Synthesis Strategies for Bioactive Natural Products

描述(由申请人提供)：这是一份开发新的 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。 相关化合物也是如此。接近(通常更简单)自然环境的类似物 产品本身就会产生结果。将对这些措施进行评估，以尝试 确定构成最小药效团的结构元素。 目标I.充分利用我们强大的“内部”专业知识 Xestospongin C(xec，I)，一种有效的膜通透性抑制剂 细胞内三磷酸肌醇(IP3)可诱导细胞内钙离子释放。发展 Xec的变体(包括xestospongin 0)作为潜在的有价值的探针 钙释放的研究。 目的II.研究新型开环β-酰氧基的反应性和稳定性 羧甲酰胺官能团及其大环化新方法 (环氧/酸开环和串联大环化/环收缩 在赞帕内酯(II)的合成过程中。 目标三.开发我们新发现的继电器合环的力量 复分解(RRCM)策略在卵蛋白合成中的应用 A/haterumalide NA(III)，一个独立发现的从两个 完全不同的生物，它们具有显著的抗真菌和 抗增殖性能。 目标四.利用强大的动力学内酯作用 关键中间体的非对称化，并展示了 RRCM在合成最近分离的结构新颖的过程中 大环内酯，鬼臼糖苷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).