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）：本提案的目标是开发新的选择性化学方法，用于实现可用于合成复杂的生物活性小分子的选择性二卤化、卤代官能化和二卤化物衍生化反应。近2，000种含有氯或溴的立体中心的化合物已被鉴定，而生物活性已在迫切的医疗需求领域得到证实（例如抗癌药、抗生素），对生物活性的治疗潜力和物理基础的进一步研究受到来自天然来源的不可靠供应以及缺乏系统的手性选择性方法的阻碍。有机卤素合成初步研究结果表明，金属刘易斯酸，亲电卤化剂，和配体的模块组合能够影响选择性二溴化，溴氯化，二氯化，和卤代醚化对各种含醇烯烃底物。本研究的第一个目的是充分发展这一战略，催化剂控制的化学，区域，非对映体，和对映体选择性二卤代和卤代官能化反应。本研究的第二个目的是将这一策略推广到卤代生物活性小分子的合成。本研究的第三个目的是确定条件，将允许富集的二卤化物的衍生化，通过立体特异性碳-杂原子和碳-碳键形成反应选择性合成生物活性小分子。这一贡献是重要的，因为它将使选择性地制备许多类别的 手性卤代和非卤代化合物用于进一步的生物学评价。创新源于开发一个通用的、可调的方法学平台，以实现多种手性卤化小分子的可预测和选择性制备。