Model-Based Nanoengineered Pharmacokinetics of Iron-Doped Copper Oxide for Nanomedical Applications

The progress in nanomedicine (NM) using nanoparticles (NPs) is mainly based on drug carriers for the delivery of classical chemotherapeutics. As low NM delivery rates limit therapeutic efficacy, an entirely different approach was investigated. A homologous series of engineered CuO NPs was designed for dual purposes (carrier and drug) with a direct chemical composition–biological functionality relationship. Model-based dissolution kinetics of CuO NPs in the cellular interior at post-exposure conditions were controlled through Fe-doping for intra/extra cellular Cu²⁺ and biological outcome. Through controlled ion release and reactions taking place in the cellular interior, tumors could be treated selectively, in vitro and in vivo. Locally administered NPs enabled tumor cells apoptosis and stimulated systemic anti-cancer immune responses. We clearly show therapeutic effects without tumor cells relapse post-treatment with 6 % Fe-doped CuO NPs combined with myeloid-derived suppressor cell silencing.     

Desymmetrization of Dicationic Diboranes by Isomerization Catalyzed by a Nucleophile

Cationic monoboranes exhibit a rich chemistry. By constrast, only a few cationic diboranes are known, that all are symmetrically substituted. In this work, the first unsymmetrically substituted dicationic diboranes, featuring sp²–sp²‐hybridized boron atoms, are reported. The compounds are formed by intramolecular rearrangement from preceding isomeric symmetrically substituted dicationic diboranes, a process that is catalyzed by nucleophiles. From the temperature‐dependence of the isomerization rate, activation parameters for this unprecedented rearrangement are derived. The difference in fluoride ion affinity between the two boron atoms and the bonding situation in these unique unsymmetrical dicationic diboranes are evaluated.     

Photo‐Induced Ruthenium‐Catalyzed C−H Arylations at Ambient Temperature

Ambient temperature ruthenium‐catalyzed C?H arylations were accomplished by visible light without additional photocatalysts. The robustness of the ruthenium‐catalyzed C?H functionalization protocol was reflected by a broad range of sensitive functional groups and synthetically useful pyrazoles, triazoles and sensitive nucleosides and nucleotides, as well as multifold C?H functionalizations. Biscyclometalated ruthenium complexes were identified as the key intermediates in the photoredox ruthenium catalysis by detailed computational and experimental mechanistic analysis. Calculations suggested that the in situ formed photoactive ruthenium species preferably underwent an inner‐sphere electron transfer.     

Recyclable Ruthenium Catalyst for Distal meta-C−H Activation

We disclose the unprecedented hybrid-ruthenium catalysis for distal meta-C−H activation. The hybrid-ruthenium catalyst was recyclable, as was proven by various heterogeneity tests, and fully characterized with various microscopic and spectroscopic techniques, highlighting the physical and chemical stability. Thereby, the hybrid-ruthenium catalysis proved broadly applicable for meta-C−H alkylations of among others purine-based nucleosides and natural product conjugates. Additionally, its versatility was further reflected by meta-C−H activations through visible-light irradiation, as well as para-selective C−H activations.     

Reaction Pathways and Redox States in α-Selective Cobalt-Catalyzed Hydroborations of Alkynes

Cobalt(II) alkyl complexes supported by a monoanionic NNN pincer ligand are pre-catalysts for the regioselective hydroboration of terminal alkynes, yielding the Markovnikov products with α:β-(E) ratios of up to 97:3. A cobalt(II) hydride and a cobalt(II) vinyl complex appear to determine the main reaction pathway. In a background reaction the highly reactive hydrido species specifically converts to a coordinatively unsaturated cobalt(I) complex which was found to re-enter the main catalytic cycle.     

Regioselective B(3,4)–H arylation of o-carboranes by weak amide coordination at room temperature

Palladium-catalyzed regioselective di- or mono-arylation of o-carboranes was achieved using weakly coordinating amides at room temperature. Therefore, a series of B(3,4)-diarylated and B(3)-monoarylated o-carboranes anchored with valuable functional groups were accessed for the first time. This strategy provided an efficient approach for the selective activation of B(3,4)–H bonds for regioselective functionalizations of o-carboranes.

