The Development of a Synthetic Strategy Toward Oxazine-Containing Natural Products Enabled by Novel Copper Catalysis

Citation

Cowper, Nicholas Glenn William (2019) The Development of a Synthetic Strategy Toward Oxazine-Containing Natural Products Enabled by Novel Copper Catalysis. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Y9WZ-TZ31. https://resolver.caltech.edu/CaltechTHESIS:06022019-233820328

Abstract

1,2-oxazine natural products are a small closely related family of highly oxidized compounds. Herein, the development of a synthetic strategy toward gliovirin and the trichodermamides is described which enabled the synthesis of the western fragments of gliovirin and trichodermamide B. To that end, we developed two novel copper-catalyzed transformations:the asymmetric propargylation of an oxime and the diasteroeselective oxidative cyclization of hydroxamic acid with a diene.

The challenge of working with tetrahydro-1,2-oxazines is their sensitivity to a variety of reaction conditions and purification methods. Extensive optimization of each transformation was accomplished, bringing to bear the state-of-the-art in oxidative modifications, including a palladium-catalyzed direct desaturation of an epoxy ketone. As well as this work led to the rare observation of a vinylogous Payne rearrangement.

The successful synthesis of the fully functionalized western and eastern fragments of gliovirin are described toward a late-stage diketopiperazine formation and thiolation. Interrogation of our late-stage strategy with these fragments demonstrates that the coupling of the fully functionalized western and eastern fragments is not an effective strategy toward gliovirin proof-of-concept experiments suggest this chemistry could be used toward the synthesis of the trichodermamides.

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