Azaspirene, a natural product isolated from the soil fungus Neosartorya sp., is a promising anti-cancer agent that inhibits the creation of new blood vessels for growth of cancer cells via a process called angiogenesis. In a normal cell growth, angiogenesis is the pinnacle of creation of new blood vessels for growth and wound repair. Tumors reroute these natural functions to support their uncontrolled growth and azaspirene has been shown to disrupt the inordinate signaling pathway associated with tumor angiogenesis, inhibiting tumor growth also without harming normal body functions. Azaspirene, unlike most modern cancer drugs, has also low level of cytotoxicity and has therefore 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. As such, we developed an efficient synthetic route is to alleviate these challenges. The presented work demonstrates an efficient asymmetric synthesis of (–)-azaspirene directly applied to simplify access of ‘pseurotin’ analogs, a group of highly bioactive natural products related to azaspirene. Utilizing scalable reactions and cheap starting materials, this work may allow for easy access to such elusive molecules, allowing for in depth biological testing and potential large scale drug synthesis. We demonstrate a unique and simple route towards (–)-azaspirene, completed in a 6% overall yield in 11 steps, compared to an over 30 steps previously reported pathway. Key reaction conversions include a 1,4-addition of silylzincate utilizing putative zinc enolates in enolate trappings to set the correct stereochemistry critical in azaspirene. A required spiro ether function was successfully incorporated using a rare ‘Margaretha’ type cyclization. A second alternate more simple synthetic approach is currently also being developed. By taking advantage of an instrumental chiral lactam establishes an even shorter route, thereby increasing the accessibility to azaspirene further.

Total synthesis of (–)-azaspirene: A promising angiogenesis inhibitor of cancer

ACS Spring 2022

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