Stereoselective Rearrangements for the Synthesis of Bioactive Small Molecules

用于合成生物活性小分子的立体选择性重排

• 批准号: 9066717
• 负责人: UTTAM Krishan TAMBAR
• 金额: $ 31.01万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066717
• 关键词: Alkenes; Amination; Amines; Amino Acids; Amino Alcohols; Ammonium; Antineoplastic Agents; Area; Belief; Biological; Cancer cell line; Carbohydrates; Catalysis; Chemicals; Chemistry; Collaborations; Complex; Development; Disease; Drug Targeting; Glycobiology; Goals; Growth; Health; Human; Libraries; Ligands; Malignant Neoplasms; Marketing; Medical center; Medicine; Metabolic; Metals; Methods; Monosaccharides; Natural Products; Nitrogen; PDH kinase; Palladium; Pharmaceutical Preparations; Pharmacologic Substance; Play; Process; Reaction; Research; Role; Structure; Therapeutic; Transition Elements; analog; base; biological systems; chemical reaction; cytotoxic; innovation; interest; novel; novel strategies; programs; small molecule; small molecule inhibitor; tertiary amine; tool; tumor; ylide

DESCRIPTION (provided by applicant): Stereoselective chemical reactions have transformed the practice of human medicine by providing access to chemical tools to study biological systems and pharmaceutical drugs to treat disease. Although several methods exist for the synthesis of biologically valuable chiral compounds, there is great potential for discovering conceptually novel strategies in catalysis for the stereoselective synthesis of classes of medicinally relevant molecules that are not easily synthesized by known methods. In particular, there are many synthetically useful rearrangements that are underdeveloped in the realm of asymmetric metal catalysis. The long- term goals for this research program include the discovery of general strategies for the catalytic conversion of simple starting materials into structurally complex and biologically active small molecules. These new methods will challenge established opinions on the chemistry of reactive zwitterions and tertiary amines as substrates for metal-catalyzed rearrangement processes. In addition to developing innovative chemical strategies, the proposed research program will explore unique opportunities for biomedical collaborations with cancer biologists at UT Southwestern Medical Center. The research strategy is divided into two project areas: A. Enantioselective [2,3]-Rearrangements of Reactive Zwitterions: Project A is guided by the innovative hypothesis that reactive zwitterionic intermediates can be subjected to metal- catalyzed enantioselective [2,3]-rearrangements, despite their propensity to undergo facile thermal sigmatropic rearrangements. Specific Aim A.1: Metal-Catalyzed Enantioselective Allylic Amination Specific Aim A.1: Stereoselective Synthesis of Amino alcohols and Selectively Protected Monosaccharides B. Tandem Allylic Amination / Rearrangement Reactions with Tertiary Amines: Project B is guided by the innovative hypothesis that tertiary amines can serve as general nucleophiles for metal-catalyzed allylic aminations in the context of stereoselective tandem processes, despite the long-held belief that these substrates are not general nucleophiles in metal catalysis. Specific Aim B.1: Development of an Enantioselective [2,3]-Stevens Rearrangement Specific Aim B.2: Stereoselective Synthesis of Small Molecule Inhibitors of PDK 2 (cancer drug target) - Collaboration with David Chuang

描述（由申请人提供）：立体选择性化学反应通过提供化学工具来研究生物系统和治疗疾病的药物，改变了人类医学的实践。尽管存在多种合成具有生物学价值的手性化合物的方法，但在催化立体选择性合成一类不易通过已知方法合成的医学相关分子的概念上发现新颖的策略具有巨大的潜力。特别是，有许多合成上有用的重排在不对称金属催化领域尚未得到开发。该研究计划的长期目标包括发现将简单起始材料催化转化为结构复杂且具有生物活性的小分子的一般策略。这些新方法将挑战关于反应性两性离子和叔胺作为金属催化重排过程底物的化学的既定观点。除了开发创新的化学策略外，拟议的研究计划还将探索与德克萨斯大学西南医学中心的癌症生物学家进行生物医学合作的独特机会。该研究策略分为两个项目领域： A. 反应性两性离子的对映选择性 [2,3]-重排：项目 A 以创新假设为指导，即反应性两性离子中间体可以进行金属催化的对映选择性 [2,3]-重排，尽管它们倾向于进行容易的热 σ 重排。具体目标 A.1：金属催化对映选择性烯丙胺化 具体目标 A.1：氨基醇和选择性保护单糖的立体选择性合成 B. 串联烯丙胺化/与叔胺的重排反应：项目 B 以创新假设为指导，即叔胺可以作为金属催化烯丙胺化的通用亲核试剂 立体选择性串联过程，尽管长期以来人们认为这些底物不是金属催化中的一般亲核试剂。具体目标 B.1：开发对映选择性 [2,3]-Stevens 重排 具体目标 B.2：PDK 2（癌症药物靶标）小分子抑制剂的立体选择性合成 - 与 David Chuang 合作