Radical Cyclization Research Articles

Boryl Radical as a Catalyst in Enabling Intra‐ and Intermolecular Cascade Radical Cyclization Reactions: Construction of Polycyclic Molecules

AbstractCascade radical cyclization constitutes an atom‐ and step‐economic route for rapid assembly of polycyclic molecular skeletons. Although an array of redox‐active metal catalysts has recently shown robust applications in enabling various catalytic cascade radical processes, the use of free organic radical as the catalyst, which is capable of triggering strategically distinct cascades, has rarely been developed. Here, we disclosed that the benzimidazolium‐based N‐heterocyclic carbene (NHC)‐boryl radical is capable of catalyzing cascade cyclization reactions in both intra‐ and intermolecular pathways, assembling [5,5] fused bicyclic and [6,6,6] fused tricyclic molecules, respectively. The catalytic reactions start with the chemo‐ and regioselective addition of the boryl radical catalyst to a tethered alkene or alkyne moiety, followed by either an intramolecular formal [3+2] or an intermolecular [2+2+2] cycloaddition process to construct bicyclo[3.3.0]octane or tetrahydrophenanthridine skeletons, respectively. Eventually, a β‐elimination occurs to release the boryl radical catalyst, completing a catalytic cycle. High to excellent diastereoselectivity is achieved in both catalytic reactions under substrate control.

Access to N-Fused Quinazolinones by Radical-Promoted Cascade Annulations of Alkenyl N-Cyanamides with Aromatic Aldehydes.

A cascade radical cyclization of alkenyl N-cyanamides with aromatic aldehydes has been achieved for an expeditious synthesis of keto-methylated dihydropyrrolo-quinazolinones. Benzoyl radicals, generated from aryl aldehydes in the presence of di-tert-butyl peroxide (DTBP), promoted the domino annulations leading to distinctive functionalized quinazolinones in good yields. In addition, the robustness of the present protocol is validated by employing heterocyclic and natural product-based aldehydes.

Microwave-Assisted Atom Transfer Radical Cyclization in the Synthesis of 3,3-Dichloro-γ- and δ-Lactams from N-Alkenyl-Tethered Trichloroacetamides Catalyzed by RuCl2(PPh3)3 and Their Cytotoxic Evaluation.

An expeditious synthesis of γ- and δ-lactams from tethered alkenyl trichloroacetamides in the presence of 5% of RuCl2(PPh3)3 is reported. In this investigation we have demonstrated that microwave activation significantly enhances reaction rates, leading to the formation of the corresponding lactams in yields ranging from good to excellent. Thus, we have been able to prepare a wide range of lactams, including indole and morphan bicyclic scaffolds, where the corresponding reactions were completely diastereoselective. This process was successfully extended to α,α-dichloroamides without affecting either their yield or their diastereoselectivity. Some of the lactams prepared in this work were evaluated for their hemolytic and cytotoxic responses. All compounds were found to be non-hemolytic at the tested concentration, indicating their safety profile in terms of blood cell integrity. Meanwhile, they exhibited interesting cytotoxicity responses that depend on both their lactam structure and cell line. Among the molecules tested, γ-lactam 2a exhibited the lowest IC50 values (100-250 µg/mL) as a function of its cell line, with promising selectivity against squamous carcinoma cells (A431) in comparison with fibroblasts (3T3 cell line).

Stereodivergent photobiocatalytic radical cyclization through the repurposing and directed evolution of fatty acid photodecarboxylases.

Despite their intriguing photophysical and photochemical activities, naturally occurring photoenzymes have not yet been repurposed for new-to-nature activities. Here we engineered fatty acid photodecarboxylases to catalyse unnatural photoredox radical C-C bond formation by leveraging the strongly oxidizing excited-state flavoquinone cofactor. Through genome mining, rational engineering and directed evolution, we developed a panel of radical photocyclases to facilitate decarboxylative radical cyclization with excellent chemo-, enantio- and diastereoselectivities. Our high-throughput experimental workflow allowed for the directed evolution of fatty acid photodecarboxylases. An orthogonal set of radical photocyclases was engineered to access all four possible stereoisomers of the stereochemical dyad, affording fully diastereo- and enantiodivergent biotransformations in asymmetric radical biocatalysis. Molecular dynamics simulations show that our evolved radical photocyclases allow near-attack conformations to be easily accessed, enabling chemoselective radical cyclization. The development of stereoselective radical photocyclases provides unnatural C-C-bond-forming activities in natural photoenzyme families, which can be used to tame the stereochemistry of free-radical-mediated reactions.

