GENERAL METHODS FOR SYNTHESIS OF BIOACTIVE MATERIALS

该研究计划的目标是开发高效的化学品 制备复杂有机分子的方法。我们的最终 目标是开发足够通用和有效的合成工具， 任何所需的分子都可以以实用的方式合成。如果 实现这一应用的目的，生物医学研究人员将有 立体化学地制备和修饰结构的新工具 复杂的多环有机分子从长远来看， 我们正在开发的新的有机合成方法将有助于 发现和生产用于治疗医学疾病的改进的化学试剂， 紊乱该项目的主要重点是两类 重要的分子，其化学合成是超越 现有方法的能力：复合腰果酚和聚吲哚啉 生物碱 该项目的具体目标是：（1）制定方法， 多吲哚啉生物碱的对映选择性合成;特异性靶点 包括-八氮杂十二环生物碱、三羟异喹啉和四羟异喹啉， 其是结构新颖的生长激素（GH）释放刺激剂; 三吡咯并吲哚啉生物碱霍奇金;代表性的手性3a- bispyrroloindoline;和更复杂的，真菌衍生的3-a 双吡咯并吲哚啉生物碱显示出多种药理学活性， 活性包括抗癌和P物质的拮抗， 神经激肽1和胆囊收缩素B型受体。(2)制备 强效Na+/K+-ATP酶抑制剂哇巴因;如果是 哇巴因被证实是该酶扩增的内源性调节剂 我们的卡片计划也是为了培养这些特工。（三） 发明/开发控制相对和绝对立体化学的新方法 在构建邻位的季碳中心上。(4)进一步发展我们 双环化路线得到吗啡。(5)药理学合作 评估我们的合成目标和选择的类似物。 建议的研究是建立在我们实验室最近的发现基础上的 邻位季铵盐合成中的立体化学控制 碳中心和分子内赫克反应的独特效用， 形成空间拥挤的碳-碳键。

The objective of this research program is to develop efficient chemical methods for the preparation of complex organic molecules. Our ultimate goal is to develop sufficiently versatile and efficient synthesis tools so that any desired molecule can be synthesized in a practical manner. If the aims of this application are achieved, biomedical researchers will have new tools for preparing and modifying the structure of stereochemically complex, polycyclic organic molecules. In the long term, the availability of the new organic synthesis methodology we are developing will facilitate discovered and production of improved chemical agents for treating medical disorders. The major focus of this project are two classes of pharmacologically significant molecules whose chemical synthesis is beyond the capability of existing methods: complex cardenolides and polyindoline alkaloids. Specific aims for the project are: (1) Develop methodology for enantioselective synthesis of polyindoline alkaloids; specific targets include- the octaazadodecacyclic alkaloids psycholeine and quadrigemine, which are structurally novel stimulants of growth hormone (GH) release; the trispyrroloindoline alkaloid hodgkinsine; representative chiral 3a- bispyrroloindoline; and more complex, fungal-derived 3-a bispyrroloindoline alkaloids which display a variety of pharmacological activities including anti-cancer and antagonism of substance P, neurokinin 1 and cholecystokinin type B receptors. (2) Prepare the powerful Na+/K+-ATPase-inhibitor ouabain; if analogs or stereoisomers of ouabain are confirmed to be endogenous regulators of this enzyme expand our cardenolide program to prepare these agents as well. (3) Invent/develop new ways to control relative and absolute stereochemistry in constructing vicinal quaternary carbon centers. (4) Further develop our bis-cyclization route to morphine. (5) Collaborate in pharmacological evaluation of our synthesis targets and selected analogs. The proposed studies are founded on recent discoveries in our laboratories on controlling stereochemistry in the synthesis of vicinal quaternary carbon centers and the unique utility of intra molecular Heck reactions to fashion sterically congested carbon-carbon bonds.