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

蒎烯衍生物的 Aza-Heck/C-C 裂解/交叉偶联级联用于合成佐安胺生物碱

• 批准号: 10540775
• 负责人: Christina Grace Na
• 金额: $ 5.28万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540775
• 关键词: Alkaloids; Alkynes; Architecture; Biological; Catalysis; Collagen Receptors; Complex; Coupling; Cyclization; Development; Disease; Hydroxylation; Laboratories; Ligands; Mediating; Methodology; Methods; Natural Products; Nitrogen; Osteoporosis; Osteoporotic; Oximes; Pharmaceutical Chemistry; Platelet Aggregation Inhibition; Preparation; Process; Property; Reaction; Reporting; Research Proposals; Route; Scheme; Structure; Structure-Activity Relationship; Transition Elements; adduct; analog; antagonist; base; catalyst; citronellal; drug synthesis; interest; metal complex; natural product inspired; norzoanthamine; pharmacologic; rapid technique; scaffold; small molecule; zoanthenol

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.

项目摘要/摘要 含氮杂环在药物化学中有相当大的兴趣，通常是关键 对分子整体药理活性有贡献的非键相互作用。黄嘌呤 生物碱是表现出各种生物活性的天然产物的一个例子，主要归因于 它们结构中的杂环部分。值得注意的例子包括具有强大的抗骨质疏松症作用的去甲苯甲胺。 它是一种选择性的胶原蛋白受体拮抗剂，用于抑制血小板聚集。 合成这些结构复杂的生物碱的困难明显体现在总生物碱的相对匮乏上。 合成：自1984年首次分离以来，只有两个去甲黄胺的全合成报道。 一种是偶氮苯酚，所有这些都相当长(40多步)。这个项目提出了一项全面的综合 对于偶氮苯酚，使用aza-Heck/C-C裂解/交叉偶联的级联过程来提供总体 对自然产物的趋同方法。 拟议的方法建立在Sarpong集团利用C-C建立的先例之上 裂解/交叉偶联作为一种策略，可以快速从简单的羟基萜烯中产生复杂性。这个 在整个序列中添加aza-Heck反应应该提供一条途径来引入N- 杂环在天然产物类结构上。具体目标I概述了引入 对C-C裂解/交叉偶联序列的aza-Heck反应，并鉴定O-酰基肟是一种多功能的 使用过渡金属催化形成N-杂环的前驱体。然后，《特定目标2》详细介绍了总的合成 以天然产物偶氮苯酚为主要偶联对象的级联过程 一步。这种方法还应该能够为潜在的结构活性准备相关的衍生物。 关系(SAR)研究，以充分阐明黄嘌呤生物碱所显示的独特生物活性。