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Marine Natural Product Neurotoxins And The Synthesis Of A Surugatoxin Progenitor

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Abstract

Marine natural products possess diverse architectures and pharmacology, and have provided scientists with a variety of neurotoxins with the potential to be used as research tools. The nicotinic acetylcholine receptors are ion channels that have been implicated in neurodegenerative diseases and tentatively linked to other processes outside the nervous system. As the pharmacological role and scope of nicotinic acetylcholine receptors becomes more complex and analysis methods improve, natural products with established agonist and antagonist affinities should be periodically reevaluated. The overlooked surugatoxin family of marine toxins is such a case because they can no longer be found in nature. Previously synthesized by Inoue and coworkers, we sought to develop an updated synthetic approach to reestablish access to this fascinating family of natural products. Our original approach focused on utilizing a DielsAlder reaction to form the C-ring with the intention of forming the spirooxindole through an oxidative spirocyclization. Both diene connectivities at the indole C2 and C3 positions were explored but proved unsuccessful. Changing tactics, a direct formation of the spirooxindole ring junction was achieved through lithium halogen exchange and conjugate addition into an unsaturated ketone. , Ultimately, we developed a thirteen-step synthesis to a surugatoxin progenitor (aglycone) via a new oxindole annulation with meta-phenylenediamine and late stage enamine oxidation.!

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2015-08-17

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alkaloid; synthesis; surugatoxin

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Union Local

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Committee Chair

Lewis,Chad Arthur

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Schroeder,Frank
Coates,Geoffrey

Degree Discipline

Chemistry and Chemical Biology

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Ph. D., Chemistry and Chemical Biology

Degree Level

Doctor of Philosophy

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Government Document

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dissertation or thesis

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