Steric Engineering of Rotaxane Catalysts: Benefits and Limits of Using the Mechanical Bond in Catalyst Design.

The mechanical bond is emerging as a novel design element in catalyst development. Here, we report a series of 1,1´­binaphthyl-2,2´-diol (BINOL) based catalysts in which the number of interlocked macrocycles is varied. Unsurprisingly, the macrocycles have a profound steric influence on the catalytic performance of these molecules. However, in the enantioselective transformations examined, the macrocycles are detrimental to catalyst stereoselectivity whereas in lactide polymerization, they increase the molecular weight of the polymeric product.

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.

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.

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.

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.

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.

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.

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.

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.

Stereoselective Sensing of l- and d-Amino Acids: Development of a Fluorescence-Array Based on Readily Available Chiral Phosphoric Acids.

The identification of structurally related analytes has become possible using sensor arrays, based on sets of cross-reactive chemosensors. This work reports the use of readily available chiral phosphoric acids for the array-based, chemo- and stereoselective sensing of l- and d-amino acids. Six bis- and trisphosphoric acids were used in combination with Ni2+ and Eu3+ , resulting in a set of twelve chiral fluorescent chemosensors. This sensor-array enables a correct classification of l-amino acids with 100 % accuracy, while the differentiation between l- and d-amino acids can be achieved with 94 % accuracy. In addition, the systematic analysis of sensor contributions has allowed the use of a reduced set of seven sensors for the classification of l-amino acids, thus drastically reducing the amount of necessary measurements.

Synthesis of Furan-Annelated BINOL Derivatives: Acid-Catalyzed Cyclization Induces Partial Racemization.

In this account, we describe the synthesis of a series of BINOL-based bis- and trisphosphoric acids 11d/e/f, which commonly feature an unusual phosphoric acid monoester motif. This motif is generated by an acid-catalyzed 5- endo- dig cyclization of the 3-alkynyl-substituted BINOL precursors to give the corresponding Furan-annelated derivatives, followed by phosphorylation of the remaining phenolic alcohols. In the cyclization reaction, we observed an unexpected partial racemization in the bis- and tris-BINOL scaffolds, leading to mixtures of diastereomers that were separated and characterized spectroscopically and by X-ray crystal structure analyses. The cyclization and racemization processes were investigated both experimentally and by DFT-calculations, showing that although the cyclization proceeds faster, the barrier for the acid-catalyzed binaphthyl-racemization is only slightly higher.

Rigidly Tethered Bis-phosphoric Acids: Generation of Tunable Chiral Fluorescent Frameworks and Unexpected Selectivity for the Detection of Ferric Ions.

We describe the straightforward synthesis of a series of bis-phosphoric acids (R,R)-1 a-d, featuring two chiral 1,1'-binaphthyl-phosphoric acid units that are tethered by rigid, π-conjugated linkers. The nature of the linker has a profound influence on the properties of the bis-phosphoric acids, such as their self-association behavior and their interaction with metal ions. This led to the identification of one preferred bis-phosphoric acid (R,R)-1 d, which shows selective fluorescence quenching in the presence of ferric ions (Fe3+ ). Thus, (R,R)-1 d could be applied for the detection of Fe3+ , even in the presence of a variety of other metal ions. The chiral nature of the bis-phosphoric acid enables the interaction with Fe3+ to be followed by CD spectroscopy, providing a complementary detection mode with the same probe.

Functional Mechanically Interlocked Molecules: Asymmetric Organocatalysis with a Catenated Bifunctional Brønsted Acid.

Interlocked molecules, such as catenanes, rotaxanes, and molecular knots, have become interesting candidates for the development of sophisticated chemical catalysts. Herein, we report the first application of a catenane-based catalyst in asymmetric organocatalysis, revealing that the catenated catalyst shows dramatically increased stereoselectivities (up to 98 % ee) in comparison to its non-interlocked analogues. A mechanistic rationale for the observed differences was developed by DFT studies, suggesting that the involvement of two catalytically active groups in the stereodetermining reaction step is responsible for the superior selectivity of the interlocked catalyst.

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.

Molecular folding governs switchable singlet oxygen photoproduction in porphyrin-decorated bistable rotaxanes.

Rotaxanes are mechanically interlocked molecules where a ring (macrocycle) is threaded onto a linear molecule (thread). The position of the macrocycle on different stations on the thread can be controlled in response to external stimuli, making rotaxanes applicable as molecular switches. Here we show that bistable rotaxanes based on the combination of a Zn(II) tetraphenylporphyrin photosensitizer, attached to the macrocycle, and a black-hole-quencher, attached to the thread, are capable of singlet oxygen production which can be switched on/off by the addition of base/acid. However, we found that only a sufficiently long linker between both stations on the thread enabled switchability, and that the direction of switching was inversed with regard to the original design. This unexpected behavior was attributed to intramolecular folding of the rotaxanes, as indicated by extensive theoretical calculations. This evidences the importance to take into account the conformational flexibility of large molecular structures when designing functional switchable systems.

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.

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.

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.

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.