Metal-Catalyzed Cross Coupling with N,O-Acetals and Acetals

描述（由申请人提供）：在药物化学、生物化学和糖生物学中最普遍的支架是？取代的胺和醚。提出的研究计划的目标是定义一种通用和模块化的催化策略，使这些结构基序的对映选择性合成成为可能，包括那些嵌入在杂环框架内的基序，就像交叉耦合作为Csp2-Csp2键组装的通用和强大的协议一样。为了实现这一目标，我们将利用低价过渡金属催化剂对铝和氧羰基离子进行氧化加成的能力，并表明这种未充分利用的激活模式为烷基交叉偶联反应提供了一个通用的入口。在这篇文章中，我们将使用有机硼酸盐和有机锌试剂进行对映选择性芳基化、杂芳基化和烷基化的催化剂设计和开发（具体目标1）。我们将从这些研究中获得取代的二氢喹啉类、哌啶类、铬胺类和吡喃类，它们构成了具有一系列药理活性的小分子的核心结构元素。在Specific Aim 2中，我们将开发一类新的稳定的Ni预催化剂，它很容易被活化成Ni(0)，从而实现更高效和方便的Suzuki-Miyaura交叉偶联反应。反应发展还将证明，铝/氧羰基离子激活模式有助于与简单的原料化学品（如缺电子烯烃和二氧化碳）构建前所未有的键，用于合成烯丙醚、烯丙胺和？-氨基酸（特异性目标3）。

DESCRIPTION (provided by applicant): Among the most ubiquitous scaffolds in medicinal chemistry, biological chemistry, and glycobiology are ?-substituted amines and ethers. The goal of the proposed research program is to define a general and modular catalytic strategy that enables the enantioselective synthesis of these structural motifs, including those imbedded within heterocyclic frameworks, in much the same way that cross coupling serves as an all-purpose and powerful protocol for the assembly of Csp2-Csp2 bonds. To achieve this goal, we will exploit the ability of low-valent transition metal catalysts to undergo oxidative addition to iminium and oxocarbenium ions and show that this underutilized activation mode offers a versatile entry to alkyl cross-coupling reactions. In this contribution, we will pursue catalyst design and development for enantioselective arylation, heteroarylation, and alkylation of readily available and stable N,O-acetals and acetals using organoboronate and organozinc reagents (Specific Aim 1). The substituted dihydroquinolines, piperidines, chromenes, and pyrans that we will obtain from these studies constitute the core structural elements of small molecules that exhibit an array of pharmacological activities. In Specific Aim 2, we will develop a new class of stable Ni precatalyst that is easily activated to Ni(0) and enables more efficient and convenient Suzuki-Miyaura cross-coupling reactions. Reaction development will also demonstrate that the iminium/oxocarbenium ion activation mode facilitates unprecedented bond constructions with simple feedstock chemicals such as electron-deficient olefins and carbon dioxide for the synthesis of allylic ethers, allylic amines, and ?-amino acids (Specific Aim 3).