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: 8516538
• 负责人: UTTAM Krishan TAMBAR
• 金额: $ 29.92万
• 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/8516538
• 关键词: Alkenes; Amination; Amines; Amino Acids; Amino Alcohols; Ammonium; Antineoplastic Agents; Area; Belief; Biological; Biological Factors; Cancer cell line; Carbohydrates; Catalysis; Chemicals; Chemistry; Collaborations; Complex; DNA Sequence Rearrangement; Development; Disease; Drug Targeting; Glycobiology; Goals; Growth; Health; Human; Libraries; Ligands; Malignant Neoplasms; Marketing; Medical center; Medicine; Metabolic; Metals; Methods; Monosaccharides; Nitrogen; PDH kinase; Palladium; Pharmaceutical Preparations; Pharmacologic Substance; Play; Process; Reaction; Research; Role; Structure; Therapeutic; Transition Elements; analog; base; biological systems; chemical reaction; cytotoxic; inhibitor/antagonist; innovation; interest; novel; novel strategies; programs; small molecule; 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药物来治疗疾病，从而改变了人类医学的实践。虽然存在几种方法用于合成具有生物学价值的手性化合物，但在催化剂中发现概念上新颖的策略用于立体选择性合成不容易通过已知方法合成的医学相关分子的类别具有很大的潜力。特别是，在不对称金属催化领域，有许多合成上有用的重排是不发达的。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和具有生物活性的小分子的一般策略。这些新方法将挑战已建立的意见，反应性两性离子和叔胺作为底物的金属催化重排过程的化学。除了开发创新的化学策略外，拟议的研究计划还将探索与UT西南医学中心癌症生物学家进行生物医学合作的独特机会。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，尽管它们倾向于经历轻易的热σ迁移重排。具体目标A.1：金属催化的对映选择性烯丙基胺化具体目标A. 1：氨基醇和选择性保护的单糖的立体选择性合成B.串联烯丙基胺化/重排反应与叔胺：项目B是由创新的假设，叔胺可以作为一般的亲核试剂的金属催化烯丙基胺化的立体选择性串联过程的背景下，尽管长期以来认为，这些底物不是一般的亲核试剂在金属催化。具体目标B.1：对映选择性[2，3]-Stevens重排反应的开发B.2：PDK 2（癌症药物靶标）小分子抑制剂的立体选择性合成-与大卫庄合作