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Transition metal-catalysed C–H hydroxylation is one of the most notable advances in synthetic chemistry during the past few decades and it has been widely employed in the preparation of alcohols and phenols. The site-selective hydroxylation of aromatic C–H bonds under mild conditions, especially in the context of substituted (hetero)arenes with diverse functional groups, remains a challenge. Here, we report a general and mild chelation-assisted C–H hydroxylation of (hetero)arenes mediated by boron species without the use of any transition metals. Diverse (hetero)arenes bearing amide directing groups can be utilized for ortho C–H hydroxylation under mild reaction conditions and with broad functional group compatibility. Additionally, this transition metal-free strategy can be extended to synthesize C7 and C4-hydroxylated indoles. By utilizing the present method, the formal synthesis of several phenol intermediates to bioactive molecules is demonstrated. Transition metal-catalysed C–H hydroxylation is one of the most notable synthetic advances to access alcohols and phenols. Here, the authors report a metal-free, mild C–H hydroxylation of (hetero)arenes via boron-mediated chelation.

Recent advances in end-to-end continuous-flow synthesis are rapidly expanding the capabilities of automated customized syntheses of small-molecule pharmacophores, resulting in considerable industrial and societal impacts; however, many hurdles persist that limit the number of sequential steps that can be achieved in such systems, including solvent and reagent incompatibility between individual steps, cumulated by-product formation, risk of clogging and mismatch of timescales between steps in a processing chain. To address these limitations, herein we report a strategy that merges solid-phase synthesis and continuous-flow operation, enabling push-button automated multistep syntheses of active pharmaceutical ingredients. We demonstrate our platform with a six-step synthesis of prexasertib in 65% isolated yield after 32 h of continuous execution. As there are no interactions between individual synthetic steps in the sequence, the established chemical recipe file was directly adopted or slightly modified for the synthesis of twenty-three prexasertib derivatives, enabling both automated early and late-stage diversification.Although strategies for the automated assembly of compounds of pharmaceutical relevance is a growing field of research, the synthesis of small-molecule pharmacophores remains a predominantly manual process. Now, an automated six-step synthesis of prexasertib is achieved by multistep solid-phase chemistry in a continuous-flow fashion using a chemical recipe file that enables automated scaffold modification through both early and late-stage diversification.

Chiral hydroxylamines are vital substances in bioscience and versatile subunits in the preparation of a variety of functional molecules. However, asymmetric and non-asymmetric synthetic approaches to these compounds are far from satisfactory. Although atom-economic metal-catalysed asymmetric hydrogenations have been studied for over 50 years, the asymmetric hydrogenation of oximes to the corresponding chiral hydroxylamines remains challenging because of the labile N–O bond and inert C=N bond. Here we report an environmentally friendly, earth-abundant, transition-metal nickel-catalysed asymmetric hydrogenation of oximes, affording the corresponding chiral hydroxylamines with up to 99% yield, 99% e.e. and with a substrate/catalyst ratio of 1,000. Computational results indicate that the weak interactions between the catalyst and substrate play crucial roles not only in the transition states, but also during the approach of the substrate to the catalyst, by selectively reducing the reaction barriers and thus improving the reaction efficiency and securing the generation of chirality. The asymmetric hydrogenation of oximes to chiral hydroxylamines is a long-standing challenge because of the labile N–O bond and inert C=N bond. Now, it has been shown that this reaction can be catalysed with a chiral nickel complex, and the weak interactions between catalyst and substrate are found to play a crucial role.

