| Chiral anthracene derivatives have been utilized as diene systems in Diels-Alder reactions where they play the role of a chiral template. This involves diastereoselective cycloadditions with maleate-derived dienophiles, followed by stereocontrolled transformations of the dienophile subunit while mounted on the anthracene, and finally the release of the desired transformed dienophile while regenerating the chiral anthracene template in a retro Diels-Alder cycloreversion. At the heart of the concept lies the ability to accomplish the initial cycloadditions in high enantiomeric purity. The modest reactivity of anthracene derivatives as dienes in cycloadditions, and the inherent difficulty in enantioselective Diels-Alder cycloadditions of maleate-derived dienophiles due to their symmetry, makes this a difficult problem. The goal of this research was to develop chiral anthracene-based templates for this cycloaddition cycloreversion strategy, then apply them in the synthesis of chiral enantiopure furanone-type compounds such as butenolides.; Two approaches to the construction of chiral enantiopure cycloadducts of anthracene were undertaken. In the first approach, cycloadditions of C 2 symmetric 1,5-disubstituted anthracenes with C2v-symmetric maleimide dienophiles in the presence of chiral Lewis acid catalysts provided the cycloadducts, but with only an optimized enantioselectivity of 33%. In the second more successful approach, chiral 9-substituted anthracenes, 9-(1-hydroxyethyl)-anthracene and 9-(2,2,2-trifluoro-1-hydroxyethyl)-anthracene (Pirkle's alcohol), protected as their corresponding ethers, were found to undergo cycloadditions with maleic anhydride and maleimide dienophiles to furnish cycloadducts with complete diastereoselectivity and high yields, both in solution phase and on solid support.; The need for a second generation of anthracene templates, which would be highly reactive, yet more stable, was addressed by utilizing 9-(1,2-dihydroxyethyl)-anthracene, a more stable analog of the 9-(1-hydroxyethyl)-anthracene, and 9-(2,2,2-trifluoro-1-hydroxyethyl)-10-methyl anthracene, a more reactive analog of Pirkle's alcohol. Subsequent regioselective and stereoselective manipulations of the cycloadducts were also explored to elucidate the origin of diastereoselection. The synthetic utility of this approach was subsequently demonstrated in the preparation of chiral butenolides such as γ-dodecanolactone, the precursor of the rove beetle pheromone. Finally, 9-(1,2-dihydroxyethyl)-anthracene was utilized as a template in the synthesis of the chiral butenolide acaterin, an acyl CoA inhibitor. |
