Simulation of the monooxygenation function of flavoenzyme (Fl-Enz) has been long-studied with N5-modified cationic flavins (FlEt+), but never with N5-unmodified neutral flavins (Fl) despite the fact that Fl is genuinely equal to the active center of Fl-Enz. This is because of the greater lability of 4a-hydroperoxy adduct of Fl, FlOOH, compared to those of FlEt+, FlEtOOH, and Fl-Enz, FlOOH-Enz. In this study, Fl incorporated into a short peptide, flavopeptide (Fl-Pep), was designed by a rational top-down approach using a computational method, which could stabilize the corresponding 4a-hydroperoxy adduct (FlOOH-Pep) through intramolecular hydrogen bonds. We report catalytic chemoselective sulfoxidation as well as Baeyer–Villiger oxidation by means of Fl-Pep under light-shielding and aerobic conditions, which are the first Fl-Enz-mimetic aerobic oxygenation reactions catalyzed by Fl under non-enzymatic conditions.

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Design of peptide-containing N5-unmodified neutral flavins that catalyze aerobic oxygenations.

Gold-catalyzed chemoselective α-methylenation of aromatic ketones was developed through the use of Selectfluor as a methylenating agent. A variety of useful 1,2-disubstituted propenone derivatives can be prepared in good yields via the present protocol. This reaction features a simple operation, good functional group tolerance, and broad scope of substrates.

Chemoselective α-Methylenation of Aromatic Ketones Using the NaAuCl4/Selectfluor/DMSO System

Near infrared (NIR) fluorescent dyes that are widely used for cancer imaging usually suffer from their hydrophobicity. To overcome this problem, a water-suspendable and biodegradable NIR-light-activating aza-BODIPY (AZB-NO2) encapsulated in polymeric nanoparticles was prepared as a new class of deep-tissue imaging agent. AZB-NO2 possesses an intense, broad NIR absorption band (600–800 nm) with a remarkably high fluorescent quantum yield. After being encapsulated with a biodegradable polycaprolactone (PCL) and a Kolliphor P188 surfactant by emulsification-solvent evaporation method, the AZB-NO2 formed a spherical shape as observed in scanning electron micrographs (SEM) with a hydrodynamic average size of 201 nm (average PDI = 0.185). The results from transmission electron micrographs (TEM) and energy dispersive X-ray spectroscopy (EDS) elemental mapping indicated that the AZB-NO2 homogeneously distributed in the polymeric shell. UV-visible-NIR and fluorescence spectra of the obtained nanoparticles, AZB-NO2@PCL, revealed that the nanoparticles prepared by using 0.8 mg dye loading exhibited the highest fluorescence quantum yield. These nanoparticles were then applied for fluorescence imaging in human glioblastoma cell line (U-251). After the cells were exposed to AZB-NO2@PCL, the materials appeared to be localized inside U-251 cells within 3 h and the fluorescence signal enhanced along with the increased incubation times. Moreover, 3D cell culture was used in this study to mimic in vivo tumor environments. The AZB-NO2@PCL exhibited bright fluorescence from U-251 cells inside 3D Ca-alginate scaffolds after 24 h incubation. Our study successfully demonstrated that the encapsulation of hydrophobic aza-BODIPY dye could enhance the water-suspendability of the dye yielding biocompatible nanoparticles efficiently used in cancer cell imaging applications.

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Aza-BODIPY based polymeric nanoparticles for cancer cell imaging

The first immobilization of a MacMillan’s first generation organocatalyst onto dendritic support is described. A modified tyrosinebased imidazolidin-4-one was grafted to a soluble high-loading hyperbranched polyglycerol via a copper-catalyzed alkyne–azide cycloaddition (CuAAC) reaction and readily purified by dialysis. The efficiency of differently functionalized multivalent organocatalysts 4a–c was tested in the asymmetric Friedel–Crafts alkylation of N-methylpyrrole with α,β-unsaturated aldehydes. A variety of substituted enals was investigated to explore the activity of the catalytic system which was also compared with monovalent analogues. The catalyst 4b showed excellent turnover rates and no loss of activity due to immobilization, albeit moderate enantioselectivities were observed. Moreover, easy recovery by selective precipitation allowed the reuse of the catalyst for three cycles.

https://www.beilstein-journals.org/bjoc/content/pdf/1860-5397-11-83.pdf

Multivalent polyglycerol supported imidazolidin-4-one organocatalysts for enantioselective Friedel-Crafts alkylations.

