Synthesis Strategies for Bioactive Natural Products

描述（由申请人提供）：这是一个开发新的 适用于化学合成的策略、概念和方法 生物活性天然产物及其结构类似物。这些 这些发现将适用于其他药物的合成。 相关化合物也是。获得（通常更简单的）自然的类似物 产品本身会产生。将对这些进行评估， 确定构成最小药效团的结构元件。 艾姆岛利用我们大量的“内部”专业知识， xestospongin C（XeC，I），一种有效的膜渗透性抑制剂， 胞内三磷酸肌醇（IP 3）诱导Ca++释放。发展 XeC的变体（包括xestospongin 0）作为潜在有价值的探针， 钙释放研究。 Aim II.新型无环β-酰氧基的反应活性和稳定性研究 甲醇酰胺官能团以及大环化的新方法 （环氧化物/酸开环和串联的大环化/环收缩， 酰化肟）。 Aim III.发挥我们新发现的接力合闸的威力 复分解（RRCM）策略在卵胞素合成中的应用 A/haterumalide NA（III），一种独立发现的从两种 完全不同的生物，具有显着的抗真菌和 抗增殖特性。 目标四。利用一个强大的动力学内酯化在 关键中间体的非对称化，并展示 RRCM在合成最近分离的，结构新颖的 大环内酯类、Peloruside A（IV）。

DESCRIPTION (provided by applicant): This is a proposal to develop new strategies, concepts, and methods applicable to the chemical synthesis of biologically active natural products and their structural analogs. These discoveries will be applicable to the synthesis of other pharmaceutically relevant compounds as well. Access to (often simpler) analogs of the natural products themselves will result. These will be evaluated in an attempt to identify the structural elements comprising the minimum pharmacophore. Aim I. Capitalize on our substantial body of "in house" expertise with xestospongin C (XeC, I), a potent, membrane permeable inhibitor of intracellular inositol triphosphate (IP3) induced Ca++ release. Develop variants of XeC (including xestospongin 0) as potentially valuable probes for study of calcium release. Aim II. Study the reactivity and stability of the novel acyclic Beta-acyloxy carbinolamide functionality as well as new methods for macrocyclization (epoxide/acid ring opening and a tandem macrocyclization/ring contraction of acylated oximes) during the synthesis of zampanolide (II). Aim III. Develop the power of our newly discovered relay ring-closing metathesis (RRCM) strategy in its application to a synthesis of oocydin A/haterumalide NA (III), an independently discovered agent isolated from two quite different organisms, which possesses remarkable antifungal and antiproliferative properties. Aim IV. Take advantage of a powerful kinetic lactonization in the desymmetrization of a key intermediate and demonstrate additional features of RRCM in the course of synthesizing the recently isolated, structurally novel macrolide, peloruside A (IV).