The fields of C–H functionalization and photoredox catalysis have garnered enormous interest and utility in the past several decades. Many different scientific disciplines have relied on C–H ...functionalization and photoredox strategies including natural product synthesis, drug discovery, radiolabeling, bioconjugation, materials, and fine chemical synthesis. In this Review, we highlight the use of photoredox catalysis in C–H functionalization reactions. We separate the review into inorganic/organometallic photoredox catalysts and organic-based photoredox catalytic systems. Further subdivision by reaction classeither sp2 or sp3 C–H functionalizationlends perspective and tactical strategies for use of these methods in synthetic applications.
Expanding the toolbox of C−H functionalization reactions applicable to the late‐stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural ...variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition‐metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic C−H bond. However, these high‐energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C−H functionalization reactions with diazoacetate derivatives, furnishing sp2–sp3 coupled products with moderate‐to‐good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transition‐metal catalyst.
An operationally simple, metal‐free, and site‐selective aromatic C−H alkylation under photoredox catalysis that utilizes equimolar quantities of coupling partners is reported. Experimental and computational studies suggest a unique mechanism, involving cyclopropanation of arene cation radicals and subsequent oxidative ring opening, that allows this transformation to be compatible with a range of aromatic substrates.
Herein we describe a cation radical-accelerated-nucleophilic aromatic substitution (CRA-SNAr) of alkoxy arenes utilizing a highly oxidizing acridinium photoredox catalyst and acetone cyanohydrin, an ...inexpensive and commercially available cyanide source. This cyanation is selective for carbon–oxygen (C–O) bond functionalization and is applicable to a range of methoxyarenes and dimethoxyarenes. Furthermore, computational studies provide a model for predicting regioselectivity and chemoselectivity in competitive C–H and C–O cyanation of methoxyarene cation radicals.
The majority of chronic myeloid leukemia (CML) cases are caused by a chromosomal translocation linking the breakpoint cluster region (BCR) gene to the Abelson murine leukemia viral oncogene-1 (ABL1), ...creating the mutant fusion protein BCR-ABL1. Downstream of BCR-ABL1 is growth factor receptor-bound protein-2 (GRB2), an intracellular adapter protein that binds to BCR-ABL1 via its src-homology-2 (SH2) domain. This binding constitutively activates growth pathways, downregulates apoptosis, and leads to an over proliferation of immature and dysfunctional myeloid cells. Utilizing novel synthetic methods, we developed four furo-quinoxaline compounds as GRB2 SH2 domain antagonists with the goal of disrupting this leukemogenic signaling. One of the four antagonists, NHD2-15, showed a significant reduction in proliferation of K562 cells, a human BCR-ABL1.sup.+ leukemic cell line. To elucidate the mode of action of these compounds, various biophysical, in vitro, and in vivo assays were performed. Surface plasmon resonance (SPR) assays indicated that NHD2-15 antagonized GRB2, binding with a K.sub.D value of 119 ± 2 muM. Cellulose nitrate (CN) assays indicated that the compound selectively bound the SH2 domain of GRB2. Western blot assays suggested the antagonist downregulated proteins involved in leukemic transformation. Finally, NHD2-15 was nontoxic to primary cells and adult zebrafish, indicating that it may be an effective clinical treatment for CML.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
As a non-invasive imaging technology, positron emission tomography (PET) plays a crucial role in personalized medicine, including early diagnosis, patient screening, and treatment monitoring. The ...advancement of PET research depends on the discovery of new PET agents, which requires the development of simple and efficient radiolabeling methods in many cases. As bioisosteres for halogen and carbonyl moieties, nitriles are important functional groups in pharmaceutical and agrochemical compounds. Here, we disclose a mild organophotoredox-catalyzed method for efficient cyanation of a broad spectrum of electron-rich arenes, including abundant and readily available veratroles and pyrogallol trimethyl ethers. Notably, the transformations not only are compatible with various affordable 12C- and 13C-cyanide (CN) sources but also could be applied to carbon-11 synthons to incorporate 11Cnitriles into arenes. The aryl 11Cnitriles can be further derivatized to 11Ccarboxylic acids, 11Camides, and 11Calkyl amines. The newly developed reaction can serve as a powerful tool for generating new PET agents.
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•Highly efficient photocatalyzed (radio)cyanation method•Site-selective and chemo-selective cyanation of various electron-rich arenes•Late-stage functionalization and aryl nitrile product derivatives•Mild conditions, affordable organocatalyst, versatile cyanide source, and aryl substrates
Isotopic labeling is utilized to track bioavailability, metabolism, and uptake studies of active pharmaceutical ingredients (APIs) in vivo. APIs with 11C isotopes are particularly useful for PET imaging applications, despite representing a significant synthetic challenge due to their short half-life (11C ∼ 20 min). Though there are reports on developing PET agents based on alkyl 11Cnitriles, efficient and facile radio-cyanation of arenes, particularly electron-rich arenes, is an unmet need. The metal-free organic photoredox-catalyzed radiocyanation method reported herein introduces a 11Cnitrile with high radiochemical conversion (RCC), which can be further elaborated to functional groups such as 11Ccarboxylic acids, 11Camides, and 11Calkyl amines. This strategy could result in easy access to new PET agents that have been previously difficult to synthesize from readily available precursors.
We developed a photoredox-catalyzed 11Ccyanide radiolabeling method to fulfill the need for a practical radiochemistry method to incorporate 11Cnitriles into (hetero)arenes. This highly efficient photoredox reaction produces aryl 11C, 12C, and 13Cnitriles using simple cyanide sources and organic photocatalysts. Under blue light (450–460 nm) irradiation, naturally abundant and readily available veratroles as well as pyrogallol trimethyl ethers were site- and chemo-selectively converted into valuable methoxy aryl nitriles in up to 99% yield.
