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 该提案的目标是开发构建多样化媒体的简化方法- 大小的氧和氮杂环，可以应用于合成和复杂性建设 生物活性小分子的多样化。中环杂环在天然存在的化合物中普遍存在。 生物活性分子，然而，这些支架仍然基本上不存在于药物支架中， 与综合有关的挑战。为了解决人们日益关注的缺乏化学品的问题， 空间探索目前的治疗分子，我们提出的方法，使使用现成的 醇和胺作为功能柄用于中等大小的杂环的简易合成。初步 本实验室的工作发现了一种新的苄醇亲电杂原子重排反应 通过一类独特的（聚）阳离子高价碘试剂促进， 中环醚。这项建议的第一个目的是继续发展这种新颖的转变， 包括仲醇和叔醇以及胺底物，提供了用于中等- 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λ 3- 碘烷，通过详细的反应性研究以及新的衍生物合成，以促进其 作为广泛使用的合成试剂。我们还将采用这些试剂作为一种新的歧管， 手性高价碘支架的合成。本建议的第三个目标是利用我们的方法， 有前途的化学治疗先导化合物的复杂中型醚类似物的赋能平台 鬼臼毒素是一种迄今为止几乎没有临床开发的化合物， 传统药物化学多样化。这项工作是有意义的，因为简化的发展， 中环杂环的方法将通过以下方式扩展药物发现可用的化学空间： 提供了以前难以获得的类似物，并促进了复杂的生物活性天然化合物的更快速的合成。 产品.此外，有前途的（聚）阳离子λ 3-碘烷的开发将提供合成 一个强大的新工具包的合成试剂社区。