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Carboxylic acids and their derivatives are powerful building blocks in dual Ir/Ni metallaphotoredox methods of decarboxylative arylation due to their abundance as feedstock compounds. However, the library of accessible carboxylic acids is limited by trends in radical stability, often necessitating the development of specific systems for challenging substrates. Herein, we disclose the application of a new Ir(III) photocatalyst and low-energy orange light Ir/Ni metallaphotoredox system with broad applicability in activating both native carboxylic acids and redox-active esters (RAEs). This method represents the first known example of complementary oxidative and reductive decarboxylative paradigms with broadly similar reaction conditions, unlocking the reactivity for challenging substrates. We further show a wide scope of aryl halide and acid coupling partners in both regimes, with added advantages over blue-light-catalyzed aryl alkylation for photosensitive substrates.

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Contemporary developments in the field of peptide macrocyclization methodology are imperative for enabling the advance of drug design in medicinal chemistry. This report discloses a Rh(III)-catalyzed macrocyclization via carboamidation, reacting acryloyl-peptide-dioxazolone precursors and arylboronic acids to form complex cyclic peptides with concomitant incorporation of noncanonical α-amino acids. The diverse and modular technology allows for expedient access to a wide variety of cyclic peptides from 4 to 15 amino acids in size and features simultaneous formation of unnatural phenylalanine and tyrosine derivatives with up to >20:1 diastereoselectivity. The reaction showcases an expansive substrate scope with 45 examples and is compatible with the majority of standard protected amino acids used in Fmoc-solid phase peptide synthesis. The methodology is applied to the synthesis of multiple peptidomimetic macrocyclic analogs, including derivatives of cyclosomatostatin and gramicidin S.

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State-of-the-art methods in photoproximity labeling center on the targeted generation and capture of short-lived reactive intermediates to provide a snapshot of local protein environments. Diazirines are the current gold standard for high-resolution proximity labeling, generating short-lived aryl(trifluoromethyl) carbenes. Here, we present a method to access aryl(trifluoromethyl) carbenes from a stable diazo source via tissue-penetrable, deep red to near-infrared light (600-800 nm). The operative mechanism of this activation involves Dexter energy transfer from photoexcited osmium(II) photocatalysts to the diazo, thus revealing an aryl(trifluoromethyl) carbene. The labeling preferences of the diazo probe with amino acids are studied, showing high reactivity toward heteroatom-H bonds. Upon the synthesis of a biotinylated diazo probe, labeling studies are conducted on native proteins as well as proteins conjugated to the Os photocatalyst. Finally, we demonstrate that the conjugation of a protein inhibitor to the photocatalyst also enables selective protein labeling in the presence of spectator proteins and achieves specific labeling of a membrane protein on the surface of mammalian cells via a two-antibody photocatalytic system.

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A method for the generation of tertiary carbanions via a deaminative radical-polar crossover is reported using redox active imines from α-tertiary primary amines. A variety of benzylic amines and amino esters can be used in this approach, with the latter engaging in a novel "aza-Reformatsky" reaction. Electronic trends correlate the stability of the resulting carbanion with reaction efficiency. The anions can be trapped with different electrophiles including aldehydes, ketones, imines, Michael acceptors, and H2 O/D2 O. Selective anion formation can be achieved in the presence of another equivalent or more acidic C-H bond in both an inter- and intramolecular fashion. Mechanistic studies suggest the intermediacy of a discrete carbanion intermediate.

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Stable isotopes such as 2H, 13C, and 15N have important applications in chemistry and drug discovery. Late-stage incorporation of uncommon isotopes via isotopic exchange allows for the direct conversion of complex molecules into their valuable isotopologues without requiring a de novo synthesis. While synthetic methods exist for the conversion of hydrogen and carbon atoms into their less abundant isotopes, a corresponding method for accessing 15N-primary amines from their naturally occurring 14N-analogues has not yet been disclosed. We report an approach to access 15N-labeled primary amines via late-stage isotopic exchange using a simple benzophenone imine as the 15N source. By activating α-1 and α-2° amines to Katritzky pyridinium salts and α-3° amines to redox-active imines, we can engage primary alkyl amines in a deaminative amination. The redox-active imines proceed via a radical-polar crossover mechanism, whereas the Katritzky salts are engaged in copper catalysis via an electron donor-acceptor complex. The method is general for a variety of amines, including multiple drug compounds, and results in complete and selective isotopic labeling.