Expanding the toolbox of C−H functionalization reactions applicable to the late‐stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural ...variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition‐metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic C−H bond. However, these high‐energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C−H functionalization reactions with diazoacetate derivatives, furnishing sp2–sp3 coupled products with moderate‐to‐good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transition‐metal catalyst.
Eine operativ einfache, metallfreie und positionsspezifische aromatische C‐H‐Alkylierung unter Photoredoxkatalyse nutzt äquimolare Mengen von Kupplungspartnern. Experimentelle und theoretische Studien sprechen für einen einzigartigen Mechanismus, bei dem eine Cyclopropanierung kationischer Arenradikale und danach eine oxidative Ringöffnung erfolgen. Diese Transformation ist kompatibel mit einer Reihe aromatischer Substrate.
The direct β-functionalization of saturated aza-heterocycles has remained a synthetic challenge because of the remote and unactivated nature of β-C–H bonds in these motifs. Herein, we demonstrate the ...β-functionalization of saturated aza-heterocycles enabled by a two-step organic photoredox catalysis approach. Initially, a photoredox-catalyzed copper-mediated dehydrogenation of saturated aza-heterocycles produces ene-carbamates. This is followed by an anti-Markovnikov hydrofunctionalization of the ene-carbamates with a range of heteroatom-containing nucleophiles furnishing an array of C–C, C–O, and C–N aza-heterocycles at the β-position.
Despite the recognized effectiveness of course-based undergraduate research experiences (CUREs), there are few examples of the development of a CURE-based course in a large-enrollment undergraduate ...organic chemistry laboratory. Herein, we describe the development and implementation of a series of undergraduate laboratory experiments centered around the synthesis and characterization of pyrylium salts in the context of photoredox catalysis. Pre- and post-survey data regarding the CURE features of collaboration, discovery, iteration, and student project ownership also highlight the strengths of the CURE implementation in this large-scale lab course.
The majority of chronic myeloid leukemia (CML) cases are caused by a chromosomal translocation linking the breakpoint cluster region (BCR) gene to the Abelson murine leukemia viral oncogene-1 (ABL1), ...creating the mutant fusion protein BCR-ABL1. Downstream of BCR-ABL1 is growth factor receptor-bound protein-2 (GRB2), an intracellular adapter protein that binds to BCR-ABL1 via its src-homology-2 (SH2) domain. This binding constitutively activates growth pathways, downregulates apoptosis, and leads to an over proliferation of immature and dysfunctional myeloid cells. Utilizing novel synthetic methods, we developed four furo-quinoxaline compounds as GRB2 SH2 domain antagonists with the goal of disrupting this leukemogenic signaling. One of the four antagonists, NHD2-15, showed a significant reduction in proliferation of K562 cells, a human BCR-ABL1.sup.+ leukemic cell line. To elucidate the mode of action of these compounds, various biophysical, in vitro, and in vivo assays were performed. Surface plasmon resonance (SPR) assays indicated that NHD2-15 antagonized GRB2, binding with a K.sub.D value of 119 ± 2 muM. Cellulose nitrate (CN) assays indicated that the compound selectively bound the SH2 domain of GRB2. Western blot assays suggested the antagonist downregulated proteins involved in leukemic transformation. Finally, NHD2-15 was nontoxic to primary cells and adult zebrafish, indicating that it may be an effective clinical treatment for CML.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Over the last decade, photoredox catalysis has emerged as a powerful tool in organic synthesis that provides access to open-shell, one-electron, intermediates. In general, these one-electron ...intermediates have complementary reactivity compared to traditional two-electron pathways, and, accordingly, have been used to accomplish difficult synthetic transformations. Moreover, photoredox catalysis uses mild reaction conditions with high functional group tolerance, and has accordingly become a popular late-stage functionalization strategy.Chapter 1 serves as a general introduction to organic photoredox catalysis which covers the photophysical and electrochemical properties of organic chromophores. In particular, the properties of acridinium salts as potent photooxidants in the generation of alkene or arene cation radicals and alpha -amino radicals is covered in more detail.Chapter 2 and 3 cover the application of acridinium salts as photooxidants in arene functionalization with carbon nucleophiles. Chapter 2 describes a selective carbon–oxygen (C–O) bond functionalization via a cation radical-accelerated-nucleophilic aromatic substitution (CRA-SNAr) of alkoxy arenes with acetone cyanohydrin, an inexpensive and commercially available cyanide source, generating the desired benzonitriles. Computational studies provide a model for predicting regioselectivity and chemoselectivity in competitive C–H and C–O cyanation of methoxyarene cation radicals. Chapter 3 reports a C–H functionalization of arene cation radicals generated via organic photoredox catalysis with diazoacetates serving as nucleophiles. Computational and experimental studies support a unique mechanism involving cation radical-meditated aromatic cyclopropanation followed by oxidative ring-opening.Chapter 4 covers a two-step acridinium catalyzed procedure for the synthesis of beta-functionalized aza-heterocycles. First, a photoredox-catalyzed copper-mediated dehydrogenation of saturated aza-heterocycles produces ene-carbamates. This is followed by an anti-Markovnikov hydrofunctionalization of the ene-carbamates with a range of heteroatom-containing nucleophiles furnishing an array of C–C, C–O and C–N aza-heterocycles at the beta-position. The utility of this transformation was highlighted with the functionalization of several pharmaceutically relevant molecules, including in the synthesis of an orexin antagonist.
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