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.

项目概要/摘要 含氮杂环是一种特权基序，广泛存在于具有以下结构的化合物中： 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。 高度修饰的哌啶环通常是具有挑战性的，并且可以依赖于多步合成来制备。 这些戒指的立体装饰。该提议旨在利用在细胞中发现的应变促进的反应性。 氮杂环丙二烯，用于进入在天然产物核心处发现的高度修饰的哌啶环 角蛋白B。 这种属于manzamine家族的天然产物显示出有效的抗癌特性， 已知一种已报道的合成方法，其产物生成步骤的产率为1%。难度 合成中固有的复杂性可以通过检查拉紧的多环生物碱的复杂性来理解。 角膜炎菌素B的核心构建在与[2.2.2]奎宁环氮杂双环稠合的哌啶环上。挑战性 化合物中的基序包括四个连续的立构中心，其中一个是四元立构中心， 大环的一员。两个大环，11-和13-元，各自具有跨环 应变和（Z）-烯烃部分。虽然这些功能很难合并，但使用非传统的 对映体富集的氮杂环丙二烯将在单个步骤中解决这些挑战中的几个。在一个（4 + 2）狄尔斯- 在桤木环加成反应中，将获得两个2-C-C键，同时设定绝对 四元中心的立体化学。由于这一步骤将发生在氮杂环丙二烯之间的分子内 和2-吡喃酮，13元环的大环化也将完成。利用这一战略， 该关键步骤应允许在少至16个步骤中简明地合成keramaphidin B。