Cyclic (Alkyl)(Amino)Carbene-Iminoboryl Compounds with Three Formal Oxidation States.

BN/CC isosterism is an effective strategy to build hybrid functional molecules with unique properties. In contrast to the alkynyl iminium salts derived from cyclic (alkyl)(amino)carbenes (CAACs) that feature only one reversible reduction wave, the isoelectronic cationic CAAC-iminoboryl adducts could be singly and doubly reduced smoothly. Both the resultant neutral radical and anionic azaborataallenes bear NBC-mixed allenic structures. The former radical has a high spin-density of 0.55e at CCAAC carbon, yet exhibits formal boron-centered radical reactivity. The latter azaborataallenes feature the nucleophilic CCAAC center and polar N(δ-)═B(δ+)═C(δ-) unit, and readily undergo nucleophilic substitution, isocyanide insertion, dipolar addition and cycloaddition reactions etc. The N-substituents have been shown to have a significant influence on the solid-state structure, thermal stability, and reactivity of azaborataallenes. This work showcases the allenic BN-unsaturated species as versatile building blocks in organic synthesis.

Palladium-Catalyzed Regioselective B(3,5)-Dialkenylation and B(4)-Alkenylation of o-Carboranes.

Picolyl group directed B(3,5)-dialkenylation and B(4)-monoalkenylation of o-carboranes has been developed with a very low palladium catalyst loading. The degree of substitution is determined by the cage C(2)-substituents due to steric reasons. On the basis of experimental results, a plausible mechanism is proposed including electrophilic palladation and alkyne insertion followed by protonation.

Catalyst-Free Regioselective Diborylation of Aryllithium with Tetra(o-tolyl)diborane(4).

A catalyst-free 1,2-diborylation of aryllithium with tetra(o-tolyl)diborane(4) has been achieved, giving a series of 1,2-diborylaryl lithium species in excellent yields under mild reaction conditions, which leads to 1,2-di(tolyl)borylarenes in 60-91 % yields upon treatment with the hydride-abstracting reagent. In these transformations, one sp2 C-H of arene is activated and both boryl units are utilized to build two new (sp2 )C-B bonds. This represents a new strategy for selective arene diborylation. Density functional theory (DFT) calculations suggest that an aromatic nucleophilic substitution is a key step in the formation of the products.

Ir-Catalyzed B(3)-Amination of o-Carboranes with Amines via Acceptorless Dehydrogenative BH/NH Cross-Coupling.

An efficient and convenient strategy for Ir-catalyzed selective B(3)-amination of o-carboranes with amines via acceptorless BH/NH dehydrocoupling was developed, affording a series of B(3)-aminated-o-carboranes in moderate to high isolated yields with H2 gas as a sole by-product. Such an oxidant-free system endues the protocol sustainability, atom-economy and environmental friendliness. A reaction mechanism via an Ir(I)-Ir(III)-Ir(I) catalytic cycle involving oxidative addition, dehydrogenation and reductive elimination was proposed.

Reaction of 4-Bpin-o-Carborane with Ketones: Sequential Carbon Vertex Alkylation and B-B Bond Activation.

Diboron compounds are important reagents in a series of transition metal catalyzed or metal-free borylation reactions. We describe herein a unique reactivity of 4-Bpin-o-carborane with ketones under basic conditions, leading to sequential cage carbon alkylation, B-B bond activation and unexpected O-migration. The reaction was compatible with a good substrate scope including dialkyl or alkyl aryl ketones. The reaction mechanism is also proposed, involving cage CH deprotonation, nucleophilic attack of ketone, and O-migration along with B-B bond cleavage.

A novel biosensor based on tetrahedral DNA nanostructure and terminal deoxynucleotidyl transferase-assisted amplification strategy for fluorescence analysis of uracil-DNA glycosylase activity.

Tetrahedral DNA nanostructure (TDN), as a classical bionanomaterial, which not only has excellent structural stability and rigidity, but also possesses high programmability due to strict base-pairs complementation, is widely used in various biosensing and bioanalysis fields. In this study, we first constructed a novel biosensor based on Uracil DNA glycosylase (UDG) -triggered collapse of TDN and terminal deoxynucleotidyl transferase (TDT)-induced insertion of copper nanoparticles (CuNPs) for fluorescence and visual analysis of UDG activity. In the presence of the target enzyme UDG, the uracil base modified on the TDN were specifically identified and removed to produce an abasic site (AP site). Endonuclease IV (Endo.IV) could cleave the AP site, making the TDN collapse and generating 3'-hydroxy (3'-OH), which were then elongated under the assistance of TDT to produce poly (T) sequences. Finally, Copper (II) sulfate (Cu2+) and l-Ascorbic acid (AA) were added to form CuNPs using poly (T) sequences as templates (T-CuNPs), resulting in a strong fluorescence signal. This method exhibited good selectivity and high sensitivity with a detection limit of 8.6 × 10-5 U/mL. Moreover, the strategy has been successfully applied to the screening of UDG inhibitors and the detection of UDG activity in complex cell lysates, which means that it has promising applications in clinical diagnosis and biomedical research.

