Synthesis of PS/PO-chimeric oligonucleotides using mixed oxathiaphospholane and phosphoramidite chemistry

Abstract

Chimeric oligonucleotides containing phosphodiester and phosphorothioate linkages have been obtained using the solid phase synthesis. The oligonucleotide parts possessing natural internucleotide phosphate bonds were assembled using commercially available nucleoside 3'-O-(2-cyanoethyl-N,N-diisopropylamino)phosphoramidites 7 whereas the phosphorothioate segment was built using nucleoside 3'-O-(2-thio-1,3,2-oxathiaphospholanes) 3. The oxidation steps, crucial for the conversion of phosphite linkages into the phosphate moieties, were conducted using tert-butylperoxy-trimethylsilane, and this reagent was not harmful to the diester phosphorothioate linkages. When P-diastereopure nucleoside 3'-O-(2-thio-1,3,2-oxathiaphospholane) monomers were employed the resulting chimeric backbone retained the P-stereoregularity of the phosphorothioate units.

P-stereocontrolled synthesis of oligo(nucleoside N3′→O5′ phosphoramidothioate)s – opportunities and limitations

“…39) (0.33 M in CH 3 CN, 30 min, room temperature). 40 In the present work, the 31 P NMR and MALDI-TOF MS measurements revealed that under these conditions the phosphoramidothioate linkage in DMT T NPS T OAc also remained unaffected (data not shown). The 9-nt DMT T PO (T PO ) 4 (T NPS ) 3 T-3 0 , was obtained in 42% yield as assessed from the DMT + cation assay.…”

Nature Chose Phosphates and Chemists Should Too: How Emerging P(V) Methods Can Augment Existing Strategies

“… 97 Similarly, since Ψ-based ASO synthesis does not use protecting groups on sulfur, it is not compatible with P(III)-based oxidative phosphodiester synthesis. 98 A P(V) approach to phosphodiester P(O) synthesis (Ψ O ) would be a fitting tribute to the origin of this field that commenced with but later abandoned P(V) due to low reactivity ( Figure 2 A). Finally, phosphorodithioates P(S) 2 are achiral linkages with reduced stereochemical complexity that maintain stability to nucleases are becoming increasingly common in this field.…”

“…In contrast, P­(III) stereorandom ASO synthesis often leads to scalemic mixtures due to substrate bias rather than reagent control . Similarly, since Ψ-based ASO synthesis does not use protecting groups on sulfur, it is not compatible with P­(III)-based oxidative phosphodiester synthesis . A P­(V) approach to phosphodiester P­(O) synthesis (Ψ O ) would be a fitting tribute to the origin of this field that commenced with but later abandoned P­(V) due to low reactivity (Figure A).…”

Determination of silyl peroxides by ultra‐performance liquid chromatography/electrospray ionisation mass spectrometry

“…Other reported applications include epoxidation of alkenes, Baeyer‐Villiger oxidation, adhesion promoters and intermediates in the synthesis of antitumour or antiparasitic drugs …”