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

描述(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？-取代胺和醚。所提出的研究计划的目标是定义一个通用的模块化催化策略，使这些结构基序，包括那些嵌入在杂环框架中的结构基序能够进行对映选择性合成，这与交叉偶联作为组装Csp2-Csp2键的通用和强大协议的方式大致相同。为了实现这一目标，我们将开发低价过渡金属催化剂与亚胺和氧卡宾离子进行氧化加成的能力，并表明这种未被充分利用的活化模式为烷基交叉偶联反应提供了一个通用的途径。在这一贡献中，我们将继续进行使用有机硼和有机锌试剂(特定目标1)对易获得和稳定的N，O-缩醛和缩醛的对映选择性芳基化、杂芳基化和烷基化反应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、哌啶、色烯和吡喃，它们构成了小分子的核心结构元素，显示出一系列的药理活性。在具体目标2中，我们将开发一种新的稳定的镍预催化剂，该催化剂易于活化为Ni(0)，并使Suzuki-Miyaura交叉偶联反应更加高效和方便。反应进展还将证明，亚胺/氧碳正离子活化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)建立前所未有的键结构，用于合成烯丙基醚、烯丙基胺和β-氨基酸(特定目标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).