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Risultati finali
As a crucial milestone towards liquid supported membrane (SLM) mediated enantioseparation processes, novel highly enantioselective carriers for specific N-acylated amino acids were developed. Comprehensive HPLC screening of various chiral selectors (SOs) identified cinchona alkaloid derivatives as promising stereodiscriminating candidates for these target compounds (SAs). Further systematic chromatographic, spectroscopic, X-ray crystal structure and computational studies allowed to elucidate the general chiral recognition mechanisms for these SO/SA combinations. Guided by this mechanistic picture, combinatorial structure optimisation led to SOs displaying exceptionally high enantioselectivities (a-values up to 30) for specific SAs. These receptor-like SOs were attached to hydrophobic scaffolds (cholestane, higher alkanes, polysiloxanes) to generate highly lipophilic carrier systems. Using pH-gradients as a driving force, these carriers promote the highly enantioselective facilitated transport of a broad range of N-acylated amino acids across SLMs. The carriers are chemically very stable, fully compatible with polar aqueous media and show little tendency to SLM-degrading leaching effects. Moreover, they are characterised by high diffusivity, allowing for excellent SLM transport rates (crossmembrane fluxes up to 20 mmol.m-2.h-1). The corresponding polysiloxane-supported carrier systems are characterised by strong adhesion to various membrane materials, considerably improving SLM stability when used as additives. Preliminary experiments suggest that the developed carriers also may find successful applications in fields beyond SLM technology, e.g. for the enantioseparation of acidic chiral compounds via liquid-liquid extraction (LLE), micellar enhanced ultrafiltration (MEU) and countercurrent partition chromatography (CPC).
An innovative strategy for the preparation of enantioselective fixed site membranes (FSMs) based on molecularly imprinted polymers (MIPs) has been developed. Technically, this approach capitalises on the in-situ generation of selective MIPs within the intestinal volume of porous support materials, e.g. polypropylene ultrafiltration membranes. Using N-acylated amino acids as chiral templates in the imprinting process, various supported MIP type FSMs have been prepared, showing in diffusion experiments significant levels of enantioselectivity for the imprinted molecules. Currently, efforts are undertaken to further optimise the mechanical properties and to improve the transport capacity of these FSMs by implementing novel types of functional monomers and crosslinking agents for MIP synthesis. The conceptual simplicity of this strategy in combination with the well-established strategies for the generation of MIPs may provide a quite general and cost-effective way to produce substrate-specific affinity FSMs. It is also justified to anticipate a broad spectrum of applications for supported MIP type FSMs in the fields of pharmaceutical and biological sciences, not necessarily being restricted by the chiral separation technology.
Within this project, an enantioseparation process based on supported liquid membrane (SLM) technology has been developed. The membrane separation process capitalises on the capability of novel cinchona alkaloid derived carriers to promote enantioselective, pH-gradient-driven facilitated transport of N-acylated amino acids. For the technical implementation, a bench-scale separation unit comprising carrier-charged hollow fibre modules has been designed, manufactured and evaluated. Results with a racemic model analyte (DNB-leucine) revealed high levels of enantiomeric enrichment (up to 70% ee) after a single separation cycle with excellent crossmembrane fluxes (10 mmol.m-2.h-1). Simulated cascade type experiments gave the enantiomerically pure compound (ee > 99%) after 7 separation cycles. Excellent stability of the SLM was observed, showing no significant degradation in transmembrane flux or enantioselectivity within 2 months of continuous use. A particularly attractive feature of the developed SLM enantioseparation process is its favorable carrier/analyte economics. Preliminary estimates for a best-case-scenario indicate a daily productivity of 1 - 2 mol of pure enantiomer/mol carrier for low-molecular-mass compounds. This value compares quite well with figures reported for simulated moving bed (SMB) chromatography, a promising technology recently introduced for continuous industrial-scale enantioseparation. These results - in combination with the specific merits of membrane separation processes (ambient temperature processing, continuous operation mode, relatively straightforward and cost-effective up-scaling) - clearly indicate the high potential of SLM technology for large-scale enantioseparations.
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