Radical-polar crossover (RPC) chemistry is an emerging field characterized by transformations that involve the coexistence of both radical and ionic species. Since the reactivities of radical and ionic intermediates are orthogonal, applying these two mechanisms in sequence provides significant advantages in the construction of complex molecular architectures. The concept of the RPC approach has become increasingly important in the total synthesis of natural products. This Synopsis presents several examples to showcase recent advancements in this area, including our research on the synthesis of Ganoderma meroterpenoids. In these selected cases, RPC reactions enhance the building of structural complexity and improve overall synthetic efficiency that cannot be achieved by standard synthetic methods.

Point mutations and single base mutations are the dominant mutations found in the KRAS gene. Systematic knockout of the KRAS gene with these point mutations is still challenging. In this study, we developed novel photo-cross-linking oligonucleotides (^pU₁–ODN and ^pU₂–ODN) that had a diazirine group at the 5-position of the uridine derivatives. Photo-cross-linking studies of the oligonucleotides with wild-type and mutated RNAs revealed that ^pU₂–ODN efficiently and selectively reacts with the mutated RNAs that contain a cytidine, guanosine, or uridine residue at the frontal position of the ^pU₂ nucleoside. These results suggest that ^pU₂–ODN is a promising candidate for use as a photo-cross-linking ODN to selectively inhibit the activity of mRNAs with a point mutation.

A highly efficient 6-endo-trig radical cyclization reaction between cyclobutanone oximes and 1-isocyano-2-vinylbenzenes via visible light-induced photoredox catalysis has been realized in the presence of 2 mol % of fac-Ir(ppy)₃ as the photocatalyst, which gave rise to a variety of 2-(3-cyanoalkyl)substituted quinoline derivatives with moderate to excellent yields under mild reaction conditions.

An efficient method for the synthesis of the polycyclic molecules via cobalt-catalyzed [2 + 2 + 2] followed by [4 + 2] consecutive cycloaddition reaction strategy has been devised. Sequential cycloaddition reactions of substituted 1,6-diynes with maleimides have been performed. This tandem cycloaddition approach has yielded polyheterocyclic compounds exhibiting remarkable diastereoselectivity and achieving yields ranging from good to excellent. Additionally, a potential reaction mechanism has been proposed to explain the observed cycloaddition process.

The chemoenzymatic dynamic kinetic resolution of 2-(quinolin-8-yl)benzylalcohols using a combination of lipases and ruthenium catalysts is described. While CalB lipase performs highly selective enzymatic kinetic resolution, the combination with Shvo′s or Bäckvall’s catalysts promotes atropisomerization of the substrate via the reversible formation of configurationally labile aldehydes, thereby enabling a dynamic kinetic resolution. This synergistic approach was applied to the synthesis of a variety of heterobiaryl acetates in excellent yields and enantioselectivities.

Two unusual alkaloids with furanopyrrolidine skeleton, harzianopyrrolidones A–B (1–2), four new compounds, harzianopyridone B (3), harzianopyrone (4), (R)-1-(3,5-dihydroxy-4-methylphenyl)-1-hydroxyhept-5E-en-2-one (5), and harzianopyrrolidone C (6), together with two known compounds (7–8) were isolated from a marine-derived fungus Trichoderma harzianum ZN-4. Structures of the isolated compounds were elucidated based on their HRESIMS data, extensive NMR spectroscopic analyses, NMR calculation in combination with DP4+, ECD calculations, and a single-crystal X-ray diffraction experiment. New compounds 1, 4, and 5 exhibited potential cardiomyocyte protective activity at concentrations ranging from 5 to 20 μM. In addition, 7 showed moderate inhibitory activity against Pestalotiopsis theae with an MIC value of 25 μg/mL.

