Development of asymmetric syntheses and valuable bioactive compounds based on alkenylphosphonates

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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.