The straightforward synthesis of sodium 4-toluenesulfonyloxymethyl-(H)-phosphinate and (H)-phosphinomethylisothiouronium tosylate as new reagents for the preparation of O- and S-methyl-(H)-phosphinic acid derivatives, respectively, is described. The reactivity of both reagents was demonstrated by the preparation of protected 2'-deoxyribonucleoside-O-methyl-(H)-phosphinates in the 5'- and 3'-series and 2',5'-dideoxyribonucleoside-5'-S-methyl-(H)-phosphinates. These compounds represent a new class of monomers compatible with the solid phase synthesis of oligonucleotides by H-phosphonate chemistry, as it was proved with the synthesis of a fully phosphonate heptamer.

We have developed a robust solid-phase protocol which allowed the synthesis of chimeric oligonucleotides modified with phosphodiester and O-methylphosphonate linkages as well as their P-S and P-N variants. The novel O-methylphosphonate-derived modifications were obtained by oxidation, sulfurization, and amidation of the O-methyl-(H)-phosphinate internucleotide linkage introduced into the oligonucleotide chain by H-phosphonate chemistry using nucleoside-O-methyl-(H)-phosphinates as monomers. The H-phosphonate coupling followed by oxidation after each cycle enabled us to successfully combine H-phosphonate and phosphoramidite chemistries to synthesize diversely modified oligonucleotide strands.

This unit comprises the straightforward synthesis of protected 2′‐deoxyribonucleoside‐O‐methyl‐(H)‐phosphinates in both 3′‐ and 5′‐series. These compounds represent a new class of monomers compatible with the solid‐phase synthesis of oligonucleotides using H‐phosphonate chemistry and are suitable for the preparation of both 3′‐ and 5′‐O‐methylphosphonate oligonucleotides. The synthesis of 4‐toluenesulfonyloxymethyl‐(H)‐phosphinic acid as a new reagent for the preparation of O‐methyl‐(H)‐phosphinic acid derivatives is described. © 2017 by John Wiley & Sons, Inc.

PAV, O.; BUDESINSKY, M.; LIBOSKA, R.; SIMAK, O.; PETROVA, M.; NOVAK, P.; ROSENBERG*, I.; Org. Lett. 18 (2016) 11, 2704-2707, http://dx.doi.org/10.1021/acs.orglett.6b01167 ; Inst. Org. Chem. Biochem., Acad. Sci. Czech Rep., CZ-166 10 Prague 6, Czech Republic; Eng.) -M. Tismer 42-206