Nitro-Assisted Brønsted Acid Catalysis: Application to a Challenging Catalytic Azidation.

A cocatalytic effect of nitro compounds is described for the B(C6F5)3·H2O catalyzed azidation of tertiary aliphatic alcohols, enabling catalyst turnover for the first time and with a broad range of substrates. Kinetic investigations into this surprising effect reveal that nitro compounds induce a switch from first order concentration dependence in Brønsted acid to second order concentration dependence in Brønsted acid and second order dependence in the nitro compounds. Kinetic, electronic, and spectroscopic evidence suggests that higher order hydrogen-bonded aggregates of nitro compounds and acids are the kinetically competent Brønsted acid catalysts. Specific weak H-bond accepting additives may offer a new general approach to accelerating Brønsted acid catalysis in solution.

Breaking the dichotomy of reactivity vs. chemoselectivity in catalytic S(N)1 reactions of alcohols.

The inability to decouple Lewis acid catalysis from undesirable Brønsted acid catalysed side reactions when water or other protic functional groups are necessarily present has forced chemists to choose between powerful but harsh catalysts or poor but mild ones, a dichotomy that restricts the substrate scope of dehydrative transformations such as the direct SN1 reaction of alcohols. A systematic survey of Lewis and Brønsted acids reveals that the strong non-hydrolyzable Lewis acid B(C6F5)3 leads to highly chemoselective alcohol substitution in the presence of acid-sensitive alkenes, protecting groups and other functional groups without the typical compromise in reaction rates, substrate scope and catalyst loading.

Evaluating how cationic lipid affects mRNA-LNP physical properties and biodistribution.

RNA therapeutics represents a powerful strategy for diseases where other approaches have failed, especially given the recent successes of mRNA vaccines against the coronavirus disease 2019 (COVID-19) and small interfering (siRNA) therapeutics. However, further developments are still required to reduce toxicity, improve stability and biodistribution of mRNA-LNPs (lipid nanoparticles). Here, we show a rational combinatorial approach to select the best formulation based on a new cationic lipid molecule (IM21.7c), which includes an imidazolium polar head. The study allowed us to select the optimal 5 lipids composition for in vivo mRNA delivery. IM21.7c based mRNA-LNPs measuring less than 100 nm had high encapsulation efficiency, protected mRNA from degradation, and exhibited sustained release kinetics for effective in vitro transfection. Most interestingly the biodistribution was significantly different from other clinically approved LNPs, with increased targeting to the lung. Further studies are now required to expand the possible applications of these new molecules.

Synthesis of tetracyclic indoles via intramolecular α-arylation of ketones.

An intramolecular palladium(0)-mediated α-arylation of ketones applied to the synthesis of various substituted tetracyclic indoles is reported. Most significantly, the efficiency of the transformation was enhanced by the use of monoligated Pd(0) complexes. This methodology was extended to double α-arylation of ketones using one-pot reactions with either simultaneous addition or sequential addition of two aryl halides for producing aryl substituted tetracyclic indoles.

New PDE4 inhibitors based on pharmacophoric similarity between papaverine and tofisopam.

Pharmacophoric comparison between papaverine and tofisopam led to identify three new series of micro- to sub-micromolar inhibitors of phosphodiesterase-4, including 7,8-dialkoxy-2,3-benzodiazepin-4-one derivatives, 7,8-dialkoxy-1,4-benzodiazepin-2-one derivatives, and dialkoxybenzophenone derivatives.

Intramolecular Aldol reaction of N-acylated (2-aminophenyl)-alpha-oxoacetic acids: rapid access to tri- and tetracyclic 1,2-dihydroquinolin-2(1H)-ones.

A four-step synthesis of tri- and tetracyclic 1,2-dihydroquinolin-2(1H)-ones via acylation of various substituted isatins with readily available N-Boc-protected aminoacids followed by an intramolecular aldol reaction and cyclization has been developed. The final products were obtained in moderate to excellent overall yields.

Synthesis of a photoactivatable probe of the anandamide re-uptake.

To date, despite extensive investigations, full understanding of the endocannabinoid system remains elusive; in particular, anandamide cellular uptake is a current controversial topic. An iodo-arylazido probe was synthesized from commercially available azelaic acid monomethyl ester, in order to shed light on the anandamide transport process.

Synthesis of the indolizino[7,6-c]quinoline alkaloid isaindigotidione.

The first synthesis of isaindigotidione has been developed utilizing a reaction sequence including an asymmetric rhodium-catalyzed 1,4-conjugate addition, an intramolecular aldol reaction, and a lactamization.

Microwave-assisted cyclic amidine synthesis using TiCl4.

Microwave-assisted treatment of various heterocyclic amides (benzodiazepinone, phthalazone) with TiCl(4) in the presence of primary or secondary amines provides the corresponding amidines. In addition to the interest of the microwaves for this reaction, our study highlights the higher reactivity of the cyclic acetamide moiety compared to the cyclic benzamide moiety towards this TiCl(4)-mediated reaction.