A general method for the stereocontrolled synthesis of (Z)-1,2-heteroatom-substituted monofluoroethylenes is described. The reaction proceeds via the Michael addition of N-, P-, and S-centered nucleophiles to 1-fluorovinyl sulfonium ylide (Ylide-VF) under mild conditions, followed by an E2 process. This general protocol exhibits broad functional group tolerance and significant application potential, as demonstrated by the late-stage functionalization of bioactive molecules and oligopeptides. Mechanistic investigations reveal that an intramolecular hydrogen bond within the Michael addition intermediate is the key stereocontrolling element, dictating the observed Z-selectivity.

Fms-like tyrosine kinase 3 (FLT3), a member of the type III receptor tyrosine kinase family, is identified as a promising drug target for treatment of acute myeloid leukemia (AML). Here, we designed and synthesized a series of new FLT3 PROTAC degraders by incorporating rigid linkers between gilteritinib and CRBN ligand. Among them, ZLC6-49 and ZLC10-3 were identified as the most potent degraders with DC50 values of 0.74 nM and 1.28 nM, and Dmax values of 85% and 88%, respectively. Mechanistic studies demonstrated that ZLC6-49 and ZLC10-3 induce FLT3 degradation in a cereblon- and proteasome-dependent manner. Furthermore, ZLC6-49 and ZLC10-3 potently inhibit FLT3 downstream signaling, suppress cell proliferation, induce apoptosis and G0/G1phase arrest in MV4-11 cells.

We report the design, synthesis, and application of novel bench-stable and scalable trifluoroallylating reagents, trifluoroallyl sulfonium salts (TFASs), which readily react with a series of organozinc reagents under copper catalysis to afford allylic trifluoromethyl-terminal alkenes with high efficiency and regioselectivity. Subsequent transformations of the resulting products further demonstrate the synthetic utility of these reagents.

The spatial distribution of endogenous small-molecule metabolites is pivotal for understanding living processes, disease mechanisms, and therapeutic principles. However, achieving high-sensitivity spatial metabolomic profiling remains challenging for atmospheric pressure mass spectrometry imaging (AP-MSI) due to low desorption/ionization efficiency, leading to the systematic omission of low-abundance yet biologically vital metabolites from spatial maps. Here, we developed a high-sensitivity MSI platform that integrated a polydopamine/covalent organic framework (PDA/COF) composite substrate with atmospheric pressure laser ablation carbon fiber ionization (LACFI) technology for spatial mapping of endogenous small-molecule metabolites in biological tissues. This substrate employed a polydopamine (PDA) interlayer to guide the ordered assembly of a COF on the substrate. The resulting PDA/COF composite substrate exhibited uniform surface coverage, strong stability, and excellent light absorption, collectively improving the laser desorption/ionization efficiency of metabolites. Moreover, the substrate was simple, easy to use, and cost-effective. Our platform demonstrated a significantly enhanced sensitivity, achieving an improvement of more than 2-fold based on the slope of the linear calibration curve for analysis of metabolites compared with MALDI, DESI, LACFI using copper-coated, graphene oxide, and COF substrate. It also exhibited excellent linear response, wide dynamic range, and broad metabolite coverage. The platform was further applied to map the metabolomes of normal, para-cancerous, and cancerous liver tissues and, through heatmap analysis, clearly revealed the spatial distribution patterns of metabolites such as NAD+ and adenine across these tissue types. This method provides a straightforward, efficient, and robust AP-MSI platform for highly sensitive and comprehensive spatial metabolomics.

Ribbon-like micelles containing an oligo(p-phenylenevinylene)-based core and a COOH-based corona are prepared by crystallization-driven self-assembly. Organic moieties and polymeric and metal nanoparticles can be immobilized on the shell of micelles by using the COOH unit as the handle via electrostatic, hydrogen-bonding and coordinating interactions.

