Latest ArticlesThe single-electron transfer-induced oxidative transformation of indoles has been extensively explored in recent years. However, research toward high enantioselective control in this reaction is rare. Herein, we report an enantioselective catalytic single-electron transfer-induced oxidative rearrangement of cyclic indoles enabled by dual chiral copper/phosphoric acid catalysis. Using atmospheric oxygen (O2) as the terminal oxidant, the reactions of tetrahydro-β-carbolines, tetrahydropyrano[3,4-b]indoles and the challenging tetrahydrocarbazoles are all realized, providing diverse rearrangement products including pyrrolidinyl-, tetrahydrofuranyl- and cyclopentyl-bearing spiroindolinones in good yields with high enantioselectivities. The synthetic utility of this protocol was demonstrated in a concise synthesis of (+)-coerulescine and (+)-horsfiline. These findings would provide new insights and opportunities for future asymmetric oxidative radical reaction design.
Available online-The enantioselective chlorination is a continuing challenge owing to the highly reactive nature of chloronium ions. Herein, tertiary ammonium salt catalysis for asymmetric chloro– and selenocyclization of 2-alkenyl anilides with high enantioselectivities were achieved at room temperature. This approach affords the green and atom-economical access to chiral 4H-3,1-benzoxazines with excellent functional-group tolerance. The catalyst could be reused for 3 runs, no obvious loss in catalytic activity and enantioselectivity was observed. This catalytic system can be applied to late-stage modification of pharmaceuticals and natural products. Computational mechanistic studies revealed that the non-classical hydrogen bond (C-H…O) between the phosphate anion and ammonium cation plays crucial role in the stereocontrol of the reaction.
An efficient method for the three-component azidopyridylation of unactivated alkenes to access β-pyridyl azides has been developed. The overall process involves a visible light-mediated radical-relay sequence that begins with an in situ generated methoxy radical, which may facilitate Si−N3 bond activation to generate azidyl radical under mild conditions. The ensuing azidyl radical adds to the alkenes to furnish the carbon-centered radicals which themselves add, in an intermolecular sense, to pyridinium salts. This three-component photocatalytic strategy is effective for a broad range of alkenes and N-heterocycles, and readily affords synthetically useful azidyl- and pyridyl-containing building blocks. This method provides new insights into methoxy radical-initiated relay reactions as well as access to a range of new molecular scaffolds.
Selective activation of C-C bonds via molecular editing is a fundamental challenge in organic synthesis. Among the various strategies, metathesis reactions have emerged as powerful tools for constructing new molecular architectures due to their well-established mechanisms. However, these reactions have largely been limited to the same types of covalent bonds, such as σ-σ or π-π bonds, leaving σ-π cross-metathesis reactions unexplored. Perhaps the bond redistribution between the σ and π bonds is highly difficult due to the lack of p orbital in σ bonds. Herein, we report the first example of a transition metal-free σ-π cross-metathesis reaction that converts methyl ketones into the corresponding carboxylic acids along with the formation of 11H-benzo[b]fluoren-11-one. A comprehensive mechanistic investigation, supported by DFT calculations, was conducted to elucidate the unique reaction pathway. This study not only provides compelling evidence for the first σ-π cross-metathesis reaction but also demonstrates the formation of a key oxetan-2-olate intermediate and its utility in organic transformations. This novel concept and strategy expand the scope of traditional metathesis reactions, offering new possibilities for selective C-C bond activation in a redox-neutral manner.
Cell-penetrating peptides (CPPs) hold great potential as a tool using non-invasive delivery of therapeutic or diagnostic molecules into mammalian cells, but their broad application has been limited by poor endosomal escape. Thus, the rational design and selection of CPPs remains a challenge and calls for deeper mechanistic understandings. Here, we developed novel stapled cell-penetrating peptides based on the highly positively charged HIV Tat47-57 peptide using decafluorobiphenyl-cysteine SNAr chemistry which selectively disrupt endosomal membranes. A series of stapled peptides with a cross-linked structure were synthesized and investigated their cellular uptake, endosomal escape and intracellular delivery of cargoes. Among these peptides, analogues P3 and P6 demonstrated the highest cellular uptake and endosomal escape activities with efficiencies 3.5−9-fold higher than that of Tat47-57. Notably, the results demonstrated that the decafluorobiphenyl bridge of stapled peptides exhibited significant ability for cellular uptake and endosomal escape. Moreover, we found that fluorine atoms of decafluorobiphenyl bridge played a key role for disrupting endosomal membranes. Finally, the utility of this strategy has been demonstrated by the intracellular delivery of biomacromolecules (avidin and negatively charged phosphopeptides). Together, these results suggest that the decafluorobiphenyl-cysteine SNAr chemistry may be an efficient strategy for the development of novel stapled CPPs.