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We report the development and characterization of a library of Ir(III) photocatalysts capable of undergoing spin-forbidden excitation (SFE) under orange light irradiation (595 nm). These catalysts were successfully applied to the construction of synthetically valuable C(sp2)-C(sp3) bonds inaccessible with existing methods of low-energy light-driven dual nickel/photoredox catalysis, demonstrating the synthetic utility of this photocatalyst family. The photocatalysts are capable of accessing both oxidatively and reductively activated coupling partners, illustrated through deaminative arylation and potassium alkyl trifluoroborate cross-coupling reactions with aryl halides. We demonstrate diverse substrate scopes of both cross-coupling paradigms under mild conditions in the first example of low-energy light-driven C(sp2)-C(sp3) metallaphotoredox coupling.

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Electric field acceleration of alkyl hydroperoxide activation to acylate amines in the scanning tunneling microscope-based break-junction is reported. Alkyl hydroperoxide mixtures, generated from hydrocarbon autoxidation in air, were found to be competent reagents for the functionalization of gold surfaces. Intermolecular coupling on the surface in the presence of amines was observed, yielding normal alkylamides. This novel mode of alkyl hydroperoxide activation to generate acylium equivalents was found to be responsive to the magnitude of the bias in the break junction, indicating an electric field influence on this novel reactivity.

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The global plastics problem is a trifecta, greatly affecting environment, energy and climate1-4. Many innovative closed/open-loop plastics recycling or upcycling strategies have been proposed or developed5-16, addressing various aspects of the issues underpinning the achievement of a circular economy17-19. In this context, reusing mixed-plastics waste presents a particular challenge with no current effective closed-loop solution20. This is because such mixed plastics, especially polar/apolar polymer mixtures, are typically incompatible and phase separate, leading to materials with substantially inferior properties. To address this key barrier, here we introduce a new compatibilization strategy that installs dynamic crosslinkers into several classes of binary, ternary and postconsumer immiscible polymer mixtures in situ. Our combined experimental and modelling studies show that specifically designed classes of dynamic crosslinker can reactivate mixed-plastics chains, represented here by apolar polyolefins and polar polyesters, by compatibilizing them via dynamic formation of graft multiblock copolymers. The resulting in-situ-generated dynamic thermosets exhibit intrinsic reprocessability and enhanced tensile strength and creep resistance relative to virgin plastics. This approach avoids the need for de/reconstruction and thus potentially provides an alternative, facile route towards the recovery of the endowed energy and materials value of individual plastics.

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N-Demethylation of trialkylamines is a useful transformation, but typically requires harsh reaction conditions and stepwise procedures, as well as judicious protection of labile functional groups. Herein we report a mild, catalytic approach for the demethylation of trialkylamines by utilizing photoinduced nickel catalysis wherein C(sp2)-bromides serve as hydrogen-atom transfer (HAT) reagents. This method achieves direct demethylation of trialkylamines with wide functional group compatibility, making it highly suitable for late-stage derivatization of complex molecules. Mechanistic investigations provide evidence that C(sp2) radicals generated via photoinduced Ni-C(sp2) bond homolysis are involved in hydrogen atom abstraction from trialkylamines. Utilizing steric control of the C(sp2)-bromides, our HAT approach achieves demethylation with excellent site selectivity in the presence of benzyl-substituted amines, which is complementary to the selectivity of classical approaches that afford debenzylation product instead.

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γ-Lactams are prevalent in small-molecule pharmaceuticals and provide useful precursors to highly substituted pyrrolidines. Despite numerous methods for the synthesis of this valuable motif, previous redox approaches to γ-lactam synthesis from α-haloamides and olefins require additional electron withdrawing functionality as well as N-aryl substitution to promote electrophilicity of the intermediate radical and prevent competitive O-nucleophilicity about the amide. Using α-bromo imides and α-olefins, our strategy enables the synthesis of monosubstituted protected γ-lactams in a formal [3 + 2] fashion. These species are poised for further derivatization into more complex heterocyclic scaffolds, complementing existing methods. C-Br bond scission occurs through two complementary approaches, the formation of an electron donor-acceptor complex between the bromoimide and a nitrogenous base which undergoes photoinduced electron transfer, or triplet sensitization with photocatalyst, to furnish an electrophilic carbon-centered radical. The addition of Lewis acids allows for further increased electrophilicity of the intermediate carbon-centered radical, enabling tertiary substituted α-Br-imides to be used as coupling partners as well as internal olefins.

