Psammaplysins A-E are a family of natural products that were isolated from marine sponges of the order Verongida. Many of these natural products display antiviral and antineoplastic activities. The most interesting structural motifs of the psammaplysins are the oxepin and isoxazoline moieties which are connected in a spirocyclic array. The synthesis of this type of ring system was accomplished in two steps. These synthetic processes involve a 1,3-dipolar cycloaddition and an intramolecular ring closure of a pendant alcohol or carboxylic acid onto an activated isoxazole. The 1,3-dipolar cycloaddition of an alkyne with an a-chlorobenzaldoxime derivative afforded the desired isoxazole. Intramolecular cyclization was achieved through the reaction of the isoxazole ring with a pyridinium tribromide (PTB) and potassium carbonate in dichloromethane. The proposed mechanism of intramolecular cyclization involves the activation of the isoxazoline ring with PTB to form a bromonium ion. Neighboring group participation of the oxygen can cause an opening of the bromonium ion intermediate and thereby give rise to an oxonium ion. Intramolecular attack of the alkoxide or carboxylate oxygen onto the oxonium ring system and loss of a proton can then afford the spiro-isoxazoline. The spiro-isoxazolines and their precursors were biologically evaluated, and the synthetic analogues were found to be active against the MCF 7 breast cancer cell line and three multi-drug resistant cell lines (MCF 7 MX, MCF 7 VP, and NCI/ADR). The synthesis, mechanistic details, isolated yields, and biological activity for the reported spiro-isoxazoline compounds and their precursors will be discussed.We thank the National Institutes of Health RCMI program (G12RR13459 (NMR and Analytical CORE facilities)).

Biological evaluation and synthesis of spiro-isoxazolines via intramolecular cyclization

245th National Meeting (2013)

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