Over the past decades, N‐heterocyclic carbene (NHC) organocatalysis has undergone a flourish of development on the basis of closed‐shell reaction paths. By contrast, the emerging area of ...single‐electron transfer (SET) reactions enabled by NHC catalysis still remain underdeveloped, but offer plenty of opportunities to develop new catalytic modes and useful synthetic methods. A number of interesting transformations were triggered by the SET process from the electron‐rich Breslow intermediates to various single‐electron acceptors. In additions, recent studies revealed that the Breslow radical cations could also be generated by single‐electron reduction of the electron‐deficient acyl azolium intermediates. These discoveries open a new avenue for NHC organocatalysis to harness radical reactions. The present review will focus on the exciting advancements in the dynamic area of radical NHC organocatalysis.
NHC organocatalysis: The development of N‐heterocyclic carbene (NHC) organocatalysis presents new opportunities in radical reactions. The Breslow intermediate‐based radical cations, which could be generated through single‐electron oxidation or reduction, enabled a series of novel radical transformations. These advancements greatly extend the synthetic potential of N‐heterocyclic carbene catalysis.
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Fluorinated ketones are widely prevalent in numerous biologically interesting molecules, and the development of novel transformations to access these structures is an important task in organic ...synthesis. Herein, we report the multicomponent radical acylfluoroalkylation of a variety of olefins in the presence of various commercially available aromatic aldehydes and fluoroalkyl reagents through N‐heterocyclic carbene organocatalysis. With this protocol, over 120 examples of functionalized ketones with diverse fluorine substituents have been synthesized in up to 99 % yield with complete regioselectivity. The generality of this catalytic strategy was further highlighted by its successful application in the late‐stage functionalization of pharmaceutical skeletons. Excellent diastereoselectivity could be achieved in the reactions forging multiple stereocenters. In addition, preliminary results have been achieved on the catalytic asymmetric variant of the olefin difunctionalization process.
Organocatalytic acylfluoroalkylation: A multicomponent radical acylfluoroalkylation of olefins through NHC organocatalysis was developed, and over 120 examples of fluoroketones were facilely accessed from simple materials. Moreover, a dearomative difunctionalization of indoles could be readily achieved in a highly diastereoselective manner. The generality and practicality were highlighted by the late‐stage modification of drug skeletons.
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A visible‐light‐mediated photoredox‐catalyzed semipinacol‐type rearrangement proceeding via 1,2 alkyl migration was developed. In this transformation, trifluoromethylation of the CC bond of ...α‐(1‐hydroxycycloalkyl)‐substituted styrene derivatives is followed by ring expansion of the 1‐hydroxycycloalkyl group to deliver novel cycloalkanones with all‐carbon quaternary centers. The reaction proceeds via a radical–polar mechanism, with trifluoromethylation (radical) and ring expansion (ionic) occurring in the same transformation.
Circle of light: A visible‐light‐mediated photoredox semipinacol‐type rearrangement proceeding by 1,2 alkyl migration was developed. The transformation involves a radical–polar mechanism, in which photoinduced trifluoromethylation of a CC bond is followed by ring expansion of a cationic intermediate. This process constitutes the first report of ionic alkyl migration in photoredox catalysis and proceeds under mild conditions with visible light.
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The efficacy and synthetic versatility of asymmetric organocatalysis have contributed enormously to the field of organic synthesis since the early 2000s. As asymmetric organocatalytic methods mature, ...they have extended beyond the academia and undergone scale-up for the production of chiral drugs, natural products, and enantiomerically enriched bioactive molecules. This review provides a comprehensive overview of the applications of asymmetric organocatalysis in medicinal chemistry. A general picture of asymmetric organocatalytic strategies in medicinal chemistry is firstly presented, and the specific applications of these strategies in pharmaceutical synthesis are systematically described, with a focus on the preparation of antiviral, anticancer, neuroprotective, cardiovascular, antibacterial, and antiparasitic agents, as well as several miscellaneous bioactive agents. The review concludes with a discussion of the challenges, limitations and future prospects for organocatalytic asymmetric synthesis of medicinally valuable compounds.
This review provides a comprehensive overview of the recent applications of organocatalytic strategies in pharmaceutical synthesis, with a focus on the preparation of antiviral, anticancer, neuroprotective, cardiovascular, antibacterial and antiparasitic agents.
The photoredox activation of organic substrates with visible light is a powerful methodology that generates reactive radical species under very mild conditions. When combined with another catalytic ...process in a dual catalytic system, novel, visible‐light‐promoted transformations have been realized that do not proceed using either catalyst in isolation. In this minireview, the state of the art in organic reactions mediated by dual catalytic systems merging photoredox activation with organo‐, acid or metal catalysis is discussed.
De(light)ful catalysis! The merger of photoredox catalysis with another catalytic mode can result in novel, visible‐light‐promoted reactions that do not proceed by using either catalyst independently. Herein, the different ways that two catalytic modes can operate in tandem are highlighted, focusing on dual‐catalyzed organic processes that merge photoredox with organo‐, acid, and transition‐metal catalysis.
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Asymmetric construction of halogenated quaternary carbon centers under mild reaction conditions remains challenging. Reported here is an unprecedented and highly stereoselective Brønsted base ...catalyzed 4+2 cycloaddition between either α‐chloro‐ or α‐bromoaldehydes and cyclic enones. The key intermediate, an α‐halogenated enolate, is susceptible to dehalogenation and can be stabilized and stereochemically controlled using bifunctional tertiary amines. This method provides facile access to a collection of optically pure bicyclic dihydropyrans having three contiguous stereocenters, including a halogen‐bearing quaternary carbon center. Of note, the product can be transformed in situ into densely functionalized spirocyclopropanes in a highly efficient and stereoselective manner.
