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.

项目概要/摘要 含氮杂环在药物化学中具有很大的意义，通常负责关键 有助于分子整体药理活性的非键相互作用。佐安他明 生物碱是天然产物的一个例子，具有多种生物活性，主要归因于 它们结构的杂环部分。著名的例子包括具有有效抗骨质疏松作用的去甲蒽醌 特性，以及 Zoanthenol，它是一种选择性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显而易见，因为总生物碱相对缺乏。 合成：自 1984 年首次分离以来，仅报道了去甲蒽醌的两种全合成方法 一个是 Zoanthenol，所有这些都相当长（40 多个步骤）。该项目提出了全合成 使用 aza-Heck/C-C 裂解/交叉偶联级联过程对 zoanthenol 进行分析，以提供整体 天然产物的趋同方法。 拟议的方法建立在 Sarpong 小组利用 C-C 建立的先例之上 裂解/交叉偶联作为从简单的羟基化蒎烯快速产生复杂性的策略。这 在整个序列中添加 aza-Heck 反应应该提供引入 N-的途径 杂环到类似天然产物的结构上。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，并将 O-酰基肟鉴定为多功能 使用过渡金属催化形成 N-杂环的前体。具体目标 II 然后详细介绍全合成 使用特定目标 I 中开发的级联工艺作为关键耦合来制备天然产物苯乙醇 步。这种方法还应该能够制备具有潜在结构活性的相关衍生物 关系（SAR）研究，以充分阐明佐安他明生物碱所表现出的独特生物活性。