UC San Diego

Angiogenesis inhibitors are being targeted for their potential as anti-tumor agents as well as theraputics to treat rhematoid arthritis and wet macular degeneration. The natural product azaspirene was shown to inhibit angiogenesis both in vitro and in vivo with low cyctotoxicity making it a compound of interest. Although three syntheses of azaspirene exist, they are lengthy (15 - 33 steps) and have low total yields (< 2%) making a reliable supply of the compound unavailable for further testing. Described in Part I of this thesis is the total synthesis of the natural product azaspirene. The synthesis is the most direct and gives the highest total yield of the published syntheses of azaspirene to date. The synthesis consisted of 11 steps from a commercially available chiral unsaturated lactone in a 6% total yield. The route described can also be performed on the multi-gram scale allowing for an ample supply of azaspirene to continue biological testing. The continued testing will hopefully shed light on the mode of action of azaspirene and the binding site to allow for analogs to by synthesized. A key step in the synthesis utilized a novel one-pot silyl conjugate addition followed by an aldol reaction. Details of the methodology applied to the total synthesis is described in Part II of this thesis.

The silyl conjugate addition was catalyzed by the copper iodine dimethyl sulfide (CuI.DMS) complex, which allowed the presence of an aldehyde at the initiation of the conjugate addition reaction, and led to high yields of the β-silylated aldol product. Also described in Part II is the conjugate addition of vinyl groups catalyzed by the CuI.DMS complex and attempts towards an asymmetric conjugate addition of both silyl and vinyl groups in an aqueous environment.