Total Synthesis of Alstilobanine A Using a Strained Cyclic Allene

使用应变环状丙二烯全合成新山班宁 A

• 批准号: 10220855
• 负责人: Nathan Joseph Adamson
• 金额: $ 6.6万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220855
• 关键词: 2-hydroxypyridine; 3-Dimensional; Acids; Affinity; Alder plant; Alkaloids; Alstonia; Antihypertensive Agents; Attention; Biochemistry; Biocompatible Materials; Biological; Biological Testing; Carbon Dioxide; Cells; Chemistry; Complex; Development; Diels Alder reaction; Face; Goals; Health; Human; Indole Alkaloids; Indoles; Laboratories; Medicine; Methodology; Methods; Minor; Molecular; Motivation; Natural Products; Nature; Organism; Periodicity; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Preparation; Property; Protocols documentation; Pyrones; Reaction; Research; Research Personnel; Skeleton; Source; Structure; Structure-Activity Relationship; System; Testing; Trees; catalyst; cost; cycloaddition; drug discovery; human disease; inhibitor/antagonist; manufacturing process; novel therapeutics; propadiene; trend

Project Summary/Abstract Increasingly, medicinal chemists are moving away from “flat” sp2-rich molecules for exploring bioactivity in recognition that the most selective compounds often contain a high degree of sp3 stereogenicity, therefore lending them three-dimensionality to match their biological targets. Additionally, stereochemically well-defined drugs frequently have fewer off-target effects owing to their high affinities for their intended targets, which can ultimately have a positive impact on human health. Therefore, synthetic methods that allow for the rapid construction of sp3-rich structures are of significant value to the drug discovery and manufacturing process. Recently, the use of strained organic intermediates to assemble stereochemically-dense products has garnered much attention. Highly strained reactive organic intermediates such as benzynes and other arynes, which were once thought to be purely theoretical, are now routinely used in conventional synthesis owing to their many uses, yet reactions with these intermediates generally give rise to planar products. However, a much less utilized strained intermediate is the strained cyclic allene (SCA) which has great potential in the construction of sp3-rich compounds. The proposed research aims to develop methodology that will allow 6-membered cyclic allenes, generated under mild conditions, to engage in highly regio- and stereoselective Diels-Alder cycloadditions with 2-pyrones and related 2-pyridones. The resulting products will be highly-functionalized, sp3-rich (hetero)cyclic structures that should prove as useful synthetic building blocks for the construction of complex molecules. Toward this goal, this methodology will be employed as the key step in a total synthesis of the indole alkaloid Alstilobanine A. This effort will result in the first asymmetric synthesis of this target and also the first use of SCAs in the total synthesis of a natural product.

项目概要/摘要 药物化学家越来越多地放弃富含 sp2 的“扁平”分子来探索生物活性 认识到最具选择性的化合物通常含有高度的 sp3 立体异构性，因此 此外，赋予它们三维性以匹配其生物目标。 由于药物与预期目标的亲和力高，因此药物的脱靶效应通常较少，这可以 最终对人类健康产生积极影响，因此，合成方法能够快速进行。 构建富含sp3的结构对于药物发现和制造过程具有重要价值。 最近，使用应变有机中间体来组装立体化学致密的产品已经获得了广泛的关注。 高度紧张的反应性有机中间体，如苯炔和其他芳炔，受到了广泛关注。 曾经被认为纯粹是理论上的，现在由于其多种用途而常规用于常规合成， 然而，与这些中间体的反应通常会产生平面产物，但使用较少。 应变中间体是应变环状丙二烯（SCA），其在构建富含sp3的结构中具有巨大潜力 拟议的研究旨在开发允许六元环丙二烯的方法， 在温和条件下产生，与具有高度区域和立体选择性的狄尔斯-阿尔德环加成反应 2-吡喃酮和相关的 2-吡啶酮 所得产品将是高度功能化的、富含 sp3 的（杂）环。 这些结构应该被证明是构建复杂分子的有用的合成构件。 为了实现这一目标，该方法将被用作吲哚生物碱全合成的关键步骤 Alstilobanine A。这项工作将导致该靶标的首次不对称合成以及 SCA 的首次使用 在天然产物的全合成中。