Transition Metal Catalyzed Reductive Carbene Transfer Reactions

过渡金属催化还原卡宾转移反应

• 批准号: 10216304
• 负责人: Christopher Uyeda
• 金额: $ 37.06万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-08 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216304
• 关键词: Biological; Catalysis; Coupling; Development; Electrons; Elements; Goals; Health; Human; Hydrogen Bonding; Metals; Methods; Nickel; Organic Synthesis; Property; Reaction; Research; System; Transition Elements; Work; carbene; catalyst; cycloaddition; design; functional group; novel; programs

Abstract Carbenes are valuable reactive intermediates in organic synthesis capable of selectively targeting non- polar π-systems and element–hydrogen bonds in the presence of common polar functional groups. The advent of transition metal catalysis has greatly expanded the utility of carbene transfer reactions, tempering the reactivity of free carbenes and enabling high levels of chemo-, regio-, and stereoselectivity to be achieved under catalyst control. Current methods for catalytic carbene transfer have predominately relied on the extrusion of N2 from diazoalkanes as a central strategy for generating metal carbenoid intermediates. Despite the synthetic utility of these approaches, many state-of-the-art methods are restricted to a relatively narrow scope of diazoacetates, and their derivatives, due to the requirement for stabilizing electron-withdrawing substituents. The overarching goal of this proposed research program is to design a new class of reductive carbene transfer reactions that use readily available and indefinitely stable 1,1-dichloroalkanes as carbene precursors. The primary impact of this work will be to enable catalytic transfer reactions of non-stabilized carbene equivalents, providing direct access to novel synthetic building blocks and facilitating challenging bond constructions. Our central hypothesis is that the elementary steps of transition metal-catalyzed cross-coupling reactions can be re-purposed to enable carbene-type reactivity. Specifically, the oxidative addition of a 1,1-dihaloalkane at a low-valent nickel catalyst is proposed to generate catalyst-bound carbenoid equivalents that can be used in broad range of transformations. Under this general catalytic manifold, we will pursue reductive cyclopropanations, methylene cyclopropanations, multicomponent cycloadditions, cyclooligomerization reactions, C(sp2)–H bonds insertion reactions, and heteroatom–H insertion reactions. In tandem with the development of synthetic methods, mechanistic studies will be conducted to highlight the unique properties of nickel-bound carbenoids. Collectively, the methods described in this proposal will enable the synthesis of novel biologically active compounds by providing rapid access to privileged substructures.

抽象的 卡宾是有机合成中有价值的反应中间体，能够选择性地靶向非 常见极性官能团存在下的极性 π 系统和元素-氢键。来临 过渡金属催化的发展极大地扩展了卡宾转移反应的实用性， 游离卡宾的反应性，能够实现高水平的化学选择性、区域选择性和立体选择性 在催化剂控制下。目前催化卡宾转移的方法主要依赖于 从重氮烷中挤出 N2 作为生成金属类胡萝卜素中间体的核心策略。尽管 尽管这些方法的综合效用，许多最先进的方法仅限于相对狭窄的范围 由于稳定吸电子的要求，重氮乙酸盐及其衍生物的范围 取代基。该研究计划的总体目标是设计一类新的还原剂 使用容易获得且无限稳定的 1,1-二氯烷作为卡宾的卡宾转移反应 前体。这项工作的主要影响将是实现非稳定化的催化转移反应 卡宾等价物，提供直接获得新型合成构件的途径并促进具有挑战性的粘合 建筑。 我们的中心假设是过渡金属催化交叉偶联反应的基本步骤 可以重新利用以实现卡宾型反应。具体来说，1,1-二卤代烷烃的氧化加成 提议使用低价镍催化剂来生成可用于催化剂结合的类胡萝卜素等价物 在广泛的变革中。在这个通用催化流形下，我们将追求还原 环丙烷化、亚甲基环丙烷化、多组分环加成、环低聚 反应、C(sp2)–H 键插入反应和杂原子–H 插入反应。与 合成方法的发展，将进行机理研究以突出其独特的性质 镍结合类胡萝卜素。总的来说，本提案中描述的方法将能够合成新颖的 通过提供快速访问特权子结构来获取生物活性化合物。