Synthesis via Metal-Catalyzed and Cationic Cyclizations

描述(由申请人提供)：开发能够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。阐明能够实现对映体选择性有机转化的新型反应类型仍然是这一努力的基础。在这项赠款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-碳键形成的多种新催化剂和反应途径。在全球机制32000的前一次供资期间，首席研究员和他的同事们已经证明，各种非茂金属(特别是Y、Sc、La、Lu和Nd)是碳-碳多键分子内氢胺化、分子内氢胺化/分子内炔碳金属化级联反应以及PhSiHS烯烃和二烯氢硅化反应的多用途和高选择性催化剂。值得注意的是，我们的第二代手性催化剂在迄今报道的不对称分子内烯烃氢胺化反应中表现出最高的对映选择性。此外，我们最近还开发了一种中性的Zr(IV)催化剂，该催化剂对炔烃和烯烃的氢胺化反应具有极高的活性。预计这些新催化剂类型及其结构修饰变体的使用将使人们能够快速获得用于药理研究的重要类别的杂环中间体。这份提案概述了我们追求这一目标的近期计划，并详细说明了在合成选定的生物活性分子方面的具体应用。

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.