Intramolecular Radical Cyclization Research Articles

Collective Synthesis of Furanocoumarin Natural Products Through a Radical‐mediated Construction of Furanocoumarin Skeletons

AbstractFuranocoumarins are attractive targets in the synthetic organic and medicinal chemistry field because of their structural diversity and interesting biological properties. Herein, we describe the synthesis of furanocoumarin natural products from common furanocoumarin skeletons. A key step was a novel intramolecular radical cyclization onto nitrile to synthesize angular and linear franocoumarins, which was optimized by reacting iodocoumarin derivatives in the presence of (Me3Si)3SiH and oxygen. These compounds served as intermediates in the syntheses of vaginidiol, vaginidin, oroselol, multivittan D, gaudichaudine, oreoselone, peucedanin, and smyrindiol, successfully demonstrating the versatility of the intermediates and utility of the radical cyclization method for accessing furanocoumarin natural products.

Divergent syntheses of complex Veratrum alkaloids

The Veratrum alkaloids are a class of highly intricate natural products renowned for their complex structural and stereochemical characteristics, which underlie a diverse array of pharmacological activities ranging from anti-hypertensive properties to antimicrobial effects. These properties have generated substantial interest among both synthetic chemists and biologists. While numerous advancements have been made in the synthesis of jervanine and veratramine subtypes over the past 50 years, the total synthesis of highly oxidized cevanine subtypes has remained relatively scarce. Building on the efficiency of our previously developed strategy for constructing the hexacyclic carbon skeleton of the Veratrum alkaloid family via a stereoselective intramolecular Diels-Alder reaction and radical cyclization, here we show the development of a unified synthetic approach to access highly oxidized Veratrum alkaloids. This includes the total synthesis of (–)-zygadenine, (–)-germine, (–)-protoverine and the alkamine of veramadine A, by capitalizing on a meticulously designed sequence of redox manipulations and a late-stage neighboring-group participation strategy.

Fe-Catalyzed Fluorosulfonylation of Alkenes via Sulfur Dioxide Insertion: Synthesis of Lactam-Functionalized Alkyl Sulfonyl Fluorides.

A novel Fe-catalyzed fluorosulfonylation of alkenes with Na2S2O4 and N-fluorobenzenesulfonimide (NFSI) for assembling various lactam-functionalized alkyl sulfonyl fluorides is disclosed. In this reaction, Na2S2O4 acts as both an SO2 source and a reductant. Furthermore, the resulting products can be efficiently transformed into valuable chemicals, including sulfonyl esters and sulfonamides, via the sulfur(VI) fluoride exchange (SuFEx) click reaction. Preliminary mechanistic studies suggest that the transformation proceeds through intramolecular radical cyclization, SO2 insertion, sulfite anion formation, and fluorination.

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.

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

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.

Photocatalytic Boryl Radicals Triggered Sequential B─N/C─N Bond Formation to Assemble Boron-Handled Pyrazoles.

Vinyldiazo compounds are one of the most important synthons in the construction of a cyclic ring. Most photochemical transformations of vinyldiazo compounds are mainly focusing on utilization of their C═C bond site, while reactions taking place at terminal nitrogen atom are largely unexplored. Herein, a photocatalytic cascade radical cyclization of LBRs with vinyldiazo reagents through sequential B─N/C─N bond formation is described. The reaction starts with the addition of LBRs (Lewis base-boryl radicals) at diazo site, followed by intramolecular radical cyclization to access a wide range of important boron-handled pyrazoles in good to excellent yields. Control experiments, together with detailed mechanism studies well explain the observed reactivity. Further studies demonstrate the utility of this approach for applications in pharmaceutical and agrochemical research.

Photochemically Induced Hydrogen Atom Transfer and Intramolecular Radical Cyclization Reactions with Oxazolones.

Photochemically induced intramolecular hydrogen atom transfer in oxazolones is reported. An acetal or thioacetal function at the side chain acts as a hydrogen donor while the photochemical exited oxazolone is the acceptor. A one-step process─the electron and the proton are simultaneously transferred─is productive, while electron transfer followed by proton transfer is inefficient. Radical combination then takes place, leading to the formation of a C-C or C-N bond. The regioselectivity of the reaction is explained by the diradical/zwitterion dichotomy of radical intermediates at the singlet state. In the present case, the zwitterion structure plays a central role, and intramolecular electron transfer favors spin-orbit coupling and thus the intersystem crossing to the singlet state. The reaction of corresponding thioacetal derivatives is less efficient. In this case, photochemical electron transfer is competitive. The photoproducts resulting from C-C bond formation easily undergo stepwise thermal decarboxylation in which zwitterionic and polar transition states are involved. A computational study of this step has also been performed.

