A novel chlorohydrin-based spirocyclization reaction has been developed that complements contemporary approaches to spiroacetals. The discovery and optimization of a silver(I)-promoted cyclization of ketochlorohydrins enabled the synthesis of a wide range of 5,5-, 5,6-, and 5,7-spiroacetal compounds. In addition, this strategy was applied in the total syntheses of (+)-cephalosporolide E and (−)-cephalosporolide F, which were accomplished in six steps. Further extension of this methodology culminated in the first total synthesis and full stereochemical assignment of (+)-ascospiroketal A. Specifically, a silver(I)-promoted cyclization cascade was developed that effected both a spirocyclization as well as an oxetane rearrangement, and generated a quaternary all-carbon stereogenic centre with complete stereocontrol. This unique reaction sequence was a critical component of the eventual total synthesis of (+)-ascospiroketal A and several diastereomers that were made available in fourteen steps. An additional study detailing efforts geared toward the total synthesis of eleutherobin, an anti-cancer natural product, is also presented. By utilizing a cyclobutanone α-arylation/Haller-Bauer fragmentation/Friedel-Crafts acylation strategy, a tetralone intermediate for the synthesis of eleutherobin was made available on multi-gram-scale. Efforts to convert this material into the bicyclo[8.4.0]tetradecane core of eleutherobin are described including the identification of an intramolecular aza-Michael strategy that secured the carbon complement of eleutherobin.
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Thesis advisor: Britton, Robert
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