Di-π-ethane Rearrangement of Cyano Groups via Energy-Transfer Catalysis.

Molecular rearrangement occupies a pivotal position among fundamental transformations in synthetic chemistry. Radical translocation has emerged as a prevalent synthetic tool, efficiently facilitating the migration of diverse functional groups. In contrast, the development of di-π-methane rearrangement remains limited, particularly in terms of the translocation of cyano functional groups. This is primarily attributed to the energetically unfavorable three-membered-ring transition state. Herein, we introduce an unprecedented di-π-ethane rearrangement enabled by energy-transfer catalysis under visible light conditions. This innovative open-shell rearrangement boasts broad tolerance toward a range of functional groups, encompassing even complex drug and natural product derivatives. Overall, the reported di-π-ethane rearrangement represents a complementary strategy to the development of radical translocation enabled by energy-transfer catalysis.

Cyclic Amine Synthesis via Catalytic Radical-Polar Crossover Cycloadditions.

The rapid assembly of valuable cyclic amine architectures in a single step from simple precursors has been recognized as an ideal platform in term of efficiency and sustainability. Although a vast number of studies regarding cyclic amine synthesis has been reported, new synthetic disconnection approaches are still high in demand. Herein, we report a catalytic radical-polar crossover cycloaddition to cyclic amine synthesis triggered from primary sulfonamide under photoredox condition. This newly developed disconnection, comparable to established synthetic approaches, will allow to construct ß, ß-disubstituted cyclic amine and ß-monosubstituted cyclic amine derivatives efficiently. This study highlights the unique utility of primary sulfonamide as a bifunctional reagent, which acts as a radical precursor and a nucleophile. The open-shell methodology demonstrates broad tolerance to various functional groups, drug derivatives and natural products in an economically and sustainable fashion.

Correlation between nuclear expression of heat shock protein 90 in dermis and glucocorticoid resistance in bullous dermatosis.

BACKGROUND: bullous dermatosis is a group of skin diseases that occur on the skin and mucous membrane, with blister and bulla as basic damage, mainly including pemphigus and bullous pemphigoid. Glucocorticoid (GC) is still the preferred drug for its treatment, but some patients respond poorly to GC and even develop glucocorticoid resistance (GCR). However, at present about the disease the understanding of the mechanisms for GCR is limited. OBJECTIVE: This study attempted to investigate the molecular mechanism of GCR in bullous dermatosis with heat shock proteins 90 (HSP90) and glucocorticoid receptor (GR) as molecular targets. METHODS: In this study, flow cytometry was used to measure and analyze the expression of HSP90 and GR in the lesions of patients with glucocorticoid-resistant bullosa dermatosis. Immunohistochemistry and immunofluorescence were used to observe the expression distribution and cell localization of HSP90 and GR. RESULTS: The expression of HSP90 in skin lesions of GCR group was significantly higher than that of glucocorticoid-sensitive (GCS) group, while the expression level of GR was lower than that of GCS group. In the epidermis, the expression and distribution of HSP90 were not different between the GCR group and the GCS group. And in the dermis, HSP90 and GR were more likely to be expressed in the nucleus in the GCR group. CONCLUSION: The overexpression and nuclear distribution of HSP90 may be related to the occurrence of GCR in patients with bullous dermatosis. And this correlation is more likely to occur in the dermis than in the epidermis.

Photocatalytic Late-Stage C-H Functionalization.

The emergence of modern photocatalysis, characterized by mildness and selectivity, has significantly spurred innovative late-stage C-H functionalization approaches that make use of low energy photons as a controllable energy source. Compared to traditional late-stage functionalization strategies, photocatalysis paves the way toward complementary and/or previously unattainable regio- and chemoselectivities. Merging the compelling benefits of photocatalysis with the late-stage functionalization workflow offers a potentially unmatched arsenal to tackle drug development campaigns and beyond. This Review highlights the photocatalytic late-stage C-H functionalization strategies of small-molecule drugs, agrochemicals, and natural products, classified according to the targeted C-H bond and the newly formed one. Emphasis is devoted to identifying, describing, and comparing the main mechanistic scenarios. The Review draws a critical comparison between established ionic chemistry and photocatalyzed radical-based manifolds. The Review aims to establish the current state-of-the-art and illustrate the key unsolved challenges to be addressed in the future. The authors aim to introduce the general readership to the main approaches toward photocatalytic late-stage C-H functionalization, and specialist practitioners to the critical evaluation of the current methodologies, potential for improvement, and future uncharted directions.

Molecular mechanisms of glucocorticoid resistance.

