bromodomain inhibitor (VIII).

Protein aggregation into amyloid deposits and oxidative stress are key features of many neurodegenerative disorders including Parkinson's and Alzheimer's disease. We report here the creation of four highly sensitive bifunctional fluorescent probes, capable of H2O2 and/or amyloid aggregate detection. These bifunctional sensors use a benzothiazole core for amyloid localization and boronic ester oxidation to specifically detect H2O2. We characterized the optical properties of these probes using both bulk fluorescence measurements and single-aggregate fluorescence imaging, and quantify changes in their fluorescence properties upon addition of amyloid aggregates of α-synuclein and pathophysiological H2O2 concentrations. Our results indicate these new probes will be useful to detect and monitor neurodegenerative disease.

Boronic acid solution speciation can be controlled during the Suzuki-Miyaura cross-coupling of haloaryl N-methyliminodiacetic acid (MIDA) boronic esters to enable the formal homologation of boronic acid derivatives. The reaction is contingent upon control of the basic biphase and is thermodynamically driven: temperature control provides highly chemoselective access to either BMIDA adducts at room temperature or boronic acid pinacol ester (BPin) products at elevated temperature. Control experiments and solubility analyses have provided some insight into the mechanistic operation of the formal homologation process.

Chemoselective Suzuki-Miyaura cross-coupling has emerged as a powerful method for the rapid preparation of sp2-and sp3-hybridized carbon frameworks based on control of the oxidative addition or transmetallation events. The field of chemoselective transmetallation has recently seen considerable development with several different strategies emerging including protected boronic acids, neighboring group activation, and chemoselective speciation. Herein, these state-of-the-art approaches towards chemoselective Suzuki-Miyaura cross-coupling are highlighted.

Control of boronic acid speciation is presented as a strategy to achieve nucleophile chemoselectivity in the Suzuki-Miyaura reaction. Combined with simultaneous control of oxidative addition and transmetalation, this enables chemoselective formation of two C-C bonds in a single operation, providing a method for the rapid preparation of highly functionalized carbogenic frameworks.

The solution speciation of boronic acids can be chemoselectively controlled to enable the formal homologation of boronic acid pinacol esters.

Boronic acid solution speciation can be controlled during the Suzuki-Miyaura cross-coupling of haloaryl N-methyliminodiacetic acid (MIDA) boronic esters to enable the formal homologation of boronic acid derivatives. The reaction is contingent upon control of the basic biphase and is thermodynamically driven: temperature control provides highly chemoselective access to either BMIDA adducts at room temperature or boronic acid pinacol ester (BPin) products at elevated temperature. Control experiments and solubility analyses have provided some insight into the mechanistic operation of the formal homologation process.

A modular synthesis of functionalised biaryl phenols from two boronic acid derivatives has been developed via one-pot Suzuki-Miyaura cross-coupling, chemoselective control of boron solution speciation to generate a reactive boronic ester in situ, and oxidation. The utility of this method has been further demonstrated by application in the synthesis of drug molecules and components of organic electronics, as well as within iterative cross-coupling.

Organoboron compounds are among the most widely used reagents in organic synthesis and underpin many of the most frequently practiced and important reactions in synthetic organic chemistry ( 1 ). These reactions are based on specific mechanistic events that are distinctive to the reaction class. Catalytic processes are usually driven by transmetallation to transition metal complexes (passing a ligand from boron to the metal), whereas stoichiometric processes are based on metallate rearrangement mechanisms—ligands undergoing redistribution around a boron center—initiated by an incoming nucleophile. On page 70 of this issue, Zhang et al. ( 2 ) report an alternative transmetallation process that harmoniously merges these usually independent mechanisms, and they demonstrate its application within a multicomponent catalytic reaction that generates specific chiral products.

Control of boronic acid solution speciation is presented as a new strategy for the chemoselective synthesis of boronic esters. Manipulation of the solution equilibria within a cross-coupling milieu enables the formal homologation of aryl and alkenyl boronic acid pinacol esters. The generation of a new, reactive boronic ester in the presence of an active Pd catalyst also facilitates streamlined iterative catalytic C—C bond formation and provides a method for the controlled oligomerization of sp2-hybridized boronic esters. Publisher PDF