Iridium-catalyzed regioselective B(3,6)-dialkenylation or B(4)-alkenylation of o-carboranes via B-H activation and 1,2-carbon migration of alkynes.

An efficient Ir-catalyzed cage boron alkenylation of 1-(2'-picolyl)-o-carboranes with diarylacetylenes has been developed, leading to a wide variety of B-H geminal addition products via 1,2-carbon migration of alkynes. The steric effect of cage carbon substituents has a great impact on the regioselectivity of such alkenylation reactions.

Double-wing switch nanodevice-mediated primer exchange reaction for the activity analysis of cancer biomarker FEN1.

DNA damage repair is one of the foremost factors leading to changes in tumor drug resistance. The analysis of Flap endonuclease 1 (FEN1), a kind of pivotal enzyme in various DNA metabolic pathways, has been of great support to tumor research and the development of chemotherapeutics. Nevertheless, few analytical techniques can achieve quantitative and simplified FEN1 measurement. Here, we constructed a double-wing switch nanodevice (DWSN)-mediated primer exchange technique for rapid and label-free quantification of FEN1 activity. Target FEN1 triggered the generation of numerous telomeric repeat fragments in different lengths through recognizing the three-base mismatched sites on the DWSN to release the 5'-Flaps. Further binding to the fluorescent dye ThT resulted in significantly enhanced fluorescence. This study broke the limitation of traditional single-site identification and demonstrated good sensitivity and specificity with detection limits up to 0.55 mU. Besides, the extraordinary analytical performance allowed the method to be utilized to monitor FEN1 extracted from cells and clinical serum samples and to compare the effect of targeted FEN1 inhibitors.

Visible-Light-Induced Palladium-Catalyzed Cross-Coupling of Iodocarboranes with (Hetero)Arenes.

This work describes a general method for the efficient production of a class of cage B-centered carboranyl radicals at the B3, B4, and B9 sites via a visible-light-promoted palladium(0)/palladium(I) pathway using readily available iodo-o-carboranes as the starting materials. The electrophilicities of these hypervalent boron-centered radicals decrease in the following order: B3 > B4 > B9. They are useful intermediates for the preparation of a family of cage B-(hetero)arylated o-carboranes at ambient temperature.

Iridium-Catalyzed Selective B(4)-H Amination of o-Carboranes with Anthranils.

We report here a catalytic selective cage B4-H amination of o-carboranes employing an Ir(III) complex as a catalyst and anthranils as aminating agents, leading to a large class of B4-aminated o-carboranes with very high yields and a broad substrate scope under mild conditions without any oxidants. In these reactions, the carboxyl group serves as a traceless directing unit to determine the site selectivity and degree of substitution.

Transition metal catalyzed selective B(3)-H or B(4)-H amination of o-carboranes via dehydrogenative BH/NH cross-coupling.

A unique approach to vertex-selective catalytic B-H amination at either the B(3)- or B(4)-position in o-carboranes has been developed. Using different transition metal catalysts, dehydrogenative BH/NH cross-coupling of o-carboranes and free amines has been achieved, leading to a wide variety of cage B(3)- or B(4)-aminated o-carboranes in moderate to high yields with excellent regioselectivity, where carboranyl carboxylic acids and amines can serve as competent coupling partners without any pre-functionalization. The isolation and structural identification of a key intermediate provide an insight into the reaction mechanism in the catalytic B(4)-H amination.

The fluorescence amplification strategy based on 3D DNA walker and CRISPR/Cas12a for the rapid detection of BRAF V600E.

