GENERAL METHODS FOR SYNTHESIS OF BIOACTIVE MATERIALS

本申请中提出的研究的总体目标是 发展立体控制合成的新化学方法 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希望的药物先导成为 发展迅速，具有潜在的治疗意义。 在拟议的项目期间，我们将尝试开发金属- 多烯催化环化为一种广泛适用的策略 有机合成。这一努力的基础是令人兴奋的新钯- 催化的二烯基芳基卤化物的环化反应 目前的GM-06-07项目年。我们认为金属催化的 多烯环化可发展为一种主要的合成方法 准备杂环和碳环，并将恭维(不 重复)基于阳离子或自由基中间体的现有方法。 我们建议的研究范围异常广泛，涵盖了 机械性的、探索性的和完全综合的努力。 总的合成目标在结构上是多样化的，包括 新近分离的天花粉草酸A和B，它们显示出细胞毒性和 抗病毒活性，以及阿希迪林，一种特异的可逆抑制物 型真核DNA聚合酶。一种新的合成方法 重要的吗啡和苯并吗啉家族的镇痛剂将 也被开发出来。这种合成应该对制备不寻常的 具有缺电子芳香环的止痛类似物。其他合计 合成目标包括海洋天然奥西平6a-表普他西汀 产品异金利那星，以及不寻常的生物碱核丝氨酸。哪里 将准备适当的类比来定义结构活动 两性关系。 将对制备的中间体和目标分子进行广泛筛选 NCI和Dow的生物活动。

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.