| Application of cycloaddition chemistry for the synthesis of several natural and unnatural products has been investigated. Studies on the asymmetric synthesis of tanshindiol A (1), a bioactive component of the Oriental traditional medicine, Tanshin, prepared from the roots of Salvia miltiorrhiza Bunge, was described. The ultrasound promoted Diels-Alder reaction of 3-methyl-4,5-benzofurandione with {dollar}(pm){dollar}-methyl 6-(benzoyloxy)-1-vinylcyclohexene-6-carboxylate gave access to {dollar}(pm){dollar}-1 in 11 steps with 14% overall yield. However, reaction of the same dienophile with {dollar}(pm){dollar}-6-hydroxy-6-(hydroxymethyl)-1-vinylcyclohexene acetonide gave {dollar}(pm){dollar}-1 with improved regioselectivity in 14 steps and 11% overall yield. The regioselectivity was enhanced by modifying the bulk and orientation of the substituents on the vinylcyclohexene.; By following the two synthetic routes above, the asymmetric synthesis of (+)-(R)-1 proceeded from the optically enriched (+)-(R)-methyl-1-(benzoyloxy)-2-oxocyclohexane-1-carboxylate (103) (92% ee). The naturally occurring enantiomer (+)-(4R)-1 was determined to be 92% optically pure by {dollar}sp1{dollar}H NMR analysis of the {dollar}(-){dollar}-(R)-2-O-methylmandelate esters. The absolute stereochemistry of natural 1 was determined as (4R) by converting (+)-103 to the known compound (+)-(1R, 2S)-1-methylcyclohexane-1.2-diol.; The dienophilicity of indole and pyrrole in intramolecular reactions with C-3 tethered 1,2,4-triazines was also studied to successfully access several canthin-6-one alkaloids and 6-azaindole analogues. The results of these inverse electron-demand Diels-Alder cycloadditions showed that the length of the tether connecting the dienophile and diene greatly influenced the reactivity: linkage of diene and dienophile by a three-methylene tether is most effective. Phase transfer catalyzed regioselective oxidation of the cycloadduct canthines using benzyltriethylammonium permanganate gave the final canthin-6-ones. Five canthin-6-one derivatives were synthesized in five steps with good overall yields (12-27%) from indole.; In a manner analogous to the indole work, pyrrole was linked via the nitrogen to the 3-position of 1,2,4-triazines with tri- and tetramethylene tethers. Cycloadducts were obtained in good yields (75-85%) using trimethylene tethers, though no cycloadducts were observed with tetramethylene tethers. This reaction demonstrated a very quick and clean route to the 6-azaindole skeleton, notoriously the most difficult of all the azaindoles to prepare. ftn*All degree requirements completed in 1993, but degree will be granted in 1994. |