Hierarchical assembly provides a rational procedure to acquire complex supramolecular architectures from basic building blocks. In this work, a novel kind of double-stranded polyrotaxane motif was reported by Ag+-directed coordination-driven assembly following the preassembly of a four-connected pseudorotaxane (cpb)2CB8 linker. Moreover, supramolecular isomerism is observed in crystalline compounds based on double-stranded polyrotaxane motifs due to differences in lattice stacking mode. Interestingly, the resultant supramolecular isomers, cross-Ag-DSP-1 and para-Ag-DSP-1, show dual thermo- and anion-responsiveness. Benefiting from high crystallinity of these coordination assemblies, a combination of characterization techniques, especially X-ray diffraction, was used to unveil precise molecular mechanisms related to the inherent dynamic behavior of these assemblies, which can be attributed to remarkable lattice rearrangement and crystal transformations as temperature increases or after anion exchange, reflecting the adaptive adjustment ability of these supramolecular architectures in response to external stimuli. Based on the anion exchange capability, these two supramolecular materials show fast removal kinetics and high sorption capacity for perrhenate (ReO4-) anion, a surrogate of radioactive pertechnetate (TcO4-) in nuclear waste eluents. This work provides a feasible way to supramolecular assemblies with customized structures and stimuli-responsiveness, and is helpful to design and synthesize more functional supramolecular systems with complex structures and tailored functions.
Alkene cross-coupling provides a simple and efficient approach for constructing C–C bonds using readily accessible alkene feedstocks. Despite significant progress in C–C bonds formation through the difunctionalization of alkenes, analogous reaction involving two distinct alkenes remains extremely limited. Herein, we report the excited-state palladium(0) catalyzed alkenylcarboxylation of two distinct alkenes with CO2, delivering a variety of carboxylic acids in moderate to excellent yields. This reaction features high regio- & chemoselectivity, broad substrate scope (> 70 examples), and facile derivatization of products. Mechanistic studies indicate that the key step for this new strategy lies in the reductive activation of electron-deficient alkenes with the excited-state palladium complex to generate alkene radical anions. The current single-electron reduction strategy for alkenes catalyzed by photoexcited palladium(0) not only broadens the scope of excited palladium chemistry but also provides a mild approach for alkenes activation. Furthermore, this method serves as an efficient tool for the rapid construction of multiple C–C bonds in a one-pot operation using two distinct alkenes.
Long-wavelength fluorescent dyes have revolutionized in vivo fluorescence imaging by offering unparalleled spatial resolution. Nevertheless, the majority of organic fluorescent dyes documented to date exhibit emission wavelengths predominantly within the range of 1000–1100 nm, with scarcely any surpassing the 1200 nm threshold. Herein, we introduce a heptamethine cyanine dye that boasts a remarkable fluorescence wavelength of 1239 nm. To our knowledge, this represents the longest fluorescence wavelength for heptamethine benzindole derivative. We have meticulously analyzed its photophysical characteristics and solvatochromic behavior, and assessed its efficacy in vivo fluorescence imaging applications.
Bile salt hydrolase (BSH), a gatekeeper enzyme in bile acid metabolism, regulates the host's bile acid profile and is closely associated with various metabolic diseases. However, suitable methods for measuring its activity in living systems remain scarce. Herein, a novel far-red fluorogenic substrate (CA-ABEI) for BSH was designed and developed by conjugating cholic acid with an aminocoumarin fluorophore. Under physiological conditions, CA-ABEI can be rapidly hydrolyzed by BSH from various bacterial sources to form ABEI, triggering strong fluorescence enhancement at 620 nm. Specifically activated by BSH, CA-ABEI enables accurate detection of BSH activity in biospecimens, including pure enzymes, bacteria and intact fecal slurries, and the first bioimaging of BSH activity in both BSH-expressing engineered Escherichia coli and natural intestinal microbiota. Moreover, a high-throughput screening platform was established using CA-ABEI, enabling the evaluation of BSH inhibitory effects from 96 herbal extracts. Pu-erh tea emerged as a potent BSH inhibitor and its active components were subsequently characterized, aiding the discovery of novel BSH inhibitors. Collectively, CA-ABEI proved to be a powerful tool for monitoring BSH activity in complex biological systems with value for exploring physiological functions and rapid screening of inhibitors.
To promote the advantages of near-infrared-Ⅱ (NIR-Ⅱ) imaging, researchers have developed various types of NIR-Ⅱ imaging contrast agents, with conjugated dyes being one of the most important categories. However, hydrophobic dyes often rely on encapsulation with amphiphilic polymers for biological applications, which lead to brightness quenching and instability in vivo. To address this, we proposed a covalent encapsulation strategy to transform the hydrophobic dye from organic solvent to aqueous solution. To achieve this, we designed a chlorine-containing NIR-Ⅱ cyanine dye (C7–1080), which covalently binds to human serum albumin (HSA), forming a stable NIR-Ⅱ fluorescent probe, HSA@C7–1080. The HSA@C7–1080 has precise molecular weight and spatial structure, making dye monodispersing in the albumin pocket with improved fluorescence and stability. This NIR-Ⅱ fluorescent probe provides high-resolution NIR-Ⅱ imaging in various biological systems. Our strategy offers a promising alternative for the clinical translation of hydrophobic NIR-Ⅱ dyes, improving their biocompatibility and imaging performance in fluorescence-guided surgery.
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