Francesca Sardelli

A mechanistically unusual CuCN-catalyzed electrophilic amidation of Grignard reagents with N-H containing O-allyl- and O-benzyl-hydroxamic acid derivatives as leaving groups to give secondary amides is reported. Computational DFT examination of the reaction points to the intermediate formation of electrophilic acyl nitrenoid species triggered by the presence of CuCN and magnesium salts. The work also provides some experimental evidence about the molecular composition and reactivity of organomagnesium cuprates, the structural nature of which remains a subject of ongoing debate.

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.

Alternating current (AC) has recently been explored as a powerful electrolysis operating mode to access synthetic intermediates, avoiding overoxidation events and electrode passivation. In this work, we explore the applications of AC to the electrooxidative nitroso Diels-Alder reaction (nDA) through the in situ formation of acyl nitroso intermediates (dienophile). Further reaction with 1,2-dihydropyridine (DHP) derivatives (dienes) unlocked a sustainable regio- and stereoselective protocol for the synthesis of oxadiazo[2.2.2]octenes.

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.

We herein report our study about the ring opening of 1,3‐diaza‐4‐oxa‐[3.3.1]‐nonene derivatives with organometallic reagents leveraging on their inherent ring strain and presence of reactive functionalities. The ring‐opening occurs with Grignard reagents at the carbon bearing the two nitrogen atoms affording unconventional functionalized trans‐2,3‐disubstituted 1,2,3,6‐tetrahydropyridines that are important structural frameworks due to their synthetic versatility and presence in bioactive molecules. The possibility to prepare enantioenriched tetrahydropyridines was also formally explored with success. A computational DFT study points to the formation of a transient iminium ion intermediate in which the coordination of magnesium to the oxygen of the carbonyl and the N−O endocyclic oxygen promotes the ring‐opening process at the gem‐diamine carbon atom.

We herein report an unprecedented ring-opening of unstrained cyclic aminals such as imidazolidines and hexahydropyrimidines by the use of Grignard and cuprate reagents to give secondary sulfonamides bearing diversely substituted tertiary amines in the β- or γ-position. This synthetic procedure can be carried out in a one-pot fashion without collateral reactions that are commonly associated with sp³-organometallic multicomponent Mannich-type reactions, indicating the fundamental role of sulfonamide protection of the second nitrogen atom in the generation of the cyclic aminal and in the ring-opening process. Computational density functional theory (DFT) data point to the formation of a transient iminium ion intermediate, in which the Lewis acidity of the cationic component of the organometallic reagent triggers the ring-opening process by coordination. The presented method allows the nucleophilic decoration of diamines including those bearing an adjacent chiral center to the tertiary amine not easily achievable by means of alternative standard synthetic procedures.

A very short stereoselective synthesis of enantiomerically pure (3S, 4aS, 10aR)-quinagolide has been developed. The key steps involved are a copper-catalyzed regioselective arylation of (S)-epichlorohydrin with 1,6-dimethoxynaphthalene and a diastereoselective trans-reduction of a cyclic enamine intermediate. The possibility to use both enantiomers of epichlorohydrin and the diastereodivergency found in the reduction process paves the way for a general preparation also in the nonracemic form of chiral trans-fused 3-substituted octahydrobenzo[g]quinolines that are privileged structures in medicinal chemistry.