TOTAL SYNTHESIS OF THE RFT INHIBITOR CP225917

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The long term objective of the proposed research is to provide the first nonracemic, efficient, total synthesis of CP-225,917. This molecule was recently isolated from the culture broth of an unidentified fungus, and was shown to inhibit the enzymes ras farnesyl transferase (RFT) and squalene synthase (SQS). As the farnesylation of ras protein is an initial step in cell division, inhibition of RFT could provide a useful chemotherapeutic process for controlling cancer growth initiated by ras gene mutations. Also, as SQS has been shown to be involved in the first committed step of cholesterol biosynthesis, its inhibition could control cholesterol levels in the body. The proposal outlines a 20 step process for the synthesis of this complex molecule from available starting materials. The key transformations involve an intramolcular [2+2]- cycloaddition forming a cyclobutene intermediate, and a novel anionic cascade process initiated by a known Michael addition forming the required bicyclo[4.3.1]deca-1(9),4-diene. This cascade will be independently explored in a model study before the total synthesis is attempted. Also, multiple contigency plans for dealing with undesired alternative reaction pathways are discussed. The convergent nature and the flexibility of the proposed total synthesis should allow for the preparation of various analogues for further biological testing.