Biomimetic Non-Heme Iron-Catalyzed Epoxidation of Challenging Terminal Alkenes Using Aqueous H2O2 as an Environmentally Friendly Oxidant

Catalysis mediated by iron complexes is emerging as an eco-friendly and inexpensive option in comparison to traditional metal catalysis. The epoxidation of alkenes constitutes an attractive application of iron(III) catalysis, in which terminal olefins are challenging substrates. Herein, we describe our study on the design of biomimetic non-heme ligands for the in situ generation of iron(III) complexes and their evaluation as potential catalysts in epoxidation of terminal olefins. Since it is well-known that active sites of oxidases might involve imidazole fragment of histidine, various simple imidazole derivatives (seven compounds) were initially evaluated in order to find the best reaction conditions and to develop, subsequently, more elaborated amino acid-derived peptide-like chiral ligands (10 derivatives) for enantioselective epoxidations

Four-Step Domino Reaction Enables Fully Controlled Non-Statistical Synthesis of Hexaarylbenzene with Six Different Aryl Groups*

Hexaarylbenzene (HAB) derivatives are versatile aromatic systems playing a significant role as chromophores, liquid crystalline materials, molecular receptors, molecular-scale devices, organic light-emitting diodes and candidates for organic electronics. Statistical synthesis of simple symmetrical HABs is known via cyclotrimerization or Diels–Alder reactions. By contrast, the synthesis of more complex, asymmetrical systems, and without involvement of statistical steps, remains an unsolved problem. Here we present a generally applicable synthetic strategy to access asymmetrical HAB via an atom-economical and high-yielding metal-free four-step domino reaction using nitrostyrenes and α,α-dicyanoolefins as easily available starting materials. Resulting domino product—functionalized triarylbenzene (TAB)—can be used as a key starting compound to furnish asymmetrically substituted hexaarylbenzenes in high overall yield and without involvement of statistical steps. This straightforward domino process represents a distinct approach to create diverse and still unexplored HAB scaffolds, containing six different aromatic rings around central benzene core. © 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH Gmb

Generation of Complex Azabicycles and Carbobicycles from Two Simple Compounds in a Single Operation through a Metal‐Free Six‐Step Domino Reaction

Aza‐ and carbobicyclic compounds possess favorable pharmaceutical properties, but they are difficult to access. Herein, we demonstrate an unprecedented organocatalytic two component six‐step chemodivergent domino reaction, which provides a straightforward, sustainable and atom economical route to difficult‐to‐access complex bicyclic architectures: azabicycles and carbobicycles, whose ratios can be controlled by the applied electrophiles and catalysts. Detailed NMR and X‐ray studies on the structures and relative stereochemistry of selected compounds are presented. Mechanistic investigations of the chemoselective branching step have been carried out with DFT methods in conjunction with semiempirical van der Waals interactions. This new domino reaction opens up a new vista of generating, in a single operation, new bioactive compounds with strong antiviral properties (EC50 up to 0.071 μm for human cytomegalovirus (HCMV)) outperforming clinically used ganciclovir (EC50 2.6 μm).Six steps in one go! An unprecedented two component six‐step domino reaction, providing a straightforward and atom economical route to bioactive azabicycles and carbobicycles is presented. DFT calculations accounting for dispersion interactions revealed that chemoselectivity might result from small differences in transition state and reaction energies of the branching step. This reaction opens up a new vista of generating, in a single operation, new antivirals outperforming clinically used drugs.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137557/1/chem201504798.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137557/2/chem201504798_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137557/3/chem201504798-sup-0001-misc_information.pd

One-pot synthesis of (R)-convolutamydine A involving in situ chiral organocatalyst formation

The application of a convenient one-pot synthetic strategy, utilizing an in situ formed organocatalyst, to the enantioselective synthesis of anti-leukaemia agent (R)-convolutamydine A has been demonstrated

Combinatorial Drug Treatments Reveal Promising Anticytomegaloviral Profiles for Clinically Relevant Pharmaceutical Kinase Inhibitors (PKIs)

Human cytomegalovirus (HCMV) is a human pathogenic herpesvirus associated with a variety of clinical symptoms. Current antiviral therapy is not always effective, so that improved drug classes and drug-targeting strategies are needed. Particularly host-directed antivirals, including pharmaceutical kinase inhibitors (PKIs), may help to overcome problems of drug resistance. Here, we focused on utilizing a selection of clinically relevant PKIs and determined their anticytomegaloviral efficacies. Particularly, PKIs directed to host or viral cyclin-dependent kinases, i.e., abemaciclib, LDC4297 and maribavir, exerted promising profiles against human and murine cytomegaloviruses. The anti-HCMV in vitro activity of the approved anti-cancer drug abemaciclib was confirmed in vivo using our luciferase-based murine cytomegalovirus (MCMV) animal model in immunocompetent mice. To assess drug combinations, we applied the Bliss independence checkerboard and Loewe additivity fixed-dose assays in parallel. Results revealed that (i) both affirmative approaches provided valuable information on anti-CMV drug efficacies and interactions, (ii) the analyzed combinations comprised additive, synergistic or antagonistic drug interactions consistent with the drugs’ antiviral mode-of-action, (iii) the selected PKIs, especially LDC4297, showed promising inhibitory profiles, not only against HCMV but also other α-, β- and γ-herpesviruses, and specifically, (iv) the combination treatment with LDC4297 and maribavir revealed a strong synergism against HCMV, which might open doors towards novel clinical options in the near future. Taken together, this study highlights the potential of therapeutic drug combinations of current developmental/preclinical PKIs

