STUDIES DIRECTED TOWARDS THE SYNTHESIS OF 10-ALPHA-FLUORO-THROMBOXANE A(2). A GENERAL STRATEGY TOWARDS EICOSANOID SYNTHESIS: THE TOTAL SYNTHESIS OF 5-, 12- AND 15 HETE. 1,2-MIGRATIONS IN CARBOHYDRATE CHEMISTRY

Thromboxane A(,2) is an extremely labile substance that possesses platelet aggregating and vasoconstricting properties. In Chapter 1 of this dissertation is described the studies directed towards the synthesis of the closest analogue of TXA(,2) known to date, 10-fluoro-thromboxane A(,2). It was reasoned that an electron withdrawing group such as fluorine would stabilize the bicyclic acetal, which is the source of instability in the natural product. That this indeed was the case is shown via the synthesis, from a carbohydrate precursor, of a model system possessing the fluoro-acetal structure. The C-8 (thromboxane numbering) stereochemistry was established by an intramolecular hydride reduction, while the crucial oxetane structure was synthesized using an intramolecular Mitsunobu reaction, following the method of Still et. al. The model system described herein may be converted to the target compound simply by elaboration of the side chains using commercially available Wittig reagents. The products of the lipoxygenase pathway of arachidonic acid metabolism have been implicated in inflammation and other allergic responses. In order to gain access to these compounds we sought a general strategy that focuses on the synthesis of the cis-trans diene system that is present in many of the HETEs and leukotrienes. The synthetic methodology involved a Heck type Pd(o) coupling of a trans-vinyl bromide and an acetylene. The acetylene is subsequently reduced with Lindlau catalyst to furnish the cis-component of the cis/trans unit. The success of this methodology for the synthesis of these compounds is illustrated in Chapter 2, where the total synthesis of 5-, 12- and 15-hydroxyeicosatetraenoic acids are described. In chapter 3 a facile 1,2-migration of oxygen, sulfur and nitrogen on pyranose systems is described. This reaction provides an easy access to anomeric fluorides that have been previously reported as being extremely useful in glycoside synthesis. Furthermore, the described methodology may be used for the simultaneous inversion of the C-2 center (as in the cases of -OAc, OMe, OBn migrations), for easy access to 2-deoxy sugars (-SPh migrations) and for the synthesis of amino sugars (-N(,3) migrations). The reaction was performed on a variety of substrates and therefore considered compatible with most protecting groups