Selective Halogenation Reactions for the Synthesis of Chiral Bioactive Small Molecules

用于合成手性生物活性小分子的选择性卤化反应

• 批准号: 9297330
• 负责人: Noah Zachary Burns
• 金额: $ 31.09万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9297330
• 关键词: Acids; Address; Alcohols; Alkenes; Antibiotics; Area; Biological; Bromine; Carbon; Chemicals; Chemistry; Chlorine; Complex; Development; Evaluation; Exhibits; Follow-Up Studies; Goals; Halogens; Hydroxyl Radical; Investigation; Letters; Ligands; Medical; Metals; Methodology; Methods; Natural Products; Optics; Pharmaceutical Preparations; Pharmacologic Substance; Preclinical Drug Evaluation; Preparation; Prevalence; Public Health; Reaction; Research; Source; Staphylococcus aureus; Structure; Technology; Therapeutic; Therapeutic Uses; catalyst; cytotoxicity; halogenation; innovation; interest; pre-clinical; progenitor; public health relevance; resistant strain; small molecule; stem

 DESCRIPTION (provided by applicant): The goal of this proposal is to develop new selective chemical methods for achieving selective dihalogenation, halofunctionalization, and dihalide derivatization reactions that can be used for the synthesis of complex, biologically active small molecules. Nearly 2,000 compounds containing either a chlorine- or bromine-bearing stereogenic center have been characterized, and while biological activity has been demonstrated in areas of pressing medical need (e.g. anticancer, antibiotic), further investigation into the therapeutic potential and physical basis for bioactivity has been hindered by an unreliable supply from natural sources as well as by a lack of selective methods for systematic chiral organohalogen synthesis. Preliminary findings indicate that the modular combination of metal Lewis acid, electrophilic halogenating agent, and ligand is capable of effecting selective dibromination, bromochlorination, dichlorination, and haloetherification on a variety of alcohol-containing alkene substrates. The first aim of this research is the full development of this strategy to catalyst-controlled chemo-, regio-, diastereo-, and enantioselective dihalogenation and halofunctionalization reactions. The second aim of this research is the extension of this strategy for the synthesis of halogenated bioactive small molecules. The third aim of this research involves identifying conditions that will allow for the derivatization of enriched dihalides for the selective synthesis of bioactive small molecules through stereospecific carbon-heteroatom and carbon-carbon bond-forming reactions. This contribution is significant because it will enable the selective preparation of numerous classes of chiral halogenated and non-halogenated compounds for further biological evaluation. Innovation stems from developing a general, tunable, methodological platform to enable the predictable and selective preparation of numerous classes of chiral halogenated small molecules.

 描述（由应用程序提供）：该提案的目的是开发新的选择性化学方法，以实现选择性二核酸化，呼射功能化和二甲酯衍生化反应，这些反应可用于合成复杂的，生物活性的小分子。已经表征了近2,000种含有氯 - 或溴的立体异源性中心的化合物，尽管在紧迫的医疗需求（例如抗癌，抗生素）的领域已经证明了生物学活性，但由于自然源的依据以及选择性的机器人的依据以及对生物供应的影响，但对生物活性的治疗潜力和物理基础的进一步研究也受到了自然源的影响。初步发现表明，金属刘易斯酸，亲电卤代剂和配体的模块化组合能够对各种含醇的烯烃基质的选择性脱纤维化，溴化，二氯化和卤化。这项研究的第一个目的是该策略的全面发展，以催化控制化学，区域性，映射和对映选择性二催化作用和盐功能化反应。这项研究的第二个目的是扩展该策略的卤化生物活性小分子。这项研究的第三个目的是确定将允许富集的二核苷的衍生化条件，以选择性合成生物活性小分子通过立体特异性的碳杂种原子和碳 - 碳键形成反应。这项贡献很重要，因为它将能够选择性准备大量类别 手性卤素和非释放化合物，以进行进一步的生物学评估。创新植物从开发一个通用，可调，方法论平台到能够预测和选择性制备多种类型的手性卤素小分子。