Azaspirene, an effective angiogenesis inhibitor isolated from the soil fungus Neosartorya sp., may be used as a milder form of chemotherapy. Angiogenesis is the body's natural process of forming blood vessels for normal growth and wound repair but can be hijacked by tumors to induce irregular blood vessel growth, which allows the tumors to grow and metastasize. Azaspirene has been shown to block the chemical signaling pathways used to grow irregular tumor blood vessels without disrupting normal blood vessel growth in the body. Azaspirene belongs to the Pseurotin family of compounds whose members share a similar spirocycle backbone and show promise as anti-fungal and anti-bacterial agents. The supply of azaspirene that has been harvested from natural sources is very small and unable to sustain further research; therefore, it is critical that an economical and efficient synthesis be established. Our approach starts with cheap and readily available L-phenyl alanine and proceeds to azaspirene in concise stereo-controlled reactions. The route utilizes various unique methodologies including a cyclization reaction used to complete the bicyclic core of the molecule and a novel copper catalyzed one-pot conjugate silyl addition to aldol reaction. The presented synthetic route is both efficient and robust with high yielding reactions that are capable of being performed on the multi-gram scale. We are close to the complete synthesis of the target molecule. We will then proceed to biological testing of azaspirene and its derivatives. With ample amounts of compound, we can begin to better characterize the biological activity of azaspirene and its analogs through SAR experiments as well as study the active site responsible for the unique biological activity of azaspirene.

New methods toward the total synthesis of azaspirene: A potent angiogenesis inhibitor

251st National Meeting (2016)

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