Explore the vast range of titles available.

Catalytic alkylation of C–H bonds is achieved via homolysis of N–H bonds of N -alkyl amides through proton-coupled electron transfer. Functionalizing unactivated aliphatic C–H bonds In two separate reports, Robert Knowles and colleagues, and John Chu and Tomislav Rovis report the selective homolysis of selected amidyl N–H bonds through a photocatalytic proton-coupled electron-transfer process. The resulting radical enables C–H abstraction and radical alkylation at the unactivated 5 position on the aliphatic chain of the N -alkyl amide. As this method does not rely on pre-activation of the amidyl N–H bond or the use of haloamides, it offers a potentially simpler solution than previous approaches to radical amidyls. Additionally, the subsequent 1,5-hydrogen-atom transfer offers a route to selective C–C bond formation in the presence of alkyl amides. Despite advances in hydrogen atom transfer (HAT) catalysis 1 , 2 , 3 , 4 , 5 , there are currently no molecular HAT catalysts that are capable of homolysing the strong nitrogen–hydrogen (N–H) bonds of N- alkyl amides. The motivation to develop amide homolysis protocols stems from the utility of the resultant amidyl radicals, which are involved in various synthetically useful transformations, including olefin amination 6 , 7 , 8 , 9 , 10 , 11 and directed carbon–hydrogen (C–H) bond functionalization 12 , 13 , 14 , 15 , 16 . In the latter process—a subset of the classical Hofmann–Löffler–Freytag reaction—amidyl radicals remove hydrogen atoms from unactivated aliphatic C–H bonds 17 , 18 , 19 , 20 , 21 . Although powerful, these transformations typically require oxidative N- prefunctionalization of the amide starting materials to achieve efficient amidyl generation. Moreover, because these N -activating groups are often incorporated into the final products, these methods are generally not amenable to the direct construction of carbon–carbon (C–C) bonds. Here we report an approach that overcomes these limitations by homolysing the N–H bonds of N -alkyl amides via proton-coupled electron transfer. In this protocol, an excited-state iridium photocatalyst and a weak phosphate base cooperatively serve to remove both a proton and an electron from an amide substrate in a concerted elementary step. The resultant amidyl radical intermediates are shown to promote subsequent C–H abstraction and radical alkylation steps. This C–H alkylation represents a catalytic variant of the Hofmann–Löffler–Freytag reaction, using simple, unfunctionalized amides to direct the formation of new C–C bonds. Given the prevalence of amides in pharmaceuticals and natural products, we anticipate that this method will simplify the synthesis and structural elaboration of amine-containing targets. Moreover, this study demonstrates that concerted proton-coupled electron transfer can enable homolytic activation of common organic functional groups that are energetically inaccessible using traditional HAT-based approaches.

Although the α-alkylation of ketones has already been established, the analogous reaction using aldehyde substrates has proven surprisingly elusive. Despite the structural similarities between the two classes of compounds, the sensitivity and unique reactivity of the aldehyde functionality has typically required activated substrates or specialized additives. Here, we show that the synergistic merger of three catalytic processes—photoredox, enamine and hydrogen-atom transfer (HAT) catalysis—enables an enantioselective α-aldehyde alkylation reaction that employs simple olefins as coupling partners. Chiral imidazolidinones or prolinols, in combination with a thiophenol, iridium photoredox catalyst and visible light, have been successfully used in a triple catalytic process that is temporally sequenced to deliver a new hydrogen and electron-borrowing mechanism. This multicatalytic process enables both intra- and intermolecular aldehyde α-methylene coupling with olefins to construct both cyclic and acyclic products, respectively. With respect to atom and step-economy ideals, this stereoselective process allows the production of high-value molecules from feedstock chemicals in one step while consuming only photons. The catalytic asymmetric α-alkylation of aldehydes has historically been a significant challenge within organic synthesis. Now, this elusive transformation has been achieved through the merger of organocatalysis, photoredox catalysis and hydrogen-atom transfer catalysis to enable the coupling of simple olefins and aldehydes.

Natural enzymes contain highly evolved active sites that lead to fast rates and high selectivities. Although artificial metalloenzymes have been developed that catalyze abiological transformations with high stereoselectivity, the activities of these artificial enzymes are much lower than those of natural enzymes. Here, we report a reconstituted artificial metalloenzyme containing an iridium porphyrin that exhibits kinetic parameters similar to those of natural enzymes. In particular, variants of the P450 enzyme CYP119 containing iridium in place of iron catalyze insertions of carbenes into C-H bonds with up to 98% enantiomeric 1 excess, 35,000 turnovers, and 2550 hours⁻¹ turnover frequency. This activity leads to intramolecular carbene insertions into unactivated C-H bonds and intermolecular carbene insertions into C-H bonds. These results lift the restrictions on merging chemical catalysis and biocatalysis to create highly active, productive, and selective metalloenzymes for abiological reactions.

