GENERAL METHODS FOR SYNTHESIS OF BIOACTIVE MATERIALS

这项研究计划的目标是开发高效的化学品 复杂有机分子的制备方法。我们的终极 目标是开发足够通用和高效的合成工具，以便 任何想要的分子都可以以一种实用的方式合成。如果 这项应用的目标实现了，生物医学研究人员将拥有 立体化学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，可用性 我们正在开发的新的有机合成方法学将促进 医用化学改良剂的发现与生产 精神错乱。这个项目的主要关注点是两类 化学合成超越的具有药理意义的分子 现有方法的能力：复杂的卡登内酯和聚吲哚 生物碱。 该项目的具体目标是：(1)为 对映体选择性合成聚吲哚生物碱.特定靶标 包括-八氮杂十环生物碱心油碱和四氢呋喃， 它们是结构新颖的生长激素(GH)释放刺激剂； 三吡咯吲哚生物碱hodgkinine；代表性手性3a- 双吡咯吲哚；以及更复杂的真菌衍生的3-a 双吡咯吲哚生物碱具有多种药理作用 包括抗癌和拮抗P物质等活性， 神经激动素1和B型胆囊收缩素受体。(2)准备 强大的Na+/K+-ATPase抑制剂哇巴因；如果类似物或立体异构体 哇巴因被证实是这种酶扩张的内源调节因子 我们的卡地奈德计划也是为了准备这些药物。(3) 发明/开发控制相对和绝对立体化学的新方法 在建设邻近的第四纪碳中心方面。(4)进一步发展我们的 双环化路线为吗啡。(5)开展药理合作 对我们的合成目标和选定的类似物进行评估。 拟议的研究是以我们实验室的最新发现为基础的。 邻季铵盐合成中立体化学的控制 碳中心和分子内Heck反应的独特用途 时髦空间密集的碳-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.