A divergent [5 + 1] cyclization reaction of o-aminobenzamides with vinylene carbonate has been developed, rapidly generating three types of cyclic molecules including quinazolinones, 2-methylquinazolinones, and 2,3-dihydroquinazolinones with high chemoselectivity. In this discovery, vinylene carbonate blooms as a multifunctional reagent to participate in cyclization. The potential of this new finding is further emphasized by assembling the benzothiazole heteroarene via the [4 + 1] version and tolerating bioactive units well.

A novel green methodology for the Oxone-mediated oxidative addition of alkenes via intramolecular acyl migration has been developed. This transformation utilizes N-acyl-N-sulfonyl allylamines and diselenides as starting materials, with Oxone serving as the oxidant and water as a partial oxygen source. The protocol enables the synthesis of a series of β-acyloxy-γ-selenyl sulfonamides with high to excellent yields and demonstrates broad substrate scope. Notably, the excellent yield was maintained in gram-scale experiments, highlighting the scalability of this method. Through comprehensive control experiments, we have elucidated the reaction mechanism, which involves rapid radical generation, a predominant cationic pathway, and intramolecular acyl migration. This study presents an efficient and environmentally benign approach to the synthesis of valuable β-acyloxy-γ-selenyl sulfonamides.

Deuterated aryl amines are increasingly sought after in pharmaceuticals, particularly in the development of deuterated drugs. Traditional methods for their synthesis often involve harsh conditions or preprepared reagents. This study introduces a mild, metal-free method for the selective deuteration of aryl amines, utilizing deuterium oxide (D₂O) and a commercially available catalyst, tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (NaBAr^F₄). The reaction is performed under moderate conditions and is compatible with a wide range of substrates, including sensitive functional groups. Mechanistic studies highlight the crucial role of noncoordinated Na⁺ in catalysis, underscoring the broader potential of NaBAr^F₄ and weakly coordinating anions (WCAs) in synthetic chemistry. This method offers an efficient and sustainable approach to synthesizing deuterated aryl amines.

An unprecedented approach involving radical-mediated sulfonylation/dearomative ipso-annulation of N-(methyl-2-phenylacetate)propiolamides using arylsulfonyl radical, generated from aryl diazonium salt in the presence of DABSO, is developed. This strategy provides uniquely substituted 3-sulfonyl azaspiro[4.5]decatrienones in good yields. The developed approach has also been extended fruitfully to 3-thiocyano aza-spirocycles through domino thiocyanation/dearomative ipso-annulation.

A general and efficient approach to the synthesis of various indole-fused δ-sultones has been developed via DBU-mediated [3+3] cyclizations of indolin-3/2-ones and β-(hetero)arylethenesulfonyl fluorides. Notably, the reaction shows a broad substrate scope, and over 70 examples were exhibited in up to 99% isolated yield. In addition, some of the synthesized compounds showed significant antitumor activity against HepG2 and Caco-2 cells in vitro, which might provide promising insights for the future discovery and rational design of novel antitumor agents.

Kinetic and product studies on the reactions of the cumyloxyl (CumO^•) and tert-butoxyl (tBuO^•) radicals with secondary and tertiary N-methyl and N-benzyl lactams and with cycloalkenes, accompanied by BDE calculations of the substrate C–H bonds involved in these reactions, are reported. Within the lactams, the rate constants for HAT (k_H) from the C–H bonds to CumO^• decrease by a factor ∼4 going from the 5- and 6-membered derivatives to the 8-membered ones. Product distributions obtained through oxygenation initiated by tBuO^• show that HAT preferentially occurs from the most electron-rich α-C–H bonds, with site selectivity that, within the N-methyl and N-benzyl series, progressively shifts from the endocyclic to the exocyclic α-C–H bonds with increasing ring size, indicative of deactivation of the former bonds that, for the 8-membered derivatives, translates into competitive oxygenation at different sites. Similar trends have been observed for the corresponding reactions of the cycloalkenes, with k_H values that decrease by a factor of ∼4 together with site selectivity for HAT from the activated allylic C–H bonds, going from cyclopentene to cyclooctene. It is proposed that the greater flexibility of the medium-sized rings decreases the extent of hyperconjugative overlap between the α-C–H bonds and the amide or C═C π-systems, increasing the kinetic barrier for HAT from these sites, with decreases in reactivity that approach factors of 83 and 18, for the endocyclic α-C–H bonds of tertiary N-methyl lactams and the allylic C–H bonds of cycloalkenes, respectively.