Circulating tumor DNA (ctDNA) is a fragment of single- or double-stranded DNA originating from tumor or circulating tumor cells and provides accurate information regarding the molecular characteristics of tumors. Therefore, sensitive detection of ctDNA is of great significance to mutation analysis and clinical diagnosis. Among various ctDNAs, the BRAF V600E is related to aggressive behavior, disease recurrence, and disease-specific mortality in papillary thyroid carcinoma. Herein, we selected the BRAF V600E gene sequence as an in vitro biomarker, and established a fluorescence detection strategy combined 3D DNA walker with CRISPR/Cas12a. In the presence of the target ctDNA, 3D DNA walker could identify and bind it, and thus released a large amount of output DNAs through cyclic cleavage with the assistance of specific endonuclease (Nb.BbvCI). The output DNAs were specifically bound to crRNA and activated the non-specific trans-cleavage activity of Cas12a. Finally, the fluorescence signal was significantly enhanced. Notably, this method can detect the BRAF V600E in a range of 1 fM ~ 20 nM with a detection limit of 0.37 fM without DNA polymerase. Due to the powerful amplification capability of 3D DNA walker and high specificity and programmability of CRISPR/Cas12a, the entire process took only a maximum of 70 min. Furthermore, it can be potentially used for the detection of ctDNA in human serum. In summary, this method not only provides a platform for the rapid detection of ctDNA, but also shows good potential for early clinical diagnosis and biomedical research.

N-Ligand-Enabled Aromatic Nucleophilic Amination of 1,2-Diaryl-o-Carboranes with (R2 N)2 Mg for Selective Synthesis of 4-R2 N-o-Carboranes and 2-R2 N-m-Carboranes.

The nucleophilic aromatic BH substitution reaction of carboranes is uncommon, compared to the electrophilic one. This work reported a pyridine-enabled transition-metal-free regioselective nucleophilic aromatic cage B(4)-H amination of 1,2-diaryl-o-carboranes with magnesium bisamides, giving a series of B(4)-aminated o-carboranes. DFT calculations showcased a stepwise B-N formation/B-H cleavage process, in which Mg-H formation/cage closure is the rate-determining step. Unprecedentedly, in the presence of 4,4'-di-tert-butyl-2,2'-dipyridyl (dtbpy), a tandem B(4)-amination/cage isomerization reaction of o-carboranes was discovered for the facile preparation of B(2)-aminated m-carboranes. Control experiments indicated that magnesium complex, bidentate ligand (dtbpy) and reaction temperature were crucial in the cage isomerization process. This direct nucleophilic aromatic cage B-H amination reaction offers an alternative strategy for selective amination of o- and m-carboranes.

Visible-Light-Promoted Nickel-Catalyzed Cross-Coupling of Iodocarboranes with (Hetero)Arenes via Boron-Centered Carboranyl Radicals.

A general strategy for the generation of hypervalent boron-centered carboranyl radicals at the B(3), B(4), and B(9) positions has been developed for the first time via visible-light-promoted iodine atom abstraction from iodo-o-carboranes by low-valent nickel complex. These radicals react with various (hetero)arenes to afford a wide range of cage B-arylated carborane derivatives at room temperature in very good to excellent yields with a broad substrate scope. Their electrophilicities are dependent on the vertex charges of the cage and follow the order B(3) > B(4) > B(9). Both visible light and nickel catalyst are proved critical to the generation of boron-centered carboranyl radicals. The involvement of boron radicals is supported by control experiments. A reaction mechanism associated with these reactions is also proposed. This strategy offers a new protocol for the generation of boron-centered carboranyl radicals at the selected boron vertex, leading to a facile synthesis of a large class of cage boron substituted carborane molecules.

A (µ-hydrido)diborane(4) anion and its coordination chemistry with coinage metals.

A tetra(o-tolyl) (µ-hydrido)diborane(4) anion 1, an analogue of [B2H5]- species, was facilely prepared through the reaction of tetra(o-tolyl)diborane(4) with sodium hydride. Unlike common sp2-sp3 diborane species, 1 exhibited a σ-B-B bond nucleophilicity towards NHC-coordinated transition-metal (Cu, Ag, and Au) halides, resulting in the formation of η2-B-B bonded complexes 2 as confirmed by single-crystal X-ray analyses. Compared with 1, the structural data of 2 imply significant elongations of B-B bonds, following the order Au > Cu > Ag. DFT studies show that the diboron ligand interacts with the coinage metal through a three-center-two-electron B-M-B bonding mode. The fact that the B-B bond of the gold complex is much prolonged than the related Cu and Ag compounds might be ascribed to the superior electrophilicity of the gold atom.

Functionalization of o-carboranes via carboryne intermediates.

