烷基羧酸α-手性保持的脱羧偶联与脱羧官能化反应研究

不对称合成和手性保持合成是向产物中引入手性中心的两种主要方法。α-位具有手性的羧酸类化合物是一种廉价易得的化合物，大量存在于自然界及化工产品中。项目的主要内容是将α-手性羧酸通过手性保持的脱羧偶联或官能化反应转化为高经济附加值的手性化合物。采用的策略是通过非手性配体与过渡金属结合对酰氧键[C(O)–O]氧化加成后再脱除羰基从而实现脱羧，再发生后续的偶联或官能化反应。拟采用的方案：一是通过在膦配体或卡宾配体中引入π酸基团、高反位基团或弱配位基团来促进CO从过渡金属上解离；二是系统考察导向基及活化基团的影响；同时详细研究脱羧过程的基元反应，掌握酰氧键断裂及脱羰过程的反应规律。通过反应条件的筛选与优化，实现α-手性羧酸化合物手性保持的脱羧偶联／官能化反应，如与锌试剂、硼试剂、芳烃及杂环的偶联，烯基化、炔基化、硼化、硅基化、卤化等反应。该方法学同时将应用于畅销药物关键手性中间体的合成。

Asymmetric synthesis and memory of chirality are the two main methods to introduce chirality in organic synthesis. α-chiral carboxyl acids, as one of the most abundant chemical building blocks, are found in a myriad of natural product and industry chemicals. This project will focus on methodology development for creating high value-added chiral molecules from decarboxylation of easily available α-chiral carboxyl acids via memory of chirality. Achiral ligand will be used with transition metal to activate acyl-oxygen bond [C(O)–O], followed by decarbonylation of acyl metal complex to achieve decarboxylation. To address this challenge, several strategies will be applied: First, a moiety of π acid group, high order trans effect group or a weak coordination unit will be introduced into commonly used phosphines and carbenes to promote the dissociation of CO from the metal center; Second, directing or activating group will be systematically studied and applied in the reaction; Meanwhile, elementary reactions of the decarboxylative process, namely oxidative addition of acyl-oxygen bond and decarbonylation will be studied in detail. After screening and optimizing reaction conditions, methodology will be established for decarboxylative coupling of α-chiral carboxyl acids via memory of chirality with organozinc, boron reagents, arenes, heterocycles. Other functionalization such as decarboxylative olefination, alkynylation, boronation, silylation and halogenations will also be explored. This methodology will be applied in the synthesis of chiral intermediate of best-selling drugs.