分子氧参与的膦酸酯类化合物α-羟基化研究

α-Hydroxy-phosphonates and their corresponding phosphonic acids are ubiquitous structural motifs in organic chemistry. They serve as valuable building blocks and are present in many biologically active compounds. For example, α-hydroxy-bisphosphonates have been used clinically for the prevention and treatment of several bone disorders, such as osteoporosis. Thus, the current goal of the research is the development of conceptually new oxidation methods for the synthesis of α-hydroxy-phosphonates by using molecular oxygen, which is no doubt the best choice of oxidants due to its inexpensive and environmentally benign nature..Aimed to achieve the α-hydroxy-phosphonate framework, we will screen three oxidation protocols that can active both the molecular oxygen and the phosphonate substrates. The first strategy is triethyl phosphite analogue promoted direct aerobic oxidation, the second is photosensitizer induced photooxygenation, and the third is transition matel catalyzed indirect aerobic oxidation. When the successfully achieved reaction conditions are in hand, we will still investigate the substrate scope of the reaction by employing a variety of phosphonates. Then, the reaction mechanism will be studied by revealing the activation route of molecular oxygen, as well as the plausible reaction pass ways of the phosphonates. Finally, the utilization of the oxidation method for the synthesis of pharmaceutical intermediates will be tested and enlarged, especially for technology research of the α-hydroxy-bisphosphonate drugs. .The unique features of our research project are the developing a novel green protocol for α-hydroxylation of phosphonates, and the extending the usage of molecular oxygen in organic chemistry.

α-羟基膦酸及其酯是一类重要的生物活性物质，特别是具有该结构的双膦酸盐化合物是一类常见的治疗骨质疏松药物。应用自然界中存在最为广泛的氧化资源-分子氧，实现该结构中C-O键生成，研究意义重大。.本项目通过选用多种分子氧活化手段，结合底物活化，实现生物活性片段α-羟基膦酸酯的绿色合成。考察的氧化手段包括：以亚磷酸三乙酯为代表的氧化助剂体系、光敏剂参与的光致氧化体系、以及氧分子驱动的通过过渡金属价态循环实现的间接氧化过程。在获得理想催化手段基础上，完成底物拓展，并开展机理研究。最终揭示氧化过程中氧气活化形式与相关反应机理，为绿色氧化过程应用于医药中间体，特别是双膦酸类药物的新工艺开发提供理论指导。.本项目创新之处不仅在于拓展了分子氧氧化手段的应用范畴，更重要的是为α-羟基膦酸酯结构合成提供新的绿色合成手段。

以氧气为氧源，实现活泼碳氢键绿色氧化过程，是近年来有机方法学领域的研究热点。我们在探索了分子氧参与的磷酰基α位羟基化过程中发现，当α位同时氰基存在时，α-羟基磷酰基化合物易于发生分子内重排，并获得O-磷酰基氰醇。将该现象结合分子氧氧化，我们实现了磷酰基化合物参与的丙二腈α位需氧氧化过程，并用于氰醇化合物新颖的绿色方法学构建。.氰醇是有机化学中最有价值和最为通用的结构单元之一，它可以容易地转化成各种多功能分子，例如α-羟基羧酸，β-氨基醇和α-氨基酸等。但是氰醇或O-保护的氰醇合成往往需要剧毒的氰化物源（HCN，金属氰化物，TMSCN等），通常还需要金属催化剂参与该过程。.在本研究课题中，我们提供了一种新的非氰化物和非过渡金属的O-膦酰基保护的氰醇合成策略。在该过程中，α-取代的丙二腈被用作氰基源，而该结构可以方便的从市售价廉的丙二腈（NC-CH2-CN）来制备。该合成方法重要特性还在于以下几点：首先，该反应是氧气参与的氧化还原过程，保护形式的羟基来自分子氧，另外有机磷在该过程中起到关键的还原剂作用。其次，具体机理研究表明，氧气首先通过自由基途径与α-取代的丙二腈反应，形成酰基氰中间体；进一步二芳基磷氧与该中间体发生亲核取代反应，生成一个新颖的含季碳原子中间体；该中间体极易发生重排，并得到最终结构稳定的O-保护氰醇。最后，磷酰基取代基还被证实是一种易于消除的羟基保护基，值得注意的是，在较低温度下，DIBAL-H可以实现膦酰基的直接脱除，而对氰基无有任何损害。基于上述机理研究，以及后续开展的产物放大与拓展应用研究，我们认为本项目开发的绿色氰醇合成策略，将具有更为广泛的应用前景。