Ligand-promoted Enantioselective C-H Activation Reactions

配体促进的对映选择性 C-H 活化反应

基本信息

批准号：
10799446
负责人：
Jin-Quan Yu
金额：
$ 10.95万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2025-06-30
项目状态：
未结题

项目摘要

Project Summary By harnessing abundant prochiral C(sp3)–H bonds as entry points for the stereoselective installation of complex functionality, enantioselective C(sp3)–H functionalization represents a potentially transformative strategy in synthesis. Although enantioselective transition metal-catalyzed C(sp3)–H activation reactions have been reported, many require bespoke directing groups – a serious synthetic limitation. The use of functional groups native to common organic substrates (amides, acids, alcohols, ethers, amines, and esters) to recruit the catalyst for C–H metalation is ideal, but many native functionalities are either weakly coordinating or have otherwise undesirable binding capabilities with the catalyst. This proposal addresses these challenges through two distinct design strategies, which aim to enable both reactivity and enantioselectivity for native functionality-directed C(sp3)–H activation reactions. In particular, our research strategy aims to achieve the enantioselective C–H activation of carboxylic acid, amide, alcohol, ester, aldehyde, ketone, and amine-containing substrates with diverse reacting partners through (A) the design of chiral bidentate L,X-type scaffolds bearing N-acetyl (NHAc) or pyridone motifs to accelerate C–H cleavage, and (B) the design of chiral transient directing groups (TDGs). The advances from this proposal can fundamentally impact both how chiral molecules are constructed and diversified in pharmaceutical and synthesis contexts. Moreover, these new catalytic platforms will be immediately applied in a pharmaceutical context through industrial (with BMS), and academic collaborations (with Prof. Benjamin Cravatt), where the synthesis of novel chiral β-lactones and lactams through enantioselective C–H activation will expedite the discovery of novel enzyme inhibitors in an anticancer context.

项目概要通过利用丰富的前手性 C(sp3)–H 键作为立体选择性安装的切入点复杂的功能，对映选择性 C(sp3)–H 功能化代表了一种潜在的变革尽管是对映选择性过渡金属催化的 C(sp3)–H 活化反应。据报道，许多需要定制的指导小组——这是一个严重的综合限制。常见有机底物（酰胺、酸、醇、醚、胺和酯）来招募 C–H 金属化催化剂是理想的，但许多天然功能要么很弱该提案解决了与催化剂协调或具有其他不良结合能力的问题。这些挑战通过两种不同的设计策略实现，旨在实现反应性和特别是我们的研究对天然功能导向的 C(sp3)–H 活化反应的对映选择性。该策略旨在实现羧酸、酰胺、醇、酯、通过 (A) 设计，醛、酮和含胺底物具有多种反应伙伴带有 N-乙酰基 (NHAc) 或吡啶酮基序的手性二齿 L,X 型支架，可加速 C–H 裂解，以及 (B) 手性瞬态导向基团 (TDG) 的设计。可以从根本上影响制药和制药领域手性分子的构建和多样化此外，这些新的催化平台将立即应用于制药领域。通过工业（与 BMS）和学术合作（与 Benjamin Cravatt 教授）的背景，其中通过对映选择性 C-H 活化合成新型手性 β-内酯和内酰胺将加速抗癌领域新型酶抑制剂的发现。