A distinctive continuous-flow synthesis of 2,2,2-trifluoro-1-(3 '-methoxy-[1,1 '-biphenyl]-4-yl)ethan-1-ol, an important intermediate for the synthesis of a tryptophan hydroxylase inhibitor LX1031, is described. The pivotal synthetic process involved a photochemically induced nickel-catalysed radical cross coupling of phthalimido trifluoroethanol with 1-bromo-4-(3-methoxyphenyl)benzene. This approach not only enhanced synthetic efficiency but also demonstrated the potential of flow photochemistry for the synthesis of a complicated pharmaceutical intermediate on a gram scale.

Herein, we report a method for the synthesis of alpha-aryl-alpha-trifluoromethyl amines via dual photoredox/nickel-catalysis between aryl bromides and N-trifluoroethyl hydroxylamine under flow conditions. This protocol enables the first direct 1-aminotrifluoroethylation of benzene derivatives under mild conditions in high yields (up to 84%) and with a wide functional group tolerance (32 examples). The transformation proceeds through photoinduced single-electron reduction of N-trifluoroethyl hydroxylamine, followed by 1,2-hydrogen atom transfer, to generate the alpha-aminotrifluoroethyl radical for cross-coupling of aryl bromides.

Sitolactone is an inexpensive, commercially available compound featuring a trans-hydrindane ring system fused to a delta-lactone. Despite its important applications in the pharmaceutical industry, this compound remains strikingly underexploited in natural product synthesis. In contrast to the widely used Hajos-Parrish ketone, only four total syntheses have employed sitolactone as a starting material. This account summarizes the background and synthetic applications of sitolactone, highlighting its considerable potential as a chiral pool material worthy of greater attention from the synthetic community.

Although trifluoromethylcarbene chemistry has garnered significant attention for its capacity to concurrently install a CF3 group and forge two new bonds-thus enabling the rapid assembly of molecular complexity-prevailing methods depend almost exclusively on transition-metal catalysis, which proceeds via metal-carbene intermediates. To overcome this limitation, we report a mild, general, and transition-metal-free photocatalytic strategy that employs bench-stable sulfonyl hydrazones as trifluoromethylcarbene precursors. Using a commercially available organic photocatalyst under visible light, this method can generate free trifluoromethylcarbene, facilitating its transfer in a range of transformations, including X-H (X = O, N, S, Si) insertions, cyclopropanation of alkenes, and the unprecedented skeletal editing of oxetanes via trifluoromethylcarbene insertion.

The highly selective construction of highly strained frameworks remains a formidable synthetic challenge. We report here an electrochemical nickel-catalyzed strategy that enables the regio-, chemo-, and stereoselective synthesis of butafulvenes, constitutional isomers of benzene featuring a cyclobutene core and two exocyclic double bonds. This protocol has been achieved via direct electroreductive coupling of propargylic esters under mild conditions with earth abundant metal catalysis of nickel and electricity, affording butafulvenes. Notably, it overcomes the significant E/Z selectivity challenge of secondary propargylic substrates, which previously yielded inseparable mixtures. The success arises from redox-governed sequential generation and transformation of allenyl-Ni, bisallenyl-Ni, bisallene, and five-membered nickelacycle intermediates under electrochemical conditions. Mechanistic studies and cyclic voltammetry support a pathway involving sequential Ni0-involved oxidative addition and reductive coupling as well as Ni0-mediated highly stereoselective cycloisomerization. The reaction exhibits a broad substrate scope accommodating many synthetically versatile functional groups, such as bromide, carboxylate, trifluoromethyl, ether, and silyl groups, and is amenable to late-stage functionalization of complex molecules. This work establishes a general and sustainable platform for accessing strained antiaromatic pi-systems and highlights the power of electro-nickel catalysis in stereoselective molecular assembly.

The chemoselective [2+1] cycloaddition of difluorocarbene with conjugated enynes has been achieved. Using TMSCF2Br as the difluorocarbene precursor in the presence of a catalytic amount of n-Bu4N+Br-, the reaction proceeded smoothly in THF at 110 degrees C, affording a series of alkenyl-substituted difluorocyclopropenes. Subsequently, these products could be hydrolyzed in one pot to furnish the corresponding alkenyl-substituted cyclopropenones.

2H-Chromenes are privileged pharmaceutical scaffolds, yet their synthesis typically requires multistep sequences or harsh conditions. We report a one-pot, visible-light-mediated strategy that directly converts 2'-hydroxychalcones and organoboronic acids into diverse 2,4-disubstituted 2H-chromenes. This approach leverages a photochemical 1,3-boronate rearrangement to achieve highly regioselective 1,2-addition to the alpha,beta-unsaturated ketone moiety of 2'-hydroxychalcones, effectively diverting from traditional 1,4-addition pathways. The method provides modular access to 40 examples, notably including the synthetically challenging 2-alkyl-4-aryl motif. Demonstrating broad functional group compatibility, the protocol was successfully implemented in a continuous-flow system, achieving an 85% reduction in reaction time and facilitating gram-scale synthesis.