Alkyl Radical Initiated Cyclization/Cascade for Synthesizing Lactam‐Substituted Alkyl Sulfones

Comprehensive SummaryAn alkyl radical initiated cyclization/tandem reaction of alkyl bromides and alkyl electrophiles by using potassium metabisulphite (K2S2O5) as a connector is developed for the synthesis of various lactam‐substituted alkyl sulfones. Notably, this process does not require a metal catalyst or metal powder reductant, highlighting its environmentally friendly features. The reaction demonstrates outstanding substrate adaptability and a high tolerance towards diverse functional groups. Furthermore, the biologically active molecules and commercially available drugs with a late‐stage modification are also highly compatible with this transformation. Mechanistic studies revealed that the reaction proceeds through a single‐step process involving intramolecular radical cyclization, "SO2" insertion, and external alkyl incorporation.

Cu(I)-Photosensitizer-Catalyzed Olefin-α-Amino Radical Metathesis/Demethylenative Cyclization of 1,7-Enynes.

A demethylenative En-Yne radical cyclization of 1,7-enynes has been successfully developed to chemoselectively afford 3,4-dihyroquinolin-2-ones or quinolin-2-ones under the catalysis of Cu(I) photosensitizers PS3 and PS6 with different redox potentials. The preliminary mechanistic experiments revealed that the reaction underwent an unprecedented olefin-α-amino radical metathesis-type process. A reasonable mechanism was proposed to illustrate the catalyst-controlled chemoselectivity of the reaction based on preliminary mechanistic experiments and DFT calculations.

Visible-Light-Triggered Difluoroacetylation/Cyclization of Chromone-Tethered Alkenes Enabling Synthesis of Tetrahydroxanthones.

Hydroxanthones have attracted considerable attention due to their significance in organic and biological chemistry, yet their synthesis remains a great challenge. In this study, a series of chromone-tethered alkenes are designed, and a radical cyclization reaction of these chromone derivatives has been achieved under photoredox conditions. The reaction uses bromodifluoroacetamides or bromodifluoroacetates as coupling partners, affording a broad range of functionalized tetrahydroxanthone products with up to 85% yields. The reaction is triggered via the generation of difluoroacetate radicals or alkene radical cations with fac-Ir(ppy)3 or 2,3,5,6-tetrakis(carbazol-9-yl)-1,4-dicyanobenzene as a photocatalyst. This approach offers access to various tetrahydroxanthone derivatives from readily available starting materials and enriches the research content of heteroarene-tethered alkenes.

Photocatalytic (3 + 3) Annnulation of Vinyldiazo Compounds and Aminocyclopropanes.

A (3 + 3) annulation of aminocyclopropanes and vinyldiazo compounds enabled by organo-photocatalysis is described. The reaction allows the regioselective synthesis of cyclohexenes bearing adjacent amino and carbonyl groups with broad functional group tolerance. In a departure from previous reports, our work demonstrated that a distonic radical cation can be preferentially intercepted by weakly nucleophilic vinyldiazo compounds, followed by an exclusive 6-endo radical cyclization for ring closure. Based on the interaction between adjacent amino and ester groups, the products can be further converted to cyclohexene-fused 1,3-oxazinane and azetidine.

Synthesis of the Cyclopentane Core Skeleton of Cranomycin and Jogyamycin.

Cranomycin and jogyamycin, two aminocyclopentitol natural products, possess complex structures and potential medicinal properties. This review describes synthetic studies about the process of making an advanced intermediate of cranomycin and jogyamycin. This highly functionalized intermediate, featuring three contiguous amine-substituted stereocenters, was constructed from cyclopentadiene through a series of reactions including the nitroso Diels-Alder reaction, nitrogen radical cyclization reaction, 1,2-nitrogen migration, and stereoselective nitrogen addition.