Unusually fast rates of nucleophilic catalysis of hydrazone ligation were observed when polyvalent anthranilic acid catalysts operating on polyvalent aldehyde substrates were used with PAMAM dendrimers as the common platform. When presented in this way, the catalyst has a strong accelerating effect at concentrations 40-400 times lower than those required for similar monovalent catalysts and displays unique kinetic parameters. We attribute these properties to polyvalent engagement between the dendrimer surface groups, and a potential "rolling" effect leading to fast interparticle kinetic turnover. The phenomenon is sensitive to the density of functional groups on each dendrimer, and insensitive to factors that promote or inhibit nonspecific particle aggregation. These findings constitute a rare experimental example of an underappreciated phenomenon in biological and chemical systems that are organized on interacting surfaces.

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Polyvalent Catalysts Operating on Polyvalent Substrates: A Model for Surface-Controlled Reactivity.

The polystyrene-supported N-alkylimidazole-based dendritic catalysts for the Baylis-Hillman reaction exhibit one of the strongest beneficial effects of multivalent architecture ever reported for an organocatalyst. The yields in the model reaction of methyl vinyl ketone with p-nitrobenzaldehyde are more than tripled when a non-dendritic catalyst is replaced by a second- or third-generation analogue. Moreover, the reaction of the less active substrates will not occur with the non-dendritic catalyst and will proceed to a significant extent only with the analogous catalysts of higher generations. A substantial additional enhancement of the reaction yield could be achieved by increasing the content of water in the reaction solvent. The plausible cause of the dendritic effect is the assistance of the second, nearby imidazole moiety in the presumably rate-determining proton transfer in the intermediate adduct, after the first imidazole unit induced the formation of the new carbon-carbon bond.

Multivalency as a Key Factor for High Activity of Selective Supported Organocatalysts for the Baylis–Hillman Reaction

While comparing analogous polystyrene-supported and homogeneous catalysts for the Baylis–Hillman reaction, we hypothesized that the hydrophobic envelopment of the imidazole catalytic sites of the former is responsible for the significantly better chemoselectivity exhibited by the heterogeneous catalysts compared to their homogeneous counterparts. In order to test this hypothesis, we prepared a series of branched/dendritic homogeneous catalysts, with an imidazole active site near the focal point and flexible tails of various lengths and polarities, capable of providing partial shielding of this site. The design of the catalysts was based on a 5-hydroxyisophthalate scaffold, and they were prepared through a number of multistep synthetic pathways. The comparison of the catalysts under a variety of conditions in a model Baylis–Hillman reaction demonstrated that long hydrophobic tales enhance the chemoselectivity parameter of the catalysis, while reducing the rate of the consumption of the substrates, and that the chemoselectivity is further improved by the presence of a free phenolic moiety in the vicinity of the catalytic imidazole unit. Moreover, in second-generation catalysts, the peripheral long tails could be either hydrophobic or polar, since the dendritic inner backbone itself presumably partially provides the necessary isolation of the catalytic site. Thus, experimental results support our hypothesis.

Chemoselectivity Improvement via Partial Shielding of an Imidazole Active Site in Branched/Dendritic Homogeneous Catalysts of the Baylis–Hillman Reaction

Capitalizing on our experience in constructing branched and dendritic monomers with functionalizable aromatic moiety at the focal point and various terminal groups, we prepared lipophilic and water-soluble dendrimers with BODIPY fluorophore in the core, emitting in the green and near IR spectral regions. The dendrimers, incorporating aliphatic tails, exhibited excellent fluorescence properties in apolar organic solvents, while those with the triethylenglycol-based tails were highly fluorescent in polar organic solvents as well. The water solubility induced by the terminal hexaethyleneglycol tails enables fluorescence of the dyes also in aqueous media. The phenolic hydroxyls in the molecules enable attachment of linkers for prospective conjugation of additional units.

Jeny Karabline-Kuks

Papers

Multivalency as a Key Factor for High Activity of Selective Supported Organocatalysts for the Baylis–Hillman Reaction

Chemoselectivity Improvement via Partial Shielding of an Imidazole Active Site in Branched/Dendritic Homogeneous Catalysts of the Baylis–Hillman Reaction

Design and Synthesis of BODIPY‐Cored Near IR‐emitting Lipophilic and Water‐Soluble Dendritic Platforms