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: 9287216
• 负责人: Sarah Elizabeth Wengryniuk
• 金额: $ 29.48万
• 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/9287216
• 关键词: Address; Adoption; Alcohols; Amination; 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; Product R; Public Health; Reaction; Reagent; Research; Therapeutic; Toxic effect; Transition Elements; Tubulin; 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.

项目总结 这项建议的目标是制定简化的方法，以建设多样化的媒体- 可用于合成和构建络合物的大小的氧和氮杂环 生物活性小分子的多样化。中环杂环化合物在天然产物中普遍存在 生物活性分子，然而，这些支架仍然很大程度上不存在于药物支架中，因为 与它们的合成相关的挑战。为了解决人们对缺乏化学品的日益加剧的担忧 目前的治疗分子所探索的空间，我们提出的方法使随时可用的 醇和胺作为功能手柄，可方便地合成中等大小的杂环。初步 我们实验室的工作发现了一种新的苄基醇的亲电杂原子重排 由一类独特的(聚阳离子)高价碘试剂促进，允许直接访问各种 中环醚。这项提议的第一个目标是继续发展这一新颖的转变，以 包括仲醇和叔醇以及胺底物，为中间体提供了一个通用平台 环杂环合成。第二个目标是进一步开发我们的使能(聚)阳离子λ3- 通过详细的反应性研究和新的衍生物合成，以促进其 作为广泛使用的合成试剂而采用。我们还将使用这些试剂作为一种新的歧管，用于 手性高价碘支架的合成。该提案的第三个目标将利用我们的方法作为 前景看好的化疗先导的复杂中型乙醚类似物的使能平台 鬼臼毒素，一种由于对鬼臼毒素的耐受性有限而迄今几乎没有临床应用的化合物 传统药物化学多样化。这项工作具有重要意义，因为它的开发简化了 中环杂环化合物的方法将通过以下方式扩大药物发现的可用化学空间 提供以前无法获得的类似物，并促进复杂生物活性天然产物的更快速合成 产品。此外，前景看好的(聚阳离子λ)3-碘烷的开发将为合成 拥有强大的合成试剂新工具包的社区。