OSW-1, a steroidal disaccharide isolated from the bulbs of Ornithogalum saundersiae, has been extensively studied for its extremely potent cytotoxicity against the National Cancer Institute's 60 cancer cell lines with an average IC50 of 0.78 nM, while exhibiting selectivity toward normal cells. Although OSBP and ORP4L have been identified as its binding targets, their known functions appear insufficient to account for the compound's exceptional potency, suggesting the involvement of additional mechanisms and targets. Therefore, elucidating novel target proteins associated with its activity is essential for the further development of this molecule. Here, we disclose that OSW-1 can block the glycolytic pathway and trigger compensatory mitochondrial oxidative phosphorylation. This previously uncharacterized mechanism is relevant to the key rate-limiting enzyme, enolase 1 (ENO1), which shows subnanomolar affinity with OSW-1. Our study repurposes OSW-1 to be a small-molecule probe to investigate the function of ENO1 and a promising candidate for metabolism-targeted anticancer therapy.

Here, we reported the first example of enantioselective Pd-catalyzed intramolecular alkynylamination of alkenes enabled by the development of a novel SPSiP ligand using alkynyl bromides as the C(sp)-electrophile. This ligand-enabled protocol allows the efficient synthesis of chiral pyrrolidine derivatives at room temperature in moderate to high yields (up to 92% yield) and high enantioselectivities (up to 95.5:4.5 er). Mechanistic and computational studies unveiled the high reactivity and enantioselectivity might originate from the electron-rich nature and large bite angle in the SPSiP ligand. The synthetic values of this reaction are demonstrated by various transformations and efficient synthesis of phenanthroindolizidine alkaloids including (+)-antofine and (+)-ficuseptine.

Antimycins feature a nine-membered dilactone core and a bioactivity-essential 3-formaminosalic acid. Herein, we demonstrate that the formation of 3-aminosalicylate is catalyzed by AntHIJKL, a multicomponent diiron monooxygenase complex, via an unusual carrier protein-dependent oxidative rearrangement. AntH and AntJ constitute the minimal catalytic unit to convert anthraniloyl thioester into 3-aminosalicyl thioester on the carrier protein AntG, while AntI, AntK, and AntL function as auxiliary redox partners. This study expands the functional scope of multicomponent diiron monooxygenases.

This contribution reports the first copolymerization of methacrylates with simple, commercially available, and biorenewable coumarin (CM). The key to this achievement lies in the rational design of a new Al(C6F5)3/P n Bu3 Lewis pair cooperative catalyst, which possesses several unique features, including high efficiency, living nature, and, more strikingly, perfectly alternating sequence control. Computational studies elucidate that kinetic control, enabled by different attractive London dispersion interactions between enolaluminate active species and two monomer substrates, is a decisive factor for alternating sequence control. Accordingly, a series of alternating vinyl copolymers with a high molecular weight (M n) of up to 330.8 kg/mol can be synthesized directly from commercial/general vinyl monomers regardless of monomer structures and feed ratios. These copolymers have been determined to be highly transparent materials with high heat resistance (T g: 130-190 degrees C), good thermal stability (T d up to 300 degrees C), and good durability and are meanwhile fully degradable at room temperature under a strong base and completely thermal depolymerizable in the presence of a strong donating solvent (e.g., DMF), thus affording a new class of robust, durable, yet fully degradable, depolymerizable C-C main-chain polymers, which are generally unachievable due to an inherent performance/degradability (depolymerizability) trade-off.

NUAK1, an AMPK-related kinase overexpressed in cancers, plays a crucial role in tumor metastasis and cell survival, making it an attractive cancer therapeutic target. Herein, we report potent, selective NUAK1 inhibitors via structure-guided repurposing of a covalent JAK3 inhibitor. By capitalizing on the critical structural difference-Cys909 in JAK3 versus Glu139 in NUAK1-we substituted the electrophilic warhead with glutamate-favoring moieties, a modification that confers selective NUAK1 targeting. Supporting this design rationale, cocrystal structures verify the specific engagement of these moieties with the Glu139 residue of NUAK1. Among the synthesized analogs, candidate compound 10i exhibits subnanomolar NUAK1 inhibition (IC50 = 0.49 nM) and kinome-wide selectivity. Besides, 10i suppresses proliferation, migration, and invasion of triple-negative breast cancer cells, reverses EMT markers, and shows robust antitumor efficacy in mouse xenografts. This study provides a promising lead and validates Glu139 as an anchor for selective NUAK1 targeting.

Osteoporosis is a chronic disease affecting over 200 million people globally. It imposes a heavy burden on healthcare systems, societies, and families. Currently, clinical anti-osteoporotic drugs have various adverse effects limiting long-term use; although natural products from traditional medicines show therapeutic potential, their clinical translation is restricted by poor druggability. This article highlights how targeted chemical modifications, including heterocycle fusion, side-chain optimization, and functional group introduction, can significantly enhance anti-osteoporotic activity, improve pharmacokinetics, and reduce toxicity. Key compound classes discussed include terpenoids, alkaloids, flavonoids, coumarins, and polyphenols, with a focus on their mechanisms involving the RANKL/RANK/OPG, NF-kappa B, MAPK, and Wnt/beta-catenin signaling pathways. The review underscores the potential of structure-activity relationship-guided design to transform traditional medicine-derived leads into promising drug candidates for osteoporosis treatment.