Development of a PROTAC-Based Targeting Strategy Provides a Mechanistically Unique Mode of Anti-Cytomegalovirus Activity

Human cytomegalovirus (HCMV) is a major pathogenic herpesvirus that is prevalent worldwide and it is associated with a variety of clinical symptoms. Current antiviral therapy options do not fully satisfy the medical needs; thus, improved drug classes and drug-targeting strategies are required. In particular, host-directed antivirals, including pharmaceutical kinase inhibitors, might help improve the drug qualities. Here, we focused on utilizing PROteolysis TArgeting Chimeras (PROTACs), i.e., hetero-bifunctional molecules containing two elements, namely a target-binding molecule and a proteolysis-inducing element. Specifically, a PROTAC that was based on a cyclin-dependent kinase (CDK) inhibitor, i.e., CDK9-directed PROTAC THAL-SNS032, was analyzed and proved to possess strong anti-HCMV AD169-GFP activity, with values of EC50 of 0.030 µM and CC50 of 0.175 µM (SI of 5.8). Comparing the effect of THAL-SNS032 with its non-PROTAC counterpart SNS032, data indicated a 3.7-fold stronger anti-HCMV efficacy. This antiviral activity, as illustrated for further clinically relevant strains of human and murine CMVs, coincided with the mid-nanomolar concentration range necessary for a drug-induced degradation of the primary (CDK9) and secondary targets (CDK1, CDK2, CDK7). In addition, further antiviral activities were demonstrated, such as the inhibition of SARS-CoV-2 replication, whereas other investigated human viruses (i.e., varicella zoster virus, adenovirus type 2, and Zika virus) were found insensitive. Combined, the antiviral quality of this approach is seen in its (i) mechanistic uniqueness; (ii) future options of combinatorial drug treatment; (iii) potential broad-spectrum activity; and (iv) applicability in clinically relevant antiviral models. These novel data are discussed in light of the current achievements of anti-HCMV drug development

Spatial Modes of Laser-Induced Mass Transfer in Micro-Gaps

We have observed the concentric deposition patterns of small molecules transferred by means of laser-induced forward transfer (LIFT). The patterns comprised different parts whose presence changed with the experimental constraints in a mode-like fashion. In experiments, we studied this previously unknown phenomenon and derived model assumptions for its emergence. We identified aerosol micro-flow and geometric confinement as the mechanism behind the mass transfer and the cause of the concentric patterns. We validated our model using a simulation

Facile access to potent antiviral quinazoline heterocycles with fluorescence properties via merging metal-free domino reactions

Most of the known approved drugs comprise functionalized heterocyclic compounds as subunits. Among them, non-fluorescent quinazolines with four different substitution patterns are found in a variety of clinically used pharmaceuticals, while 4,5,7,8-substituted quinazolines and those displaying their own specific fluorescence, favourable for cellular uptake visualization, have not been described so far. Here we report the development of a one-pot synthetic strategy to access these 4,5,7,8-substituted quinazolines, which are fluorescent and feature strong antiviral properties (EC$_{50}$ down to 0.6±0.1 μM) against human cytomegalovirus (HCMV). Merging multistep domino processes in one-pot under fully metal-free conditions leads to sustainable, maximum efficient and high-yielding organic synthesis. Furthermore, generation of artesunic acid–quinazoline hybrids and their application against HCMV (EC$_{50}$ down to 0.1±0.0 μM) is demonstrated. Fluorescence of new antiviral hybrids and quinazolines has potential applications in molecular imaging in drug development and mechanistic studies, avoiding requirement of linkage to external fluorescent markers

Iron-Catalyzed Carbonyl−Alkyne and Carbonyl−Olefin Metathesis Reactions

Construction of carbon–carbon bonds is one of the most important tools for the synthesis of complex organic molecules. Among multiple possibilities are the carbonyl–alkyne and carbonyl–olefin metathesis reactions, which are used to form new carbon–carbon bonds between carbonyl derivatives and unsaturated organic compounds. As many different approaches have already been established and offer reliable access to C=C bond formation via carbonyl–alkyne and carbonyl–olefin metathesis, focus is now shifting towards cost efficiency, sustainability and environmentally friendly metal catalysts. Iron, which is earth-abundant and considered as an eco-friendly and inexpensive option in comparison to traditional metal catalysts, fulfils these requirements. Hence, the focus of this review is on recent advances in the iron-catalyzed carbonyl–alkyne, carbonyl–olefin and related C–O/C–O metathesis reactions. The still large research potential for ecologically and economically attractive and sustainable iron-based catalysts is demonstrated

Asymmetric cycloaddition reactions catalyzed by bifunctional thiourea and squaramide organocatalysts: recent advances

High on the list of challenges in organic chemistry is the development of new efficient chiral catalysts for enantioselective cycloaddition reactions, which are among the most useful processes in chemical synthesis. In the past few decades, various highly enantioselective bifunctional organocatalysts for different versatile cycloaddition reactions have been developed. In most cases, these organocatalytic cycloadditions (e.g. [4 + 2], [3 + 2], formal [3 + 2], formal [3 + 3], formal [5 + 1], [5 + 2], 1,3-dipolar cycloadditions and Tamura cycloaddition) provide the most convenient and economical routes to nitrogen- and oxygen-containing heterocyclic bioactive molecules. This minireview summarizes the recent developments in this field using chiral bifunctional amine-thiourea and amine-squaramide organocatalysts