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

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.