2012 Theses Doctoral

The Development of Cyclobutenone, and Other Work

Ross, Audrey Graham

This dissertation describes projects falling into two general programs. The first three chapters detail work centered around the peculiar small molecule cyclobutenone. A practical preparation of this previously inaccessible compound is reported. This allowed exploration of applied and academic questions.

Cyclobutenone was seen to break from classical patterns due to its extreme inherent strain, polarization, and other factors. These unique properties were harnessed toward enhanced dienophilicity and endo directivity in Diels-Alder reactions. Intramolecular Diels-Alder (IMDA) reactions are described in the second chapter. Cyclobutenone and larger cycloalkenone substrates again diverged in reactivity and selectivity. Lewis acid catalysis reduced this gap to give high levels of endo addition across the series.

This stereochemical information was then translated to trans hydrindene junctions by controlled fragmentation of erstwhile dienophile moieties. Observations within these two projects inspired the idea discussed in the third chapter. Here the groundwork is laid out for substitution of cyclobutenone to modulate its properties and carry functionality. In an early example, certain halogenation patterns are shown to further activate cyclobutenone as a dienophile, as well as provide a reactive handle to diversify the possible structures originating from a cyclobutenone core.

The last chapter describes two total synthesis projects and their connection. A group of resveratrol-based natural products and analogs were prepared by branching from a master intermediate. Subsequently, a variant of this polyphenol intermediate was used to guide the route toward dalesconol A and B. These polyketides are potent immunosuppressants. A common synthetic strategy unifies these total syntheses, much as the cyclobutenone program is comprised of three related projects.