Development of Highly Efficient Synthetic Method of Biologically Active Phosphonic Acid Derivatives via Key Intermediate Bis(phosphono)ethylene

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In this research project, we aimed at development of synthesis of key intermediate gem-bis(phosphono)ethylenes (1), and at achievement of highly efficient synthetic method of biologically active compounds such as heteroaromatic-substituted bisphosphonic acids, aminophosphonic acids, etc. via1. The following results were obtained.1. The gem-bis(phosphono)ethylenes 1 were achieved to synthesize in good yields by Pd-catalyzed cross-coupling reaction of α-phosphonononaflates with dialkylphosphites.2. The bis(phosphono)ethylenes 1 underwent Michael addition of heteroaromatics-substituted 1,3-dithiane carbanions, and imidazole or 3-pyridyl anion to give 2-functional group substituted-1, 1-bis(phosphono)ethylenes in high yields. When the same reaction was quenched with cationic halogenating agents such as NCS and SELECTFLUOR, the corresponding 1-halo*1-bisphosphonates (X=Cl, F) were produced. Treatment of the phosphonates with Me_3Sil led to the desired phosphonic acids quantitatively, which can be expected to act as curatives for osteoporosis and bone disease therapy.3. The reaction of 1 with a tribromomethyl carbanion gave a new type of small-ring compound, 1, 1-dibromo-2, 2-bis(phosphono)cyclopropane.4. Treatment of 1 with sulfonamide in the presence of iodosylbenzene and copper chloride led to 1-sulfonyl-2, 2-bis(phosphono)aziridines in 75-54% yields. Reduction of the aziridines converted into β-amino phosphonic acid analogue, N-[2, 2bis(phosphono)ethyl]sulfonamides in good yields.In conclusion, we achieved convenient synthesis of gem-bisbis(phosphono)ethylenes. We have shown that synthesis of various type of gem-bisphosphono-substituted compounds expecting to exhibit not only biologically active but also other interesting properties can be made by utilizing gem-bis(phosphono)ethylenes.