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: 9142324
• 负责人: Noah Zachary Burns
• 金额: $ 30.93万
• 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/9142324
• 关键词: Acids; Address; Alcohols; Alkenes; Antibiotics; Area; Biological; Bromine; Carbon; Chemicals; Chemistry; Chlorine; Complex; Development; Evaluation; Exhibits; Goals; Halogens; Health; Hydroxyl Radical; Investigation; Letters; Ligands; Medical; Metals; Methodology; Methods; Natural Products; Pharmaceutical Preparations; Pharmacologic Substance; Preclinical Drug Evaluation; Preparation; Prevalence; Public Health; Reaction; Research; Source; Staphylococcus aureus; Structure; Technology; Therapeutic; Therapeutic Uses; antineoplastic antibiotics; base; catalyst; cytotoxicity; follow-up; halogenation; innovation; interest; pre-clinical; progenitor; 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（由申请人提供）：该提案的目标是开发新的选择性化学方法，用于实现选择性二卤化、卤代官能化和二卤化物衍生反应，这些方法可用于合成含有其中之一的复杂的、具有生物活性的小分子。含氯或溴的立体中心已被表征，并且虽然生物活性已在紧迫的医疗需求领域（例如抗癌、抗生素）得到证实，但进一步由于天然来源的不可靠供应以及缺乏系统性手性有机卤素合成的选择性方法，对生物活性的治疗潜力和物理基础的研究受到阻碍。初步研究结果表明，金属路易斯酸、亲电子卤化剂的模块化组合。 ，并且配体能够对多种含醇烯烃底物进行选择性二溴化、溴氯化、二氯化和卤醚化。该研究的第二个目标是将该策略扩展到卤化生物活性小分子的合成。这项研究涉及确定富二卤化物的衍生化条件，以便通过立体定向碳杂原子和碳碳键形成反应选择性合成生物活性小分子。意义重大，因为它将能够选择性地准备许多类别的 用于进一步生物学评估的手性卤化和非卤化化合物的创新源于开发通用的、可调节的方法平台，以实现多种类别的手性卤化小分子的可预测和选择性制备。