Synthetic biology enables microbial hosts to produce complex molecules from organisms that are rare or difficult to cultivate, but the structures of these molecules are limited to those formed by reactions of natural enzymes. The integration of artificial metalloenzymes (ArMs) that catalyse unnatural reactions into metabolic networks could broaden the cache of molecules produced biosynthetically. Here we report an engineered microbial cell expressing a heterologous biosynthetic pathway, containing both natural enzymes and ArMs, that produces an unnatural product with high diastereoselectivity. We engineered Escherichia coli with a heterologous terpene biosynthetic pathway and an ArM containing an iridium–porphyrin complex that was transported into the cell with a heterologous transport system. We improved the diastereoselectivity and product titre of the unnatural product by evolving the ArM and selecting the appropriate gene induction and cultivation conditions. This work shows that synthetic biology and synthetic chemistry can produce, by combining natural and artificial enzymes in whole cells, molecules that were previously inaccessible to nature.Natural products are produced by living organisms practising nature’s chemical transformations. Now, an unnatural product has been generated by creating hybrid biosynthetic microorganisms. These microorganisms combine an unnatural chemical transformation—catalysis by an artificial metalloenzyme containing an iridium-based, unnatural cofactor—with a natural biosynthetic pathway within the same cell.

The development of hydrogen-based energy sources as viable alternatives to fossil-fuel technologies has revolutionized clean energy production using fuel cells. However, to date, the slow rate of the hydrogen oxidation reaction (HOR) in alkaline environments has hindered advances in alkaline fuel cell systems. Here, we address this by studying the trends in the activity of the HOR in alkaline environments. We demonstrate that it can be enhanced more than fivefold compared to state-of-the-art platinum catalysts. The maximum activity is found for materials (Ir and Pt 0.1 Ru 0.9 ) with an optimal balance between the active sites that are required for the adsorption/dissociation of H 2 and for the adsorption of hydroxyl species (OH ad ). We propose that the more oxophilic sites on Ir (defects) and PtRu material (Ru atoms) electrodes facilitate the adsorption of OH ad species. Those then react with the hydrogen intermediates (H ad ) that are adsorbed on more noble surface sites. Hydrogen is an attractive alternative to fossil fuels, but the slow rate of the hydrogen oxidation reaction in alkaline fuel cells hinders their development. It is now proposed that bifunctional materials can be devised to offer the optimal balance between hydrogen and hydroxyl adsorption, thus significantly reducing the amount of precious metal on the anode.

Hydroamination of alkenes, the addition of the N–H bond of an amine across an alkene, is a fundamental, yet challenging, organic transformation that creates an alkylamine from two abundant chemical feedstocks, alkenes and amines, with full atom economy 1 – 3 . The reaction is particularly important because amines, especially chiral amines, are prevalent substructures in a wide range of natural products and drugs. Although extensive efforts have been dedicated to developing catalysts for hydroamination, the vast majority of alkenes that undergo intermolecular hydroamination have been limited to conjugated, strained, or terminal alkenes 2 – 4 ; only a few examples occur by the direct addition of the N–H bond of amines across unactivated internal alkenes 5 – 7 , including photocatalytic hydroamination 8 , 9 , and no asymmetric intermolecular additions to such alkenes are known. In fact, current examples of direct, enantioselective intermolecular hydroamination of any type of unactivated alkene lacking a directing group occur with only moderate enantioselectivity 10 – 13 . Here we report a cationic iridium system that catalyses intermolecular hydroamination of a range of unactivated, internal alkenes, including those in both acyclic and cyclic alkenes, to afford chiral amines with high enantioselectivity. The catalyst contains a phosphine ligand bearing trimethylsilyl-substituted aryl groups and a triflimide counteranion, and the reaction design includes 2-amino-6-methylpyridine as the amine to enhance the rates of multiple steps within the catalytic cycle while serving as an ammonia surrogate. These design principles point the way to the addition of N–H bonds of other reagents, as well as O–H and C–H bonds, across unactivated internal alkenes to streamline the synthesis of functional molecules from basic feedstocks. Hydroamination with high enantio- and regioselectivity is achieved across a wide range of internal alkenes by using a cationic iridium complex that adds an ammonia surrogate containing a pyridine group.

Practical photodynamic therapy calls for high-performance, less O 2 -dependent, long-wavelength-light-activated photosensitizers to suit the hypoxic tumor microenvironment. Iridium-based photosensitizers exhibit excellent photocatalytic performance, but the in vivo applications are hindered by conventional O 2 -dependent Type-II photochemistry and poor absorption. Here we show a general metallopolymerization strategy for engineering iridium complexes exhibiting Type-I photochemistry and enhancing absorption intensity in the blue to near-infrared region. Reactive oxygen species generation of metallopolymer Ir-P1 , where the iridium atom is covalently coupled to the polymer backbone, is over 80 times higher than that of its mother polymer without iridium under 680 nm irradiation. This strategy also works effectively when the iridium atom is directly included ( Ir-P2 ) in the polymer backbones, exhibiting wide generality. The metallopolymer nanoparticles exhibiting efficient O 2 •− generation are conjugated with integrin αvβ3 binding cRGD to achieve targeted photodynamic therapy. Iridium-based photosensitizers exhibit good photocatalytic performance, but the in vivo applications are hindered by conventional O 2 -dependent Type-II photochemistry and poor absorption. Here, the authors report a general metallopolymerization strategy for engineering iridium complexes exhibiting Type-I photochemistry and enhancing absorption intensity in the blue to near-infrared region.

