Palladium-Catalyzed Enantioselective Oxidation Reactions

钯催化的对映选择性氧化反应

• 批准号: 7085437
• 负责人: BRIAN M STOLTZ
• 金额: $ 31.01万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7085437
• 关键词: alkaloids; antineoplastic antibiotics; cell line; chemical synthesis; cyclization; drug design /synthesis /production; drug resistance; enzyme inhibitors; harringtonines; heterocyclic compounds; neuropharmacologic agent; nitric oxide synthase; oxidation; oxidizing agents; palladium; phosphatase inhibitor; stereochemistry

The objective of this research program is the discovery and development of new reaction methodology en route to the synthesis of complex bioactive molecules. Our proposed studies will focus on the advancement of enantioselective palladium- catalyzed oxidation reactions that do not involve oxygen atom transfer. These reactions include the oxidative kinetic resolution of secondary alcohols and new cyclizations that deliver enantiopure heterocycles and carbocycles. The processes that we develop will find utility in the synthesis of a variety of complex biologically active molecules for which there is currently no efficient synthetic roadmap. As a consequence of this approach, we will have a) access to novel, medicinally relevant structures, b) a general method for their synthesis, and c) new synthetic methods that will be beneficial for a host of general applications. Specifically, we plan to target two classes of highly biologically relevant complex alkaloids, the Dragmacidins (1-3) and the Cephalotaxines (e.g., 4). The former have been shown to selectively inhibit brain Nitric Oxide Synthase (bNOS), and may have therapeutic importance for the treatment of Alzheimer's and other neurodegenerative disorders. The latter are potent antitumor agents, and have been used to overcome the Multiple Drug Resistance problems associated with many chemotherapeutic agents. The ultimate impact of our research will resonate across numerous disciplines including synthetic and organometallic chemistry, chemical biology, and human medicine.

该研究计划的目标是发现和开发合成复杂生物活性分子的新反应方法。 我们提出的研究将集中于不涉及氧原子转移的对映选择性钯催化氧化反应的进展。 这些反应包括仲醇的氧化动力学拆分和产生对映体纯杂环和碳环的新环化。 我们开发的工艺将可用于合成各种复杂的生物活性分子，目前尚无有效的合成路线图。 通过这种方法，我们将能够a）获得新颖的、医学相关的结构，b）合成它们的通用方法，以及c）有利于许多一般应用的新合成方法。具体来说，我们计划针对两类高度生物学相关的复杂生物碱，即 Dragmacidins (1-3) 和 Cephalotaxines (例如 4)。 前者已被证明可以选择性抑制大脑一氧化氮合酶（bNOS），并且可能对治疗阿尔茨海默病和其他神经退行性疾病具有重要的治疗意义。 后者是有效的抗肿瘤药物，并已用于克服与许多化疗药物相关的多重耐药性问题。 我们研究的最终影响将在合成和有机金属化学、化学生物学和人类医学等众多学科中产生共鸣。