BACKGROUND: As a powerful anti-inflammatory, immunosuppressive, and antiproliferative drug, glucocorticoid (GC) plays an important role in the treatment of various diseases. However, some patients may experience glucocorticoid resistance (GCR) in clinical, and its molecular mechanism have not been determined. METHODS: The authors performed a review of the literature on GCR focusing on mutations in the NR3C1 gene and impaired glucocorticoid receptor (GR) signalling, using METSTR (2000 through May 2022) to identify original articles and reviews on this topic. The search terms included 'glucocorticoid resistance/insensitive', 'steroid resistance/insensitive', 'NR3C1', and 'glucocorticoid receptor'. RESULTS: Primary GCR is mainly caused by NR3C1 gene mutation, and 31 NR3C1 gene mutations have been reported so far. Secondary GCR is caused by impaired GC signalling pathways, including decreased expression of GR, impaired nuclear translocation of GR, and impaired binding of GR to GC and GR to target genes. However, the current research is more on the expression level of GR, and there are relatively few studies on other mechanisms. In addition, methods for improving GC sensitivity are rarely reported. CONCLUSION: The molecular mechanisms of GCR are complex and may differ in different diseases or different patients. In future studies, when exploring the mechanism of GCR, methods to improve GC sensitivity should also be investigated.

Catalytic defluorinative ketyl-olefin coupling by halogen-atom transfer.

Ketyl-olefin coupling reactions stand as one of the fundamental chemical transformations in synthetic chemistry and have been widely employed in the generation of complex molecular architectures and natural product synthesis. However, catalytic ketyl-olefin coupling, until the recent development of photoredox chemistry and electrosynthesis through single-electron transfer mechanisms, has remained largely undeveloped. Herein, we describe a new approach to achieve catalytic ketyl-olefin coupling reactions by a halogen-atom transfer mechanism, which provides innovative and efficient access to various gem-difluorohomoallylic alcohols under mild conditions with broad substrate scope. Preliminary mechanistic experimental and computational studies demonstrate that this radical-to-polar crossover transformation could be achieved by sequentially orchestrated Lewis acid activation, halogen-atom transfer, radical addition, single-electron reduction and ß-fluoro elimination.

Radical Brook Rearrangements: Concept and Recent Developments.

The Brook rearrangement has already become established as one of the most important molecular rearrangements in synthetic chemistry and has been applied in the generation of complexes, drug discovery, material science, and natural products synthesis. Compared to the widely known ionic mechanism, the radical Brook rearrangement is less explored because of the difficulty in generating alkoxyl radical species. This Minireview summarizes the early developments and general concept of the radical Brook rearrangement and highlights recent advances in photocatalytic reactions and transition-metal-catalyzed cross-coupling reactions involving radical Brook rearrangements. We hope this survey will inspire further developments in this emerging area.

Merging Carbonyl Addition with Photocatalysis.

The carbonyl group stands as a fundamental scaffold and plays a ubiquitous role in synthetically important chemical reactions in both academic and industrial contexts. Venerable transformations, including the aldol reaction, Grignard reaction, Wittig reaction, and Nozaki-Hiyama-Kishi reaction, constitute a vast and empowering synthetic arsenal. Notwithstanding, two-electron mechanisms inherently confine the breadth of accessible reactivity and topological patterns.Fostered by the rapid development of photoredox catalysis, combing well-entrenched carbonyl addition and radicals can harness several unique and increasingly sustainable transformations. In particular, unusual carbon-carbon and carbon-heteroatom disconnections, which are out of reach of two-electron carbonyl chemistry, can be conceived. To meet this end, a novel strategy toward the utilization of simple carbonyl compounds as intermolecular radical acceptors was developed. The reaction is enabled by visible-light photoredox-initiated hole catalysis. In situ Brønsted acid activation of the carbonyl moiety prevents ß-scission from occurring. Furthermore, this regioselective alkyl radical addition reaction obviates the use of metals, ligands, or additives, thus offering a high degree of atom economy under mild conditions. On the basis of the same concept and the work of Schindler and co-workers, carbonyl-olefin cross-metathesis, induced by visible light, has also been achieved, leveraging a radical Prins-elimination sequence.Recently, dual chromium and photoredox catalysis has been developed by us and Kanai, offering a complementary approach to the revered Nozaki-Hiyama-Kishi reaction. Leveraging the intertwined synergy between light and metal, several radical-to-polar crossover transformations toward eminent molecular motifs have been developed. Reactions such as the redox-neutral allylation of aldehydes and radical carbonyl alkylation can harvest the power of light and enable the use of catalytic chromium metal. Overall, exquisite levels of diastereoselectivity can be enforced via highly compact transition states. Other examples, such as the dialkylation of 1,3-dienes and radical carbonyl propargylation portray the versatile combination of radicals and carbonyl addition in multicomponent coupling endeavors. Highly valuable motifs, which commonly occur in complex drug and natural product architectures, can now be accessed in a single operational step. Going beyond carbonyl addition, seminal contributions from Fagnoni and MacMillan preconized photocatalytic HAT-based acyl radical formation as a key aldehyde valorization strategy. Our group articulated this concept, leveraging carboxy radicals as hydrogen atom abstractors in high regio- and chemoselective carbonyl alkynylation and aldehyde trifluoromethylthiolation.This Account, in addition to the narrative of our group and others' contributions at the interface between carbonyl addition and radical-based photochemistry, aims to provide core guiding foundations toward novel disruptive synthetic developments. We envisage that extending radical-to-polar crossovers beyond Nozaki-Hiyama-Kishi manifolds, taming less-activated carbonyls, leveraging multicomponent processes, and merging single electron steps with energy-transfer events will propel eminent breakthroughs in the near future.

