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。 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 其结构的杂环部分值得注意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在总生物碱的相对深度上是显而易见的。 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 一种是Zoanthenol，所有这些都相当冗长（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。 在整个序列中添加 aza-Heck 反应应该提供引入 N-的途径 具体目标 I 概述了引入杂环的关键考虑因素。 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-杂环的前体然后详细介绍了全合成。 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 该方法还应该能够制备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。