New strategy for the synthesis of functionalized phosphonic acids

Various approaches leading to mono-, diand poly-functionalized phosphonates as well as phosphoryl heterocycles were reported for the systematic study of relationship between chemical structure and biological activities of this most important class of organophosphorus compounds. Introduction Functionalization of phosphonic acid molecules opens enoi-nious possibilities of structural variation of this important class of organophosphorus compounds with potential biological activities. This is particularly true for 1-aminoalkylphosphonic acid and related peptides which have been found wide applications both as agrochemicals and medicinal products. Numerous synthetic approaches were described for the formation of monofunctionalized phosphonic acid which is usually required multistage manipulation. Introduction of additional functionalized group to these molecules by traditional method is complicated due to interor intramolecular interactions. Consequently, design of synthesis of mono-, diand polyfunctionalized phosphonic acids and study the structural effect-of these compounds on their biological activity are of great interest both in synthetic organophosphorus chemistry and for the development of lead structure for biologically active molecules. Results and Discussion 1. Monofunctionalized phosphonic acids 1.1 1-Heteroatom substituted phosphonic acids 1 -Heteroatom substituted phosphonic acids cover a wide spectrum of important organophosphorus compounds. Unfortunately, the conventional method of preparation based on nucleophilic substitution of 1-halogen-alkylphosphonates is under greater challenge associated with low reactivity of 1-halogen atom, MITOW scope of applications as well as inaccessibility of the intermediates. As found by us, upon substitution of 1-methanesulfonyl 1-alkylphosphonate by a phosphite anion provided alkylidene bisphosphonates. ' Since -OMS behaviours as good leaving group, this nucleophilic substitution was extended as a general way of preparation of 1 -heteroatom substituted alkylphosphonate. __* NU: 1 R p: P(0)(OEt)Z P(O)(OW2 R P(O)(OEt)2 3 ' + R 2 1 R = Et, Ph Nu = n-BUS, PhS, PhCH,NH, (EtO),PO, PhCONHNH, PhNHNH