GENERAL METHODS FOR SYNTHESIS OF BIOACTIVE MATERIALS

本申请中提出的研究的总体目标是 开发新的化学方法，用于立体控制合成 复杂的多环分子新型高效化学品的发展 合成方法将使未来有前途的药物线索， 发展迅速，具有潜在的治疗意义。 在项目期间，我们将尝试开发金属- 多烯的催化环化成为广泛适用的策略， 有机合成这项奋进是建立在令人兴奋的新钯- 二烯基芳基卤化物的催化环化反应， 当前GM-06-07项目年份。我们相信金属催化的 多烯环化可以发展成为一种主要的合成方法， 制备杂环和碳环，并将互补（不 重复）现有的基于阳离子或自由基中间体的方法。 我们提议的研究范围非常广泛，包括 机械的、探索性的和全合成的努力。 全合成靶标在结构上是多样的，包括 最近分离的东莨菪碱酸A和B，它们显示细胞毒性， 抗病毒活性，和阿非迪霉素，一种特异性可逆抑制剂， α型真核DNA聚合酶。一种新的合成方法 吗啡喃和苯并吗喃家族的重要镇痛药将 也要发展。这种合成方法应该有助于制备不寻常的 具有缺电子芳环的镇痛剂类似物。其他总 合成目标包括6a-epiprezettine，氧杂环庚烯海洋天然 产品异阿耳滨那新和不常见的生物碱nauclefiline。哪里 将制备适当的类似物，以确定结构活性 关系。 将对制备的中间体和靶分子进行广泛筛选， 在NCI和Dow的生物活性。

The overall objective of the research proposed in this application is to develop new chemical methods for the stereocontrolled synthesis of complex polycyclic molecules. The evolution of new efficient chemical synthesis methods will allow future promising pharmaceutical leads to be developed rapidly with potential therapeutic implications. During the proposed project period we will attempt to develop metal- catalyzed cyclizations of polyenes into a broadly applicable strategy for organic synthesis. This endeavor is founded on exciting new palladium- catalyzed cyclizations of dienyl aryl halides which were developed during the current GM-06-07 project years. We believe that metal-catalyzed polyene cyclinzations can evolve into a major synthesis method for preparing heterocycles and carbocycles and will compliment (not duplicate) existing methods based on cationic or radical intermediates. Our proposed studies are unusually broad in scope and encompass mechanistic, exploratory, and total synthesis endeavors. The total synthesis targets are structurally diverse and include the recently isolated scopadulcic acids A and B, which display cytotoxic and antiviral activity, and aphidicolin, a specific reversible inhibitor of type alpha eucaryotic DNA polymerases. A new approach for the synthesis of important analgesics of the morphinan and benzomorphan families will also be developed. This synthesis should be useful for preparing unusual analgesic analogs with electron-deficient aromatic rings. Other total synthesis targets include 6a-epipretazettine, the oxepene marine natural product isolaurepinnacin, and the unusual alkaloid nauclefiline. Where appropriate, analogs will be prepared to define structure activity relationships. Intermediates and target molecules prepared will be broadly screened for biological activity at NCI and Dow.