基于脂肪族酰胺键选择性活化的还原偶联反应研究

Selective activation of aliphatic amides by transition-metal catalysis has an enormous potential for extensive applications in both chemistry and biology due to the widespread occurrence of amides in natural products and biologically active compounds. In the last three years, transition metal catalyzed cross-coupling reactions via amide N-C bonds activation have shown an exponential growth. However, a major disadvantage of the widespread applications of the amide bond N-C cross-coupling reactions is the using of prepared organometallic reagents which are not only costly stepwise but also sensitive to moisture and air. So, this project aims to develop transition metal catalyzed reductive cross-coupling of aliphatic amides with other electrophiles to circumvent this challenge. The highly chemoselectivity between two different electrophiles will be detailed on the basis of aliphatic amides are known to be poor electrophiles. Meanwhile, the synthesis of complex molecules via an intermolecular three component reductive dicarbofunctionalization of a variety of π-systems could be shorter, simpler, and more atom and step economical. This method represents a mechanistically distinct approach to functionalize π-systems through the selective activation of two different electrophiles. Finally, this project proposes to develop a transition metal catalyzed desymmetrizing cross coupling of meso-aliphatic amides with various electrophiles. As the field of asymmetric cross-electrophile coupling continues to expend, this method is likely to an important component of the efficient synthesis of valuable α-C chiral carbonyl compounds. The above research will help to expand the application scope of transition metal catalyzed selective inert amide N-C bond cross-coupling reactions and provide a new way and technical support for inert amide bond activation.

脂肪族酰胺化合物广泛存在于天然产物和生物活性物质中，开发脂肪族酰胺键的选择性活化反应具有重要意义。首先，针对目前酰胺键偶联反应存在需要预先制备对空气和水敏感的有机金属试剂的弊端，本项目拟开发过渡金属催化脂肪族酰胺参与的还原偶联反应。该反应能够实现高选择性的交叉偶联，主要原因在于脂肪族酰胺亲电性较弱，使得两种亲电试剂形成金属试剂的难易程度有了显著差异。同时，通过选择性活化两种不同的亲电试剂，拟开发脂肪族酰胺参与的三组分还原偶联反应，实现不饱和体系的双官能团化。最后，拟开发脂肪族酰胺作为消旋亲电试剂参与的去对称化还原偶联反应。该反应不仅为不对称还原偶联反应提供了新的思路，还丰富了各种有价值的α-碳手性羰基化合物的合成方法。上述高效催化体系的建立，有望进一步拓展脂肪族酰胺键选择性活化策略的应用范围，为惰性酰胺键活化提供新的方法和技术支撑。

酰胺广泛存在于现代药物和生物活性物质中，选择性活化、转化酰胺键等惰性化学键具有重要意义。尽管近年来取得了一定进展，但选择性断裂C-N键、C-O键、P-Z键仍然是有机化学中一个有吸引力但具有挑战性的课题。本项目围绕开发惰性化学键的活化策略形成新的C-C或者C-X键为研究目标。本项目的主要研究内容包括：第一，烯烃Csp2-OTf与脂肪族酰胺的直接偶联反应；第二、镍催化酰氟作为酰基亲电试剂与氯代烃直接构筑Csp2(CO)-Csp3键的反应；第三，手性磷试剂与芳烃Csp2-OR的分子内直接偶联反应；第四，通过P-S键立体选择性地构建P-H键和P-C键，获得手性三烃基膦氧化合物；第五，通过P-O键的功能化，实现了轴手性向中心手性的转移，为构建P-手性化合物提供了一个灵活且通用的平台，合成了各类型的手性叔膦化合物。