GENERAL METHODS FOR SYNTHESIS OF BIOACTIVE MATERIALS

本申请建议开发新的有机金属化学，该化学 将允许具有重要药理特性的化合物 为详细的生物学研究准备了足够的数量。这个 提出的强大的有机合成新方法学的开发是 本申请中提出的研究的基本健康意义。 我们的目标是提供多功能的新有机合成工具，以使 治疗疾病的新化学试剂的开发。次要的 拟议研究的健康意义来自于拟议的 合作生物学研究我们的总合成目标和 类比。 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(分子内 见鬼的反应)以非凡的效率继续构建 拥堵的第四纪碳中心，通常是最难 在合成复杂的有机分子时形成的。这项研究建议 多年来致力于进一步开发和利用电力。 分子内Heck反应。拟议的探索性调查 重点研究季碳的催化不对称合成 中锋。在总合成区：(A)顺序分子内Heck 将为不对称全合成开发反应 东五味子二萜(H+，K+-ATPase的强力抑制剂)和 五环阿片类药物，(B)分子内Heck环化 氧化的三氟化烯醇酯将作为计划中的关键步骤进行探索 哇巴因(内源香豆素)等复杂洋葱内酯的全合成 Na+，K+-ATPase的配体)，(C)不对称Heck环化 被用来锻造MDR的两个连续的第四级中心- (D)双不对称Heck环化反应 将研究生长激素刺激剂的合成 精神错乱。 这几个项目年度的总综合指标表现异常。 前景看好的药理活性具有一系列潜在的治疗作用 用途：例如，用于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.