Non-native Intramolecular Radical Cyclization Catalyzed by a B12 -Dependent Enzyme.

Despite the unique reactivity of vitamin B12 and its derivatives, B12 -dependent enzymes remain underutilized in biocatalysis. In this study, we repurposed the B12 -dependent transcription factor CarH to enable non-native radical cyclization reactions. An engineered variant of this enzyme, CarH*, catalyzes the formation γ- and δ-lactams through either redox-neutral or reductive ring closure with marked enhancement of reactivity and selectivity relative to the free B12 cofactor. CarH* also catalyzes an unusual spirocyclization by dearomatization of pendant arenes to produce bicyclic 1,3-diene products instead of 1,4-dienes provided by existing methods. These results and associated mechanistic studies highlight the importance of protein scaffolds for controlling the reactivity of B12 and expanding the synthetic utility of B12 -dependent enzymes.

NHC-Catalyzed Regioselective Intramolecular Radical Cyclization Reaction for the Synthesis of Benzazepine Derivatives.

A novel and efficient strategy for the synthesis of a series of structurally interesting benzazepine derivatives via an N-heterocyclic carbene-catalyzed regioselective intramolecular radical cyclization has been developed. This protocol features good regioselectivity, good functional-group compatibility, and wide substrate scope, providing a transition-metal- and oxidant-free pathway to access the seven-membered rings under mild reaction conditions. Additionally, further transformation of benzazepines and a large-scale experiment were also conducted.

Total Synthesis of Sculponin U through a Photoinduced Radical Cascade Cyclization.

We have accomplished the total synthesis of sculponin U, a polycyclic C-20-oxygenated kaurane diterpenoid featuring a 7,20-lactone-hemiketal bridge, through a radical cascade cyclization triggered by photoinduced electron transfer (PET) of a silyl enolate to form the cyclohexanone-fused bicyclo[3.2.1]octane skeleton. Other key points in our synthetic strategy encompass a Diels-Alder reaction to construct the middle six-membered ring of sculponin U, and an intramolecular radical cyclization induced by iron-catalyzed hydrogen atom transfer to close the western cyclohexane ring. Successful preparation of the enantiopure silyl enolate as the PET precursor enables the asymmetric total synthesis of sculponin U, opening a new avenue for divergent syntheses of structurally related C-20-oxygenated kaurane congeners and pharmaceutical derivatives thereof.

Total Synthesis of Sculponin U through a Photoinduced Radical Cascade Cyclization

AbstractWe have accomplished the total synthesis of sculponin U, a polycyclic C‐20‐oxygenated kaurane diterpenoid featuring a 7,20‐lactone‐hemiketal bridge, through a radical cascade cyclization triggered by photoinduced electron transfer (PET) of a silyl enolate to form the cyclohexanone‐fused bicyclo[3.2.1]octane skeleton. Other key points in our synthetic strategy encompass a Diels–Alder reaction to construct the middle six‐membered ring of sculponin U, and an intramolecular radical cyclization induced by iron‐catalyzed hydrogen atom transfer to close the western cyclohexane ring. Successful preparation of the enantiopure silyl enolate as the PET precursor enables the asymmetric total synthesis of sculponin U, opening a new avenue for divergent syntheses of structurally related C‐20‐oxygenated kaurane congeners and pharmaceutical derivatives thereof.

Three‐Component Synthesis of 3‐(Arylsulfonyl)benzothiophenes Using Acetic Acid as a Quencher for Methyl Radical‐Mediated Side Reactions

AbstractA one‐pot, three‐component synthesis of 3‐(arylsulfonyl)benzothiophenes was developed. The reaction did not require any catalysts or additives. The desired products were obtained via an intramolecular radical cyclization. Acetic acid was employed as the solvent and a quencher for side reactions involving methyl radicals. Moreover, inexpensive potassium metabisulfite was used as a sulfur dioxide surrogate. This process provides more opportunities for synthesizing benzothiophene derivatives, which are found in many bioactive compounds.magnified image

Catalyst-free intramolecular radical cyclization cascades initiated by the direct homolysis of Csp3–Br under visible light

A visible light-mediated Csp3–Br homolysis-initiated radical cyclization cascade delivering diverse 3-difluorolactam substituted chroman-4-ones with excellent regioselectivity and diastereoselectivity.

Concise Total Synthesis of Salimabromide.

We achieved a concise total synthesis of salimabromide by using a novel intramolecular radical cyclization to simultaneously construct the unique benzo-fused [4.3.1] carbon skeleton and the vicinal quaternary stereocenters. Other notable transformations include a tandem Michael/Mukaiyama aldol reaction to introduce most of the molecule's structural elements, along with hidden information for late-stage transformations, an intriguing tandem oxidative cyclization of a diene to form the bridged butyrolactone and enone moieties spontaneously, and a highly enantioselective hydrogenation of a cycloheptenone derivative (97% ee) that paved the way for the asymmetric synthesis of salimabromide.

