氮杂环卡宾催化酯的新活化模式:有机催化合成的前沿探索

The development of fundamentally new catalytic activation modes is a core frontier in chemical synthesis. It provides new insights that improve our understanding of science, and offers practically impactful methods for effective and green manufacturing of fine chemicals, pharmaceuticals, and agriculture chemicals. In the field of organocatalytic synthesis emerged in the last decade or so, we're particularly interested in addressing two major challenges. One is to achieve asymmetric organocatalytic activations of inert substrates (such as carboxylic esters) and inert chemical bonds (such as β-sp3 C-H bond of saturated esters; another is to realize unusual activation modes and unprecedented reaction patterns. In this project, we aim to develop strategies for the activation of carboxylic esters and related compounds via the use of N-heterocyclic carbene organocatalysts. Carboxylic esters and the related compounds such as carboxylic acids are inexpensive and readily available raw materials. However, asymmetric catalytic activation of carboxylic esters for chemical synthesis remains a long-standing challenge. Built on our preliminary explorations on NHC-catalyzed activation of esters, here we seek to achieve four specific objectives: (1) develop widely applicable methods with broad scope for NHC-catalyzed activation of the inert C-H bond of esters (such as the β-sp3 CH bond of saturated esters); (2) develop an unprecedented strategy for a direct catalytic conversion of saturated esters to unsaturated aldehydes through NHC-catalyzed ester β-carbon activation and internal redox-shifting; (3) realize unusual activation of the saturate ester α-carbon, i.e., activate the ester α-carbon (normally nucleophilic carbon as enolate intermediate) as electrophilic reactive carbon; (4) using our new ester activation modes to develop concise, cost-effective and green approaches for the synthesis of bioactive molecules such as amino acid-type compounds.

发展基础创新的催化活化模式是有机合成的前沿课题，对科学认知提升和高效环保地进行工业生产都具有重大意义。在近年兴起的有机催化合成领域中，我们对其中两个挑战有着浓厚的兴趣：一是实现对不活泼的反应物（如羧酸及羧酸酯）或不活泼化学键（如sp3型碳氢键）的活化；二是发展非常规的活化方案。本项目致力于以氮杂环卡宾为有机催化剂，发展用于羧酸酯类化合物的新催化活化模式。羧酸酯是来源广泛、便宜、稳定易用的合成原材料，然而对羧酸酯的有机催化活化一直是科学上的难点。在我们前期工作的基础上，现计划实现四个目标：（1）发展广泛适用于羧酸酯不活泼碳氢键的有机催化活化方法；（2）通过酯β-位sp3型碳原子的活化从而实现由饱和酯向不饱和醛的直接转化；（3）实现酯α-位碳原子的非常规活化，即是把通常意义上的亲核α-位碳原子活化为亲电反应中心；（4）用酯的新活化模式实现生物活性分子（如非天然氨基酸类等）简洁高效地合成。

在本项目的研究中，我们开发与发展了一些列基础创新的催化活化模式，这些新型的有机催化活化模式代表了当今有机催化领域的前沿方向，对科学认知的提升和高效环保地进行工业生产都具有重大意义。总体里说，我们解决了传统有机催化中所面临的两大难题，即：对不活泼的反应物（如羧酸及羧酸酯）或不活泼化学键（如sp3 型碳氢键）的活化，与非常规的活化方案的开发。在这个过程中，我们致力于以氮杂环卡宾为有机催化剂，发展用于羧酸酯类化合物的新催化活化模式。羧酸酯是来源广泛、便宜、稳定易用的合成原材料，然而对羧酸酯的有机催化活化一直是科学上的难点。我们在前期工作的基础上，进一步实现了四个新型催化活化模式的开发：（1）发展了广泛适用于羧酸酯不活泼碳氢键的有机催化活化方法；（2）通过酯β-位sp3 型碳原子的活化实现了由饱和酯向不饱和醛类衍生中间体的转化；（3）实现了饱和烷基羧酸酯的β-位亲点性活化，饱和芳香羧酸酯的远程碳-硅活化等多种新型催化活化反应模式；（4）用酯的新活化模式实现生物活性分子（如非天然氨基酸类等）简洁高效地合成。

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