Synthesis via Metal-Catalyzed and Cationic Cyclizations

描述（由申请人提供）：开发可提高药物合成效率的新工艺仍然是生物医学研究的核心优先事项。阐明新的反应类型，使对映选择性有机转化仍然是这项奋进的基础。该资助申请中提出的研究涉及发现，改进和应用用于不对称碳-氮和碳-碳键形成的多功能新催化剂和反应途径。在GM 32000的前一个资助期内，主要研究者和他的同事已经表明，第3族金属的各种非茂金属络合物（特别是钇、钪、镧、镥和钕）是用于碳-碳多重键的分子内加氢胺化的通用和高选择性催化剂，分子内氢化胺化/内部炔碳甲烷级联和PhSiHS烯烃和二烯氢化硅烷化。值得注意的是，我们的第二代手性催化剂表现出最高的对映体选择性，迄今为止报道的不对称分子内烯烃氢胺化。此外，我们最近开发了一种中性Zr（IV）催化剂，对炔和联烯的氢胺化具有极好的活性。预期使用这些新的催化剂类型以及它们的结构改性变体将允许快速获得用于药理学研究的重要类别的杂环中间体。该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.