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.  Many of these bromotyrosine natural products possess the spiroisoxazoline moiety.  Purpose of this project was to find a synthetic methodology towards the synthesis of the spiroisoxazoline ring core.  Synthesis of the 4,5-dihydroisoxazole precursor to an analogue of 11-deoxyfistularin-3 was accomplished by using 1,3-dipolar cycloaddition with a functionalized alkene.  In order to improve and accelerate our process of forming the spiroisoxazoline, 4-acetyl-5-oxo-hexanoic acid ethyl ester, 30% aqueous formaldehyde and aqueous potassium carbonate were used to form 5-acetyl-3-phenyl-4,5-dihydro-isoxazol-5-yl-propionic acid ethyl ester.  The 1,3-dipolar cycloadditon of 5-acetyl-3-phenyl-4,5-dihydro-isoxazol-5-yl-propionic acid ethyl ester with analogous nitrile oxide formed 5-acetyl-3-phenyl-4,5-dihydro-isoxazol-5-yl-propionic acid ethyl ester.  Finally, 8-methoxy-3-phenyl-1-5-acetyl-3-phenyl-4,5-dihydro-isoxazol-5-yl-propionic acid ethyl ester oxa-2-aza-spiro[4.5]deca-2,7-dien-6-one was synthesized by intramolecular cyclization, and methylation of 5-acetyl-3-phenyl-4,5-dihydro-isoxazol-5-yl-propionic acid ethyl ester.    Our synthesis route reduced from 4 to 3 steps, and the spirocyclization/methylation yields increased for the spiroisoxazolines.

Studies toward the synthesis of spiroisoxazolines

243rd National Meeting (2012)

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