Aza-Heck/C-C cleavage/cross coupling cascades of pinene derivatives for the synthesis of zoanthamine alkaloids

项目总结/摘要 含氮杂环化合物在药物化学中具有相当大的意义，通常是药物化学中的关键组成部分。 非键相互作用，有助于分子的整体药理活性。Zoanthamine 生物碱是显示出多种生物活性的天然产物的一个例子， 其结构杂环部分。值得注意的例子包括去甲虫胺， 和zoanthenol，其是用于抑制血小板聚集的选择性胶原受体拮抗剂。 合成这些结构复杂的生物碱的困难明显表现在总生物碱的相对缺乏。 合成：自1984年首次分离以来，仅报道了2个去甲虫胺的总合成 和一个zoanthenol，所有这些都是相当长的（40+步骤）。该项目提出了一个全面的综合 对于zoanthenol，使用氮杂-Heck/C-C裂解/交叉偶联级联方法，以提供总体的 对天然产物的收敛方法。 拟议的方法建立在Sarpong集团在利用C-C方面建立的先例基础上 裂解/交叉偶联作为从简单的羟基化的蒎烯快速产生复杂性的策略。的 将氮杂-Heck反应添加到该总序列中应该提供引入N- 杂环化合物到天然产物样结构上。具体目标一概述了引入 aza-Heck反应的C-C裂解/交叉偶联序列，并确定O-酰基肟作为一个通用的 使用过渡金属催化形成N-杂环的前体。具体目标二，然后详细介绍了一个全面的综合 使用特定目标I中开发的级联过程作为关键偶联， 步这种方法也应该使相关衍生物的潜在结构活性的准备工作 相关性（SAR）研究，以充分阐明zoanthamine生物碱显示的独特生物活性。

PROJECT SUMMARY/ABSTRACT Nitrogen-containing heterocycles are of considerable interest in medicinal chemistry, often responsible for key non-bonding interactions that contribute to a molecule’s overall pharmacological activity. The zoanthamine alkaloids are an example of natural products that display a variety of biological activities mostly attributed to the heterocyclic portion of their structures. Notable examples include norzoanthamine with potent anti-osteoporotic properties, and zoanthenol, which is a selective collagen receptor antagonist for inhibiting platelet aggregation. The difficulties in synthesizing these architecturally complex alkaloids are apparent in the relative dearth of total syntheses: since their initial isolation in 1984, only two total syntheses have been reported for norzoanthamine and one for zoanthenol, all of which are considerably lengthy (40+ steps). This project proposes a total synthesis for zoanthenol using an aza-Heck/C–C cleavage/cross coupling cascade process to provide an overall convergent approach to the natural product. The proposed methodology builds upon precedent established by the Sarpong group in utilizing C–C cleavage/cross coupling as a strategy for rapidly generating complexity from simple, hydroxylated pinenes. The addition of an aza-Heck reaction to this overall sequence should provide an avenue for introducing N- heterocycles onto natural product-like structures. Specific Aim I outlines key considerations for introducing an aza-Heck reaction to the C–C cleavage/cross coupling sequence, and identifying O-acyl oximes as a versatile precursor for N-heterocycle formation using transition metal catalysis. Specific Aim II then details a total synthesis of the natural product zoanthenol using the cascade process developed in Specific Aim I as the key coupling step. This approach should also enable preparations of related derivatives for potential structure-activity relationship (SAR) studies to fully elucidate the unique bioactivities displayed by the zoanthamine alkaloids.