Synthetic Applications of Formal [3+3] Cycloadditions

描述(由申请人提供)：在先前的提案中，我们确定形式[3+3]环加成是合成有效的乙酰胆碱酯酶[AChE]抑制剂阿利沙星A的一种可行方法。我们还认识到[3+3]反应作为构建包括氮杂环在内的杂环的一般方法的潜力。我们已经实现了这些目标。 为了证明这种形式环加成方法的有效性，探索其在天然产物合成中的应用已成为一个重要的焦点。因此，在这次竞争性更新中，除了按照最初的建议进一步发展阿里沙星A治疗痴呆症的医学知识外，我们打算继续合成含氧杂环的天然产物，并围绕生物碱合成开发一个可见的计划，特别是使用形式氮杂-[3+3]环加成反应。虽然我们正在进行几项不同的努力，但这次更新的重点是选定的主题，以最好地说明这些努力，并按以下四个目标组织。 具体目标1[先前提案中的目标3]侧重于利用形式氧-[3+3]环加成反应合成阿里沙星A的类似物，并对其进行体外实验，以探索阿里沙星A与AChE的结合。 具体目标2重点介绍了形式氧-[3+3]环加成反应在天然产物红栎素A和植物生长素A全合成中的应用。 具体目标3重点是利用氧-[3+3]和碳-[3+3]形式的环加成反应合成金丝桃素类天然产物。 具体目标4集中于形式氮杂-[3+3]环加成在瘦素和圆柱菌素全合成中的应用，以及进一步发展分子内形式氮杂-[3+3]环加成反应，包括其使用手性Lewis酸和胺盐的不对称变体。

DESCRIPTION (provided by applicant): In the previous proposal, we identified the formal [3 + 3] cycloaddition as a viable approach to arisugacin A, a potent inhibitor of acetylcholinesterase [AChE]. We also recognized the potential of the [3 + 3] reaction as a general methodology for constructing heterocycles including nitrogen heterocycles. We have accomplished those goals. To demonstrate the usefulness of this formal cycloaddition methodology, pursuing its applications in natural product syntheses has become an important focus. Thus, in this competitive renewal, in addition to furthering the medicinal knowledge of arisugacin A for dementias as originally proposed, we intend to pursue syntheses of natural products containing oxygen heterocycles, and to develop a visible program around alkaloid synthesis particularly using the formal aza-[3 + 3] cycloaddition. While we are pursuing several different endeavors, this renewal focuses on selected topics to best illustrate these efforts, and is organized in the following four aims. Specific Aim 1 [Aim 3 in the previous proposal] focuses on synthesis of analogs of arisugacin A using the formal oxa-[3 + 3] cycloaddition and in vitro assay of the analogs to explore binding of arisugacin A to AChE. Specific Aim 2 focuses on applications of formal oxa-[3 + 3] cycloadditions in total syntheses of the natural products hongoquercin A and phomactin A. Specific Aim 3 focuses on employing the oxa-[3 + 3] along with the carbo-[3 + 3] formal cycloaddition toward the synthesis of the hyperforin family of natural products. Specific Aim 4 focuses on applications of formal aza-[3 + 3] cycloadditions toward total syntheses of lepadins and cylindricines, and further development of the intramolecular formal aza-[3 + 3] cycloaddition including its asymmetric variants using chiral Lewis acids and amine salts.