Selective transformation of C-H bonds represents a frontier research area in synthetic chemistry. While the high reactivity of radicals provides an alternative and efficient pathway for C-H bond functionalization, controlling their selectivity-particularly in processes such as site-selective hydrogen atom abstraction (HAA)-remains a long-standing and unresolved challenge in radical chemistry, largely due to the lack of effective regulation strategies. This review deliberately avoids a comprehensive discussion of the field's current state or landmark discoveries in C-H functionalization. Instead, by focusing on recent advances in metal-catalyzed, highly site-selective C-H bond transformations, this Perspective elucidates how metal-bound radicals enable precise hydrogen abstraction for targeted functionalization. This emerging paradigm offers innovative strategies for regulating radical behavior, potentially unlocking novel radical-mediated selective transformations-including but not limited to the precise functionalization of C-H bonds.

Asymmetric allylic C(sp(3))-H oxidation of terminal alkenes provides a streamlined process for accessing allylic alcohols and their derivatives; however, it represents a long-standing challenge in the field for several decades. Herein, we disclosed a copper-catalyzed approach for the enantioselective allylic C(sp(3))-H oxidation of terminal alkenes, facilitated by introducing a sterically bulky B(2)Im(C6F5)(6) anion. Notably, a wide range of aryl-substituted terminal alkenes were used as limiting reagents, delivering various products with excellent enantioselectivity and regioselectivity (up to 99% ee, >20:1 b/l). Mechanistically, the bulky counteranion was found to be essential for achieving excellent enantioselective control and high catalytic efficiency

A decarboxylative bromination protocol of (hetero)aryl carboxylic acids was achieved via iron photocatalysis. The photocatalytic decarboxylative functionalization of carboxylic acids was mostly limited to alkyl carboxylic acids. While several decarboxylative functionalization reactions of aryl carboxylic acids by copper photocatalysis have been disclosed in the last five years, the iron-catalyzed version is still rare. This work takes one step further to iron catalysis and uses NaBrO3 as both the oxidant and the bromine source, with simple operation and readily available raw materials. A diverse range of (hetero)aryl carboxylic acids can undergo decarboxylative bromination through the iron catalyzed photocatalytic ligand-to-metal charge-transfer (LMCT) process, providing a feasible synthetic approach for multisubstituted bromoarenes.

Asymmetric transition-metal catalysis stands as a cornerstone in the construction of molecules with stereogenic centers, profoundly impacting modern organic synthesis. Over the past decades, catalytic asymmetric synthesis has witnessed remarkable advancements, largely driven by the development of sophisticated chiral ligands. While chiral phosphorus ligands have experienced rapid growth and widespread application, chiral N-heterocyclic carbene (NHC) ligands remain underexplored, primarily due to the inherent challenges in designing and synthesizing suitable chiral frameworks. Given the unique topology and modular steric environment of NHCs, the development of novel NHC ligands holds significant promise.In our pursuit of broadly applicable and privileged catalysts with innovative structural motifs, we have developed a family of induced-fit chiral NHC ligands based on the privileged chiral fragment strategy using a C 2-symmetric chiral aniline. These ligands are characterized by their ease of structural modification, bulky yet flexible nature, and versatile utility in asymmetric metal catalysis. Notably, they can be synthesized on a large scale from inexpensive starting materials without the need for column chromatography, offering a modular and straightforward preparation method that facilitates further exploration of their applications in asymmetric reactions. In this Account, we summarize recent progress in our group regarding the diverse and unique applications of these induced-fit NHC ligands in Pd-, Ni-, and Cu-catalyzed asymmetric reactions, encompassing reaction types, substrate scope, stereocontrol steps, and mechanistic insights. Our work is categorized into five sections based on reaction types: asymmetric cross-coupling reactions, asymmetric functionalization of alkenes, asymmetric hydrogen transfer reactions, asymmetric C-H functionalization reactions, and asymmetric nucleophilic addition reactions. These studies demonstrate the broad utility of the ligands in asymmetric catalysis, with their bulky yet flexible nature enabling adaptive stereocontrol across diverse elementary steps and challenging transformations.We anticipate that this Account will not only broaden the application of this class of chiral ligands but also inspire the design of new chiral NHC ligands for transition-metal-catalyzed asymmetric reactions. We believe that continued efforts focused on bulky yet flexible NHC ligands will offer practical solutions to critical challenges in chemical synthesis, further advancing the field of asymmetric catalysis.

