A series of natural products isolated from the sponge of Verongida have been intensively studied due to the presence of alkaloids with one, or more bromotyrosine residues.  Many of these alkaloid metabolites show interesting bioactivity and cytotoxic properties in tumor cell lines.  11-deoxyfistularin-3 is cytotoxic against human breast carcinoma cell line MCF-7.  The purpose of this project was to find a synthetic methodology that will be applied towards the total synthesis of the 11-deoxyfistularin-3 and other spirocyclic isoxazolines.  Aromatic ring and ester containing nitrile oxides reacted with disubstituted geminal alkenes in a 1,3-dipolar fashion to afford the analogous 5,5-isoxazolines which were then used to construct the corresponding spiroisoxazolines through an intramolecular cyclization/methylation reaction in one reaction vessel.  Due to the fact that the methylation process yields two regioisomeric spiroisoxazolines, other methods were investigated to selectively methylate one enolate oxygen over the other.  Subsequent bromination of the spiroisoxazoline affords a product that is a few steps away from the natural product core.  The synthesis, mechanistic details, and isolated yields for the reported spirocyclic isoxazoline compounds will be discussed.Acknowledgments:   The project described was supported by Award Numbers SC3GM094081 and G12RR13459 (NMR and Analytical CORE facilities) from the National Institute of General Medical Sciences.

Synthetic studies toward the synthesis of 11-deoxyfistularin-3

245th National Meeting (2013)

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