Mild and Chemoselective Phosphorylation of Alcohols Using a Ψ-Reagent

Abstract

An operationally simple, scalable, and chemoselective method for the direct phosphorylation of alcohols using a P(V)-approach based on the Ψ-reagent platform is disclosed. The method features a broad substrate scope of utility in both simple and complex settings and provides access to valuable phosphorylated alcohols that would be otherwise difficult to obtain.

Straightforward Synthesis of the Poly(ADP-ribose) Branched Core Structure

“…To complete the synthesis of 1 , we chemo- and regioselectively phosphorylated the fully unprotected substrate 5 at its primary hydroxyl groups ( Scheme 5 ). Although several regioselective phosphorylation methods using P(V) reagents 22 have been reported, the phosphoramidite method that uses a P(III) reagent, 23 which is widely used in nucleic acid syntheses, was chosen. We hypothesized that the acid used to activate the phosphoramidite reagent protonates the free amino group, thereby decreasing its reactivity.…”

From green innovations in oligopeptide to oligonucleotide sustainable synthesis: differences and synergies in TIDES chemistry

“…80 Please do not adjust margins Please do not adjust margins Then in 2021, Baran and co-workers proposed three new reagents, known as ψ 2 (56), rac-ψ (57) and ψ 0 reagents (58) (Figure 16), to introduce stereodefinition in ONs containing contextual PS, PO and PS 2 linkages. 81,82 These reagents have been successfully applied for the synthesis of chimera ONs, but the use of a more stable solid-support (functionalized by UNILINKER®) was required to tolerate the use of DBU as an activating agent and N-methylpyrrolidine (Pya) protecting groups on the nucleobases. The synthesis of several ONs was achieved with yields ranging between 12% and 27%, which is a poorer result than the 30-60% achieved from stereorandom approaches, but it is still promising considering the upgrade to stereodefinition.…”

Practical Stereocontrolled Access to Thioisosteres of Essential Signaling Molecules and Building Blocks for Life: Nucleoside Di- and Triphosphates

“…Generally, the yields obtained on a larger scale are improved by 10-20% due to more facile purification. Finally, the overall robustness of the Ψ-platform is highlighted by the 1 mmol-scale synthesis of γ-thioAG cap reagent 41 (thioisostere of TriLink's blockbuster CleanCap® reagent) wherein 3 out of 4 phosphate groups present in the molecule were incorporated by sequential Ψ O -based nucleoside-nucleoside coupling, 27 chemoselective phosphorylation, 32 and stereocontrolled thiotriphosphorylation.…”

“…To evaluate the impact of the configuration of the thiophosphate moiety on the biochemical properties of nucleotide thioisosteres, the bioactivity of adenosine (20,32) and uridine (12, 13,24,25) analogues was evaluated in the context of P2X and P2Y receptors (Figure 2A). P2X receptors are ion channels that are principally activated by ATP.…”

“…Stereoselectivity was observed for the P2X3 and P2X4 receptors (from 3 to 5-fold) favouring RP isomers. As a testament to the importance of controlling Pstereochemistry, the thioisosteric adenosine analogues are potent P2Y13 receptor agonists with very high stereoselectivity [178-fold in case of compounds 32 (RP > SP)] (Figure 2A-1).…”