Deuterated silanes are crucial reagents for deuteration, with a diverse range of applications in materials science, pharmaceuticals, and isotopic labeling. While most methods for synthesizing deuterated silanes rely on stoichiometric environmentally harmful processes or noble metal catalysts, research into more sustainable alternatives has received relatively less attention. In this study, we introduce a catalyst based on a nickel PBP-pincer system (PBP = bis(phosphino)boryl), which effectively facilitates catalytic hydrogen/deuterium exchange for primary, secondary, and tertiary silanes, as well as tertiary siloxanes and certain boranes, utilizing a catalyst loading of 2 mol % at 25 °C. DFT calculations identify two reaction pathways that require overcoming similar energy barriers for the H/D exchange step: silane activation assisted by the PBP ligand (ΔG^⧧ = 24.1 kcal mol^–1) and H/D exchange promoted by nucleophilic Ni-hydride (ΔG^⧧ = 22.4 kcal mol^–1). These results suggest that both pathways are feasible, with a slight energetic preference for the latter. We also present detailed mechanistic studies, including control experiments, an analysis of catalyst deactivation pathways, and kinetic studies that are in excellent agreement with the outcome of the theoretical calculations.

The detailed mechanism of propylene carbonate (PC) formation from propylene oxide (PO) and CO₂ is investigated using density functional theory (DFT) methods, catalyzed by amine/MeOH binary systems, in propylene oxide under conditions of room temperature and 1 atm. In these systems, amines (MeNH₂, Me₂NH, Me₃N, and pyrrolidine) serve as nucleophiles, while MeOH acts as a hydrogen bond donor (HBD). The catalyzed reaction pathways for PC formation consistently proceed through two transition states, ts1 and ts2, corresponding to the oxide ring-opening and final ring-closing steps, respectively. The ring-closing step was identified as the rate-determining step in all amine/MeOH binary systems. Notably, the three aliphatic amine/MeOH binary systems significantly lower activation barriers for PC formation by approximately 20 kcal mol^–1 compared to the uncatalyzed ring-closing pathway under standard conditions. The Me₂NH/MeOH binary system demonstrates slightly higher catalytic efficiency than the MeNH₂ and Me₃N systems. Furthermore, the pyrrolidine/MeOH binary system exhibits comparable catalytic performance to the Me₂NH/MeOH system. Since pyrrolidine is liquid under standard conditions, it can act as a homogeneous catalyst when paired with MeOH, enhancing mixing with PO and improving catalytic activity relative to gaseous Me₂NH.

Herein, we report an efficient, organophotocatalyzed decarboxylative (amino)alkylation of azomethine imines using readily available carboxylic acids as alkylating agents. This transformation exhibits wide scope, and a variety of carboxylic acids, including glycine derivatives, were employed as radical precursors. The use of 4CzIPN as the photocatalyst allowed the application of nonbenzylic secondary and tertiary carboxylic acids also, overcoming previous limitations. The wide scope, applicability of nonprefunctionalized precursors, and mild conditions are the highlights of this method. The intermediacy of key radical intermediates was established by radical trapping experiments.

Perfluoroalkyl alkenyl iodides (PFAIs) are emerging as highly reactive, storage-stable, and multifunctional fluoroalkyl-bearing reagents, facilitating the manufacture of value-added organofluorides through multi-halo-functionalization. Herein, we developed a water-involved 1,3-aminoxylation of PFAIs with sulfonamides for the chemo-, regio-, and Z-stereoselective synthesis of valuable β-fluoroacyl vinylamines. This reaction proceeded via a sequential deiodoamination and defluoroxylation process under transition-metal-free conditions, featuring a broad substrate scope and good functional group tolerance. Compared to reported methods, some drawbacks, such as multistep manipulation, harsh reaction conditions, the need for expensive catalysts, and the use of toxic/sensitive reagents, could be eliminated. Furthermore, the synthetic potential of this method was demonstrated through scale-up synthesis, postfunctionalization of complex molecules, and ready transformation of the products.

