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.

项目摘要通过利用丰富的术前C（SP3） - h键作为立体选择安装的入口点复杂的功能性，对映选择性C（SP3） - H功能化表示潜在的变换合成中的策略。尽管对映选择性过渡金属催化的C（SP3） - H激活反应据报道，许多人需要定制的指导组 - 这是一个严重的合成限制。使用原生有机底物的官能团（酰胺，酸，醇，醚，胺和酯）要募集C – H金属化催化剂是理想的，但是许多天然功能都弱协调或与催化剂具有不可见力的结合能力。该提案解决了这些挑战通过两种不同的设计策略，旨在使反应性和天然功能指导C（SP3） - H活化反应的对映选择性。特别是我们的研究策略旨在实现羧酸，酰胺，酒精，酯，羧酸激活的对映选择性C – H激活醛，酮和含胺的底物的潜水员通过（a）设计对伴侣做出反应手性边界L，带有N-乙酰基（NHAC）或吡啶酮基序的X型支架以加速C – H 裂解和（b）手性瞬态指导组（TDG）的设计。该提议的进步可以从根本上影响手性分子在药物和综合上下文。此外，这些新的催化平台将立即应用于药品通过工业（与BMS）和学术合作（与本杰明·克拉瓦特教授）的背景通过对映选择性C – H激活的新型手性β-内乳酮和乳糖的合成将加快在抗癌背景下发现新型酶抑制剂。