Synthesis of nucleic acid fragments with 3'-deoxy-3'-C-Methylene-phosphonate linkages-oxidation of nucleoside 3'-deoxy-3'-C-Methylene-phosphinate esters

摘要

A study on the iodine oxidation of protected thymidine 5'-(uridine 3'-deoxy-3'-C-methylenephosphinate) (1) to the correspondingthymidine 5'-(uridine 3'-deoxy-3'-C-methylenephosphonate)(2) is reported.Oxidation with 80 mM iodine in pyridine/water required 24h for completion.The reaction is catalyzed by pyridinium ion as well as by triethylamine (TEA).The reactionsappear to occur via the tricoordination form of 1: the anionin the TEA-promoted reaction and the neutral tautomer for the acid (pyridinium ion) catalyzed reaction.Several setsof conditions are suggested for oxidation of oligo(nucleoside methylenephosphinate)s to the corresponding phosphonates.Solutions of 200 mM I_2 in pyridine/water,with either 1 M TEA or 1 M pyridine hydrochloride,gave half-lives of less than 2 and 10 min,respectively.