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State-of-the-art photoactivation strategies in chemical biology provide spatiotemporal control and visualization of biological processes. However, using high-energy light (λ < 500 nm) for substrate or photocatalyst sensitization can lead to background activation of photoactive small-molecule probes and reduce its efficacy in complex biological environments. Here we describe the development of targeted aryl azide activation via deep red-light (λ = 660 nm) photoredox catalysis and its use in photocatalysed proximity labelling. We demonstrate that aryl azides are converted to triplet nitrenes via a redox-centric mechanism and show that its spatially localized formation requires both red light and a photocatalyst-targeting modality. This technology was applied in different colon cancer cell systems for targeted protein environment labelling of epithelial cell adhesion molecule (EpCAM). We identified a small subset of proteins with previously known and unknown association to EpCAM, including CDH3, a clinically relevant protein that shares high tumour-selective expression with EpCAM.

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Herein we report a modular peptide ligation methodology that couples dioxazolones, arylboronic acids, and acrylamides to construct amide bonds in a diastereoselective manner under mild conditions, facilitated by Rh(III) catalysis. By converting the C-terminus of one peptide into a dioxazolone and the N-terminus of a second peptide into an acrylamide, the two pieces can be bridged by an arylboronic acid to construct unnatural phenylalanine, tyrosine, and tryptophan residues at the junction point with diastereoselectivity for their corresponding d-stereocenters. The reaction exhibits excellent functional group tolerance with a large substrate scope and is compatible with a wide array of protected amino acid residues that are utilized in Fmoc solid phase peptide synthesis. The methodology is applied to the synthesis of six diastereomeric proteasome inhibitor analogs, as well as the ligation of two 10-mer oligopeptides to construct a 21-mer polypeptide with an unnatural phenylalanine residue at the center.

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Hydroamination of terminal alkenes represents a powerful and well-established way to introduce nitrogenous functionality to feedstock chemicals. Remote hydroamination reactions are far less known, and represent a way to functionalize unactivated C(sp3) centers distal to the site of the alkene. These transformations commonly take place via metal hydride-mediated chain walking, and as such, regioselectivity can be challenging. The remote introduction of amides is of particular interest due to their prevalence in pharmaceuticals. Herein we report a Rh(III)-catalyzed hydroamidation procedure to functionalize the terminal position of internal alkenes, using dioxazolones as amidation reagents and i-PrOH as a hydride source. The reaction proceeds with high yield and regioselectivity, and tolerates a variety of functionality. Regioconvergent synthesis of a single linear amide from a mixture of isomeric alkenes is demonstrated. Key to the development of this reaction was determining that inorganic bases poison the catalyst, and identifying a suitable trialkylamine replacement.

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The amide is one of the most prevalent functional groups in all of pharmaceuticals, and for this reason, reactions that introduce the amide moiety are of particular value. Intermolecular hydroamidation of alkenes remains an underexplored method for the synthesis of amide-containing compounds. The majority of hydroamidation procedures exhibit Markovnikov regioselectivity, while current methods for anti-Markovnikov hydroamidation are somewhat limited to activated alkene substrates or radical processes. Herein, we report a general method for the intermolecular anti-Markovnikov hydroamidation of unactivated alkenes under mild conditions, utilizing Rh(III) catalysis in conjunction with dioxazolone amidating reagents and isopropanol as an environmentally friendly hydride source. The reaction tolerates a wide range of functional groups and efficiently converts electron-deficient alkenes, styrenes, and 1,1-disubstituted alkenes, in addition to unactivated alkenes, to their corresponding linear amides. Mechanistic studies reveal a reversible rhodium hydride migratory insertion step, leading to exquisite selectivity for the anti-Markovnikov product.

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Aryl amination is an essential transformation for medicinal, process, and materials chemistry. In addition to classic Buchwald-Hartwig amination conditions, blue-light-driven metallaphotoredox catalysis has emerged as a valuable tool for C-N cross-coupling. However, blue light suffers from low penetration through reaction media, limiting its scalability for industrial purposes. In addition, blue light enhances unwanted side-product formation in metallaphotoredox catalysis, namely hydrodehalogenation. Low-energy light, such as deep red (DR) or near-infrared (NIR), offers a solution to this problem as it can provide enhanced penetration through reaction media as compared to higher-energy wavelengths. Herein, we show that low-energy light can also enhance the desired reactivity in metallaphotoredox catalysis by suppressing unwanted hydrodehalogenation. We hypothesize that the reduced side product is formed by direct photolysis of the aryl-nickel bond by the high-energy light, leading to the generation of aryl radicals. Using deep-red or near-infrared light and an osmium photocatalyst, we demonstrate an enhanced scope of (hetero)aryl bromides and amine-based nucleophiles with minimal formation of hydrodehalogenation byproducts.

