Palladium-Catalyzed Reactions Using C-C Bond Activation of Strained Tertiary Alcohols and their Applications in Complex Molecule Synthesis

我们的研究旨在开发创新和高效的复杂小分子合成，在药物发现中具有很高的价值。在我们的工作中，一个关键的设计元素是使用钯催化的碳-碳键激活张力叔醇。钯催化的交叉偶联反应彻底改变了合成的方式，特别是在药物化学研究中。这些反应大多能有效地在sp2杂化碳之间形成新的碳-碳键，通常不会在产物中传递新的立体化学信息。有人认为，过度依赖这些方法无意中导致了对化学空间的有限探索，并对药物发现工作产生了负面影响。我们将使用张力叔醇开发的所有反应都会在环产物中形成至少一个立体碳原子，并且在药物发现的背景下，这种增加的立体化学信息将促进对化学空间的更广泛探索。虽然其中一些反应是非对映选择性的，但许多反应是对映选择性的，并且可以通过改变交叉偶联伙伴来制备小分子文库。除了这些实际应用之外，我们的工作还需要探索新的反应性，并解决有机合成和钯催化中的一些长期存在的问题，因此将导致基础知识的进步。最后，拟议的研究计划也将成为高素质人才的优秀培训工具，并将为他们未来在化学和科学相关领域的工作提供大量宝贵的技能。

Our research aims to develop innovative and efficient syntheses of complex small molecules that are of high value in pharmaceutical discovery. A key design element in our work is the use of palladium-catalyzed carbon-carbon bond activation of strained tertiary alcohols. Palladium-catalyzed cross-coupling reactions have revolutionized the way in which synthesis is conducted, particularly in medicinal chemistry research. Most of these reactions are effective at forging new carbon-carbon bonds between sp2-hybridized carbons, and generally do not impart new stereochemical information in the products. It has been suggested that an over-reliance on these methods has inadvertently resulted in limited exploration of chemical space, and negatively impacts drug discovery efforts. All of the reactions we will develop using strained tertiary alcohols result in the formation of at least one stereogenic carbon atom in the cyclic products and, in the context of pharmaceutical discovery, this added stereochemical information will facilitate a broader exploration of chemical space. While some of these reactions are diastereoselective, many are enantioselective and are also amenable to the preparation of small-molecule libraries through variation of the cross-coupling partners. In addition to these practical applications, our work also entails exploration of new reactivity and addresses some long-standing problems in organic synthesis and palladium catalysis, and will therefore result in advancement of fundamental knowledge. Finally, the proposed research program will also serve as an excellent training tool for highly qualified personnel, and will provide them with a host of valuable skills for future work in chemistry and science related areas.