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Description
Azaspirene, a natural product isolated from the soil fungus Neosartorya sp., is a promising new anti-cancer agent that inhibits angiogenesis, the creation of new blood vessels. Angiogenesis is normally utilized for the creation of new blood vessels for growth and wound repair. Tumors reroute these natural functions to support uncontrolled growth. Azaspirene has been shown to disrupt this inordinate signaling pathway associated with tumor angiogenesis, thus halting tumor growth without harming normal body functions. Due to its mechanism of action, azaspirene, unlike most modern cancer drugs, has extremely low levels of cytotoxicity and therefore has a high potential for use as a synergistic form of chemotherapy. Currently, the supply of azaspirene from either natural sources or synthetic methods is too small for further biological research or drug use. This thesis presents progress towards an efficient asymmetric route for the synthesis of azaspirene. Beginning with D-malic acid, this route pursues a 13-step total synthesis, which would greatly shorten the route compared to the previously published asymmetric syntheses. Additionally, through the use of scalable reactions and inexpensive starting materials, we seek to increase access to azaspirene, allowing for in depth biological testing and large-scale drug synthesis. Following the synthesis of azaspirene, the intent is to determine binding site of azaspirene and perform additional evaluation of the anti-angiogenic and anti-tumor properties of the natural product. Additionally, as a key step in the total synthesis of azaspirene, a “one pot” method for the addition of silyl groups followed by an aldol reaction across α,β unsaturated carbonyls has been developed. Specifically, a safe and scalable copper catalyzed alternative to more common pyrophoric zinc reagents. While investigating the nature of this reaction, it has been discovered that this methodology allows for the use of monosilyl zinc reagents which have previously been reported to have little reactivity. The monosilyl zinc reagents offer a potentially cheaper alternative to the corresponding disilyl zinc reagents. Utilizing these reagents, studies into the nature of the mechanism have been performed. Additionally, efforts have been made into optimizing the reaction conditions in order to take advantage of the more attractive monosilyl zinc reagents.