Divergent total synthesis of sesquiterpene (hydro)quinone meroterpenoids dysideanones A and E–G

The first total synthesis of marine sesquiterpene (hydro)quinone meroterpenoids dysideanones A and E–G (1 and 4–6) has been accomplished in an enantioselective and divergent way. The sesquiterpene fragment and the aromatic moiety were efficiently connected via a site-selective and diastereoselective intermolecular alkylation of Wieland–Miescher ketone derivative 9 and benzyl bromide 10. The core 6/6/6/6-fused backbone of dysideanones was efficiently constructed through an intramolecular radical cyclization reaction. Dysideanone G (6) was easily prepared on a gram-scale and dysideanones A, E, and F (1, 4, and 5) were divergently transformed from dysideanone G (6) in one or two steps

Thermal vs. Visible‐Light Photoredox‐Catalyzed Cascade Radical Cyclization Involving SO2 Fixation to Access 6‐Alkylsulfonylmethyl Phenanthridines

AbstractConvenient access to 6‐alkylsulfonylmethyl phenanthridines has been demonstrated both under non‐catalytic thermal and visible‐light photoredox‐catalyzed conditions. A cascade of radical cyclization is triggered by the exposure of biphenyl vinyl azides to the in‐situ generated alkyl sulfonyl radicals from 4‐substituted Hanztsch esters in the presence of an SO2 surrogate. Transition metal‐free, mild reaction conditions, and broad substrate scope constitute some of the highlights of the approach. Also, the synthetic utility of the accessed 6‐alkylsulfonylmethyl phenanthridines has been demonstrated.

Photocatalytic Proton-Coupled Electron Transfer Enabled Radical Cyclization for Isoquinoline-1,3-diones Synthesis.

Radical cyclization has been demonstrated to be an efficient method to access functionalized heterocycles from easily accessible raw materials. Described herein is the development of a photocatalytic proton-coupled electron transfer (PCET) strategy for the synthesis of isoquinoline-1,3-diones using readily prepared naphthalimide (NI)-based organic photocatalysts. The process features free metal-complex photocatalysts, acids, and mild reaction conditions. This mild radical cyclization protocol has a broad substrate scope and can be effectively applied to a variety of medicinally relevant substrates. Furthermore, control experiments were conducted to elucidate the mechanism of this visible light-induced methodology.

Synthetic Studies toward Pseudolaric Acids: Radical Cyclization to Form Bridged Scaffold

Comprehensive SummaryPseudolaric acids are a family of diterpenoid natural products that exhibit a broad spectrum of biological activities. The main structural feature of their framework is a trans‐fused perhydroazulene bearing a bridged lactone positioned at the junction of the rings. Herein, we have developed a radical cyclization strategy that allows flexible tuning of the cyclization process through diverse silicon substitutions on the substrates. This strategy can assist in constructing a series of skeletons with structural resemblance to pseudolaric acids and expedites the construction of the bridged lactone. Finally, it facilitates the synthesis of the entire skeletal structure of the pseudolaric acid family of natural products, excluding the B‐ring functionalization.

Photocatalytic Site‐Selective Cascade Radical Addition of Biaryl Ynones for the Construction of Spiro‐ and Fused Carbon Rings

Comprehensive SummaryFunctionalized free radical addition/cyclization reactions represent an efficient way for introducing new functionality or coupling fragments to molecules. Ynones are good regional selectivity radical acceptors in organic synthesis, and many of bio‐relevant cyclic compounds could be easily obtained by direct radical cyclization reaction. Here, we report a photocatalytic cascade radical addition of biaryl ynones, for the divergent synthesis of privileged carbon cycles. Additionally, further transformation of the multi‐functional group product into a variety of other derivatives demonstrates the synthetic value of this developed method.

Couple-close construction of polycyclic rings from diradicals.

Heteroarenes are ubiquitous motifs in bioactive molecules, conferring favourable physical properties when compared to their arene counterparts1-3. In particular, semisaturated heteroarenes possess attractive solubility properties and a higher fraction of sp3 carbons, which can improve binding affinity and specificity. However, these desirable structures remain rare owing to limitations in current synthetic methods4-6. Indeed, semisaturated heterocycles are laboriously prepared by means of non-modular fit-for-purpose syntheses, which decrease throughput, limit chemical diversity and preclude their inclusion in many hit-to-lead campaigns7-10. Herein, we describe a more intuitive and modular couple-close approach to build semisaturated ring systems from dual radical precursors. This platform merges metallaphotoredox C(sp2)-C(sp3) cross-coupling with intramolecular Minisci-type radical cyclization to fuse abundant heteroaryl halides with simple bifunctional feedstocks, which serve as the diradical synthons, to rapidly assemble a variety of spirocyclic, bridged and substituted saturated ring types that would be extremely difficult to make by conventional methods. The broad availability of the requisite feedstock materials allows sampling of regions of underexplored chemical space. Reagent-controlled radical generation leads to a highly regioselective and stereospecific annulation that can be used for the late-stage functionalization of pharmaceutical scaffolds, replacing lengthy de novo syntheses.

