Master of Science (M.Sc.)
Jonathan R. Scheerer
[2.2.2]-Diazabicyclic alkaloids are a natural product family with diverse biological activities. The development of a synthetic methods towards the synthesis of [2.2.2]-diazabicyclic alkaloids is described. I: Diels-Alder Reactions of a C2-Carboxy Pyrazinone Using an N-heterocyclic carbene catalyzed aroylation of a proline 3,5-dichloropyrazinone, a synthetic route to C2-carboxy pyrazinones was developed to study the intermolecular and intramolecular Diels-Alder reactions of these compounds to form the bicyclo[2.2.2]diazaoctane core. Studies showed that having oxidation present α to the pyrazinone ring did not provide any significant increase in reactivity or selectivity as compared to pyrazinones without oxidation α to the ring. In some cases, the oxidation completely hindered reactivity. II: Intermolecular Diels-Alder Reaction of a Proline Derived Pyrazinone with Symmetric Dienophiles The intermolecular Diels-Alder reaction of a proline derived pyrazinone with maleic anhydride allows for selective access the anti-C19 isomer of the [2.2.2]-diazabicylic alkaloid. Selective opening of the resulting anhydride cycloadduct followed by radical excision of the C18 carboxy group provides a known intermediate in the Williams’ synthesis of Brevianamide B. The overall route provides the desired anti-C19 isomer of the methyl ester product in 6 steps and 12% overall yield from the proline derived pyrazinone. This route constitutes a 15 step formal synthesis of Brevianamide B.
© The Author
Perkins, Jonathan Clarence, "Synthesis of [2.2.2]-Diazabicyclic Alkaloids: I: Diels-Alder Reactions of a C2-Carboxy Pyrazinone & Ii: Intermolecular Diels-Alder Reaction of a Proline Derived Pyrazinone with Symmetric Dienophiles" (2017). Dissertations, Theses, and Masters Projects. William & Mary. Paper 1516639679.