Carborynes (1,2-dehydro-o-carborane and 1,3-dehydro-o-carborane), three-dimensional analogues of benzyne, can be generated in situ from the precursors 1-X-2-Li-1,2-C2B10H10 (X = Br, I, OTs, OTf), or 1-Me3Si-2-[IPh(OAc)]-1,2-C2B10H10 or [1-Li-3-N2-1,2-C2B10H10][BF4]. They are a class of very useful synthons for the synthesis of a large variety of functionalized carborane derivatives for potential application in medicine, materials science and organometallic/coordination chemistry. The experimental data demonstrate that there is a correspondence between the reactions of carborynes and those of benzyne with alkenes, dienes, alkynes, aromatics or heteroaromatics in a pericyclic reaction fashion. On the other hand, carborynes have unique properties of their own owing to their steric/electronic features. They undergo regioselective sp2/sp3 C-H bond and N-Li bond insertion reactions, which has not been observed for benzyne. This review provides a comprehensive overview of recent advances in this interesting research field with considerable attention devoted to the reaction modes and the mechanisms involved.

A novel fluorescence amplification strategy combining cascade primer exchange reaction with CRISPR/Cas12a system for ultrasensitive detection of RNase H activity.

Ribonuclease H (RNase H), which plays a vital role in various cellular processes, is to be closely related to the emergence of many diseases. As an essential therapeutic target, it shows great prospects in the development of associated drugs. Herein, a DNA-RNA chimeric hairpin (DR HP) was designed to introduce a new signal amplification strategy based on cascade primer exchange reaction (cPER) and CRISPR/Cas12a system for sensitive and specific analysis of RNase H activity. In the presence of RNase H, the RNA fragment of DR HP was specifically degraded and the blocked primer DNA was released. The process of enzymatic hydrolysis of substrate hairpin and cyclic signal amplification was completed in a one-step method under isothermal conditions, enriching many activator strands to initiate trans-cleavage of CRISPR/Cas system, thereby restoring the fluorescence signal. Under optimized conditions, the developed strategy exhibited a good linear relationship ranging from 0.005 to 0.1U/mL and offered a detection limit of 0.00061U/mL. Moreover, this method was used for RNase H activity assay in complicated human serum and real cell lysates with good stability and repeatability, and was also demonstrated to apply for RNase H inhibitors screening and inhibitory capability assessment. Therefore, the proposed system is a promising platform not only for determination of RNase H activity, but open up new thoughts for the biological enzyme research and inhibitor screening.

Iridium-Catalyzed Selective B(4)-H Acylmethylation of o-Carboranes with Sulfoxonium Ylides.

A highly efficient Ir-catalyzed regioselective cage B(4)-H acylmethylation of o-carboranyl acids using sulfoxonium ylides as alkylating regents has been developed, leading to the preparation of a large class of B(4)-acylmethylated o-carboranes in good to excellent yields with a broad substrate scope under redox neutral conditions. The -COOH moiety serves as the traceless directing group and controls the regioselectivity and monoselectivity.

Rhodium-catalyzed sequential B(3)-, B(4)-, and B(5)-trifunctionalization of o-carboranes with three different substituents.

A rhodium-catalyzed one-pot trifunctionalization of o-carboranes with three different substituents via a carboxy group directed sequential B(5)-alkenylation, B(4)-alkyne annulation and B(3)-acyloxylation has been developed for the first time, leading to the synthesis of a new class of B(3,4,5)-trisubstituted o-carborane derivatives. Treatment of 1-COOH-2-CH3-o-C2B10H10 with ArCCAr in the presence of a [Cp*RhCl2]2 catalyst and a Cu(OPiv)2 oxidant gave 1,4-[COOC(Ar)C(Ar)]-2-Me-3-OPiv-5-[C(Ar)CH(Ar)-o-C2B10H7 in good to high yields. This protocol represents a new strategy for the catalytic selective polyfunctionalization of carboranes with different substituents.

Ir-catalyzed enantioselective B-H alkenylation for asymmetric synthesis of chiral-at-cage o­carboranes.

The asymmetric synthesis of chiral-at-cage o-carboranes, whose chirality is associated with the substitution patterns on the polyhedron, is of great interest as the icosahedral carboranes have wide applications in medicinal and materials chemistry. Herein we report an intermolecular Ir-catalyzed enantioselective B-H alkenylation for efficient and facile synthesis of chiral-at-cage o-carboranes with new skeletons under mild reaction conditions. Generally very good to excellent yields with up to 99% ee can be achieved in this Ir-catalyzed B-H alkenylation. The enantiocontrol model is proposed based on Density Functional Theory calculations in which the use of chiral phosphoramidite ligand is essential for such asymmetric o-carborane B-H alkenylation.