Radical Carbonyl Umpolung Arylation via Dual Nickel Catalysis.

The formation of carbon-carbon bonds lies at the heart of synthetic organic chemistry and is widely applied to construct complex drugs, polymers, and materials. Despite its importance, catalytic carbonyl arylation remains comparatively underdeveloped, due to limited scope and functional group tolerance. Herein we disclose an umpolung strategy to achieve radical carbonyl arylation via dual catalysis. This redox-neutral approach provides a complementary method to construct Grignard-type products from (hetero)aryl bromides and aliphatic aldehydes, without the need for pre-functionalization. A sequential activation, hydrogen-atom transfer, and halogen atom transfer process could directly convert aldehydes to the corresponding ketyl-type radicals, which further react with aryl-nickel intermediates in an overall polarity-reversal process. This radical strategy tolerates─among others─acidic functional groups, heteroaryl motifs, and sterically hindered substrates and has been applied in the late-stage modification of drugs and natural products.

Bifunctional reagents in organic synthesis.

Developments in synthetic chemistry are increasingly driven by improvements in the selectivity and sustainability of transformations. Bifunctional reagents, either as dual coupling partners or as a coupling partner in combination with an activating species, offer an atom-economic approach to chemical complexity, while suppressing the formation of waste. These reagents are employed in organic synthesis thanks to their ability to form complex organic architectures and empower novel reaction pathways. This Review describes several key bifunctional reagents by showcasing selected cornerstone research areas and examples, including radical reactions, C-H functionalization, cross-coupling, organocatalysis and cyclization reactions.

Radical Carbonyl Propargylation by Dual Catalysis.

Carbonyl propargylation has been established as a valuable tool in the realm of carbon-carbon bond forming reactions. The 1,3-enyne moiety has been recognized as an alternative pronucleophile in the above transformation through an ionic mechanism. Herein, we report for the first time, the radical carbonyl propargylation through dual chromium/photoredox catalysis. A library of valuable homopropargylic alcohols bearing all-carbon quaternary centers could be obtained by a catalytic radical three-component coupling of 1,3-enynes, aldehydes and suitable radical precursors (41 examples). This redox-neutral multi-component reaction occurs under very mild conditions and shows high functional group tolerance. Remarkably, bench-stable, non-toxic, and inexpensive CrCl3 could be employed as a chromium source. Preliminary mechanistic investigations suggest a radical-polar crossover mechanism, which offers a complementary and novel approach towards the preparation of valuable synthetic architectures from simple chemicals.

Transition metal-catalysed allylic functionalization reactions involving radicals.

Transition metal-catalysed allylic functionalization reactions have been established as a central synthetic transformation to enable the construction of carbon-carbon and carbon-heteroatom bonds. Although they have been widely investigated by numerous research groups all over the world, frequently applied in drug discovery and natural product synthesis, most research endeavours focus on ionic mechanisms. Transition metal-catalysed allylic functionalization reactions involving radicals are comparatively underexplored, but provide a powerful alternative strategy to current approaches, considerably extending the amenable coupling partners. This tutorial review highlights the recent advances in this rapidly expanding area, which experienced an unprecedented momentum thanks to the rapid development of radical chemistry. The rationalization of the main scenarios in the generation of allylic intermediates, radical species as formal nucleophiles, and activated transition metals as well as the utilization of allylic radical intermediates in ß-functionalization of carbonyls will highlight the common mechanistic threads. In addition the extension of amenable substrates and the new product motifs that can be generated will be summarized.

Three-Component, Interrupted Radical Heck/Allylic Substitution Cascade Involving Unactivated Alkyl Bromides.

