Stereoselective Rearrangements for the Synthesis of Bioactive Small Molecules

描述(申请人提供)：立体选择性化学反应提供了研究生物系统的化学工具和治疗疾病的药物，从而改变了人类医学的实践。尽管存在几种合成具有生物价值的手性化合物的方法，但仍有巨大的潜力在催化方面发现概念上的新策略，用于立体选择性地合成一类药物相关分子，这些分子不容易用已知的方法合成。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。这项研究计划的长期目标包括发现将简单的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。研究战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简单的热S型重排。具体目标A.1：金属催化的对映选择性烯丙酸胺化特殊目标A.1：立体选择性合成氨基醇和选择性保护的单糖B。与叔胺的串联烯丙酸胺化/重排反应：项目B是以创新假设为指导的，即叔胺在立体选择性串联过程中可以作为金属催化的烯丙胺化反应的一般亲核剂，尽管长期以来人们认为这些底物在金属催化中不是一般的亲核剂。特定目标B.1：开发对映体选择性[2，3]-Stevens重排特定目标B.2：立体选择性合成PDK-2(抗癌药物靶标)小分子抑制剂--与David Chuang合作

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