Synthesis of α,δ-Disubstituted Tetraphosphates and Terminally-Functionalized Nucleoside Pentaphosphates

Abstract

The anion [P4O11]2–, employed as its bis­(triphenylphosphine)­iminium (PPN) salt, is shown herein to be a versatile reagent for nucleophile tetraphosphorylation. Treatment under anhydrous conditions with an alkylamine base and a nucleophile (HNuc1), such as an alcohol (neopentanol, cyclohexanol, 4-methylumbelliferone, and Boc-Tyr-OMe), an amine (propargylamine, diethylamine, morpholine, 3,5-dimethylaniline, and isopropylamine), dihydrogen phosphate, phenylphosphonate, azide ion, or methylidene triphenylphosphorane, results in nucleophile substituted tetrametaphosphates ([P4O11Nuc1]3–) as mixed PPN and alkylammonium salts in 59% to 99% yield. Treatment of the resulting functionalized tetrametaphosphates with a second nucleophile (HNuc2), such as hydroxide, a phenol (4-methylumbelliferone), an amine (propargylamine and ethanolamine), fluoride, or a nucleoside monophosphate (uridine monophosphate, deoxyadenosine monophosphate, and adenosine monophosphate), results in ring opening to linear tetraphosphates bearing one nucleophile on each end ([Nuc1(PO3)3PO2Nuc2]4–). When necessary, these linear tetraphosphates are purified by reverse phase or anion exchange HPLC, yielding triethylammonium or ammonium salts in 32% to 92% yield from [PPN]2[P4O11]. Phosphorylation of methylidene triphenylphosphorane as Nuc1 yields a new tetrametaphosphate-based ylide ([Ph3PCHP4O11]3–, 94% yield). Wittig olefination of 2′,3′-O-isopropylidene-5′-deoxy-5′-uridylaldehyde using this ylide results in a 3′-deoxy-3′,4′-didehydronucleotide derivative, isolated as the triethylammonium salt in 54% yield.

The Aryne Phosphate Reaction

“…All arylcyclophosphates 73-77 were subsequently linearized using N-nucleophiles, based on an SN type mechanism (scheme 5, C). [34] The reaction sequence enabled the isolation of various arylated polyphosphate chains (P3-P8, scheme 5, B…”

“…All arylcyclophosphates 73-77 were subsequently linearized using N-nucleophiles, based on an SN type mechanism (scheme 5, C). [34] The reaction sequence enabled the isolation of various arylated polyphosphate chains (P3-P8, scheme 5, B). Most polyphosphate products were purified by automated strong-ion exchange chromatography (SAX) and isolated as Na salts.…”

“…in analytical biochemistry, has driven innovative synthesis strategy development in the past years. [33][34][35][36][37] Here, we present a detailed study of the phosphate aryne reaction. We demonstrate that phosphates, phosphate esters and anhydrides are arynophiles, which can be converted into Oarylated phosphate derivatives.…”

“…in analytical biochemistry, has driven innovative synthesis strategy development in the past years. [33][34][35][36][37] Scheme 1. A: Previously reported aryne chemistry of organophosphorous compounds based on o-silylphenyltriflates.…”

The Aryne Phosphate Reaction**

“…[30][31][32] Despite the many studies scrutinizing the reactivity of diverse arynophiles,t he ability of phosphates to engage in reactions with arynes is absent from the literature.T his is remarkable,a st he urgent need to access probes for interrogation of phosphate functions,f or example,i na nalytical biochemistry,h as driven innovative synthesis strategy development in the past years. [33][34][35][36][37] Here,wepresent adetailed study of the phosphate aryne reaction. We demonstrate that phosphates,p hosphate esters and anhydrides are arynophiles,which can be converted into O-arylated phosphate derivatives.S tarting from various substituted Kobayashi aryne precursors,w er eacted the…”