B–H: site-selective B(3,4)–H arylations were accomplished at room temperature by versatile palladium catalysis enabled by weakly coordinating amides.

o-Carboranes, icosahedral carboranes – three-dimensional arene analogues – represent an important class of carbon–boron molecular clusters.¹ The regioselective functionalization of o-carboranes has attracted growing interest due to its potential applications in supramolecular design,² medicine,³ optoelectronics,⁴ nanomaterials,⁵ boron neutron capture therapy agents⁶ and organometallic/coordination chemistry.⁷ In recent years, transition metal-catalyzed cage B–H activation for the regioselective boron functionalization of o-carboranes has emerged as a powerful tool for molecular syntheses. However, the 10 B–H bonds of o-carboranes are not equal, and the unique structural motif renders their selective functionalization difficult, since the charge differences are very small and the electrophilic reactivity in unfunctionalized o-carboranes reduces in the following order: B(9,12) > B(8,10) > B(4,5,7,11) > B(3,6).⁸ Therefore, efficient and selective boron substitution of o-carboranes continues to be a major challenge.Recently, transition metal-catalyzed carboxylic acid or formyl-directed B(4,5)–H functionalization of o-carboranes has drawn increasing interest, since it provides an efficient approach for direct regioselective boron–carbon and boron–heteroatom bond formations (Scheme 1a),⁹ with major contributions by the groups of Xie,¹⁰ and Yan,¹¹ among others.¹² Likewise, pyridyl-directed B(3,6)–H acyloxylations (Scheme 1b),¹³ and amide-assisted B(4,7,8)–H arylations¹⁴ (Scheme 1c) have been enabled by rhodium or palladium catalysis, respectively.^15,16 Despite indisputable progress, efficient approaches for complementary site-selective functionalizations of o-carboranes are hence in high demand.¹⁷ Hence, metal-catalyzed position-selective B(3,4)–H functionalizations of o-carboranes have thus far not been reported.Open in a separate windowScheme 1Chelation-assisted transition metal-catalyzed cage B–H activation of o-carboranes.Arylated compounds represent key structural motifs in inter alia functional materials, biologically active compounds, and natural products.¹⁸ In recent years, transition metal-catalyzed chelation-assisted arylations have received significant attention as environmentally benign and economically superior alternatives to traditional cross-coupling reactions.¹⁹ Within our program on sustainable C–H activation,²⁰ we have now devised a protocol for unprecedented cage B–H arylations of o-carboranes with weak amide assistance, on which we report herein. Notable features of our findings include (a) transition metal-catalyzed room temperature B–H functionalization, (b) high levels of positional control, delivering B(3,4)-diarylated and B(3)-monoarylated o-carboranes, and (c) mechanistic insights from DFT computation providing strong support for selective B–H arylation (Scheme 1d).We initiated our studies by probing various reaction conditions for the envisioned palladium-catalyzed B–H arylation of o-carborane amide 1a with 1-iodo-4-methylbenzene (2a) at room temperature (Tables 1 and S1^†). We were delighted to observe that the unexpected B(3,4)-di-arylated product 3aa was obtained in 59% yield in the presence of 10 mol% Pd(OAc)₂ and 2 equiv. of AgTFA, when HFIP was employed as the solvent, which proved to be the optimal choice (entries 1–5).²¹ Control experiments confirmed the essential role of the palladium catalyst and silver additive (entries 6–7). Further optimization revealed that AgOAc, Ag₂O, K₂HPO₄, and Na₂CO₃ failed to show any beneficial effect (entries 8–11). Increasing the reaction temperature fell short in improving the performance (entries 12 and 13). The replacement of the amide group in substrate 1a with a carboxylic acid, aldehyde, ketone, or ester group failed to afford the desired arylation product (see the ESI^†). We were pleased to find that the use of 1.0 equiv. of trifluoroacetic acid (TFA) as an additive improved the yield to 71% (entry 14). To our delight, replacing the silver additive with Ag₂CO₃ resulted in the formation of B(3)–H mono-arylation product 4aa as the major product (entries 15–16).Optimization of reaction conditions^a

"Cofactor"-controlled enantioselective catalysis

We report an achiral bisphosphine rhodium complex equipped with a binding site for the recognition of chiral anion guests. Upon binding small chiral guests--cofactors--the rhodium complex becomes chiral and can thus be used for asymmetric catalysis. Screening of a library of cofactors revealed that the best cofactors lead to hydrogenation catalysts that form the products with high enantioselectivity (ee's up to 99%). Interestingly, a competition experiment shows that even in a mixture of 12 cofactors high ee is obtained, indicating that the complex based on the best cofactor dominates the catalysis.