Annulation-Induced Hidden Reactivity of the 1,2,4-Triazole Backbone

Triazoles are an important class of compounds with widespread applications. Functionalization of the triazole backbone is thus of significant interest. In comparison to 1,2,3-triazoles, C−H activation-functionalization of the congeners 1,2,4-triazoles is surprisingly underdeveloped. Indeed, no such C−H activation-functionalization has been reported for 4-substituted 1,2,4-triazole cores. Furthermore, although denitrogenative ring-opening of 1,2,3-triazoles is well-explored, 1,2,4-triazole/triazolium substrates have not been known to exhibit N−N bond-cleaving ring-opening reactivity so far. In this work, we unveiled an unusual hidden reactivity of the 1,2,4-triazole backbone involving the elusive N−N bond-cleaving ring-opening reaction. This new reactivity was induced by a Satoh-Miura-type C−H activation-annulation at the 1,2,4-triazole motif appended with a pyridine directing group. This unique reaction allowed ready access to a novel class of unsymmetrically substituted 2,2′-dipyridylamines, with one pyridine ring fully-substituted with alkyl groups. The unsymmetrical 2,2′-dipyridylamines were utilized to access unsymmetrical boron-aza-dipyridylmethene fluorescent dyes. Empowered with desirable optical/physical properties such as large Stokes shifts and suitable hydrophobicity arising from optimal alkyl chain length at the fully-substituted pyridine-ring, these dyes were used for intracellular lipid droplet-selective imaging studies, which provided useful information toward designing suitable lipid droplet-selective imaging probes for biomedical applications.     

Steering the Selectivity of Electrocatalytic Glucose Oxidation by the Pt Oxidation State

Electrocatalytic glucose oxidation can produce high value chemicals, but selectivity needs to be improved. Here we elucidate the role of the Pt oxidation state on the activity and selectivity of electrocatalytic oxidation of glucose with a new analytical approach, using high-pressure liquid chromatography and high-pressure anion exchange chromatography. It was found that the type of oxidation, i.e. dehydrogenation of primary and secondary alcohol groups or oxygen transfer to aldehyde groups, strongly depends on the Pt oxidation state. Pt⁰ has a 7-fold higher activity for dehydrogenation reactions than for oxidation reactions, while PtO_x is equally active for both reactions. Thus, Pt⁰ promotes glucose dialdehyde formation, while PtO_x favors gluconate formation. The successive dehydrogenation of gluconate is achieved selectively at the primary alcohol group by Pt⁰, while PtO_x also promotes the dehydrogenation of secondary alcohol groups, resulting in more complex reaction mixtures.     

Collective Total Synthesis of 4-Azafluorenone Alkaloids

4-Azafluorenones are typically obtained by acid-mediated cyclization of 2-arylnicotinates. However, this approach fails to give 5-oxygenated 4-azafluorenones due to lactonization of 2-(2-alkoxy)phenylnicotinate intermediates. Herein, we report two modifications of established approaches to 4-azafluorenone synthesis that, either in combination or by themselves, enable the flexible preparation of 4-azafluorenones with diverse oxygenation patterns in the benzenoid ring. Undesired lactonization was circumvented via tert-butyl hydroperoxide (TBHP)-mediated radical cyclization of 2-aryl-3-(hydroxymethyl)pyridines. In the absence of suitable protecting groups for phenolic intermediates, bromide substituents were regioselectively introduced as latent hydroxy groups and later converted under palladium catalysis. We present the first total syntheses of five 4-azafluorenone alkaloids muniranine, darienine, 5,8-dimethoxy-7-hydroxyonychine, 5,6,7,8-tetramethoxyonychine, and 6,8-dihydroxy-7-methoxyonychine in addition to new total syntheses of six 4-azafluorenone alkaloids and one related pyridocoumarin alkaloid.     

Solvent Dependency of Catalyst-Substrate Aggregation Through π-π Stacking in Photoredox Catalysis

Assemblies of photoredox catalysts and their target substrates prior to photoexcitation is a phenomenon naïvely overlooked by the majority of synthetic chemists, but can have profound influences on reactivity and selectivity in photocatalytic reactions. In this study, we determine the aggregation states of triarylamine radical cationic photocatalysts with various target arene substrates in different solvents by specifically parameterized polarizable molecular dynamics simulations. A π-stacking interaction previously implicated by more expensive, less-representative quantum calculations is confirmed. Critically, this study presents new insights on: i) the ability of solvents (MeCN vs DMF) to make or break a photocatalytic reaction by promoting (MeCN) or demoting (DMF) its catalyst-substrate assemblies, which is a determining factor for reactivity, ii) the average “lifetimes” of assemblies in solution from a dynamic simulation. We find that both in the ground state and the photoexcited state, the cationic radical assemblies remain intact for periods often higher than 60 ps, rendering them ideally suitable to undergo intra-assembly electron transfer reactions upon photoexcitation. Such aspects have not addressed by previous studies on synthetic photocatalytic reactions involving non-covalent assemblies.     

The Role of Mechanical Properties and Structure of Type I Collagen Hydrogels on Colorectal Cancer Cell Migration

Mechanical interactions between cells and their microenvironment play an important role in determining cell fate, which is particularly relevant in metastasis, a process where cells invade tissue matrices with different mechanical properties. In vitro, type I collagen hydrogels have been commonly used for modeling the microenvironment due to its ubiquity in the human body. In this work, the combined influence of the stiffness of these hydrogels and their ultrastructure on the migration patterns of HCT-116 and HT-29 spheroids are analyzed. For this, six different types of pure type I collagen hydrogels by changing the collagen concentration and the gelation temperature are prepared. The stiffness of each sample is measured and its ultrastructure is characterized. Cell migration studies are then performed by seeding the spheroids in three different spatial conditions. It is shown that changes in the aforementioned parameters lead to differences in the mechanical stiffness of the matrices as well as the ultrastructure. These differences, in turn, lead to distinct cell migration patterns of HCT-116 and HT-29 spheroids in either of the spatial conditions tested. Based on these results, it is concluded that the stiffness and the ultrastructural organization of the matrix can actively modulate cell migration behavior in colorectal cancer spheroids.