Reusable Glucose-Based Crown Ethers Anchored to PVC.

The recovery and reuse of the enantioselective catalysts produced by tedious work are important not only from the perspective of green chemistry, but also from the point of view of productivity. Some of the carbohydrate-based crown ethers prepared in our research group were able to generate significant asymmetric induction in certain cases. However, they were not recoverable after the synthesis. Therefore, we modified the most effective structure with a propargyl group so that it can be attached to a polymer with an azide-alkyne reaction. It was investigated whether the position of the bonding affects the activity of the crown ethers, hence, the propargyl group was introduced either to the side chain, to the anomeric center or to the benzylidene protecting group. To anchor the macrocycles, low molecular weight PVC was modified with azide groups in 4% and 10%, respectively. It was found that glucose-based crown ether bearing the propargyl group on the benzylidene unit and grafted to PVC in 4% has the highest activity regarding the enantioselectivity (77% ee). The catalyst was recoverable in the Michael addition of diethyl acetamidomalonate to nitrostyrene and it could be reused five times without the loss of enantioselectivity.

Continuous flow synthesis of 6-monoamino-6-monodeoxy-ß-cyclodextrin.

The first continuous flow method was developed for the synthesis of 6-monoamino-6-monodeoxy-ß-cyclodextrin starting from native ß-cyclodextrin through three reaction steps, such as monotosylation, azidation and reduction. All reaction steps were studied separately and optimized under continuous flow conditions. After the optimization, the reaction steps were coupled in a semi-continuous flow system, since a solvent exchange had to be performed after the tosylation. However, the azidation and the reduction steps were compatible to be coupled in one flow system obtaining 6-monoamino-6-monodeoxy-ß-cyclodextrin in a high yield. Our flow method developed is safer and faster than the batch approaches.

Fully Symmetric Cyclodextrin Polycarboxylates: How to Determine Reliable Protonation Constants from NMR Titration Data.

Acid-base properties of cyclodextrins (CDs), persubstituted at C-6 by 3-mercaptopropionic acid, sualphadex (Suα-CD), subetadex (Suß-CD) and sugammadex (Suγ-CD, the antidote of neuromuscular blocking steroids) were studied by 1H NMR-pH titrations. For each CD, the severe overlap in protonation steps prevented the calculation of macroscopic pKa values using the standard data fitting model. Considering the full symmetry of polycarboxylate structures, we reduced the number of unknown NMR parameters in the "Q-fitting" or the novel "equidistant macroscopic" evaluation approaches. These models already provided pKa values, but some of them proved to be physically unrealistic, deceptively suggesting cooperativity in carboxylate protonations. The latter problem could be circumvented by adapting the microscopic site-binding (cluster expansion) model by Borkovec, which applies pairwise interactivity parameters to quantify the mutual basicity-decreasing effect of carboxylate protonations. Surprisingly, only a single averaged interactivity parameter could be calculated reliably besides the carboxylate 'core' microconstant for each CD derivative. The speciation of protonation isomers hence could not be resolved, but the optimized microscopic basicity parameters could be converted to the following sets of macroscopic pKa values: 3.84, 4.35, 4.81, 5.31, 5.78, 6.28 for Suα-CD; 3.82, 4.31, 4.73, 5.18, 5.64, 6.06, 6.54 for Suß-CD and 3.83, 4.28, 4.65, 5.03, 5.43, 5.81, 6.18, 6.64 for Suγ-CD. The pH-dependent charge of these compounds can now be accurately calculated, in support of designing new analytical methods to exploit their charge-dependent molecular recognition such as in cyclodextrin-aided chiral capillary electrophoresis.

Sugammadex analogue cyclodextrins as chiral selectors for enantioseparation of cathinone derivatives by capillary electrophoresis.

The present contribution describes the application of three single-isomeric cyclodextrin derivatives for the first time - Sugammadex, Subetadex and Sualphadex as chiral selectors. Their recognition ability was investigated by means of chiral capillary electrophoresis, on a pool of cathinone and amphetamine derivatives. The selectors differ in cavity sizes and in the number of ionizable groups which evidently influenced their enantioselectivity performance. Their common feature is their high isomeric purity that enabled the detailed study of the molecular association between the cathinone guest and the cyclodextrin host at the atomic level. With the aid of enantiopure cathinone derivatives, the migration order could also be determined in capillary electrophoresis. As the result of the capillary electrophoresis screening, partial or baseline chiral separation of 19 cathinones and an amphetamine derivative could be achieved, and the systematic study was performed focusing on three different pH conditions pH = 7.0, pH = 5.0 and pH = 2.5 and several different selector concentrations. Among the tested derivatives Subetadex is the best performing chiral selector, especially under acidic pH values for separating enantiomers, proven not only by capillary electrophoresis but also by 1D and 2D NMR measurements.

Cyclodextrin-mediated quorum quenching in the Aliivibrio fischeri bioluminescence model system - Modulation of bacterial communication.

Bacterial Quorum Sensing is a cell-to-cell communication process, in which, bacteria, performing cooperative behaviour, produce and detect extracellular signalling chemicals, to monitor cell population density. Numerous bacterial processes including bioluminescence, virulence factor production, biofilm formation etc. are known to be influenced by this bacterial communication network. Interest in QS systems has emerged in response to the fact that these processes have significant impact on the environment, human health as well as agriculture. Cyclodextrins-mediated quorum quenching is an innovative approach and the available information about their effects is very scarce. We selected Aliivibrio fischeri, a bacterium, producing light, based on Quorum Sensing, to be the first to investigate the cyclodextrins' effect on this bioluminescence. A systematic study was performed with twelve different cyclodextrin compounds in order to determine their concentration- and time-dependent bioluminescence inhibitory effect in the A. fischeri model system. Especially high quorum quenching effect was found for α-cyclodextrin: 10 mM α-cyclodextrin at 120 min contact time which caused ~64% inhibition of bioluminescence. Experiments with the co-administration of α-cyclodextrin and N-(3-oxohexanoyl)-L-homoserine lactone, the signalling molecule of A. fischeri clearly showed, that the stimulating effect of this signal was diminished by α-cyclodextrin, suggesting, that complexation was responsible for the observed Quorum Sensing suppression. Although ß-cyclodextrin and its hydroxypropyl derivative significantly inhibited bioluminescence at as low as 0.156 mM concentration, their efficiency did not reach the level of α-cyclodextrin. According to our results, the autoinducer-dependent quorum sensing mechanism in Aliivibrio fischeri was markedly inhibited, the quorum quenching effect of cyclodextrins was clearly demonstrated. The efficiency was influenced by several parameters; the size of the interior cavity, the structure and the concentration of the cyclodextrins, as well as the contact time with the cells. The application of a cyclodextrin-trap for complexation of signal molecules may be a novel, promising method for influencing QS interfering strategies, for example, to enhance the efficiency of various biotechnologies, as well as to find alternative approaches against bacterial proliferation and infections. Furthermore, our results could also serve as a basis for further research with bacterial or plant model systems, in which the same chemical signals may induce physiological responses.