Trifluoromethylthio-substituted hypervalent iodine precursor (SCF(3)-EBX) was developed for the efficient in situ generation of trifluoromethylthio cyanocarbene upon reaction with TMSN3. The SCF3 group plays a dual role: its strong electron-withdrawing inductive effect maintains high carbene electrophilicity, while sulfur lone-pair conjugation stabilizes the singlet ground state via a large singlet-triplet gap (Delta G = 14.6 kcal/mol). This unique electronic modulation enables the carbene to achieve an unprecedented balance between reactivity and selectivity under mild, metal-free conditions. It facilitates highly diastereoselective [2+1] cyclopropanation of styrenes (dr > 85:15) and, notably, enables Doyle-Kirmse reactions with allylic, propargylic, allenic, and homoallenic sulfides- transformations previously challenging for triplet-dominated cyanocarbenes. The system exhibits broad functional group tolerance and gram-scale applicability. Comparative experiments and DFT calculations confirm that SCF3 substitution substantially lowers the barrier for carbene generation and suppresses triplet side pathways. This work not only presents a cyanocarbene system that achieves both high activity and selectivity, but also establishes a general strategy for modulating carbene electronic structure through rational substituent design.

Iron-catalyzed metal hydride hydrogen atom transfer (MHAT) is a powerful strategy for hydrofunctionalization of alkenes, where reactive Fe-H is generated from a hydride donor through an oxidative process. Here, we report an iron-electrocatalytic MHAT reaction based on reductive generation of Fe-H directly from protons. Using an iron porphyrin catalyst and urea as the proton source, this protocol enables the selective C-F bond activation of CF3 alkenes to furnish gem-difluoroalkenes with a broad substrate scope under mild conditions. Mechanistic studies support the generation of proton-derived Fe-H intermediates, followed by MHAT and C-F bond cleavage. Removing the iron catalyst switches the reaction to a distinct pathway, selectively furnishing CF2H alkenes. Together, these complementary pathways provide independently accessible fluorinated isosteres of the keto and enol tautomeric states, which exhibit enhanced anti-inflammatory activity with distinct biological profiles in representative bioactive scaffolds. This work establishes the reductive model for iron-catalyzed MHAT reaction while providing a new strategy for the design and evaluation of carbonyl bioisosteres in medicinal chemistry.

Non-canonical amino acids (ncAAs) are privileged building blocks for the synthesis of natural products, biocatalysts, and drug molecules. Among them, gamma-tertiary-nitro-alpha-amino acids are highly valuable yet remain scarcely explored due to challenges in synthetic accessibility. Although pyridoxal-5 '-phosphate (PLP)-dependent enzymes are powerful biocatalysts for ncAA production, no enzymatic platform has, to the best of our knowledge, enabled efficient access to gamma-tertiary-nitro-alpha-amino acids. Here, we report a PLP-dependent enzymatic platform that selectively couples O-acetyl-serine with secondary nitroalkanes to yield gamma-tertiary-nitro-alpha-amino acids. Through reaction design, enzyme screening, and directed evolution, we repurpose SidM, an enzyme that catalyzes pyrrole ring formation in the siderochelin biosynthetic pathway, into a highly active and stereoselective biocatalyst, affording gamma-tertiary-nitro-alpha-amino acids in up to 99% yield and 99% diastereomeric excess. This enzyme exhibits broad substrate scope and good evolvability, allowing enhancement of catalytic efficiency or inversion of diastereoselectivity at the C gamma nitro center, and is readily scalable to gram synthesis. Mechanistic analyses combining computation and mutagenesis elucidate the structural determinants of activity and stereocontrol. This work establishes a general, tunable and scalable biocatalytic platform for the synthesis of gamma-tertiary-nitro-alpha-amino acids, expanding the synthetic repertoire of PLP-dependent enzymes for asymmetric C-C bond formation.

A general micellar catalysis protocol has been developed for ligand-assisted copper-catalyzed Ullmann-type C & horbar;N coupling reactions in water using commercially available surfactant TPGS-750-M. This sustainable and cost-effective method demonstrates broad substrate scope, efficiently coupling diverse (aryl)heteroaryl bromides with privileged nitrogen heterocycles including indoles, pyrazoles, imidazoles, and benzimidazoles. Notably, >20 examples of heteroaryl bromides are accommodated with good functional group tolerance. The green methodology provides practical access to biologically important N-arylated azoles, including structurally challenging polyheteroatomic frameworks, thereby offering significant advantages for pharmaceutical applications.