Heterobifunctional rotaxanes featuring two chiral subunits - synthesis and application in asymmetric organocatalysis.

Rotaxanes can serve as scaffolds for the generation of bifunctional catalysts. We have now generated acid-base functionalized rotaxanes featuring two chiral subunits. The mechanical bond leads to increased reaction rates and also to strongly altered enantioselectivites in comparison to the non-interlocked control catalysts.

Multifunctional Organocatalysts - Singly-Linked and Macrocyclic Bisphosphoric Acids for Asymmetric Phase-Transfer and Brønsted-Acid Catalysis.

The linking of phosphoric acids via covalent or mechanical bonds has proven to be a successful strategy for the design of novel organocatalysts. Here, we present the first systematic investigation of singly-linked and macrocyclic bisphosphoric acids, including their synthesis and their application in phase-transfer and Brønsted acid catalysis. We found that the novel bisphosphoric acids show dramatically increased enantioselectivities in comparison to their monophosphoric acid analogues. However, the nature, length and number of linkers has a profound influence on the enantioselectivities. In the asymmetric dearomative fluorination via phase-transfer catalysis, bisphosphoric acids with a single, rigid bisalkyne-linker give the best results with moderate to good enantiomeric excesses. In contrast, bisphosphoric acids with flexible linkers give excellent enantioselectivities in the transfer-hydrogenation of quinolines via cooperative Brønsted acid catalysis. In the latter case, sufficiently long linkers are needed for high stereoselectivities, as found experimentally and supported by DFT calculations.

Dual activity inhibition of threonine aspartase 1 by a single bisphosphate ligand.

Therapy resistance remains a challenge for the clinics. Here, dual-active chemicals that simultaneously inhibit independent functions in disease-relevant proteins are desired though highly challenging. As a model, we here addressed the unique protease threonine aspartase 1, involved in various cancers. We hypothesized that targeting basic residues in its bipartite nuclear localization signal (NLS) by precise bisphosphate ligands inhibits additional steps required for protease activity. We report the bisphosphate anionic bivalent inhibitor 11d, selectively binding to the basic NLS cluster (220KKRR223) with high affinity (K D = 300 nM), thereby disrupting its interaction and function with Importin α (IC50 = 6 µM). Cell-free assays revealed that 11d additionally affected the protease's catalytic substrate trans-cleavage activity. Importantly, functional assays comprehensively demonstrated that 11d inhibited threonine aspartase 1 also in living tumor cells. We demonstrate for the first time that intracellular interference with independent key functions in a disease-relevant protein by an inhibitor binding to a single site is possible.

Computational model predicts protein binding sites of a luminescent ligand equipped with guanidiniocarbonyl-pyrrole groups.

The 14-3-3 protein family, one of the first discovered phosphoserine/phosphothreonine binding proteins, has attracted interest not only because of its important role in the cell regulatory processes but also due to its enormous number of interactions with other proteins. Here, we use a computational approach to predict the binding sites of the designed hybrid compound featuring aggregation-induced emission luminophores as a potential supramolecular ligand for 14-3-3ζ in the presence and absence of C-Raf peptides. Our results suggest that the area above and below the central pore of the dimeric 14-3-3ζ protein is the most probable binding site for the ligand. Moreover, we predict that the position of the ligand is sensitive to the presence of phosphorylated C-Raf peptides. With a series of experiments, we confirmed the computational prediction of two C 2 related, dominating binding sites on 14-3-3ζ that may bind to two of the supramolecular ligand molecules.

BINOL as a chiral element in mechanically interlocked molecules.

In this minireview we present the use of the axially chiral 1,1'-binaphthyl-2,2'-diol (BINOL) unit as a stereogenic element in mechanically interlocked molecules (MIMs). We describe the synthesis and properties of such BINOL-based chiral MIMs, together with their use in further diastereoselective modifications, their application in asymmetric catalysis, and their use in stereoselective chemosensing. Given the growing importance of mechanically interlocked molecules and the key advantages of the privileged chiral BINOL backbone, we believe that this research area will continue to grow and deliver many useful applications in the future.

Tetraphenylethylene-embedded [15]paracyclophanes: AIEgen and macrocycle merged novel supramolecular hosts used for sensing Ni2+ ions.

Transformation of [15]paracyclophanes ([15]PCP) into fluorophores has been achieved by embedding tetraphenylethene (TPE) units into their skeletons at the meso-positions. The obtained two hosts demonstrated distinct aggregation-induced emission (AIE) properties and their fluorescence could be selectively quenched by Ni2+ ions.

