基于脱羧反应构建C-P键的研究

Organophosphorus compounds play a significant role in chemical synthesis, and are of great importance in bioactive natural products and pharmaceuticals. The methods for the construction of organophosphorus compounds have some disadvantages, such as harsh reaction conditions, poor stereoselectivity, limited functional group tolerance, and so on. Recently, decarboxylation reaction is one of the most important methods for the construction of new carbon carbon bonds and carbon-heteroatom bonds. The research on the construction of C-P bonds through decarboxylation reaction focused on α,β-unsaturated carboxylic acids. There is no report about decarboxylation phosphorylation of carboxylic acid active esters. Transition metal or visible light catalyzed decarboxylation phosphorylation of carboxylic acids has been designed. Kinds of carboxylic acids (aliphatic dicarboxylic acid, aromatic carboxylic acid, α-amino acids and α- substituted carboxylic acids) could be used in the decarboxylation phosphorylation reaction. Moreover, this method could be applied in the synthesis of series of chiral amino phosphonates as angiotensin-converting enzyme inhibitors. Accordingly, we would explore and reveal the catalytic mechanism of decarboxylation phosphorylation reaction and initially establish the theoretical guiding principles of screening and optimization of the reaction. This project may not only develop a new versatile and stereoselective synthetic strategy for the formation of the C-P bonds from easily prepared starting materials, but also identify a drug candidate targeting angiotensin converting enzyme.

有机膦化合物在化学合成中扮演着重要的角色，且广泛存在于天然产物和药物分子中。目前，构建有机膦化合物的方法，具有条件苛刻、立体选择性差、官能团兼容性差等缺点。脱羧偶联反应是构建新型碳碳键、碳杂键的重要方法之一。脱羧偶联反应构建C-P键的研究仅在α,β-不饱和羧酸直接脱羧，而对于羧酸活性酯的脱羧磷化反应尚未报道。本项目拟开展过渡金属催化或可见光催化的脱羧磷化反应，实现脂肪羧酸、芳香羧酸、α-氨基酸和α-取代羧酸等各类羧酸的脱羧磷化反应，并将其应用于手性氨基膦酸（酯）类血管紧张素转化酶（ACE）抑制剂的合成。在此基础上，探索和揭示反应的催化作用机理和规律,初步建立反应体系筛选和优化的理论指导原则。本项目不仅有望发展一种原料易得、通用、立体选择性控制的C-P键构建方法，而且有望获得一个活性高的ACE酶抑制剂候选药物。

本项目开展过渡金属催化的脂肪羧酸、芳香羧酸和α-氨基酸等各类羧酸的脱羧磷化反应，后续研究工作将继续进行。与此同时，发展了一系列有机膦化合物的高效构建方法。炔丙基化合物与二苯基氧膦的偶联反应，构建一系列联烯基膦类化合物；联烯的磷胺化反应，构建了一系列烯基膦取代的含氮杂环化合物。还发展了一系列有机硼化合物的高效构建方法。联烯的氯硼化反应，为２-硅基烯丙基硼化合物的合成提供了一种高效的方法；用三氯化硼做硼源，实现了联烯的硼胺化反应，这为直接构建烯基硼取代的含氮杂环化合物提供一种高效的方法；三氯化硼促进的1,6-联烯炔的环化硼化反应，提供了一种高效合成四氢吡咯及氮杂䓬类化合物的方法。