Palladium-Catalyzed Enantioselective Oxidation Reactions

该研究项目的目标是在合成复杂生物活性分子的过程中发现和发展新的反应方法。我们建议的研究将集中在不涉及氧原子转移的对映选择性钯催化氧化反应的进展上。这些反应包括仲醇的氧化动力学拆分和生成对映异构环和碳环的新环化反应。我们开发的工艺将用于合成各种复杂的生物活性分子，目前还没有有效的合成路线图。作为这种方法的结果，我们将有a)获得新的、医学上相关的结构，b)它们的合成的一般方法，以及c)对许多一般应用有利的新的合成方法。具体地说，我们计划针对两类具有高度生物相关性的复杂生物碱，Dragmacidins(1-3)和Cephaloaxines(例如，4)。前者已被证明可以选择性地抑制大脑一氧化氮合酶(BNOS)，并可能对治疗阿尔茨海默氏症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，已被用于克服与许多化疗药物相关的多重耐药问题。我们的研究的最终影响将在包括合成和有机金属化学、化学生物学和人类医学在内的许多学科中产生共鸣。

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.