Total Synthesis of Rameswaralide Utilizing a Pharmacophore-Directed Retrosynthetic Strategy.

A pharmacophore-directed retrosynthetic strategy was applied to the first total synthesis of the cembranoid rameswaralide in order to simultaneously achieve a total synthesis while also developing a structure-activity relationship profile throughout the synthetic effort. The synthesis utilized a Diels-Alder lactonization process, including a rare kinetic resolution to demonstrate the potential of this strategy for an enantioselective synthesis providing both the 5,5,6- and, through a ring expansion, 5,5,7-tricyclic ring systems present in several Sinularia soft coral cembranoids. A pivotal synthetic intermediate, a tricyclic epoxy α-bromo cycloheptenone, displayed high cytotoxicity with interesting selectivity toward the HCT-116 colon cancer cell line. This intermediate enabled the pursuit of three unique D-ring annulation strategies including a photocatalyzed intramolecular Giese-type radical cyclization and a diastereoselective, intramolecular enamine-mediated Michael addition, with the latter annulation constructing the final D-ring to deliver rameswaralide. The serendipitous discovery of an oxidation state transposition of the tricyclic epoxy cycloheptenone proceeding through a presumed doubly vinylogous, E1-type elimination enabled the facile introduction of the required α-methylene butyrolactone. Preliminary biological tests of rameswaralide and precursors demonstrated weak cytotoxicity; however, the comparable cytotoxicity of a simple 6,7-bicyclic β-keto ester, corresponding to the CD-ring system of rameswaralide, to that of the natural product itself suggests that such bicyclic β-ketoesters may constitute an interesting pharmacophore that warrants further exploration.

Synthesis of 3‐Amino‐1‐(difluoromethylidene)tetralins via Relay Photocatalytic Cascade Reactions of Arylalanines and 2‐Bromo‐3,3,3‐trifluoropropene

AbstractA relay photocatalytic cascade reaction for the synthesis of 3‐amino‐1‐(difluoromethylidene)tetralins was described. The reaction used readily available N‐Boc protected arylalanines and bulk industrial chemical 2‐bromo‐3,3,3‐trifluoropropene (BTP) as the starting materials combining two photoredox catalytic cycles with a single photocatalyst. In the first catalytic cycle, the defluorinative coupling of N‐Boc arylalanines with BTP provided 2‐bromo‐1,1‐difluoroalkenes. In the second catalytic cycle, 2‐bromo‐1,1‐difluoroalkenes underwent intramolecular radical cyclization by photoredox activation of C(sp2)−Br bond, affording the desired 3‐amino‐tetralins bearing an exo‐difluoroethylene unit in good yields. Moreover, the reactions of 3‐aryl propanoic acids and BTP for the construction of 1‐(difluoromethylidene)tetralins were also demonstrated.magnified image

(Arylethyl)amine Synthesis through Intramolecular Radical Cyclization of Sulfonamides and Alkenes

(Arylethyl)amine Synthesis through Intramolecular Radical Cyclization of Sulfonamides and Alkenes

Catalyst‐Free, One‐Pot, Three‐Component Synthesis of 3‐Arylsulfonylated Thioflavones

AbstractA one‐pot, three‐component synthesis of 3‐arylsulfonylated thioflavones has been developed. The reactions were carried out without using any catalysts or additives. The desired products were obtained through intramolecular radical cyclization. This process provides an alternative route for the synthesis of thioflavone derivatives, which have been found in various bioactive compounds.magnified image

Iron‐Catalyzed Reductive Cyclization of Alkenyl Vinylogous Carbonates for Stereoselective Synthesis of Substituted Tetrahydrofurans, Tetrahydropyrans, and Chromans

AbstractA method for the stereoselective synthesis of substituted tetrahydrofurans (THFs), tetrahydropyrans (THPs), as well as chromans using intermolecular hydrogen atom transfer (HAT) followed by intramolecular radical cyclization of alkenyl vinylogous carbonates is described. This Fe(acac)3‐catalyzed reaction uses PhSiH3 as H‐source and works under ambient conditions in HFIP/ethylene glycol (5:1 mixture) as solvent. The methodology developed has broad substrate scope and is amenable to gram‐scale synthesis. The method gives ready access to even hexa‐substituted cyclic ethers containing two quaternary carbons. This strategy is used in the construction of oxaspirocyclic systems. Diastereoselective synthesis of fused bicyclic as well as tricyclic motifs could be achieved. The stereochemistry of the products was assigned using NOE experiments and was further confirmed by single‐crystal X‐ray diffraction studies on two derivatives.magnified image