GENERAL METHODS FOR SYNTHESIS OF BIOACTIVE MATERIALS

本申请提出开发新的有机金属化学， 将使具有重要药理学特性的化合物 制备足够的量用于详细的生物学研究。的 一种强大的新有机合成方法学的发展建议是 本申请中提出的研究的主要健康意义。 我们的目标是提供多功能的新有机合成工具， 用于治疗疾病的新化学药剂的开发。次级 拟议研究的健康意义来自拟议的 我们的全合成目标的合作生物学研究， 类似物 在目前的项目期间，我们证明了芳基的插入- 和链烯基钯中间体转化为栓系烯烃（分子内 赫克反应）进行建设的特殊功效 拥挤的季碳中心，往往是最难的中心， 在复杂有机分子的合成中形成。建议的研究 项目年的目标是进一步开发和利用 分子内的赫克反应拟议的探索性研究 重点研究了季碳的催化不对称合成 中心.在全合成领域：（a）连续分子内Heck 反应将被开发用于不对称全合成 scopadulan二萜（H+，K +-ATP酶的强效抑制剂）和 五环阿片类药物，（B）分子内Heck环化的高度 氧化的烯醇三氟甲磺酸酯将被探索作为一个计划的关键步骤， 全合成复杂的强心内酯如哇巴因（内源性 Na+，K +-ATP酶的配体），（c）不对称Heck环化将是 用于锻造MDR的两个相邻的四元中心- 抑制剂5-N-乙酰亚胺，和（d）双重不对称Heck环化 将研究生长激素刺激剂的合成 心理学 这些项目年的综合指标显示出异常 具有一系列潜在治疗作用的有前景的药理学活性 用途：例如，为了逆转癌症化疗中的多药耐药性， 治疗阿尔茨海默病，治疗消化性溃疡及相关疾病， 作为生长激素释放的刺激剂和镇痛剂。

This application proposes to develop new organometallic chemistry that will allow compounds with important pharmacological properties to be prepared in sufficient quantities for detailed biological studies. The proposed development of powerful new organic synthesis methodology is the primary health significance of the research proposed in this application. It is our aim to provide versatile new organic synthesis tools to enable the development of new chemical agents for treating disease. A secondary health significance of the proposed research derives from the proposed collaborative biological studies of our total synthesis targets and analogs. During the current project period we demonstrated that insertions of aryl- and alkenyl-palladium intermediates into tethered alkenes (intramolecular Heck reactions) proceed with exceptional efficacy for constructing congested quaternary carbon centers, often the most difficult centers to form in the synthesis of complex organic molecules. The studies proposed for the project years aim at further developing and exploiting the power of intramolecular Heck reactions. Proposed exploratory investigations focus heavily on the catalytic asymmetric synthesis of quaternary carbon centers. In the total synthesis area: (a) sequential intramolecular Heck reactions will be developed for the asymmetric total synthesis of scopadulan diterpenes (powerful inhibitors of H+, K+-ATPase) and pentacyclic opiates, (b) intramolecular Heck cyclization of a highly oxidized enol triflate will be explored as the key step in a projected total synthesis of complex cardenolides such as ouabain (an endogenous ligand for Na+, K+-ATPase), (c) an asymmetric Heck cyclization will be employed to forge the two contiguous quaternary centers of the MDR- inhibitor 5-N-acetylardeemin, and (d) double asymmetric Heck cyclizations will be investigated for the synthesis of the growth hormone stimulant psycholeine. The targets of total synthesis for these project years display unusually promising pharmacological activities with a range of potential therapeutic uses: e.g., for reversing multidrug resistance in cancer chemotherapy, treating Alzheimer's disease, treating peptic ulcer and related diseases, as stimulants of growth hormone release and as analgesics.