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

基本信息

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
项目类别：
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

项目摘要

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治疗疾病的方法，从而改变了人类医学的实践。尽管存在几种合成生物有价值的手性化合物的方法，但在催化中发现概念性的新型策略具有巨大的潜力，用于立体选择性合成药物相关分子类别的类别，这些分子无法通过已知方法轻易合成。特别是，在不对称金属催化的领域中，有许多合成有用的重排。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zwittions和第三胺作为金属催化重排过程的底物的既定意见。除了制定创新的化学策略外，拟议的研究计划还将探索与UT西南医学中心与癌症生物学家进行生物医学合作的独特机会。 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.特定目的A.1：金属催化的对映选择性的烯丙基胺化特异性A.1：对氨基醇和选择性保护的单糖的立体选择性合成B.串联丙二醇胺化 /与第三级胺的重排反应。尽管长期以来，这些底物在金属催化中不是一般的亲核试剂，但立体选择串联过程。特定目标B.1：开发对映选择性[2,3] - 静态重排特异性目标B.2：PDK 2的小分子抑制剂的立体选择性合成（癌症药物靶标） - 与David Chuang合作