铜催化酰亚胺与非活泼烯烃的不对称还原偶联反应研究

Chiral alpha-amines, alpha-branched alkyl substituted chiral alpha-amino acids and their corresponding derivatives have been widely used as fundamental building blocks of natural products and pharmacologically active molecules. On the other hand, C-acylimines (R1N=CHCOR2) or N-acylimines (R1CON=CHR2) have served as versatile acceptors of nucleophiles, their corresponding asymmetric reductive coupling reactions with inactive olefins will possibly provide a concise synthetic approach to these compounds. Although transition-metal catalyzed coupling reactions of imines with functionalized olefins have been widely explored, but most olefin substrates were limited to functionalized alpha, beta-unsaturated carbonyl compounds, enol derivatives, and allylboranes or allylsilanes. In comparison, the use of an unactivated olefin as one of the pi-coupling partners is highly uncommon due to its poor reaction activity. Moreover, the transition-metal catalyzed asymmetric reductive coupling of acylimines with inactive olefins is also a challenging new research filed. The project will focus on the design, synthesis and screening various kinds of acylimines and chiral ligands, and further exploring and studies on the Schwartz reagent (Cp2ZrHCl)/copper salt/chiral ligand system-catalyzed asymmetric reductive coupling reaction of acylimines with inactive olefins in order to realize the concise and rapid construction of chiral alpha-amines, alpha-branched alkyl substituted chiral alpha-amino acids and their corresponding derivatives with high enantioselectivities.

手性alpha-胺和alpha-烷基支链的手性alpha-氨基酸及其衍生物是许多天然产物及药物分子的重要结构单元。含有C=N双键的C-酰基亚胺(R1N=CHCOR2)或者N-酰基亚胺(R1CON=CHR2)与非活泼烯烃分子的不对称还原偶联反应则为这类化合物的快速构建提供了一可能途径。目前尽管过渡金属催化亚胺与功能化烯烃分子的相关反应已取得不错的进展，但非活泼烯烃与酰亚胺化合物的线性还原偶联反应却研究甚少，而其中有关非活泼烯烃与酰亚胺的不对称还原偶联更是一挑战性很强的研究领域。本项目旨在通过设计、合成、筛选不同的酰基亚胺和手性配体分子，利用Schwartz reagent (Cp2ZrHCl)作为还原剂，探索铜盐/手性配体体系催化酰亚胺与非活泼烯烃进行不对称还原偶联的反应性能，以期实现高对映选择性地构建手性alpha-胺和alpha烷基支链的手性alpha-氨基酸及其衍生物的目的。

alpha-手性胺和alpha烷基支链的手性alpha-氨基酸及其衍生物是许多天然产物及药物分子的重要结构单元。含有C=N双键的C-酰基亚胺(R1N=CHCOR2)或者N-酰基亚胺(R1CON=CHR2)与非活泼烯烃分子的不对称还原偶联反应则为这类化合物的快速构建提供了一可能途径。目前尽管过渡金属催化亚胺与功能化烯烃分子的相关反应已取得不错的进展，但非活泼烯烃与酰亚胺化合物的线性还原偶联反应却研究甚少，而其中有关非活泼烯烃与酰亚胺的不对称还原偶联更是一挑战性很强的研究领域。本项目通过设计、合成、筛选不同的酰基亚胺和手性配体分子，利用9-BBN作为还原剂，探索了铜催化酰亚胺与非活泼烯烃进行不对称还原偶联的反应性能，高效实现了构建alpha-烷基支链的alpha-氨基酸及其衍生物的目的，产率高达85%。进一步的机理研究表明：其很可能涉及自由基和离子型两种反应路径。同时,我们还探索了不同类型手性配体对这类反应的对映选择性影响，现有铜催化酰亚胺与非活泼烯烃不对称还原偶联已取得一定进展，我们将后续继续研究此工作的不对称还原偶联反应性能。在本项目资助下，我们在开展本项目工作的同时，还发现了其他新型有机反应，到目前为止，已经发表了24篇高水平学术论文，申请并获得了授权专利2项。