Developing efficient and selective strategies to approach complex architectures containing (multi)stereogenic centers has been a long-standing synthetic challenge in both academia and industry. Catalytic cascade reactions represent a powerful means of rapidly leveraging molecular complexity from simple feedstocks. Unfortunately, carrying out cascade Heck-type reactions involving unactivated (tertiary) alkyl halides remains an unmet challenge owing to unavoidable ß-hydride elimination. Herein, we show that a modular, practical, and general palladium-catalyzed, radical three-component coupling can indeed overcome the aforementioned limitations through an interrupted Heck/allylic substitution sequence mediated by visible light. Selective 1,4-difunctionalization of unactivated 1,3-dienes, such as butadiene, has been achieved by employing different commercially available nitrogen-, oxygen-, sulfur-, or carbon-based nucleophiles and unactivated alkyl bromides (>130 examples, mostly >95:5 E/Z, >20:1 rr). Sequential C(sp3)-C(sp3) and C-X (N, O, S) bonds have been constructed efficiently with a broad scope and high functional group tolerance. The flexibility and versatility of the strategy have been illustrated in a gram-scale reaction and streamlined syntheses of complex ether, sulfone, and tertiary amine products, some of which would be difficult to access via currently established methods.

Catalytic cascade reactions by radical relay.

Radical cascade reactions are an attractive tool for the rapid construction of complex molecular architectures. Although a large number of powerful radical cascades have been developed, stoichiometric amounts of reagents and/or additives are often required to mediate these processes. Radical relay strategies, in which radical character is recycled, require only a catalytic amount of reagent and are particularly attractive as they promise cascades that are high in atom economy. This tutorial review highlights recent advances in this rapidly developing area by setting out and dissecting the reaction designs underpinning state-of-the-art processes involving radical relays. Advances in the field of radical relay cascades will open the door to more efficient synthesis with far-reaching benefits for the makers and end-users of complex molecules.

Heterologous production, reconstitution and EPR spectroscopic analysis of prFMN dependent enzymes.

The recent discovery of the prenylated FMN (prFMN) cofactor has led to a renewed interest in the prFMN-dependent UbiD family of enzymes. The latter catalyses the reversible decarboxylation of alpha-beta unsaturated carboxylic acids and features widely in microbial metabolism. The flavin prenyltransferase UbiX synthesizes prFMN from reduced FMN and phosphorylated dimethylallyl precursors. Oxidative maturation of the resulting prFMNreduced species to the active prFMNiminium form is required for UbiD activity. Heterologous production of active holo-UbiD requires co-expression of UbiX, but the levels of prFMN incorporation and oxidative maturation appear variable. Detailed protocols and strategies for in vitro reconstitution and oxidative maturation of UbiD are presented that can yield an alternative source of active holo-UbiD for biochemical studies.

Reductive cyclisations of amidines involving aminal radicals.

Amidines bearing simple alkenes undergo aminal radical cyclisation upon treatment with SmI2. The mild, reductive electron transfer process delivers medicinally-relevant, polycyclic quinazolinone derivatives in good to excellent yield and typically with complete diastereocontrol.

Radical Anions from Urea-type Carbonyls: Radical Cyclizations and Cyclization Cascades.

Radical anions generated from urea carbonyls by reductive electron transfer are exploited in carbon-carbon bond formation. New radical cyclizations of urea radical anions deliver complex nitrogen heterocycles and, depending upon the proton source used in the reactions, a chemoselective switch between reaction pathways can deliver two heterobicyclic scaffolds. A computational study has been used to investigate the selectivity of the urea radical processes. Furthermore, radical cyclization cascades involving urea radical anions deliver unusual spirocyclic aminal architectures.

Radical Heterocyclization and Heterocyclization Cascades Triggered by Electron Transfer to Amide-Type Carbonyl Compounds.

Radical heterocyclizations triggered by electron transfer to amide-type carbonyls, using SmI2 -H2 O, provide straightforward access to bicyclic heterocyclic scaffolds containing bridgehead nitrogen centers. Furthermore, the first radical heterocyclization cascade triggered by reduction of amide-type carbonyls delivers novel, complex tetracyclic architectures containing five contiguous stereocenters with excellent diastereocontrol.

Selective construction of quaternary stereocentres in radical cyclisation cascades triggered by electron-transfer reduction of amide-type carbonyls.

Radical-radical cyclisation cascades, triggered by single-electron-transfer to amide-type carbonyls using SmI2-H2O-LiBr, result in the selective construction of quaternary carbon stereocentres. The cascades deliver tricyclic barbiturates with four stereocentres in good yield and with excellent diastereocontrol.