title: Synthesis of novel aminophosphonate scaffolds from UGI-multicomponent reaction and their application as selectors for liquid chromatography
Creators: name: Gargano, Andrea
Publisher: name: :none
Year: 2013

description: Synthese von neuartigen Aminophosphonat Gerüste aus UGI-Mehrkomponenten-Reaktion und ihre Anwendungen als Selektoren für die Flüssigchromatographie. Die vorliegende Dissertation beschreibt eine neue Ugi Mehrkomponentenreaktion zur Herstellung von potentiellen phosphopeptidomimetic funktionalen Molekülen und ihre Anwendung bei der Entwicklung von neuartigen, zwitterionischen, chromatographischen Selektoren.
description: The present doctoral thesis describes a novel Ugi Multicomponent Reaction for the production of potential phosphopeptidomimetic functional molecules and its application to the development of novel zwitterionic chromatographic selectors. These novel amido aminophosphonate structures were synthesized as racemic mixtures starting from aminophosphonic acids reacted together with aldehydes and isonitriles educts. The design and the optimization of such one pot microwave based Ugi five-center four-component reaction (U-5C-4CR) synthetic pathway constitute the first part of the present work. Reaction conditions such as temperature, solvent and reaction time were extensively investigated in order to obtain optimal parameters. Based on the established reaction conditions we explored the synthetic scope using a variety of educts, generating the corresponding amido-aminophosphonates in moderate to high yields. Since in the development of bioactive structures the chirality is a fundamental parameter to be investigated, part of my research interest has been invested in the development of liquid chromatography methods to enantiomerically resolve both the aminophosphonic acid educts and the Ugi products. Aminophosphonic acids synthons were separated by means of HPLC on cinchona-based chiral zwitterionic ion-exchangers under polar organic chromatographic elution conditions. The application of this method for chiral educts in preparative scale offers the possibility of using enantiomerically pure synthons, conditions that reduce the stereochemicalcomplexity of the generated product (e.g. yielding two diastereomers instead of four stereoisomers). The separation of the Ugi-MCR phoshonate molecules was investigated as well adopting cinchona carbamate based stationary phases under chiral anion exchange conditions. This method offered the important advantage of obtaining by a single step both chemically and (when this was possible) enantiomerically pure compounds. Moreover from both of these studies the heterogeneity in terms of structural elements of the analytes allowed us to evaluate the influence of various structural motifs on enantioselectivity. Such elements of structure-enantioselectivity relationship are useful for the application of these methods to other structurally related analytes. The developed UGI combinatorial chemistry concept was exploited to devise new chromatographic ligands. Molecules selected for their interesting structural motifs were immobilized by thiol-ene click chemistry on silica beads. The chromatographic characteristics of these stationary phases were evaluated comparatively to corresponding commercially available columns. Interestingly multimodal separation capabilities were found for the novel selectors i.e. columns can be operated both in interaction liquid chromatography (HILIC) and in reversed-phase (RP) mode with good selectivity and efficiency. Moreover, the adopted synthetic approach offer the capability to generate chemical diversity simply by the variation of the starting aldehyde, aminophosphonic acid and/or isonitrile components. This unique characteristic offers great flexibility for the design of novel selectors for mixed mode chromatography, HILIC, affinity and chiral chromatography