Bipleiophylline is a highly complex monoterpene indole alkaloid composed of two pleiocarpamine units anchored on an aromatic spacer platform. The synthesis of bipleiophylline is considered as a mountain to climb by the organic chemistry community. Here, a unified oxidative coupling protocol between indole derivatives and 2,3-dihydroxybenzoic acid, mediated by silver oxide, has been developed to produce the core of bipleiophylline. This method also allows the independent preparation of benzofuro[2,3- b ]indolenine and isochromano[3,4- b ]indolenine scaffolds, depending only on the nature of the aromatic platform used. The procedure has been applied to simple indole derivatives and to more challenging monoterpene indole alkaloids, thereby furnishing natural-product-like structures. The use of scarce pleiocarpamine as the starting indole allows the first syntheses of bipleiophylline and of its biosynthetic precursor, voacalgine A. The structure of the latter has been reassigned in the course of our investigations by 2D NMR and displays an isochromano[3,4- b ]indolenine motif instead of a benzofuro[2,3- b ]indolenine. The biomimetic syntheses of bipleiophylline, one of the most complex monoterpene indole alkaloids, and voacalgine A, its biosynthetic precursor, have been achieved from pleiocarpamine starting material. The development of a divergent oxidative coupling for the formation of the benzofuro[2,3- b ]indolenine and isochromano[3,4- b ]indolenine moieties was key to this accomplishment.

Skeletal editing is a straightforward synthetic strategy for precise substitution or rearrangement of atoms in core ring structures of complex molecules; it enables quick diversification of compounds that is not possible by applying peripheral editing strategies. Previously reported skeletal editing of common arenes mainly relies on carbene- or nitrene-type insertion reactions or rearrangements. Although powerful, efficient and applicable to late-stage heteroarene core structure modification, these strategies cannot be used for skeletal editing of pyridines. Here we report the direct skeletal editing of pyridines through atom-pair swap from CN to CC to generate benzenes and naphthalenes in a modular fashion. Specifically, we use sequential dearomatization, cycloaddition and rearomatizing retrocycloaddition reactions in a one-pot sequence to transform the parent pyridines into benzenes and naphthalenes bearing diversified substituents at specific sites, as defined by the cycloaddition reaction components. Applications to late-stage skeletal diversification of pyridine cores in several drugs are demonstrated. Skeletal editing enables diversification of compounds not possible by applying peripheral editing strategies. Now, a catalyst-free atom-pair swap strategy for pyridine editing has been developed via one-pot sequential dearomatization, cycloaddition and rearomative retrocyclization. Benzenes and naphthalenes with precisely installed functional groups are produced, and the mild conditions enable late-stage skeletal diversification of pyridine cores.

A new aminonitrile-functionalized Fe 3 O 4 has been synthesized via the Strecker reaction, the designed aminonitrile ligand on the surface of the magnetic core coordinated to copper(II) to obtain the final new catalyst. The fabricated nanocatalyst was characterized by Fourier transform Infrared (FT-IR), Field Emission Scanning Electron Microscopy (FESEM), Energy-Dispersive X-ray spectroscopy (EDX), Transmission Electron Microscopy (TEM), Vibrating-Sample Magnetometer (VSM), Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES), and Thermogravimetric Analysis (TGA). The high tendency of nitrogens in the aminonitrile functional group to make a complex with Cu(II) has caused the practical activity of this nucleus in this catalyst. This nanocatalyst performance was investigated in azide–alkyne Huisgen cycloaddition (3 + 2) reaction for achieving to 1,4-disubstituted 1,2,3-triazoles in water as a green media at room temperature. In another try, Classic Ullmann Reaction was investigated for the synthesis of biaryls at 85 °C promoted by ultrasonic condition (37 kHz). The reaction scope was explored using different reactants and the results of using this developed catalytic system demonstrated its capacity to reduce the reaction time and enhance the reaction efficiency to provide good to excellent product yield. Conversely, the simple recycling and reusability of this catalyst for at least six times without any noticeable leaching of copper makes it a potential future catalyst for synthesizing such compounds.

Building molecular complexity from simple feedstocks through precise peripheral and skeletal modifications is central to modern organic synthesis. Nevertheless, a controllable strategy through which both the core skeleton and the periphery of an aromatic heterocycle can be modified with a common substrate remains elusive, despite its potential to maximize structural diversity and applications. Here we report a carbene-initiated chemodivergent molecular editing of indoles that allows both skeletal and peripheral editing by trapping an electrophilic fluoroalkyl carbene generated in situ from fluoroalkyl N -triftosylhydrazones. A variety of fluorine-containing N-heterocyclic scaffolds have been efficiently achieved through tunable chemoselective editing reactions at the skeleton or periphery of indoles, including one-carbon insertion, C3 gem -difluoroolefination, tandem cyclopropanation and N1 gem -difluoroolefination, and cyclopropanation. The power of this chemodivergent molecular editing strategy has been highlighted through the modification of the skeleton or periphery of natural products in a controllable and chemoselective manner. The reaction mechanism and origins of the chemo- and regioselectivity have been probed by both experimental and theoretical methods. The rapid generation of molecular complexity from a given molecular scaffold is crucial to drug discovery and development. Now the chemodivergent molecular editing of indoles using fluoroalkyl carbenes has been developed to modularly access four different types of fluorine-containing N-heterocyclic compound with high molecular complexity.

