TOTAL SYNTHESIS OF THE RFT INHIBITOR CP225917

这项研究的长期目标是提供第一个 CP-225，917的非外消旋、高效、全合成。这个分子 最近从一种不明真菌的培养液中分离出来， 显示抑制酶ras法尼基转移酶（RFT）和 角鲨烯合酶（SQS）。 因为ras蛋白的法尼基化是一种 在细胞分裂的初始步骤中，抑制RFT可以提供有用的 控制由ras启动的癌生长的化学治疗方法 基因突变此外，由于SQS已被证明参与了第一次 胆固醇生物合成的关键步骤，其抑制可以控制 体内胆固醇水平。 该提案概述了一个20步的过程 为了从可用的起始原料合成该复合物分子， 材料. 关键的转变涉及分子内[2+2]- 形成环丁烯中间体的环加成反应，和一种新的阴离子 由已知的迈克尔加成引发的级联过程形成 需要双环[4.3.1]癸-1（9），4-二烯。 这个瀑布将是 在全合成之前， 企图。 此外，多个应急计划，以处理不希望的 讨论了替代反应途径。 收敛性和 拟议的全面综合的灵活性应考虑到 制备用于进一步生物学测试的各种类似物。

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.