Necroptosis and apoptosis are two alternatively regulated cell death pathways. Activation of RIPK1 upon engagement of TNFR1 by TNF alpha may promote necroptosis by interacting with RIPK3 or apoptosis by activating caspases. RIPK1 is extensively regulated by a variety of dynamic posttranslational modifications which control its kinase activity and formation of downstream complexes to mediate necroptosis and apoptosis. Here, we investigate the functional significance and mechanism by which PARP12, a mono-ADP-ribosyltransferase, interacts with RIPK1 and RIPK3 in cells stimulated by IFN gamma and TNF alpha. We show that PARP12 catalyzes the mono-ADP-ribosylation (MARylation) of RIPK1 in both the intermediate domain and the kinase domain, as well as the MARylation of RIPK3. PARP12 deficiency reduces necroptosis by inhibiting the activation of RIPK1 kinase and its interaction with RIPK3, as well as sensitizes to apoptosis by promoting the binding of RIPK1 with caspase-8. Thus, upon induction by IFNs, PARP12 may function as a cellular checkpoint that controls RIPK1 to promote necroptosis and inhibit apoptosis. Importantly, while PARP12 is a known interferon-stimulated gene (ISG), PARP12 deficiency promotes the expression of a subset of ISGs and confers protection against influenza A virus-induced mortality in mice. Our study demonstrates that PARP12 is an important modulator of cellular antiviral response.

Dearomative photocycloaddition of heteroarenes is an efficient method for replacing planar arenes with three-dimensional (3D) scaffolds, such as bicyclo[2.1.1]-hexane (BCH) containing heterocycles. Herein, we report intramolecular dearomative [2 pi + 2 sigma] photocycloadditions of bicyclo[1.1.0]butanes (BCBs) with (benzo)furans and (benzo)thiophenes. These photocycloadditions are initiated through an energy transfer pathway (EnT) or single electron transfer pathway (SET), efficiently yielding unique BCH-pyrrolidinone-fused heterocyclic scaffolds. Moreover, the synthetic utility of this photochemical reaction was demonstrated on the basis of large-scale synthesis and diversified transformations. Mechanistic investigations, in conjunction with density functional theory (DFT) calculations, were taken to support the proposed reaction mechanisms.

A sequential [2 + 2] cycloaddition of unsaturated N-acylindoles was developed under visible light irradiation in the presence of a photosensitizer, forming unprecedented cage-like medium-ring frameworks in high yields. By exploiting the distinct reactivity and selectivity of two types of olefins within the substrate, the transformation provides a single-step and atom-economical approach to such molecules with exclusive regio- and diastereoselectivity, excellent functional group tolerance, and mild reaction conditions. Experimental mechanistic and calculation studies suggest that this reaction proceeds through an energy transfer pathway in this double [2 + 2] cycloaddition process.

Two types of 5-trifluoromethyl tetrazole-based energetic salts were successfully synthesized from trifluoroacetamide and sodium azide. The synthetic approach is characterized by its simplicity and safety. The Xray diffraction analysis reveals the presence of both intermolecular and intramolecular hydrogen bonding within the crystal lattice of energetic salts. The synthesized compound 4 demonstrated notable physical properties, including high densities (1.64 g cm-3), great thermal stability (with decomposition temperatures of 167 degrees C), and excellent insensitivity (impact sensitivity exceeding 40 J). These attributes suggest that the compound 4 possess promising energetic performance and is potential candidates for use as insensitive high-energy materials.

