Mauro Pineschi

The present work reports a straightforward approach for the mechanochemical oxidative nitroso Diels–Alder (DA) reaction for the rapid synthesis of oxadiazo[2.2.2]octenes and a mechanochemical [3+3] hetero‐Cope rearrangement to access the corresponding dioxazines within reduced reaction time (up to 1.5 min and 1.5 h, respectively), high yields and reproducibility toward different functional groups.

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.

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.

Luminescent Lanthanide (III) (Ln (III)) bioprobes (LLBs) have been extensively used in the last two decades as intracellular molecular probes in bio-imaging for the efficient revelation of analytes, to signal intracellular events (enzymes/protein activity, antigen-antibody interaction), target specific organelles, and determine parameters of particular biophysical interest, to gain important insights on pathologies or diseases. The choice of using a luminescent Ln (III) coordination compound with respect to a common organic fluorophore is intimately connected to how their photophysical sensitization (antenna effect) can be finely tuned and especially triggered to respond (even quantitatively) to a certain biophysical event, condition or analyte. While there are other reviews focused on how to design chromophoric ligands for an efficient sensitization of Ln (III) ions, both in the visible and NIR region, this mini-review is application-driven: it is a small collection of particularly interesting examples where the LLB’s emissive information is acquired by imaging the emission intensity and/or the fluorescence lifetime (fluorescence lifetime imaging microscopy, FLIM).

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.