Hello Halo! An unprecedented highly enantioselective, Brønsted base catalyzed 4+2 cycloaddition of α‐haloaldehydes and electron‐deficient cyclic enones has been developed. A series of fused bicyclic dihydropyrans featuring a halogenated quaternary stereocenter was synthesized in excellent yields with up to >99 % ee under mild reaction conditions. These products were further transformed into spirocyclopropanes having two vicinal all‐carbon quaternary centers.
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The direct functionalization of inert C(sp3)−H bonds under environmentally benign catalytic conditions remains a challenging task in synthetic chemistry. Here, we report an organocatalytic remote ...C(sp3)−H acylation of amides and cascade cyclization through a radical‐mediated 1,5‐hydrogen atom transfer mechanism using N‐heterocyclic carbene as the catalyst. Notably, a diversity of nitrogen‐containing substrates, including simple linear aliphatic carbamates and ortho‐alkyl benzamides, can be successfully applied to this organocatalytic system. With the established protocol, over 120 examples of functionalized δ‐amino ketones and isoquinolinones with diverse substituents were easily synthesized in up to 99 % yield under mild conditions. The robustness and generality of the organocatalytic strategy were further highlighted by the successful acylation of unactivated C(sp3)−H bonds and late‐stage modification of pharmaceutical molecules. Then, the asymmetric control of the radical reaction was attempted and proven feasible by using a newly designed chiral thiazolium catalyst, and moderate enantioselectivity was obtained at the current stage. Preliminary mechanistic investigations including several control reactions, KIE experiments, and computational studies shed light on the organocatalytic radical reaction mechanism.
An N‐heterocyclic carbene catalyzed remote C(sp3)−H acylation of amides was developed, and also combined with a cascade cyclization. Over 120 functionalized δ‐amino ketones and isoquinolinones with diverse substituents were synthesized in up to 99 % yield under mild conditions. Preliminary mechanistic investigations shed light on the organocatalytic radical reaction mechanism.
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The efficient and enantioselective construction of cyclic compounds with a halogenated tetrasubstituted carbon through various catalytic strategies remains challenging. Thus, research on modern ...asymmetric catalysis is important. In this review, recent achievements that streamlined the synthesis of halogenated cyclic molecules through organocatalysis or transition‐metal catalysis were introduced.
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We report here a stereoselective 3+2 cyclization of 5‐alkenyl thiazolones and ketimines that allows the assembly of three diastereoisomers through the combination of stereodivergent organocatalysis ...and the following diastereoselective transformation of products. A broad spectrum of pyrrolidinyl spirooxindoles featuring stereochemical diversity has been synthesized through organocatalytic formal 1,3‐dipolar cycloadditions with up to 98% yield, >20:1 dr and 99:1 er.
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Microglia become activated during cerebral ischemia and exert pro‐inflammatory or anti‐inflammatory role dependent of microglial polarization. NADPH oxidase (NOX)‐dependent reactive oxygen species ...(ROS) production in microglia plays an important role in neuronal damage after ischemic stroke. Recently, NOX and ROS are consistently reported to participate in the microglial activation and polarization; NOX2 inhibition or suppression of ROS production are shown to shift the microglial polarization from M1 toward M2 state after stroke. The voltage‐gated proton channel, Hv1, is selectively expressed in microglia and is required for NOX‐dependent ROS generation in the brain. However, the effect of Hv1 proton channel on microglial M1/M2 polarization state after cerebral ischemia remains unknown. In this study, we investigated the role of microglial Hv1 proton channel in modulating microglial M1/M2 polarization during the pathogenesis of ischemic cerebral injury using a mouse model of photothrombosis. Following photothrombotic ischemic stroke, wild‐type mice presented obvious brain infarct, neuronal damage, and impaired motor coordination. However, mice lacking Hv1 (Hv1−/−) were partially protected from brain damage and motor deficits compared to wild‐type mice. These rescued phenotypes in Hv1−/− mice in ischemic stroke is accompanied by reduced ROS production, shifted the microglial polarization from M1 to M2 state. Hv1 deficiency was also found to shift the M1/M2 polarization in primary cultured microglia. Our study suggests that the microglial Hv1 proton channel is a unique target for modulation of microglial M1/M2 polarization in the pathogenesis of ischemic stroke.
The voltage‐gated proton channel, Hv1, is selectively expressed in microglia and is required for NOX‐dependent generation of reactive oxygen species (ROS) in the brain. ROS participate in microglial activation and polarization. However, the effect of Hv1 on microglial M1/M2 polarization state after cerebral ischemia remains unknown. Hv1 deficiency was found to shift the microglial polarization from M1 to M2 state in ischemic stroke accompanied by reduced ROS production. Our study suggests that the microglial Hv1 proton channel is a unique target for modulation of microglial M1/M2 polarization in the pathogenesis of ischemic stroke.
The voltage‐gated proton channel, Hv1, is selectively expressed in microglia and is required for NOX‐dependent generation of reactive oxygen species (ROS) in the brain. ROS participate in microglial activation and polarization. However, the effect of Hv1 on microglial M1/M2 polarization state after cerebral ischemia remains unknown. Hv1 deficiency was found to shift the microglial polarization from M1 to M2 state in ischemic stroke accompanied by reduced ROS production. Our study suggests that the microglial Hv1 proton channel is a unique target for modulation of microglial M1/M2 polarization in the pathogenesis of ischemic stroke.
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