The effective assembly of benzazepine skeletons in a sustainable and atom-economical fashion remains a challenging goal in modern organic synthesis. Presented herein is a novel synthesis of indazole fused 2-benzazepine derivatives based on a formal [4 + 3] annulation of 3-aryl-1H-indazoles with cyclopropenones. The formation of products proceeds through Ir(III)-catalyzed aryl C–H bond metalation and cyclopropenone ring-opening leading to aryl acylation, followed by an intramolecular N-nucleophilic conjugated addition. By using this method, a number of valuable benzazepine derivatives were effectively generated. This protocol addresses the challenges in constructing medium-sized rings through cascade C–H/C–C bond activation and C–C/C–N bond formation. Moreover, the photophysical properties of the products thus obtained were also evaluated. It turned out that all compounds tested showed solvent polarity-dependent fluorescence features, which could be potentially applied for revealing the polarity of their immediate environments.

Carbohydrates constitute an important class of biologically relevant natural products. Among the synthetic glycomimetics, C-glycosides are particularly interesting due to their chemical and metabolic stability toward acidic and enzymatic hydrolysis at the anomeric position. The stereochemical outcomes of traditional methodologies to access C-glycosides rely heavily on substrate control. Herein, we report a novel synthetic strategy to access diverse C-glycosides with precise stereochemical control at the anomeric position via formal functional group deletion, where both α- and β-anomers of furanoses and pyranoses can be obtained as single stereoisomers. Additionally, the broad scope of heterocyclic C-glycosides obtained via this strategy further illustrates its potential for empowering future application in both chemical biology research and drug discovery.

Phochrodines A, B, and C have been synthesized using a CH-activation protocol and palladium-catalyzed carbonylation. To avoid issues of regioselectivity, the inherent symmetry of a common intermediate was exploited.

Enamides and enecarbamates offer an excellent balance between stability and reactivity. Decarboxylation of widely available amino acids offers a green and efficient alternative to accessing these reagents. The present study describes a photocatalytic approach for the direct decarboxylative synthesis of enamides via sequential radical decarboxylation and putative halogen-atom transfer (XAT). This operationally simple, economical protocol is scalable and allows for mild reaction conditions and short reaction times. In addition, it obviates the need for transition metals and preactivation of carboxylic acids.

Unprecedented CO–Cα bond cleavage of 1,3-dicarbonyls and enaminone, catalyzed by a well-defined Ru(III)-complex (1) featuring a redox-active triamine ligand (L¹) with a free –NH₂ arm, opening a new route to accessing substituted pyrroles with broad substrate scope and functional group tolerance in good isolated yields via multicomponent coupling of 1,3-dicarbonyls, amines, and diol, is reported. The hydrogen bonding interaction offered by 1 facilitates the formation of critical reaction intermediates, favoring the formation of pyrroles.

An electrochemical approach with iodoarene as a mediator using recyclable ionic liquids to achieve dibromonative cyclization of 1,n-enynes has been reported. With recyclable bromine sources, in situ generation of iodine(III) compounds through electrochemical oxidation to achieve cyclization, a variety of heterocyclic frameworks containing both vinyl and alkyl bromide groups had been obtained in high yields with good selectivity.

An enantioselective synthesis of 2-aryl 3,3-disubstituted 3H-indoles has been successfully developed via a deracemization process involving borane-catalyzed hydrogenation and chiral phosphoric-acid-catalyzed asymmetric transfer hydrogenation. A variety of 3H-indoles were effective substrates to afford the desired indolines in 86–95% yields with 45–92% ee’s.