A supramolecular double-helix based on complementary phosphate-guanidinium pairing.

A double-helical supramolecular structure was formed by self-assembly of 1,1'-binaphthyl-based bisguanidines and bisphosphoric acids. Interestingly the homochiral (S,S) + (S,S)-pair forms a left-handed double-helix, while the heterochiral (S,S) + (R,R)-pair forms a non-helical dimer.

Reversible Self-Assembly of Gold Nanoparticles Based on Co-Functionalization with Zwitterionic and Cationic Binding Motifs*.

We report a pH- and temperature-controlled reversible self-assembly of Au-nanoparticles (AuNPs) in water, based on their surface modification with cationic guanidiniocarbonyl pyrrole (GCP) and zwitterionic guanidiniocarbonyl pyrrole carboxylate (GCPZ) binding motifs. When both binding motifs are installed in a carefully balanced ratio, the resulting functionalized AuNPs self-assemble at pH 1, pH 7 and pH 13, whereas they disassemble at pH 3 and pH 11. Further disassembly can be achieved at elevated temperatures at pH 1 and pH 13. Thus, we were able to prepare functionalized nanoparticles that can be assembled/disassembled in seven alternating regimes, simply controlled by pH and temperature.

Heteroternary cucurbit[8]uril complexes as supramolecular scaffolds for self-assembled bifunctional photoredoxcatalysts.

The self-assembly of bifunctional photoredoxcatalysts is reported. A series of photosensitizers and water-reducing catalysts were functionalized with viologen- and naphthol-units, respectively. Subsequent formation of the heteroternary cucurbit[8]uril-viologen-naphthol complexes was used for the constitution of bifunctional photoredoxcatalysts for hydrogen generation.

Supramolecular polymers with reversed viscosity/temperature profile for application in motor oils.

We report novel supramolecular polymers, which possess a reversed viscosity/temperature profile. To this end, we developed a series of ditopic monomers featuring two self-complementary binding sites, either the guanidiniocarbonyl pyrrole carboxylic acid (GCP) or the aminopyridine carbonyl pyrrole carboxylic acid (ACP). At low temperatures, small cyclic structures are formed. However, at elevated temperatures, a ring-chain transformation leads to the formation of a supramolecular polymer. We demonstrate that this effect is dependent on the concentration of the solution and on the polarity of the solvent. This effect can counteract the loss of viscosity of the solvent at elevated temperatures, thus opening an application of our systems as viscosity index improvers (VIIs) in working fluids. This was tested for different motor oils and led to the identification of one compound as a promising VII.

Functional Rotaxanes in Catalysis.

Mechanically interlocked molecules (MIMs) have gained attention in the field of catalysis due to their unique molecular properties. Central to MIMs, rotaxanes are highly promising and attractive supramolecular catalysts due to their unique three-dimensional structures and the flexibility of their subcomponents. This Minireview discusses the use of rotaxanes in organocatalysis and transition-metal catalysis.

A Metallosupramolecular Coordination Polymer for the 'Turn-on' Fluorescence Detection of Hydrogen Sulfide.

A coumarin based probe for the efficient detection of hydrogen sulfide in aqueous medium is reported. The investigated coumarine-based derivative forms spherical nanoparticles in aqueous media. In presence of Pd2+, a metallosupramolecular coordination polymer is formed, which is accompanied by quenching of the coumarin emission at 390 nm. Its Pd2+ complex could be used as a probe for chemoselective detection of monohydrogensulfide (HS-). Presence of HS- leads to a'turn-on' fluorescence signal, resulting from decomplexation of Pd2+ from the metallosupramolecular probe. The probe was successfully applied for qualitative and quantitative detection of HS- in different sources of water directly collected from sea, river, tap and laboratory drain water, as well as in growth media for aquatic species.

Dual pH-Induced Reversible Self-Assembly of Gold Nanoparticles by Surface Functionalization with Zwitterionic Ligands.

The dual pH-induced reversible self-assembly (PIRSA) of Au-nanoparticles (Au NPs) is reported, based on their decoration with the self-complementary guanidiniocarbonyl pyrrole carboxylate zwitterion (GCPZ). The assembly of such functionalized Au NPs is found at neutral pH, based on supramolecular pairing of the GCPZ groups. The resulting self-assembled system can be switched back to the disassembled state by addition of base or acid. Two predominant effects that contribute to the dual-PIRSA of Au NPs are identified, namely the ionic hydrogen bonding between the GCPZ groups, but also a strong hydrophobic effect. The contribution of each interaction is depending on the concentration of GCPZ on NPs, which allows to control the self-assembly state over a wide range of different water/solvent ratios.