Photochemical C(sp3)-H Activation for Diversity-Oriented Synthesis of 3-Functionalized Oxindoles.

Heteroatom-adjacent C(sp3) radical cyclization of N-arylacrylamides provides a straightforward pathway to synthesize valuable 3-functionalized oxindoles. Traditional cyclization reactions normally require harsh conditions or transition-metal catalysts. Here, we developed a metal-free, diversity-oriented synthesis of 3-functionalized oxindoles via photochemically induced selective cleavage of C(sp3)-H bonds. A variety of 3-substituted oxindoles with functionalities such as ethers, polyhalogens, benzyl, and formyl groups can be obtained by a rational design. This strategy is characterized by its simple operation and mild conditions, aligning well with the developmental requirements for sustainable chemistry. The gram-scale continuous-flow synthesis and efficient construction of bioactive molecules highlight its practical utility.

Visible‐light Catalysed Trifluoromethylthiolation and Related Dearomative Spirocyclizations

AbstractWe conceptualized a radical cyclization approach for the synthesis of SCF3, SAr, SO2Ar and COAr featured spirocyclic [4.5] and [5.5] trienone between biaryls and ArSO2H or ArCOCO2H in presence of RFTA as a photocatalyst whereas the insertion of ArSSAr or AgSCF3 devoid of photocatalyst via an energetically demanding dearomative transformation under visible‐light catalysis. The photo‐excited charge transfer complex with biaryl tethered ynones provides a way to promote S‐centered radical generation followed by its insertion to enable a wide range of biologically important molecules.

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters.

Due to their ease of preparation, stability, and diverse reactivity, N-hydroxyphthalimide (NHPI) esters have found many applications as radical precursors. Mechanistically, NHPI esters undergo a reductive decarboxylative fragmentation to provide a substrate radical capable of engaging in diverse transformations. Their reduction via single-electron transfer (SET) can occur under thermal, photochemical, or electrochemical conditions and can be influenced by a number of factors, including the nature of the electron donor, the use of Brønsted and Lewis acids, and the possibility of forming charge-transfer complexes. Such versatility creates many opportunities to influence the reaction conditions, providing a number of parameters with which to control reactivity. In this perspective, we provide an overview of the different mechanisms for radical reactions involving NHPI esters, with an emphasis on recent applications in radical additions, cyclizations and decarboxylative cross-coupling reactions. Within these reaction classes, we discuss the utility of the NHPI esters, with an eye towards their continued development in complexity-generating transformations.

Iron-Mediated Hydrogen Atom Transfer Radical Cyclization of Alkenyl Indoles and Pyrroles Gives Their Fused Derivatives: Total Synthesis of Bruceolline E and H

Iron-Mediated Hydrogen Atom Transfer Radical Cyclization of Alkenyl Indoles and Pyrroles Gives Their Fused Derivatives: Total Synthesis of Bruceolline E and H

Tethering Three Radical Cascades for Controlled Termination of Radical Alkyne peri-Annulations: Making Phenalenyl Ketones without Oxidants.

Although Bu3Sn-mediated radical alkyne peri-annulations allow access to phenalenyl ring systems, the oxidative termination of these cascades provides only a limited selection of the possible isomeric phenalenone products with product selectivity controlled by the intrinsic properties of the new cyclic systems. In this work, we report an oxidant-free termination strategy that can overcome this limitation and enable selective access to the full set of isomerically functionalized phenalenones. The key to preferential termination is the preinstallation of a "weak link" that undergoes C-O fragmentation in the final cascade step. Breaking a C-O bond is assisted by entropy, gain of conjugation in the product, and release of stabilized radical fragments. This strategy is expanded to radical exo-dig cyclization cascades of oligoalkynes, which provide access to isomeric π-extended phenalenones. Conveniently, these cascades introduce functionalities (i.e., Bu3Sn and iodide moieties) amenable to further cross-coupling reactions. Consequently, a variety of polyaromatic diones, which could serve as phenalenyl-based open-shell precursors, can be synthesized.