Crystallization-driven self-assembly (CDSA) has emerged as a facile strategy to generate donor-acceptor (D-A) pi-conjugated nanofibers with potential applications from photocatalysis to nanomedicine. However, the reports on CDSA of D-A pi-conjugated-polymer-based block copolymers (BCPs) are rather rare. In this context, we report two types of BCPs containing the same corona-forming poly(N-isopropylacrylamide) segment, but different core-forming D-A pi-conjugated blocks, one of which (BT-OPE5-BT) contains an OPE5 segment flanked by two electron-deficient benzothiadiazole (BT) unit and another one of which (B-alt-BT) contains four phenylene (B) units and three BT units placed in an alternate way. The BT-OPE5-BT-based seed micelles were not kinetically frozen with obvious micellar dissolution at room temperature, whereas almost no micellar dissolution occurred for B-alt-BT-based seed micelles. However, only polydisperse fiber-like micelles can be formed by self-seeding approach owing to presence of multiple packing modes for B-alt-BT-b-PNIPAM36 over the micellar elongation. The B-alt-BT exhibited much more pronounced intra/intermolecular charge transfer effect than BT-OPE5-BT, and thus the micelles of B-alt-BT-b-PNIPAM36 exhibited about 50 nm red-shift in UV/vis absorption band than that of BT-OPE5-BT-b-PNIPAM36 and appealing photocatalytic hydrogen evolution activities. This work highlights the importance of sequence structure of D/A units of D-A segments on both CDSA behavior and photophysical/ chemical properties.

An asymmetric intramolecular reductive coupling of bisimines has been accomplished for the first time under mild conditions with bis((+)-pinanediolato)diboron as the template, providing the unprecedented chiral dihydrophenanthrene-9,10-cis-diamines in high yields and excellent enantioselectivities. The chiral exocyclic cis-diamine products have served as effective chiral ligands for asymmetric catalysis. A DFT study highlights the crucial roles of the uncommon twisted-boat pathway (instead of the common chair type) and the steric effect in exclusively forming the cis-diamines and achieving high enantioselectivity. This reductive coupling protocol represents a significant expansion of the diboron-promoted [3,3]-sigmatropic rearrangement.

Ovarian cancer is the sixth leading cause of cancer death among American women, with most fatalities attributable to tubo-ovarian high-grade serous carcinoma (HGSC). This malignancy usually develops resistance to conventional chemotherapy, underscoring the need for robust preclinical models to guide the development of novel therapies. Here, we introduce an HGSC mouse model generated via Ovgp1-driven Cre recombinase effecting CRISPR/Cas9-mediated deletion of Trp53, Rb1, and Nf1 tumor suppressors in mouse oviductal epithelium (m-sgPRNmodel). Cyclin-dependent kinase 12 (CDK12) inactivation-frequently observed in human HGSC-is associated with poorer outcomes, DNA damage accumulation (including tandem duplications), and increased tumor immunogenicity. In our system, coablation of Cdk12 (m-sgPRN;Cdk12KO) recapitulated hallmark features of HGSC, while accelerating tumor progression and reducing survival. In a conventional (Cre-lox-mediated) Trp53/Nf1/Rb1 triple knockout model with concurrent Cdk12 ablation (PRN;Cdk12KO mice), we observed T cell-rich immune infiltrates mirroring those seen clinically. We established both models as subcutaneous or intraperitoneal syngeneic allografts of CDK12-inactivated HGSC that exhibited sensitivity to immune checkpoint blockade. Furthermore, a CRISPR/ Cas9 synthetic lethality screen in PRN;Cdk12KO-derived cell lines identified CDK13- an essential paralog of CDK12-as the most depleted candidate, confirming a previously reported synthetic lethal interaction. Pharmacologic CDK13/12 degradation (employing YJ1206) demonstrated enhanced efficacy in cell lines derived from both m-sgPRN;Cdk12KO and PRN;Cdk12KO models. Our results define CDK12 as a key tumor suppressor in tubo-ovarian HGSC and highlight CDK13 targeting as a promising therapeutic approach in CDK12-inactive disease. Additionally, we have established valuable in vivo resources to facilitate further investigation and drug development in this challenging malignancy.