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We report computationally-guided protein engineering of monomeric streptavidin Rh(iii) artificial metalloenzyme to enhance catalysis of the enantioselective coupling of acrylamide hydroxamate esters and styrenes. Increased TON correlates with calculated distances between the Rh(iii) metal and surrounding residues, underscoring an artificial metalloenzyme's propensity for additional control in metal-catalyzed transformations by through-space interactions.

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The SARS-CoV-2 3CL protease is a critical drug target for small molecule COVID-19 therapy, given its likely druggability and essentiality in the viral maturation and replication cycle. Based on the conservation of 3CL protease substrate binding pockets across coronaviruses and using screening, we identified four structurally distinct lead compounds that inhibit SARS-CoV-2 3CL protease. After evaluation of their binding specificity, cellular antiviral potency, metabolic stability, and water solubility, we prioritized the GC376 scaffold as being optimal for optimization. We identified multiple drug-like compounds with <10 nM potency for inhibiting SARS-CoV-2 3CL and the ability to block SARS-CoV-2 replication in human cells, obtained co-crystal structures of the 3CL protease in complex with these compounds, and determined that they have pan-coronavirus activity. We selected one compound, termed coronastat, as an optimized lead and characterized it in pharmacokinetic and safety studies in vivo. Coronastat represents a new candidate for a small molecule protease inhibitor for the treatment of SARS-CoV-2 infection for eliminating pandemics involving coronaviruses.

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We herein report a modular strategy, which enables Rh(III)-catalyzed diastereoselective 3,4-amino oxygenation and diamination of 1,3-dienes using different O- and N-nucleophiles in combination with readily available 3-substituted 1,4,2-dioxazolones (78 examples, 37-91% yield). Previous attempts to functionalize the internal double bond rested on the use of plain alcoholic solvents as nucleophilic coupling partners thus dramatically limiting the scope of this transformation. We have now identified hexafluoroisopropanol as a non-nucleophilic solvent which allows the use of diverse nucleophiles and greatly expands the scope, including an unprecedented amino hydroxylation to selectively install valuable, unprotected ß-amino alcohols across 1,3-dienes. Moreover, various elaborate alcohols prove to be compatible providing unique access to complex organic molecules. Finally, this method is employed in a series of intramolecular reactions to deliver valuable nitrogen heterocycles as well as γ- and δ-lactones.

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Redox processes are at the heart of synthetic methods that rely on either electrochemistry or photoredox catalysis, but how do electrochemistry and photoredox catalysis compare? Both approaches provide access to high energy intermediates (e.g., radicals) that enable bond formations not constrained by the rules of ionic or 2 electron (e) mechanisms. Instead, they enable 1e mechanisms capable of bypassing electronic or steric limitations and protecting group requirements, thus enabling synthetic chemists to disconnect molecules in new and different ways. However, while providing access to similar intermediates, electrochemistry and photoredox catalysis differ in several physical chemistry principles. Understanding those differences can be key to designing new transformations and forging new bond disconnections. This review aims to highlight these differences and similarities between electrochemistry and photoredox catalysis by comparing their underlying physical chemistry principles and describing their impact on electrochemical and photochemical methods.

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Oximes are valuable synthetic intermediates for the preparation of a variety of functional groups. To date, the stereoselective synthesis of oximes remains a major challenge, as most current synthetic methods either provide mixtures of E and Z isomers or furnish the thermodynamically preferred E isomer. Herein we report a mild and general method to achieve Z isomers of aryl oximes by photoisomerization of oximes via visible-light-mediated energy transfer (EnT) catalysis. Facile access to (Z)-oximes provides opportunities to achieve regio- and chemoselectivity complementary to those of widely used transformations employing oxime starting materials. We show an enhanced one-pot protocol for photocatalyzed oxime isomerization and subsequent Beckmann rearrangement that enables novel reactivity with alkyl groups migrating preferentially over aryl groups, reversing the regioselectivity of the traditional Beckmann reaction. Chemodivergent N- or O- cyclizations of alkenyl oximes are also demonstrated, leading to nitrones or cyclic oxime ethers, respectively.

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