Total Synthesis of Alstilobanine A Using a Strained Cyclic Allene

项目摘要/摘要 越来越多的药物化学家正在从“扁平的”富含sp2的分子转向探索生物活性。 认识到最具选择性的化合物通常含有高度的SP3立体致病活性，因此 借给他们三维图像来匹配他们的生物目标。此外，立体化学的定义也很明确 药物通常具有较少的非靶向效应，因为它们对预期目标的高度亲和力，这可以 最终会对人类健康产生积极影响。因此，允许快速合成的合成方法 构建富含Sp3的结构对于药物的发现和制造过程具有重要的价值。 最近，使用应变的有机中间体来组装立体化学致密的产品已经获得了 备受关注。高度紧张的活性有机中间体，如苯炔和其他芳烃，它们是 曾经被认为纯粹是理论上的，现在由于它们的许多用途而在常规合成中被常规使用， 然而，与这些中间体的反应通常会产生平面产品。然而，利用率要低得多 应变中间体是应变环烯丙烯(SCA)，在构建富含Sp3的化合物方面具有很大的潜力 化合物。拟议的研究旨在开发允许6元环烯的方法学， 在温和的条件下生成，进行区域和立体选择性很高的Diels-Alder环加成反应 2-吡喃酮及其相关的2-吡啶酮。得到的产物将是高度官能化的，富含SP3(杂环) 应该被证明是构建复杂分子的有用的合成构件的结构。 为了实现这一目标，这一方法学将被用作吲哚生物碱全合成的关键步骤 Alstilobanine A.这项工作将导致该目标的首次不对称合成，也是SCA的首次使用 在天然产物的全合成中。

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.