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 含氮的杂环是一个特权基序，在具有的化合物中广泛发现 药品和天然产品中的药用特性。更具体地说，是最常见的 含氮的杂环是哌啶环，它以多种销售的药物表示。 访问高度装饰的载流齿环通常会受到挑战，并且可以依靠多步合成 这些环的立体定义装饰。该建议旨在利用在 Azacyclic Allenes，用于访问天然产品的核心上装饰高度装饰的哌啶戒指 角磷脂B。 这种属于曼氮胺家族的天然产物显示潜在的抗癌特性，仅显示 一项报告的合成已知，生成步骤的产量为1％。困难 可以通过检查紧张的多囊性菌类的复杂性来理解合成中固有的固有。 角脂蛋白B的核心建立在与[2.2.2] quinuclidine azabicycle融合的哌啶环上。具有挑战性的 该化合物中的图案包括四个连续的立体中心，一个是第四纪立体中心的 大环环的成员。两个大环环，11元和13元，每个都具有跨夜地 菌株和（z） - 烯烃部分。虽然这些功能将很难合并，但使用非常规 对映体的Azacycle Allene将在一个步骤中解决其中一些挑战。在一个（4+2）Diels - Alder Cycloadition反应，将访问两个2 C – C键，同时设置绝对 第四纪中心的立体化学。由于此步骤将在Azacyclic Allene之间进行内分子发生 还将完成13元环的2-吡咯的大环化。将此策略用作 关键步骤应允许在16个步骤中简明地合成角脂蛋白B。