Guanidiniocarbonyl-Pyrroles (GCP) - 20 Years of the Schmuck Binding Motif.

In this Minireview, an overview about the past 20 years of the guanidiniocarbonyl-pyrrole (GCP) binding motif, which was designed, investigated and applied by Prof. Dr. Carsten Schmuck, is presented. Here we highlight the first steps from design and discovery, initial binding studies, applications in material science to advanced biomedical use in protein modulation and delivery of genetic material.

Functionalized Macrocycles in Supramolecular Organocatalysis.

Supramolecular organocatalysis has emerged as a novel research field in the context of homogeneous catalysis. In particular, the use of functionalized macrocycles as supramolecular catalysts is highly promising, as these systems are oftentimes easily accessible and offer distinct advantages in catalysis. Macrocyclic catalysts can provide defined binding pockets, such as hydrophobic cavities, and can thus create a reaction microenvironment for catalysis. In addition, macrocycles can offer a preorganized arrangement of functional groups, such as binding sites or catalytically active groups, thus enabling a defined and possibly multivalent binding and activation of substrates. The aim of this Minireview is to provide an overview of recent advances in the area of supramolecular organocatalysis based on functionalized macrocycles (including cyclodextrins, calixarenes, and resorcinarenes), with a focus on those examples where certain catalytically active groups (such as hydrogen bond donors/acceptors, Brønsted acid or base groups, or nucleophilic units) are present in or have been installed on the macrocycles.

A combined experimental and modelling approach for the Weimberg pathway optimisation.

The oxidative Weimberg pathway for the five-step pentose degradation to α-ketoglutarate is a key route for sustainable bioconversion of lignocellulosic biomass to added-value products and biofuels. The oxidative pathway from Caulobacter crescentus has been employed in in-vivo metabolic engineering with intact cells and in in-vitro enzyme cascades. The performance of such engineering approaches is often hampered by systems complexity, caused by non-linear kinetics and allosteric regulatory mechanisms. Here we report an iterative approach to construct and validate a quantitative model for the Weimberg pathway. Two sensitive points in pathway performance have been identified as follows: (1) product inhibition of the dehydrogenases (particularly in the absence of an efficient NAD+ recycling mechanism) and (2) balancing the activities of the dehydratases. The resulting model is utilized to design enzyme cascades for optimized conversion and to analyse pathway performance in C. cresensus cell-free extracts.

What is the role of acid-acid interactions in asymmetric phosphoric acid organocatalysis? A detailed mechanistic study using interlocked and non-interlocked catalysts.

Organocatalysis has revolutionized asymmetric synthesis. However, the supramolecular interactions of organocatalysts in solution are often neglected, although the formation of catalyst aggregates can have a strong impact on the catalytic reaction. For phosphoric acid based organocatalysts, we have now established that catalyst-catalyst interactions can be suppressed by using macrocyclic catalysts, which react predominantly in a monomeric fashion, while they can be favored by integration into a bifunctional catenane, which reacts mainly as phosphoric acid dimers. For acyclic phosphoric acids, we found a strongly concentration dependent behavior, involving both monomeric and dimeric catalytic pathways. Based on a detailed experimental analysis, DFT-calculations and direct NMR-based observation of the catalyst aggregates, we could demonstrate that intermolecular acid-acid interactions have a drastic influence on the reaction rate and stereoselectivity of asymmetric transfer-hydrogenation catalyzed by chiral phosphoric acids.

Heterobifunctional Rotaxanes for Asymmetric Catalysis.

Heterobifunctional rotaxanes serve as efficient catalysts for the addition of malonates to Michael acceptors. We report a series of four different heterobifunctional rotaxanes, featuring an amine-based thread and a chiral 1,1'-binaphthyl-phosphoric-acid-based macrocycle. High-level DFT calculations provided mechanistic insights and enabled rational catalyst improvements, leading to interlocked catalysts that surpass their non-interlocked counterparts in terms of reaction rates and stereoselectivities.

Multi-Stimuli-Responsive Supramolecular Polymers Based on Noncovalent and Dynamic Covalent Bonds.

Several modes of supramolecular assembly relying on noncovalent as well as dynamic covalent interactions were combined in a single molecule. The supramolecular self-assembly of 1 can be controlled by three stimuli, namely light, pH, and addition of metal ions, in both organic and aqueous media. The multi-stimuli-responsive nature of 1 was used successfully for the controlled encapsulation and on-demand release of hydrophobic molecules, such as dyes and drugs.