Development of asymmetric syntheses and valuable bioactive compounds based on alkenylphosphonates

磷酸盐是我们身体中的重要成分，作为能量储存和细胞内信号传导的中间体。膦酸酯衍生物是磷酸酯的类似物，可以作为磷酸酯介导的生物化学反应的激动剂或拮抗剂。其中一些已经被用作真实的毒品。另一方面，从合成有机化学的角度来看，膦酸酯是通用的作为烯烃形成反应的底物，Horner-Wadsworth-Emmons反应，以及作为过渡金属催化剂的手性膦配体的合成中间体。因此，在基于膦酸酯的研究中，我们可以期待有机合成化学和生物化学相结合的研究的发展。本研究的目的是利用我们开发的合成技术，创造基于膦酸酯的有用的生理活性化合物。在本研究中，我专注于免疫抑制剂的开发。已知免疫抑制剂FTY-720通过其羟基之一的磷酸化而活化。激活的FTY-720与鞘氨醇-1-磷酸受体结合，导致淋巴细胞归巢至淋巴结。因此，我预期通过应用磷酸化FTY-720来提高活性。然而，膦酸盐可能在体内水解。因此，本研究合成了FTY-720稳定的磷酸酯化衍生物环状磷酸酯。环状磷酸酯不仅稳定，而且是非对称的化合物，这有利于药物的进一步开发。我们还合成了FTY-720的膦酸酯衍生物。正在评价衍生物的免疫抑制活性。

Phosphates are vital components in our body as an intermediate of the energy storage and the intracellular signaling. Phosphonate derivatives are analogues of phosphates and can be act as agonists or antagonists of the biochemical reactions mediated by phosphates. Some of them have already been used as real drugs. On the other hand, from the synthetic organic chemistry point of view, phosphonates are versatile as substrates for an olefin forming reaction, Horner-Wadsworth-Emmons reaction, and also as synthetic intermediates of chiral phosphine ligands for the transition metal catalysis. Thus, in the study based on phosphonates, we can expect the development of the research in which both synthetic organic chemistry and biological chemistry are combined together. The purpose of this study is the creation of useful physiologically active compounds based on phosphonates using synthetic technology we have developed.In the present study, I focused on the development of immunosuppressive agent. An immunosuppressant FTY-720 is known to be activated by phosphorylation in one of its hydroxyl groups. The activated FTY-720 binds to sphingosine-1-phosphate receptor and cause the homing of the lymphocytes to lymph node. Thereby, I expected the increase of the activity with the application of phosphorilated FTY-720. The phosphonates, however, likely to be hydrolysed in the body. It is, therefore, we synthesized cyclic phosphates as a stable phosphorilated derivatives of FTY-720 in this study. Cyclic phosphates are not only stable but also non-asymmetric compounds which is advantageous for the further development for drugs. We also synthesized phosphonate derivatives of FTY-720. The immunosuppressive activity of the derivatives is being evaluated.