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: 10455060
• 负责人: Nathan Joseph Adamson
• 金额: $ 3.15万
• 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 2023-01-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455060
• 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; 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.

项目总结/摘要 越来越多的药物化学家正在远离“扁平”的富含sp2的分子来探索生物活性。 因此，认识到最具选择性的化合物通常含有高度的sp3立体定向性， 赋予它们三维空间来匹配它们的生物目标。此外，立体化学上明确定义的 药物通常具有较少的脱靶效应，这是由于它们与其预期靶点的高亲和力， 最终对人类健康产生积极影响。因此，允许快速合成 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，使用应变的有机中间体来组装立体化学致密的产物已经获得了广泛的应用。 多注意。高度紧张的反应性有机中间体，如苯炔和其他芳炔， 曾经被认为是纯理论的，现在由于其许多用途而被常规用于常规合成， 然而与这些中间体的反应通常产生平面产物。然而，一个使用较少的 应变中间体是应变环丙二烯（SCA），其在构建富含sp 3的 化合物.这项拟议中的研究旨在开发一种方法， 在温和条件下生成，以进行高度区域和立体选择性的Diels-Alder环加成， 2-吡喃酮和相关的2-吡啶酮。所得产物将是高度官能化的、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建块。 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.这一努力将导致该目标的第一次不对称合成，也是SCA的第一次使用 天然产物的全合成。

项目成果

Total synthesis of lissodendoric acid A via stereospecific trapping of a strained cyclic allene.

通过应变环状丙二烯的立体定向捕获来全合成 lissodendoric Acid A。

• DOI: 10.1126/science.ade0032
• 发表时间: 2023
• 期刊: Science (New York, N.Y.)
• 作者: Ippoliti,FrancescaM;Adamson,NathanJ;Wonilowicz,LauraG;Nasrallah,DanielJ;Darzi,EvanR;Donaldson,JoyannS;Garg,NeilK
• 通讯作者: Garg,NeilK