4-Toluenesulfonyloxymethyl-(H)-phosphinate: A Reagent for the Introduction of O- and S-Methyl-(H)-phosphinate Moieties

Abstract

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.

Phosphonomethyl Oligonucleotides as Backbone-Modified Artificial Genetic Polymers

“…Alternatively, the adenine H-phosphinate building block containing a benzoyl-protected adenine base, compound 3e, could be obtained by directly introducing the H-phosphinate functionality into the sugar moiety of threose nucleoside intermediate 7, as described by Kostov et al (Scheme 1). 26 The selective hydrolysis of the benzoyl group at the 2′ position of fully protected nucleoside 4 24 under basic conditions gave compound 5 in 82% yield. The protection of the 2′ hydroxyl group of 5 with MMTrCl afforded nucleoside 6 in 50% yield, along with the recovery of 42% of the starting material.…”

Solid-Phase Synthesis of Phosphorothioate/Phosphonothioate and Phosphoramidate/Phosphonamidate Oligonucleotides

“…Our results on novel nucleoside- O -methyl-( H )-phosphinates [2,3] as monomers for H -phosphonate chemistry prompted us to develop robust synthetic protocols that would allow the synthesis of oligonucleotides bearing any combination of phosphodiester 3 , phosphorothioate 4 , phosphoramidate 6 , O -methylphosphonate 8a , O -methylphosphonothioate 9a , O -methyl-phosphonamidate 10 , S -methylphosphonate 8b and S -methylphosphonothioate 9b internucleotide linkages (Figure 1). The optimization of the oxidative couplings affording the abovementioned modified bonds was performed on a model dimer.…”

“…The optimization of coupling reaction of H -phosphinate monomers 2 [2,3] was performed at 0.1 M concentration in acetonitrile-pyridine mixture (1:1) with a series of activating agents [13] commonly used in H -phosphonate chemistry such as pivaloyl chloride, adamantanecarbonyl chloride, 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane 2-oxide (DMOCP), diphenyl chloro-phosphate (DPCP), and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (OXP) at 0.3 M concentration in acetonitrile-pyridine mixtures (95:5). Of all tested coupling agents, we selected DMOCP as the activator of choice for the condensation of both H -phosphonate 1 and H -phosphinates 2 .…”

“…As we published previously [2,3], the use of water-containing oxidation mixtures such as 0.1 M iodine in pyridine-water mixture (98:2) reported for the oxidation of H -phosphonate linkage 12a [7,8] could not be used for the oxidation of H -phosphinate bond 12b due to its lability under aqueous conditions and very fast hydrolytic cleavage. The use of 0.1 M iodine in pyridine-methanol (50:50) mixture led to only 80% yield of the expected MeO-P (V) product.…”

“…To improve the synthesis of MePNA, we developed the straightforward synthesis of nucleoside- O -methyl-( H )-phosphinates and 5′-deoxynucleoside-5′- S -methyl-( H )-phosphinates [2,3] that were closely related to the well-known nucleoside H -phosphonates, [4,5] and demonstrated their compatibility with the H -phosphonate chemistry of the oligonucleotide synthesis. Recently, Herdewijn [6] has exploited this methodology to introduce various nucleoside phosphonates into oligonucleotides.…”