Ubiquitous tyrosinase catalyses the aerobic oxidation of phenols to catechols through the binuclear copper centres. Here, inspired by the Fischer indole synthesis, we report an iridium-catalysed tyrosinase-like approach to catechols, employing an oxyacetamide-directed C–H hydroxylation on phenols. This method achieves one-step, redox-neutral synthesis of catechols with diverse substituent groups under mild conditions. Mechanistic studies confirm that the directing group (DG) oxyacetamide acts as the oxygen source. This strategy has been applied to the synthesis of different important catechols with fluorescent property and bioactivity from the corresponding phenols. Finally, our method also provides a convenient route to 18 O-labelled catechols using 18 O-labelled acetic acid. Catechols are common structural motifs in bioactive molecules and synthetic building blocks. Here the authors report a method to convert phenol derivatives into catechols via an iridium-catalysed redox-neutral C–H hydroxylation, giving diversely substituted products under mild conditions.

Tertiary stereogenic centres containing one fluorine atom are valuable for medicinal chemistry because they mimic common tertiary stereogenic centres containing one hydrogen atom, but they possess distinct charge distribution, lipophilicity, conformation and metabolic stability 1 – 3 . Although tertiary stereogenic centres containing one hydrogen atom are often set by enantioselective desymmetrization reactions at one of the two carbon–hydrogen (C–H) bonds of a methylene group, tertiary stereocentres containing fluorine have not yet been constructed by the analogous desymmetrization reaction at one of the two carbon–fluorine (C–F) bonds of a difluoromethylene group 3 . Fluorine atoms are similar in size to hydrogen atoms but have distinct electronic properties, causing C–F bonds to be exceptionally strong and geminal C–F bonds to strengthen one another 4 . Thus, exhaustive defluorination typically dominates over the selective replacement of a single C–F bond, hindering the development of the enantioselective substitution of one fluorine atom to form a stereogenic centre 5 , 6 . Here we report the catalytic, enantioselective activation of a single C–F bond in an allylic difluoromethylene group to provide a broad range of products containing a monofluorinated tertiary stereogenic centre. By combining a tailored chiral iridium phosphoramidite catalyst, which controls regioselectivity, chemoselectivity and enantioselectivity, with a fluorophilic activator, which assists the oxidative addition of the C–F bond, these reactions occur in high yield and selectivity. The design principles proposed in this work extend to palladium-catalysed benzylic substitution, demonstrating the generality of the approach. Enantioselective activation of a single C–F bond in a difluoromethylene group is achieved using a chiral transition metal catalyst and a fluorophilic activator.

Asymmetric catalysis is a powerful approach for the synthesis of optically active compounds, and visible light constitutes an abundant source of energy to enable chemical transformations, which are often triggered by photoinduced electron transfer (photoredox chemistry). Recently, bis-cyclometalated iridium(III) and rhodium(III) complexes were introduced as a novel class of catalysts for combining asymmetric catalysis with visible-light-induced photoredox chemistry. These catalysts are attractive because of their unusual feature of chirality originating exclusively from a stereogenic metal center, which offers the prospect of an especially effective asymmetric induction upon direct coordination of the substrate to the metal center. As these chiral catalysts contain only achiral ligands, special strategies are required for their synthesis. In this protocol, we describe strategies for preparing two types of chiral-at-metal catalysts, namely the Î>- and Î\"-enantiomers (left- and right-handed propellers, respectively) of the iridium complex IrS and the rhodium complex RhS. Both contain two cyclometalating 5-tert-butyl-2-phenylbenzothiazoles in addition to two acetonitrile ligands and a hexafluorophosphate counterion. The two cyclometalated ligands set the propeller-shaped chiral geometry, but the acetonitriles are labile and can be replaced by substrate molecules. The synthesis protocol consists of three stages: first, preparation of the ligand 5-tert-butyl-2-phenylbenzothiazole; second, preparation of salicylthiazoline (used for iridium) and salicyloxazoline (used for rhodium) chiral auxiliaries; and third, the auxiliary-mediated synthesis of the individual enantiopure Î>- and Î\"-configured catalysts. This class of stereogenic-only-at-metal complexes is of substantial value in the field of asymmetric catalysis, offering stereocontrolled radical reactions based on visible-light-activated photoredox chemistry. Representative examples of visible-light-induced asymmetric catalysis are provided.