Simplified Approaches to Medium-Sized Heterocycles for the Synthesis of Bioactive Small Molecules

用于合成生物活性小分子的中型杂环的简化方法

• 批准号: 9897570
• 负责人: Sarah Elizabeth Wengryniuk
• 金额: $ 30.12万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897570
• 关键词: Address; Adoption; Alcohols; Amines; Architecture; Benzazepines; Cations; Charge; Chemicals; Communities; Complex; Development; Ethers; Goals; Investigation; Iodine; Laboratories; Lead; Libraries; Ligands; Literature; Methodology; Methods; Motivation; Natural Products; Nitrogen; Organic Synthesis; Oxygen; Periodicity; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Podophyllotoxin; Process; Public Health; Reaction; Reagent; Research; Structure; Therapeutic; Toxic effect; Transition Elements; Work; alcohol availability; alkaloid skeleton; analog; bioactive natural products; chemotherapy; clinical development; cost; drug discovery; invention; method development; novel; oxepane; scaffold; small molecule

PROJECT SUMMARY The goal of this proposal is to develop simplified approaches to the construction of diverse medium- sized oxygen and nitrogen heterocycles that can be applied to the synthesis and complexity-building diversification of bioactive small molecules. Medium-ring heterocycles are ubiquitous in naturally occurring bioactive molecules, however these scaffolds remain largely absent from pharmaceutical drug scaffolds due to challenges associated with their synthesis. In order to address rising concerns regarding the lack of chemical space explored by current therapeutic molecules, we propose methods that enable the use of readily available alcohols and amines as functional handles for the facile synthesis of medium-sized heterocycles. Preliminary work in our laboratory has discovered a novel electrophilic heteroatom rearrangement of benzylic alcohols facilitated by a unique class of (poly)cationic hypervalent iodine reagents that allows direct access to diverse medium-ring ethers. The first aim of this proposal is the continued development of this novel transformation to include secondary and tertiary alcohols as well as amine substrates, providing a general platform for medium- ring heterocycle synthesis. The second aim is the further development of our enabling (poly)cationic λ3- iodanes, both through detailed reactivity studies as well as novel derivative syntheses, in order to facilitate their adoption as broadly utilized synthetic reagents. We will also employ these reagents as a novel manifold for the synthesis of chiral hypervalent iodine scaffolds. The third aim of this proposal will utilize our methodology as an enabling platform for complex medium-sized ether analogues of the promising chemotherapeutic lead podophyllotoxin, a compound that has seen little clinical development to date due to limited tolerance for traditional medicinal chemistry diversification. The work is significant because the development of simplified approaches to medium-ring heterocycles will expand the chemical space available for drug discovery by providing previously inaccessible analogues and facilitating more rapid syntheses of complex bioactive natural products. Furthermore, the development of promising (poly)cationic λ3-iodanes will provide the synthetic community with a powerful new toolkit of synthetic reagents.

项目摘要 该提案的目的是开发简化的方法来构建各种媒介 大小的氧气和氮杂环可以应用于合成和复杂性建造 生物活性小分子的多样化。中环杂环无处不在 但是，生物活性分子，但是这些脚手架在很大程度上仍然没有药物支架。 与它们的合成相关的挑战。为了解决有关缺乏化学物质的不断上升的担忧 通过当前的治疗分子探索的空间，我们提出的方法可以使用随时使用 酒精和胺作为功能手柄，可轻松合成中大小的杂环。初步的 我们实验室的工作发现了一种新型的苯并醇的亲电杂原子重排 由独特的（Poly）（Poly）阳离子高价值碘试剂促进，可以直接进入潜水员 中环。该提案的第一个目的是这种新颖的转变持续发展为 包括二级和三级酒精以及胺基材料，为中等 环杂环合成。第二个目的是进一步发展我们的启用（poly）阳离子λ3- 碘通过详细的反应性研究和新颖的衍生合成，以促进它们 广泛使用的合成试剂。我们还将使用这些试剂作为一种新颖的形式 手性高温碘支架的合成。该提案的第三个目标将利用我们的方法作为 有希望的化学治疗铅的复杂中型以太类似物的启用平台 podophyllotoxin，一种化合物，迄今为止，由于对的临床发育很少 传统的药物化学多样化。这项工作很重要，因为简化的发展 中型杂环的方法将扩大可用于药物发现的化学空间 提供以前难以访问的类似物，并支持复杂生物活性自然的更快的合成 产品。此外，有希望的（poly）阳离子λ3-碘的发展将提供合成 具有强大新工具包的合成试剂的社区。