Synthesis via Metal-Catalyzed and Cationic Cyclizations

描述（由申请人提供）：开发可以提高药物合成效率的新工艺仍然是生物医学研究的中心优先事项。阐明新的反应类型，使对映选择性有机转化仍然是这一努力的基础。本资助申请所提出的研究涉及发现、改进和应用多用途的新型催化剂和不对称碳氮和碳碳键形成的反应途径。在GM 32000之前的资助期间，首席研究员和他的同事们已经证明了各种3族金属的非茂金属配合物（特别是钇、钪、镧、镥和钕）是碳-碳多键分子内氢胺化、分子内氢胺化/内炔碳金属化级联反应和PhSiHS烯烃和二烯氢硅化反应的多功能和高选择性催化剂。值得注意的是，我们的第二代手性催化剂显示出迄今为止报道的不对称分子内烯烃氢胺化的最高对映选择性。此外，我们最近开发了一种中性的Zr（IV）催化剂，它对炔和烯的氢胺化具有极好的活性。预计这些新型催化剂的使用，以及它们的结构修饰变体，将允许快速获得用于药理研究的重要杂环中间体类别。本提案概述了我们追求这一目标的近期计划，并详细介绍了合成选定生物活性分子的具体应用。

DESCRIPTION (provided by applicant): The development of new processes by which the efficiency of pharmaceutical synthesis can be improved remains a central priority of biomedical research. The elucidation of novel reaction types that enable enantioselective organic transformations remains fundamental to this endeavor. The research proposed within this grant application is concerned with the discovery, improvement and application of versatile new catalysts and reaction pathways for asymmetric carbon-nitrogen and carbon-carbon bond formation. During the preceding funding period of GM 32000, the Principal Investigator and his coworkers have shown that a variety of non-metallocene complexes of the group 3 metals (particularly yttrium, scandium, lanthanum, lutetium and neodymium) are versatile and highly selective catalysts for the intramolecular hydroamination of carbon-carbon multiple bonds, intramolecular hydroamination / internal alkyne carbometallation cascades and PhSiHS alkene and diene hydrosilylations. Significantly, our second-generation chiral catalysts exhibit the highest enantioselectivities reported to date for asymmetric intramolecular alkene hydroamination. In addition, we have recently developed a neutral Zr(IV) catalyst that has superb activity for the hydroamination of alkynes and allenes. It is expected that the use of these new catalyst types, as well as structurally modified variants of them, will permit rapid access to important classes of heterocyclic intermediates for pharmacological research. This proposal outlines our immediate plans for the pursuit of this objective and details specific applications to the synthesis of selected bioactive molecules.