Sulfolane cycloreversion: Attemps to lower the activation energy for sulfur dioxide extrusion

The possibility to develop a practical synthesis of alkenes by SO2 extrusion from sulfolanes provides the basis for this thesis work.; Chapter 1 reviews the SO2 extrusion reaction and provides a brief overview of other olefination methods. While many alkene syntheses have been developed, new approaches could address the limitations of present methods, such as the low stereoselectivity or efficiency often encountered in complex molecule synthesis.; Chapter 2 outlines attempts to lower the activation energy for SO 2 extrusion from novel sulfolanes. Specifically, the design and synthesis of a fused, bicyclic sulfolane is described. Synthetic routes to two novel bicyclic sulfolanes containing key design criteria are described. The results of their thermally-induced SO2 extrusion reactions are presented, and these show the potential of the cycloreversion reaction in alkene synthesis.; Chapter 3 describes my research on analogs of our original sulfolane target. This research fortuitously resulted in the discovery of a new, improved method for the synthesis of 2-aminopyridines. Comparison of our method with previous syntheses of 2-aminopyridines clearly shows comparable product yields, yet our approach uses milder reaction conditions. Furthermore, the new synthesis circumvents the need for a transition metal catalyst. The key reagent, 2,3-dihydrothiazolo[3,2-a]pyridin-4-ylium bromide (3.2), is prepared in a single step in 91% yield. Purification of 3.2 is accomplished by simple recrystallization from ethanol. Its regioselective coupling to amines requires stirring with excess amine (>4 equivalents) at 50°C to furnish the 2-aminopyridine products in good yield (56--94%).; Chapter 4 describes additional syntheses of heterocyclic small molecule targets. This work aims to identify activators of CFTR, the chloride channel implicated in cystic fibrosis. During the course of these studies, a surprisingly mild intermolecular Diels-Alder reaction between anthracene and maleic anhydride was discovered. Initial investigations revealed that 9-hydroxymethylanthracene and 9-methoxymethylanthracene undergo room temperature cycloadditions in dichloromethane.; Flavonoid, pyrazole, thiophene and bicyclooctane panels prepared during the course of these studies were assayed for CFTR activation. Several active compounds were identified, including flavone UCCF-023, bicyclooctane 4.7 and thiophene 4.3. These compounds now serve as leads for QSAR optimization using combinatorial chemistry methods.