Palladium-Catalyzed Enantioselective Oxidation Reactions

该研究计划的目标是发现和开发新的反应方法，以合成复杂的生物活性分子。 我们的研究重点是不涉及氧原子转移的钯催化氧化反应的研究进展。 这些反应包括仲醇的氧化动力学拆分和提供对映体纯杂环和碳环的新环化。 我们开发的方法将在目前没有有效合成路线图的各种复杂生物活性分子的合成中找到实用性。 作为这种方法的结果，我们将有a）获得新的，医学相关的结构，B）其合成的一般方法，和c）新的合成方法，这将有利于一系列的一般应用。具体而言，我们计划靶向两类高度生物学相关的复合生物碱，Dragmacidins（1-3）和Cefetaxines（例如，4）。 前者已显示出选择性地抑制脑一氧化氮合酶（bNOS），并且可能对治疗阿尔茨海默氏症和其他神经退行性疾病具有治疗重要性。 后者是有效的抗肿瘤剂，并已用于克服与许多化疗剂相关的多重耐药性问题。 我们研究的最终影响将在众多学科中产生共鸣，包括合成和有机金属化学，化学生物学和人类医学。

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.