Total Synthesis of Keramaphidin B via an Azacyclic Allene Intermediate

通过氮杂环丙二烯中间体全合成 Keramaphidin B

• 批准号: 10220854
• 负责人: James L Bachman
• 金额: $ 1.96万
• 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 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220854
• 关键词: Address; Alder plant; Alkaloids; Alkenes; Alkylation; Alkynes; Biomimetics; Cancer cell line; Carbon Dioxide; Complex; Diels Alder reaction; Electrons; Family; Handedness; Ketones; Methodology; Natural Products; Nitrogen; Pharmaceutical Preparations; Pharmacologic Substance; Positioning Attribute; Property; Pyrones; Quinuclidines; Reaction; Reporting; Research; Route; Structure; System; Translating; anti-cancer; anticancer activity; base; cycloaddition; cytotoxicity; decalin; manzamine A; member; piperidine; preference; propadiene; small molecule; small molecule therapeutics; stereochemistry; success

Project Summary/abstract The nitrogen-containing heterocycle is a privileged motif that is found widely in compounds with medicinal properties, in both pharmaceuticals and natural products. More specifically, the most common nitrogen-containing heterocycle is the piperidine ring, which is present in a number of top-selling drugs. Accessing highly decorated piperidines rings is often challenging and can rely on multi-step synthesis for stereo-defined decoration of these rings. This proposal aims to leverage the strain-promoted reactivity found in azacyclic allenes for access to the highly decorated piperidine ring found at the core the natural product keramaphidin B. This natural product belonging to the manzamine family shows potent anticancer properties and only one reported synthesis is known, which proceeded in 1% yield for the product-generating step. The difficulty inherent in the synthesis can be understood by examining the complexity of the strained polycyclic alkaloid. The core of keramaphidin B is built on a piperidine ring fused to a [2.2.2] quinuclidine azabicycle. Challenging motifs in the compound include four contiguous stereocenters with one being a quaternary stereocenter that is a member of a macrocyclic ring. The two macrocyclic rings, 11- and 13-membered, each possess transannular strain and (Z)-olefin moieties. While these functionalities will be difficult to incorporate, using an unconventional enantioenriched azacyclic allene will address several of these challenges in a single step. In one (4+2) Diels– Alder cycloaddition reaction, two 2 C–C bonds will be accessed, while simultaneously setting the absolute stereochemistry of the quaternary center. As this step will occur intramolecularly between an azacyclic allene and a 2-pyrone, macrocyclization of the 13-membered ring will also be accomplished. Using this strategy as the key step should allow for a concise synthesis of keramaphidin B, in as few as 16 steps.

项目摘要/摘要 含氮杂环是一种特殊的基序，广泛存在于具有 药物和天然产品中的药用特性。更具体地说，最常见的 含氮杂环是哌啶环，它存在于许多畅销药物中。 获得高度装饰的哌啶环通常是具有挑战性的，并可能依赖于多步骤合成 这些戒指的立体定义装饰。这项提议旨在利用在 氮杂环烯类化合物用于获得高度装饰的哌啶环，发现在核心的天然产物 Keramapidin B 这种属于甘露糖胺家族的天然产品显示出强大的抗癌性能，只有 已知一种已报道的合成，产物生成步骤以1%的产率进行。困难之处 可以通过检查应变多环生物碱的复杂性来理解合成中所固有的。 Keramapidin B的核心被构建在与[2.2.2]奎努卡丁氮杂环融合的哌啶环上。具有挑战性 该化合物中的主题包括四个连续的立体中心，其中一个是四元立体中心，即 大环环中的一员。两个大环环，11个和13个成员，每个都具有跨环 菌株和(Z)-烯烃部分。虽然这些功能很难合并，但使用非传统的 富含对映体的氮杂环丙二烯将在一步内解决这些挑战中的几个。在一个(4+2)Diels中- Alder环加成反应，将获得两个2C-C键，同时设定绝对 第四纪中心的立体化学。由于这一步骤将发生在氮环烯之间的分子内 并且13元环的2-吡喃酮大环化也将完成。使用此策略作为 关键步骤应该允许在短短16个步骤中简明地合成Keramapidin B。