2-Alkyl substituted four-membered carbocycles and heterocycles are relevant motifs in pharmaceuticals and agrochemicals. However, synthetic methods to access these scaffolds mostly rely on functional group interconversion of a narrow subset of preformed cyclic building blocks, impeding access to a broad chemical space. In this report, we introduce a general method to transform readily available unactivated alkenes into 2-alkyl four-membered rings. In contrast to classic [2 + 2] cycloaddition chemistry─which is not viable for this class of products─our strategy leverages a homologative alkene dielectrophilic activation, converting the starting alkene into a transient 1,3-iodo-sulfonium intermediate, which undergoes sequential nucleophilic substitutions to promote ring formation. The chemical versatility of the intermediate enables modulation of the order of substitutions, crucial to targeting the full matrix of four-membered rings─i.e., azetidines, oxetanes, thietanes, and cyclobutanes. This functional group tolerant process is applicable to a wide range of alkenes─including complex structures─opening new avenues for applications in pharmaceutical and agrochemical synthesis.

The chemical introduction of heteroatoms via alkene difunctionalization (e.g., dihydroxylation, diamination, dihalogenation) is a traditional route to convert abundant olefins into highly functionalized building blocks. While the transformation of unactivated alkenes to difunctionalized products bearing the newly installed heteroatom handles in 1,2-relationship is well established, access to the corresponding 1,3-pattern remains elusive. Herein, we disclose a thianthrenium salt mediated homologative dielectrophilic activation method for unactivated alkenes with wide functional group tolerance. The strategy opens access to 1,3-diazides, diamines, diols, dihalides, dithiols as well as to the full matrix of their heterodifunctionalized products from abundant olefins. At the core of our strategy is the design of a novel sulfonium atom-transfer reagent, which undergoes selective bond cleavage to reveal a methyl thianthrenium radical, a versatile electrophilic homologative synthon which is unprecedented in synthesis.

Background: Diabetes-associated neurodegeneration is amplified by methylglyoxal (MGO)-driven dicarbonyl stress linking hyperglycemia to neuronal insulin resistance and maladaptive neuroinflammation. We tested the neuroprotective activity of MNP-021, a non-electrophilic TRPA1 modulator, in neurons and glial cells in vitro . Methods: SH-SY5Y neurons were pretreated with MNP-021 and challenged with MGO, then profiled by high-content imaging, RNA-seq, Seahorse OCR/ECAR, glycolytic stress assays and AKT/ERK/CREB immunoblotting ± insulin. In parallel, HMC3 glial cells were treated with MNP-021, exposed to LPS/TNF-α or Aβ _(25–35) and tested for viability and inflammatory markers by ELISA and qRT-PCR. Results: MGO increased nucleus-to-cytoplasm area ratio by 49% and dysregulated glucose handling, increasing 2-NBDG uptake by ∼25%, with GLUT1/GLUT4 membrane redistribution; MNP-021 normalized morphology, uptake, and transporter localization without cytotoxicity up to 10 µM. RNA-seq identified 754 MGO-deregulated genes, including ISR/metabolic nodes (GCK, SESN2, PHGDH/PSAT1, PCK2); MNP-021 buffered stress-induced transcription with limited baseline effects, remodeled mitochondrial redox readouts consistent with controlled ROS signaling, while improving mitochondrial content/architecture and blunting stress-evoked compensatory glycolysis. MNP-021 restored pro-survival signaling (pAKT/pERK and nuclear pCREB), including insulin responsiveness during MGO exposure. MNP-021 reduced IL-6/TNF-α release while increasing IL-10 and ARG1 (∼1.9-fold vs LPS/TNF-α) in HMC3 glial cells, shifting them toward a pro-resolving IL-10/ARG1 program with reduced Aβ _(25–35)- evoked cytokine release with GLP-1 remaining very low (≤10 pg/mL) and not significantly increased in this system. Conclusions: MNP-021 coordinates transcriptomic restraint, transporter-level glucose handling, mitochondrial resilience, and pro-survival/pro-resolving signaling across neuron–microglia compartments, supporting TRPA1-tuned small-molecule modulation as a candidate strategy against dicarbonyl-linked neuro-metabolic stress.