Part I. Total synthesis of azaspiracid-3. Part II. Molecular recognition studies in aqueous solutions facilitated by a receptor modified polymer

Part I. Azaspiracids are novel marine toxins produced by microalgae of the genus Protoperidinium. They were first identified in 1995 following an incident of food poisoning in the Netherlands. The major toxin azaspiracid-1 was isolated in 1998 and its structure was unambigously determined in 2004 after its first total synthesis by Nicolaou et al. At least 11 analogues have been isolated and among them azaspiracid-1, -2 and -3 are the most potent toxins. Due to the difficulty of obtaining sufficient amount of toxin the studies towards their mechanism of action have been limited. The total synthesis of these toxins can provide sufficient material for biological studies as well as an opportunity to study structure activity relationships. Part I of this thesis reports the first total synthesis of azaspiracid-3. The synthetic strategy includes the same key reactions as those reported for the synthesis of azaspiracid-1; however, this synthetic route is shorter and more efficient.; Part II. It is well established that therapeutic drugs are designed to bind substrates through various types of noncovalent interactions such as electrostatic, hydrogen bonding, pi-pi stacking and Van der Waals interactions. Hosts based on electrostatic, hydrophobic and pi-pi stacking interactions have been reported in the literature for potential applications in aqueous media to emulate functions in biological systems. However, to enable specific binding of hydrogen bonding based artificial receptors for aqueous solution applications such as in sensor and biomedicine technology, one must circumvent the competing effect of water. We introduce a general approach for applying hydrogen bonding based receptors in water, by covalently attaching a purely hydrogen bonding based barbiturate receptor to a water-soluble amphiphilic polymer. Amphiphilic polymers are known to self-associate in aqueous media forming micelle-like microdomains. The hydrophobic environment of the micelle allows hydrogen bonding based recognition to occur. The binding of barbiturates to the receptor-modified polymer is studied via UV spectroscopy and affinity capillary electrophoresis.