Overcoming the blood-brain barrier remains one of the most formidable challenges in the diagnosis and treatment of central nervous system disorders. In this account, we showcase our contributions to the field of redox-responsive heterocycles, most notably 1,4-dihydroquinolines and 1,4-dihydropyridines, designed as powerful platforms for targeted brain delivery. Our work builds on the chemical delivery system and bioprecursor prodrug strategies pioneered by Bodor et al. We have focused on the development of redox-activated drug carriers and "bio-oxidizable" prodrugs, which enable efficient transport of neurotransmitters, neuropeptides, and radiotracers for advanced brain imaging, as well as cholinesterase and kinase inhibitors for the treatment of Alzheimer's disease. Last but not least, these versatile heterocyclic systems offer unprecedented perspectives in synthetic methodology, driving breakthrough advances in peptide synthesis and atroposelective amide bond construction.

An electrochemical Minisci-type reaction for the regioselective C2-alkylation of N-oxide heteroarenes is reported herein. N-Hydroxyphtalimide redox-active esters were used as primary, secondary, and tertiary alkyl radical precursors. A variety of 2-alkylheterocyclic N-oxides were prepared in the absence of catalyst and exogeneous oxidant. Preliminary mechanistic studies suggested a radical addition pathway via sequential paired electrolysis.

Amongst the electron-deficient alkene derivatives, as molecular platforms widely used in organic synthesis, the readily available alkylidene Meldrum's acid derivatives hold a unique place due to the high electrophilicity and chemical versatility of the 1,3-dioxan-4,6-dione moiety. This short review intends to give an overview of recent advances in the asymmetric catalytic transformation of alkylidene Meldrum's acids into valuable chiral heterocycles, evolving from seminal investigations into C-C bond construction from the alkene moiety, to more recent enantioselective C-N and C-S bond formation, vinylogous processes, and the exploitation of the reactivity of the 1,3-dioxan-4,6-dione moiety to develop efficient annulation sequences.

Based on a multitarget approach implementing rivastigmine-INDY hybrids 1, we identified a set of pseudo-irreversible carbamate-type inhibitors of eqBuChE that, after carbamate transfer at the active site serine residue, released the corresponding INDY analogues 2 endowed with hDYRK1A/hCLK1 kinases inhibitory properties. A SAR study and molecular docking investigation of both series of compounds 1 and 2 revealed that appropriate structural modifications at the carbamate moiety and at the N-appendage of the benzothiazole core led to potent and selective eqBuChE inhibitors with IC50 up to 27 nM and potent hDYRK1A and hCLK1 inhibitors with IC50 up to 106 nM and 17 nM respectively. Pleasingly, identification of the matched pair of compounds 1b/2b with a good balance between inhibition of eqBuChE and hDYRK1A/hCLK1 kinases (IC50 = 68 nM and IC50 = 529/54 nM, respectively) further validated our multitarget approach based on a sequential mechanism of action. In addition, target compound 1b exhibited a suitable ADMET profile, including good brain permeability and high stability in PBS, encouraging further biological investigation as a drug candidate. Promising multitargets ligands in Alzheimer's disease: sequential BuChE and DYRK1A/CLK1 kinases inhibition.

Thanks to the versatile vinylogous hexafluoro iso-propyl acrylate molecular platforms, a regio- and enantioselective sulfa-Michael reaction was achieved upon organocatalytic conditions, allowing the subsequent amidation, one-pot oxidation, and Mislow-Bravermann-Evans [2,3]-sigmatropic rearrangement along with a 1,3-chirality transfer, leading eventually to a formal asymmetric 1,6-hydroxylation sequence.

The study of Pd(0)‐catalyzed C−H bond arylation of methyl 5H‐imidazo[2,1‐a]isoindole‐3‐carboxylates with aryl bromides is reported. This methodology gives ready access to a wide range of methyl 5H‐imidazo[2,1‐a]isoindole‐3‐carboxylates that are monoarylated at their benzylic sites. The C(sp3)−H bond arylation methodology is driven by regioselectivity under weakly basic conditions avoiding remarkably side C(sp2)−H poly‐arylation of the (hetero)aromatic unit. The process was applied to the preparation of novel imidazo[2,1‐a]isoindole‐based neurotransmitter Neuropeptide S antagonist analog.

Although the metal-based catalyzed cyanomethylation of aldehydes is well-developed, a similar approach to ketones with acetonitrile derivatives remains a challenge. Thanks to Tolman type complexes, Ni-II-complexes with a pyridine(dicarboxamide) pincer ligand, an alternative metal-catalyzed (1-5 mol% catalyst) cyanomethylation of an array of isatins and activated ketones is reported at room temperature. High isolated yields (up to 99%) were obtained not only with the poorly acidic acetonitrile but also with more challenging substituted alkyl cyanide nucleophiles. The in situ generated putative ion paired catalysts [NiCR2CN](-)Cat(+) likely benefit from the cation part (Cs+ or n-Bu4N+) to facilitate their formation and catalytic activity.

The DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases is involved in the pathogenesis of several neurodegenerative diseases. Among them, the DYRK1A protein kinase is thought to be implicated in Alzheimer's disease (AD) and Down syndrome, and as such, has emerged as an appealing therapeutic target. DYRKs are a subset of the CMGC (CDK, MAPKK, GSK3 and CLK) group of kinases. Within this group of kinases, the CDC2-like kinases (CLKs), such as CLK1, are closely related to DYRKs and have also sparked great interest as potential therapeutic targets for AD. Based on inhibitors previously described in the literature (namely TG003 and INDY), we report in this work a new class of dihydroquinolines exhibiting inhibitory activities in the nanomolar range on hDYRK1A and hCLK1. Moreover, there is overwhelming evidence that oxidative stress plays an important role in AD. Pleasingly, the most potent dual kinase inhibitor 1p exhibited antioxidant and radical scavenging properties. Finally, drug-likeness and molecular docking studies of this new class of DYRK1A/CLK1 inhibitors are also discussed in this article.

Recently, radical chemistry has grown exponentially in the toolbox of organic synthetic chemists. Upon the (re)introduction of modern catalytic and technology-driven strategies, the implementation of highly reactive radical species is currently facilitated while expanding the scope of numerous synthetic methodologies. In this context, this review intends to cover the recent advances in radical-based transformations of N,N-disubstituted iminium substrates that encompass unique reactivities with respect to imines or protonated iminium salts. In particular, we have focused on the literature concerning the dipole type substrates, such as nitrones or azomethine imines, together with the chemistry of N+-X− (X = O, NR) azaarenium dipoles, which proved to be very versatile platforms in that field of research. The N-alkylazaarenium salts were been considered, which demonstrated specific reactivity profiles in radical chemistry.

The electrocarboxylation of α,α-dichloroarylmethane derivatives in the presence of CO2 was achieved, providing several α-chloroarylacetic acid derivatives with modest yields but high selectivity (chlorinated vs. non-chlorinated or dicarboxylic acid products). The obtained products were then involved in several chemical transformations, underlining their potential as versatile intermediates in synthetic chemistry. A mechanism was also proposed based upon a control experiment and cyclic voltammetry (CV) study.

Thanks to metal- and catalyst-free electrochemical conditions in an undivided cell, a series of readily available redox-active N-(acyloxy)phthalimide esters led to an efficient and highly stereoselective addition (85 : 15 to 95 : 5 dr) of putative radical species to chiral (racemic and enantioenriched) C5-substituted azomethine imines to provide an array of 31 polyaminated hydrazine derivatives as a single diastereoisomer.

An organocatalyzed one-pot sequential deracemization of aromatic ketones bearing a stereogenic center at the alpha-position was achieved thanks to an acid-base strategy involving an enantioselective protonation reaction as a key step. This simple and efficient protocol yields enantioenriched ketones in up to 89% ee without the need to isolate sensitive intermediates such as silyl enolates. The key role of water in this process was underlined. This one-pot sequence constitutes a useful extension to previously reported chemically driven red-ox protocols, thus increasing the panel of molecules eligible to a deracemization strategy.

Nucleophilic dearomatization of azaarenium salts is a powerful strategy to access 3D scaffolds of interest from easily accessible planar aromatic azaarene compounds. Moreover, this approach yields complex dihydroazaarenes by allowing the functionalization of the scaffold simultaneously to the dearomatization step. On the other side, organocatalysis is nowadays recognized as one of the pillars of the asymmetric catalysis field of research and is well-known to afford a high level of enantioselectivity for a myriad of transformations thanks to well-organized transition states resulting from low-energy interactions (electrostatic and/or H-bonding interactions…). Consequently, in the last fifteen years, organocatalysis has met great success in nucleophilic dearomatization of azaarenium salts. This review summarizes the work achieved up to date in the field of organocatalyzed nucleophilic dearomatization of azaarenium salts (mainly pyridinium, quinolinium, quinolinium and acridinium salts). A classification by organocatalytic mode of activation will be disclosed by shedding light on their related advantages and drawbacks. The versatility of the dearomatization approach will also be demonstrated by discussing several chemical transformations of the resulting dihydroazaarenes towards the synthesis of structurally complex compounds.

We report herein a strategy to afford a multicomponent catalytic enantioselective synthesis of beta-substituted isoxazolidin-5-ones via a KMC process promoted by a suited cupreine used as bifunctional organocatalyst. The hydroxamic acid component, with a sterically hindered amide moiety, proved to be key for the successful formation and transformation of the obtained original N-amide isoxazolidin-5-ones.

An unprecedented enantioselective conjugate addition reaction of sodium bisulfite to various nitrostyrenes occurred upon the influence of a bifunctional amino-thiourea organocatalyst; a strategy that opens a straightforward route to unprotected chiral taurine derivatives thanks to the reduction of the obtained β-nitroethanesulfonic acids into the corresponding amino derivatives.

A straightforward synthesis of original 1,6-diazabicyclo[4.3.0]nonane-2,7-diones was achieved through a DBU-organocatalyzed multicomponent Knoevenagel-aza-Michael-Cyclocondensation reaction which takes advantage of an unprecedented highly regio- and diastereoselective conjugate addition of pyridazinones to alkylidene Meldrum's acid intermediates. The key reactive intermediates of this complex process were analyzed by means of electrospray ionization mass spectrometry coupled to ion mobility spectrometry, allowing us to validate the proposed mechanism.

The palladium-catalyzed arylation and alkenylation of N-substituted methyl imidazole-4-carboxylates are described through inter- and intramolecular pathways. Both direct C2–H and C5–H arylation and alkenylation proceed under Pd(0)/Cu(I) cooperative catalysis and Pd(0) catalysis, respectively, in low-polarity 1,4-dioxane solvent. The methodology gives access to C2 (hetero)aryl or alkenyl imidazoles as well as innovative C2- and C5-arylated fused imidazoles tricycles with a five- to seven-membered middle ring.