Haouamine A is a marine metabolite natural product with an interesting polycyclic structure. In biological testing it exhibited potent, selective cytotoxic activity against human colon carcinoma cells. The mode of action unlying this remarkable activity remains unknown. Thus, haouamine A is considered a lead compound for the development of new anti-cancer treatments. The long term goal of this project is to promote research in chemotherapy through the laboratory total synthesis of (-)-haouamine A. In addition to affording a supply of study material, this project will clarify the absolute configuration of the natural product, which has yet to be determined. Furthermore, assembling the complex molecular architecture of haouamine A will provide an opportunity to expand and test some modern methods of chemical synthesis. The approach to be used in this project can be broken into three phases. In the first phase, simple chemical building blocks will be combined in a convergent fashion to create the heterocyclic core of haouamine A. The key step of this short sequence will be made possible through the use of metal vinylidene-mediated catalysis. Phase two of the synthesis will address the most challengingjStructural feature of haouamine A - the strained 11-membered paracyclophane ring that is fused to its heterocyclic core. A number of promising strategies are available for the closure of this ring, including a further application of metal vinylidene-mediated catalysis. With racemic haouamine A in hand, phase three of the project will focus on carrying out an asymmetric synthesis of the natural product. Several strategies are proposed to achieve this goal without major alterations to the synthetic route put forth in phases one and two. Overall, our approach to the houamine A structure will be efficient and flexible, allowing state-of-the-art synthetic procedures to be rapidly tested in a complex environment. The better understanding of chemical tools gained from this endeavor will allow synthetic chemists in the future to more rapidly prepare biologically active substances for use in medicine. Relevance: Haouamine A, a unique chemical substance discovered in marine organisms, has shown a potent ability to specifically kill human colon cancer cells. A proposed laboratory synthesis of haouamine A will help clarify its chemical structure and provide study material for biologists' ongoing efforts toward the treatment of colon cancer.