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.

项目摘要/摘要 越来越多的药物师正在探索生物活性的“平坦”富含SP2的分子 为了认识到最选择性化合物通常含有高度的SP3立体生成性，因此 借给他们三维以匹配其生物学靶标。另外，立体化学上定义明确 由于其对预期目标的高亲和力，药物经常具有较少的脱靶效应，这可以 最终对人类健康产生积极影响。因此，允许快速的合成方法 富含SP3的结构的构建对于药物发现和制造过程具有重要价值。 最近，使用紧张的有机中间体组装立体化学密集的产品已获得 很多关注。高度紧张的反应性有机中间体，例如苯甲酸盐和其他Arynes，它们是 曾经被认为纯粹是理论上的，现在常规用于常规合成，因为它们的许多用途， 然而，与这些中间体的反应通常会产生平面产品。但是，使用少得多 紧张的中间体是紧张的环状艾琳（SCA），它在富含SP3的构建方面具有巨大的潜力 化合物。拟议的研究旨在开发将允许6元循环艾伦的方法论， 在轻度条件下产生，从而与高度区域和立体选择性Diels-Alder-alder Cyclotitions一起 2-碳和相关的2-吡啶酮。最终的产品将高度功能化，富含SP3（Hetero）周期 应该证明作为复杂分子构建的有用的合成构件的结构。 朝向这个目标，将聘请该方法作为吲哚生物碱完全合成的关键步骤 藻氨酸A.这项工作将导致该靶标的首次不对称合成，也是SCA的首次使用 在天然产物的总合成中。