Efforts aimed at enriching the chemical and structural diversity of small molecules have invigorated synthetic exploration in the last two decades. Spatially defined molecular functionality serves as the foundation to construct unique chemical space to further advance discovery science. The chiral SuFEx reagent t -BuSF provides a modular platform for the stereocontrolled bifunctionalization of sulfur. Here we report a third functional feature of t -BuSF enabled by carbamoyl torsional strain-release that further expands the S(IV) and S(VI) chemical space accessible as showcased in over seventy examples, multiple applications in medicinal chemistry, organocatalysis, and diversity-oriented synthesis. The methods presented herein allow for rapid asymmetric diversification around a stereodefined sulfur center with readily available building blocks, improving upon the current state-of-the-art for sulfinyl and sulfonimidoyl synthesis. Spatially defined molecular functionality serves as the foundation to construct unique chemical space to further advance discovery science. Herein the authors report a third functional feature of t-BuSF enabled by carbamoyl torsional strain-release that further expands the S(IV) and S(VI) chemical space.

Securinega alkaloids have fascinated the synthetic chemical community for over six decades. Historically, major research foci in securinega alkaloid synthesis have been on the efficient construction of the fused tetracyclic framework that bears a butenolide moiety and tertiary amine-based heterocycles. These “basic” securinega alkaloids have evolved to undergo biosynthetic oxidative diversifications, especially on the piperidine core. However, a general synthetic solution to access these high-oxidation state securinega alkaloids is lacking. In this study, we have completed the total synthesis of various C4-oxygenated securinine-type alkaloids including securingines A, C, D, securitinine, secu’amamine D, phyllanthine, and 4- epi -phyllanthine. Our synthetic strategy features stereocontrolled oxidation, rearrangement, and epimerization at N1 and C2–C4 positions of the piperidine core within (neo)securinane scaffolds. Our discoveries provide a fundamental synthetic solution to all known securinine-type natural products with various oxidative and stereochemical variations around the central piperidine ring. A general synthetic solution toward high-oxidation state securinega alkaloids could be useful for systematic biological studies. Here, the authors report a divergent synthesis of C4-oxygenated securinega alkaloids via stereocontrolled diversifications on the piperidine core.

Bicyclic hydrocarbons, and bicyclo[1.1.1]pentanes (BCPs) in particular, are playing an emerging role as saturated bioisosteres in pharmaceutical, agrochemical and materials chemistry. Taking advantage of strain-release strategies, prior synthetic studies have featured the synthesis of bridgehead-substituted (C1, C3) BCPs from [1.1.1]propellane. Here, we describe an approach to access multisubstituted BCPs via intramolecular cyclization. In addition to C1,C3-disubstituted BCPs, this method also enables the construction of underexplored multisubstituted (C1, C2 and C3) BCPs from readily accessible cyclobutanones. The broad generality of this method has also been examined through the synthesis of a variety of other caged bicyclic molecules, ranging from [2.1.1] to [3.2.1] scaffolds. The modularity afforded by the pendant bridgehead boron pinacol esters generated during the cyclization reaction has been demonstrated through several downstream functionalizations, highlighting the ability of this approach to enable the programmed and divergent synthesis of multisubstituted bicyclic hydrocarbons.Bicyclic hydrocarbons, and bicyclo[1.1.1]pentanes in particular, are playing an emerging role as saturated bioisosteres in pharmaceutical, agrochemical and materials intramolecular coupling approach has been developed for the modular construction of underexplored multisubstituted strained bicyclic hydrocarbons, ranging from [1.1.1] to [3.2.1] scaffolds.