Reactions of 3′-C-Halomethyl and 3′-C-Sulfonylmethyl Uridines with Phosphinic Acid Derivatives − Synthesis of Building Blocks for Oligonucleotides Containing 3′-C-Methylenephosphonate Linkages

Abstract

An efficient method for the synthesis of nucleoside 3′-C-methylenephosphinates, building blocks for oligo(ribonucleoside methylenephosphonate)s, has been developed. Treatment of bis(trimethylsilyl)hypophosphite (BTSP) with a 3′-deoxy-3-C-(iodomethyl)uridine resulted both in substitution to give the corresponding 3′-C-methylenephosphinate and in reduction of the iodomethyl group to afford the uridine 3′-deoxy-3′-C-methyl derivative. Optimisation of solvent and temperature gave a substitution/reduction ratio of 5:4 at best. Through the use of a trifluoromethanesulfonyl leaving group and further optimisation of reaction conditions, however, the triethylammonium 2′-O-(tert-butyldimethylsilyl)-3′-deoxy-5′-O-(4-methoxytriphenylmethyl)uridine-3′-C-methylenephosphinate was obtained in 93% isolated yield. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)